“This new technology will make it much faster and more cost-effective to diagnose these infections,” said Mike Farrell, a Georgia Tech Research Institute (GTRI) principal research scientist who is leading the project. “You would obtain a sample, put it into a device, diagnose the underlying pathogen, and be able to provide a treatment. This could be a huge leap forward in rapidly diagnosing these diseases where sophisticated laboratory testing isn’t available.”
Funded by DARPA’s Detect It with Gene Editing Technologies (DIGET) program, the project – known as Tactical Rapid Pathogen Identification and Diagnostic Ensemble (TRIAgE) – also includes researchers from Emory University and two private sector companies. The goal will be to detect 10 different pathogens with each device.
Detection Reaction Begins with CRISPR Cas13a Enzyme
Detection of a pathogen will begin with exposure of a patient sample to the CRISPR Cas13a enzyme with guide proteins containing RNA genetic sequences from the targeted pathogens. If a genetic sequence in the device matches a sequence in the patient sample, the enzyme will begin breaking down the targeted RNA.
Development of the CRISPR Cas13a component of the project will be led by Phil Santangelo, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and one of the team’s collaborators. CRISPR Cas13a differs from Cas9 technology, which has become known for its ability to edit DNA, which Cas13A will not do.
Once the Cas13a enzyme breaks down the pathogen RNA, that will trigger additional reactions to amplify the signal and create a visible blue line in the device within 15 minutes.
Synthetic Biology Workflow Signals Pathogen Presence
“We will be assembling a synthetic biology workflow that takes an initial signal created by CRISPR-based nucleic acid detection and amplifies it using the same cell-free synthetic biology approaches we have used to create sensors for detecting small molecules and metals: turning on genes that create a visual readout so that expensive instruments, and even electricity, are unnecessary,” explained Mark Styczynski, a professor in Georgia Tech’s School of Chemical and Biomolecular Engineering and another team collaborator.
“As part of the DIGET project, we will be leveraging my group’s expertise in minimal-equipment diagnostics,” he added. “The biological ‘parts’ we develop can be reused to transduce signals for the detection of essentially any nucleic acid sequence.”
Another Georgia Tech researcher, I. King Jordan, professor and director of the Bioinformatics Graduate Program in the School of Biological Sciences, will mine the genomes of the targeted pathogens for optimal Cas13a target sequences as well as the corresponding Cas13a RNA guide sequences.
Devices Must be Both Sensitive and Specific
Beyond specifically identifying the pathogen or pathogens causing an infection, the diagnostic devices being developed must also be very sensitive – able to detect as few as 10 copies of the target pathogen in a sample. “A major technological challenge is achieving the level of signal amplification within the device’s synthetic biology circuit to reach the needed level of sensitivity,” Farrell said.
The ability to detect 10 different pathogens with a single lateral-flow assay is an ambitious goal for a device that depends on a synthetic biology circuit and is designed for use in the field, he added. Lateral-flow assays commonly used in home or point-of-care medical tests operate by applying a liquid sample to a pad containing reactive molecules. The molecules may create visible positive or negative reactions, depending on the design.
“You just put the sample on the device and it does its thing,” Farrell said. “If the target pathogen is present, a line turns blue and you can see it with your eye.”
Early Diagnosis Can be Life-Saving
Sepsis is an infection of the bloodstream by any of a number of different bacteria. These bacteria can originate from a lower respiratory infection, kidney or bladder infection, digestive system breakdown, catheter site, wound, or burn. Sepsis results in a severe and persistent inflammatory response that can lead to disrupted blood flow, tissue damage, organ failure, and death.
“It’s important to identify the specific bacteria causing the sepsis because that informs the type of antimicrobial therapy that’s needed,” said Farrell. “The sooner you can identify the underlying pathogen, the faster you can provide the proper medical care, and the more likely it is that the patient will survive. Current laboratory-based diagnostic methods can take between 24 and 72 hours, and that is just too long.”
Improving diagnostics for sepsis and respiratory diseases will have applications to both the military and civilian worlds, particularly in locations without easy access to laboratory testing.
“Wounded soldiers in the field are very susceptible to sepsis blood infections, and common respiratory diseases can affect troop readiness, so from a military standpoint, having this rapid diagnostic test would be very significant,” Farrell said. “In low-resource environments, being able to diagnose these diseases with a single test would be huge as well. Being able to identify the underlying bacteria behind sepsis more quickly could save a lot of lives.”
Beyond the university researchers, the project includes Global Access Diagnostics, a manufacturer of lateral-flow devices, and Ginkgo Bioworks, which manufactures proteins essential to the diagnostics.
The five-phase project is expected to last for four years and will conclude with field validation and a transition to manufacturing. The devices will need to win FDA approval before they can be used, so there is a significant regulatory review aspect to the project, Farrell said.
Approved for Public Release, Distribution Unlimited
Writer: John Toon
GTRI Communications
Georgia Tech Research Institute
Atlanta, Georgia
The Georgia Tech Research Institute (GTRI) is the nonprofit, applied research division of the Georgia Institute of Technology (Georgia Tech). Founded in 1934 as the Engineering Experiment Station, GTRI has grown to more than 2,900 employees, supporting eight laboratories in over 20 locations around the country and performing more than $800 million of problem-solving research annually for government and industry. GTRI's renowned researchers combine science, engineering, economics, policy, and technical expertise to solve complex problems for the U.S. federal government, state, and industry.
]]>There are times when John McDonald, emeritus professor in the School of Biological Sciences and founding director of Georgia Tech’s Integrated Cancer Research Center, is asked to share his special insight into cancer.
“Over the years, I’ve gotten calls from non-scientist friends and others who have been diagnosed with cancer, and they call me to get more details on what’s going on, and what options are available,” said McDonald, also a former chief scientific officer with the Atlanta-based Ovarian Cancer Institute.
That’s the primary motivation why McDonald wrote A Patient's Guide to Cancer: Understanding the Causes and Treatments of a Complex Disease, which was published by Raven Press LLC (Atlanta) and is now available at Amazon or Barnes and Noble in paperback and ebook editions. The book describes in non-technical language the processes that cause cancer, and details on how recent advances and experimental treatments are offering hope for patients and their families.
A book for the proactive patient
McDonald said he couldn’t go into detail for every type of cancer, but provides a generally applicable background for the disease. For those who want more information, he provides links to other resources, including videos, that provide more detail on specific types of cancer. “There’s not much out there in one place for patients who want to understand the underlying causes of cancer, and the spectrum of therapies currently available,” he said.
McDonald, who was honored in January by the Georgia Center for Oncology Research and Education (CORE) as one of “Today’s Innovators,” also didn’t want A Patient’s Guide to Cancer to be a lengthy book, and it checks in at only 86 pages.
McDonald believes that when patients talk to their physicians about cancer treatments, they should ideally have a basic understanding of the underlying cause of their cancer, as well as a general awareness of the range of therapies currently available, and what may be coming down the road in the future.
“My book is specifically designed to provide newly diagnosed cancer patients who are not scientists with this kind of background information, empowering them to play a more informed role in the selection of appropriate treatments for their disease”.
The current experimental treatment landscape; McDonald’s 2023 research goals
McDonald’s own cancer research has led to two related startup companies, co-founded with School of Biological Sciences colleagues.
McDonald is working with postdoctoral researcher Nick Housley on using nanoparticles to deliver powerful drugs to cancer cells while sparing healthy tissue. The other company, founded in collaboration with Jeffrey Skolnick, Regents' Professor, Mary and Maisie Gibson Chair & Georgia Research Alliance Eminent Scholar in Computational Systems Biology, uses machine learning to create personalized diagnostic tools for ovarian cancer.
He and his lab team are also preparing to submit a research paper that builds off their 2021 study on gene network interactions that could provide new chemotherapy targets for breast cancer. That paper focuses on the three major subtypes of breast cancer. McDonald and his colleagues will also soon submit another study detailing genetic changes that happen with the onset and progression of ovarian cancer.
When it comes to current experimental treatments, McDonald says he’s especially excited about the potential of cancer immunotherapy, which uses the body’s own immune system to fight cancer cells. But he writes in A Patient’s Guide to Cancer that because these drugs are also delivered systemically, healthy tissues can also be affected, potentially leading to autoimmunity or the self-destruction of our normal cells.
“In the future, I believe many of the negative side-effects currently associated with the system-wide delivery of cancer drugs will be averted by the use of nanoparticles designed to target therapies specifically to tumors”.
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Editor: Jess Hunt-Ralston, Communications Director
College of Sciences
Despite the progress in healthcare over the last century, resulting in longer life expectancy and better disease survival outcomes, significant disparities between various population groups remain a major global health issue.
A new study by Georgia Institute of Technology researchers in the open-access journal PLOS Global Health probes ethnic health disparities and mortality risk factors in the United Kingdom. Their work points to mortality risk factors that are group-specific, but modifiable, supporting the notion of targeted interventions that could lead to greater health equity.
“Different ethnic groups show very different levels of disease-specific mortality along with distinct mortality risk factors,” said I. King Jordan, professor in the School of Biological Sciences, and principal investigator on the study. “Unfortunately, when it comes to health, ethnicity still matters.”
Both environmental and genetic factors, and the interaction between them over time, have been cited as main contributors of health disparities. Closing the gap will require a long-term, complex series of solutions.
“Taking a one-size fits all approach to healthcare will only exacerbate the very health disparities that already disproportionately burden ethnic minorities,” said Jordan, whose collaborators on the study were lead author Kara Keun Lee, as well as Emily Norris, Lavanya Rishishwar, Andrew Conley, and John McDonald, emeritus professor in the School of Biological Sciences and founding director of Georgia Tech’s Integrated Cancer Research Center.
The work was done in collaboration with, and with support from, the NIH’s National Institute on Minority Health and Health Disparities (NIMHD) and Leonardo Mariño-Ramírez, a researcher working on epidemiology and genetics research at NIMHD’s Division of Intramural Research (DIR).
The research team analyzed data on 490,610 Asian, Black, and White participants from the UK Biobank, a study that enrolled 500,000 people in the UK aged 40 to 69 between 2006 and 2010. The UK Biobank includes data spanning physical measures, lifestyle, blood and urine biomarkers, imaging, genetic, and linked medical and death registry records.
Certain causes of mortality were more common among the different ethnic groups: Asian individuals had the highest mortality from ischemic heart disease, while individuals in the Black community had the highest mortality from COVID-19, and White individuals had the highest mortality from cancers of respiratory/intrathoracic organs.
In addition, some preexisting medical conditions and biomarkers showed specific associations with ethnicity and mortality. Mental health diagnoses, for instance, were a major risk factor for mortality in the Asian group, whereas parasitic diseases and C-reactive protein (CRP) serum levels were associated with higher mortality in the Black group.
“These results underscore the importance of population-specific studies that can help decompose health disparities and inform targeted interventions towards, shrinking the health disparity gap,” said Jordan, who praised Lee’s approach to the study, “which highlights the importance of considering individuals’ self-reported identity as it relates to their health outcomes, disease risks, and exposures.”
For future work, the team plans to look at racial and ethnic health disparities in the US, in collaboration with the NIMHD.
CITATION: Kara Keun Lee, Emily T. Norris, Lavanya Rishishwar, Andrew B. Conley, Leonardo Mariño-Ramírez, John F. McDonald, and I. King Jordan. “Ethnic disparities in mortality and group-specific risk factors in the UK Biobank.” doi.org/10.1371/journal.pgph.0001560
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Inside a typical human cell are tens of thousands of proteins. We need so many because proteins are the skilled laborers of the cell with each one performing a specific job. Some lend firmness to muscle cells or neurons. Others bind to specific, targeted molecules, ferrying them to new locations. And there are others that activate the process of cell division and growth.
A protein’s specific function depends on its shape, and to achieve its functional shape – it’s native state – a protein folds. A protein begins its life as a long chain of amino acids, called a polypeptide. The sequence of amino acids determines how the protein chain will fold and form a complex, 3D structure that allow the protein to perform an intended task.
In the lab of Loren Williams, researchers are using “creative destruction” as a model for protein fold evolution and innovation. The term, coined by Austrian economist and political scientist Joseph Schumpeter in the 1940s, describes the deliberate dismantling of an established thing, like the wired telephone, to develop a new thing, like the smart phone.
“We have protein structures that have evolved over almost four billion years, and we don’t really understand where they came from or how they came to be what they are,” said Claudia Alvarez-Carreño, a postdoctoral researcher in the Williams lab, which is called the Center for the Origin of Life, or COOL. “It’s a very complex process forming these structures, and there are many hypotheses on how they could have emerged in early evolution.”
Out with the Old, In with the New
Alvarez-Carreño is the lead author of the paper, “Creative Destruction: New Protein Folds from Old,” published recently in the journal Proceedings of the National Academy of Sciences, or PNAS. She and her co-authors (Williams, Rohan Gupta, and Anton Petrov) excavated the deepest evolutionary history found within the translation machinery – which resides within all cells in the ribosome and is the birthplace of all proteins.
The researchers provide evidence supporting the common origins of some of the simplest, oldest, and most common protein folds. It suggests a form of creative destruction at work, explaining how simple protein folds spawn more complex folds.
They discovered that once a protein can fold and achieve its 3D structure, when it is combined with another protein which has folded into a different 3D structure, that combination can easily become a new structure. “So maybe it’s not as difficult as we thought to go from one structure to another,” said Williams, professor in the School of Chemistry and Biochemistry. “And maybe this can explain the diversity of protein structures that we see today.”
In Schumpter’s creative destruction model, developing “daughter products” involves the destruction of ancestral products. “Daughter products can inherit features of ancestors but can in essence be different from them,” they write in the paper. In the smart phone example ancestral wired phones, computers, cameras, global positioning, and other technologies that are merged to create a daughter, i.e. the smart phone.
The daughter inherits many features of the ancestors. These features, which interact in specific ways in the daughter, create new functional niches that were not accessible, or even possible, in the ancestors.
“So, the creative destruction of protein folds might account for a lot of the diversity we see,” Williams said.
Molecular Mergers
Ever since the simplest and most ancient protein folds emerged on Earth billions of years ago, the number of folds has expanded to form the universe of protein function we see in modern biology.
But the origins of protein folds and the evolutionary mechanisms at play pose central questions in biology that Williams and his team considered. For instance, how did protein folds arise, and what led to the diverse set of protein folds in contemporary biological systems, and why did nearly four billion years of fold evolution produce fewer than 2,000 distinct folds?
The researchers believe that creative destruction can be generalized to explain a lot of this.
In creative destruction, they explain, one open reading frame – the span of DNA sequence that encodes a protein – merges with another to produce a fused polypeptide. The merger forces these two ancestors into a new structure. The resulting polypeptide can achieve a form that was inaccessible to either of the independent ancestors, before the merger. But these new folds are not totally independent of the old. That is, a daughter fold inherits some things from the ancestral fold.
This, broadly speaking, is what Williams and his team observed, and they think their creative destruction model has some application in studying disease – proteins that fold improperly can impact the health of the cells and the human comprised of those cells.
“For example, we think this process is important in the biology of cancer – there are many, many proteins that have fused and, we believe have refolded, in cancers,” said Williams. “And there’s the world of protein aggregation diseases, like Parkinson’s or Alzheimers, and proteins that have not folded correctly, or have refolded.”
But right now, Williams and his team are most interested in how their creative destruction model helps them understand some of the deepest questions of our evolution.
“Like, where did we come from,” Williams said. “Creative destruction could help us understand where the proteins in our body came and how we came to be what we are.”
CITATION: Claudia Alvarez-Carreño, Rohan J. Gupta, Anton S. Petrov and Loren Dean Williams. “Creative destruction: New protein folds from old.” PNAS Journal.
https://doi.org/10.1073/pnas.2207897119
]]>“But I didn’t realize the role that real estate can play in that,” said Lawler, general manager of BioSpark Labs – the collaborative, shared laboratory environment taking shape at Science Square at Georgia Tech.
Sitting adjacent to the Tech campus and formerly known as Technology Enterprise Park, Science Square is being reactivated and positioned as a life sciences research destination. The 18-acre site is abuzz with new construction, as an urban mixed-use development rises from the property.
Meanwhile, positioned literally on the ground floor of all this activity is BioSpark Labs, located in a former warehouse, fortuitously adjacent to the Global Center for Medical Innovation. It’s one of the newer best-kept secrets in the Georgia Tech research community.
BioSpark exists because the Georgia Tech Real Estate Office, led by Associate Vice President Tony Zivalich, recognized the need of this kind of lab space. Zivalich and his team have overseen the ideation, design, and funding of the facility, partnering with Georgia Advanced Technology Ventures, as well as the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and the core facilities of the Petit Institute for Bioengineering and Bioscience.
“We are in the middle of a growing life sciences ecosystem, part of a larger vision in biotech research,” said Lawler, who was hired on to manage the space, bringing to the job a wealth of experience as a former research scientist and lab manager with a background in molecular and synthetic biology.
BioSpark was designed to be a launch pad for high-potential entrepreneurs. It provides a fully equipped and professionally operated wet lab, in addition to a clean room, meeting and office space, to its current roster of clients, five life sciences and biotech startup, a number certain to increase – because BioSpark is undergoing a dramatic expansion that will include 11 more labs (shared and private space), an autoclave room, equipment and storage rooms.
“We want to provide the necessary services and support that an early-stage company needs to begin lab operations on day one,” said Lawler, who has put together a facility with $1.7 million in lab equipment. “I understand our clients’ perspective, I understand researchers and their experiments, and their needs, because I have first-hand proficiency in that world. So, I can advocate on their behalf.”
CO2 incubators, a spectrophotometer, a biosafety cabinet, a fume hood, a -80° freezer, an inverted microscope, and the autoclave are among the wide range of apparatus. Plus, a virtual treasure trove of equipment is available to BioSpark clients off-site through the Core Facilities of the Petit Institute for Bioengineering and Bioscience on the Georgia Tech campus.
“One of the unique things about us is, we’re agnostic,” Lawler said. “That is, our startups can come from anywhere. We have companies that have grown out of labs at Georgia State, Alabama State, Emory, and Georgia Tech. And we have interest from entrepreneurs from San Diego, who are considering relocating people from mature biotech markets to our space.”
Marvin Whiteley wants to help humans win the war against bacteria, and he has a plan, something he’s been cooking up for about 10 years, which has now manifested in his start-up company, SynthBiome, one of the five startups based at BioSpark Labs.
“We can discover a lot of antibiotics in the lab but translating them into the clinic has been a major challenge – antibiotic resistance is the main reason,” said Whiteley, professor in the School of Biological Sciences at Georgia Tech. “Something might work in a test tube easily enough and it might work in a mouse. But the thing is, bacteria know that mice are different - and and so bacteria act differently in mice than in humans.”
SynthBiome was built to help accelerate drug discovery. With that goal in mind, Whiteley and has team set out to develop a better, more effective preclinical model. “We basically learned to let the bacteria tell us what it’s like to be in a human,” Whiteley said. “So, we created a human environment in a test tube.”
Whiteley has said a desire to help people is foundational to his research. He wants to change how successful therapies are made. The same can be said for Dr. Pooja Tiwari, who launched her company, Arnav Biotech, to develop mRNA-based therapeutics and vaccines. Arnav Biotech also serves as a contract researcher and manufacturer, helping other researchers and companies interested in exploring mRNA in their work.
“There are only a handful of people who have deep knowledge of working in mRNA research, and this limits the access to it” said Tiwari, a former postdoctoral researcher at Georgia Tech and Emory. “We’d like to democratize access to mRNA-based therapeutics and vaccines by developing accessible and cost-effective mRNA therapeutics for global needs”.
Arnav – which has RNA right there in the name – in Sanskrit means ‘ocean.’ An ocean has no discernible borders, and Tiwari is working to build a biotech company that eliminates borders in equitable access to mRNA-based therapeutics and vaccines.
With this mission in mind, Arnav is developing mRNA-based, broad-spectrum antivirals as well as vaccines against pandemic potential viruses before the next pandemic hits. Arnav has recently entered in a collaboration with Sartorius BIA Separations, a company based on Slovenia, to advance their mRNA pipeline. While building its own mRNA therapeutics pipeline, Arnav is also helping other scientists explore mRNA as an alternative therapeutic and vaccine platform through its contract services.
“I think of the vaccine scientist who makes his medicine using proteins, but would like to explore the mRNA option,” Tiwari posits. “Maybe he doesn’t want to make the full jump into it. That’s where we come in, helping to drive interest in this field and help that scientist compare his traditional vaccines to see what mRNA vaccines looks like.”
She has all the equipment and instruments that she needs at BioSpark Labs and was one of the first start-ups to put down roots there. So far, it’s been the perfect partnership, Tiwari said, adding, “It kind of feels like BioSpark and Arnav are growing up together.”
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One factor V. cholerae uses to cause disease is a toxin-loaded “nano-harpoon,” in the words of Brian Hammer, associate professor in the School of Biological Sciences. “Many pathogenic bacteria, including V. cholerae, are successful in the environment and human body because they compete for food and space by lancing their neighbors with that harpoon. The harpoon’s toxic ‘contact-antibiotics’ kill bacteria from the inside. Thwarting human pathogens will require an understanding of these arsenals.”
Now, Hammer is on a team of scientists from Georgia Tech who have found a previously unknown weapon in the arsenal of cholera bacteria: a toxin that impairs a cell’s membrane and looks like none described prior — hence the title of the team’s research study: “A New Contact Killing Toxin Permeabilizes Cells and Belongs to a Broadly Distributed Protein Family,” published July 21 in mSphere, part of the American Society of Microbiology Journals.
Team members include Hammer (the study’s corresponding author), his graduate student Christian Crisan (the study’s lead author), and undergraduate researcher Catherine Everly; along with assistant professor Peter Yunker and his postdoctoral student Gabi Steinbach of the School of Physics; and professor Raquel Lieberman and her postdoctoral student Shannon Hill in the School of Chemistry and Biochemistry. Hammer and Yunker are members of Georgia Tech’s Center for Microbial Dynamics and Infection; and Hammer, Lieberman, and Yunker are also members of the Parker H. Petit Institute for Bioengineering and Bioscience.
The technical term for V. cholerae’s “nano-harpoon” is a Type 6 Secretion System, (T6SS). “While many microbiologists have focused their efforts on a few toxins made by V. cholerae obtained from patients, we sequenced the DNA of Vibrios from non-human environmental sources and developed computational tools to find new contact-antibiotic toxin genes,” Hammer says of his lab’s work. “In doing so, my student Cristian Crisan, who just defended his Ph.D., discovered a new T6 toxin that doesn't look like any other protein characterized prior. He showed this toxin” — which the team named TpeV (type VI permeabilizing effector Vibrio) — “kills competitors by altering their cell membranes.” Doing so results in cell damage or death.
Hunting through a database, Crisan also discovered that hundreds of other bacteria, including pathogens like Salmonella and Proteus, also carry this novel toxin. “Our current work is studying exactly how this contact-antibiotic works, and ways that bacteria can adapt to become resistant to it and other T6 toxins,” Hammer says.
Cholera remains a well-studied disease since it touches many disciplines including microbiology, epidemiology, aquatic ecology, and water resource management, Hammer says. Outbreaks still occur in places such as Bangladesh, Yemen, and Haiti.
Learning more about V. cholerae’s toxins, and their antimicrobial abilities, could mean more effective ways to deal with antibiotic resistance, now an area of concern for microbiologists.
“We demonstrate that TpeV has antimicrobial activity by permeabilizing cells, eliminating membrane potentials, and causing severe cytotoxicity,” the team writes in its study. “We propose that TpeV-like toxins contribute to the fitness of many bacteria. Finally, since antibiotic resistance is a critical global health threat, the discovery of new antimicrobial mechanisms could lead to the development of new treatments against resistant strains.”
The School of Biological Sciences, the National Science Foundation, the U.S.-Israel Binational Science Foundation, and the German National Academy of Natural Sciences Leopoldina contributed to this research study.
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Reappointments to the title of Regents Professor are:
Appointments to the title of Regents Professor are:
Appointments to the title of Regents Researcher are:
And one reappointment to the title of Regents Researcher:
“It was a pleasure to nominate these outstanding faculty members for recognition by the Board of Regents,” said Steven W. McLaughlin, provost and executive vice president for Academic Affairs. “I'd like to congratulate and thank each of them for their exemplary leadership and service, commitment to excellence in research and scholarship, and dedication to the education, growth, and well-being of our students.”
Each year, the college deans may nominate two academic faculty members for the Regents Professor title and one research faculty member for the Regents Researcher title. GTRI may nominate two research faculty members for Regents Researcher. The titles are awarded upon approval of the USG chancellor and its Committee on Academic Affairs only with unanimous recommendation of the Institute Regents Professor and Researcher Selection Committee, the Institute’s president, the executive vice president for Research, and the provost and executive vice president for Academic Affairs.
The BOR approved the nominations on Aug. 10.
]]>Institute Communications
]]>Fernandez provides a highly accessible insight into his laboratory’s work on ambient mass spectrometry, analytical problems crucial to space travel, and characterizing pharmaceutical compounds and the molecular signatures of disease. The interview provides a good introduction into many diverse applications of state-of-the-art mass spectrometry, which, in the Fernandez lab, translates to bringing highly sophisticated molecular characterization to bear in non-traditional environments and on important biological questions.
Fernandez is the twenty-fourth investigator to be profiled in the “Faces” series, which began in 2018. Mostly from the US, the honorees work across a variety of organizations – universities, companies, and national laboratories – and on all aspects of mass spectrometry.
]]>Resistant to the natural process of cell death, or apoptosis, they no longer contribute to tissue repair or homeostasis and instead are known to release harmful substances, causing inflammation and damage to cells nearby and in distant organs.
So-called zombie cells increase as we age, and they are thought to be a central cause of age-related diseases and frailty. That’s why Denis Tsygankov and his collaborators are trying to dig up the underlying workings of senescence with the help of the National Institutes of Health.
The NIH has awarded Tsygankov, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, a two-year, $275,000 R21 grant for his project, “Patterns of Aging and the Role of Biomarkers in Senescence.” R21 grants are designed to support exploratory research with potential to lead to advances in biomedical research.
“This project will build the first mathematical model to characterize senescence in the entire human organism, unveiling its regulation and dynamics, and its role in the physiological or pathological processes during human aging,” said Tsygankov, an expert in computational biology and mathematical modeling.
His collaborators include Dr. Hyman Muss, clinical researcher from the University of North Carolina, and Dr. Natalia Mitin, former cancer researcher at UNC, who is now CEO and co-founder of Sapere Bio, a company focused on studying senescence and interpreting its clinical significance. Dr. Muss has been interested in understanding senescence in his clinical practice for over a decade and published numerous papers on the connection between a central biomarker of senescence, p16, and chemotherapy-induced age-acceleration.
“The company is built around measuring a protein and tumor suppressor called p16,” said Tsygankov, who also is a researcher in the Petit Institute for Bioengineering and Bioscience at Georgia Tech, and who has experience with that particular protein. “There is very strong evidence that p16 is a true biomarker of aging, perhaps the most trustworthy biomarker, and with great clinical value.”
Research interest in p16 has grown in the past 10 years or so, since Ned Sharpless’ lab at UNC identified the protein in human T cells as an easily measured biomarker of human senescence or molecular age. The researchers identified a subset of blood cells that express p16, “which made it possible to measure p16 efficiently and precisely, unlike the attempts of measuring in whole blood,” said Tsygankov, who was a postdoc at UNC before coming to Georgia Tech/Emory BME in 2015.
“Our top goal in this project is to develop quantitative, mechanistic models of p16 dynamics at the cellular and the whole organism scales, and determine if the p16 measured in T cells actually reflects the overall senescence load at the systems level,” Tysgankov added.
Tsygankov and his collaborators are working under the broad theme that aging may not be reversed, but it can be slowed down. A quantitative understanding of p16’s role as a biomarker of senescence, and the ability to control it, could improve health care, particularly when it comes to guiding clinical decisions.
“Treatment plans such as chemotherapy can be dependent on a patient’s age,” Tsygankov said. “But chronological age and molecular or biological age are different things. We all age differently.”
Preliminary analysis of data from studies by Muss and Sapere Bio has shown that p16 levels — those indicators of senescence — can be used to predict patient risk for adverse side effects of treatment, such as kidney failure in patients undergoing cardiovascular surgery or peripheral neuropathy in breast cancer patients undergoing chemotherapy.
“Better data and predictive mathematical models on p16’s role in senescence could lead to better personalized treatment,” Tsygankov said. “Then we can expand the scope of our research, potentially leading to a precise, reliable set of clinically important biomarkers of aging.”
Links:
]]>After a campuswide search, Xiaoming Huo is joining IDEaS as Associate Director for Research. New Thrust Lead positions were created positions to focus on and opportunistically expand capabilities in important areas. Joining IDEaS in this capacity are Jeffrey Skolnick as Thrust Lead for Precision Medicine and Drug Discovery and Umakishore Ramachandran as Thrust Lead for Cloud Computing.
In addition, IDEaS is increasingly being called upon to support data and cyber infrastructure technical design and management needs of large, center-scale projects. To adress these needs, senior research scientist Tony Pan will be assuming the role of Assistant Director for Data Infrastructure. David Sherrill, who is already serving as Associate Director for Research and Education, is taking on additional responsibility as Director of the Center for High Performance Computing (CHiPC).
Xiaoming Huo, Associate Director for Research
Xiaoming Huo is an A. Russell Chandler III Professor in the H. Milton Stewart School of Industrial and Systems Engineering at Georgia Tech. Dr. Huo's research interests include statistical theory, statistical computing, and issues related to data analytics. He has made numerous contributions on topics such as sparse representation, wavelets, and statistical problems in detectability. His papers appeared in top journals, and some of them are highly cited. He is a senior member of IEEE since May 2004.
In this new role, Huo brings experience in creating teams to tackle various challenges in science and society. He believes that nurturing and fusing teams within IDEaS will results in more funding opportunities, experience sharing, shaping future programs at the national level, and enhancing the visibility of IDEaS and Georgia Tech.
Jeffrey Skolnick, Thrust Lead for Precision Medicine and Drug Discovery
Jeffrey Skolnick, Regent’s Professor of Biological Sciences, research has focused
on health and life sciences, having developed novel AI approaches for precision medicine, disease mode of action prediction, and drug efficacy and side effect prediction that is at the state of-the-art. He has developed and applied algorithms to proteomes for the prediction of protein structure and function, the prediction of small molecule ligand-protein interactions with applications to drug discovery and the prediction of off-target uses of existing drugs with applications to aging, cancer and chronic fatigue syndrome, cancer metabolomics, precision medicine, fundamental studies on the nature and completeness of protein structure space and the exploration of the interplay between protein physics and evolution in determining protein structure and function, prediction of protein-protein and protein-DNA interactions, and molecular simulations of subcellular processes.
Skolnick hopes to catalyze the development of novel big data-based approaches to Precision Medicine and Drug discovery. In particular, he hopes to identify and catalyze teams that would to transformation research in these areas. Some representative projects include Cancer Multi-omics where the goal would be to stratify patients to predict which patients are likely to respond to specific drugs. Ideally, this would push the development of cancer therapeutics to treat currently intractable cancers such as pancreatic and triple negative breast cancer. Another area is neuroscience, with particular emphasis on Alzheimer’s Disease and Parkinson’s Disease, which currently lack effective, long term treatments. Here, the goal is to identify patient specific disease drivers and key mode of action proteins and non-coding regions responsible for disease onset and progression and then identify, and in collaboration with Emory, test predicted novel repurposed drugs in patients. The goal would also be to create a knowledgebase and website which would make the resulting tools widely available.
Umakishore Ramachandran, Thrust Lead for Cloud Computing
Kishore Ramachandran received his Ph.D. in Computer Science from the University of Wisconsin, Madison in 1986, and has been on the faculty of Georgia Tech since then. He led the definition of the curriculum and the implementation for an online MS program in Computer Science (OMSCS) using MOOC technology for the College of Computing, which is currently providing an opportunity for students world-wide (with an enrollment of over 10,000) to pursue a low-cost graduate education in computer science. He has served as the Director of STAR Center from 2007 to 2014, and as the Director of Korean Programs for the College of Computing from 2007 to 2011. Ramachandran has also served as the Chair of the Core Computing Division within the College of Computing. His research interests are in architectural design, programming, and analysis of parallel and distributed systems. Currently, he is leading a project that deals with large-scale situation awareness using distributed camera networks and multi-modal sensing with applications to surveillance, connected vehicles, and transportation. He is the recipient of an NSF PYI Award in 1990, the Georgia Tech doctoral thesis advisor award in 1993, the College of Computing Outstanding Senior Research Faculty award in 1996, the College of Computing Dean's Award in 2003 and 2014, the College of Computing William "Gus'' Baird Teaching Award in 2004, the "Peter A. Freeman Faculty Award" from the College of Computing in 2009 and in 2013, the Outstanding Faculty Mentor Award from the College of Computing in 2014, and became an IEEE Fellow in 2014.
Ramachandran will help establish a “Cloud Hub” at Georgia Tech partnering with Microsoft. The Cloud hub will provide Microsoft Azure resources for both education and research for faculty and students wishing to use the Cloud for their computational needs. While the Cloud hub will initially be started with support from Microsoft, the aspirational goals for the hub include expansion to include other Cloud providers who may want to partner with Georgia Tech. Further, Ramachandran hopes to use the experience with the Cloud hub to help evolve a Cloud strategy for Georgia Tech as a whole.
Tony Pan, Assistant Director for Data Infrastructure
Tony Pan joined the Institute for Data Engineering and Science in 2018 after graduating from Georgia Institute of Technology with a Ph.D. in Computational Science and Engineering. For over two decades, Pan has focused his research efforts on developing data science methods to enable large scale biomedical and bioinformatic studies, specifically through flexible and extensible data management, high performance computing (HPC) approaches, and efficient parallel algorithms. He is leading the data management infrastructure definition and implementation to support the NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT) at Georgia Tech, and developing HPC algorithms for high-throughput sequencing data, gene networks, and single cell sequence analysis. Pan is also leading the development of data management infrastructure and gene association studies for the Arthrogryposis Registry in collaboration with Shriner’s Hospitals for Children.
In this role, Pan hopes to engage and support IDEaS members, partners, and collaborators in large scale, systematic data management and analysis efforts. Towards this end, he will focus on defining and implementing an IDEaS core data management strategy and corresponding infrastructure, as well as developing common optimization approaches and algorithms for large scale data analytics. Pan hope to foster an environment for data, knowledge, and best practice sharing between researchers, collaborators, and institutional support as part of IDEaS' data infrastructure efforts.
David Sherrill, Director, Center for High Performance Computing
Professor David Sherrill is the new Director for the Center for High Performance Computing (CHiPC). Sherrill is currently the assistant director for research and education in IDEaS. Sherrill is one of the co-PI's on the NSF MRI grant that funded the Georgia Tech Hive computer, and recently organized the Hive Supercomputer Symposium hosted by IDEaS. His background is in theoretical chemistry, and he develop new models in quantum chemistry, with a particular focus on biophysics, drug docking, and molecular crystals. Sherrill's group makes heavy use of high performance computing (HPC) resources, especially now, pioneering how to apply machine learning (ML) to intermolecular interactions. They are creating quantum chemistry datasets of unprecedented size to train these ML models. The existing quantum chemistry software is too slow for this, so they have developed their own very popular open-source program, Psi4.
In this new role, Sherrill hopes to strengthen connections between HPC users in science and engineering with HPC researchers in computing. One goal is to ensure Georgia Tech is prepared to respond to new national initiatives in which HPC may be a key component. Maintaining significant local HPC resources is a key part of that, and CHiPC should facilitate the organization of teams to compete for equipment grants. Sherrill plans to set up education and outreach workshops, and continue the excellent CHiPC efforts related to the student cluster competition and the Georgia Tech booth at Supercomputing.
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The W.M. Keck Foundation and the G. Harold and Leila Y. Mathers Foundation have awarded grants of $1 million and $300,000, respectively, to boost the research of Francesca Storici, professor in the School of Biological Sciences and principal investigator for the projects. Both grants are directed toward decrypting the hidden message of ribonucleotide incorporation in human nuclear DNA.
“We have a lot to learn about the role ribonucleotides play in the structure and function of human DNA,” said Storici, also a researcher with the Petit Institute for Bioengineering and Bioscience at Georgia Tech, whose lab already has contributed much to what the world knows about ribonucleotides, or rNMPs – the basic building blocks of RNA – when they are embedded in DNA.
Storici and her collaborators have developed new tools and techniques to find and characterize rNMPs in DNA. Their studies of yeast DNA suggest that rNMPs aren’t just random “noise,” as had been previously alleged, but rather offer a code – Storici and her colleagues call it “cryptic language,” capable of regulating DNA functions.
The grants will help researchers begin to translate that cryptic language.
“These ribonucleotides may represent novel biomarkers for human diseases such as cancer and other degenerative disorders,” Storici said.
Mistaken Replication
For an organism to grow, its cells must divide. For a cell to divide, its DNA must replicate. In humans, nearly 2 trillion cells divide every day. DNA polymerases, enzymes that facilitate DNA replication, mis-incorporate – or incorporate – rNMPs. These embedded rNMPs are known for changing the character of DNA and posing a threat to genomic stability.
Storici’s lab developed and tested a technique called ribose-seq that let them determine the whole profile of rNMPs incorporated into yeast DNA. Using ribose-seq, they discovered hot spots and patterns where rNMP insertions accumulate – accumulations that were assumed to be random noise.
Based on their recent findings, the researchers hypothesize that some rNMPs form specific motifs, or cryptic words, in human DNA, comprising previously hidden signals for specific metabolic functions of DNA, such as gene expression and replication.
“We don’t think this cryptic language of ribonucleotides is random. So, our goal is to decode the cryptic language,” Storici said. “Currently, we know nothing about that. There may be a particular sequence, or patterns of regularity that we can identify.”
Using ribose-seq to map rNMPs in DNA, via next-generation sequencing, and a computational toolkit they developed called Ribose-Map, the Storici team will build libraries of rNMP sites from a number of human cell types.
Through bioinformatic analyses and computational methods, they intend to identify and decipher the cryptic words of rNMP incorporation, “setting the stage to discover rNMPs’ role,” Storici said.
The foundations are both supporting the same scope of work, but at different scales, and the researchers will work with different human cell lines for each grant.
The Mathers Foundation will cover work with the Storici lab only. The Keck Foundation is supporting a collaborative effort between Storici and Natasha Jonoska, professor of mathematics at the University of South Florida. Both Storici and Jonoska are founding members of the Southeast Center for Mathematics and Biology.
“Through the combination of our molecular biology tools at Georgia Tech, with Natasha’s mathematical expertise in modeling and data analysis, there is great potential here for a big breakthrough – for developing a greater understanding of the biology of the human genome,” Storici said.
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About The G. Harold and Leila Y. Mathers Foundation
The mission of The G. Harold and Leila Y. Mathers Foundation is to advance knowledge in the life sciences by sponsoring scientific research that will benefit humankind. Basic scientific research, with potential translational application, is central to this goal. Since commencing grantmaking activities in 1982, the Mathers Foundation has granted more than $350 million. For many years, the foundation has enjoyed special recognition in the research community in supporting basic scientific research, realizing that true transformative breakthroughs usually occur after a thorough understanding of the fundamental mechanisms underlying natural phenomena. More recently, and with the advent of newer investigative methodologies, technology, and tools, the foundation now embraces innovative translational research proposals.
About the W.M. Keck Foundation
The W.M. Keck Foundation was established in 1954 in Los Angeles by William Myron Keck, founder of The Superior Oil Company. One of the nation’s largest philanthropic organizations, the W.M. Keck Foundation supports outstanding science, engineering, and medical research. The foundation also supports undergraduate education and maintains a program within Southern California to support arts and culture, education, health, and community service projects.
About the Georgia Institute of Technology
The Georgia Institute of Technology, or Georgia Tech, is a top 10 public research university developing leaders who advance technology and improve the human condition.
The Institute offers business, computing, design, engineering, liberal arts, and sciences degrees. Its nearly 40,000 students, representing 50 states and 149 countries, study at the main campus in Atlanta, at campuses in France and China, and through distance and online learning.
As a leading technological university, Georgia Tech is an engine of economic development for Georgia, the Southeast, and the nation, conducting more than $1 billion in research annually for government, industry, and society.
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IDEaS is one of Georgia Tech's 11 interdisciplinary research institutes within the Georgia Tech Research enterprise.
What is your field of expertise and why did you choose it?
As a graduate student in the early 90s, I chose high performance computing for the same thrill people experience when driving sports cars. There are these wonderful, expensive, and high-performance supercomputers readily available, and writing superfast code and solving the largest-scale problems is such a rush!
My core areas of expertise are high performance computing and data science. Using these as a launching pad, I work in large-scale applications in science and engineering. For the past 25 years, I have done so much work in bioinformatics and computational biology that it has become another core area.
What makes the way in which your IRI enables campus research unique?
Data science is everywhere – it is relevant to almost every unit on campus. This breadth provides both challenges and opportunities for IDEaS. To make progress, we support working groups and events in many focused areas and at the same time look for opportunities to avoid silos. We also leverage Georgia Tech’s vaunted position as leading technological university to drive forward big data driven science and engineering. We support data cyberinfrastructure needs of major centers such as the National Science Foundation (NSF) Cell Manufacturing Technologies (CMaT) Engineering Research Center and expect to serve upcoming projects in artificial intelligence (AI). Our services are valuable to many other IRIs and centers.
What couldn’t have happened without your IRI?
Catalyzation of Georgia Tech community in data engineering and science. The collective visibility is instrumental in winning large center-scale grants such as the South Big Data Regional Innovation Hub, the NSF TRIPODS institute, and the Hive supercomputer project. The IRI also exerts thought leadership at national and international levels and ensures GT has a seat at the table in U.S. data science leadership summits. For example, we organized the first US-Japan Big Data meeting for NSF.
What impact is your IRI GT research having on the world?
IDEaS has over 200 affiliated faculty working in many theoretical and applied areas. It is hard to summarize their impact in a just few words. Considering COVID situation as an example, we worked collaboratively with other big data regional hubs to launch COVID Information Commons for NSF, enabled faculty COVID research on HIVE which led to disease spread simulations advising the state, and supported events such as pandemic prevention workshop. I would also single out our management of the South Hub for outsized external impact. With 290 participating organizations, the Hub leads in community mobilization, tackling regional big data challenges, and education and workforce training.
]]>So the Oak Ridge National Laboratory (ORNL) partnered with the USDA Forest Service to develop a one-of-its-kind field lab in the Marcel Experimental Forest, where below and above ground heating elements are gradually warming the bog in greenhouse-like enclosures big enough to include trees. The enclosures are roofless so that rain and snow can get in.
It’s called the SPRUCE (Spruce and Peatland Responses Under Changing Environments) experiment, and it was designed as a window into what would happen to peat bogs in a warmer world. A recent study, headed by Georgia Institute of Technology microbiologist Joel Kostka and published June 14 in the journal PNAS, provides a sobering outlook.
“The real concern and one of the major conclusions of this paper is that the ecosystem we’re studying is becoming more methanogenic,” said Kostka, professor and associate chair of research in the School of Biological Sciences, who holds a joint appointment in the School of Earth and Atmospheric Sciences and focuses on microbial ecology. “In other words, the warmed bog is enhancing the rate of methane production faster than that for carbon dioxide. This is what we think is going to happen in a warming world, based on our results.”
Methanogens are microbes that produce methane, a harmful greenhouse gas that traps up to 30 times more heat than carbon dioxide. Warming the peatland, the researchers found, basically creates a methane production line.
“This occurs because the plant community changes in response to warmer temperatures – mosses decrease and vascular plants increase,” said the paper’s lead author, Rachel Wilson, a researcher with Florida State University’s Department of Earth, Ocean, and Atmospheric Science, where she works in the lab of professor Jeff Chanton, co-author and co-principal investigator of the study.
The process forms a complete cycle: Vascular plants – shrubs and grass-like plants – produce more simple sugars, which are broken down by fermentative bacteria, and the breakdown products then fuel methane-producing microbes use to produce more methane.
While peatlands comprise just 3 percent of the Earth’s landmass, they store about one-third of the planet’s soil carbon. The thinking goes, as global temperatures rise, microbes could break into the carbon bank and the resulting decomposition of the ancient, combustible plant biomass would lead to increased levels of carbon dioxide and methane being released into the atmosphere, accelerating climate change.
“Methane is a stronger greenhouse gas than carbon dioxide,” said Wilson. “Warming the climate stimulates methane production, which will contribute to more warming in a positive feedback loop.”
It’s a scenario that Chanton called, “a critical ecosystem shift. Peat soils that have been stable for thousands of years are giving up the ghost, so to speak. It’s a testy little process.”
That unpleasant outcome is being delayed somewhat by the extreme conditions found in many peat bogs around the world, including at the SPRUCE experiment site.
“Although most peatlands are in northern regions undergoing some of the most rapid warming on the planet, we’re talking about generally cold, acidic soils where there’s no oxygen,” Kostka noted. “Methanogens grow really slowly under these extreme conditions. We do see their activity increasing with warming, but they’re not yet growing that fast.”
He has a good idea of what could happen, though. Several years ago, Kostka took soil samples from the Minnesota site and tested them in his lab at Georgia Tech, exaggerating the temperature to a much greater degree than would be possible in a large-scale experiment like SPRUCE.
Raising the temperature by 20 degrees Celsius, about twice the temperature range used in the field experiment, “we saw huge increases in methane and large changes in the microbes that break down soil carbon into greenhouse gases,” he said.
It's a sped-up version of what they’re seeing in the field where the research team, Kostka explained, “and it is just beginning to scratch the surface of the changes we’re seeing in this ecosystem.”
The SPRUCE site experiment involves two kinds of treatment, warming and also elevated carbon dioxide. The warming treatment started in 2014. All of the data sets for the PNAS paper are from 2016. The elevated carbon dioxide treatment began in the final days of data collection, so it wasn’t particularly relevant for this study. “Going forward, we’re thinking the effects of elevated carbon dioxide will be one potential future story to tell,” Kostka said. “This is a long-term experiment and many of these large scale climate change field experiments do not observe substantial changes to microbial communities until 10 years after they start.”
Ultimately, SPRUCE experimental activity is designed and intended to develop a quantitative mechanistic understanding of carbon cycling processes, according to Paul Hanson, the Oak Ridge National Laboratory scientist leading the long-range project as principal investigator.
“SPRUCE provides experimental insights for a broad range of plausible future warming conditions for an established peatland ecosystem, combined with or without elevated carbon dioxide,” Hanson said.
So far, the evidence is pointing to a grim possibility: Warming enhances the production of carbon substrates from plants, stimulating microbial activity and greenhouse gas production, possibly leading to amplified climate-peatland feedbacks. Think, gasoline on a fire.
“That would be the worst case scenario,” Kostka said. “We don’t really know yet how plants and microbes will exchange carbon and nutrients in a warmer world. Will that carbon be locked up by the plants and stored in the soil? Will it be respired by microbes and released as a gas?
We are just beginning to see major changes in the microbes and plants at the SPRUCE peatland. Although the first few years of the experiment indicate that a lot more methane will be released to the atmosphere, we will be looking to see if these changes are sustained over the long term.”
CITATIONS: Rachel M. Wilson, Malak M. Tfaily, Max Kolton, Eric Johnston, Caitlin Petro, Cassandra A. Zalman, Paul J. Hanson, Heino M. Heyman, Jennifer E. Kyle, David W. Hoyt, Elizabeth K. Eder, Samuel O. Purvine, Randy K. Kolka, Stephen D. Sebestyen, Natalie A. Griffiths, Christopher W. Schadt, Jason K. Keller, Scott D. Bridgham, and Jeffrey P. Chanton, and Joel E. Kostka. “Soil metabolome response to whole ecosystem warming at the Spruce and Peatland Responses Under Changing Environments experiment” (PNAS, June 2021) https://doi.org/10.1073/pnas.2004192118
AERIAL PHOTO: Hanson, P.J., M.B. Krassovski, and L.A. Hook. 2020. SPRUCE S1 Bog and SPRUCE Experiment Aerial Photographs. Oak Ridge National Laboratory, TES SFA, U.S. Department of Energy, Oak Ridge, Tennessee, U.S.A. https://doi.org/10.3334/CDIAC/spruce.012 (UAV image number 0050 collected on October 4, 2020).
RELATED LINKS:
“Soil metabolome response to whole ecosystem warming at the Spruce and Peatland Responses Under Changing Environments experiment”
Joel Kostka – Microbial Ecology
“Shaking a Sleeping Bog Monster” (Research Horizons)
NSF Supports Research on the Microbes in Peat Moss
ScienceMatters Podcast: Digging Up Climate Clues in Peat Moss
]]>Two School of Biological Sciences researchers have joined the effort to find answers to the crisis. Jeffrey Skolnick, Regents’ Professor, Mary and Maisie Gibson Chair, and GRA Eminent Scholar in Computational Systems Biology; and Hongyi Zhou, Senior Research Scientist in the school, are on a team that recently captured top honors in a recent National Institutes of Health-sponsored competition to find novel, outside-the-box approaches to the opioid problem.
Their plan, “Development of a Comprehensive Integrated Platform for Translational Innovation in Pain, Opioid Abuse Disorder and Overdose” — which will use artificial intelligence, data and molecular analysis, cloud computing, and predictive algorithms in the search for new drugs — was one of five winning applications in a November 2020 competition. The results were announced April 26.
Skolnick and Zhou have now won two stages of the National Center for Advancing Translational Sciences (NCATS) ASPIRE Challenge, part of the NIH’s HEAL (Helping to End Addiction Long-Term) program. (ASPIRE stands for A Specialized Platform for Innovative Research Exploration.)
Skolnick’s group includes Andre Ghetti with ANABIOS Corporation, and Nicole Jung with Karlsruhe Institute of Technology in Germany.
“We’re extremely grateful,” Skolnick says. “We’re very excited about this. The problem of opioid addiction and chronic pain is a real plague in America and for most of the world, and there aren’t a lot of real, good answers, so this is motivating us to get people to think of novel solutions. We really appreciate the chance to put this team together.”
Rapidly translating scientific advances into immediate help for patients
NCATS defines translational science as “the process of turning observations in the laboratory, clinic, and community, into interventions that improve the health of individuals and the public — from diagnostics and therapeutics, to medical procedures and behavioral changes.”
The 2018 NCATS ASPIRE Challenge involved design competition in four component areas: integrated chemistry database, electronic synthetic chemistry portal; predictive algorithms, and biological assays (strength/potency tests.) Skolnick and Zhou were also part of a winning team in that stage.
Skolnick calls his group’s predictive algorithms “our unfair competitive advantage” — data programs that can predict in advance the probability of a drug’s success. “In principle you could screen every molecule under the sun if you had infinite resources. You could test everything, but that’s very expensive and time-consuming. We can go through this list and prioritize them and say, this one has an 80 percent probability it will work.”
Skolnick’s group added Ghetti and June for the 2020 ASPIRE Reduction-to-Practice Challenge. “The goal of this Challenge is to combine the best solutions and develop a working platform that integrates the four component areas. The Reduction-to-Practice Challenge consists of three stages: planning; prototype development and milestone delivery; and prototype delivery, independent validation, and testing,” notes the NCATS website.
Skolnick says his team’s application is designed to be accessed digitally as part of a cloud service. It will use artificial intelligence and machine learning to investigate molecules that could be turned into new drugs, as well as explore undiscovered uses for existing drugs.
“Andre’s company is going to do the testing of the molecules, and Nicole Jung will organize all the data and store it so we can have a platform that is used not just by us, but by the (scientific) community,” Skolnick explains. “We’re looking for novel mechanisms for drugs that relieve pain and treat addiction. The goal is to do this at high throughput, rather than one at a time. This is really designed to test the ideas at scale. You can get it to people a lot quicker.”
Skolnick hopes to have a robust working platform built within a year. Given the extent of the opioid crisis in the U.S. alone, the faster new non-addictive pain management drugs can be found and tested, the better, he adds.
“The need is critical. It’s one of these horrible societal problems that really require novel solutions, which means you want to understand all the mechanisms of pain, but do we understand the gears you want to turn to alleviate it?”
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The new initiative will create pilot research projects and tools that align with the needs and aims of the SHC network of clinicians to enable state-of-the-art clinical research and facilitate clinical practice. The seed grants will support Georgia Tech faculty and research associates working directly with SHC physicians and surgeons. The overall goal remains to improve the lives of children treated at SHC.
Leanne West, chief engineer of pediatric technologies at Georgia Tech, added, “This particular round of research is all about going further with information and data and making it accessible for research and patient care. With the unique data from SHC and Tech’s expertise in data analytics, we’re going to be able to provide more specific information for diagnosis and treatment of Shriners patients.”
The seed grant opportunity inspired investigator partners to conceptualize seven successful clinical research projects. Coleman Hilton, Shriners’ Research Informatics manager, who is responsible for addressing resource needs from the teams, noted that “these seven projects represent the breadth of care provided at Shriners and they are very focused on the specific research needs for each of the patient populations.”
The teams, awarded two-year seed grants of either $50,000 or $150,000, are led by principal investigators from each institution. May Dongmei Wang, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, is the Georgia Tech principal investigator for three of the seven projects this year.
Her lab has been busy working with SHC, “to establish a new Fast Healthcare Interoperability Resources (FHIR) prototype as the backend server. We want to enable interoperable clinical data management across all SHC hospitals,” Wang said. Fast Healthcare Interoperability Resources (FHIR) is the standard for joining disparate systems together in the exchange of electronic health records. It was developed by HL7 International, the non-profit organization that develops standards and solutions to empower global health data interoperability.
In the 2021 round of seed projects, Wang said, “we’ll assist four Shriners hospitals to develop three FHIR applications to showcase the acceleration of the clinical informatics pipeline from idea, to data, to insights, using FHIR.”
“This program will allow us to capture, access, share, and analyze data, including diagnostics, radiographic images, and genomics in a way that is not currently available in existing Shriners Hospital for Children patient registries and research databases,” said Marc Lalande, vice president of SHC’s research programs. “The infrastructure that will be developed will not only enhance our clinical research capabilities, but also advance our clinical practices.”
Here’s a rundown of the seven projects funded for 2021:
3D Graphical Scale for Assessing Hip Functional Range of Motion
Principal Investigators: Megan Denham, Senior Research Associate, Georgia Tech Research Institute; Harold van Bosse, SHC-Philadelphia
Project Synopsis: Hip pathology in babies and children can affect long-term development and lead to malformations and deformations and other conditions. While surgery can correct pediatric hip conditions and optimize functionality and range of motion, there currently are no outcome measurements that can adequately analyze hip function across the spectrum of conditions; no way to compare results of different treatment modalities; and none that follow results over time and growth.
Utilizing a computer model to graph range of motion, the team will develop a pediatric hip score system, allowing for more precise evaluation of various treatments of hip contractures in children across the spectrum of neuromuscular conditions (such as cerebral palsy and muscular dystrophies). They intend to develop a mobile application that can quantify function with a single figure, to help clinicians make more practical evaluations, leading to more valid comparisons of treatment options.
Craniofacial Microsomia (CFM) Informatics Infrastructure
Principal Investigators: May Dongmei Wang, Professor, Wallace H. Coulter Department of Biomedical Engineering (Georgia Tech and Emory University); Chad Purnell, M.D., SHC-Chicago
Project Synopsis: CFM is a clinical conundrum – it is the second most common craniofacial anomaly, but its pathogenesis is not clearly understood. The research team’s long-term goal is to develop an AI model of how genes and environmental factors conspire in CFM. This seed grant will establish the first step in the process, creating a framework for sharing phenotypic, clinical, radiologic, and genetic data between SHC-Chicago and Georgia Tech.
Specific aims for the seed project include creating a set of minimum common data elements for CFM research data, and developing a system to allow secure, high-volume data sharing between institutions, which will leverage the Wang lab’s expertise in developing parallel FHIR infrastructure, enabling flexible integration of data sets within the SHC system.
GL-SMART (Greenville-Lexington Shriner Multisite AI-enabled Rehabilitation Technology)
Principal Investigators: May Dongmei Wang, Professor, Wallace H. Coulter Department of Biomedical Engineering; J. Michael Wattenbarger, M.D., Chief of Staff, SHC-Greenville; Henry J. Iwinski, M.D., Chief of Staff, SHC-Lexington
Project Synopsis: This is a multi-site collaboration between Shriners Hospitals for Children in Greenville (SC) and Lexington (KY), the Wallace H. Coulter Department of Biomedical Engineering (BME) at Georgia Tech and Emory University, and Georgia Tech’s School of Electrical and Computer Engineering (ECE). Together, they intend to develop an advanced technology platform to improve scoliosis patient care at multiple Shriners sites.
The two Shriners sites involved in the study have accumulated extensive data from more than 1,000 patients over the past decade – insight that can help clinicians make better care decisions. Wang’s lab will develop a FHIR application to enable clinicians at both Shriners sites to share and access clinical data seamlessly. Wang also is developing a multimodal AI algorithm to streamline the process of predicting clinical outcomes in scoliosis patients.
HR-pQCT Informatics Infrastructure
Principal Investigators: May Dongmei Wang, Professor, Wallace H. Coulter Department of Biomedical Engineering; Gary S. Gottesman, M.D., Center for Metabolic Bone Disease, SHC-St. Louis
Project Synopsis: For patients with musculoskeletal disorders, bone mineral density scans are critical in the evaluation, surveillance, and treatment. High resolution peripheral computed tomography (HR-pQCT) is a revolutionary advancement as a new 3-D skeletal imaging tool with the ability to differentiate internal structures from cortical bone, and inform the pathophysiology of bone diseases, providing insights into bone biology, and better treatments.
Using all of that illuminating information is hampered by the inability to query the data based on significant research parameters, which is crucial to gaining deeper insight into bone disorders. So the researchers plan to build an integrative, relational database to house the data, design a FHIR interface, then populate the database with patient data, and explore options for automating the extraction, transformation, and loading of new HR-pQCT data as it is generated.
Machine Learning to Predict Fentanyl Efficacy and Adverse Effects to Advance Precision Medicine
Principal Investigators: Jeffrey Skolnick, School of Biological Sciences, Georgia Tech; Kristin Grimsrud, Assistant Clinical Professor, University of California-Davis
Project Synopsis: Personalized pain management continues to be a challenging issue for patients and clinicians. Although advances in pharmacogenetics aid in decoding genetic variants, no one really knows how a given patient will respond to a particular drug until it is administered.
To address this problem, data from two ongoing SHC studies will be used as input for machine learning (ML) algorithms to predict if a patient will experience a decrease in pain or adverse events following fentanyl administration. Skolnick’s lab will then use an ML tool it developed, MEDICASCY, for disease indication, mode of action, small molecule drug efficacy, and side effect predictions. MEDICASCY predictions will then be combined with an enzyme inference algorithm, patient clinical data, and information on fentanyl blood concentrations to generate specific predictions for fentanyl efficacy and adverse effects.
Platform Architecture and Machine Learning for Arthrogryposis
Principal Investigators: Tony Pan, Research Scientist, institute for Data Engineering and Science (IDEaS) at Georgia Tech; Noémi Dahan-Oliel, SHC-Montreal
Project Synopsis: Three Shriners Hospitals – Chicago, Greenville, and Montreal – are involved in this project with Georgia Tech to address important knowledge gaps in understanding arthrogryposis multiplex congenita (AMC), a rare (1 in 3,000 live births) chronic musculoskeletal disease. Shriners will identify the underlying causes, risk factors, and distribution of AMC, documenting interventions and outcomes, and determining genetic and/or environmental factors.
Pan and his team at Georgia Tech are essentially going to help make the data more accessible, developing a computational framework for machine learning to ultimately enable precision medicine. The researchers will design and implement a system to meet the needs for this project, deploying high-performance computing and cloud friendly cyber infrastructure to enable ad-hoc, on-demand, and reproducible data analysis with low deployment cost.
Sports Medicine Registry
Principal Investigators: Minoru Shinohara, Associate Professor, School of Biological Sciences, Georgia Tech; Corinna Franklin, director of sports medicine, SHC-Philadelphia
Project Synopsis: Six Shriners Hospitals for Children (Northern California, Erie, Chicago, Portland, Philadelphia, Montreal), as part of the Shriners Sports Medicine Consortium, are working with researcher Minoru Shinohara, who directs the Human Neuromuscular Physiology Lab at Georgia Tech. Their goal is to develop a comprehensive registry that will help clinical researchers answer many large-scale questions in pediatric sports medicine.
Shinohara, and his Georgia Tech and SHC colleagues will identify the core data elements to use from Shriners system motion analysis centers, surgical procedures, and rehab/clinical information. Ultimately, they intend to create a sports medicine registry that will be easily accessible to researchers within the consortium, giving Shriners clinicians an opportunity to have a greater impact in the treatment of pediatric sports injuries.
]]>New insights into how these tiny structures work could be exploited to bioengineer crops that can better withstand the drought and heatwaves associated with climate change.
“If you ate any corn, wheat, or rice today, you enjoyed sugars made from carbon that passed through stomata,” Cheung says. “Together, these three grass species provide half of all calories consumed by humans, and much of their agricultural success is credited to how fast their stomata work."
According to a United Nations statistic, the world will need to produce 50% more food by the middle of the century to account for population growth rates, changing diets, and the harmful effects of climate change on current agricultural practices.
“Ensuring food security, via biotechnology or any other means, is one of the biggest challenges of the 21st century,” says Cheung, who is collaborating with biophysicist Anne-Lisa Routier Kierzkowska of the University of Montreal and plant biologist Michael Raissig of the University of Heidelberg on the three-year HFSP project.
The HFSP funds international, multidisciplinary collaborations focused on creating novel approaches to problems in fundamental biology. Cheung’s team, one of seven selected Early Career awards from a total of 158 letters of intent, joins a cohort of 94 awardees from 20 different countries.
]]>A School of Biological Sciences professor who specializes in molecular and genomic evolution has uncovered some new information about how DNA methylation evolved in the human brain — and how that compares to brains of some of our primate relatives. She and a global team of researchers have published their findings, “Evolution of DNA methylation in the human brain” in Nature Communications.
“The large and complex brain is a distinguishing trait of the human lineage,” explains Soojin Yi, who directs the Yi Lab of Comparative Genomics and Epigenomics at Georgia Tech. “Scientists have been very interested in finding genetic and gene expression changes that are associated with the evolution of human brains.”
DNA methylation is a biological process by which methyl groups — organic compounds made up of three hydrogen atoms and a carbon atom — are added to DNA, which in turn sets off molecular processes to help regulate gene expression and other genetic factors that are necessary in healthy brains and nervous systems. When something goes wrong with DNA methylation, it can lead to certain diseases, including cancer and neuropsychiatric conditions such as schizophrenia.
“To understand the contribution of DNA methylation to human brain-specific gene regulation and disease susceptibility, it is necessary to extend our knowledge of evolutionary changes in DNA methylation during human brain evolution,” Yi says.
Science has long known about the DNA methylation connection to certain conditions, but the evolutionary aspect has so far been largely unexplored. “Previous studies used bulk tissues, while DNA methylation is known to vary substantially between cell types,” Yi shares, so her team, including the paper’s co-corresponding author Genevieve Konopka’s lab at UT Southwestern Medical Center, focused on the search for cell-type-specific epigenetic (gene-activity-changing) marks, including DNA methylation and histone (basic protein) modifications. Those are implicated in cell-type-specific gene expression and disease susceptibility in humans.
“Data from bulk tissues can be biased toward specific cell types and consequently, underpowered to detect cell-type-specific evolutionary changes,” Yi explains. “Therefore, to fully understand the role of DNA methylation in human brain evolution, it is necessary to study cell-type-specific changes of DNA methylation.”
Yi and her team found suitable samples for chimpanzees and macaques in the specimen archives of the Yerkes National Primate Research Center at Emory University. “We also separated neurons and oligodendrocytes (which forms the protective sheaths for neural transmission) from bulk brain samples, so that we can study cell-type specific patterns of DNA methylation,” Yi says.
“We found that the human brains are particularly heavily methylated compared to chimpanzee and rhesus macaque brains — both in neurons and oligodendrocytes.”
Yi and her team found that some positions that have unique patterns of DNA methylation in human brains were previously implicated in neuropsychiatric diseases including schizophrenia.
“Our work extends the knowledge of the unique roles of . . . methylation in human brain evolution, and offers a new framework for investigating the role of the epigenome evolution in connecting the genome to brain development, function, and diseases.”
Yi’s research team included colleagues from the Yerkes National Primate Research Center, and the Department of Pathology, at Emory University; the Center for Cooperative Research in Biosciences, Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Spain; The Department of Neuroscience at UT Southwestern Medical Center; the Center for Medical Research and Education, Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, Japan; the Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Metropolitan Institute of Medical Science, Japan; and the College of Nursing, The Research Institute of Nursing Science, Seoul National University, South Korea.
For human samples, UT Southwestern Medical Center Institutional Review Board (IRB) has determined that as this research was conducted using post-mortem specimens, the project does not meet the definition of human subjects research and does not require IRB approval and oversight. Non-human primate samples were obtained from archival, post-mortem brain tissue opportunistically collected from subjects that died from natural causes, and following procedures approved by the Emory Institutional Animal Care and Use Committee and in accordance with federal and institutional guidelines for the humane care and use of experimental animals. No living great apes were used in this study.
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But to realize this future, scientists need to build better risk assessments containing as much genetic information as possible regarding human populations — without compromising security and privacy, and without marginalizing or overrepresenting any groups. To date, existing datasets of this type of information have largely focused on individuals of European ancestry — which has meant that most people in the world have either been critically underrepresented, or at times not represented at all, among these important genomic studies and resources.
Many groups are working together to improve those datasets, including School of Biological Sciences Patton Professor Greg Gibson, who recently teamed up with Emory University School of Medicine’s Subra Kugathasan, M.D. and other colleagues to publish a new study based on what Gibson shares as the largest whole genome-sequencing study of inflammatory bowel disease for African-Americans to date.
“Whole-Genome Sequencing of African-Americans Implicates Differential Genetic Architecture in Inflammatory Bowel Disease,” published February 17 in the American Journal for Human Genetics, researches inflammatory bowel disease (IBD) and Crohn’s disease in more than 3,000 Americans of African descent. IBD patients made up 1,774 members of the group, while the control group numbered 1,644 individuals without IBD.
“The huge concern in the field is that all minorities are dramatically underrepresented” in genetic studies, Gibson notes, underscoring the need for more diverse studies and highlighting his interest in pursuing the current study. “It’s comprehensive, it’s incredibly powerful and it way overperforms what came before, in terms of magnitude of accomplishment. We started three years ago, which I think is pretty amazing. There are still not many studies out there as large in terms of true genomic sequencing of population.”
The group’s work hopes to build a better understanding of potential population divergence and genetic risk of specific complex diseases like IBD — as well as identify any possible corresponding evolution of susceptibility and origins of health disparities.
To achieve this, the research group set out to further resolve the genetic architecture of inflammatory bowel disease — and also to better define the differential genetic structure of the disease across divergent ancestries. The team notes that their resulting analyses “include many alleles that were not previously examined, in a population that remains very significantly understudied.”
So, what exactly is an allele?
A brief tutorial on alleles and genomics
Alleles are alternative forms of a gene, and they’re born from mutations. “Every person’s genome has about a million out of a billion pairs that are different,” Gibson explains. These are polymorphisms, or alleles, which are “the flavor of a gene.” When a new mutation happens, its frequency is extremely rare, but some mutations do become more common over time, and contribute ever so subtly to disease.
Most of these alleles are shared by European and African-Americans, but small differences in frequency and effect can add up — especially over several thousand of them — to real differences in risk of disease progression.
Gibson also highlights the importance of understanding and taking into account the many environmental factors that can be related to IBD and Crohn’s, such as stress, diet, access to quality nutrition, access to healthcare and preventative medicine, and even differences in socioeconomic status and opportunities that also tally up to significant health and risk disparities across divergent populations.
More diverse genomics assessments coming soon?
Gibson and Kugathasan’s research was a collaborative study involving self-identified African-American subjects recruited from five primary sites across the country: Emory University (recruited as part of the Emory African-American Inflammatory Bowel Disease Consortium), Johns Hopkins/Rutgers (recruited as part of the Multicenter African-American Inflammatory Bowel Disease Study), Cedars Sinai Medical Center, Mount Sinai Medical Center, and Washington University (recruited as part of the Centers for Common Disease Genomics network).
The study was approved by the institutional review boards at each of the participating sites and informed consent was obtained from all the participants. To protect privacy, de-identified datasets including genetic data were housed at Emory University with the approval of the local ethical board.
All DNA samples investigated in the study (a total of 3,610 before quality control) were processed and sequenced at the Broad Institute of Harvard and the Massachusetts Institute of Technology following the same protocol.
More of this needs to happen, Gibson notes, so that the real work on narrowing the gaps and differences in healthcare among a diverse spectrum of populations can begin. He adds that the African genetic structure requires complete gene sequencing for all sorts of technical reasons, making it harder than more studies of Europeans — as well as essential and well worth the effort.
“If you try to predict the onset of disease and you don’t account for ancestry differences, your assessments are just way off. In any sort of medicine, you want to be as accurate as you can. That’s why it’s so critical to include diversity in genetic studies as we progress to equitable access of all health care in all populations.”
Gibson says his next research study will deal with how genetics interacts with the other factors involved in health in underrepresented communities, such as nutrition and the impact of so-called “food deserts,” environmental issues, access to important health care, and other socio-economic indicators.
“It’s probably the most important paper I’ll ever work on,” he says.
]]>Nazanin Bassiri-Gharb is the Harris Saunders Jr. Chair Professor in the George W. Woodruff School of Mechanical Engineering and her research interests are in ferroelectric and multiferroic materials and their application to nano- and micro-electromechanical systems as sensors and actuators. Her research projects integrate micro and nanofabrication techniques and processes, with fundamental science of ferroelectric materials. Bassiri-Gharb was elected to the AIMBE for "outstanding contributions to development of innovative sensor materials applicable in personalized medicine and biomedical engineering applications."
Professor Brandon Dixon's research focuses on elucidating and quantifying the molecular aspects that control lymphatic function as they respond to the dynamically changing mechanical environment they encounter in the body. Through the use of tissue-engineered model systems and animal models, his group's research is shedding light on key functions of lymphatic transport, and the consequence of disease on these functions. Dixon was elected to the AIMBE for "outstanding contributions to technology development furthering our understanding of the structure - function relationships in the lymphatic vasculature."
The College of Fellows is comprised of the top two percent of medical and biological engineers in the country. The most accomplished and distinguished engineering and medical school chairs, research directors, professors, innovators, and successful entrepreneurs comprise the College of Fellows. AIMBE Fellows are regularly recognized for their contributions in teaching, research, and innovation. AIMBE Fellows have been awarded the Nobel Prize, the Presidential Medal of Science and the Presidential Medal of Technology and Innovation and many also are members of the National Academy of Engineering, National Academy of Medicine, and the National Academy of Sciences.
A formal induction ceremony will be held during AIMBE’s 2021 Annual Event on March 26. Bassiri-Gharb and Dixon will be inducted along with 174 colleagues who make up the AIMBE Fellow Class of 2021. For more information about the AIMBE Annual Event, visit here.
AIMBE’s mission is to recognize excellence in, and advocate for, the fields of medical and biological engineering in order to advance society. Since 1991, AIMBE’s College of Fellows has led the way for technological growth and advancement in the fields of medical and biological engineering. AIMBE Fellows have helped revolutionize medicine and related fields to enhance and extend the lives of people all over the world. They have successfully advocated for public policies that have enabled researchers and business-makers to further the interests of engineers, teachers, scientists, clinical practitioners, and ultimately, patients.
]]>This annual symposium, in its 29th year, provides a forum for researchers to share the latest research in bioengineering and bioscience. Each year the symposium topic changes and is held to celebrate the life and contributions of F.L. “Bud” Suddath, a Georgia Tech professor who excelled at research, teaching, and in administrative roles.
The 2021 symposium “Origins and Early Evolution of Life” was co-chaired by Nicholas Hud and Loren Williams. Nicholas Hud, Ph.D., is a Regents’ professor in the School of Chemistry and Biochemistry, director of the NSF/NASA Center for Chemical Evolution, and associate director of the Petit Institute. Loren Williams, Ph.D., is a professor in the School of Chemistry and Biochemistry at Georgia Tech, director of the Georgia Tech Center for the Origin of Life, and researcher at the Petit Institute.
“This year's Suddath Symposium was the perfect opportunity for us to share our latest research on the origins of life and to celebrate 10 years of the Center for Chemical Evolution, said Nicholas Hud. “Our center has been focused on a grand challenge… to discover plausible prebiotic syntheses for the polymers of life or their predecessors. Now that our center has completed 10 years, the maximum number of years that can be supported by NSF, we have a cadre of early career scientists ready to take the reins on future research efforts. It’s exciting to see the impact we have made on the field, and to share these accomplishments through the Suddath Symposium with the broader scientific community.”
The 2021 Suddath Symposium was the first in this 29 year series of symposia to go virtual with 251 attendees from 18 countries around the world.
Each year, the symposium kicks off with a presentation from a Georgia Tech Ph.D. candidate who has won the annual Suddath Memorial Award, which was established by the family, friends, and colleagues of Bud Suddath. This year’s 2021 award went to Cristian Crisan, a doctoral candidate advised by Brian Hammer, Ph.D., associate professor in the school of biological sciences at Georgia Tech.
Crisan’s presentation, “Antimicrobial Competition Dynamics of the Vibrio cholerae Type VI Secretion System,” began at 11 a.m. EST on Thursday, January 28th, and was followed by the 1 p.m. start of the 2021 Suddath Symposium on “Origins and Early Evolution of Life.”
VIEW PRESENTATION RECORDINGS
The lineup of “Origins and Early Evolution of Life” speakers included:
“Something we’ve all experienced over the past year is the importance of mathematical modeling,” says SCMB Director Christine Heitsch, a professor in the School of Mathematics with courtesy appointments in the Schools of Biological Sciences, and Computational Science and Engineering. “The better the interaction between mathematics and biology, the better the quality of the data modeling and analysis.”
Along with bringing mathematics and biosystems into sharp focus, the pandemic year of 2020 has also continuously evolved how we meet to share knowledge with one another.
SCMB hosted its 3rd Annual Symposium December 7-10, 2020 — marking the group’s first virtual annual meeting. The previous two symposia featured plenary talks and poster sessions at the Marcus Nanotechnology Building. This time, online sessions ran from noon to 2 p.m. EST each day. This year’s virtual environment featured junior researchers showcasing their work at the frontiers of the math-bio interface via screenshare. There was also a lively virtual session for contributed posters, three engaging panels focusing on cross-disciplinary communication from different perspectives, and a closing plenary talk.
Created in 2018, SCMB is funded by the National Science Foundation and the Simons Foundation. It is headquartered at Georgia Tech, and has six partner institutions around the southeast --- ORNL, Clemson, Duke, Florida, South Florida, and Tulane. SCMB is one of four NSF-Simons Research Centers for Mathematics of Complex Biological Systems. The other Centers are located at Harvard University, the University of California, Irvine, and Northwestern University.
Like several other research centers at Georgia Tech, SCMB stands as a truly interdisciplinary effort, with Hang Lu, Love Family Professor in the School of Chemical and Biomolecular Engineering, serving as SCMB Associate Director.
Seed projects at SCMB take advantage of a unique structure of pairing scientists in non-traditional, cross-disciplinary teams of principal investigators and junior researchers. The results promise a wider range of perspectives on scientific problems and potential solutions.
There are seven studies underway at SCMB, with the teams evenly split between mathematics and biosystems researchers — not just at the senior personnel (SP) level, but also among the postdoctoral researchers and graduate students who are an integral part of the Center.
Current research projects include using math models to learn more about DNA and RNA interaction — and where breaks in that connection could lead to genetic disorders — as well as how biological agents exploit disorder and randomness to survive their treks through hosts. One SCMB research team is investigating RNA structural ensembles in evolution, while another is investigating how stem cells pattern within colonies due to specific cell to cell communication.
Q&A with the Southeast Center for Mathematics and Biology
How would you explain the "math-biology interface" to the layperson? What's the connection between mathematical areas of study like geometry and topology to, say, molecular biology or genetics?
Christine Heitsch:
We usually refer to it as the “math-bio interface.” The reason is because the mathematical sciences are really broad, including optimization, statistics, parts of computer science, as well as the areas that we think of as more classic core mathematics.
“Bio” certainly includes biology and biomedical engineering but also physics, chemistry and chemical engineering, so we use the shortened form to indicate the breadth of studies here too.
Hang Lu:
Molecules, networks of genes, and images (of cells, tissues, organisms, and animal behavior) all have shapes, and interestingly shapes and changes in shapes can tell us a lot about function and dysfunction. Fields like geometry and topology are equipped with dealing with these things.
Christine Heitsch:
A fundamental premise for our center is “theory plus data.” The idea is that the math side brings the theoretical expertise, and the bio side brings the experimental expertise. These two domains of expertise meet at the interface that is the modeling and analysis of the data.
In some sense, any researcher is fundamentally seeking to better understand the world. We differ in the range and types of tools used, and in the aspects of the problems that we find interesting.
Geometry is fundamentally the study of shapes as, in some sense, is molecular biology. But a molecular biologist traditionally has very different ways of thinking about shapes, experimenting with the shapes of interest, than a geometer does. Classically, a molecular biologist will use physical experiments, whereas a geometer will use thought experiments. Now, though, both of them are increasingly likely to use computational experiments, especially when collaborating with each other.
Is this a "big data" approach to math and biological sciences? Are you using computational models to search for patterns or connections in the biological sciences?
Heitsch:
We are always searching for patterns and connections. However, the phrase “big data” has a certain resonance in the common usage, which is not the best description of our approaches.
One of our senior personnel, Matthew Torres, an associate professor at the School of Biological Sciences, said at the very beginning of this initiative that his interest wasn't in having someone do a better analysis of his current data. Rather, he said, the greatest advantage to a biologist in participating in efforts like this is gaining a new way to ask questions that weren't known before. Matt put a huge effort into the planning and execution of this year’s Symposium, so he’s clearly invested in the center’s success. He also shared how excited he was about the recent results from his SCMB collaboration, so stay tuned for further developments on that front.
The structure for your research teams is designed to make sure there's a math principal investigator and a bio principal investigator, along with a bio graduate research assistant and a math postdoctoral scholar, on every project. I know this is designed to share knowledge and train practitioners of one discipline in the foundations of the other discipline. How has that been working out since SCMB opened?
Heitsch:
Even better than we had hoped! That’s one of the reasons our Symposium this week focused on exactly this critical skill of ``interactional expertise’’ in cross-disciplinary collaborations. It really does seem to be the secret sauce for success.
The way that I keep track of it in my head is by picturing a square. You always have the vertical/disciplinary sides, which are the standard senior mentor and junior trainee relationships. What SCMB is doing is bringing in those horizontal, cross-disciplinary connections — the bio grad students interacting with math postdocs, the senior personnel engaging with each other — as well as the diagonal connections being forged.
In that vein, one of the things that the center is always trying to communicate is that there’s great value to studying more complimentary discipline. If you do, then you have some groundwork to interact with experts. You won’t necessarily develop research expertise, but you’ll have some fundamental vocabulary. A little bit of fluency in another discipline can go a very long way.
As an SCMB trainee , how do you like the interdisciplinary diversity within the center’s research teams?
Hector Banos, SCMB mathematics postdoctoral junior researcher:
I really enjoy it. I am trying to develop a micro-evolutionary model to describe allele variation in tRNA (transfer ribonucleic acid). Certainly, it’s something new to me, but being able to get constant feedback from both the math and the bio sides really helps and keeps it interesting and relevant.
In our seed project, we have a nice collaborative system. I get to participate in the Bio PI lab's meetings, and I am treated as another [within the] cohort. They also are very welcoming and address any questions or ‘inquietudes’ I have regardless of the type of question. Sometimes it may be a little frustrating not being able to keep up with all the concepts and techniques, but I guess that is part of the learning curve for someone without formal bio training, and they help me with that. I also try to provide my perspective from the math side. All these interactions have led to great discussions.
How has this arrangement helped you with your research?
Massively. Being able to collaborate with biologists on a daily basis has changed my perspective on math and biology. I became more aware of the challenges, techniques, and topics in the area. I have been able to communicate better with other biologists and bio-mathematicians. Also, being part of a center enhances the whole experience. We get to see different projects and talk to experts on math and biology. The center organizes activities that promote interactions within the fields. I am getting more comfortable in terms of biology and I think that is something someone who does math-biology needs to work on, so I am getting there.
Can you give a status report on progress within the research teams?
Hang Lu:
In all projects, the bio researchers are now exposed to a whole new set of tools and ways of thinking. The multitudes of center activities certainly lowered the barriers for bio researchers to interact with mathematicians, particularly their partners. Most pairs have moved to defining better questions to ask and address together, which is exciting.
Heitsch:
We had our 2nd Annual Symposium in February 2020 which was coupled with the second Advisory Board meeting. All seven pairs of junior researchers got up in front of these senior experts and presented a unified picture of the progress made on each of their seed projects. The Advisory Board was definitely pleased with the center’s progress overall. Internally we think things are going quite well, and we’re delighted that that was validated by outside experts.
How hard has it been to get these seven research projects up and running since SCMB was founded?
Heitsch:
Initially, the research aspect was about as seamless as it could be.
By design the organization of the Center was intended to be very nimble, because we knew we would need to quickly ramp up on a number of research projects. It was great to see it working out as planned.
Recently, though, we’ve had to make some adjustments. A significant changes in plans was the postponement of our “postdocs in residence” program planned for May 2020. The four off-site postdocs (distributed around our partner institutions in the Southeast) were going to join the three GT ones in being embedded in the research labs of their seed project collaborators for almost a month. We’re still hoping to reschedule so that the math PhDs really get an opportunity to experience the data side — this “theory plus data” balancing act.
On a more positive note, the bio grad students did have an opportunity to experience the theory side through a new “Math for Bio” graduate student course that was offered in spring 2020. A current SCMB postdoc, Daniel Cruz, and I taught that class, and the students have told us what a positive experience it was. They felt like they gained an understanding of some mathematics they had not previously been exposed to in a way that was accessible to them, and could be useful in the future.
What kinds of applications could result from this research in the next five to ten years? Where could math and biological sciences go from here?
Hang Lu:
The Center addresses questions from molecular scale all the way to organism behavior. In five to ten years, the Center will be looking at these questions from unconventional angles; that is, making predictions about biological functions and figuring out mechanisms of actions in proteins, RNA/DNA, designing molecular transport and cellular differentiation patterns, detecting subtle changes in organism aging process, and making better biomimetic robots.
Heitsch:
I’m not a good prognosticator. I will say that one thing we’ve seen over the past year is how important the modeling and analysis of biosystems can be. The level of interaction between math theory and bio data can have profound implications for our lives. It’s really been a lesson in the importance of researchers who may not necessarily be experts in both sides but who can collaborate with experts from the other side.
For SCMB, this all circles back to our “theory plus data” approach. There are a lot of people who have expertise in math and a lot with expertise in bio, and if SCMB can facilitate their interacting with each other, then really great things can come of this. We’re already seeing how these new collaborations --- as well as all the intra-center interactions --- are challenging us to think about our projects in new ways and helping to train the next generation of cross-disciplinary researchers.
When we went to New York (in February 2018) to make the pitch for the center, somebody asked, “How will you know it’s been a success?”
It’s similar to the question you’re asking. By that point I was a little slap-happy, so I said, “when a biologist sitting in the audience thinks, ‘Oh expletive, I need to find a mathematician to collaborate with.’”
We won’t necessarily see the full impact directly, but what we’re expecting to do is break new ground in our seed project areas. Throw down the gauntlet — this is the level of math-bio interaction needed to achieve these kinds of results.
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But just as there are well-documented disparities in health and health care, there is a pharmacogenomic research gap.
“The vast majority of clinical genomics research that serves as the foundation for the potential revolution in personalized health care is conducted on people of white European ancestry,” noted Georgia Institute of Technology researcher King Jordan. “Under-represented minorities are not participating as much in this research, people who already bear a disproportionate health burden. If we don’t address this genomic research gap, it has the potential to exacerbate existing disparities.”
Jordan and his collaborators work to bridge the divide in a paper they recently published in the journal BME Biology, entitled, “Population structure and pharmacogenomic risk stratification in the United States.” This research follows up on a similar pharmacogenomic study the lab published in 2019, addressing the concept of precision public medicine in Colombia.
“We broaden our lens from the focus on individuals – which is really the focus of precision medicine – to a focus on the level of populations,” said Jordan, a professor in the School of Biology and director of the Bioinformatics Graduate Program at Tech, whose collaborators on the study were lead author Shashwat Deepali Nagar (a Bioinformatics graduate student in Jordan’s lab) and Andrew Conley (a scientist with the Applied Bioinformatics Laboratory, ABiL, a collaboration between Georgia Tech, IHRC, Inc., and ASRT, Inc.).
“Whereas precision medicine is built around the mantra of ‘the right treatment to the right patient at the right time,’ the mantra with precision public health is ‘the right intervention for the right population at the right time,’” explained Jordan.
For the U.S. study, his team set out to compare the utility of self-identified race/ethnicity (SIRE, the kind of information that is readily available to clinicians) with genetic ancestry (GA, the kind of information that isn’t), identifying pharmacogenomic variants, which mediate how individuals respond to drugs.
“We hypothesized that genetic ancestry would provide higher resolution for stratifying pharmacogenomic risk,” said King, whose team focused on the three largest SIRE groups in the U.S. – White, Black (African-American), and Hispanic (Latino). They analyzed a cohort of 8,628 individuals for whom the team had both SIRE information and whole genome genotypes – data that had been collected from the University of Michigan’s Health and Retirement Study.
King and his colleagues found that genomic ancestry did, in fact, provide a higher resolution for stratifying risk at the population level – but not my much. Ultimately, they report, genetic ancestry provided only a marginal increase over SIRE in pharmacogenomic risk stratification. In light of such concordance, the researchers conclude that SIRE is clinically valuable for stratifying risk, supporting the concept of population pharmacogenomics, and consequently, precision public health.
“The idea is to use population structure as a surrogate or a proxy for genetic information, in making clinical decisions on, say, which drug to prescribe,” said King, who quickly points out that the concept of population pharmacogenomics is just a temporary solution to help address health disparities.
“We point out that it this is a suboptimal solution, albeit one that will benefit those groups that are underrepresented in biomedical research,” said King. “We’re working toward a best case scenario, when everyone will have access to their genetic or genomic information. The reality is, we aren’t there yet. So the hope is that this genomic research gap will begin to close and more people will have access to their genomic information, in which case this population stratification will become obsolete.”
Basically, the approach King and his team are advocating would avoid what he calls, “the one-size fits all approach to drug prescription. The populations that currently are underrepresented in medical research stand the most to gain by considering population structure when making treatment decisions. Conversely, they stand the most to lose when it isn’t considered.”
CITATION: Shashwat Deepali Nagar, Andrew B. Conley, I. King Jordan, “Population structure and pharmacogenomic risk stratification in the United States.” (BMC Biology, 2020) https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-020-00875-4
]]>The tension between awareness and fatigue can lead to case-count plateaus, shoulder-like dynamics, and oscillations as rising numbers of deaths cause people to become more cautious before they let down their guard to engage once again in behaviors that increase risk for transmission, which, in turn, leads to rising death counts — and renewed awareness.
“Epidemics don’t necessarily have a single peak after which the risk subsides,” said Joshua Weitz, Patton Distinguished Professor of Biological Sciences and founding director of the Interdisciplinary Ph.D. in Quantitative Biosciences at the Georgia Institute of Technology. “People’s behaviors are both influenced by and influence epidemic dynamics, potentially driving plateaus, and oscillations in incidence.”
A paper describing the connection between human behavior and viral spread was published this month in the journal Proceedings of the National Academy of Sciences. It was authored by researchers at Georgia Tech, McMaster University, Princeton University, and Texas A&M.
In the early days of the pandemic, many scientists turned to traditional epidemiological studies, which showed epidemic cases could rise to a peak and then fall smoothly as immunity to the infection reached high levels in a population in the absence of large-scale interventions. Public health messages urged the population to “flatten the curve” to prevent disease from overwhelming hospitals.
“We were concerned that a focus on ‘the peak’ was potentially misguided because it implied that the shape was a feature of the disease alone without considering the consequence of behavior,” Weitz said. “In reality, there does not have to be a single peak during an epidemic.”
“If people are aware of the severity of the epidemic, they may change their behavior, and if they change their behavior, there will be fewer severe outcomes,” Weitz said. “But if awareness is short-term, individuals may tire of public health regulations and the virus will come roaring back. Instead of a single peak in cases, there can be plateaus or oscillations balanced between cautious behavior and relaxation.”
The research team analyzed data from the early phase of the epidemic and found evidence that the decrease in fatalities after a peak was slower than the rise toward it. However, in contrast to simple models of awareness-driven behavior, the research team also found evidence that individuals tended to increase their activity — as measured by mobility indicators — before epidemic severity waned. This means that individuals may have grown fatigued, worsening the epidemic severity. The study also found that other preventive measures, like mask wearing, have the potential to avert worst-case outcomes in disease transmission even as mobility increases in light of fatigue.
“This study underlines the importance of human behavior in driving epidemic outcomes,” said Jonathan Dushoff from the Department of Biology at McMaster University. “To make good predictions beyond the short term, we need to understand all of the factors driving human responses to the virus — fear, fatigue, information, misinformation, and so forth. We have a long way to go.”
Weitz and Dushoff share optimism as well as concerns on the potential effects of anticipation of imminent vaccine distribution on behavior associated with transmission.
“It’s hard to be sure what impacts vaccine distribution will have on behavior,” Dushoff said. “There is concern in public health circles that people who think the vaccine is just around the corner could relax their guard. Human behavior is complicated.”
Lessons for future public health responses may help focus on the role of human behavior as well as communications that make disease impacts personal, fostering long-term awareness and changes in behavior that can reduce collective transmission.
Weitz and Dushoff coauthored the study with Sang Woo Park from the Department of Ecology and Evolutionary Biology at Princeton University and Professor Ceyhun Eksin from the Department of Industrial and Systems Engineering at Texas A&M.
This research was supported by the Simons Foundation (SCOPE Award ID 329108), the Army Research Office (W911NF1910384), National Institutes of Health (1R01AI46592-01), and National Science Foundation (1806606 and 1829636). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the funding agencies.
CITATION: Joshua S. Weitz, Sang Woo Park, Ceyhun Eksin, and Jonathan Dushoff, “Awareness-driven Behavior Changes Can Shift the Shape of Epidemics Away from Peaks and Towards Plateaus, Shoulders and Oscillations.” (Proceedings of the National Academy of Sciences, 2020) https://doi.org/10.1073/pnas.2009911117
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]]>“Double-strand breaks are one of the most dangerous types of DNA damage a cell can experience,” said Chance Meers, a postdoctoral researcher at Columbia University who earned his Ph.D. in molecular genetics in 2019 in the lab of Francesca Storici at the Georgia Institute of Technology. “They inhibit the cell’s ability to replicate its DNA, stalling cell division until the damage is repaired.”
The most accurate pathway of DNA-break repair is by using a homologous DNA sequence to template the re-synthesis of the damaged DNA region. Researchers in the Storici lab previously showed that a homologous RNA sequence could also mediate this break repair, and sought to understand the molecular mechanisms that control this process. They wrote about it in a recently published paper for the journal Molecular Cell.
“This is really about RNA’s capacity to transfer information to DNA that could be used in repairing damage,” explained Storici, professor in the School of Biological Sciences and a researcher in the Petit Institute for Bioengineering and Bioscience at Georgia Tech.
In a 2014 article published in Nature, her team explained how transcript-RNA could serve as a template for the repair of a DNA double-strand break. In this new study, according to lead author Meers, “we found that not only can RNA serve as a template for the repair of double-strand breaks, but that it was modifying genomic information in the absence of double-strand breaks.”
This modification of DNA even in the absence of an induced double-strand break was very surprising to the team. Also unanticipated, said Meers, was that the process of transferring information depended on the presence of an unexpected enzyme, DNA polymerase Zeta.
“This is quite surprising, because DNA polymerase Zeta is part of a large class of enzymes known as DNA polymerases characterized by their ability to catalyze the synthesis of DNA molecules from a DNA template,” Meers said.
Polymerase Zeta is part of a subset of DNA polymerases known as translesion DNA polymerases, which have unique properties that allow them to synthesize damaged DNA caused by mutagens like UV radiation. Translesion DNA polymerases also are important in cellular processes like the diversification of B-cell receptors used to recognize foreign elements like viruses.
Meers explained that RNA molecules can be thought of as the cache on a computer – or a short-term memory that is not stably maintained.
“We use a novel assay in which the yeast chromosomal DNA was genetically engineered to contain a piece of DNA sequence that allows it to be removed only in the RNA that is actively transcribed from the chromosomal DNA, generating a change in the RNA sequence but not in the DNA,” he said.
If this “short-term memory,” in the form of RNA, is transferred back into the DNA sequence during the process of RNA-templated DNA repair, it becomes “long-term memory” stored in the DNA, which can be thought of as the hard drive.
“We placed this system into a particular gene in yeast, which gives an observable characteristic trait if this process occurred, allowing us to track the repair process,” Meers said.
Exploiting such an assay, along with the discovery of a new role for DNA polymerase Zeta in RNA-templated DNA repair and modification, the study contains a series of new findings that helped the team better understand the genetic and molecular mechanisms by which RNA can change DNA sequences in cells.
This research essentially lays the groundwork for exploring the role that RNA can play in modifying genomic sequence and should allow future studies to more directly explore the role of RNA in genomic instability and, in particular, in other organisms, like humans.
This work was supported by the National Cancer Institute (NCI) and the National Institute of General Medical Sciences (NIGMS) of the NIH (grant numbers CA188347, P30CA056036 and GM136717 to A.V.M.), Drexel Coulter Program Award (to A.V.M.), the National Institute of General Medical Sciences (NIGMS) of the NIH (grant number GM115927 to F.S.), the National Science Foundation fund (grant number 1615335 to F.S.), the Howard Hughes Medical Institute Faculty Scholar (grant number 55108574 to F.S.), and grants from the Southeast Center for Mathematics and Biology (NSF, DMS-1764406 and Simons Foundation, 594594 to F.S.). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the NSF.
CITATION: Chance Meers, Havva Keskin, Gabor Banyai, Olga Mazina, Taehwan Yang, Alli L. Gombolay, Kuntal Mukherjee, Efiyenia I. Kaparos, Gary Newnam, Alexander Mazin, and Francesca Storici. “Genetic characterization of three distinct mechanisms supporting RNA-driven DNA repair and 3 modification reveals major role of DNA polymerase Zeta.” (Molecular Cell, 2020) (https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30554-2
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]]>They’re friends because clathrate-trapped natural gas could be another source of energy for the oil and gas industry. Yet clathrates are also foes if they heat up too fast inside offshore wells. They can rapidly expand with dangerous results, as was suggested in the 2010 Deepwater Horizon oil spill. Clathrates buried deep within the Arctic permafrost can also trap methane, which is a major greenhouse gas, and rising global temperatures could unlock those chilly 'crystal cages' and add to climate change concerns.
If science can figure out a safe, eco-friendly way to manipulate clathrates, then a wide range of disciplines and industries could benefit from the applications. A unique interdisciplinary team of Georgia Tech researchers may have found a way to accomplish that goal, using proteins embedded in bacteria from deep below the Earth’s surface to bind to clathrates and change them.
“Mainly on the Plane: Deep Subsurface Bacterial Proteins Bind and Alter Clathrate Structure”, published July 23 in Crystal Growth & Design (an American Chemical Society publication) is the result of a 2018 grant from the NASA Exobiology program. The researchers are Abigail Johnson and Jennifer Glass from the School of Earth and Atmospheric Sciences, Dustin Huard and Raquel Lieberman from the School of Chemistry and Biochemistry, Priyam Raut from the School of Biological Sciences, and Sheng Dai and Jongchan Kim from the School of Civil and Environmental Engineering.
The petroleum industry currently tries to slow and cool off clathrates in pipelines and wells with synthetic compounds, but “there is a strong need for alternative, ‘green,’ antifreeze materials” to lower the temperature at which hydrates (clathrates) will form, says Lieberman, a professor in the School of Chemistry and Biochemistry. “While antifreeze proteins derived from cold water fish show some promise, our unique proteins come from those found in microbes that natively inhabit gas clathrates, and thus hold promise as more potent and tailored inhibitors of natural gas clathrate.”
Making protein magic in the lab
The researchers found that their cocktail of protein-embedded bacteria changed the structure of clathrate crystal lattices to “polycrystalline and plate-like, instead of forming single, octahedral crystals,” as the study’s abstract notes.
“A big takeaway here is that this is one of the very first times that any group has created proteins in the lab using bacterial gene sequences from Earth’s deep biosphere,” says Glass, an associate professor in the School of Earth and Atmospheric Sciences. “Deep biosphere” refers to organic materials found beneath the Earth’s surface. “Due to the great difficulty of culturing and isolating microbes from the deep biosphere, we have taken the approach of expressing these novel proteins recombinantly, using workhorse bacteria like E. coli.”
Glass says the study shows scientists can make these proteins in the lab and that they are stable enough to use in experiments. “This opens up huge possibilities for exploring functions of novel proteins from the deep biosphere in our laboratories. It’s possible these proteins could have use in biotechnology, medicine, industry, environmental remediation, and many other fields.”
Huard, a research scientist in the School of Chemistry and Biochemistry, marvels at how nature is capable of evolving simple yet elegant solutions to complex problems like figuring out clathrate structure. A simple amino acid sequence, when blended into proteins that bind to clathrates, “allows for organisms to thrive in extremely harsh, cold environments,” he says.
Huard adds that clathrates are known to exist elsewhere in the solar system. “Our clathrate-binding proteins, produced by bacteria, could provide a clue as to how life might survive on other planetary bodies that have gas clathrates, such as Mars.”
Don’t forget about discoveries in the past few years about the role methane clathrates may play in maintaining subsurface liquid oceans on icy moons and planetary bodies in the outer solar system, adds Glass. “Gas clathrates are thought to be possible habitable zones for microbial life. I’m very excited to connect our research to results from future [NASA] missions.”
The full extent of the capabilities of clathrate-binding proteins is not yet known, Huard says. For example, the food industry could benefit if the proteins also inhibit ice growth, since antifreeze proteins are already found in many food products.
The perfect mix of Georgia Tech researchers and disciplines
Huard researches in Lieberman’s lab, which has produced studies of the protein structure found in certain forms of glaucoma. Lieberman and Huard ended up being part of a team that Glass says illustrates Georgia Tech’s interdisciplinary strengths.
“This project is a perfect example of the exciting results that emerge when fields that often don’t talk come together to try something new,” Glass says. “Our team at Georgia Tech is truly one of the only in the world, to my knowledge, that has the scientific and engineering expertise to do this work.”
The clathrate project brought together marine microbiologists and geochemists from the Glass Lab, bioinformaticians from the Georgia Tech Bioinformatics Graduate Program, and geosystems engineers. It was catalyzed by the Ocean Science and Engineering program (OSE), in which doctoral candidate Johnson is an inaugural class member. “OSE uniquely encourages graduate projects on ocean-related research that bridge the disciplinary divides between marine science and engineering,” Glass says.
The impact of clathrates on climate science
For Johnson, the study afforded her an opportunity to offer a better understanding of clathrates, which have trapped methane under the ocean floor and deep in the Arctic permafrost.
Clathrates “basically occur anywhere there is low temperature, high pressure, water, and sufficient gas concentrations,” Johnson says. “Gigatons of methane, a known potent greenhouse gas, are stored in gas clathrates. A warming global climate could cause clathrate dissociation, potentially leading to a disastrous snowball effect. This is why it’s so critical that we have a firm understanding on the forces controlling clathrate stability.”
Johnson says the role microbiology plays in that stability is important to consider but has not been well researched. “Our study elucidates a potential role that bacteria have in stabilizing gas clathrates by producing CBPs (clathrate binding proteins). We found that CBPs bind and significantly change the morphology of the clathrate structure, which hints at a potential role in stability. Our future research will help us determine if these CBPs work to inhibit or nucleate (crystallize) gas clathrate. We hypothesize that CBPs are secreted by bacteria into their fluid habitat within the clathrate, and then bind to the clathrate, thereby inhibiting further clathrate growth; this mechanism would allow the bacteria to maintain their fluid habitat."
]]>For many researchers, the answer lies within the ‘RNA World,’ a widely-accepted hypothesis in which self-replicating RNA proliferated, serving a dual role as both genetic polymer and catalytic polymer, long before the evolution of DNA and protein.
The RNA World model is an attractive cradle-of-life premise, according to Georgia Institute of Technology researcher Moran Frenkel-Pinter, “because it avoids the extreme improbability of simultaneous independent origins of two different types of polymers. According to that theory, over time the RNA World incrementally invented the ribosome, giving rise to the current biological system comprised of RNA, DNA, and protein.”
She adds, “it’s kind of a parsimonious idea, basically saying that RNA made everything. But there is a much simpler solution.” Frenkel-Pinter and her research partners have offered an alternative – the concerted evolution of polymers – of nucleic acids and proteins. “A Ribonucleoprotein World,” quips Frenkel-Pinter, a research scientist and former NASA Postdoctoral Fellow who works in the labs of Nick Hud and Loren Williams at Georgia Tech, and is the lead author of a recently published paper that provides experimental support for this model.
The paper, “Mutually stabilizing interactions between proto-peptides and RNA,” in the journal Nature Communications, describes the chemical linkage that could have been at play during the origins of biopolymers. Their results suggest that neither nucleic acids or proteins came first, but that RNA and proteins were selected together through a process of co-evolution. In other words, it wasn’t a single selfish gene competing for survival that drove evolution; it was the rising tide of collaboration between molecules from the very beginning.
“People have wondered, ‘was it protein first, was it nucleic acid first?’ This work says is, they were connected from early on,” says co-author Hud, regents professor in the School of Chemistry and Biochemistry, director of the NSF/NASA Center for Chemical Evolution, and associate director of the Petit Institute for Bioengineering and Bioscience.
So, there was more interdependence than independence underlying the machinery of early life. Or as co-author and Petit Institute researcher Williams puts it, “it isn’t really an independent dog eat dog world. You have systems working together – birds that eat the bugs off zebras, microbes in our gut, plants that make the oxygen we breathe.”
The researchers hypothesized that positively-charged (cationic) proto-peptides might functionally interact with nucleic acids, and then experimentally prove it. The cationic proto-peptides (either produced as mixtures from plausibly prebiotic dry-down reactions or synthetically prepared) directly interact with RNA, resulting in mutual stabilization: The proto-peptides significantly increase the thermal stability of folded RNA structures, and in turn, RNA increases the lifetime of the proto-peptide.
“There are all kinds of mutualistic relationships in biology, and we’re saying that maybe molecules work this way, too – the origin of life was matter of molecules working together,” says Williams, professor in the School of Chemistry and Biochemistry and director of the NASA Center for the Origin of Life at Tech.
Ultimately, the research team determined that collaborative molecules are the molecules that survived.
“It’s like the difference between a jungle and a cornfield,” says Williams. “The RNA World model is kind of like a cornfield in Ohio. Under certain circumstances, it works well – for example, Ohio grows a lot of corn. We’re looking at the origin of life like it was a jungle – a jungle of molecules interacting, working together for mutual benefit.”
In addition to Frenkel-Pinter, Hud, and Williams, the other authors were: Jay Haynes (graduate researcher in Williams lab); Ahmad Mohyeldin (graduate researcher in Williams lab), Martin C (graduate researcher in Hud lab), Alyssa Sargon (undergraduate researcher in Hud lab), Anton Petrov (research scientist, School of Chemistry and Biochemistry), Ramanarayanan Krishnamurthy (associate professor, Scripps Research Institute), Luke Leman (assistant professor, Scripps Research Institute). The work was supported by the NSF and NASA Astrobiology Program under the Center for Chemical Evolution (based at Georgia Tech).
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The Georgia Tech Alumni Association has announced 40 distinguished honorees who have innovated industries and positively impacted communities across the globe. More than 250 individuals were nominated by colleagues, peers, and Georgia Tech faculty this April.
The inaugural list includes a trio College of Sciences alumni: Kathryn Lanier, Director of STEM Education Outreach at Southern Research (PhD Chem 17); Maria Soto-Giron, Translational Bioinformatics Lead at Solarea Bio (PhD BI 18); and Nseabasi Ufot, CEO of the New Georgia Project (Psy 02).
“I am amazed and humbled by the accomplishments of these innovators and trendsetters. They epitomize the focus that our Georgia Tech alumni have to make the world a better place,” shares Dene Sheheane, president of the Georgia Tech Alumni Association.
Those nominated must have completed at least one semester at Georgia Tech, be under the age of 40 as of June 30, 2020, and have made an impact in their profession or community, spanning all industries and sectors. A committee of 26 faculty, staff, and volunteer leaders, who collectively represented all Georgia Tech colleges, scored each nominee using a 25-point rubric.
Selection Committee member Bert Reeves, MGT 2000, State Representative in the Georgia House of Representatives, expressed that, “I was blown away at the nearly impossible task of scoring the applicants. These are folks who are not just impacting their community and state, but in some cases, their country and the entire world. It is truly inspiring to see the innovation and passion that our alumni are contributing to many of the greatest issues our world faces today.”
Director of STEM Education Outreach at Southern Research
Kathryn Lanier is a problem-solver, a doer, and a builder of things never before imagined. She’s also pioneering the first-ever position of director of statewide STEM education outreach programs for Southern Research. Without a playbook of operations, she’s enjoyed the freedom of building a “STEMpire,” that includes everything from deep policy discussions with representatives at the state level to hosting students and teachers in the Southern Research STEM lab in Alabama. At the same time, she can sometimes be found dressed like a cat performing as her alter-ego, The Chemistry Kat, and traveling the state to host STEM pep rallies for hundreds of students. “Middle schoolers inspire me,” Kathryn says. Of course, they can be awkward and smell sometimes, she says, but their resilience is stronger than titanium. And no matter what’s going on in their private lives, they allow themselves to dream. “To live in such a way that you wear your hopes so clearly for the world to see is brave, and it's inspiring.”
Fun Fact: She has a reoccurring dream of getting stuck in the tunnels beneath the Biotech Quad. While it changes each time, her favorite version has been one where she meets and mingles with the legendary George P. Burdell.
Translational Bioinformatics Lead at Solarea Bio
In the U.S., about 10 million Americans are currently living with osteoporosis or osteopenia and the majority are women. For Maria Soto-Giron, that statistic is personal. Her motivation for working in biotech looking for treatments to reduce chronic inflammation is her mother who has rheumatoid arthritis and osteoporosis. “For more than 30 years she has suffered the serious side effects of the current drugs,” Maria says. In her pursuit at Solarea Bio, a biotech startup, she’s searching for a preventative approach using probiotics and plant fibers from fruits and vegetables as a treatment to reduce chronic inflammation without the negative side effects from drugs currently on the market. In her role leading the bioinformatics team, she created a computational platform to analyze hundreds of microbial genomic components to identify microbial candidates that could result in human health applications. As a Colombian, female scientist, she’s also passionate about increasing access and building STEM opportunities for young girls in Colombia.
Fun fact: She used to play underwater hockey (yes, you can play hockey underwater) back in Colombia.
CEO of the New Georgia Project
From corporate lawyer to labor lawyer to lobbyist to community organizer and now nonprofit executive, Nseabasi Ufot has taken an unconventional path. No matter the endeavor though, she never forgot what she learned at Tech—notably, how to apply the scientific method to solve any challenge she faced. “While my formal GT education prepared me to understand cognition and how the human brain works, it also forged my habit of Questioning, Researching, Hypothesizing, Experimenting, Observing, and Communicating Results,” she says. She uses it to answer the smaller questions in life like what haircare products to use, and to answer the larger ones, like what messaging and engagement tactics are most likely to turn a first-time voter into a super voter? At New Georgia Project, Nseabasi leads a team of more than 125 to build campaigns and technology to register, educate, and mobilize citizens from underserved and underrepresented communities. The organization has helped nearly 450,000 Georgians register to vote through face-to-face conversations, mobile apps, and video games.
Fun fact: She’s an avid gamer and speaks four languages.
A list of all 40 inaugural honorees is available here.
Check out data visualization of the 40 Under 40 list here.
About the Georgia Tech Alumni Association
The Georgia Tech Alumni Association, chartered in 1908, is an exclusive network of more than 172,000 worldwide tied together by their experience at Georgia Tech. Through the Association, Tech alumni gain immediate access to its extensive, global alumni network, as well as numerous alumni programs and services designed to enrich both careers and lives. The Georgia Tech Alumni Association is a participation-driven non-profit corporation governed by a board of alumni volunteers. Since 1947, the Association’s Roll Call program has raised money to financially support Tech’s academic mission, a tradition that has transformed the Institute into the place it is today. Learn more at gtalumni.org.
An interactive dashboard that estimates Covid-19 incidence at gatherings in the U.S. has added a new feature: the ability to calculate county-level risk of attending an event with someone actively infected with Coronavirus (Covid-19). Previously, the dashboard estimated exposure for different size events by state.
The new “Covid-19 Event Risk Assessment Planning Tool” is the work of Joshua Weitz, professor in the School of Biological Sciences and founding director of Georgia Tech’s Ph.D. in Quantitative Biosciences program, in collaboration with the lab of Clio Andris, an assistant professor in the School of City and Regional Planning with a joint appointment in the School of Interactive Computing at Georgia Tech, and with researchers from the Applied Bioinformatics Laboratory (a public/private partnership between Georgia Tech, IHRC Inc., and ASRT Inc.).
“We have developed an interactive county-level map of the risk that one or more individuals may have Covid-19 in events of different sizes,” Weitz says. “The issue of understanding risks associated with gatherings is even more relevant as many kinds of businesses, including sports and universities, are considering how to re-open safely.”
The dashboard accounts for widespread gaps in U.S. testing for the Coronavirus, which can silently spread through individuals who display mild or no symptoms of illness. “Precisely because of under-testing and the risk of exposure and infection, these risk calculations provide further support for the ongoing need for social distancing and protective measures. Such precautions are still needed even in small events, given the large number of circulating cases,” states the dashboard’s website.
For example: As of Monday, July 6, for an event with 100 attendees in Fulton County, Georgia, the estimated risk of someone in attendance being actively infected with Coronavirus is 76 percent. For that same day at an event with 1,000 attendees, the estimated risk in all but 16 of Georgia’s 159 counties exceeds 99 percent.
The dashboard’s technical development was made possible by contributions from Seolha Lee, a master’s student in Andris' group, and Aroon Chande, a Ph.D. candidate in Bioinformatics at Georgia Tech.
The dashboard’s website, which is updated daily, incorporates data from The New York Times case count and Covidtracking.com dashboard (a resource led by journalist Alexis Madrigal of The Atlantic). Both of these databases record confirmed case reports from state-level departments of public health.
“The Covid-19 Event Risk Assessment Planning Tool takes the number of cases reported in the past 14 days in each county, and multiplies these by an under-testing factor to estimate the number of circulating cases in a particular county,” Weitz explains. (In late June, Robert Redfield, director of the U.S. Centers for Disease Control and Prevention (CDC), stated on a press call that “now that serology tests are available, which test for antibodies, the estimates we have right now show about 10 times more people have antibodies in the jurisdictions tested than had documented infections.”)
Tracking tools developed earlier this year by Weitz and colleagues at Georgia Tech and other institutions are also factored into the team’s new county-level calculator. “The model is simple, intentionally so, and provided context for the rationale to halt large gatherings in early-mid March and newly relevant context for considering when and how to re-open,” states the dashboard website.
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The health benefits of physical activity are well known, but we do not fully understand why, especially at the molecular level. The National Institutes of Health-funded Molecular Transducers of Physical Activity Consortium (MoTrPAC) aims to increase understanding by measuring molecular changes in healthy adults and children before, during, and after exercise.
“There have been a lot of studies and there is plenty of information out there about exercise and its benefits, but what is truly unique about this study is the magnitude and depth,” says Facundo Fernández, professor and Vasser-Woolley Chair in Bioanalytical Chemistry in the School of Chemistry and Biochemistry at Georgia Tech, where he is a researcher in the Petit Institute for Bioengineering and Bioscience.
Emory and Georgia Tech are two of nine MoTrPAC chemical analysis sites around the country. Together they comprise the Georgia Comprehensive Metabolomics and Proteomics Unit. Fernández is one of two principal investigators for the group. The other principal investigator and unit project leader is Eric Ortlund, professor in the Department of Biochemistry at Emory’s School of Medicine.
Fernández, Ortlund, and Georgia Tech research scientist David Gaul are co-authors of a paper that MoTrPAC researchers published in the journal Cell detailing their approach to this ambitious research project. They are currently reviewing lessons from an initial phase with a smaller group of adult volunteers and multiple rounds of preclinical animal model studies to optimize their protocols and prepare to scale-up for full recruitment.
“Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise,” the authors write. “From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how activity mitigates disease.”
While the Georgia Tech team is focusing on abundant lipids, using non-targeted lipidomics (with the goal of discovering new lipids involved in the effects of physical exercise), the Ortlund lab at Emory is targeting low abundance bioactive lipids, which play a key role in stress response and inflammatory signaling pathways, “to understand how they change during exercise and potentially drive exercise adaptation,” says Ortlund. “Though lipid metabolism is complicated, bioactive lipids are generated by well-defined biochemical pathways permitting straightforward integration with other ‘omics such as transcriptomics and proteomics. Such tight integration is critical for deriving actionable scientific insight from the MoTrPAC consortium.”
MoTrPAC set the goal at its 11 clinical sites to recruit about 2,600 healthy volunteers across a wide age range (10 to 60-plus years-old) and with balanced participation by gender. Part of the study will test how the response to exercise changes after generally inactive participants complete a 12-week supervised exercise regimen. Sedentary adults will be randomly assigned to an endurance training regimen (treadmill, cycling), a resistance training regimen (weightlifting), or an inactive control group. Low-activity children will be randomly assigned to an endurance training regimen, or to a control group where they pursue their normal activities.
Meanwhile, a separate group of highly-active adults and youths will contribute to the overall size of the study, helping researchers understand what exercise looks like at the molecular level in those who have exercised vigorously and consistently over an extended period.
Another unique facet of MoTrPAC is that volunteers provide samples – or biospecimens – before, during, and after exercise that will go through a complex array of molecular assays. MoTrPAC researchers implemented an early study phase with a limited number of adult volunteers that is meant to ensure the complex study design is feasible both for the researchers and the participants before scaling up. The researchers and their data and safety monitoring board are reviewing lessons learned, so that recruitment may continue under optimized protocols. Recruitment currently is on-hold due to safety concerns over COVID-19.
Preclinical studies in an animal model also set the stage for full-scale MoTrPAC clinical studies, enabling researchers like Gaul (the metabolomics lead of the Systems Mass Spectrometry core facility at the Petit Institute) to generate data from tissues that cannot be collected from humans, expanding the scope of the consortium.
Researchers at three preclinical animal study sites conducted both a single round of exercise and an exercise training regimen in young and aged rats. Following the exercise round or training, 19 biospecimens were collected per animal, which gives a nearly whole-body look at the effects of exercise, which has never been done before. The biospecimens also provided raw material for the nine chemical analysis sites (such as those at Emory and Georgia Tech) to generate data on exercise responsive biomolecules like genes, indicators of gene activity, proteins, molecules involved in metabolism, and molecular signals in cell-to-cell communication.
Some data from the preclinical studies is available through the MoTrPAC Data Hub, and more is expected soon – MoTrPAC researchers alone cannot answer every question about the molecular basis of the health benefits of exercise. Making the data widely available brings new perspectives to the topic than would be otherwise possible.
Ultimately, MoTrPAC aims to have a positive impact on human health. The information gathered about endurance and resistance exercise in a wide range of individuals and in different tissues may influence exercise guidelines, making them more tailored for specific groups of people. One day, a doctor may be able to prescribe a personalized exercise routine based on what is likely to create the best outcome for an individual. Other researchers may use the data to identify drugs that mimic the molecular signals of exercise, so-called exercise-mimetics, which could help people who are unable to exercise.
It's a massive six-year study that Fernández calls, “a once in a lifetime opportunity. We know that the changes you see following exercise are nothing short of dramatic. And the data that we will be generating is something that will probably be analyzed for generations to come.”
MoTrPAC is funded by the NIH Common Fund and overseen in collaboration with the National Institute on Aging , the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases. A list of funded MoTrPAC projects is at https://motrpac.org/aboutUs.cfm. MoTrPAC’s adult and pediatric clinical studies are registered with clinicaltrials.gov under NCT03960827 and NCT04151199, respectively.
]]>Researchers have been aware of the abundance of ribonucleotides for about a decade, and the lab of Francesca Storici at the Georgia Institute of Technology has been at the forefront, researching the relationship between RNA and DNA in genome stability and instability, and DNA modification.
“There is much that is unknown about the phenomenon of ribonucleotides in DNA, andit needs to be uncovered,” says Storici, professor in the School of Biological Sciences and a researcher in the Petit Institute of Bioengineering and Bioscience at Georgia Tech, where her lab’s previous studies have led to the development of new-age tools and techniques, to collect and analyze data and answer some of the questions surrounding ribonucleotides.
“It’s important to establish a framework for better directing future studies to uncover physiological roles of ribonucleotides in DNA,” she says. And that’s exactly what she and her colleagues have done in their latest research paper, “Ribonucleotide incorporation in yeast genomic DNA shows preference for cytosine and guanosine preceded by deoxyadenosine,” published recently in the journal Nature Communications.
Namely, they use the tools and techniques they’ve developed over the past few years to characterize sites of ribonucleotide incorporation in DNA, demonstrating clearly that ribonucleotides in yeast DNA are not randomly distributed but show preferences for being incorporated in specific DNA sequence contexts. “We specifically reveal a bias for ribonucleotide incorporation both in yeast mitochondrial and nuclear DNA,” Storici says.
In a previous study published in January 2015, the lab introduced ribose-seq, a high-throughput sequencing technique that allows researchers to establish a full profile of ribonucleotides embedded in genomic DNA, generating large, complex data sets. In late 2018, the lab published its work on a new bioinformatics toolkit called Ribose-Map, which effectively and efficiently transforms the massive amounts of raw sequencing data obtained from the ribose-seq process into summary datasets and publication-ready results.
For their latest work described in Nature Communications, the team deployed ribose-seq to generate the data and Ribose-Map to analyze it, identifying sites of ribonucleotides in yeast DNA and explore their genome-wide distribution. Consequently, the paper’s four co-lead authors included Sathya Balachander (part of the ribose-seq development team and co-author of that paper, now licensing associate for the Bill Harbert Institute for Innovation and Entrepreneurship/University of Alabama-Birmingham) and Alli Gombolay (lead author of the Ribose-Map study).
Contributing equally as co-lead authors of the new research were Taehwan Yang and Penghao Xu, who, like Gombolay, are Ph.D. students in Storici’s lab (where Balachander was a Ph.D. student and postdoctoral researcher).
The team studied three different yeast species and detected a number of similar patterns. In all three species, the deoxyribonucleotide that is immediately upstream of the ribonucleotide was shown to have the greatest impact on the incorporation of ribonucleotides in DNA. “This rule was not clear before,” Storici says. “The study also highlights hotspots of ribonucleotides in DNA sequences containing di- and tri-nucleotide repeats, showing that specific sequence contexts have higher likelihood of ribonucleotide incorporation in DNA. This might be associated with ribonucleotide physiological/pathological functions that are yet to be discovered.”
The lab is now working toward better understanding of how cells control and benefit from ribonucleotide incorporation in DNA by uncovering the patterns and hotspots of incorporation in yeast cells of different genotypes, as well as cells from other species and organisms.
“Now we are interested to see if the rule that we have discovered for yeast applies to other cell types beyond yeast, like human cells for example, and to what extent,” says Storici. “As long term goal, we aim to determine whether there is a sort of language of ribonucleotide incorporation that cells utilize for regulating different cell metabolic functions.”
In addition to those mentioned, other authors of this multi-institutional study were Fredrik Vannberg (former professor in the School of Biological Sciences at Georgia Tech and former Petit Institute researcher), Gary Newnam (manager of the Storici Lab), Anton Bryksin (director of the Petit Institute’s Molecular Evolution Core), Havva Keskin (former Storici grad student, now a researcher with Omega Bio-tek), Kyung Duk Koh (former member of Storici lab, now a researcher at the University of California-San Francisco), Waleed M. M. El-Sayed (former visiting scholar in the Storici’s lab, now researcher at the National Institute of Oceanography and Fisheries in Egypt), and Sijia Tao, Nicole Bowen, Raymond Schinazi, and Baek Kim from the Emory School of Medicine’s Department of Pediatrics.
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Over four years and two degrees as a student at Georgia Tech, Kristine Lacek has seen many sides of research. As a recent graduate who now holds a bachelor’s degree in biology and a master’s in bioinformatics, Lacek reflects on the themes of collaboration and interdisciplinary discovery that prevailed throughout her education at the Institute.
During the fall semester of her freshman undergraduate year, Lacek met with Mindy Millard-Stafford, a professor in the School of Biological Sciences, to learn about the Exercise Physiology Lab. Millard-Stafford encouraged Lacek to enroll in her spring semester sports science class to learn about the lab’s work. After completing the course, Lacek knew it was exactly where she wanted to work. In the fall semester of her sophomore year, she joined Millard-Stafford's lab and began her research journey at Tech.
In the Exercise Physiology Lab, Lacek’s work focused on analyzing bone mineral density of members of the Georgia Tech Track & Field Team Distance Squad.
“I performed DEXA (bone densitometry) body scans and analyzed their diets to examine evidence for something called the ‘Male Athlete Triad,’” Lacek says. “Specifically, I found a significant link between insufficient caloric intake and depleted bone mineral density in the male runners.”
Her research won her a President’s Undergraduate Research Award that paid for a stipend, as well as travel to two national conferences where she presented her findings.
Upon beginning her master's degree, Lacek left the Exercise Physiology Lab to start work in the Bioinformatics Lab. There, under biology professor Greg Gibson, Lacek began researching the human genome and how it influences individual risk for medical conditions. Through this work, Lacek was soon met with a dilemma between nature and nurture influencing a human’s lifestyle.
“We grow up being told that it is always about nature versus nurture, or maybe nature plus nurture,” shares professor Gibson. “This becomes genetics plus environment when you get to college. But the reality is that who we are is a complex combination of the two."
Although this area of research was not directly related to her previous work, Lacek easily applied the skills she gained in the Exercise Physiology Lab to her new research environment. She credits Georgia Tech’s interdisciplinary environment for aiding her transition, noting that it helped make her comfortable in various laboratory settings.
In the Bioinformatics Lab, Lacek studied over half a million full human genomes to look for patterns in behaviors that influence a human’s risk for medical conditions. She calls herself a “dry researcher,” explaining that all her research occurred on the computer.
One of her most interesting discoveries was related to the relationship between fruit consumption and the incidence rate of inflammatory bowel disease, or IBD. When comparing individuals at high-risk of contracting the disease, she observed that those who consume below-average levels of fruit have an incidence rate of IBD that’s around twice as high as those who consume above-average levels of fruit.
Lacek shares that in tandem with these unique and exciting discoveries came a fair share of disappointments and challenges. One of Lacek’s greatest obstacles was finding accurate data to analyze.
“I once spent six months on a dataset that was giving me wonky results, only to discover that the mathematics used to generate the original data rendered them inappropriate for the work to which I was trying to apply them,” she says.
Other times, Lacek was stumped by the responses that individuals shared on self-reported data points.
“When reporting glasses of wine consumed per week, one individual reported 120,” says Lacek. “That’s more than 17 each day! Really makes you question how thoroughly volunteers read the questions.”
Despite setbacks and failures, Lacek says that the moments of success made every challenge worth it. And, at 21 years old, those research findings landed her a co-authorship on a paper in The Annual Review of Genetics.
“My research advisor told me that the results I generated were the first ever he’s seen confirming a theory he’s had for over ten years!” says Lacek.
Lacek shares that her most fulfilling personal moment happened while presenting preliminary findings to medical doctors at Emory University. As the doctors provided their ideas and feedback on the potential clinical applications of the findings, Lacek recognized that she had officially joined the professional research world.
“It really put all my work into a real-world perspective, beyond the code and statistics, impacting very real people,” says Lacek. “At that moment, every error message and crashed program was worth it.”
As a result of years of hard work and persistence, Lacek was recently awarded an Oak Ridge Institute for Science and Education (ORISE) Fellowship to begin work at the Centers for Disease Control, as a Bioinformatics Fellow in the Influenza Division. There, she will use the skills and knowledge from her time at Georgia Tech to analyze the human genome and the influenza genome to solve human health problems.
“As current events have shown, along with history, the more we can understand about a disease, the better equipped we are to combat it and save lives,” says Lacek.
Lacek shares that she’s especially grateful for the support of her advisors, Millard-Stafford in applied physiology and Gibson in bioinformatics, who have helped her achieve her career goals.
“They showed me that even ‘bad’ results can be good science,” says Lacek. “None of this would have been possible for me without the growth I underwent as an undergraduate and graduate researcher at Georgia Tech.”
By: Grace Pietkiewicz
Caroline Genzale, associate professor in the George W. Woodruff School of Mechanical Engineering at Georgia Tech, has received a NASA Innovative Advanced Concepts Phase 1 funding award for a project titled “Fueling a Human Mission to Mars.” Genzale will serve as the primary investigator and NIAC Fellow on the nine-month project which is a collaborative effort involving Georgia Tech colleagues Wenting Sun, associate professor in the Daniel Guggenheim School of Aerospace Engineering, and Pamela Peralta-Yahya, associate professor in the School of Chemistry and Biochemistry.
"I grew up during the heyday of the Space Shuttle and always dreamed about being part of the U.S. space program in some way," said Genzale. "I guess that dream has finally come full circle. My grandfather was a material scientist for Rockwell International during the development of the Space Shuttle and he’d show me pictures of the new engines he was helping to design and build. Those moments really instilled a lifelong fascination with the U.S. space program, and especially with NASA’s mission to foster human exploration of our solar system."
The NASA Innovative Advanced Concepts (NIAC) Program nurtures visionary ideas that could transform future NASA missions with the creation of breakthroughs — radically better or entirely new aerospace concepts — while engaging America's innovators and entrepreneurs as partners in the journey.
The program seeks innovations from diverse and non-traditional sources and NIAC projects study innovative, technically credible, advanced concepts that could one day “change the possible” in aerospace. Sixteen new concepts received funding this year, along with seven projects that are continuations of previously funded work.
The multidisciplinary Georgia Tech team aims to co-develop a renewable, liquid, storage stable rocket propellant that can be produced and burned on Mars. The proposed technology uses bio-organisms to perform atmospheric in-situ resource utilization (ISRU) to produce a propellant entirely from Mars resources. The aim is to reduce the Entry Descent Landing (EDL) mass of a crewed mission to Mars by approximately 7 tons by eliminating the need to transport, land, and store rocket propellant for the return launch. This technology will also enable long-term human presence on Mars and beyond because repeated costly propellant deliveries from Earth would be unnecessary.
The plan calls for the genetic engineering of organisms to efficiently convert the abundant CO2 in the Martian atmosphere into liquid hydrocarbons suitable for rocket propulsion and other energy needs on Mars. The proposed system grows algae biofilms that consume atmospheric CO2 and sunlight with minimal water resources. The algae would then provide a food source to the genetically optimized organisms engineered to produce a monomer with ideal combustion behavior and liquid properties.
The monomers would serve as fuel in a propellant combination to power a human-crewed Mars Ascent Vehicle (MAV). The chemical and physical properties and energy density of these monomers suggest that they are capable of sufficient energy conversion through combustion for a crewed launch from Mars, making them excellent candidates for an ISRU rocket propellant. They are also liquid over a wide range of typical Mars temperatures, making them non-cyrogenic and storage stable.
The oxygen atoms in the designed monomer will also enable a cleaner burn than conventional hydrocarbon propellants, supporting the reuse of rocket engines for multi-mission and interplanetary trips.
“I’m really interested in the idea of designer biofuels,” said Genzale. “Combustion is has fallen out of favor lately due to carbon emissions, but liquid fuels are extremely valuable energy-dense resources. Current fuels used for combustion and propulsion are based on naturally-occurring resources, but they are not necessarily optimal for combustion efficiency or for controlling the types of pollutants formed, and they do not utilize renewable sources of carbon. Biofuel synthesis can not only leverage renewable carbon resources, but we now have an exciting opportunity to tailor the physiochemical properties of a fuel for optimal performance as a high-efficiency clean combustion energy source.”
The group’s approach will test the thermo-physical-chemical properties and combustion behavior of a suite of monomer rocket propellant candidates, while simultaneously developing the biological system for synthesizing them on Mars. By working together and in parallel, the collaborators will efficiently integrate testing feedback to quickly arrive at a co-optimized ISRU monomer rocket propellant.
In theory these advantages will reduce infrastructure and resources needed to support human missions to Mars, and could lead to more ambitious efforts to expand human presence throughout the solar system.
“Working with experts like Pamela Peralta-Yahya in the School of Chemistry, we can genetically engineer microbes to synthesize chemical structures that are not found in nature, enabling us to tailor design a renewable clean fuel from the ground up,” said Genzale. “An innovation like this could transform future transportation on Mars and Earth.”
Caroline Genzale joined the Woodruff School faculty at Georgia Tech in December 2010 and currently directs the Spray Physics and Engine Research Lab. Her group develops and applies laser-based diagnostics for high-speed multi-phase reacting flows and sprays. Prior to arriving at Georgia Tech, she was a post-doctoral researcher at Sandia National Laboratories’ Combustion Research Facility in Livermore, California. She obtained her Ph.D. in Mechanical Engineering from the University of Wisconsin – Madison.
]]>The presumed immunity of those who have recovered from the infection could allow them to safely substitute for susceptible people in certain high-contact occupations such as healthcare. Dubbed “shield immunity,” the anticipated protection against short-term reinfection could allow recovered patients to expand their interactions with infected and susceptible people, potentially reducing overall transmission rates when interactions are permitted to expand.
New modeling of the virus’ behavior suggests that an intervention strategy based on shield immunity could reduce the risk of allowing the higher levels of human interaction needed to support expanded economic activity. The number of Americans infected by the novel coronavirus is likely much higher than what has been officially reported, and that could be good news for efforts to utilize their presumed immunity to protect the larger community.
However, there are two important caveats to the strategy. The first is that the duration of immunity to reinfection by SARS-CoV-2 remains unknown; however, individuals who survived infections by related viral infections, like SARS, had persistent antibodies for approximately two years – and those who survived infection to MERS had evidence of immunity for approximately three years. The second issue is that determining on a broad scale who has antibodies that may protect them from the coronavirus will require a level of reliable serological testing not yet available in the United States.
“Our model describes ways in which serological tests used to identify individuals who have been infected by and recovered from COVID-19 could help both reduce future transmission and foster increased economic engagement,” said Joshua Weitz, professor in the School of Biological Sciences and founding director of the Interdisciplinary Ph.D. in Quantitative Biosciences at the Georgia Institute of Technology. “The idea is to think in advance about how identifying recovered individuals could help serve the collective good, using information collected on neutralizing antibodies in new ways.”
A paper describing the modeling behind the concept of shield immunity was published May 7 in the journal Nature Medicine by a team of researchers from Georgia Tech, Princeton University and McMaster University. The researchers studied the potential impacts of presumed immunity among recovered persons using a computational model of COVID-19 epidemiological dynamics, building upon a SEIR (susceptible-exposed-infectious-recovered) framework.
In a population of 10 million citizens, for example, the model predicts that in a worst-case transmission scenario, implementation of an intermediate shielding strategy could help reduce deaths from 71,000 to 58,000, while an enhanced shielding plan could cut deaths from 71,000 to 20,000. The model also suggests that shielding could enhance the effects of social distancing strategies that may remain in place once higher levels of economic activity resume.
Identification of individuals who have protective antibodies against the novel coronavirus has begun only recently. Antibody tests are not 100% specific, implying that tests can lead to false positives. However, targeted use of antibody testing in groups with elevated exposure will lead to increases in positive predictive value, even with imperfect tests. The serological antibody test differs from widespread polymerase chain reaction (PCR) testing being done to determine whether people are actively infected with the virus.
Among healthcare professionals, serological testing could identify recovered individuals who might then be able to interact with patients with reduced concern for infection. Other recovered individuals could be used to help reduce transmission risk in nursing homes, the food service industry, emergency medical services, grocery stores, retailing and other essential operations. Across society, the relatively small number of individuals with immunity could substitute for people whose immunity status isn’t known; reducing transmission risk both for recovered individuals and those who remain immunologically naive.
“We want to think about serology as an intervention,” Weitz said. “Finding out who is immune to the coronavirus could make a big difference in trying to reduce the risk to people who would be vulnerable by interacting with someone who could pass on the disease.”
Serological testing to identify those with immunity might begin with healthcare workers, who may be more likely to have been infected by the coronavirus because of their exposure to infected persons, Weitz said. Because so many infections do not produce the distinctive COVID-19 symptoms, it’s likely that many people have recovered from the illness without knowing they’ve had had it, potentially expanding the pool of recovered persons.
“There may be a deeper pool of individuals who can help within their own fields and other fields of specialization to reduce transmission,” Weitz said. “The reality is that people within high-contact jobs probably are likely to have a higher incidence of infection than other groups.”
But using antibody information about individuals would create potential privacy issues, and require that those individuals make informed decisions about accepting additional risks for the greater good of the community.
“What this model says is that if we could identify individuals who are immune, there is a chance that some individuals would not have to reduce their level of interaction with others because that interaction would be less risky,” he added. “Rather than trying to keep reducing interactions, which is helpful for reducing transmission but bad for what it does for the economy, we might be able to maintain interactions while reducing the risk, combined with other mitigation approaches.”
Ultimately, addressing the pandemic will require development and mass production of a vaccine that could boost immunity levels beyond 60 percent in the general population. Until that is available, Weitz believes that shield immunity could become part of the approach to the challenge.
“We don’t have a silver bullet,” he said. “Until we have a vaccine, we will have to use a combination of strategies to control COVID-19, and shield immunity is potentially one of them.”
In addition to Weitz, co-authors of the paper included Dr. Stephen J. Beckett, Ashley R. Coenen, Dr. David Demory, Marian Dominguez-Mirazo, Dr. Chung-Yin Leung, Guanlin Li, Andreea Magalie, Rogelio Rodriguez-Gonzalez, Shashwat Shivam, and Conan Zhao, all from Georgia Tech; Prof. Jonathan Dushoff of McMaster University, and Sang Woo Park of Princeton University.
This research was supported by the Simons Foundation (SCOPE Award ID 329108), the Army Research Office (W911NF1910384), National Institutes of Health (1R01AI46592-01), and National Science Foundation (1806606 and 1829636). Any findings, conclusions, and recommendations are those of the authors and not necessarily of the sponsoring agencies.
CITATION: Joshua S. Weitz, et al., “Intervention Serology and Interaction Substitution: Modeling the Role of `Shield Immunity' in Reducing COVID-19 Epidemic Spread.” (Nature Medicine, 2020) http://dx.doi.org/10.1038/s41591-020-0895-3
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]]>The goal is to supply a broad initiative by the governor’s office involving multiple universities and partners to rapidly produce and administer more tests. At least 35 volunteers at Georgia Tech, while adhering to social distancing, are reorienting labs normally used for scientific discovery to do larger-scale production of biochemical components.
“We are inventing new ways of doing things like an electronic buddy system so people can be alone – but not alone – while they work in the lab. The technical part is actually the easiest. The logistics of testing, data security, and regulatory considerations – those things are more challenging,” said Loren Williams, a professor in Georgia Tech’s School of Chemistry and Biochemistry.
Williams and the researchers are supporting Georgia Governor Brian Kemp’s COVID-19 State Lab Surge Capacity Task Force, which is a project managed through the Georgia Tech Research Institute (GTRI). GTRI is also leading the coordination and integration of data management across the lab surge effort.
“We are providing technical and project management of the effort which is focused on increasing the state’s ability to expand testing beyond current limitations,” said Mike Shannon, GTRI’s lead in the project and a principal research engineer at GTRI.
The science behind coronavirus testing is complementary to the researchers’ usual work. That includes understanding proteins associated with glaucoma, figuring out how RNA and DNA evolved in the first place, or whether ribosomes – lumps of RNA and protein key to translating genetic code into life – may exist on exoplanets.
Williams’ research team studies the last topic, and some of their work is related to the core of coronavirus testing, a chemical reaction that amplifies the virus’ genetic fingerprint. It is called a reverse transcription polymerase chain reaction (RT-PCR), and it transcribes trace amounts of coronavirus’ RNA code into ample amounts of corresponding DNA in the lab for easy analysis.
“His lab members are very familiar with RT-PCR, and when the lack of tests became apparent, they swung into action. The group grew from there, based on the technical needs for the project,” said Raquel Lieberman, another leading scientist in the effort and also a professor in Georgia Tech’s School of Chemistry and Biochemistry.
“Every day, very talented, hardworking people with perfect skill sets come out of the woodwork and ask to help,” Williams said.
The group has teams that engineer the production of enzymes or other chemicals needed for RT-PCR to work: Two central enzymes are reverse transcriptase, which converts RNA to DNA and Taq polymerase, which rapidly replicates DNA. Another important component is ribonuclease inhibitor, which slows coronavirus RNA decay.
Other researchers develop processes for mass production or implementation of COVID-19 safety procedures; the list goes on. Some colleagues telework; others work in labs but spaced far from each other while they wear masks.
“The group is planning to produce enough enzyme components for hundreds of tests per day,” said Vinayah Agarwal, an assistant professor in Georgia Tech’s School of Chemistry and Biochemistry and School of Biological Sciences. “Using these components, we will also build cheaper and more robust testing kits going forward.”
Instructions already exist for some of the ingredients for the test, but they are not readily available because the rights to them are exclusive.
“Intellectual property and other proprietary issues hinder our effort,” Lieberman said. “But we have received help from scientists all over the world to piece together protocols on how to make what we need.”
The state wants to increase current testing capacities by 3,000 more tests per day. The task force also includes teams from Augusta University Health System, Georgia State University, Emory University, University of Georgia, and the Georgia Public Health Laboratory. The task force lead is Captain Kevin Caspary who is with the Georgia National Guard.
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Also read this: Interactive COVID-19 tool shows the importance of staying at home
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]]>An explosion on the Deepwater Horizon marine oil platform leased by British Petroleum kills 11 workers and sends thousands of barrels of crude oil pumping into the water, all just 40 miles off the Louisiana coast. At its peak, it was estimated that 60,000 barrels of oil a day went into the Gulf, creating a 57,000 square-mile slick and causing damage to more than 1,000 miles of shoreline.
Deepwater’s 10th anniversary is a chance to recall compelling videos and interviews regarding the world’s worst environmental disaster. But advances in microbial research have also helped scientists learn more about the ecological effects of the spill, according to an article written by a Georgia Tech professor for a top scientific magazine.
“Deepwater Horizon and the Rise of the Omics,” written by Joel Kostka, professor and associate chair in the School of Biological Sciences and professor in the School of Earth and Atmospheric Sciences, with co-authors Samantha Joye and Rita Colwell, is featured in the April 2020 issue of Eos, the research magazine of the American Geophysical Union. The AGU has more than 60,000 members, and it is one of the largest scientific organizations in the world (College of Sciences Dean Susan Lozier is AGU’s president-elect).
Kostka, who researches microbial ecology, is currently studying Deepwater’s legacy of microbial genomics for the Gulf of Mexico Research Initiative, or GoMRI, a $500-million effort funded by British Petroleum. The GoMRI has already supported thousands of research scientists, Kostka says.
“Today scientists have the gene sequencing techniques to properly study the role microbes play and the mechanisms with which they break down oil — with the hope that one day we might be able to deploy them deliberately to protect or restore the environment around a spill,” writes Heather Goss, Eos editor-in-chief, in her “From The Editor” introduction in the magazine.
The previous record-holder for environmental disaster before Deepwater Horizon was the Exxon Valdez oil tanker spill off the coast of Alaska in 1989. At that time, “environmental microbiology was a relatively nascent field,” writes Kostka, who is also Associate Chair of Research in the School of Biological Sciences. “But in the past decade, a variety of so-called omics techniques, focused on parsing the genetic makeup of cells, have emerged and offered researchers powerful new ways to study microbial communities and the roles played by specific groups of microbes.”
Omics refers to the suffix applied to relative new fields within biological sciences, including genomics, the study of genomic structures and processes. “The DWH spill was also the first major environmental disaster for which genomics technologies had matured to such an extent that they could be deployed to quantify microbial responses over large spatial and temporal scales,” Kostka writes. “As a result, the field of environmental genomics matured during the past decade in parallel with the DWH response. Technical advances in genomics enabled direct, comprehensive analyses of the microbes in their natural habitat, be it oil-contaminated or uncontaminated seawater or sediments. Researchers studying the effects of the DWH spill presided over an explosion of microbial genomics data that enabled major advances in oil spill science and allowed scientists to ask, ‘What microbes are there?’ in complex communities in unprecedented detail.”
Kostka adds that combining genomics with knowledge and tools from other disciplines, including biogeochemistry and oceanography, have allowed scientists to “identify disturbances that might otherwise go unnoticed” by looking for microbial populations that represent bioindicators of ecosystems.
“With these efforts, global ecosystems can be better protected and, when necessary, restored in the face of diverse environmental stressors,” Kostka says.
Although microbes have been used to help clean up spills, current methods are expensive and not natural to the environment being cleaned. But scientists have isolated a “superbug” that, while belonging to the same genus as E. coli and Salmonella, could also help break down petroleum products in multiple, different environments.
Better study of the organisms, genes, and metabolic pathways in microbial communities allow scientists to use them as biomarkers, giving them information on the health of an ecosystem “like a blood test can point physicians to disease diagnosis and treatment options,” Kostka writes.
“The overall goal of this work is to chart a course for future research on using microbial genomics to understand fundamental change in the oceans due to disturbances such as climate change or oil spills,” he says.
Read more about Kostka’s research and findings in Eos magazine. Read the Spanish version of the Eos magazine article: "Deepwater Horizon: La Plataforma Petrolera y el Surgimiento de las Técnicas Ómicas".
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In many well-documented ways, this was among the darkest epochs of human history. But the massive demographic upheaval also had profound effects at the genomic level, resulting in the rapid adaptive evolution of the human beings who have lived in this part of the world for the last 500 years, according to King Jordan and his research partners.
“Five hundred years is like batting an eye in the evolution of humans,” says Jordan, professor in the School of Biological Sciences at the Georgia Institute of Technology, where he directs the Bioinformatics Graduate Program. “It’s less than one percent of the time that has passed since modern humans first left Africa.”
The three distinct ancestral source populations that converged in the Americas – Africans, Europeans, and Native Americans – had been separated and adapting to their own local environments for tens of thousands of years since their initial migration out of Africa. Jordan and his colleagues hypothesized that when these diverse populations came together and exchanged genetic material in the Americas – the process referred to as admixture – the previously adapted variants were able to rapidly increase in frequency based on their utility in the new environment.
They refer to this rapid evolution as admixture-enabled selection and they write about it in the latest research paper from the Jordan lab, “Admixture-enabled selection for rapid adaptive evolution in the Americas,” published in the journal Genome Biology.
“A big question in the lab was, can populations that have been separated for millennia come back together and form completely new, novel genomes that have never been seen before – can you adapt in 500 years?” says Emily Norris, lead author of the paper, who graduated with her PhD from Georgia Tech in November 2019. “Our premise is, yes, that it has happened.”
To test their hypothesis, the researchers analyzed whole genome sequences (utilizing data from the 1000 Genome Project) sampled from admixed Latin American populations in Colombia, Mexico, Peru, and Puerto Rico. And their results showed evidence of admixture-enabled polygenic selection in these populations.
“Given the ubiquity of admixture among previously diverged populations, it should be considered as a fundamental mechanism for the acceleration of human evolution,” the researchers write.
“We’ve developed a new way of looking at natural selection that is predicated upon the reality of admixture,” says Jordan, who is also a faculty researcher in the Petit Institute for Bioengineering and Bioscience at Tech.
“In admixture-enabled evolution, you’re introducing novel variants at high frequencies – you’re creating combinations of variants that had never existed before on the same genomic background,” Jordan adds. “So, instead of introducing adaptation at low frequency via mutation – a slow process constrained by the rate and introduction of mutation into populations – admixture-enabled selection facilitates rapid adaptive evolution.”
And it isn’t unique to the Americas. Human evolution has been constantly characterized by long periods of genetic divergence, after populations have become physically and reproductively isolated, followed by a period of unification, or reunification, and interbreeding and the resulting genetic admixture.
“Admixture represents a fundamental mechanism by which human adaptation has been sped up,” Jordan asserts. “And it’s happened many, many times across human evolution.”
In addition to Norris and Jordan, the other authors were Lavanya Rishishwar (research scientists, former grad student in Jordan lab), Aroon Chande (graduate researcher in Jordan lab), Andrew Conley (research scientist in Jordan lab), Kaixon Ye (assistant professor, University of Georgia), and Augusto Valderrama-Aguirre (Universidad Santiago de Cali, Colombia).
]]>That theory, called the Knudson Hypothesis, argued that two mutations in the type of genes that suppress tumors are needed to lead to changes that could cause cancer. However, John McDonald, a School of Biological Sciences professor and the director of Georgia Tech’s Integrated Cancer Research Center, says the research, published in Oncotarget, “shows, for the first time, that nearly all normal healthy individuals carry at least one potentially cancer-causing tumor suppressor gene mutation. The implication is that a majority of the human population is, to a greater or lesser extent, predisposed to develop cancer.”
McDonald and his fellow researchers — Evan A. Clayton, Shareef Khalid, Dongjo Ban, Lu Wang and Professor I. King Jordan, all of Georgia Tech — relied on several databases, including the Catalogue of Somatic Mutations in Cancer (COSMIC), the world’s largest database of mutations associated with cancer onset and progression. The scientists combined that database with the One Thousand Genomes Project (1KGP), which lists genetic variants present, in 2,504 normal, healthy individuals. That list reflects the diversity of racial and ethnic groups randomly selected from 26 human populations around the world.
The Knudson Hypothesis, developed in 1971 by Alfred Knudson, helped physicians identify cancer-related genes, and won Knudson the prestigious Albert Lasker Award in Clinical Medical Research in 1998.
“Inconsistent with the Knudson two-hit hypothesis, we present evidence that acquisition of a second cancer-causing tumor suppressor mutation is not necessary to drive cancer onset/progression. Rather, we present evidence that, in many cases, individuals with only a single cancer-causing tumor suppressor mutation develop cancer,” McDonald says. “In these individuals, we show that the mutant gene is significantly overexpressed relative to the normal gene, thus overriding the influence of the non-mutated gene and driving cancer onset and development. Thus, in many individuals, a change in gene expression, rather than a ‘second mutational hit,’ is responsible for the cancer.”
All humans have two copies of every gene, each copy supplied by a biological parent. Two classes of genes are believed to cause the onset and progression of cancer. Oncogenes are genes that can drive cancer after a single mutation in one of the copies of the gene. In other words, those mutations are said to be “dominant” with respect to their ability to result in cancer.
Unlike oncogenes, a second class of cancer-driving genes, called tumor suppressor genes, are considered to be recessive. Knudson’s hypothesis took the point of view that mutations in each of the two copies of the tumor suppressor genes had to happen in order to drive cancer development. McDonald says the hypothesis is still widely held in 2020 by the cancer community.
“We believe that our findings are of major significance and call into question many of the assumptions underlying current methods to diagnose and treat cancer based on genomic profiling,” McDonald says.
This research was supported by the Ovarian Cancer Institute (Atlanta), Northside Hospital (Atlanta), the Deborah Nash Endowment Fund, and National Institute of Health Bioinformatics Training Grant: CRP 10-2012-03.
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The program was created to give Petit investigators an opportunity to perform novel experiments that will result in valuable preliminary data with equipment they have not used before. The amount of equipment time given through the seed grants will allow researchers to gather preliminary data for future grant proposals.
Cheung (assistant professor, School of Chemical & Biomolecular Engineering) is working on a project called, “Transporters for the Microbial Biosynthesis of Plant Products," and will utilize the Next Generation Sequencing MiniSeq equipment at the Petit Institute’s Molecular Evolution Core Facility. This project will engineer biomolecular sensors for the functional characterization of transporters – the proteins embedded in membranes that allow the traffic of compounds between cells and subcellular compartments. Sensors can dramatically accelerate the identification of the substrates for transporters, which can help engineer strategies to increase the yield of drug biosynthetic pathways.
Goodisman (associate professor, School of Biological Sciences) also will utilize the Molecular Evolution Core Facility for his project, “Population Genetics of Yellowjackets." Goodisman will leverage state-of-the-art equipment in this core and see if he can expedite his team’s DNA fragment analysis processing. The goal of the project is to better understand the evolution and ecology of highly social species (such as yellowjackets).
Torres (associate professor, School of Biological Sciences) will make it three-for-three for Molecular Evolution. He is working on a project called, “"Transitioning from Yeast to Humans: Proposal for Usage of the GT Tissue Culture Facility." Torres’s team use a yeast model system to study and identify novel G protein regulatory mechanisms which will provide foundations for the development of better drugs in the future. They will use space dedicated for human cell culture in the Molecular Evolution Core Facility to establish a sustained human cell signaling research program.
The dollar value of each grant awarded varies based on the equipment utilized in the research project and does not include reagents. To learn more here about the seed grant program, click here.
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Examine your hands. The right is a mirror image of the left. They look very similar, but you know they’re not when you try to put your left hand inside a right glove.
The molecules of life have a similar handedness. Proteins for example are like your left hand, made up of amino acids that are all left-handed. This phenomenon is called chirality. How chiral systems emerged is one of the key questions of origins-of-life research.
Many explanations have been proposed. Now a Georgia Tech team examining the problem suggests that stability is what drove the emergence of chiral systems. Led by Jeffrey Skolnick, a professor in the School of Biological Sciences, the team includes research scientists Hongyi Zhou and Mu Gao. The work was supported in part by the Division of General Medical Sciences of the National Institutes of Health (NIH Grant R35-118039) and published on Dec. 10, 2019, in PNAS.
They reached their conclusion from computer simulations examining the stability and properties of a prepared protein library made up of
Their simulations showed that nonchiral proteins, even the demi-chiral ones, have many properties of chiral proteins. They fold and form cavities just like ordinary proteins. They could have performed many of the biochemical functions of ordinary proteins, especially the most ancient and essential ones. These nonchiral proteins also can adopt the structures of contemporary proteins including ribosomal proteins, necessary for protein transcription.
“This ability of nonchiral proteins to fold and function might have been an essential prerequisite for the life on Earth,” says Eugene Koonin, a senior investigator at the National Center for Biotechnology Information, in the National Institutes of Health. “If so, this result is a truly fundamental finding that contributes to our understanding of the origins of life.”
However, nonchiral proteins have fewer hydrogen bonds than those made of all D or all L amino acids. The demi-chiral ones have the fewest. Thus chiral proteins are much more stable than demi-chiral ones. “The biochemistry of life as we know it likely results from stability driven by hydrogen bonds,” says Skolnick, who is a member of the Parker H. Petit Institute of Bioengineering and Bioscience.
The PNAS study examines the properties of proteins from the point of view of physics alone, without the intervention of evolution, Skolnick says. “It explains how the chemistry of life emerged from basic physical principles. It also strongly suggests that simple life might be quite ubiquitous throughout the universe.”
“I wish to understand how life emerged and to know its design principles,” Skolnick says. “On the most academic level, I wish to explain the origin of life based on physics with well-defined testable ideas.”
The newly published “work offers a non-intelligent-design perspective as to how the biochemistry of life might have gotten started,” Skolnick says. “It shifts the emphasis from evolution to the inherent physical properties of proteins. It removes that chicken-and-egg quandary that chiral RNA is required to produce chiral proteins. Rather, such excess chirality is shown to emerge naturally from a nonchiral system.”
What the work does not address is why L-amino acids and L-proteins emerged dominant on Earth. It is know that some meteorites have an excess of L-amino acids. “If one assumes that many primordial amino acids were seeded by meteorites, many of them have an excess of L over D amino acids,” Skolnick says. “All it would take is just a little bias to get the whole process started.”
Skolnick says the next step is to test the computer simulations by studying the emergent chemistry of nonchiral proteins. A key unanswered question is how did replication emerge? “We can explain life’s biochemistry and many of the parts associated with replication from this study, but not replication itself,” he says. “If we can do this, then we have all of life’s components. If this works, ultimately I want to recreate what could be the early living systems in a test tube.”
]]>The 21st class of Petit Undergraduate Research Scholars has been selected. These 14 scholars will immerse themselves into the multidisciplinary pool of research at the Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology in January 2020. Among them are five from Georgia Tech who are majoring in the sciences or mathematics.
"This is a diverse cohort of students whose expertise spans a wide range of majors, and not only at Georgia Tech, but other Atlanta universities also,” notes Raquel Lieberman, Petit Scholar faculty advisor, a professor in the School of Chemistry and Biochemistry, and a Petit Institute researcher.
With eight women and six men in the new class, next year’s group of Scholars reflect a growing trend of more women entering STEM fields. Of the 14 students, 10 are from Georgia Tech, two are from Emory University, with one each from Agnes Scott College and Georgia State University. Five of the students are based in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.
“I'm excited for all of them, because this is a unique opportunity, an entire year diving deep into an actual research project,” Lieberman says. “They'll also contribute substantially to papers that will be published and have a chance to present their work at conferences and other gatherings.”
“I'm excited for all of them, because this is a unique opportunity, an entire year diving deep into an actual research project. They'll also contribute substantially to papers that will be published and have a chance to present their work at conferences and other gatherings.”
Raquel Lieberman
Meet the 2020 class of Petit Scholars (listed here with their university, major, and the principal investigator’s lab they’ll be a part of):
• Cindy Aguilera-Navarro, Agnes Scott College, Neuroscience, Tim Cope;
• Berna Aliya, Georgia Tech, Neuroscience, Young Jang;
• Kasey Cervantes, Emory, Biology, Arijit Raychowdhury;
• Ana Cristian, Georgia Tech, Biomedical Engineering, James Dahlman;
• Carolann Espy, Georgia Tech, Chemistry and Biochemistry, Ingeborg Schmidt-Krey;
• Rachel Fitzgerald, Georgia Tech, Chemistry and Biochemistry, M.G. Finn;
• Marina Holguin-Lopez, Georgia State, Neuroscience, Todd Sulchek;
• Brandon Kassouf, Georgia Tech, Biomedical Engineering, Mike Davis;
• Amy Liu, Georgia Tech, Biomedical Engineering, Shuichi Takayama;
• Ananthu Pucha, Emory, Neuroscience, Nick Willett
• Milan Riddick, Georgia Tech, Biomedical Engineering, Andrés García;
• Kevin Tao, Georgia Tech, Biomedical Engineering, Gabe Kwong;
• Paxton Threatt, Georgia Tech, Chemistry and Biochemistry, Neha Garg;
• Kevin Yin, Georgia Tech, Mathematics, Shuyi Nie.
The Petit Undergraduate Research Scholarship program began in 2000 with the goal of developing a new generation of leading bio-researchers by providing them with an opportunity to conduct independent research in Petit Institute labs, and other bio-related labs at Georgia Tech, for a full year. Since 2000, the program has funded more than 300 students, with about 80 percent of them moving on to pursue graduate degrees.
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The research, which used multiple lines of evidence to determine the microbe causing changes in the gut microbiome during a diarrheal episode, may be significant for applying new diagnostic technologies that could enable personalized medical treatments of intestinal diseases.
The project, led by researchers from the Georgia Institute of Technology, the Emory Rollins School of Public Health, and Universidad San Francisco de Quito, is part of a study funded by the National Institute of Allergy and Infectious Diseases (NIAID) that integrates epidemiological, molecular, and metagenomic data to understand how enteric (food and waterborne) pathogens and the gut microbiome vary across an urban-rural gradient in Ecuador. Frequent illness can affect the growth and development of children during their critical early years.
“We wanted to understand where the illnesses are coming from and what the consequences are for the development of the children,” said Kostas Konstantinidis, a professor in the School of Civil and Environmental Engineering at Georgia Tech. “Knowing more about the causative agent may allow us to prevent infections. This would be relevant not just for the developing world, but for children everywhere.”
The findings were reported Oct. 4 in the journal Applied and Environmental Microbiology. The research team also included researchers from the Universidad Central del Ecuador.
Information the study provided on the likely causative agent of enteric diseases raises questions about long-held definitions of pathogenic agents, said Karen Levy, an associate professor at Rollins. Many so-called “pathogenic E. coli” infections are asymptomatic — not causing diarrhea — she noted. If a microbe considered a pathogen can be detected in a stool sample, but it is not causing disease, is it a pathogen?
“The approach we used in this analysis helps to not only detect whether or not the pathogenic E. coli is present in the stool, but also if it is the likely cause of diarrhea experienced by study subjects,” she said. “This holds promise that, in the future, we could use metagenomic approaches to diagnose not just the presence of the so-called ‘pathogenic E. coli,’ but also of the actual pathogenicity of these organisms.”
Enteric infections often go undiagnosed in children, though they can in some circumstances be fatal. For the study, researchers collected more than 1,000 samples from infected children in Ecuador and analyzed them using traditional culture-based methods in which samples are placed onto selective cell culture media, allowed to grow, and then studied to determine the pathogen present.
A subset of 30 samples were also sent to the Konstantinidis lab at Georgia Tech, where his team has been developing new culture-independent genomics testing that can identify microbes that may not be detectable using standard culture techniques. The researchers examined the total gut microbiome and its shifts during diarrheal infections to assess the effects of three specific pathogenic genotypes of E. coli on the indigenous gut microbiota.
“We looked at the microbes in stool samples using culture-independent genomic techniques,” said Konstantinidis, who also has a faculty position in the Georgia Tech School of Biological Sciences. “We took the DNA out of the samples, sequenced it, and used bioinformatics tools to see what microorganisms were there. By looking at the entire microbiome, we can get more precise information about the pathogens that are causing disease and their effects on the commensal microbes of the gastrointestinal tract: the microbiome. We found that the effects were different for different E. coli pathogens, which is important for diagnosis and distinguishing among them.”
One major finding was that the metagenomics technique disagreed with the culture-based study. “In 50% of the cases where the lab suggested E. coli was the agent, we didn’t see evidence from metagenomics that this was the case,” Konstantinidis said. “We saw evidence that it was something else, potentially an enteric virus.”
The researchers were able to combine different diagnostic approaches in a way that could provide a more complete picture of the microbiome, creating signatures that could potentially identify the microbial agent of the disease. “Compared to the traditional approach, our technique uses multiple lines of evidence, including relative pathogen abundance, population clonality level and detection of virulence factors, and effects on the gut’s natural microbiome that haven’t been used together before,” Konstantinidis said.
The researchers also discovered that a strain known as diffuse adherent E. coli (DAEC) was accompanied by large amounts of co-eluted human DNA in the stool sample. Though DAEC is not generally considered a particularly virulent strain, the presence of human DNA suggests that the DAEC may have been damaging epithelium cells in the gastrointestinal tract.
“Understanding changes in the gut microbiome can help us understand how different strains cause distinct pathogenicity and symptoms such as the elution of high amount of human DNA and changes in the abundance of commensal microbiota,” Konstantinidis said. “If infections like this happen often, that could have implications for a child’s growth and development.”
The metagenomics technique could help provide a foundation for personalized medicine that would select therapies based on the specifics of the microbe – including its virulence and antibiotic resistance profiles. The study shows that the technology works and can be done quickly, but trained personnel are needed to make it more widely available.
“In the next five or 10 years, we are going to see some big changes in which these new methodologies are adopted in the clinic, and that could lead, in the long term, to innovation in diagnosis and treatment,” he added.
Future work as part of another NIAID award will examine how environmental factors – such as water quality, presence of animals in the home, and the chemical environment – affect the microbiomes of small children. In this cohort of children from different geographic areas, the team will examine additional enteric pathogens, and follow children for their first two years of life. This will offer the opportunity to understand whether infections are cleared from the body – or if they continue to lurk in low levels.
In addition to those already mentioned, the authors included recent Georgia Tech School of Biological Sciences graduates Angela Peña-Gonzalez and Maria J. Soto-Girón, Shanon Smith, Jeticia Sistrunk, Lorena Montero, Maritza Páez, Estefanía Ortega, Janet K. Hatt, William Cevallos, and Gabriel Trueba.
Funding for the study was provided by the National Institute of Allergy and Infectious Diseases through grant 1K01AI103544. The contents are solely the responsibility of the author and do not necessarily represent the official views of the NIH.
CITATION: Angela Peña-Gonzalez, et al., “Metagenomic signatures of gut infection caused by different Escherichia coli pathotypes” (Applied and Environmental Microbiology, 2019). https://aem.asm.org/content/early/2019/10/01/AEM.01820-19
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]]>Fall is yellow jacket season. Not football or basketball, but the time of year when colonies of yellow jackets — the insects — reach their maximum size. It’s also when Professor Michael Goodisman and the Goodisman Research Group collect their nests.
“We typically collect nests for a month or so beginning in late October, which is prime time for collecting. The colonies usually die off around Thanksgiving, and are completely dead by Christmas — although climate change may be moving the dates,” said Goodisman, associate professor and associate chair for Undergraduate Education in the School of Biological Sciences.
Humans usually cross paths with the yellow jackets’ underground nests a couple of times a year. The first is between April and June, when people tend to mow their lawns frequently. The second is fall, when it’s time to rake leaves.
“Yellow jackets are particularly aggressive this time of year,” said Goodisman, whose team collects the insects alive, albeit somewhat sedated. The underground nests typically have a single hole, about the size of a silver dollar, for entering and exiting.
“We pour a little bit of anesthetic into the hole. It does the same thing to them that it does to us — it knocks them out,” Goodisman said. “Then we try to dig up the nest very quickly before they come to. We pull the nest out and bring it back to the lab.”
When collecting nests, Goodisman and the team wear beekeepers’ uniforms with long pants underneath for additional protection. Yellow jackets are aggressive and will push their way through air holes in the pith helmets, so the researchers cover them with tape to keep the insects out.
“I have had that happen to me, and it’s no fun at all!” said Goodisman. “If there’s an opening, they will find it and get in.”
The Goodisman Research Group is studying yellow jackets to learn about highly social behavior.
“Yellow jackets are an example of some of the most extreme and impressive social behavior that you will see in any animal, even more so than in humans,” Goodisman said. “Their social structure is similar to honeybees in that they typically have a single queen, though not always. She produces a bunch of selfless workers that work until the colony succeeds.”
The researchers are also interested in studying multiyear super colonies. Nests usually last only one season, from May to December. But when temperatures are mild, a colony can survive the winter and become massive the next year.
“We have seen this in New Zealand, Australia, and South Africa. We’re starting to see it in Florida, South Alabama, and California — super colonies the size of a car,” Goodisman said.
These changes bring up other questions, such as, are yellow jackets facing the same environmental threats as honeybees?
“The short answer is we don’t know. There’s no one studying yellow jackets the same way they’re studying honeybees,” Goodisman said. “But not all of the things that affect honeybees will affect yellow jackets.”
Honeybees have been partially domesticated and bred for successful pollination, reduced aggression, and increased honey production. Unfortunately, domestication often has unwanted side effects. For example, domesticated honeybees may display fewer behavioral defenses against parasites than feral honeybees as a consequence of the domestication process.
“Yellow jackets don’t really have that. We don’t associate yellow jackets with having a lot of diseases. They still could be subjected to pesticides, but it’s not really known,” Goodisman said.
It’s hard to tell if there has been a decrease in the yellow jacket population based on the calls the Goodisman Research Group receives.
“There has been no systematic survey that I know of,” he said. “I think a widespread survey over many years would be interesting.”
Goodisman’s interest in insects began when he was a child in Syracuse, New York.
“There are yellow jackets in Syracuse and all across North America, from Mexico to Alaska,” he said — indeed, they can be found all across the northern hemisphere. They are one of the most common and successful social insects.
“They’re great fun, as you might imagine. They have a lot of personality,” he said. “It’s exhilarating when you’re trying to pull them out of the ground or get them out of the house.”
His undergraduate research at Cornell University included work with insects, and he did his doctoral thesis at the University of Georgia on fire ants.
While at UGA he saw fire ants in a tray in the lab, and he thought it was “so cool.” But his work with yellow jackets didn’t start until he did postdoctoral work in Australia.
“There was some interesting research being done on invasive yellow jackets in Australia and New Zealand. I’ve been working on yellow jackets well before I came to Georgia Tech.”
It was purely coincidental that Goodisman became a professor at Georgia Tech, home of the Yellow Jackets. But it still causes the occasional raised eyebrow when he tells people about his research.
“People do a double take and ask if I’m at Tech because of my yellow jacket research. They ask if I have a yellow jacket professorship, or if I’m the ‘Chair of Yellow Jacket Research.’ It’s always a fun conversation, especially with Georgia Tech alumni.”
NOTE: Free yellow jacket nest removal. Nests will be used for research in the School of Biological Sciences. E-mail michael.goodisman@biology.gatech.edu to arrange a pickup.
]]>Scientists at Georgia Tech have identified three antimicrobial agents—including hordenine, a compound in malted barley—that increase the motility of colon cells, which may result in your need to head to the restroom.
This finding comes from the researchers’ interest in finding agents to treat irritable bowel syndrome with constipation, or IBS-C. The condition is triggered when a special receptor of the compound serotonin is activated. This receptor, called serotonin receptor 4, is present throughout the human colon. It turns out that 95% of serotonin in the body is in the gut.
Serotonin is a well-known neurotransmitter associated with feelings of well-being and happiness. Its biological functions are myriad, modulating processes from cognition to physiology.
Pamela Peralta-Yahya, an associate professor in the Georgia Tech School of Chemistry and Biochemistry, wanted to identify other compounds that would bind serotonin receptor 4. She and her team believed they could have potential as novel IBS-C treatments.
They developed a rapid, high-throughput assay to screen chemicals for serotonin receptor 4 activation at a rate of one chemical per second. “This new screening technology alone was game changing,” Peralta-Yahya says. “Previously, the two-day culture time in colon cells prevented the testing of such a large number of chemicals.”
Emily Yasi, the graduate student leading the research project, then screened more than 1,000 natural products and anti-infection agents. She identified three compounds that affected colon cells: Hordenine, halofuginone, and revaprazan either increased the movement of colon cells or hastened the healing of colon cells after being wounded. Any of the three compounds could be found in your gut, if you have imbibed a pint of Pilsner, eaten half an egg from a chicken treated with a common antiparastic agent, or are undergoing treatment with a certain gastritis medication.
The findings were published on Nov. 12, 2019, in ACS Synthetic Biology. The study was supported by the National Institutes of Health.
“This assay can now be used to screen large pharmaceutical libraries and potentially opens the door for the identification of new pharmaceuticals for the future treatment of IBS-C,” Peralta-Yahya says.
To be clear, the findings are preliminary and have no clinical significance at this stage. Researchers emphatically reject the suggestion that beer might be good for you, given the well-known adverse effects of alcohol on human health.
]]>Diaz is a Ph.D. student in the Quantitative Biosciences (QBios) program at Georgia Tech, and part of the first wave of junior researchers in the Southeast Center for Mathematics and Biology at Tech, one of the four research centers funded by the NSF and Simons. She’s working in the lab of Dan Goldman, professor of physics, member of the Petit Institute for Bioengineering and Bioscience and a team lead at SCMB. Diaz is exactly the kind of trainee that SCMB and the national endeavor needs, exemplifying the kind of interdisciplinary acuity necessary to do innovative research at the intersection of mathematics and molecular, cellular, and organismal biology.
Diaz comes by her wide-ranging interests naturally. Growing up in Puerto Rico, she used to follow her father around on his small farm, surrounded by animals and plants, “learning as much as I could,” she says. “Over time, I was convinced that I would eventually pursue undergraduate studies in biology.
“However, this plan changed abruptly when I took my first physics course in 12th grade,” Diaz added. “Physics felt like my ‘calling,’ but living systems remained at the core of what I care most passionately about. When it came to applying to graduate school, it seemed like an obvious choice: to join a Physics Ph.D. program with faculty that carry out research of physics of living systems.”
That made Goldman’s biomechanics lab and the QBioS program perfect fits for her interests. “Tackling biosciences questions with quantitative approaches is intuitive to me,” she says, adding that the SCMB is taking the integrative approach to another level. “Collaborating with people that have a background in math can bridge gaps between biology and math to develop and use mathematical tools to study underlying processes in biology. This is an opportunity to drive both fields forward. As math is further developed to study biology, a repertoire of tools will be available for researchers to use in the biomedical field.”
Diaz sees herself as part of the vanguard in one of the newest interdisciplinary approaches to understanding the depth and breadth of living systems. And she’s got some good company in the first cohort of SCMB junior researchers, an international group of eager, talented young investigators, like Margherita Maria Ferrari, a postdoctoral researcher from Italy with a classical mathematical training in analytics and statistics.
“During my Ph.D., I went to a conference and met a professor who was giving a talk about mathematics applied to biological processes and chemical processes, which I thought was very interesting, and unexpected,” says Ferrari, who had not been exposed to this kind of integrative research before. “I learned that there were people using tools that I was familiar with, but in a completely different research area.”
So after earning her Ph.D., she sought opportunities that would satisfy her growing interest in this kind of integrative research, and found her current post in the lab of Nataša Jonoska, professor at the University of South Florida and an SCMB team lead.
Ferrari, Diaz, and their fellow junior researchers had a chance to gather and formally meet each other, along with the fourteen faculty team leads and administrators of SCMB, at a center-wide meeting held on September 13 on the Georgia Tech campus. “It was nice to meet all the other researchers and have the chance to give informal presentations of our projects, and to really get an idea of what the center is doing, up close,” Ferrari said.
While the meeting at Tech provided a way for SCMB members to meet and work in person—and a number of junior researchers bonded on Tech’s leadership challenge course while on campus—they’ve been gathering on a regular basis virtually since the center was launched last year. Since this is a center comprised of institutions from across the Southeast, they meet monthly; Georgia Tech personnel gather in one room, and everyone else joins via video conference.
“It was fantastic to have everybody in one space, to hear directly from the junior researchers about the progress of each seed project,” said Annalise Paaby, an SCMB team lead and assistant professor of Biological Sciences at Tech, and a researcher in the Petit Institute. Each project is a collaboration between a faculty member and a trainee from the math side, and a faculty member and trainee from the bio side. “The seed projects have been cooking for a while now, and the trainee pairs gave short, pecha kucha style research reports—so we had a lot of fun with questions and discussion.”
For Kelimar Diaz, SCMB and its interdisciplinary opportunities represents the new leading edge of bioresearch, and will help provide a roadmap for her own future.
“I have not decided what kind of career path to take after I finish my Ph.D., but I believe that the way things are structured in SCMB, I will end up with a repertoire of skills that will allow me to pursue the career of my choosing,” she says. “I am contributing to driving biology and math forward. The Center and all of its members are advancing our knowledge of the living world quantitatively, while providing insight to biological applications and expanding math.”
Meet the first class of SCMB junior researchers who will be advancing that knowledge:
Hector Baños earned his bachelor degree in applied mathematics at Universidad Autónoma de Querétaro in Mexico, then earned a master’s degree in mathematics and statistics at then his Ph.D. in mathematics the University of Alaska (Fairbanks). Now a postdoctoral researcher in the lab of Christine Heitsch, mathematics professor at Georgia Tech and director of the SCMB (and also a Petit Institute researcher), he’s working on an SCMB seed project called “RNA structural ensembles in evolution,” a collaboration between Heitsch and Annalise Paaby, assistant professor in the School of Biological Sciences at Tech. As he and his fellow researchers work to uncover the processes behind evolution in the species and molecular levels, he’ll work on models for secondary structure inference.
Keisha Cook earned a bachelor’s degree in mathematics at the University of Alabama, where she stayed on to earn both a master’s and Ph.D. in applied mathematics. Now a postdoctoral researcher in the lab of Scott McKinley at Tulane University, she’s working on a SCMB seed project entitled “Stochastic modeling in cellular internalization and transport,” a collaboration between McKinley and the lab of Christine Payne at Duke University. “My ultimate research goal is to become well versed in many applications of mathematics and cell biology, in order to teach mathematics students how to speak the language of a scientist,” said Keisha, who will analyzing particle tracking data (collected in the Payne Lab) using probabilistic and statistical methods to provide greater insight into the functions of intracellular particle motion.
Daniel Cruz, who earned both his bachelor’s degree (mathematics with a minor in computer science) and Ph.D. (mathematics) at the University of South Florida, is now a postdoctoral researcher at Georgia Tech, though his primary advisor is Elena Dimitrova, currently at California Polytechnic State University but until recently at Clemson University. His SCMB seed project is a collaboration between Dimitrova and Petit Institute researcher Melissa Kemp, associate professor of biomedical engineering at Georgia Tech, and it’s entitled “Modeling emergent patterning within pluripotent colonies through Boolean canalizing functions.” He’s primarily interested in using discrete models to understand how self-assembly and self-organization arises from molecular and/or cellular interactions. “I’m a math postdoc studying how boolean networks and other discrete models can improve our understanding of pattern and structure formation resulting from the differentiation of pluripotent colonies,” he said.
Kelimar Diaz earned her bachelor degree in physics at the University of Puerto Rico (Rio Piedras campus). Now, as a Ph.D. student based in the lab of Dan Goldman, professor in the School of Physics at Georgia Tech, she’s working on an SCMB seed project called “Optimization of limbless locomotion via algebraic kinematics,” a collaboration between Goldman and Greg Blekherman at Georgia Tech. She plans to satisfy her interest in biomechanics an locomotion by exploring undulatory locomotion across length scales to understand control principles.
Margherita Maria Ferrari, a postdoctoral researcher, earned an undergraduate degree and a master’s degree in mathematics at Università degli Studi di Modena e Reggio Emilia in Italy, and her Ph.D. in mathematical models and methods in engineering at Politecnico di Milano. Based in the lab of Nataša Jonoska at the University of South Florida, her SCMB seed project, “Discrete and topological models for DNA-RNA interactions,” is a collaboration between that group and the lab of Petit Institute researcher biologyFrancesca Storici, an associate professor of biology at Georgia Tech. My goal is to develop and apply mathematical tools to advance our understanding of biological and chemical processes,” she said. “My role is modeling RNA structure formation and R-loop structures, which we feel will help us in describing the process of DNA double-strand break repair.”
Gemechis Degaga, who earned his Ph.D. in theoretical chemistry at Michigan Technological University, is currently based at Oak Ridge National Laboratory in the lab of Julie Mitchell, director of the Biosciences Division. His SCMB seed project, entitled “Identifying disorder-to-order transitions in post-translationally modified proteins,” is a collaboration between Mitchell and the lab of Matt Torres, associate professor in the School of Biological Sciences at Georgia Tech (and a Petit Institute researcher). “My main research interest involves the use of machine learning models to understand protein folding,” he said, describing his role in the project as building “generative adversarial artificial neural networks to learn, predict, and generate new protein sequences which form beta-hairpin secondary structure.”
Youngkyu Jeon, who earned a bachelor of science in life sciences at Korea University, is a Ph.D. student currently based in the lab of Francesca Storici, associate professor in the School of Biological Sciences at Georgia Tech. He contributes to the seed project on DNA-RNA interactions with Storici, Jonoska and Ferrari. The goal is to understand the topology of RNA-mediated DNA modification and/or repair, which Youngkyu is studying through experiments based on mathematical modeling.
Wei Li, a postdoctoral researcher in the lab of Matt Torres at Georgia Tech, earned her Ph.D. from Wake Forest University. She’s contributing to the SCMB seed project on protein disorder-to-order transitions with Torres, Mitchell and Degaga. Wei’s role is to test candidate proteins using experimental spectroscopic methods, testing for impacts on biological function.
Bo Lin, who earned a Ph.D. in mathematics at the University of California-Berkeley, is now a postdoctoral researcher in the lab of Greg Blekherman, associate professor of mathematics at Georgia Tech, where he’s working on the SCMB seed project on limbless locomotion with Blekherman, Goldman and Diaz. Basically, Lin is using his expertise in math to analyze data generated from biological experiments.
Eunbi Park, who earned her undergraduate degree in agricultural science from Kyungpook National University in Korea, is now Park a Ph.D. student in Bioinformatics at Georgia Tech in the lab of associate professor of Biomedical Engineering, contributing to the seed project on modeling emergent patterning within pluripotent colonies with Kemp, Dimitrova, and Cruz. Park collects fluorescent microscopy images of live, dividing stem cells, generating time-lapse movies that capture the behavioral dynamics of the cells. With the input of Cruz and Dimitrova, she is using agent-based models to define that behavior mathematically.
Nathan Rayens earned two bachelor degrees at Miami University: one in mechanical engineering and manufacturing engineering, and another in music. Now a Ph.D. student in mechanical engineering and materials science, he’s based in the lab of Christine Payne at Duke University. Now he is working with Payne, McKinley and Cook on the seed project modeling cellular internalization and transport. Rayens said, “this is the first time I’ve been involved in biological research, so my current goal is to learn as much as I can. I’m currently working on analyzing cell samples incubated with and without TiO2 to evaluate lysosome trajectories and see the effect of nanoparticles on cell transport.”
Ashleigh Thomas, who earned an undergraduate degree in electrical engineering and math at the University of Pennsylvania, got her master’s and Ph.D. in mathematics at Duke University. Now based in the lab of Peter Bubenik at the University of Florida, she’s working on an SCMB seed project entitled, “Topological data analysis to understand genetic control of morphological phenotype,” a collaboration between Bubenik and Hang Lu, professor in the School of Chemical and Biomolecular Engineering at Georgia Tech.
Ling Wang, who earned both her bachelor and master’s degrees in biological science at Georgia State University, is a Ph.D. researcher in the lab of Annalise Paaby, assistant professor in the School of Biological Sciences at Georgia Tech. Her work is in collaboration with Paaby, Heitsch, and Baños on the RNA folding seed project. Wang’s ultimate research interest is in combining computational and biological approach to study how RNA folding structure matters in biological evolution and she’s currently working with Paaby, “to design experiments to test if RNA’s secondary structure will have an impact on early-stop codon readthrough, and ultimately determine its impacts on biological functions.”
Keren Zhang earned his undergraduate degree in chemical engineering at the University of California-Berkeley. Now he’s a Ph.D. student in the lab of Hang Lu at Georgia Tech, where he’s working with Lu, Bubenik and Thomas on the seed project studying morphological phenotype with topological analysis. Zhang’s goal is to establish pipeline methods to quantify the developmental plasticity in the C. elegans connectome.
]]>The grant, valued at $1.88 million over five years, will support Lachance’s research strategy, which includes the analysis of ancient and modern genomes, mathematical modeling, and the development of new bioinformatics tools.
Lachance, whose research bridges the gap between evolutionary genetics and genetic epidemiology, is motivated by several questions: How have hereditary disease risks evolved in the recent past? What sorts of genetic architectures are more likely to result in health inequities? How can genomic medicine be extended to people with different ancestries?
“We’ve taken an evolutionary perspective toward genetic medicine and global health,” says Lachance, assistant professor in the School of Biological Sciences, whose research is directly related to the NIH’s All of Us initiative.
The R35 MIRA program was designed to increase the stability of funding for NIGMS-supported investigators like Lachance, improving their ability to take on ambitious projects and take more creative approaches to biomedical problems.
“This grant, I think, demonstrates great confidence in our approach to the research,” Lachance said. “It enables us to devote more our time and energy on doing the actual science and developing the next generation of researchers.”
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The protected Pacific reefs were populated by diverse corals and shimmered with colorful fish, said researchers who snorkeled off of Fiji to collect samples for the study. Oceanic ecologists from the Georgia Institute of Technology compared coral potions from these reefs, where fishing was prohibited, with those from heavily fished reefs, where seaweed inundated corals because few fish were left to eat it.
The medicated solutions, or potions, may contain a multitude of chemicals, and the researchers did not analyze their makeup. This is a possible next step, but here the researchers simply wanted to establish if the potions offered any real defense against pathogens and how warming and overfishing might weaken it.
“I thought I probably wouldn’t see antibiotic effects from these washes. I was surprised to see such strong effects, and I was surprised to see that reef protections made a difference,” said the study’s first author, Deanna Beatty.
“There is a lot of argument now about whether local management can help in the face of global stresses – whether what a Fijian village does matters when people in London and Los Angeles burn fossil fuels to drive to work,” said Mark Hay, the study’s principal investigator, Regents Professor and Harry and Linda Teasley Chair in Georgia Tech’s School of Biological Sciences.
“Our work indicates that local management provides a degree of insurance against global stresses, but there are likely higher temperatures that render the insurance ineffective.”
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The researchers collected three coral species along with seawater surrounding each species at protected reefs and at overfished reefs. In their Georgia Tech lab, they tested their solutions against the pathogen Vibrio coralliilyticus at 24 degrees Celsius (75.2 Fahrenheit), an everyday Fijian water temperature, and at 28 degrees (82.4 F), common during ocean heating events.
“We chose Vibrio because it commonly infects corals, and it’s associated with coral bleaching in these warming events. It’s related to other bleaching pathogens and could serve as a model for them as well,” Hay said.
“We chose 24 C and 28 C because they’re representative of the variations you see on Fijian reefs these days. Those are temperatures where the bacteria are more benign or more virulent,” Beatty said.
The data showed that warming disadvantaged all potions against Vibrio and conservation aided a potion from a key coral species. The team, which included coauthor Kim Ritchie from the University of South Carolina Beaufort, published its study in the journal Science Advances on Oct. 2. The research was funded by the National Institutes of Health’s Fogarty International Center, the National Science Foundation, and the Simons Foundation.
The unprotected reefs’ shabby appearance portended their effects on the one potion associated with a key coral species.
“When you swim out of the no-fishing area and into the overfished area, you hit a hedge of seaweed. You have about 4 to 16% corals and 50 to 90% seaweed there. On the protected reef, you have less than 3% seaweed and about 60% corals,” Hay said.
Hay has researched marine ecology for over four decades and has seen this before, when coral reefs died off closer to home.
“Thirty years ago, when Caribbean reefs were vanishing, I saw overfishing as a big deal there, when seaweed took over,” he said, adding that global warming has become an overriding factor. “In the Pacific, many reefs that were not overfished have been wiped out in warming events. It just got too hot for too long.”
The potions are products of the corals and associated microbes, which comprise a biological team called a holobiont.
To arrive at potions focused on chemical effects, the researchers agitated the coral holobionts and ocean water then freeze-dried and irradiated the resulting liquid to destroy remnants of life that could have augmented chemical action. Some viruses may have withstood sterilization, but it would have weakened any effect they may have had, if there were any.
Then the researchers tested the potions on Vibrio.
“All of the solutions’ defenses were compromised to varying extents at elevated temperatures where we see corals getting sick in the ocean,” Hay said.
But reef protection benefited the potion taken from the species Acropora millepora.
“The beneficial effect in the solution tested in the lab was better when Acropora came from protected areas, and this difference became more pronounced at 28 degrees Celsius,” said Beatty, who finished her Ph.D. with Hay and is now a postdoctoral researcher at the University of California, Davis.
Of the three species with potions that were tested, Acropora millepora may be a special one.
It is part of a genus – larger taxonomic category – containing about 150 of the roughly 600 species in Pacific reefs, and Acropora are core builders of reef structures. They grow higher as sea level rises, helping maintain healthy positions for whole reefs.
“Acropora are big and branching and make lots of crevices where fish live. The evolution of lots of reef fish parallels the evolution of Acropora in particular,” Hay said.
If fish can hang on, they may buy Acropora more time, and coral reefs perhaps, too.
Also READ: When Coral Species Vanish, Their Absence Can Imperil Surviving Corals
These researchers coauthored the study: Deanna Beatty, Jinu Valayil, Cody Clements, and Frank Stewart of Georgia Tech. The research was funded by the National Institutes of Health (grant 2 U19 TW007401-10), the National Science Foundation (grant OCE 717 0929119), the Simons Foundation (grant 346253), and the Teasley Endowment. Any findings, conclusions, or recommendations are those of the authors and not necessarily of the sponsors. DOI: https://doi.org/10.1126/sciadv.aay1048
Writer & Media Representative: Ben Brumfield (404-272-2780), email: ben.brumfield@comm.gatech.edu
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Those Americans usually have family roots near the traditional homes of the respective tribes found in their genes, according to research led by the Georgia Institute of Technology. But where the descendants are today differs between these groups.
“People of Western European heritage have Native gene sequences from tribes that were located near where they now live,” said Andrew Conley, who led the study and is a research scientist in Georgia Tech’s School of Biological Sciences. “For African descendants, Native American ancestry looks like it came from regional groups of Native Americans in the southeastern United States.”
Many Americans descending from enslaved Africans later left the South in the Great Northward Migration, took those Native American sequences with them, and apparently no longer significantly reproduced with indigenous populations.
Americans with European heritage going back to Spain, mostly people who immigrated to the U.S. from Mexico, carry sequences from Native American ancestors who were traditionally located in what is Mexico today. This group also carries the most Native American genetic sequences by far, roughly 40% of their total genome, according to the study.
The researchers came to their conclusions by tracking haplotypes, patterns of genetic variants that are passed on by one parent, and that are typical for certain regions and peoples. They published their results in the journal PLoS Genetics on September 23, 2019.
“Haplotype combinations are very different between European, African and Native American ancestries and specific to locations,” Conley said.
The data was extracted from a much larger study, The Health and Retirement Study, sponsored by the National Institute on Aging (NIA) and conducted by the University of Michigan. That study also followed health and finance over time but included genomes and geography. Neither the NIA nor Michigan was part of the Georgia Tech study.
Americans of early African heritage have about 1.0% and of Western European heritage about 0.1% Native American haplotypes, though the difference in those numbers can be deceiving. The native ancestry probably lies a similar number of generations back for both groups.
“With African Americans, it correlates to about eight to nine generations back and probably ends there,” Conley said. “With Western European ancestors, we think about eight to 10 generations ago, and the contact with Native Americans could have also been more continuous.”
Further immigration from Europe likely dropped the percentage of Native American ancestry for the overall sample of Americans with Western European heritage.
“Particularly in the Mid-Atlantic and the Northeast there is almost no Native American ancestry among European descendants,” Conley said. “When you go out West, that’s where you have the most Native American ancestry in European populations.”
There was also an outlier group with European heritage from Spain.
“In parts of the Southwest, there are people of Spanish descent with also distinctive Native American ancestry. These groups call themselves Hispanos or Nuevomexicanos,” Conley said. “Their native American ancestry does not come from present-day Mexico. There were Spanish settlers in the region 400 years ago, and they could be the European ancestors of the Nuevomexicanos.”
The following coauthors from Georgia Tech collaborated on the study: King Jordan and Lavanya Rishishwar. Any findings, conclusions, or recommendations are those of the study’s authors.
Writer & Media Representative: Ben Brumfield (404-660-1408), email: ben.brumfield@comm.gatech.edu
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Over the five years of the award, Joshua Weitz of the School of Biological Sciences at Georgia Tech and Laurent Debarbieux of the Institut Pasteur, in Paris, will jointly lead teams in the U.S. and France to research interactions between bacteriophage and the host’s immune response in treating acute respiratory infections caused by multi-drug-resistant bacteria.
The spread of antibiotic-resistant pathogens represents a significant public health challenge. In response, scientists and clinicians are exploring alternative ways to cure bacterial infections that cannot be treated with antibiotics. One approach is to use bacteriophage, which exclusively infect and eliminate bacteria. In a 2017 study published in Cell Host and Microbe, the teams of Weitz and Debarbieux showed that a synergy between an infected animal’s immune system and phage is essential to curing an infection.
Advancing the fundamental understanding of phage therapy will help advance its robust and reliable use in the clinic. The five-year NIH grant (1R01AI46592-01; Synergistic Control of Acute Respiratory Pathogens by Bacteriophage and the Innate Immune Response) will enable the U.S. and French teams to examine the dynamics of the synergy between phage and the immune response in treating acute respiratory infections.
“This project represents an important opportunity to integrate mathematical modeling into the foundations of phage therapy research,” Weitz says. “We look forward to extending our ongoing collaboration with the experimental phage therapy team led by Laurent Debarbieux to iteratively refine a mechanistic understanding of how phage therapy works in vivo and to develop candidate approaches to deploy phage therapy in translational settings.”
To achieve their goals, the principal investigators will combine mathematical modeling (at Georgia Tech) and animal experiments (at the Institut Pasteur). Building on their 2017 findings, the team will examine the interactions between therapeutic phage; neutrophils, which are the cells of the immune system involved in the synergy; and multi-drug-resistant Pseudomonas aeruginosa in an acute respiratory pneumonia mouse model system. The project will focus on understanding and optimizing synergistic interactions between phage and neutrophils in eliminating bacteria, even when the animal host’s immune response is impaired.
Overall, this project aims to provide a framework for advancing principles of phage ecology and innate immunology in the rational design of phage therapy for therapeutic use.
]]>According to the study, ovarian cancer has a distinct metabolite signature, a unique combination of presence and abundance of small molecules that can be used to detect the disease at an early stage. So far the signature has been validated only in mice that manifest human ovarian cancer very closely. "With that information," Fernandez says, "we can now look at human samples and see if similar pathways and metabolites are altered by ovarian cancer."
Ovarian cancer is the most lethal of gynecological diseases; it is the seventh most commonly diagnosed cancer among women worldwide. Most ovarian cancers are diagnosed in the late stages, for which the five-year survival rate is only 29%.
The most common and deadliest type of ovarian cancer is high-grade serious carcinoma, accounting for up to 80% of deaths. Most cases are diagnosed at an advanced stage, when survival rates are low.
The Fernandez Lab has shown the ability to detect HGSC in mice with 95% accuracy. "We view this as the first step in looking for similar patterns in humans and pursuing a blood test that can detect this deadly disease," he says.
]]>In the laboratory, under conditions mimicking those on pre-life Earth, a small selection of amino acids linked up spontaneously into neat segments in a way that surprised researchers at the Georgia Institute of Technology. They had given these amino acids found in proteins today some stiff competition by adding amino acids not found in proteins, thinking these non-protein, or non-biological, amino acids would probably not allow predominantly biological segments to come together.
The non-biological amino acids had the potential to chemically react equally well or better than the biological ones and frequently become part of the tiny chains, perhaps serving as an in-between step in the greater evolution toward proteins. The experiment dashed those expectations -- but to the researchers’ delight. The reactions resulted mostly in strings that were closer to today’s actual proteins and less in chains that included non-biological amino acids.
“The non-biological amino acids were being excluded to some extent,” said Nick Hud, one of the study’s principal investigators, a Regents Professor in Georgia Tech’s School of Chemistry and Biochemistry and associate director of the Petit Institute for Bioengineering and Bioscience at Georgia Tech.
In particular, the researchers had thought the non-biological amino acids would outcompete the biological amino acid lysine, but it was not the case. They also thought lysine would often not fit neatly into the chains the way it does in proteins. The reaction surprised them again.
“Lysine went into the chains predominantly in the way that it is connected in proteins today,” said Hud, who is also director of the National Science Foundation/NASA Center for Chemical Evolution (CCE), which is headquartered at Georgia Tech and explores chemistry that may have paved the way to first life.
The research team, which included collaborators from The Scripps Research Institute, published their results in the journal Proceedings of the National Academy of Sciences on July 29, 2019. The research was funded by the NSF and NASA.
The study’s experiment points to chemical evolution having prefabricated some amino acid chains useful in living systems before life had evolved a way to make proteins. The preference for the incorporation of the biological amino acids over non-biological counterparts also adds to possible explanations for why life selected for just 20 amino acids when 500 occurred naturally on the Hadean Earth.
“Our idea is that life started with the many building blocks that were there and selected a subset of them, but we don’t know how much was selected on the basis of pure chemistry or how much biological processes did the selecting. Looking at this study, it appears today’s biology may reflect these early prebiotic chemical reactions more than we had thought,” said Loren Williams, another principal investigator in the study and a professor in Georgia Tech’s School of Chemistry and Biochemistry as well as a Petit Institute researcher.
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To help understand the study’s significance, let’s look at how proteins form, then at the study’s core experiment, which revealed an unexpectedly high preference for bonds between sites called alpha-amines (α-amines) on the biological amino acids. Those bonds gave resulting molecular segments a protein-like shape in the lab.
In a protein, one amino acid is a single chemical unit, or monomer. A few of them linked together is called an oligomer, and really long chains are polymers. In proteins, the polymer is called a polypeptide -- named after the peptide bonds that link its monomers together.
Polypeptides are long chains that often form helices, like old phone cords, or flat sheets. They kink and fold up into specific, mostly functional wads, sheets, and other shapes, which are called proteins. The study looked at how amino acid monomers linked up to make interesting oligomers that look like small pieces of proteins.
Late in the Hadean Eon, Earth’s earliest phase, when prebiotic chemistry was taking shape, the planet’s surface was awash in vulcanism and rain, and large meteors pummeled it with new chemicals. The researchers’ experimental lab setup reflected relatively mild conditions for those times and feasibly present ingredients.
First author Moran Frenkel-Pinter placed the biological amino acids lysine, arginine, and histidine together with three non-biological competitors in water containing hydroxy acids. Hydroxy acids are known to facilitate amino acid reactions and would have been common on prebiotic Earth.
The mixture was heated to 85 degrees Celsius, pushing the reaction and evaporating the water, and the researchers analyzed the products formed.
“We found this high preference for the inclusion of these biological amino acids and the linkage via the α-amine,” said Frenkel-Pinter, a NASA postdoctoral researcher in the CCE.
Amine groups are made of nitrogen and hydrogen and are quite reactive, but the α-amine is part of the core of an amino acid, and other amines in this experiment were at the end of a sidechain extending off the core. The latter is often more reactive.
“It surprised us that this chemistry favored the α-amine connection found in proteins, even though chemical principles might have led us to believe that the non-protein connection would be favored,” Frenkel-Pinter said. “The preference for the protein-like linkage over non-protein was about seven to one.”
Most resulting oligomers had evenly placed links in the chain, which are used in life, as opposed to non-α-amine bonded oligomers, which built more irregular chains.
The finished products were mostly depsipeptides, which the CCE previously established as stepping stone products in an easy, reliable pathway to peptides.
In another reflection of life chemistry, the abiotic depsipeptide transition to peptides is the same basic reaction (ester-amide) carried out by ribosomes, the cellular machines that make proteins today.
Surprise reactions, in which potential pre-life chemistry casually falls into place, have happened often in the CCE’s research. They have shored up the center’s core hypothesis that most biological polymers formed in wet and dry cycles, perhaps on rain-swept dirt flats or lakeshore rocks regularly baked by the sun’s heat.
Despite its grounded simplicity, the premise of everyday wet-dry cycles being key to the origin of life is unconventional, challenging a more established narrative that improbable concurrences of cataclysms and multiple ingredients were necessary to produce life’s early materials in rare and volatile events.
These researchers coauthored the study: Jay Haynes, Martin C, Anton Petrov, and Bradley Burcar of Georgia Tech; and Ramanarayanan Krishnamurthy and Luke Leman of Scripps. All researchers are members of the NSF/NASA Center for Chemical Evolution. The research was funded by the National Science Foundation and NASA under the center’s grant (CHE-1504217). Any findings, conclusions, and recommendations are those of the authors and not necessarily of the funding agencies.
Writer & Media Representative: Ben Brumfield (404-660-1408), email: ben.brumfield@comm.gatech.edu
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"Multinuclear silver clusters encapsulated by DNA are known to fluoresce and otherwise harbor interesting photophysical properties, but their atomic organization has been poorly understood," Lieberman says.
The paper presents the first crystal structure of a fluorescent silver-DNA adduct, with eight silver atoms encased between two strands of DNA. The work shows a fully reciprocal relationship between the encapsulating, flexible DNA host and the silver cluster, with the eight atoms arrayed like the Big Dipper.
"These findings provide a guide for future studies to correlate DNA sequence, metal organization, and photophysical properties of these of these light-emitting, emissive biomolecule–metallocluster hybrids," Lieberman says.
]]>About half of the world’s total underground carbon is stored in the soils of these frigid, northern latitudes. That is more than twice the amount of carbon currently found in the atmosphere as carbon dioxide, but until now most of it has been locked up in the very cold soil. The new study, which relied on metagenomics to analyze changes in the microbial communities being experimentally warmed, could heighten concerns about how the release of this carbon may exacerbate climate change.
“We saw that microbial communities respond quite rapidly – within four or five years – to even modest levels of warming,” said Kostas T. Konstantinidis, the paper’s corresponding author and a professor in the School of Civil and Environmental Engineering and the School of Biological Sciences at the Georgia Institute of Technology, where he also is a researcher in the Petit Institute for Bioengineering and Bioscience. “Microbial species and their genes involved in carbon dioxide and methane release increased their abundance in response to the warming treatment. We were surprised to see such a response to even mild warming.”
The new study was supported by the U.S. Department of Energy and the National Science Foundation, and reported July 8 in the early edition of the journal Proceedings of the National Academy of Sciences. Researchers from the University of Oklahoma, Michigan State University and Northern Arizona University collaborated with Georgia Tech on the study.
The study provides quantitative information about how rapidly microbial communities responded to the warming at critical depths, and highlights the dominant microbial metabolisms and groups of organisms that are responding to warming in the tundra. The work underscores the importance of accurately representing the role of soil microbes in climate models.
The research began in September 2008 at a moist, acidic tundra area in the interior of Alaska near Denali National Park. Six experimental blocks were created, and in each block, two snow fences were constructed about five meters apart in the winter to control snow cover. Thicker snow cover in the winter served as an insulator, creating slightly elevated temperatures – about 1.1 degrees Celsius (2 degrees Fahrenheit) in the experimental plots.
Other than the temperature difference, the soil conditions were similar in the experimental and control plots. Soil cores were taken from the experimental and control plots at two different depths at two different times: 1.5 years after the experiment began, and 4.5 years after the start. Microbial DNA was extracted from the cores and sequenced using the Genomics Core at Georgia Tech.
“Our analysis of the resulting data showed which species were there, in what abundances, which species responded to warming and by how much – and what functions they possessed related to carbon use and release,” said Eric R. Johnston, now a postdoctoral researcher at Oak Ridge National Laboratory, who conducted the study’s analysis as a Georgia Tech Ph.D. student.
Cores from the experimental and control plots were compared to assess the effects of the warming. Cumulative ecosystem respiration was also sampled during the month following removal of the cores.
“The response we observed differed markedly between the two soil depths (15 to 25 centimeters and 45 to 55 centimeters) that were sampled for this study,” said Johnston. “Specifically, at the upper boundary of the initial permafrost boundary layer – 45 to 55 centimeters below the surface – the relative abundance of genes involved in methane production (methanogenesis) increased with warming, while genes involved in organic carbon respiration — the release of carbon dioxide — became more abundant at shallower depths.”
Measurement of the community respiration showed increases in the rate of carbon dioxide and methane release in the plots that were warmed. “Similar measurements have also shown that these gases are being released at a greater rate throughout the entire region in recent years as a result of climate warming,” Johnston added.
The two soil depths correspond to an active layer near the surface that freezes during the winter but thaws during warmer months, exposing the carbon. The deeper measurements examined soil just above the permafrost that thaws for only a brief time each year. These variations create fundamental differences in the biology and chemistry at the two depths.
“We expected to observe warming responses that differed between the two sampling depths,” Johnston said. “Ongoing thaw of permafrost soil is being observed on the global scale, so we were particularly interested in evaluating microbiological responses to thawing permafrost.”
The research highlights the importance of microbial communities in contributing atmospheric methane and carbon dioxide to climate change, Konstantinidis said.
“Because of the very large amount of carbon in these systems, as well as the rapid and clear response to warming found in this experiment and other studies, it is becoming increasingly clear that soil microbes – particularly those in the northern latitudes – and their activities need to be represented in climate models,” he said. “Our work provides markers – species and genes – that can be used in this direction.”
In addition to those already mentioned, the paper’s authors included Janet K. Hatt from Georgia Tech, Zhili He and Liyou Wu from the University of Oklahoma, Xue Guo from Tsinghua University, Yiqi Luo and Edward A. G. Schuur from Northern Arizona University, James M. Tiedje from Michigan State University, and Jizhong Zhou from Lawrence Berkeley National Laboratory.
This research was supported by U.S. Department of Energy award DE-SC0004601 and by the National Science Foundation awards 1356288 and 1759831. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the sponsoring organizations.
CITATION: Eric R. Johnston, et al., “Responses of tundra soil microbial communities to half a decade of experimental warming at two critical depths" (Proceedings of the National Academy of Sciences, 2019)
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]]>These are just some of the exciting advances likely to emerge from the 20-year-old field of engineering biology, or synthetic biology. Engineering biology/synthetic biology involves taking what we know about the genetics of plants and animals and then tweaking specific genes to make these organisms do new things.
The field is now mature enough to provide solutions to many societal problems, according to a roadmap released on June 19 by the Engineering Biology Research Consortium. This public-private partnership is partially funded by the National Science Foundation and centered at the University of California, Berkeley (UCB).
The roadmap is the consensus of more than 80 scientists and engineers from various disciplines, from more than 30 universities and a dozen companies. Among them is Pamela Peralta-Yahya, recently promoted to associate professor in the School of Chemistry and Biochemistry. She was the technical theme lead for host and consortia engineering.
"The Engineering Biology Research Roadmap identifies the technological challenges to be addressed over the next 20 years to solve global societal challenges in various areas, from industrial and environmental biotechnology, to health and medicine, to food and agriculture, to energy, and beyond,” Peralta-Yahya says. “Addressing the technological challenges in gene, biomolecules, host and consortia engineering, and developing the necessary data analytics and modeling tools will allow us to realize the promise of a next-generation bioeconomy."
The report urges the federal government to invest in this area, not only to improve public health, food crops, and the environment, but also to fuel the economy and maintain the country’s leadership in synthetic biology.
“This field has the ability to be truly impactful for society, and we need to identify engineering biology as a national priority, organize around that national priority and take action based on it,” said Douglas Friedman in a UCB press release. He is one of the leaders of the roadmap project and executive director of the Engineering Biology Research Consortium.
Engineering biology research at Georgia Tech cuts across colleges, according to Peralta-Yahya. In the College of Sciences, Peralta-Yahya specializes in engineering biological systems for the production of chemicals and fuels. M.G. Finn, professor and chair in the School of Chemistry and Biochemistry, engineers virus-like particles for healthcare applications.
In the College of Engineering, Mark Styczynski, an associate professor in the School of Chemical and Biomolecular Engineering, engineers point-of-care diagnostic tools for the developing world. His colleague Associate Professor Corey Wilson engineers gene regulatory elements for biotechnology applications.
“If you look back in history, scientists and engineers have learned how to routinely modify the physical world though physics and mechanical engineering, learned how to routinely modify the chemical world through chemistry and chemical engineering,” Friedman said. “The next thing to do is figure out how to utilize the biological world through modifications that can help people in a way that would otherwise not be possible. We are at the precipice of being able to do that with biology.”
The current broad application of antibiotics helps resistant bacterial strains evolve forward. But using data about bacteria’s specific resistances when prescribing those same drugs more precisely can help put the evolution of resistant strains in reverse, according to researchers from the Georgia Institute of Technology, Duke University, and Harvard University who conducted the study.
One researcher cautioned that time is pressing: New strategies against resistance that leverage antibiotics need to be in place before bacteria resistant to most every known antibiotic become too widespread. That would render antibiotics nearly useless, and it has been widely reported that this could happen by mid-century, making bacterial infections much more lethal.
“Once you get to that pan-resistant state, it’s over,” said Sam Brown, who co-led the study and is an associate professor in Georgia Tech’s School of Biological Sciences. “Timing is, unfortunately, an issue in tackling antibiotic resistance.”
The new study, which was co-led by game theorist David McAdams, a professor of business administration and economics at Duke University, delivers a mathematical model to help clinical and public health researchers devise new concrete prescription strategies and those supporting health strategies. The measures center on the analysis of bacterial strains to determine what drugs they are resistant to, and which not.
Some medical labs already scan human genomes for hereditary predispositions to certain medical conditions. Bacterial genomes are far simpler and much easier to analyze, and though the analytical technology is currently not standard equipment in doctors’ offices or medical labs they routinely work with, the researchers think this could change in a reasonable amount of time. This would enable the study’s approach.
The researchers published their study in the journal PLOS Biology on May 16, 2019. The work was funded by the Centers for Disease Control and Prevention, the National Institute of General Medical Sciences, the Simons Foundation, the Human Frontier Science Program, the Wenner-Gren Foundations, and the Royal Physiographic Society of Lund.
Here are some questions and answers on how the study’s counterintuitive approach could beat back antibiotic resistance:
The real problem is the broad application of antibiotics. They treat human infections and farm animals, and in the process are killing off a lot of non-resistant bacteria while bacteria resistant to those drugs survive. The resistant strains can then reproduce and with fewer competitors in their space, then they dominate bacterial communities in the host animals and people.
The resistant bacteria get passed to other hosts and become more prevalent in the world altogether. New prescription strategies would outsmart that evolutionary scenario by exposing through genomic (or other) analysis bacteria’s resistance but also their vulnerabilities.
“Right now, there are rapid tests for the pathogen. If you’ve got strep throat, the clinic swabs the bacteria and does a rapid assay that says yes, that’s streptococcus,” Brown said. “But it won’t tell you if it’s resistant to the drug usually prescribed against it. In the future, diagnostics at the point-of-care could find out what strain you’ve got and if it’s resistant.”
Then clinicians would choose the specific antibiotics that the bacteria are not resistant to, and kill the bacteria, thus also stopping them from spreading the genes behind their resistance to other antibiotics. So, identifying an infector’s resistance hits two birds with one stone.
“It’s great for fighting antibiotic resistance, but it’s also good for patients because we’ll always use the correct antibiotic,” Brown said.
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Plenty. Antibiotics still work as a rule.
In addition, searching out and destroying resistant bacteria could help refresh existing antibiotics’ effectiveness.
“The idea is prevalent that we will use antibiotics up, and then they’re gone,” Brown said. “It doesn’t have to be that way. This study introduces the concept that antibiotics could become a renewable resource if we act on time.”
Correct. Resistance evolution has some tricky complexities.
“A lot of bacteria with the potential to make us sick like E. coli spend most of their time just lurking peacefully in our bodies. These are bystander bacteria, and they are exposed to lots of antibiotics that we take for other things such as sore throats or ear aches,” Brown said. “This frequent exposure is probably the major driver of resistance evolution.”
The antibiotic prescription strategy needs those additional health care measures to win the fight, but those measures are pretty straightforward.
Diagnostics need to apply to bystander bacteria, too. E. coli in the intestine or, for example, Strep pneumoniae living peacefully in nostrils would be checked for resistance, say, during annual checkups.
“If the patient is carrying a resistant strain, you work to beat it back before it can break out,” Brown said. “There could be non-antibiotic treatments that do this like, perhaps, bacteria replacement.”
Bacteria replacement therapy would introduce new bacteria into the patient’s body to outcompete the undesirable antibiotic-resistant bacteria and displace it. Also, people would stay home from school and work for a few days so as not to spread the bad bacteria to other people while their immune systems and possibly alternative therapies, such as bacteriophages or non-antibiotic drugs battle the bad bacteria.
“The study’s mathematical models are broad simplifications of real life,” Brown said. “They don’t take into account that pathogens spend a lot of time in other antibiotic-exposed environments such as farms. Dealing with that is going to require some more research.”
The study also purposely leaves out "polymicrobial infections," which are infections by multiple kinds of bacteria at the same time. The researchers believe that the study’s models can still be relevant to them.
“We expect the logic of combating drug resistance to still hold in these more complex scenarios, but diagnostics and treatment rules will have to be honed for them specifically,” Brown said.
Also read: Want to beat antibiotic resistance? Rethink that strep throat prescription
These researchers coauthored the study: David McAdams from Duke University, Kristofer Wollein Waldetoft from Georgia Tech, and Christine Tedijanto and Marc Lipsitch from Harvard University. The research was funded by the Centers for Disease Control and Prevention (grant OADS BAA 2016-N-17812), the National Institute of General Medical Sciences at the National Institutes of Health (grant U54GM088558), the Simons Foundation (grant 396001), the Human Frontier Science Program (grant RGP0011/2014), the Wenner-Gren Foundations, and the Royal Physiographic Society of Lund.
Media contact/writer: Ben Brumfield
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As a teacher, Lachance believes his primary role is to help students learn. To accommodate students’ different learning styles, he integrates lectures with a various activities. These can be discussions of the literature or computer simulations of real data. Because empirical datasets can be messy and complex, Lachance says, students must apply critical thinking to get meaningful results, “as opposed to just applying techniques by rote”
Two examples demonstrate the innovative spirit Lachance has brought to the teaching of population genetics and other topics in biology.
For the course Mathematical Models in Biology (BIOL 2400), Lachance organized an iterated Hawk-Dove tournament. Each round involved pairs of students choosing to be aggressive (Hawk) or cooperative (Dove). As the tournament progressed, students adapted to the behaviors of their classmates. “Not only was it fun,” Lachance says, “but the evolving strategies that arose were evidence that every student had gained a deep understanding of game theory.”
"[I]t’s my role to do the best I can to facilitate student learning. Besides, what could be more fun than having a chance to share cutting-edge details about subjects you love?”
For the course Introduction to Evolutionary Biology (BIOL 3600), Lachance hosted an evolution-themed festival, modeled after the annual film festival held by the Society for the Study of Evolution. During the semester, students produced short videos to illustrate concepts of evolutionary biology. On the penultimate class of the semester, Lachance held a film festival featuring the student projects, complete with popcorn, ballots, and a trophy for the top video.
Lachance’s passion for teaching doesn’t go unnoticed. Students note his excitement, enthusiasm, and innovation in class. “His classes have given me and my peers unique opportunities to exercise our creativity with what we are learning,” one student says.
Lachance demonstrates his care for students above and beyond what students expect, this student adds. “He goes out of his way to express his vested interest in his students’ achievements and well-being in the classroom and beyond.”
“It is an honor to be one of this year’s recipients of the CTL/BP Teaching Award,” Lachance says. “As an instructor, it’s my role to do the best I can to facilitate student learning. Besides, what could be more fun than having a chance to share cutting-edge details about subjects you love?”
]]>Ratcliff was recently promoted to associate professor in the School of Biological Sciences and a member of the Center for Microbial Dynamics and Infection. Yunker is an assistant professor in the School of Physics. Both are members of the Parker H. Petit Institute of Bioengineering and Bioscience.
The award recognizes the authors of an outstanding paper. Ratcliff and Yunker are co-principal authors of the paper “Cellular packing, mechanical stress and the evolution of multicellularity,” published in Nature Physics in 2018.
“[The paper] exemplifies the power of interdisciplinary collaboration and best reflects Georgia Tech’s institutional culture of creative and rigorous exploration.”
The paper was the first to recognize the role of mechanics in the early evolution of multicellular organisms. Ratcliff and Yunker showed “how physical stress may have significantly advanced the evolutionary path from single-cell to multicellular organisms,” according to a 2017 story about this work. “In experiments with clusters of yeast cells called snowflake yeast, forces in the clusters’ physical structures pushed the snowflakes to evolve.
“Like the first ancestors of all multicellular organisms, in this study the snowflake yeast found itself in a conundrum: As it got bigger, physical stresses tore it into smaller pieces. So, how to sustain the growth needed to evolve into a complex multicellular organism?
“In the lab, those shear forces played right into evolution’s hands, laying down a track to direct yeast evolution toward bigger, tougher snowflakes.”
The partnership has profoundly shaped the two scientists’ research programs. “The paper reflects the deep collaboration between the Yunker and Ratcliff labs,” a colleague says. “It exemplifies the power of interdisciplinary collaboration and best reflects Georgia Tech’s institutional culture of creative and rigorous exploration.”
“There are few things better than doing exciting, creative science with good friends,” Ratcliff says.
“I’m delighted to share this recognition with such a great team,” Yunker says.
]]>The team is led by Georgia Tech’s J. Todd Streelman and MPIN’s Herwig Baier. Streelman is a professor in, and the chair of, the Georgia Tech School of Biological Sciences. Baier is the director of MPIN.
“It remains incredibly difficult to identify the cellular basis and the genetic variants underlying complex behavior,” Streelman says. “Understanding how behavior is encoded requires solving a dual problem involving neurodevelopment and circuit function.”
To find answers, Streelman and Baier will develop a model system to chart the complex path from genome to brain to behavior in cichlid fish from Lake Malawi.
Male cichlid fish build bowers to attract females for mating. The bowers are either pits, which are depressions in the sand, or castles, which look like volcanoes. Each type corresponds to a specific behavior encoded in a fish strain.
When the two strains mate, their male offspring display a remarkable behavior: First they construct a pit then a castle. This behavior indicates that a single brain containing two genomes can produce each behavior in succession.
Moreover, gene expression in the brain is biased toward the pit variant of the genome – or pit allele -- when the fish are digging pits and toward the castle allele when they are building castles. “This phenomenon offers the chance to identify both the genome regulatory logic and the neural circuitry underlying complex behavior in one sweep,” Baier says.
Streelman’s group will use single-cell RNA sequencing to pinpoint the cell populations that mediate context-dependent, allele-specific expression in male bower builders. Baier’s team will use genome editing and optogenetic tools to manipulate particular neurons in the brains of behaving bower builders.
“Our collaborative work will thus identify the neurons in which behavior-specific alleles are expressed and then, ideally, match those neurons to the corresponding behavioral output,” Baier says.
“Achieving our goals will demonstrate how the genome is activated in particular cell types to produce context-dependent natural social behaviors,” Streelman says.
The award is one of only 25 made from a total of 654 letters of intent HFSP received from around the world. HFSP provides funding for frontier research in the life sciences. The highly competitive program is implemented by the International Human Frontier Science Program Organization, based in Strasbourg, France.
]]>If validated, the general technique for the work could also have a variety of other applications. “In my dream world, a single blood test could be used to screen for multiple diseases,” said John McDonald, the leader of the research and a professor in the School of Biological Sciences at the Georgia Institute of Technology.
Ovarian cancer is especially dangerous because women often don’t show symptoms until the disease is in an advanced stage and difficult to treat. In contrast, when caught early “about 94 percent of patients live longer than five years after diagnosis,” according to the American Cancer Society.
The problem is that there is no good test for detecting the disease at an early stage.
About seven years ago McDonald and colleagues decided to see if they could change that by merging the disparate disciplines of biology, analytical chemistry and computer science. “Bringing the computer into it was novel at the time,” said McDonald, who is also director of Georgia Tech’s Integrated Cancer Research Center.
His Georgia Tech collaborators on the initial work were Professor Facundo Fernández, the Vasser Woolley Foundation Chair in Bioanalytical Chemistry, and Alex Gray, an assistant professor of computer science (Gray has since left Georgia Tech to become VP for Artificial Intelligence Science at IBM). They were joined by clinical consultant Dr. Benedict Benigno, a gynecological oncologist and CEO of the Ovarian Cancer Institute in Atlanta.
Promising Results
The researchers initially analyzed blood samples from 49 healthy women and 46 with early-stage ovarian cancer. They specifically focused on metabolites in those samples. Metabolites are molecules like fatty acids that our cells produce through enzymatic reactions.
In the molecular equivalent of finding needles in a haystack, they proceeded to analyze some 40,000 metabolites to see if there were any associated with the cancer patients that differed from those in samples from the healthy women. These could be biomarkers for the disease; molecules to screen for in an annual test.
Through a variety of techniques, the team first pared down the original thousands of metabolites to a collection of 255 candidate biomarkers. They then applied machine learning to that set, asking the computer to find any metabolites that were over- or under-expressed in the cancer samples.
“That’s what machine learning is all about,” McDonald said. “The computer is simply looking for correlations in very large data sets, then it comes back to you with what it has found.”
In 2015 the team reported in the journal Scientific Reports the discovery of 16 metabolites that could distinguish women with ovarian cancer from those without the disease with 100 percent accuracy. “Basically we modeled the face of cancer at the metabolic level,” McDonald said.
Moving Forward
With the new $100,000 grant, the researchers hope to validate their earlier work with samples from some 1,000 women, as compared to the roughly 100 they originally studied. The new study will also include samples from a much more diverse set of women (the original samples were from Caucasian women).
They also aim to expand the work to look for biomarkers associated with different types of ovarian cancer. “We want to be able to distinguish between a Type II cancer with high malignant potential – one that’s highly likely to spread outside the ovary – and a Type I with low malignant potential. A cancer with high malignant potential you’d want to treat right away, while a cancer with low malignant potential might not require immediate surgery,” McDonald said.
In conclusion, McDonald said, “it’s exciting because the initial results look like [our approach] might work.”
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]]>“Mutualisms are persistent and reciprocal exchange of benefit. A species proficient in obtaining certain benefits confers those on a reciprocating partner,” Loren Williams says. Williams is a professor in the School of Chemistry and Biochemistry at Georgia Tech. He will lead COOL. The NASA-funded interdisciplinary team based in Georgia Tech is one of several groups cooperating to identify planetary conditions that might give rise to life.
The COOL team itself is enabled by mutualistic scientific collaborations. Joining Williams as co-investigators are Georgia Tech’s Jennifer Glass and Anton Petrov, Kate Adamala and Aaron Engelhart of the University of Minnesota, George Fox from University of Houston, and Nita Sahai from University of Akron.
Glass is an assistant professor in the School of Earth and Atmospheric Sciences. Petrov is a research scientist in the Schools of Chemistry and Biochemistry and of Biological Sciences. Williams and Glass are members of the Parker H. Petit Institute for Bioengineering and Bioscience.
“We represent a rare symbiosis of biochemists and geochemists,” Glass says. “This gives us a unique vantage point from which to tackle this big question that no single discipline can solve alone.”
Williams and his team have discovered that inanimate species – such as molecules, metals, and minerals – engage in mutualism relationships. Those interactions can explain much about modern biology and the origin of life, Williams says. “Mutualisms are fundamental drivers in evolution, ecology, and economics. They sponsor coevolution, foster innovation, increase fitness, inspire robustness, and foster resilience.”
The COOL team aims to use mutualism phenomena to develop tools to study the origins and evolution of life on Earth. One area of study is the mutualism between metals and biomolecules under ancient-Earth conditions, such as between ferrous iron and proteins to form metalloproteins.
Another is the mutualism between minerals and biomolecules, such as between metal sulfide nanoclusters and RNA, peptides, and lipids to form functional biopolymers.
“Understanding how minerals interact with small organic molecules or biopolymers could help predict whether similar processes could occur on other worlds,” Sahai says.
The team will also study mutualisms in the most ancient universal life processes: translation and replication. “We are studying how nucleic acids and proteins joined forces as the biochemical foundation of life,” Petrov says.
The ribosome, the universal cellular machine where proteins are made, is a molecular relict where nucleic and acids and proteins work side by side to translate genotype to phenotype.
“The ribosome is a molecular fossil. It’s a window to the emergence of life,” Engelhart says.
“We are exploring alternative pathways for the evolution of the translation system,” Adamala says.
“A key to understanding the translation system is by integrating a vast array of information,” Fox says.
COOL is one of four Teams in NASA’s recently launched Prebiotic Chemistry and Early Earth Environments (PCE3) Consortium. One of PCE3’s goals is to guide future NASA missions to discover habitable worlds by understanding how conditions on Earth gave rise to life.
Williams is a member of the steering committee of PCE3. “I am particularly excited to frame the beginnings of life within the context of our planet’s early, dynamic habitability and to use those lessons to imagine how planets around distant stars similarly could have favored the origins and evolution of life,” Williams said about PCE3.
Figure Caption
COOL principal investigators are (clockwise from top left) Kate Adamala, Aaron Engelhart, George Fox, Loren Williams, Nita Sahai, Anton Petrov, and Jennifer Glass.
One of these, cerebral cavernous malformation (CCM), the abnormal development of blood vessels in the brain, has long captured the attention of Denis Tsygankov, assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and a researcher in the Petit Institute for Bioengineering and Bioscience at Tech.
“This actually started for me as a project when I was at the University of North Carolina and was approached with a challenge,” said Tsygankov, who worked in a computational lab of his principal investigator, Timothy Elston, in collaboration with the experimental lab of Gary Johnson, who studied molecular mechanisms of CCM pathogenesis. “There is no cure. Some people who have the disease may live their whole lives and not know it.”
The thing is, CCM can be a genetic hand-me down: Children stand a 50 percent of inheriting CCM from a parent with the condition. Typically, the disease lies quietly within a person’s brain or spinal cord until there are symptoms. These include seizures, headaches, paralysis, lost vision, cerebral hemorrhage. And sometimes, because of severe bleeding or pressure, CCMs can be deadly.
The few treatment options vary. Anti-epileptic drugs can control seizures, but surgery (with all the potential side effects of an invasive procedure) may be necessary to remove a CCM.
“People go under the knife again and again,” Tsygankov said. “It’s not a super common disease, but it is important to find a pharmacological alternative to its treatment.”
Toward that end, Tsygankov’s lab recently produced a research paper in iScience (an interdisciplinary open-access publication in the Cell press family of journals), entitled, “Biomechanics of Endothelial Tubule Formation Differentially Modulated by Cerebral Cavernous Malformation Proteins.” Their findings in the article are significant in developing a fuller understanding of CCM.
“We know about the mutations that cause it. On a molecular level we can do genetic studies, biochemical studies, and say, ‘here is the signaling network involved.’ But when you look at the disease you look at collective cell behavior,” Tsygankov said. “You see how the blood vessels form and then you see there is a huge gap between what you know on the molecular level and what you know on the tissue level. This is a challenging problem in general for any disease.”
He and his team took an integrative approach, using computer modeling and experiments in studying coordinated endothelial cell behavior at the earlier stages of vasculogenesis.
“Through iterative cycling of modeling and experiments, we investigated the biomechanics of multicellular patterning in the context of healthy and diseased cell populations,” said Tsygankov, whose team developed a comprehensive simulation model with a sufficient level of detail to account for single-cell dynamics – protrusive activity, cytoskeletal stiffness, shape change, and then used it to simulate thousands of interacting cells.
“This approach allowed us to relate molecular regulation of the cytoskeleton to the multicellular patterns that developed during endothelial tubule formation,” said Tsygankov. The team used a well-controlled disease model and endothelial cells with a knockdown of each of the three CCM proteins known to be responsible for similarly disruptive (but mechanistically different) effects on the formation of tubular structures.
“Specifically, our methodology allowed us to dissect causal effects of CCM-1, CCM-2, and CCM-3 knockdowns on the resulting multicellular structures and explain the incomplete rescue of the disease phenotypes by the inhibition of one of the key regulators of the cytoskeleton, Rho kinase, which become overactivated in CCM,” said Tsygankov, whose study also addressed a somewhat controversial observation – despite well-documented commonalities in the effects of the three proteins on the downstream signaling, CCM-3 cells have surprisingly low cytoskeletal stiffness as compared to CCM-1 and CCM-2.
“We’ve taken very, very nascent steps,” Tsygankov said. “But ultimately the goal is to learn enough about this system and how it works so that we can interfere and fix it.”
For Tsygankov, this project also served as a proof of the power of integrative systems biology, an important factor to a researcher who started his scientific journey as a theoretical physicist interested in complex dynamical systems and soon discovered that biological tissue is the ultimate complex dynamical system.
“Signaling and regulatory networks don’t just happen in a well-mixed soup or a vacuum,” he said. “They happen within the complex cytoskeletal organization of cells, and cells are active. They are moving and interacting. So, my ultimate goal is to bridge two fields – biomechanics and traditional molecular systems biology. And I’m very proud that we could merge our careful computational modeling with experimentation. That’s sort of our lab’s philosophy.”
***
In addition to Tsygankov, the iScience paper’s authors were Olga Chernaya (postdoctoral researcher in Tsygankov’s lab); Todd Sulchek (assistant professor in Woodruff School of Mechanical Engineering with appointment in Coulter Department, and a Petit Institute researcher); Anastasia Zhurikhina, Siarhei Hladyshau, and William Pilcher (graduate researchers in Tsygankov’s lab), Katherine M. Young, Jillian Ortner, and Vaishnavi Andra (BME undergraduate researchers).
The work was funded by the U.S. Army Research Office (ARO) grant W911NF-17-1-0395 and by funds from the Marcus Foundation, The Georgia Research Alliance, and the Georgia Tech Foundation through their support of the Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M) at Georgia Tech.
]]>In the lab, researchers at the Georgia Institute of Technology were surprised to see them do it under conditions thought to be common on Earth just before first life evolved: in plain water, with no catalysts, and at room temperature.
The neat spiraling also elegantly integrated another compound which today forms the backbone of RNA and DNA. The resulting structure had features that strongly resembled RNA.
The study has come a step closer to answering a chicken-egg question about the evolutionary path that led to RNA (from which DNA later evolved): Did the spiral come first, and did this structure influence which molecular components made it later into RNA because they fit well into the spiral?
“The spiraling could have had a reinforcing effect. It could have facilitated the molecules getting connected together that have the same chirality (curve) to connect into a common backbone that is compatible with the helical twist,” said the study’s principal investigator Nicholas Hud, a Regents Professor in Georgia Tech’s School of Chemistry and Biochemistry.
The researchers published the new study in the journal Angewandte Chemie in December 2018. The research was funded by the National Science Foundation and the NASA Astrobiology Program under the Center for Chemical Evolution. The center is headquartered at Georgia Tech, and Hud is its principal investigator.
The study’s resulting polymers were not RNA but could be have been an important intermediate step in the early evolution of RNA. For building blocks, the researchers used base molecules referred to as “proto-nucleobases,” highly suspected to be precursors of nucleobases, main components that transport genetic code in today’s RNA.
[Thinking about grad school? Here's how to apply to Georgia Tech.]
The study had to work around a paradox in chemical evolution:
Making RNA or DNA using their actual nucleobases in the lab without the aid of the enzymes of living cells that usually do this job is more than a herculean task. Thus, although RNA and DNA are ubiquitous on Earth now, their evolution on pre-life Earth would appear to have been an anomaly requiring erratic convergences of extreme conditions.
By contrast, the Georgia Tech researchers’ model of chemical evolution holds that precursor nucleobases self-assembled easily to into ancestral prototypes -- that were polymer-like and referred to as assemblies -- which later evolved into RNA.
“We would call these ‘proto-nucleobases’ or ‘ancestral nucleobases,’” Hud said. “For our overall model of chemical evolution, we’re saying that these proto-nucleobases, which self-assemble into these long strands, could have been part of a very early stage before modern nucleobases were incorporated.”
One main suspected proto-nucleobase in this experiment -- and in previous experiments on the possible the evolution of RNA -- was triaminopyrimidine (TAP). Cyanuric acid (CA) was another. The researchers highly suspect TAP and CA were parts of a proto-RNA.
The chemical bonds that hold together assemblies of the two suspected proto-nucleobases were surprisingly strong but non-covalent, which is akin to connecting two magnets. In RNA the main bonds holding together modern nucleobases are covalent bonds, akin to welding, and enzymes make those bonds in cells today.
A helix can spiral two ways, left-handed or right-handed. In chemistry, a molecule can also be handed, or chiral, making for “L” or “D” forms of the molecule.
Incidentally, the building blocks of today’s RNA and DNA are all the D form, which make a right-handed helix. Why they evolved like this is still a mystery.
Batches of TAP and CA the researchers started out with produced roughly equal amounts of right and left-handed helices, but something stood out: Whole regions of a batch were biased in one direction and were separate from other regions that spiraled mostly the other way.
“The propensity for the molecules to choose one helical direction was so strong that large regions of the batches were made up predominantly of assemblies that were unidirectionally twisted,” Hud said.
This was surprising because the individual molecules of TAP and CA had no chirality of their own, neither L nor D. Still, the twists had a preferred direction.
The researchers added two more experiments to test how strongly their RNA-like assemblies preferred making one-handed helices.
First, they introduced a smidgeon of compounds similar to TAP and CA, but which had L or D chirality, to nudge the spiraling direction. The whole batch conformed to the chirality of the respective additive, resulting in assemblies twisting in a unified direction as helices do in RNA and DNA today.
“It was the new world record for the smallest amount of a chiral dopant (additive) that would flip a whole solution,” said Suneesh Karunakaran, the study’s first author and a graduate researcher in Hud’s lab. “This demonstrated how easy it would be in nature to get abundant amounts of unified helices.”
Second, they put the sugar compound ribose-5-phosphate together with TAP to more closely emulate the current building blocks of RNA. The ribose fell into place, and the resulting assembly spiraled in a direction dictated by the ribose chirality.
“This molecule easily formed an RNA-like assembly that was surprisingly stable, even though the pieces were only held together by non-covalent bonds,” Karunakaran said.
The study’s results under such simple conditions represent a leap forward in experimental evidence for how the helical twist of biomolecules could have already been in place long before life emerged.
The research also expands a growing body of evidence supporting an unconventional hypothesis by the Center for Chemical Evolution, which dispenses with the need for a narrative that rare cataclysms and unlikely ingredients were necessary to produce life’s early building blocks.
Instead, most biomolecules likely arose in several gradual steps, on quiet, rain-swept dirt flats or lakeshore rocks lapped by waves. Precursor molecules with the right reactivity enabled those steps readily and produced abundant materials for further evolutionary steps.
In the lab, helix self-assemblage was so productive that it outstripped a detection device’s capacity to examine the output. Regions a square millimeter or more in size were packed with unidirectionally spiraled polymer-like assemblies.
“To look at them I had to make adjustments to the equipment,” said Karunakaran. “I punched holes in a foil and put it in front of the beam of our spectropolarimeter.”
That worked but needed improvement, so Hud took to his basement at home to build an automated scanner that could handle the experiment’s bountiful results. It revealed large regions of helices with the same handedness.
Also READ: This actually happened: Strip all the lynchpins from the ribosome and it still works
Brian J. Cafferty, Angela Weigert-Muñoz and Gary B. Schuster of Georgia Tech co-authored the research. It was funded by the National Science Foundation and the NASA Astrobiology Program under the NSF Center for Chemical Evolution (grant CHE-1504217). Nicholas Hud is also Associate Director of the Parker H. Petit Institute for Bioengineering and Bioscience. Any findings, recommendations or conclusions are those of the authors and not necessarily of the funding agencies.
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]]>As an undergraduate student, and using computational approaches, Sarthak worked on the evolution of CRISPR-Cas systems. These systems form the innate immune systems in bacteria. “It was here that I learned about molecular biology and bioinformatics,” Sarthak says.
In IIT Guwahati, Sarthak joined the robotics club, participating in various intercollegiate robotics events. He also played for the institute's football club.
In his second-year at IIT Guwahati, Sarthak came across a piece of news: Georgia Tech researchers had combined biology and machine learning to seek biology-inspired – bio-inspired – solutions to various problems.
“This single article drove me to research various courses at Georgia Tech,” Sarthak says. “I found that the bioinformatics program at Georgia Tech was flexible and highly computation-oriented. It was perfect for someone like me – interested in computer science and biology. Not only was I impressed, I was inspired to join Georgia Tech.”
Sarthak started the Master of Science program in Bioinformatics in August 2017. In early 2018, he received the J. Leland Jackson Fellowship in Bioinformatics for the outstanding master’s student in the program.
For his research, Sarthak studied the nervous system of tunicates, “our closest living invertebrate relatives,” he says. His work resulted in first use of a technique called single-cell RNA sequencing to characterize the gene expression profiles of neurons in tunicates.
Sarthak has been working with Alberto Stolfi, an assistant professor in the School of Biological Sciences and a member of the Parker H. Petit Institute for Bioengineering and Bioscience. “Sarthak’s accomplishments speak for themselves,” Stolfi says. “He so quickly and fundamentally elevated the research in the lab in such a short time. In addition, Sarthak is a courteous, kind, and mature student. Mentoring him has been a joyous experience.”
Sarthak graduates with a Master of Science in Bioinformatics.
What is the most important thing you learned at Georgia Tech?
The most important thing I learned at Georgia Tech is management – managing multiple projects simultaneously, managing stress, managing group work, and managing time.
I was aware that Georgia Tech is a tough school. I was also certain that it would be an enriching, albeit challenging, experience.
Georgia Tech met my expectations and then some! Instructions are excellent and instructors are very approachable. They are willing to attend to your problems almost anytime. Everyone at Tech is willing to give their time to you if you are interested in learning.
What are your proudest achievements at Georgia Tech?
Within one year, I submitted a paper as first author in the peer-reviewed journal Developmental Biology, and I received the Outstanding (Master’s) Bioinformatics Student Award. I am proud of these achievements because working on publishing a paper while taking difficult courses and maintaining a GPA of 4.0 was really challenging.
Which professor(s) or class(es) made a big impact on you?
Dr. Alberto Stolfi has been my research guide and mentor ever since I came to Georgia Tech. I was the first student in his lab. He has been a perfect leader for me. He clearly stated his research goals and his expectations of me. And then he gave me utmost freedom to deliver results.
Not only has he been understanding throughout, but he has also been extremely supportive of my career choices and aspirations. If ever I hold a leadership position anywhere in life, I hope I can be half as good a leader as he has been for me.
What is your most vivid memory of Georgia Tech?
I witnessed the first snowfall of my life at Georgia Tech. I was in Dr. Stolfi's office. We were discussing some project when he abruptly pointed toward his office window. It was snowing! We quickly finished the discussion, and I left for home early.
I walked in the falling snow for more than a mile, slipping almost five times on the way. In the evening, when the entire campus was covered in snow, I got together with a few friends and made my first snowman.
It's still as clear in my memory as if it happened only yesterday. It was a special day. Although I fell ill the next day, it was all worth it!
In what ways did your time at Georgia Tech transform your life?
I have made significant contributions to various projects, developed skills that I had never even imagined, and evolved work ethics that had seemed impossible to me.
Georgia Tech drove me to push myself and get out of my comfort zone. I am a very different person today from who I was before attending Georgia Tech.
What unique learning activities did you undertake?
I took a special-problems course to do research alongside my studies. This enabled me to apply my classroom learning to real-world problems and to devise new methods and tools for answering intriguing questions.
What advice would you give to incoming graduate students at Georgia Tech?Manage your time. Otherwise, you will be in a sea of problems.
Do not take anything for granted, especially your health. At times, you'll have deadlines, exams, and presentations in a single week. Make sure you give yourself enough time and space to unwind. It’s not always be possible, but do the best you can.
Challenge yourself by taking a tough course, if you find one that interests you, without worrying about the grade. You might never get the opportunity to study those subjects again.
Where are you headed after graduation?
I will not immediately go for a Ph.D. I’m looking for a bioinformatics software engineer position.
Georgia Tech stresses ethical behavior in the workplace. These principles will guide me in making tough decisions.
Georgia Tech has equipped me with a unique combination of technical and soft skills. My experience at Georgia Tech has made me capable of handling multiple projects simultaneously and work efficiently in both collaborative and independent work settings.
]]>Having bacterial cooties in common with anemones may help the clownfish cozily nest in anemones’ venomous tentacles, a weird symbiosis that life scientists - including now a team from the Georgia Institute of Technology - have tried for decades to figure out. The marine researchers studied how populations of microbes shifted on clownfish who mixed and mingled with fish-killing anemones.
“It’s the iconic mutualism between a host and a partner, and we knew that microbes are on every surface of each animal,” said Frank Stewart, an associate professor in Georgia Tech’s School of Biological Sciences. “In this particular mutualism, these surfaces are covered with stuff that microbes love to eat: mucus.”
Clownfish and anemones swap lots of mucus when they rub. So, the researchers brought clownfish and anemones together and analyzed the microbes in the mucus covering the fish when they were hosted by anemones and when they weren’t.
“Their microbiome changed,” said Zoe Pratte, a postdoctoral researcher in Stewart’s lab and first author of the new study. “Two bacteria that we tracked in particular multiplied with contact with anemones.”
“On top of that, there were sweeping changes,” said Stewart, the study’s principal investigator. “If you looked at the total assemblages of microbes, they looked quite different on a clownfish that was hosted by an anemone and on one that was not.”
The researchers chased 12 clownfish in six fish tanks for eight weeks to swab their mucus and identify microbes through gene sequencing. They published their results in the journal Coral Reefs. The research was funded by the Simons Foundation.
Here are some questions and answers about the experiment, which produced some amusing anecdotes, along with fascinating facts about anemones and clownfish. For example, fish peeing on anemones makes the latter stronger. Clownfish change genders. And it was especially hard to catch one fish the researchers named “Houdini.”
No, but it’s a new approach to the clownfish-anemone conundrum.
“It’s a first step that’s asking the question, ‘Is there part of the microbial relationship that changes?’” Stewart said. The study delivered the answer on the clownfish side, which was “yes.”
An earlier hypothesis on the conundrum held that clownfish mucus was too thick to sting through. Current ideas consider that mucus swapping also covers the clownfish with anemone antigens, i.e. its own immune proteins, or that fish and fish killer may be exchanging chemical messages.
“The anemone may recognize some chemical on the clownfish that keeps it from stinging,” Stewart said. “And that could involve microbes. Microbes are great chemists.”
Going forward, the researchers want to analyze mucus chemistry. They also don’t yet know to what extent the microbes on the fish change because of bacteria the fish gleans from the anemone. It’s possible the fish mucus microbiome just develops differently on the fish due to the contact.
Kill them and eat them.
“The anemone evolved to kill fish. It shoots little poison darts into the skin of a fish to kill it then pull it into its mouth,” Stewart said. “The clownfish gets away with living right in that.”
By the way, the tentacles are not harmful to people.
“If you touch an anemone, it feels like they’re sucking on your finger,” Pratte said. “Their little harpoons feel like they’re sticking to you. It doesn’t hurt.”
For starters, they protect each other from potential prey. But there’s lots more. Some clownfish even change genders by living in an anemone.
“When they start being hosted, the fish make a big developmental switch,” Stewart said. “The first fish in a group that establishes itself in an anemone in the wild transitions from male to female, grows much bigger and becomes the dominant member of the group.”
She is then the sole female in a school of smaller male mates.
Anemones appear to grow larger and healthier, partly because the clownfish urinate on them.
“When the fish pee, algae in the anemone take up the nitrogen then secrete sugars that feed the anemone and make it grow,” Pratte said. “Sometimes the fish drop their food, and it falls into the anemone which eats it.”
Plenty: It was scientifically straightforward but laborious to carry out, partly because the researchers were taking meticulous care of the fish at the same time.
“You have to get fish and anemones to pair up, and the fish can host in other places, like nooks in the rock,” Pratte said.
“Clownfish are smarter than other fish, so they’re harder to catch, especially when we want to minimize stress on the animals,” said Alicia Caughman, an undergraduate research assistant in the School of Biological Science’s Fast Track to Research program. “We named one fish ‘Houdini.’ He could wiggle between nets and tight spaces and usually outsmart whoever was trying to catch him."
“We also had 'Bubbles,' who blew a lot of bubbles, 'Biggie' and 'Smalls,' 'Broad,' 'Sheila,' 'Earl,' and 'Flounder,' who liked to flounder (flop around),” Pratte said. Clownfish have differing sizes and details in their stripes, which allow people to tell them apart.
The anemone side of the microbial question may prove harder to answer because for all Houdini's wiles, anemones, which are squishy non-vertebrates, are even more trying. They can squeeze into uncomfortable niches or plug up the aquarium drainage, and they also have temperamental microbiomes.
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Also READ: When boy fish build castles to impress girl fish, boy genes get a rise
Also READ: Teeny bacteria do a dirty job to clean a huge fish tank
The following researchers coauthored the paper: Nastassia V. Patin, Mary E. McWhirt and Darren J. Parris, all of Georgia Tech. DOI: 10.1007/s00338-018-01750-z. The research was funded by the Simons Foundation (award 346253). Any findings, opinions or recommendations are those of the authors and not necessarily of the Simons Foundation.
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]]>The scientists at the Georgia Institute of Technology and Stanford University who led the new study hope in the future to see if some behaviors are indeed genetic programs and if gene regulation is clicking off neuronal firing patterns in real time to create behavior.
“We’re not there yet, but we’re beginning to get a handle on gene regulation patterns that drive the neuronal patterns,” said Todd Streelman, professor and chair of Georgia Tech’s School of Biological Sciences and also its chair, and a researcher in the Petit Institute for Bioengineering and Bioscience. “We were able to see that there’s a clear connection between gene expression and behavior.”
The research also may contribute to a better understanding of autism because the genes behind the fish behavior have human cousins that are implicated in autism spectrum disorder. And some typical autism behaviors like “stacking,” in which a child compulsively arranges objects into neat rows or towers, have parallels in how the fish, called cichlids, repetitively pile up sand to make symmetrical formations.
But for now, the researchers explored male cichlids trying to attract a mate in Lake Malawi in Africa and found that the regulation of specific genes and associated repetitive behavior occurred nearly hand-in-glove, a novel discovery.
They published their results in the journal Proceedings of the National Academy of Sciences. The research was funded by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the National Institute of General Medicine, all part of the National Institutes of Health.
Let’s start with the behavior then go to the matching gene regulation:
Boy cichlids knock themselves out building stuff out of sand to impress girl fish ready to mate. Most of the cichlid species’ guys build a pit, or crater, and other species build a castle.
Both pits and castles are known as “bowers” and require the male fish to swim in the same circular way, scooping up sand in one place and spitting it out somewhere else.
The difference is that the pit builders scoop up the sand from inside their swimming pattern and deposit it outside, leaving a hole in the middle of the bower with a raised rim surrounding it that makes the bower resemble a crater. Castle builders scoop the sand from outside the circle and deposit it inside. That creates a raised structure in the middle of the bower, making it resemble a volcano.
“A switch goes on once the females become reproductively active. Suddenly, the males begin scooping and spitting thousands of times to build their structure,” said Zachary Johnson, a postdoctoral researcher in Streelman’s Lab. Johnson was a co-author on the new study and Streelman a co-principal investigator.
Scooping and spitting are so incessant that two-inch fish shovel up two-foot-wide structures: pit bowers for some species, castle bowers for others. The difference serves in attracting the right mate.
“Various species make their pits and castles in a common area, and structures have to be very specific, so the right female species can see, ‘This is the guy that I want’ compared to the other guys from other species that build the other thing. And she then has to pick the specific guy she wants from her own species,” said Chinar Patil, a co-first author of the study and a graduate research assistant in Streelman’s lab.
Now for the gene regulation part:
To observe the genes connected to either of these building behaviors, researchers have cross-mated pit-building species with castle-building species to make hybrid cichlids that have both sets of genes. These hybrids have delivered a lucky surprise.
The hybrid fish performed both behaviors neatly in sequence: first the pit making, then the castle making, always in that order.
“That’s amazing,” Johnson said. “You might expect hybrid behavior to be jumbled, or take on some intermediate form. Instead, they perform one species-specific behavior and then transition to performing the other species-specific behavior.”
This is useful to research because the hybrids have one full copy of genes from the pit parent and one from the castle parent. The cleanly separated behaviors have allowed for matching each behavior with increased and decreased activation in either set of genes in the fish’s brains.
The Georgia Tech and Stanford researchers were able to clearly match pit gene activation with pit behavioral mode as well as castle gene activation with castle behavioral mode.
“A lot of genes in the pit copy got up-regulated while the fish was in pit-making mode and the castle copy got up-regulated during castle-making mode,” Patil said. The genes and the behavior got visibly “turned on” and “tuned in” in tandem.
The difference in expression of either pit vs. castle genes was less of an absolute click-clack-on-off switch and more like inching one set of levers down on an audio mixer while tuning up the other set to a dominant level.
This was the study’s big achievement, which almost sounds like genes directly creating behavior, but that’s unconfirmed as of yet and could be the topic of future studies.
The study also brought new insights into genetic evolution in tandem with behavioral evolution, about which little is known. The genetic component may center around gene regulation in response to what’s going on in the animal’s environment in this case when females are ready to mate.
Pit making appears to be the evolutionarily older and better-established bower building behavior, and castle making is widely accepted as being the newer evolutionary development. But pit and castle species have very similar genomes, so where’s the evolutionary change?
When the team sequenced the DNA of pit and castle species, it was differences in regulatory genes that stuck out, and many up-regulated specific other genes connected to the respective bower building behaviors when mating time hit. It appeared the evolution of the regulatory genes was linked to the evolution of the behavior.
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Read MORE: On genetics of neuroscience and behavior
The following researchers also co-authored this study: Ryan York, Hunter Fraser and Russel Fernald of Stanford University; Kawther Abdilleh and Patrick McGrath of Georgia Tech; Mathew Conte of the University of Maryland; and Martin Genner of the University of Bristol. The research was funded by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (grant R01NINDS034950), the National Institute on Aging (grant R21AG050304), and National Institute of General Medicine (grants R01GM101095, 2R01GM097171-05A1, R01GM114170). Findings, conclusions, opinions, and recommendations in the material are those of the authors and not necessarily of the funding agencies.
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]]>Whether the clathrates are on Earth or the Jovian moon Europa, science wants to know: What role did microbes play in their formation and stability? How are they involved when Earthbound clathrates start deteriorating, releasing this greenhouse methane gas into an already-warming global atmosphere? Is that process underway millions of miles from Earth?
An interdisciplinary team of Georgia Tech geo-microbiologists, biochemists, and geo-engineers will have a chance to answer those questions, thanks to a grant from the NASA Exobiology Program that comes with a heady title: Microbial Interactions with Methane Clathrate: Implications for Habitability of Icy Moons. The investigators, which include College of Sciences researchers, will search for DNA blueprints of potential clathrate-binding proteins, will reproduce those proteins in a laboratory, and will test their impact on methane clathrate properties.
“This is a truly interdisciplinary project to understand how microbial life survives in methane clathrates under the seafloor,” says Jennifer Glass, assistant professor in the School of Earth and Atmospheric Sciences. Glass will serve as the team’s principal investigator.
“These deep microbes encode genes that are different from any found on the Earth's surface,” Glass says. “This grant will be one of the first efforts to study the biochemistry of these new biomolecules, and how they affect the structure and properties of methane clathrate. This research is only possible because our Georgia Tech team is uniquely working at the interface between microbial ecology, biochemistry, and geoengineering."
Clathrates are lattice-like structures made of a solid similar to ice. They are buried in polar permafrost and under the world’s oceans, and scientists believe they could hold anywhere from 100,000 to 1 million Tcf (trillion cubic feet) of natural gas. The gas molecules are trapped inside the crystalline structures, but large-scale commercial extraction isn’t available yet. However, plumes of methane have been recorded leaking from Arctic permafrost thanks to global warming. (Methane is already produced via decaying organic matter in landfills, traditional oil and gas exploration, and within the stomachs of domestic livestock.)
Visits from planetary probes, spectroscopy readings, and other research indicate that methane clathrates may exist on the icy moons of Jupiter and Saturn. They may be part of developing ecosystems. Did microbes interact with those clathrates? Could they be tapped in the search for life in the solar system? Could those gas resources help sustain human habitats on the Jovian moon Europa?
"We are excited to learn more about the fascinating molecules that bind methane ice in this unique environmental niche,” says Raquel Lieberman, professor in the School of Chemistry and Biochemistry, and one of the methane clathrate team members. “These proteins don’t look like any others known in temperate environments."
In addition to Glass and Lieberman, other team members include research scientist Anton Petrov and Professor Loren Williams, both with the School of Chemistry and Biochemistry; and Sheng Dai, assistant professor in the School of Civil and Environmental Engineering. Abbie Johnson, an EAS graduate student in the Ocean Science & Engineering Program, will work on the project for her doctoral dissertation.
Glass has a courtesy appointment with the School of Biological Sciences. She also is on the faculty of the Parker H. Petit Institute for Bioengineering and Biosciences.
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]]>In the system inside cells that translates genetic code into life, he replaced about 1,000 essential linchpins with primitive substitutes to see if the translational system would survive and function. It seemed impossible, yet it went swimmingly, and Bray had compelling evidence that the system would have worked as it is today in extremely harsh conditions 4 billion years ago when it evolved.
The experiment’s success reaffirmed the translational system’s place at the earliest foundations of life on Earth and its robustness through the eons.
Every living thing exists because the translational system receives messages from DNA delivered to it by RNA and translates the messages into proteins. The system centers on a cellular machine called the ribosome, which is made of multiple large molecules of RNA and protein and is ubiquitous in life as we know it.
“There’s nothing alive without ribosomes,” said Loren Williams, a professor at the Georgia Institute of Technology’s School of Chemistry and Biochemistry. “The ribosome is about the oldest and most universal part of biology, and its origins go very far back to a time not too long after Earth had formed and cooled.”
Those linchpins that hold it all together and that Bray yanked out and replaced were metal ions (atoms with charges, in this case positive).
In today’s ribosome, and in the whole translational system, the linchpins are magnesium ions, and Bray’s experiment replaced them all with iron ions and manganese ions, which were overabundant on primordial Earth. Williams and Jennifer Glass, the principal investigators in the new study, also had their doubts the system would hold up without the magnesium.
“I thought, ‘It’s not going to work, but we might as well try the moonshot’,” said Williams who has led similar work before but on simpler molecules. “The fact that swapping out all the magnesium in the translational system actually worked was mind-boggling.”
That’s because in living systems today, magnesium helps shape ribosomes and help them work. It is needed in addition to the ribosome for some 20 enzymes of the translational system. It’s one reason why dietary magnesium (Mg) is so important.
“The number of different things magnesium does in the ribosome and in the translational system is just enormous,” said Williams. “There are so many types of catalytic activities in translation, and magnesium is involved in almost all of them.”
When first life evolved, fissures in Earth’s crust still belched lava and meteor impacts were still common. There was no breathable oxygen and the planet was brimming with iron and manganese.
This may have made them attractive for the translational system to use as the dominant ions. Magnesium was likely involved, too, though it was probably less available than today.
The researchers wanted to know if the translational system first evolved to function with those other metals as their linchpins. So, Bray, a graduate research assistant in Williams’s and in Glass’s lab, swapped out the magnesium ions for them, tabula rasa.
“We didn’t have any substantial reason to believe it would work, and it was a huge surprise to all of us when it did,” Bray said. And it strongly corroborated that the translational system would have thrived under early Earth conditions.
Bray, co-first author Timothy Lenz and co-principal investigators Glass and Williams published their results in the journal Proceedings of the National Academy of Sciences on November 9, 2018. The research was funded by the NASA Exobiology program. Glass is an assistant professor in Georgia Tech’s School of Earth and Atmospheric Sciences.
Amazingly, the atomic swaps barely changed the shape of the ribosome.
“It’s totally unbelievable this would work because biology makes very specific use of things. Change one atom and it can wreck a whole protein,” Williams said. “When we probed the structure, we saw that all three metals do essentially the same thing to the structure.”
When they tested the performance of the translational system with iron replacing magnesium, it was 50 to 80 percent as efficient as normal (with magnesium). “Manganese worked even better than iron,” Bray said.
“I think these may be textbook-rewriting results since the whole field of ribosome research involves magnesium,” Bray said. “Now, with what we’ve done, it’s no longer the case that only magnesium works.”
Bray incubated ribosomes in the presence of magnesium, iron, or manganese inside a special chamber with an artificial atmosphere devoid of oxygen, like the Earth four billion years ago.
He found that the magnesium replacement went far beyond atoms in the ribosome.
“Surrounding the ribosome is also a huge cloud of magnesium atoms. It’s called an atmosphere, or shell, and engulfs it completely. I replaced everything, including that, and the whole system still worked.”
Eons down the road, the evolution of the translational system in the presence of magnesium may have given it an adaptive advantage. As oxygen levels on Earth rose, binding up free manganese and iron, and making them less available to biology, magnesium probably comfortably assumed the thousands of roles it occupies in the translational system today.
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Also READ: Laughing Gas May Have Helped Warm Early Earth and Given Breath to Life
These researchers coauthored the study: Jay Haynes, Jessica Bowman, Anton Petrov, Amit Reddi, and Nicholas Hud, all of Georgia Tech. The research was funded by the NASA Exobiology program (grants NNX14AJ87G, NNX16AJ28G, and NNX16AJ29G). Findings, conclusions, opinions, and recommendations in the material are those of the authors and not necessarily of NASA.
Study in PNAS: http://www.pnas.org/content/early/2018/10/30/1810140115
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]]>That’s where Georgia Institute of Technology researchers believe their new open source decision support tool could come in. Using machine learning to analyze RNA expression tied to information about patient outcomes with specific drugs, the open source tool could help clinicians chose the chemotherapy drug most likely to attack the disease in individual patients.
In a study using RNA analysis data from 152 patient records, the system predicted the chemotherapy drug that had provided the best outcome 80 percent of the time. The researchers believe the system’s accuracy could further improve with inclusion of additional patient records along with information such as family history and demographics.
“By looking at RNA expression in tumors, we believe we can predict with high accuracy which patients are likely to respond to a particular drug,” said John McDonald, a professor in the Georgia Tech School of Biological Sciences and director of its Integrated Cancer Research Center. “This information could be used, along with other factors, to support the decisions clinicians must make regarding chemotherapy treatment.”
The research, which could add another component to precision medicine for cancer treatment, was reported November 6 in the journal Scientific Reports. The work was supported in part by the Atlanta-based Ovarian Cancer Institute, the Georgia Research Alliance, and a National Institutes of Health fellowship.
As with other machine learning decision support tools, the researchers first “trained” their system using one part of a data set, then tested its operation on the remaining records. In developing the system, the researchers obtained records of RNA from tumors, along with with the outcome of treatment with specific drugs. With only about 152 such records available, they first used data from 114 records to train the system. They then used the remaining 38 records to test the system’s ability to predict, based on the RNA sequence, which chemotherapy drugs would have been the most likely to be useful in shrinking tumors.
The research began with ovarian cancer, but to expand the data set, the research team decided to include data from other cancer types – lung, breast, liver and pancreatic cancers – that use the same chemotherapy drugs and for which the RNA data was available. “Our model is predicting based on the drug and looking across all the patients who were treated with that drug regardless of cancer type,” McDonald said.
The system produces a chart comparing the likelihood that each drug will have an effect on a patient’s specific cancer. If the system were to be used in a clinical setting, McDonald believes doctors would use the predictions along with other critical patient information.
Because it measures the expression levels for genes, analysis of RNA could have an advantage over sequencing of DNA, though both types of information could be useful in choosing a drug therapy, he said. The cost of RNA analysis is declining and could soon cost less than a mammogram, McDonald said.
The system will be made available as open source software, and McDonald’s team hopes hospitals and cancer centers will try it out. Ultimately, the tool’s accuracy should improve as more patient data is analyzed by the algorithm. He and his collaborators believe the open source approach offers the best path to moving the algorithm into clinical use.
“To really get this into clinical practice, we think we’ve got to open it up so that other people can try it, modify if they want to, and demonstrate its value in real-world situations,” McDonald said. “We are trying to create a different paradigm for cancer therapy using the kind of open source strategy used in internet technology.”
Open source coding allows many experts across multiple fields to review the software, identify faults and recommend improvements, said Fredrik Vannberg, an assistant professor in the Georgia Tech School of Biological Sciences. “Most importantly, that means the software is no longer a black box where you can’t see inside. The code is openly shared for anybody to improve and check for potential issues.”
Vannberg envisions using the decision-support tool to create “virtual tumor boards” that would bring together broad expertise to examine RNA data from patients worldwide.
“The hope would be to provide this kind of analysis for any new cancer patient who has this kind of RNA analysis done,” he added. “We could have a consensus of dozens of the smartest people in oncology and make them available for each patient’s unique situation.”
The tool is available on the open source Github repository for download and use. Hospitals and cancer clinics may install the software and use it without sharing their results, but the researchers hope organizations using the software will help the system improve.
“The accuracy of machine learning will improve not only as the amount of training data increases, but also as the diversity within that data increases,” said Evan Clayton, a Ph.D. student in the Georgia Tech School of Biological Sciences. “There's potential for improvement by including DNA data, demographic information and patient histories. The model will incorporate any information if it helps predict the success of specific drugs."
In addition to those already mentioned, the research team included Cai Huang, Lilya Matyunina, and DeEtte McDonald from the Georgia Tech School of Biological Sciences, and Benedict Benigno from the Georgia Tech Integrated Cancer Research Center and the Ovarian Cancer Institute.
Support for the project came from the Ovarian Cancer Institute, and equipment used was provided by the Georgia Research Alliance. In addition, the National Institutes of Health supported a graduate fellowship.
CITATION: Cai Huang, et al., “Machine learning predicts individual cancer patient responses to therapeutic drugs with high accuracy,” (Scientific Reports 2018). http://dx.doi.org/10.1038/s41598-018-34753-5
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]]>“I didn’t expect this,” said Petit Institute researcher Frank Stewart, principal investigator of a study led by the Georgia Institute of Technology. “The microbial communities are seeded from microbes coming from the animals and their food in an aquarium that does not tap into the ocean. But these looked like natural marine microbial communities.”
That’s happy news for the thousands of creatures who live in Georgia Aquarium’s Ocean Voyager, the largest indoor oceanic exhibit in the United States. Watch the video and read the story in Georgia Tech’s Research Horizons right here.
]]>By providing new information about the role of communication among cells, the research could lead to a better understanding of how multicellular organoids form from colonies of independent cells. The information could lead to new methods for controlling how multicellular constructs develop, and that could have applications in regenerative medicine, pharmaceutical testing and other research areas.
The research resulted from collaboration between the Georgia Institute of Technology and the Gladstone Institutes, and was reported October 5 in the journal Nature Communications. The National Science Foundation’s (NSF) Emergent Behaviors of Integrated Cellular Systems Science and Technology Center (EBICS) supported the research.
“The goal is to control a system of cells like this to direct tissues to take on different phenotypes, to develop into different complex mixtures, and to self-assemble and emerge into very complicated structures,” said Melissa Kemp, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “For developing tissues that could be used as surrogates for screening drugs or as eventual implants for therapeutic purposes, we need to how to control and direct them properly.”
Scientists believe that the patterning of stem cell differentiation affects what kinds of cells will ultimately emerge from the differentiation process.
Despite the importance of local cell-to-cell interactions in evolving multicellular systems, little has been known about how the overall system regulates its morphological processes. To learn more about this, the paper’s first author, Chad Glen, studied how communication between adjacent mouse cells informs the fate of those cells. Beyond understanding this communication, Glen discovered a potential mechanism for “braking” the rate of differentiation without affecting the overall patterning of the resulting multicellular tissue.
“The amount of coordination among cells that are tightly coupled gives us an idea about how they work as a group,” said Todd McDevitt, senior investigator at the Gladstone Institutes and a professor of bioengineering and therapeutic sciences at the University of California, San Francisco. “This reflects the behavior of a team versus individuals. They really do coordinate activity in a rapid way. This study shows how quickly some important cell behaviors are mediated by gap junction communication.”
Glen, a recent Ph.D. graduate of Georgia Tech, began the project by studying communication between pairs of adjacent cells, which have pores that allow small molecules to enter. By introducing a signaling molecule into a colony containing hundreds of these homogeneous mouse stem cells, the researchers observed that differentiation began with a change in a single cell. That cell triggered a pattern of differentiation that flowed through the cells and eventually led to changes in the entire colony.
On a larger scale and in three dimensions, such changes lead to development of bodily organs. Understanding how that happens – and how it could be controlled – could be key to directing this transition from individual cells.
Based on experimental observations, Glen developed a model of the process, which allowed the researchers to study the impact of a series of interrelated variables that would have been impossible to study experimentally. The modeling of several hundred individual cells led to specific predictions that the researchers then tested experimentally.
To understand and measure the cell communication process, the researchers used a fluorescent dye to show when signaling molecules had moved from one cell to its neighbors. They then used a laser to bleach the dye from a single cell. Measuring how long it took for the dye to be replaced showed the permeability of the cell membrane – and how well the cell was communicating with its neighbors.
“If you zap a cell and it immediately returns to green, you know there is a lot of fluidity and cross-talk between the cell membranes,” Kemp explained. “If you zap a cell and it stays dark, the cell is effectively isolated and has no communication with its neighbors.”
By partially blocking communication between cells and otherwise perturbing the communications, the researchers slowed the differentiation process – but didn’t change its pattern. “We were able to shift the way the cells were behaving to slow things down – effectively ‘braking’ the process – while preserving the spatial information,” said Kemp. “Cells that were at 48 hours in the process could look like 24-hour cells.”
The combination of computational modeling and experiment allowed the research team to arrive at answers that neither technique by itself could have provided, McDevitt noted.
“With modeling, you can study a much larger set of conditions and parameters than we could experimentally,” he said. “The model could make predictions that we could go back and study experimentally to see how those conditions actually affected the behaviors. The behaviors we measured experimentally matched what the computer predicted, and validated that we had a robust model.”
McDevitt and Kemp have been studying this system of embryonic stem cells for several years, and the new study moves them closer to a more complete understanding of the complex system.
“We have demonstrated in a series of papers over the past six years that this system’s complexity can be modeled,” he said. “This paper represents a further step toward the greater goal of integrating information about this system. With each of these steps, we are much closer to taking a bigger leap into potentially controlling these systems.”
This research was supported by the National Science Foundation Emergent Behaviors of Integrated Cellular Systems Science and Technology Center (CBET 0939511). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.
CITATION: Chad M. Glen, Todd C. McDevitt, Melissa L. Kemp, “Dynamic intercellular transport modulates the spatial patterning of differentiation during early neural commitment, (Nature Communications 9, 2018). http://dx.doi.org/10.1038/s41467-018-06693-1
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]]>DNA, the blue print of life, which we know to be made of deoxyribonucleotides, contains many scattered ribonucleotides (ribonucleoside monophosphates, or rNMPs) embedded in its sequence. rNMPs in DNA alter DNA structure and properties, and often are sites of mutation and strand breakage. Specific high-throughput sequencing techniques have been recently developed to mark the presence of the rNMPs in genomic DNA. The discovery of hotspot sites and particular patterns of rNMP presence in genomic DNA requires the analysis of large sets of sequencing data. Currently, computational methods to study rNMPs embedded in DNA are highly customized and are not designed as platform-independent, automated pipelines that allow for fast, scalable analyses. Alli Gombolay, a PhD student in the bioinformatics program in the group of Dr. Francesca Storici, in collaboration with Dr. Fredrik Vannberg, designed and tested the scripts of the Ribose-Map software. By accommodating data from each technique available for rNMP mapping, Ribose-Map is a unique pipeline to standardize the analysis of rNMPs embedded in DNA, increasing the reproducibility of rNMP-capture experiments and enabling a head-to-head comparison of these techniques. Ribose-Map transforms raw sequencing data into summary datasets and publication-ready visualizations of results.
The Storici’s lab recently set up a molecular biology technique, ribose-seq, to build genomic libraries of rNMP sites by directly capturing DNA sequences containing an rNMP. “We can build ribose-seq libraries form any DNA of interest, and now, with Ribose-Map, we can also analyze the sequencing data from ribose-seq or other techniques in a straightforward and efficient manner” says Storici.
The Ribose-Map pipeline standardizes and speeds up the analyses of sequencing data obtained from libraries of rNMP sites. It will help the scientific community in the efforts to uncover rNMP spectra, biomarkers and sites of potential distortion or fragility in any type of DNA source, bacterial, fungus, plant or animal cells, from healthy or diseased cells.
The study is just published as an article in the journal Nucleic Acids Res (Monday October 1, 2018):
https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gky874/5112988
This project was supported by the National Institute of Health grants (R01ES026243-01 to F.S. and R01EB025022-01 to F.O.V.), the Parker H. Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology grant (12456H2 to F.S.), the Howard Hughes Medical Institute Faculty Scholar grant (55108574 to F.S.).
]]>The 2018 winners “found ways to alert immune cells to recognize cancer cells as non-self and destroy them,” says Francesca Storici, a professor in the School of Biological Sciences and a member of the Parker H. Petit Institute for Bioengineering and Bioscience (IBB). Working with both healthy and cancer cells, she studies what happens inside cells and the DNA damage that occurs with cancer. “Research in this direction has the potential to save many lives not only from cancer but possibly also from many other cell degenerative disorders,” Storici says.
The immune system is well-designed to attack cells that the body considers foreign. The system is tightly regulated to avoid attacking our own normal healthy cells. “This year's winners are long-time students of the mechanisms underlying this regulatory aspect of immune function,” says John McDonald, a professor in the School of Biological Sciences whose lab uses an integrated systems approach to the study of cancer. He directs the Integrated Cancer Research Center at Georgia Tech and is a member of IBB.
Most cancer cells are sufficiently mutated to be viewed as “foreign.” But they often escape attack by shrouding themselves with proteins that block the immune response. By developing strategies to inhibit these blocking mechanisms, McDonald says, the Nobel Prize winners “unleashed the natural anti-cancer properties of the immune system.”
Specifically, Allison and Honjo unraveled the mechanisms that inhibit T-cells, the major immune system components that attack foreign cells, says Fredrik Vannberg, an assistant professor in the School of Biological Sciences and IBB member.
Their basic science discovery led to what is now known as immune checkpoint therapy, which works by reversing T-cell inhibition and allowing the body’s own immune system to destroy cancer cells. Immune checkpoint therapy has saved the lives of many late-stage cancer patients, Vannberg says.
However, not every patient benefits from any particular therapy. Research at Georgia Tech aims to provide additional tools to find the treatment that suits the patient. For example, McDonald and Vannberg collaborate in using genomic profiling to help predict which specific therapy will lead to the best clinical outcome for a given cancer patient.
Toward this goal, last year they offered to cancer researchers – for free – a new program that predicts cancer drug effectiveness via machine learning and raw genetic data. They hoped to attract other researchers who will share their cancer and computer expertise and data to improve upon the program and save more lives together.
“The hope is that – by exploiting these new discoveries alone and in combination with other novel strategies to target treatment to tumors – cancer will soon be transformed from a lethal to a manageable chronic disease,” McDonald says.
]]>By combining technologies based on their discoveries with other ways to treat cancer, the hope is to transform the lethal disease to a manageable, chronic one.
]]>How the molecules of life formed on Earth is the subject of extensive studies. Researchers have long suggested that minerals may have played a role in the formation of peptides in prebiotic Earth. However, most past attempts to use minerals to catalyze amino acid polymerization have not shown a significant improvement or difference in products compared to the same reactions in the absence of minerals.
The study – by Georgia Tech researchers in the National Science Foundation (NSF)/NASA Center for Chemical Evolution (CCE) – finds that drying and heating a mixture of amino and α-hydroxy acids in the presence of silica yields peptides that are longer than those formed in its absence. (Peptides are the precursors of proteins; amino acids are the building blocks of peptides; α-hydroxy acids are chemically similar to amino acids and could have been present in prebiotic Earth; silica would have been abundant on Earth billions of years ago.)
The findings suggest a mechanism by which organic compounds and silica on prebiotic Earth could have worked together to produce peptides. Designated a VIP (Very Important Paper), the paper reporting results is the front-cover article of the Sept. 17, 2018, issue of ChemBioChem.
The work was supported by the NSF and NASA Astrobiology Program under the NSF Center for Chemical Evolution (CHE-1504217). “The study shows silica, a major constituent of Earth’s crust, could play an important role in prebiotic evolution,” says NSF’s Acting Deputy Division Director in Chemistry Lin He. “It provides the grounds to better understand the rules of life and enables a wide range of applications in biomedical engineering, biosensors, chemical, and biological research.”
“The production of peptides in model prebiotic reactions has been a bottleneck in origins-of-life research,” says Thomas Orlando, a professor in the School of Chemistry and Biochemistry and the paper’s corresponding author. “With this discovery we can move to the next level and ask even deeper questions about the origins of life: Could minerals have played a role in selecting some of the organic molecules that participated in the origins of life? Are there common mineral properties that allow them to interact with prebiotic building blocks in a productive way?”
CCE researchers reported in 2015 that drying and heating mixtures of hydroxy acids and amino acids produces polymers called depsipeptides. While depsipeptides may also have played a role in the origin of life, finding an efficient prebiotic method to produce pure peptides remains of great interest.
“It is well-known that minerals react with organic acids, making mineral-organic interfaces that could have existed on early Earth,” Orlando says. Since the founding of the CCE, more than 10 years ago, affiliated researchers have been investigating the possible impacts of minerals on model prebiotic reactions.
“We have been asking: Could minerals, through their cooperation with simple organic molecules on early Earth, have facilitated the synthesis of complex polymers that, ultimately, gave rise to life?” says Nicholas Hud, professor of chemistry and biochemistry, CCE director, and a coauthor of the paper.
“Like almost everyone, we are curious about the origins of life,” says Aaron McKee, a Ph.D. candidate and the paper’s first author. “But we are also interested in the relevance to modern life.” For example, McKee says, scientists are developing nanoparticles that are essentially tiny functionalized mineral surfaces as biomolecule detectors or drug delivery agents.
“There is a vast matrix of minerals and organic molecules related to those used in this study. Some of these would have also been present on prebiotic Earth,” McKee says. “We are now in an excellent position to investigate the numerous combinations of these minerals and organic molecules to see if there is any other chemical cooperation between inorganic and organic substances that could have facilitated the production of molecules important for starting life.”
]]>Hammer and Kostka are two of the eight ASM Distinguished Lecturers recently named to serve until 2020. Selection is based on a competitive process. Only the most distinguished individuals are named to the ASM Distinguished Lecturer Program.
The two microbiologists study microbe-microbe microbe-host interactions important in humans and in ecosystem health. Georgia Tech is emerging as a leader in this burgeoning research area.
As distinguished lecturers, Hammer and Kostka will speak at ASM branch meetings throughout the U.S. Their visits to various parts of the country will provide opportunities for students and early-career research microbiologists to interact with prominent scientists.
A Passion for Training Young Researchers
Hammer's research aims to understand the mechanisms bacteria use to cooperate and compete in niches they occupy. His work focuses on the waterborne microbe Vibrio cholerae, which causes outbreaks of cholera disease in places like Yemen where people have no option but to consume contaminated water.
His lab has identified components of regulatory networks in this bacterium that control secreted enzymes, biofilm matrix material, a molecular harpoon for toxifying neighboring cells, and an apparatus to take up foreign DNA.
Next, his lab aims to identify new genes and regulatory connections of these networks, characterize the behaviors they control, and determine the contribution of these activities to the fitness and adaptability of this waterborne microbe in host and ecological settings.
“I enjoy the challenge and excitement of engaging students and postdocs in conversations – about my lab’s research, about microbiology, and about being a research scientist,” Hammer says. “My passion for training young researchers stems from the mentoring I received from my own advisors, who are extraordinary scientists and communicators. As an ASM Distinguished Lecturer, I will relish the opportunity to serve as a model for students and postdocs discovering their unique career paths.
On the lecture circuit, Hammer will be talking about the following topics:
On a Mission to Catalyze Students
Kostka is well-known for his research in environmental microbiology. His lab characterizes the role of microorganisms in the functioning of ecosystems, especially in the context of bioremediation and climate change. He is co-principal investigator of C-IMAGE-III. This consortium is funded by the Gulf of Mexico Research Initiative to study the environmental consequences of the release of petroleum hydrocarbons on living marine resources and ecosystem health.
“I was first introduced to ASM by attending a branch meeting in Gatlinburg, Tennessee, while I was a master’s student. My experience there was largely responsible for my decision to enter the field of environmental microbiology,” Kostka says. “I wanted to participate in the ASM Distinguished Lecturer Program so that I can give back the support and encouragement that I received at many ASM meetings. I very much believe that it is my professional mission to excite students about the myriad ways that microbes benefit society, thereby catalyzing their entrance into the field.”
On the lecture circuit, Kostka will be discussing the following:
Dahlman is a bioengineer working at the interface of nanotechnology, gene editing, and genomics. His lab develops novel ‘big data’ technologies and applies them to the study of nanomedicine. One such application is the use of DNA barcodes to track thousands of nanoparticles directly in vivo; typically, labs will study a few nanoparticles in vivo.
His lab also has pioneered the use of DNA barcoded nanoparticles, and is using this powerful new technology to design nanoparticles that deliver genetic drugs to target tissues. He has designed nanoparticles that deliver RNA drugs to blood vessels; these nanoparticles have worked in more than 20 labs and are under consideration for clinical development. At the age of 31, he already has published in Nature Nanotechnology (twice), Nature Biotechnology, Cell, Nature Cell Biology, Science Translational Medicine, PNAS (twice), JACS, and other prestigious journals.
In addition to the Technology Review honor, Dahlman has won many national and international awards, and since 2014, has given dozens of invited talks at leading universities around the world on drug delivery and DNA barcoding.
For more than a decade, Technology Review has recognized exceptionally talented technologists whose work has great potential to transform the world. Previous Innovators Under 35 include Larry Page and Sergey Brin, the cofounders of Google, Mark Zuckerberg, the cofounder of Facebook, Helen Greiner, the cofounder of iRobot, and Jonathan Ive, the chief designer of Apple.
Gideon Lichfield, editor-in-chief of MIT Technology Review, said: “MIT Technology Review inherently focuses on technology first - the breakthroughs and their potential to disrupt our lives. Our annual Innovators Under 35 list is a chance for us to honor the outstanding people behind those technologies. We hope these profiles offer a glimpse into what the face of technology looks like today as well as in the future.”
Learn more about this year’s honorees on the MIT Technology Review website here and in the July/August print magazine, which will hit newsstands worldwide on July 3. The honorees are also invited to appear in person at the upcoming EmTech MIT conference, MIT Technology Review’s flagship event exploring future trends and technologies that will impact the global economy, happening September 11-14, 2018 in Cambridge, Massachusetts.
About MIT Technology Review
Founded at the Massachusetts Institute of Technology in 1899, MIT Technology Review is a world-renowned, independent media company whose insight, analysis, reviews, interviews and live events explain the commercial, social and political impact of new technologies. MIT Technology Review derives its authority from the world's foremost technology institution and from its editors' deep technical knowledge, capacity to see technologies in their broadest context, and unequaled access to leading innovators and researchers. MIT Technology Review’s mission is to bring about better-informed and more conscious decisions about technology through authoritative, influential and trustworthy journalism.
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According to a new study, the answer is the microbiome – the community of bacteria found in homes, offices and aircraft cabins. Believed to be the first to comprehensively assess the microbiome of aircraft, the study found that the bacterial communities accompanying airline passengers at 30,000 feet have much in common with the bacterial communities surrounding people in their homes and offices.
Using advanced sequencing technology, researchers from the Georgia Institute of Technology and Emory University studied the bacteria found on three components of an airliner cabin that are commonly touched by passengers: tray tables, seat belt buckles and the handles of lavatory doors. They swabbed those items before and after ten transcontinental flights and also sampled air in the rear of the cabin during flight.
What they found was surprisingly unexciting.
“Airline passengers should not be frightened by sensational stories about germs on a plane,” said Vicki Stover Hertzberg, a professor in Emory University’s Nell Hodgson Woodruff School of Nursing and a co-author of the study. “They should recognize that microbes are everywhere and that an airplane is no better and no worse than an office building, a subway car, home or a classroom. These environments all have microbiomes that look like places occupied by people.”
The results of the FlyHealthy™ study were reported June 6, 2018, in the journal Microbial Ecology. In March, the researchers reported on a separate part of the study that examined potential routes for transmitting certain respiratory viruses – such as the flu – on commercial flights.
Given the unusual nature of an aircraft cabin, the researchers hadn’t known what to expect from their microbiome study. On transcontinental flights, passengers spend four or five hours in close proximity breathing a very dry mix of outdoor air and recycled cabin air that has been passed through special filters, similar to those found in operating rooms.
“There were reasons to believe that the communities of bacteria in an aircraft cabin might be different from those in other parts of the built environment, so it surprised me that what we found was very similar to what other researchers have found in homes and offices,” said Howard Weiss, a professor in Georgia Tech’s School of Mathematics and the study’s corresponding author. “What we found was bacterial communities that were mostly derived from human skin, the human mouth – and some environmental bacteria.”
The sampling found significant variations from flight to flight, which is consistent with the differences other researchers have found among the cars of passenger trains, Weiss noted. Each aircraft seemed to have its own microbiome, but the researchers did not detect statistically significant differences between preflight and post-flight conditions on the flights studied.
“We identified a core airplane microbiome – the genera that were present in every sample we studied,” Weiss added. The core microbiome included genera Propionibacterium, Burkholderia, Staphylococcus, and Strepococcus (oralis).
Though the study revealed bacteria common to other parts of the built environment, Weiss still suggests travelers exercise reasonable caution. “I carry a bottle of hand sanitizer in my computer bag whenever I travel,” said Weiss. “It’s a good practice to wash or sanitize your hands, avoid touching your face, and get a flu shot ever year.”
This new information on the aircraft microbiome provides a baseline for further study, and could lead to improved techniques for maintaining healthy aircraft.
“The finding that airplanes have their own unique microbiome should not be totally surprising since we have been exploring the unique microbiome of everything from humans to spacecraft to salt ponds in Australia. The study does have important implications for industrial cleaning and sterilization standards for airplanes,” said Christopher Dupont, another co-author and an associate professor in the Microbial and Environmental Genomics Department at the J. Craig Venter Institute, which provided bioinformatics analysis of the study’s data.
The 229 samples obtained from the aircraft cabin testing were subjected to 16S rRNA sequencing, which was done at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama. The small amount of genetic material captured on the swabs and air sampling limited the level of detail the testing could provide to identifying genera of bacteria, Weiss said. The extensive bioinformatics, or sequence analysis, was carried out at the J. Craig Venter Institute in La Jolla, Calif.
In the March 19 issue of the journal Proceedings of the National Academy of Sciences, the researchers reported on the results of another component of the FlyHealthy™ study that looked at potential transmission of respiratory viruses on aircraft. They found that an infectious passenger with influenza or other droplet-transmitted respiratory infection will most likely not transmit infection to passengers seated farther away than two seats laterally and one row in front or back on an aircraft.
That portion of the study was designed to assess rates and routes of possible infectious disease transmission during flights, using a model that combines estimated infectivity and patterns of contact among aircraft passengers and crew members to determine likelihood of infection. FlyHealthy™ team members were assigned to monitor specific areas of the passenger cabin, developing information about contacts between passengers as they moved around.
Among next steps, the researchers would like to study the microbiome of airport areas, especially the departure lounges where passengers congregate before boarding. They would also like to study long-haul international flights in which passengers spend more time together – and are more likely to move about the cabin.
In addition to those already mentioned, the paper’s authors include Josh L. Espinoza and Karen Nelson of the J. Craig Venter Institute, Shawn Levy of the HudsonAlpha Institute for Biotechnology, and Sharon Norris of The Boeing Company.
This work was supported by contract 2001-041-1 between the Georgia Institute of Technology and The Boeing Company.
CITATION: Howard Weiss, et al., “The Airplane Cabin Microbiome,” (Microbial Ecology, 2018). https://link.springer.com/article/10.1007/s00248-018-1191-3
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]]>Among the differences are increased expression of genes responsible for antibiotic resistance, the bane of drugs currently used to treat a wide range of infections. The new research could help scientists understand how to draw more accurate conclusions from their laboratory work – and provide doctors with better information on treating bacterial infections.
“Bacteria in human infections are often tolerant of antibiotics, but when we culture them outside the human they are highly susceptible,” said Marvin Whiteley, a professor in the School of Biological Sciences at the Georgia Institute of Technology and co-director of the Emory-Children’s Cystic Fibrosis Center. “In this paper, we show that several genes important for antibiotic tolerance are highly induced in humans compared to our laboratory and mouse modeling systems. There appears to be something unique in the human that is promoting resistance.”
What might be causing that difference remains a mystery, though bacteria are known to be affected by their environment. Understanding how bacterial genes and their expression levels differ in humans could allow researchers to search for laboratory conditions that better mimic the human conditions – and provide better guidance for the use of antibiotics.
“Understanding which antibiotic resistance genes are highly expressed in humans may inform our therapeutic decisions on antibiotic usage,” said Whiteley, who holds the Bennie H. & Nelson D. Abell Chair in Molecular and Cellular Biology at Georgia Tech and is a Georgia Research Alliance Eminent Scholar. “For instance, one might predict antibiotic resistance of an infecting community from gene expression data without the need for culturing microbes in the clinical lab.”
The study was supported by the National Institutes of Health, the Cystic Fibrosis Foundation, and the Lundbeck Foundation. In addition to the Georgia Tech researchers, the research team included scientists at the Texas Tech University Health Sciences Center, the University of Mississippi Medical Center, the University of California, and several clinical and research organizations in Denmark.
Pseudomonas aeruginosa is an important pathogen that threatens immunocompromised people, including those with cystic fibrosis, diabetes and obesity. It is a major hospital-acquired infection, and the Centers for Disease Control and Prevention characterizes multi-drug resistant strains of the bacteria as a serious threat.
In their research, the scientists analyzed RNA sequencing data from both human clinical infections and laboratory experiments. The human samples were obtained from collaborating clinicians, who took the samples directly from patients and put them into a chemical that preserved their RNA for later processing. The laboratory experiments studied different strains of the bacterium under a variety of growth conditions, from antibiotic treatment to competition with other bacteria.
The researchers also included previously published in vitro and mouse experiment data from the Whiteley laboratory and other research teams. Data analysis techniques included a machine learning approach known as Support Vector Machines, which was used to distinguish between gene expression profiles of samples taken from human and in vitro sources.
“We saw high expression in several genes notorious for antibiotic resistance, including genes that encode efflux pumps that extrude antibiotics from the cell as well as an enzyme that degrades certain antibiotics, such as ampicillin,” said Daniel Cornforth, a research scientist in Whiteley’s laboratory and the paper’s first author. “There were also less studied antibiotic resistance genes, including three related to zinc transport that our previous work has identified as critical antibiotic resistance determinants that were also highly expressed in the human patients.”
Though the research focused only on a single troublesome pathogen, Whiteley believes the results could have broader implications. “We actually know very little about bacteria behaviors during human infection and most model systems cannot replicate most aspects of human infection. I expect that this work would be generalizable to other bacteria.”
By identifying how bacteria behave differently in humans compared to standard laboratory settings, the work could provide a foundation for additional study with more samples and different types of infection.
“The key takeaway from this work is that now microbiologists can perform transcriptomics on bacterial populations in a range of human infections, so we can better understand what bacteria are actually doing in these clinical infections,” said Cornforth. “We can also determine where our laboratory models succeed and where they fail in mimicking these infection environments.”
This study was funded by National Institutes of Health Grant R01GM116547-01A1, a Human Frontiers Science grant, Cystic Fibrosis Foundation Grant WHITEL16G0, Lundbeck Foundation Grant R204-2015-4205 and Lundbeck Foundation Grant R105-A9791, and by Cystic Fibrosis postdoctoral Fellowships CORNFO15F0 and IBBERS16F0.
CITATION: Daniel Cornforth, et al., “Pseudomonas aeruginosa transcriptome during human infection,” (Proceedings of the National Academy of Sciences, 2018). https://doi.org/10.1073/pnas.1717525115
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]]>For centuries, together mathematics and physics have shifted paradigms in science and rattled human perception by predicting planetary orbits, theorizing relativity or explaining how one particle can be in two places at the same time. Can theoretical math and biosystems team up to similarly shake the foundations of knowledge?
“We certainly think it’s possible,” said Christine Heitsch, a professor in Georgia Tech’s School of Mathematics who leads the new regional center. “But our immediate goals are more realistic,” she said. “Our first step is getting more mathematicians and bioscience researchers working together in research collaborations."
Bio-math synergy
On an everyday basis, that means the Southeast Center for Mathematics and Biology (SCMB) headquartered at Georgia Tech will tackle open questions in biology using novel math.
“Math can potentially change the way we do our experiments,” said Hang Lu, a professor in Georgia Tech’s School of Chemical and Biomolecular Engineering who co-leads of the center. “If you model your data with topology (a field of mathematics) you see that your data can have a shape,” Lu said. “And that can make you go look for different kinds of data.”
“It will be a two-way street,” Heitsch said. “Math always benefits when it’s challenged by reality.”
Over time, the math-bio spiral could lead to eureka moments.
“Biological systems can look overwhelmingly complex, and that just means we haven’t found the right way of looking at them yet,” Heitsch said.
NSF vision
The SCMB is one of three NSF-Simons Research Centers for Mathematics of Complex Biological Systems. The other two are based at Harvard University and at the University of California, Irvine. Together, they will not only advance the math-biosciences synergy but also spread their knowledge to hundreds of undergraduate and K-12 students throughout the region through educational outreaches.
The SCMB comprises 14 researchers, including collaborators throughout the Southeastern United States. Tulane University, the University of Florida, the University of South Florida, Clemson University, and the Oak Ridge National Laboratory are each contributing a mathematician, and one bioscientist is based at Duke University.
“This project has visionary potential to shake up the way we view biological systems, and also expand mathematics,” said Julia Kubanek, Associate Dean of Research in Georgia Tech’s College of Sciences. “The National Science Foundation and the Simons Foundation have shown tremendous foresight in creating these three centers, and I think headquartering one at Georgia Tech is a great fit because cross-connecting research disciplines is already one of our core missions.”
Biosciences enigmas
To understand the particular value of combining math with biosciences, it’s important to not conflate the latter with physics.
A graphic depiction of canalization. The path of the ball represents the development toward a phenotype, which may start with varying genetic foundations but roll out to secure phenotypical outcomes. But canalization can also lead to more than one possible phenotypical outcome from one set of genes.
For example, in relativity, near-light speeds change an object’s mass, its length, and its passage through time. Those warped phenomena and their equations aren’t so applicable in the world of experimental biosciences, which live in a more Newtonian reality, but one with intricate enigmas for math to demystify.
Take the phenomenon called canalization, which saves living things from the little genetic snafus inside of us all by making sure that proper physical traits usually get produced in spite of mutations.
Clone contradictions
Canalization shatters a stubborn popular notion that genes determine how an organism is built.
“Genes are not deterministic,” said Lu, who is Love Family Professor. She studies the intricate pathways that lead from genetic foundations to measurable physical or behavioral traits, or phenotypes, in C. elegans roundworms. “You often have two individuals with identical genotypes (specific sets of genes) that have different sets of phenotypes.”
That means that canalization may not offer just one but two options -- or more -- to form a trait based on a single set of genes. “What fascinates me is that you can have (C. elegans) clones that are genetically identical but exhibit different behavior,” Heitsch said.
Canalization is not new; it dates to 1942. But its labyrinthine mechanisms and how they “chose” one phenotypical pathway over the other still contain many mysteries. “Maybe math can help us find answers,” Lu said.
Labyrinthine intricacies
Algebra has already taken up canalization but at the SCMB, more maths will join in. Topology, computation, stochastics (principles of randomness), and geometry may enlighten canalization’s myriad interworkings of DNA, RNA, enzymes, protein folding, and just plain randomness.
Other questions SCMB bioscientists and mathematicians are pursuing:
How do stem cells know whether to become a neuron or a skin cell?
How does one cell transport molecules to others?
What exactly does RNA do to help repair DNA damage?
Heitsch, for example, specializes in a field of mathematics called combinatorics, and she applies it to the way molecules of RNA fold.
Historical divergence
Biology is no stranger to stochastics or computation in the analysis of its data, but it has been much less connected than other sciences to the aerial acrobatics of theoretical mathematics.
“There is enormous unrealized potential in applying more theoretical areas of math like algebra, topology, and geometry,” Heitsch said. “That’s new territory, which also means new risks. But we’ve hedged our bets with mathematics already more used in biology to get guaranteed returns.”
Biology and theoretical math have not interfaced much in the past for a couple of reasons.
The endless intricacies of biology, from hundreds of thousands of species to countless biomolecular structures, has made it a gathering and cataloging science for centuries with data that is tough to unify. Also, much data has had to wait for technology to be invented to collect it.
“Biology hasn’t had the measurement tools until just recently, like mass spectrometry and high-end microscopy, to get the hard data needed for math to work with,” Lu said. “Now is a great time for biology and math to come together,” she said.
Cultural exchange
Also, history has separated the disciplines. For centuries, physicists were also mathematicians and vice versa. “And they were engineers,” Lu said. But biologists?
“Darwin was assuredly not a mathematician,” Heitsch said. “He said he didn’t understand as much math as he would have liked to.”
Not many mathematicians have been biologists either.
The NSF-Simons Foundation centers are building the bridge to join them, and the SCMB at Georgia Tech makes for a good pillar. Most of its bioscience researchers already know engineering or physics math, and its mathematicians are already delving into life sciences.
Editor's Note: This article is a slightly modified clone of the feature story by Ben Brumfield published on May 24, 2018 in Research Horizons online.
This article was corrected on May 30, 2018, to reflect corrections in the original story about the number of centers (four), total funding ($40 M), and the Georgia Tech's share (one-fourth).
]]>When he was eight he heard a rumor that pinching the skin around the area where a mosquito was biting would make the mosquito explode. So, he tested his hypothesis. After enduring several hundred bites (without taking malaria prophylaxis), he concluded the rumor was false. He couldn’t make a single mosquito blow up.
Overholt had always been curious about the natural world. Growing up in Kenya allowed him to go on countless safaris and spend many nights camping in the wild, immersed in nature. At age five, he voraciously memorized field guide books to identify the birds of Kenya.
This curiosity drew Overholt to Florida State University, where he graduated with a B.S. in Biology; to Malawi, where he taught mathematics and science as a member of the Peace Corps; and then to Georgia Tech, where he is graduating with a Ph.D. in Bioinformatics.
He chose Tech for two reasons. First, he had realized that to specialize in microbial ecology he would have to learn bioinformatics, a field upon which microbial ecology increasingly relied. Second, he had started working in the lab of Joel Kostka at Florida State on manipulating bacteria to assist in uranium containment at a nuclear waste site in Oak Ridge, Tennessee.
“I was hooked,” Overholt says, “During my last two years as an undergraduate, I spent much of my free time in the lab.”
When Kostka transferred to Tech in 2012, Overholt followed. That was two years after the Deepwater Horizon oil spill in the Gulf of Mexico. Overholt was drawn to a project to investigate the ecological consequences and fate of the oil discharged in the Gulf.
As Overholt heads to Germany to continue studying nature, memories from teaching in Malawi – far from running water and electricity – stay vivid. He remembers staying up late one night, struggling under weak candle light to finish grading exams. It had been a trying day, and he felt he was failing in his goal to teach students to apply knowledge to solve a problem.
As he prepared for bed, he heard a knock on his door. It was a student, excitedly waving a piece of paper covered with scribbles. The student had continued working on the problem through the night, finally solved it, and couldn’t wait to tell the teacher.
“I was as exuberant as he was,” Overholt says. “In that moment I felt the reward of teaching, the joy of seeing the spark of understanding shining in another’s eye.”
What is the most important thing you learned at Georgia Tech?
I gained a better understanding of the scientific process, which has encouraged me to continue working in science.
Georgia Tech has exceeded my expectations, from state-of-the-art courses to the excellent guidance and support from my thesis adviser, committee members, faculty, postdocs, and fellow students. It has been wonderful to be a part of this supportive and collegial community. Everyone has gone out of their way to help when I have encountered problems in my classes and my research.
“Georgia Tech has exceeded my expectations, from state-of-the-art courses to the excellent guidance and support from my thesis adviser, committee members, faculty, postdocs, and fellow students.”
What are your proudest achievements at Georgia Tech?
My proudest moment was right after I defended my dissertation. The outpouring of congratulations and support from friends and colleagues was humbling.
A very close second was when I heard back from a journal that my first first-author publication was accepted!
Which professors or classes made a big impact on you?
Joel Kostka, my advisor, has been an incredible mentor. His guidance, advice, and help on my research were boundless. His background and experience in biogeochemistry and microbiology provided the foundation for my work.
It hasn’t just been professional though. His guidance on health, happiness, fulfillment, and handling stress has been invaluable. He has encouraged, supported, and challenged me at every step. I am fortunate to have worked so closely with him all these years.
In my first year, I took two bioinformatics courses with King Jordan. I’ve never learned so much in such a short time. Jordan and his students always helped me when I was stuck. Jordan went above and beyond his professional duties to support me through unexpected challenges, for which I am extremely grateful.
What is your most vivid memory of Georgia Tech?
The times I spent at my desk talking with my lab mates and advisor about various topics – cultural differences, politics, newest scientific findings, successes, failures, etc.
I also have fond memories of spending time with other students at biology social hours and the Cherry Emerson coffee hour.
How did Georgia Tech transform your life?
Georgia Tech has shaped me personally and professionally. I’ve learned to keep working when nothing seems to be working. I’ve made connections with colleagues and friends that will last for life. I’ve been inspired by science and comforted by the knowledge that the skills I’ve learned will help make the world a better and more understandable place.
What unique learning activities did you undertake?
I participated on four oceanic expeditions in the Gulf of Mexico, collecting samples of seafloor sediments. These trips were exhausting as we tried to collect as many samples and conduct as many experiments as possible. I regularly pulled 36-hour shifts and took only catnaps between multicore deployments, sleeping only while we motored from one location to the next. What was great about these trips was the close contacts with others and how we pulled together during stressful times.
What advice would you give to incoming graduate students at Georgia Tech?
Take time for yourself outside of Georgia Tech. It is easy to be overwhelmed while trying to balance classes, research, and teaching. Having a hobby and making free time for myself was critical to my mental health.
Many resources are available to students – intermural sports, clubs and student-run organizations, amazing health care at Stamps Health Services, and mental health resources. Reach out to faculty or other students for guidance or help.
Do not lose sight of the big picture. It is easy to get bogged down on small details. Spend a few hours a week to put efforts into perspective. Focus your time on high-priority projects.
Recognize that graduate school is a long process. It’s okay to feel as if nothing is working. I’ve learned as much from failed experiments as from those that succeeded.
Where are you headed after graduation?
I’m starting a postdoctoral research position at Friedrich Schiller University in Jena, Germany. I’ll be part of the AquaDiva collaborative research center under Kirsten Küsel, studying microorganisms in the terrestrial subsurface and their roles in governing carbon transformations and flow within aquifers.
Georgia Tech provided the qualifications I needed to be a strong candidate for this position. I’m so excited to move overseas to experience a new scientific culture and to transition to new research questions.
]]>CZI announced today new funding for 85 projects (from an advised fund of the Silicon Valley Community Foundation), including Qiu’s, to support the Human Cell Atlas, a global effort to map every type of cell in the healthy human body as a resource for studies of health and disease. The grants total $15 million over one year.
Projects are focused on developing open computational tools, algorithms, visualizations, and benchmark datasets to enable researchers around the globe to work with the large variety of molecular and imaging data being generated by scientists working on the Human Cell Atlas. The grantees will also collaborate with each other, and with CZI’s scientists and software engineers, to maximize the impact of the new tools and technologies.
Qiu’s main research interests are in bioinformatics and computational biology, focusing on machine learning big data, genomics, and single-cell analytics.
“I am thrilled to welcome this distinguished group of grantees to the CZI family, and I am excited about how they will support the ambitious Human Cell Atlas effort,” said Priscilla Chan MD, co-founder of the Chan Zuckerberg Initiative. “Working together and with our team of scientists and engineers, these partners will create new ways for scientists to use information about healthy and diseased cells. Their efforts will help to accelerate progress toward our goal of curing, preventing, or managing all diseases by the end of the century.”
There are 85 collaborative projects being recommended for funding in response to an open Request for Applications issued by CZI in July 2017. Funding is being awarded to 83 principal investigators at 53 institutions, and in nine countries spanning four continents. Detailed information on each project is available at this link: https://www.chanzuckerberg.com/human-cell-atlas/comp-tools
“We are excited to begin working on these promising projects with new partners from across the globe,” said Cori Bargmann, Head of Science for the Chan Zuckerberg Initiative. “These grantees include experts in experimental biology, engineering, and computational biology. Enabling them to collaborate and bring their diverse perspectives to the work is the core of our approach to advancing biomedical science.”
Over the course of the next year, the grantees will work together and share progress to coordinate efforts and maximize the usability of these tools. Working with CZI’s science and software engineering teams, they will work to bring these tools to the broader scientific community and where appropriate, link them to the Human Cell Atlas Data Coordination Platform.
This new funding round marks the third set of projects CZI is funding in support of the Human Cell Atlas. Last year, CZI announced funding and engineering support to build a Data Coordination Platform, and funding for 38 pilot projects to help new technologies, best practices, and data analysis techniques.
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About the Chan Zuckerberg Initiative
The Chan Zuckerberg Initiative was launched in December 2015 by Mark Zuckerberg, founder and CEO of Facebook, and Priscilla Chan, a pediatrician and founder and CEO of The Primary School in East Palo Alto. The Chan Zuckerberg Initiative is a new kind of philanthropy that seeks to engineer change at scale. By pairing world-class engineering with grant-making, impact investing, policy, and advocacy work, CZI hopes to build a future for everyone. Initial areas of focus include supporting science through basic biomedical research and education through personalized learning. CZI is also exploring ways to address barriers to justice and opportunity - from criminal justice reform, to expanded access, to economic opportunity and affordable housing.
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The awards are distinctive because they come from the students themselves. Every year, female undergraduate engineering students are invited to nominate a faculty member who has had a positive impact on their lives.
The 2018 Faculty Award Winners are James Dahlman, Ph.D., from the Wallace H. Coulter Department of Engineering and Linda Wills, Ph.D., from the School of Electrical and Computer Engineering.
]]>Stewart is an associate professor in the School of Biological Sciences and the advisor of Parris, a fifth-year Ph.D. student.
“I am honored and humbled to have the SWiMS partnership recognized by this award,” Stewart says. “SWiMS has been one of the most rewarding experiences of my career, largely because it fosters connections to people like Jennifer and Josh. These are the connections that are honored here and that are so critical for advancing science literacy in our schools and elsewhere.”
Stewart conceived SWiMS in 2012 as a way to promote understanding of ocean science and microbiology. With oil spills, coral reef collapse, sea level rise, and ocean acidification often being front-page news, he believes the general public should have a basic understanding of these phenomena. For Stewart, these issues are just as important to policymakers and the general public as they are to researchers.
SWiMS is a five-day workshop to help middle and high school teachers develop curricula and project-learning exercises to teach marine science in the context of global change. “My overarching goal was to use marine science to enhance earth and life science education in middle and high schools, specifically targeting those in academically underperforming districts in Fulton County,” Stewart says. SWiMS draws on the expertise of marine scientists at Georgia Tech and education experts at Georgia Tech’s Center for Education Integrating Science, Mathematics, and Computing (CEISMC).
Parris joined the program in summer 2015. “To put it bluntly, this program would likely not have been possible without Josh,” Stewart says.
Parris has roles throughout all stages of the program. He wrote, edited, and tested several of the education modules used in SWiMS. During workshops, he serves as instructor, preparing rigorously to guide the workshop participants.
SWiMS includes a two-day trip to Sapelo Island, a barrier island located in McIntosh County, Georgia. The trip provides participants firsthand experience and an opportunity to collect samples to take back to their classrooms. For this trip, Parris has served as primary field team leader, planning the logistics as well as conducting activities.
Most impressively, Stewart says, Parris continues to engage with teachers after the workshop. He helps teachers with curriculum-related problems arising during the school year and continues to prepare modules for teachers upon request. He recently visited Central Gwinnet High School to lecture about marine pollution.
“I am very grateful to have been a part of the SWiMS program,” Parris says. “I have been able to see firsthand the positive impact scientists can have outside of research. SWiMS is an awesome example of using partnerships between scientists and educators to advance science education in schools.”
Jones began as a participant in the workshop in 2015, returned as a mentor in 2016, and joined again in 2017 as an education consultant. A veteran teacher of 16 years, Jones had a keen sense of which concepts would translate into the classroom and which wouldn’t. Her unique insight was vital to identifying and troubleshooting obstacles and translating the curricula into targeted lesson plans. She also helped other teachers develop classroom-specific plans.
The collaboration of a scientist, a Ph.D. student, and a high school teacher has yielded remarkable outcomes. “The SWiMS program has enhanced my instruction in the classroom,” Jones says. “My students were able to understand that topics in science overlap: marine science touched Earth science, which touched environmental science, which touched chemistry. I am grateful to all the participants; they have inspired me to explore and expand my teaching so that students may experience science in a memorable way.”
]]>Skolnick is the Mary and Maisie Gibson Chair, the Georgia Tech Alliance Eminent Scholar in Computational Systems Biology, and a professor in the School of Biological Sciences. He is also the director of the Center for the Study of Systems Biology.
In his research, Skolnick has developed algorithms to predict protein structure and function and ligand-protein interactions. Applications include drug discovery and prediction of off-target uses of already approved drugs.
Skolnick pioneered the field of ligand homology modeling, using the modeling algorithm FINDSITEcomb to infer protein function, predict a protein’s binding site, and screen virtual ligands. The insights from this work has enabled use of even low-resolution protein structures in virtual ligand screening. Skolnick is applying this knowledge to find other diseases that approved drugs could treat.
Drugs of interest include granisetron (Kytril), an antinausea and antiemetic agent; progesterone, a female hormone; acetaminophen, a pain reliever; and naproxen an anti-inflammatory and analgesic agent. Among diseases that existing drugs might help treat are cancer, pain, cardiovascular diseases, neurological diseases, cystic fibrosis, and diseases caused by genetic variations.
“The biochemical seeds of life could be prevalent.”
Using another algorithm, Skolnick has found a way to boost the odds that disease organisms will not quickly develop resistance to an antibiotic. The algorithm identifies compounds that target two or more receptor sites on proteins that inhibit a key cellular function. To develop resistance to such drugs, microbes would have to simultaneously develop mutations in all the target receptor pockets. Simultaneous mutations would be more challenging to the bugs than developing resistance in only one receptor site. The technique has been validated for a drug-resistant Escherichia coli.
Skolnick’s adventures with protein structures and functions have profound implications for the origins of life. For example, Skolnick and coworkers have shown that the ability to catalyze biochemical reactions is an intrinsic property of protein molecules, defined only by their structure and the principles of chemistry and physics. Accordingly, evolution is not necessary for the existence of proteins’ biochemical functions, although evolutionary selection may have optimized proteins for specific roles.
“The biochemical seeds of life could be prevalent,” Skolnick said about the work in 2016. “If you rain meteorites containing amino acids and somehow these polymerize to form small proteins, then a subset of these would fold to stable structure and a small subset of these could engage in rudimentary metabolism, all without any selection for biochemical function. Thus, the background probability for function is much larger than had been previously appreciated.”
By extension, extraterrestrial life could be ubiquitous.
The ability to do out-of-the-box research has been a hallmark of Skolnick’s career. “I am most grateful,” Skolnick says, “to the environment provided by Georgia Tech and to my collaborators who have enabled these ideas to come to fruition.”
]]>JOSEPH RABINOFF: Helping both students and faculty
Joseph Rabinoff was recently promoted to associate professor in the School of Mathematics. Because many undergraduates take the fundamental mathematics courses he teaches, Rabinoff has had a broad impact on Georgia Tech undergraduates.
Students say Rabinoff makes mathematics relevant and engaging, especially the introductory classes he teaches. For his part, Rabinoff seeks to ensure that all students, whatever their majors, understand and even appreciate the material.
Rabinoff was heavily involved in developing the curriculum and course materials for Math 1553, Introduction to Linear Algebra. This is an engineering core course that is taken by thousands of Georgia Tech students every year. He created lecture slides, interactive demonstrations, and online homework problems. With colleague Dan Margalit, Rabinoff wrote a free online textbook for the course, “Interactive Linear Algebra.”
Beyond the classroom, Rabinoff spearheaded the creation of the School of Mathematics’ course repository and has been the main contributor to its infrastructure and content. The repository contains up-to-date curated materials that a new teacher can just pick up and use.
The students are the most exciting part about being at Georgia Tech, Rabinoff said in a 2016 Q&A. “Some students are extremely hard-working and talented. I derive a lot of pleasure from interactions in class and office hours,” he said.
In turn, students praise Rabinoff for his enthusiasm, engaging lectures, friendliness, accessibility, and, yes, his “super” “Rabinoffice” hours, which one students says “are fantastic during exam weeks.”
“It is an honor to be recognized with this award,” Rabinoff says. “The students I see every week in class and in office hours are great kids, and all of the effort is for them. Pedagogy is special in this way: The reward is not abstract; it is visible every time I see in a student's face that a light went on in their head. I’m very fortunate to have the opportunity to teach in a place like Georgia Tech.”
MATTHEW TORRES: Teaching life skills
Matthew Torres also was recently promoted to associate professor, in the School of Biological Sciences. Although he always knew he would be a scientists, he never thought about being a teacher. At Georgia Tech he has recognized that, “first and foremost,” he is a teacher.
Having embraced the role of an educator, his dedication is obvious to students and colleagues. Students regard him not only as an excellent teacher, but also as someone who believes in them and sees their potential. Students say Torres’s mentorship goes beyond biology: Torres helps them develop critical skills that will serve them throughout their lives – such as written and spoken scientific communication, self-reflection, and how to confront failure productively.
Colleagues say Torres is a natural teacher, taking every opportunity to teach and mentor students in Georgia Tech and beyond. He gives students personal attention and invests time and resources to ensure student learning. A colleague describes Torres as “dedicated, caring, thoughtful, and highly successful in both teaching and research.”
Torres regularly invites undergraduates to do research in his lab, participating in work to address chemical biology questions that Torres’s research seeks to answer. These undergraduates are listed as coauthors on publications. In running his lab and in his teaching, Torres instills open communications and mutual respect as values that advance everyone’s progress.
Community engagement is important to Torres. He has volunteered to mentor high school students from the Gwinnett School of Mathematics, Science, and Technology. He routinely gives laboratory tours to local high schools focusing on science, technology, engineering, and mathematics (STEM).
“Winning this award is fantastic, but I’m also very lucky,” Torres says. “Lucky enough to have had wonderful students – undergraduate, graduate, and beyond – willing to join me on a journey in pursuit of greater understanding and scientific progress. Such a journey can’t happen because of a teacher alone – it takes bright, receptive, and brave students to help guide the way.”
]]>An evolutionary biologist, Ratcliff studies how organisms change over time. In particular, he wants to understand how multicellular organisms can evolve from single cells. This question remains one of the fundamental problems in biology.
His approach is “extremely creative,” a colleague says. “Rather than trying to infer what happened hundreds of millions of years ago, William cut the Gordian knot by evolving novel multicellularity in the laboratory....Few scientists would attempt such an ambitious experiment.”
In a 2016 interview, Ratcliff explained his approach.
“In our lab, we do evolutionary time travel in a test tube, by creating new multicellular organisms, using yeast and algae, in a way that’s simple but which we can examine with huge precision, using all the tools of biology, mathematics, and physics. We’re not trying to explain what happened historically. Rather, we’re trying to show how it can happen in principle.
“We’re interested in how the geometry of cellular clusters influences the outcome of evolution, tipping the balance between cellular cooperation and conflict, and how cells lose their Darwinian autonomy, evolving from individual organisms into parts of a new organism. These are fundamental principles that should be broadly applicable.”
Ratcliff has shown that multicellularity can evolve quickly. The simple multicellular “snowflake” yeasts he has evolved in the lab – by selection for rapid settling through liquid media– possess a multicellular life cycle, reproducing through small propagules, like stem cuttings. Over 1,500 generations, they adapted to the selection pressure by growing faster and evolving a more hydrodynamic shape. They also evolved a simple division of labor, using programmed cell death to sever links between cells and produce more propagules. Experiments with a unicellular algae have yielded broadly similar results.
“[T]his award really reflects the strength of our research community and the benefits of working in an environment so conducive to collaboration.”
From these observations, fundamental insights have emerged about the evolution of multicellular complexity. For example, mutations that are beneficial to the multicellular aggregate but costly to the single cell can accelerate evolution of increased multicellular complexity. In addition, his work has shown how the 3D geometry of yeast clusters allows a rudimentary form of development to arise, guiding the emergence of new multicellular traits from mutations that only directly affect the properties of single cells. Taken together, Ratcliff’s research upends conventional wisdom that the transition to multicellularity must have been slow and difficult and must have required extraordinary conditions.
Ratcliff’s scientific creativity is recognized by generous external support for his research, including the prestigious Packard Fellowship. Even the popular press has noticed: Popular Science named Ratcliff one of the Brilliant 10 in 2016, the magazine’s way of “honoring the brightest young minds reshaping science, engineering, and the world.”
“William has helped define the field of modern multicellularity research,” the same colleague says, “and in so doing, has become one of its leaders.”
“I am of course deeply honored by this recognition” Ratcliff says. “But this award really reflects the strength of our research community and the benefits of working in an environment so conducive to collaboration. Since arriving at Tech in 2014, my research directions have evolved much like snowflake yeast have – in wonderful and unexpected ways. This has been the direct result of having such amazing students, collaborators and colleagues.”
]]>The discovery, detailed in the Proceedings of the National Academy of Sciences, “was remarkable and unexpected,” the authors write.
The researchers – from the University of Oregon, Georgia Institute of Technology, and Memorial-Sloan Kettering Cancer Center – used genetic manipulation and cutting-edge three-dimensional microscopy to monitor what happens when the disease-causing microbe is initially introduced into the larvae of zebrafish, an organism commonly studied as a model for understanding health and disease in vertebrates, including humans.
The multidisciplinary team of physicists, molecular biologists, and microbiologists focused on the harpoon-like injection capabilities of the type VI secretion system. This appendage, found in many bacteria including Vibrio cholerae, transfers toxic proteins into competing healthy cells.
The scientists engineered Vibrio cholerae mutants with variations in that secretion system and then observed the behavior of the microbes as they invaded zebrafish colonized with Aeromonas veronii, a native species in that animal’s gut.
SWIFT ACTION
Instead of simply killing native Aeromonas gut bacteria upon contact, as expected, when Vibrio cholerae entered the gut the native bacteria were swiftly flushed out.
“The secretion system induced dramatic increases in the strength of the peristalsis process, the contractions that move gut contents down the gastrointestinal tract much like squeezing a tube of toothpaste from the end to the top,” says coauthor Brian K. Hammer, a microbiologist and associate professor in the School of Biological Sciences at Georgia Tech.
The researchers hypothesized that the unexpected bacterial manipulation in the digestive system might be driven by a particular piece of the type VI machinery known to bind to actin, a cellular scaffolding protein. When the scientists deleted the actin-binding domain from the bacterial gene, they saw that Vibrio cholerae lost its ability to enhance peristalsis and its ability to expel native Aeromonas.
The findings shed new light on how the waterborne Vibrio cholerae functions. According to the Centers for Disease Control and Prevention, Vibrio cholerae triggers more than 3 million cases of acute diarrheal illness and 100,000 deaths in people worldwide each year.
“Knowing the strategies by which the bacterium is able to invade the intestine can open doors to therapies that might disrupt these paths,” says corresponding author Raghuveer Parthasarathy, a professor of physics at the University of Oregon, whose imaging and analysis techniques were used in the study.
Because the type VI secretion system is also found in native gut bacteria, including those in the human gut microbiome, it could be harnessed for therapies, including specially designed probiotics, to promote beneficial species or to defend against disease invasion, Hammer says.
“We suspect that other gut microbes, both pathogenic and beneficial, might similarly make use of this secretion system to reshape their environment,” Parthasarathy says.
Most previous research on this secretion system has relied on studying bacteria outside of animals – on a Petri dish for example, or by examining fecal samples – to infer what is happening in the gut during infection.
While the research team captured the impact of invasion by Vibrio cholerae, understanding just how it takes root in the host, such as what specific cells in the animal are targeted, is an open question, Parthasarathy says.
“We still have no idea how the action of his secretion system’s harpoon is causing the changes in the muscle contractions,” Hammer says. “We suspect that what we are observing may be an immune response to irritation in the gut lining. But what cells in the gut are being poked?”
How the findings may reflect the colonization of Vibrio cholerae in humans is not known, but the role of the secretion system makes a similar result plausible, the researchers wrote in their conclusion.
BIRTH OF COLLABORATION
The findings emerged from a collaboration born in 2015 when Hammer, Parthasarathy, and coauthor Joao Xavier, a researcher at the Memorial Sloan-Kettering Cancer Center, discussed joint research possibilities during a conference, Scialog: Molecules Come to Life, in Tucson, Arizona.
The Scialog (Science and Dialog) was organized by the Research Corporation for Science Advancement and sponsored jointly with the Gordon and Betty Moore Foundation, with additional support from the Simons Foundation. The goal of Scialog is to rapidly catalyze new interdisciplinary collaborative teams, such as the one formed by Hammer, Parthasarathy, and Xavier, to work on high-risk, high-reward projects.
As a result, their three labs received an award from the Gordon and Betty Moore Foundation and the Simons Foundation to pursue their Scialog idea. The National Science Foundation, National Institutes of Health, M.J. Murdock Charitable Trust, and Kavli Microbiome Ideas Challenge also supported the research.
PHOTO CAPTION
Trajectories of Vibrio cholerae bacteria (blue) swimming inside the gut of a larval zebrafish. The gut is visible as a gray background. The total duration of the movie that was “squashed” into this image is 3.5 seconds, and the total image width is about 0.3 mm. (Courtesy of Raghuveer Parthasarathy)
The new study demonstrated the advantages of an in vivo DNA barcoding technique, which attaches small snippets of DNA to different lipid-based nanoparticles that are then injected into living animals; more than a hundred nanoparticles can be tested in a single animal. DNA sequencing techniques are then used to identify which nanoparticles enter the cells of specific organs, making the particles candidates for transporting gene therapies to treat such killers as heart disease, cancer and Parkinson’s disease.
The traditional technique for identifying promising nanoparticles examines how the particles enter living cells kept in lab dishes. To compare the new and old screening techniques, the researchers added barcoded nanoparticles to living cells in lab dishes, and injected identical barcoded nanoparticles into living animal models. They found almost no correlation between the nanoparticles identified as promising in the lab dish tests and those that actually performed well in the mice.
“DNA barcoding has the potential to advance the science of selecting nanoparticles for delivering gene therapies,” said James Dahlman, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University and the study’s principal investigator. “Using this technique, companies and academic labs could pick out promising nanoparticles much more efficiently. That could accelerate the rate at which nanoparticle-based therapies move into the clinic, while reducing the amount of animal testing required.”
The research, which is supported by the National Institutes of Health, the Cancer Research Institute, Cystic Fibrosis Foundation and Parkinson’s Disease Foundation, was reported February 28 in the journal ACS Nano Letters. The research was conducted by scientists from the Georgia Institute of Technology and Emory University.
Genetic therapies, such as those made from DNA or RNA, face challenges because of the difficulty in delivering the nucleic acid to the right cells. For the past two decades, scientists have been developing nanoparticles made from a broad range of materials and adding compounds such as cholesterol to help carry these therapeutic agents into cells. But the development of nanoparticle carriers has been slowed by the challenges of testing them, first in cell culture to identify promising nanoparticles, and later in animals. With millions of possible combinations, identifying the optimal nanoparticles to target each organ has been overwhelming.
Using DNA strands just 58 nucleotides long to uniquely identify each particle allows researchers to skip the cell culture screening altogether – and test a hundred or more different types of nanoparticles simultaneously in just a handful of animals.
“If you wanted to test 200 nanoparticles in the traditional way, you would need 600 mice – three for each type of nanoparticle,” said Dahlman. “Using the DNA barcoding technique, which we call Joint Rapid DNA Analysis of Nanoparticles (JORDAN), we are able to do the testing in just three animals.”
The study examined nanoparticle entry into endothelial cells and macrophages for the in vitro study, and the same type of cells from the lung, heart and bone marrow for the in vivo component. The two cell types are important to a broad range of organ systems in the body and play active roles in diseases that could be targets for nucleic acid therapies. The study compared how the same 281 lipid nanoparticles delivered the barcodes in lab dishes and living animals.
“There was no predictive capability between the lab dish tests and the animal tests,” Dahlman said. “If the in vitro tests had been good predictors, then particles that did well in the dish would also have done well in the animals, and particles that did poorly in the dish would also have done poorly in the animals. We did not see that at all.”
The research team, led by co-first authors Kalina Paunovska and Cory D. Sago, also studied how nanoparticle delivery changes with the microenvironment of specific tissue types. For that, they quantified how 85 nanoparticles delivered DNA barcodes to eight cell populations in the spleen, and found that cell types derived from myeloid progenitors tended to be targeted by similar nanoparticles.
Researchers are interested not only in which nanoparticles deliver the therapeutics most effectively, but also which can deliver them selectively to specific organs. Therapeutics targeted to tumors, for example, should be delivered only to the tumor and not to surrounding tissues. Therapeutics for heart disease likewise should selectively accumulate in the heart.
The single-strand DNA barcode sequences use in the technique are about the same size as antisense oligonucleotides, microRNA and siRNA being developed for possible therapeutic uses. Other gene-based therapeutics are larger, and additional research would be needed to determine if the technique could be used with them.
Once the promising nanoparticles are identified with the screening, they would be subjected to additional testing to verify their ability to deliver therapeutics. To avoid the possibility of nanoparticles merging, only structures that are stable in aqueous environments can be tested with this technique. Only nontoxic nanoparticles can be screened, and researchers must control for potential inflammation generated by the inserted DNA.
“Nucleic acid therapies hold considerable promise for treating a range of serious diseases,” said Dahlman. “We hope this technique will be used widely in the field, and that it will ultimately bring more clarity to how these drugs affect cells – and how we can get them to the right locations in the body.”
In addition to those already mentioned, the research team included Christopher M. Monaco, Marielena Gamboa Castro, Tobi G. Rudoltz, Sujay Kalathoor, Daryll A. Vanover and Professor Philip J. Santangelo of the Coulter Department; William H. Hudson and Rafi Ahmed of the Emory Vaccine Center and Department of Microbiology and Immunology at Emory University, and Anton V. Bryksin of the Parker H. Petit Institute for Bioengineering and Bioscience at Georgia Tech.
This research was supported the NIH/NIGMS-sponsored Cell and Tissue Engineering (CTEng) Biotechnology Training Program (T32GM08433), the NIH/NIGMS-sponsored Immunoengineering Training Program (T32EB021962), the Cancer Research Institute Irvington Fellow program supported by the Cancer Research Institute, the Cystic Fibrosis Research Foundation, the Parkinson’s Disease Foundation, and the Bayer Hemophilia Awards Program. This study was also supported with funding from the National Institutes of Health GT BioMAT Training Grant under Award Number (5T32EB006343). This work was performed in part at the Georgia Tech Institute for Electronics and Nanotechnology, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (Grant ECCS-1542174). The content of this news release is solely the responsibility of the authors and does not necessarily represent the official views of the sponsoring organizations.
CITATION: Kalina Paunovska and Cory D. Sago, et al., “A direct comparison of in vitro and in vivo nucleic acid delivery mediated by hundreds of nanoparticles reveals a weak correlation,” (Nano Letters 2018). https://pubs.acs.org/doi/10.1021/acs.nanolett.8b00432
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]]>It is show time for the Southeast’s talent in chemical biology – the interdisciplinary field that uses chemistry tools and methods to understand and manipulate biological systems.
“Atlanta institutions are becoming a hotbed for research in chemical biology and related fields,” says Matthew Torres, an associate professor in the Georgia Tech School of Biological Sciences. “Institutional commitments and federal funding in the past five years,” he says, “have enhanced infrastructure to support world-class chemical biology research programs,” not only at Georgia Tech, but also at the symposium’s other host institutions: Emory University, Georgia State University, and the University of Georgia.
Faculty hiring has expanded the breadth of chemical biology research in the host institutions. “New hires, myself included, have been attracted to the community that is developing here,” says William Wuest, who joined Emory University in 2017 and chairs the symposium’s organizing committee.
“A lot is going on,” says M.G. Finn, professor and chair of the School Chemistry and Biochemistry and a member of the symposium’s organizing committee. “Chemical biology underpins vast activity in Atlanta on immunology, drug development, diagnostics, and many other applications. The symposium’s host institutions boast an impressive number and quality of chemical biology investigators.”
“Atlanta institutions are becoming a hotbed for research in chemical biology and related fields.”
In Georgia Tech alone, Finn notes, chemical biology research spans at least seven schools in the Colleges of Sciences and Engineering: Biological Sciences, Biomedical Engineering, Chemical and Biomolecular Engineering, Chemistry and Biochemistry, Electrical and Computer Engineering, and Physics. Chemical biology is also one of the main research areas supported by the Parker H. Petit Institute of Bioengineering and Bioscience (IBB), where the labs and offices of many Georgia Tech faculty doing chemical biology research are located.
In planning the April 21 symposium, Wuest drew upon his experience at his previous institution. Temple University regularly participates in an annual symposium on the chemistry-biology interface that highlights local talent in the Mid-Atlantic region, focusing on early-career faculty and students and featuring some keynote speaker, Wuest says. “It was wildly successful. I believe the time is right to start one in Atlanta.”
“The idea,” Finn says, “is to give chemical biologists in Atlanta – including undergraduate and graduate students, postdoctoral researchers, and faculty scientists – a venue to exchange results and ideas.”
“Chemical biology underpins vast activity in Atlanta on immunology, drug development, diagnostics, and many other applications."
The organizers have invited a diverse and interdisciplinary slate of nine keynote speakers, five of whom are from outside Georgia. Among the speakers from host institutions is Torres, who is also a member of IBB.
“My lab’s mission,” Torres says, “is to understand how post-translational modifications regulate the signaling of G proteins.” G proteins comprise a family of proteins mediating the transmission of myriad signals from outside the cell into the cell interior. They are major targets in the search for drugs to treat a variety of diseases. At the symposium, Torres will describe his lab’s work on the use of machine learning and neural networks to identify protein modifications involved in pharmacology and disease.
The symposium offers a way to liberate “chemical biology perspectives that are often maintained in isolation and rarely cross institutional boundaries,” Torres says. “A great deal can be gained by breaking these boundaries to create a more fluid and open community that is bigger and better than any one lab or any one institution alone.”
The symposium is free to all attendees, thanks to the generosity of the host institutions, the Georgia Research Alliance, and five journals: Journal of Medicinal Chemistry, ChemBioChem, ACS Medicinal Chemistry Letters, ACS Infectious Diseases, and ACS Combinatorial Science, whose editor-in-chief is Finn.
Registration, abstract submission, schedule, and other information are available at the symposium website, https://scholarblogs.emory.edu/gacbs/schedule/.
]]>But for researcher Nicholas Hud, asteroids play an entirely different role: that of time capsules showing what molecules originally existed in our solar system. Having that information gives scientists the starting point they need to reconstruct the complex pathway that got life started on Earth.
Director of the NSF-NASA Center for Chemical Evolution at the Georgia Institute of Technology, Hud says finding molecules in asteroids provides the strongest evidence that such compounds were present on the Earth before life formed. Knowing what molecules were present helps establish the initial conditions that led to the formation of amino acids and related compounds that, in turn, came together to form peptides, small protein-like molecules that may have kicked off life on this planet.
“We can look to the asteroids to help us understand what chemistry is possible in the universe,” said Hud. “It’s important for us to study materials from asteroids and meteorites, the smaller versions of asteroids that fall to Earth, to test the validity of our models for how molecules in them could have helped give rise to life. We also need to catalog the molecules from asteroids and meteorites because there might be compounds there that we had not even considered important for starting life.”
Hud was a panelist at a press briefing “Asteroids for Research, Discovery, and Commerce” February 17 at the 2018 annual meeting of the American Association for the Advancement of Science (AAAS) in Austin, Texas.
NASA scientists have been analyzing compounds found in asteroids and meteorites for decades, and their work provides a solid understanding for what might have been present when the Earth itself was formed, Hud says.
“If you model a prebiotic chemical reaction in the laboratory, scientists can argue about whether or not you had the right starting materials,” said Hud. “Detection of a molecule in an asteroid or meteorite is about the only evidence everyone will accept for that molecule being prebiotic. It’s something we can really lean on.”
The Miller-Urey experiment, conducted in 1952 to simulate conditions believed to have existed on the early Earth, produced more than 20 different amino acids, organic compounds that are the building blocks for peptides. The experiment was kicked off by sparks inside a flask containing water, methane, ammonia and hydrogen, all materials believed to have existed in the atmosphere when the Earth was very young.
Since the Miller-Urey experiment, scientists have demonstrated the feasibility of other chemical pathways to amino acids and compounds necessary for life. In Hud’s laboratory, for instance, researchers used cycles of alternating wet and dry conditions to create complex organic molecules over time. Under such conditions, amino acids and hydroxy acids, compounds that differ chemically by just a single atom, could have formed short peptides that led to the formation of larger and more complex molecules – ultimately exhibiting properties that we now associate with biological molecules.
“We now have a really good way to synthesize peptides with amino acids and hydroxy acids working together that could have been common on the early Earth,” he said. “Even today, hydroxy acids are found with amino acids in living organisms – and in some meteorite samples that have been examined.”
Hud believes there are many possible ways that the molecules of life could have formed. Life could have gotten started with molecules that are less sophisticated and less efficient than what we see today. Like life itself, these molecules could have evolved over time.
“What we find is that these compounds can form molecules that look a lot like modern peptides, except in the backbone that is holding the units together,” said Hud. “The overall structure can be very similar and would be easier to make, though it doesn’t have the ability to fold into as complex structures as modern proteins. There is a tradeoff between the simplicity of forming these molecules and how close these molecules are to those found in contemporary life.”
Geologists believe the Earth was very different billions of years ago. Instead of continents, there were islands protruding from the oceans. Even the sun was different, producing less light but more cosmic rays – which could have helped power the protein-forming chemical reactions.
“The islands could have been potential incubators for life, with molecules raining down from the atmosphere,” Hud said. “We think the key process that would have allowed these molecules to go to the next stage is a wet-dry cycling like what we are doing in the lab. That would have been perfect for an island out in the ocean.”
Rather than a single spark of life, the molecules could have evolved slowly over time in gradual progression that may have taken place at different rates in different locations, perhaps simultaneously. Different components of cells, for example, may have developed separately where conditions favored them before they ultimately came together.
“There is something very special about peptides, nucleic acids, polysaccharides and lipids and their ability to work together to do something they couldn’t have done separately,” he said. “And there could have been any number of chemical processes on the early Earth that never led to life.”
Knowing what conditions were like on the early Earth therefore gives scientists a stronger foundation for hypothesizing what could have taken place, and could offer hints to other pathways that may not have been considered yet.
“There are probably a lot more clues in the asteroids about what molecules were really there,” said Hud. “We may not even know what we should be looking for in these asteroids, but by looking at what molecules we find, we can ask different and more questions about how they could have helped get life started.”
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]]>It’s time to develop alternatives to antibiotics for small infections, according to a new thought paper by scientists at the Georgia Institute of Technology, and to do so quickly.
It has been widely reported that bacteria will evolve to render antibiotics mostly ineffective against them by mid-century, and current strategies to make up for the projected shortfalls haven’t worked.
One possible problem is that drug development strategies have focused on replacing antibiotics in extreme infections, such as sepsis, where every minute without an effective drug increases the risk of death.
But the evolutionary process that brings forth antibiotic resistance doesn’t happen nearly as often in those big infections as it does in the multitude of small ones like sinusitis, tonsillitis, bronchitis, and bladder infections, the Georgia Tech researchers said.
“Antibiotic prescriptions against those smaller ailments account for about 90 percent of antibiotic use, and so are likely to be the major driver of resistance evolution,” said Sam Brown, an associate professor in Georgia Tech’s School of Biological Sciences. Bacteria that survive these many small battles against antibiotics grow in strength and numbers to become formidable armies in big infections, like those that strike after surgery.
“It might make more sense to give antibiotics less often and preserve their effectiveness for when they’re really needed. And develop alternate treatments for the small infections,” Brown said.
Brown, who specializes in the evolution of microbes and in bacterial virulence, and first author Kristofer Wollein Waldetoft, a medical doctor and postdoctoral research assistant in Brown’s lab, published an essay detailing their suggestion for refocusing the development of bacteria-fighting drugs on December 28, 2017, in the journal PLOS Biology.
The evolution of antibiotic resistance can be downright two-faced.
“If you or your kid go to the doctor with an upper respiratory infection, you often get amoxicillin, which is a relatively broad-spectrum antibiotic,” Brown said. “So, it kills not only strep but also a lot of other bacteria, including in places like the digestive tract, and that has quite broad impacts.”
E. coli is widespread in the human gut, and some strains secrete enzymes that thwart antibiotics, while other strains don’t. A broad-spectrum antibiotic can kill off more of the vulnerable, less dangerous bacteria, leaving the more dangerous and robust bacteria to propagate.
“You take an antibiotic to go after that thing in your throat, and you end up with gut bacteria that are super-resistant,” Brown said. “Then later, if you have to have surgery, you have a problem. Or you give that resistant E. coli to an elderly relative.”
Much too often, superbugs have made their way into hospitals in someone’s intestines, where they had evolved high resistance through years of occasional treatment with antibiotics for small infections. Then those bacteria have infected patients with weak immune systems.
Furious infections have ensued, essentially invulnerable to antibiotics, followed by sepsis and death.
Drug developers facing dwindling antibiotic effectiveness against evolved bacteria have looked for multiple alternate treatments. The focus has often been to find some new class of drug that works as well as or better than antibiotics, but so far, nothing has, Brown said.
Wollein Waldetoft came across a research paper in the medical journal Lancet Infectious Diseases that examined study after study on such alternate treatments against big, deadly infections.
“It was a kind of scorecard, and it was almost uniformly negative,” Brown said. “These alternate therapies, such as phage or anti-virulence drugs or, bacteriocins -- you name it -- just didn’t rise to the same bar of efficacy that existing antibiotics did.”
“It was a type of doom and gloom paper that said once the antibiotics are gone, we’re in trouble,” Brown said. “Drug companies still are investing in alternate drug research, because it has gotten very, very hard to develop new effective antibiotics. We don’t have a lot of other options.”
But the focus on new treatments for extreme infections has bothered the researchers because the main arena where the vast portion of resistance evolution occurs is in small infections. “We felt like there was a disconnect going on here,” Brown said.
The researchers proposed a different approach: “Take the easier tasks, like sore throats, off of antibiotics and reserve antibiotics for these really serious conditions.”
Developing non-antibiotic therapies for strep throat, bladder infections, and bronchitis could prove easier, thus encouraging pharmaceutical investment and research.
For example, one particular kind of strep bacteria, group A streptococci, is responsible for the vast majority of bacterial upper respiratory infections. People often carry it without it breaking out.
Strep bacteria secrete compounds that promote inflammation and bacterial spread. If an anti-virulence drug could fight the secretions, the drug could knock back the strep into being present but not sickening.
Brown cautioned that strep infection can lead to rheumatic heart disease, a deadly condition that is very rare in the industrialized world, but it still takes a toll in other parts of the world. “A less powerful drug can be good enough if you don’t have serious strep throat issues in your medical history,” he said.
Sometimes, all it takes is some push-back against virulent bacteria until the body’s immune system can take care of it. Developing a spray-on treatment with bacteriophages, viruses that attack bacteria, might possibly do the trick.
If doctors had enough alternatives to antibiotics for the multitude of small infections they treat, they could help preserve antibiotic effectiveness longer for the far less common but much more deadly infections, for which they’re most needed.
Want to Learn More? Read: FDA Taps Georgia Tech to Help Reduce Cost of Making Antibiotics
Research was funded by the Simons Foundation (grant 396001), the Centers for Disease Control and Prevention (grant OADS-2016-N-17812), the Wenner-Gren Foundation, and the Physiographic Society of Lund. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the sponsors.
]]>Georgia Institute of Technology
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When his team’s ‘nanohydrogel’ delivered a payload of RNA to malignant cells, combined with standard chemotherapy, the results were dramatic, “the massive reduction or complete eradication of the tumor,” McDonald, a researcher with the Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology, explained at the time.
Essentially, the new nanoparticle-based treatment makes chemotherapy more effective. It’s the kind of research with a successful track record that national funding agencies tend to support. That’s exactly what happened in November, when the National Cancer Institute’s Nanotechnology Characterization Laboratory (NCL) gave McDonald’s lab a big boost in its research, which was accepted into the NCL’s quarterly Assay Cascade characterization and testing program.
“Getting one of these grants is highly competitive, and I was pleased to see we were one of only three academic institutions to get the award,” said McDonald, professor in the School of Biological Sciences, who heads Georgia Tech’s Integrated Cancer Research Center. “Most of these awards typically go to start-up companies.”
Each quarter the NCL accepts the most promising cancer nanomedicine candidates into the program. The nanomedicines then undergo a rigorous evaluation and testing, including in vivo studies to evaluate safety, efficacy, and pharmacokinetics.
The other NCL awardees include researchers from Stanford University and the University of Utah, as well as the companies, EVOQ Therapeutics, Oncolmmune, Synergene Therapeutics, and ZY Therapeutics.
The treatment McDonald’s team developed targets epidermal growth factor receptors (EGFRs), which are found in the epithelial cells that line the body’s organs. EGFRs spark a variety of functions in healthy cells, but in cancer cells they are overproduced. As a result of this overexpression, many cellular functions, including cell replication and resistance to certain chemotherapy drugs, are cranked up. An overabundance of EGFRs found in biopsy typically means a bad prognosis for a cancer patient.
The new nanoparticle therapy uses a minute gel pellet to deliver short interfering (si) RNA, combined with the chemotherapy drug cisplatin, reducing resistance to the medication and shrinking carcinomas or eliminating them completely. The goal is to use the same nanohydrogel with other kinds of RNA to treat different cancers.
Current law requires more trials to show the treatment’s efficacy before researchers can move onto preliminary human trials. So, while the treatment is still years away from clinical use, the NCL assist through the characterization program helps bring it another step closer to the bedside.
“The services they provide would amount to about $1 million if we had to out-source them,” McDonald said. “So this is a big advantage in moving forward to FDA approval for Phase 1 human trials.”
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As an undergrad, he learned how to do research by working in the Computational and Structural Biology Laboratory at NSIT. In his spare time, Shashwat was president of the NSIT Quiz Club and enjoyed participating in quiz competitions in all over India.
“Georgia Tech has a great academic reputation around the world,” Shashwat says. “The cutting-edge and impressive research being done in the Georgia Tech Bioinformatics Program is what attracted me. Additionally, Georgia Tech is a premier institute for computer science, making it ideal for someone like me who wanted to work at the interface of biology and computer science."
Nagar is graduating with a Master of Science in Bioinformatics.
What is the most important thing you learned at Georgia Tech?
To manage my time and effectively working in large groups.
Georgia Tech lived up to my expectations. The instructors, peer group, and level of rigor were as spectacular as I had hoped for.
What surprised you most at Georgia Tech?
I was pleasantly surprised by how much individual attention professors were willing to give each student. One would not expect this at a school as big as Tech.
My mentors and professors have been approachable and available throughout my time here. It really makes the graduate experience significantly better. I hope this continues for future students.
Which professor(s) or class(es) made a big impact on you?
Professor I. King Jordan had the largest impact on me. He had been my mentor and principal investigator (PI) for the past three semesters, and I couldn’t have asked for anyone better. He has been patient with me when I was not at my best, has been a dynamic and responsive PI for all my research projects, and he has always tried to bring out the best in me.
I am honored to have worked with him and hope to be able to continue working with him in the future.
What is your most vivid memory of Georgia Tech?
The first finals week – the immense pressure and the delight of midnight breakfast! It was a new experience for me and one that I will not forget.
What was the most valuable outcome of your participation in experiential learning activities?
In summer 2017, I interned in the Department of Health Science Research at Mayo Clinic. The experience was invaluable. It gave me a taste of what it is to be in the working world and a great opportunity to apply the skills I had developed over two semesters in the Georgia Tech Bioinformatics Program.
What advice would you give to incoming graduate students at Georgia Tech?
Start managing your time from day 1. Procrastinating will land you in delayed submissions and a sink full of dirty dishes.
Where are you headed after graduation? How did your Georgia Tech education prepare you for this next step?
I plan on working with ABiL, a bioinformatics consulting firm starting next year. It will be a great way to apply all that I have learned in the Georgia Tech Bioinformatics Program. After gaining some experience, I would like to start working toward a Ph.D., which would help me round-out my skill set and become a better researcher.
]]>“Since we launched in 2012, the core has evolved quite a bit,” says Dalia Arafat-Gulick, who manages the lab of Petit Institute researcher Greg Gibson (professor in the School of Biological Sciences) and the Genome Analysis Core (contained within the Gibson lab space), in the Krone Engineered Biosystems Building. “The usage and diversity of equipment has definitely increased since then, and so have the services we provide.”
It all started with the Fluidigm Biomark quantitative real-time PCR (polymerase chain reaction). PCR, sometimes called “molecular photocopying,” is a fast technique to amplify small segments of DNA. The PCR technique was invented more than 30 years ago and it has transformed the study of DNA – mapping in the Human Genome Project.
PCR can be inexpensive if you’re only looking at a few genes, according to Gibson. “The costs can add up quickly,” he says. “But the Fluidigm platform brings the costs down further.”
This makes it possible, for example, to monitor the expression of 96 genes in 96 samples for around $1,000 (or 10 cents per reaction), “with high accuracy,” Gibson adds.
The latest transformative tool in Georgia Tech’s Genome Analysis Core is the ddSEQ, part of the single-cell sequencing system co-developed by Illumina and Bio-Rad. The Marcus Foundation collaborated with the Petit Institute in providing funding support, as Georgia Tech last April became the first research institution in the Southeast to deploy the ddSEQ.
“The ddSEQ is essentially a sample preparation platform,” explains Steve Woodard, director of core facilities for the Petit Institute. “You’re preparing samples to go downstream for sequencing in the Molecular Evolution Core or the High-Throughput DNA Sequencing Core. Just another example of how our core facilities are integrated.”
The process typically begins upstream in the Cellular Analysis and Cytometry Core, where researchers will utilize flow cytometry to isolate specific cell populations. Then the ddSEQ separates those cells into a sub-nanoliter oil based droplets on a disposable cartridge, in under five minutes, “which gives you a fast turnaround for each cell captured,” Arafat-Gulick says.
Each cartridge can accommodate up to four samples, which allows each sample to be processed simultaneously. Cell lysis, reverse transcription, and bar-coding occur inside the individual droplets, which allow researchers to amplify several thousand transcripts in each cell.
“The next step is to actually get them sequenced,” Arafat-Gulick says. “That’s where the downstream cores [High Throughput and Molecular Evolution] come in. They have the equipment that allows us to ultimately analyze the gene expression levels of these cells.”
In this way, researchers can peek inside hundreds – or even thousands – of cells, seeing how much diversity in the mixture there is, or monitoring how individual cells are responding to treatments, all for around $10 a cell. The technology also exists to sequence the DNA, and measure methylation states of genes, “which is transforming genomic analysis,” Gibson says.
“The next step is to actually get them sequenced,” Arafat-Gulick says. “That’s where the downstream cores [High Throughput and Molecular Evolution] come in. They have the equipment that allows us to ultimately analyze the gene expression levels of these cells.”
A number of Petit Institute researchers, including Krish Roy, Ed Botchwey, and Gibson, are working in the single-cell arena now, utilizing the equipment, techniques, and services available through the Genome Analysis Core.
“It’s a quantitative way to look at RNA sequencing on a single cellular level,” Arafat-Gulick says. “Principal investigators really want to see what’s happening on a cell to cell basis, and this new technology makes this accessible, at a much faster rate than before.”
•••
The Petit Institute's state-of-the-art research facilities, known as "Core Facilities," serve as a shared resource for the bioengineering and bioscience community. Consultation, training, and technical support is available for a variety of research projects. Users have access to over 100 pieces of lab equipment totaling over $24 million.
Learn more about the Petit Institute’s core facilities and how they can support your research projects.
CONTACT:
Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience
Research by School of Biological Sciences Associate Professor Sam Brown aims to understand the dynamics of the bacterial populations – or microbiomes – associated with the disease. The hope is to develop treatments targeting the specific microbiomes of individual patients.
To this end, the Centers for Disease Control and Prevention (CDC) has awarded Brown a grant of $300,000 for one year to develop new treatment strategies that are tailored to the individual microbiome profile of a person with cystic fibrosis. Brown is one of 25 investigators to receive funding from CDC as part of the agency’s push to combat antibiotic resistance.
The project – titled “Optimization of Therapeutic Strategies to Manage Polymicrobial CF Lung Infections: Clinical Assessment –will be carried out with co-investigator Arlene Stecenko, a cystic fibrosis expert at Emory University School of Medicine. Brown and Stecenko will track infection microbiomes in a small group of patients. They will monitor the impact of existing antibiotic treatments. They also will explore whether patients who naturally carry candidate “probiotic,” or beneficial, species are more resistant to colonization by notorious pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus.
“This funding takes us closer to the long-term goal of effective personalized-medicine solutions to improve the lives of people with cystic fibrosis,” says Brown, who is a researcher with the Petit Institute for Bioengineering and Bioscience.
]]>The researchers who built the program at the Georgia Institute of Technology would like cancer fighters to take it for free, or even just swipe parts of their programming code, so they’ve made it open source. They hope to attract a crowd of researchers who will also share their own cancer and computer expertise and data to improve upon the program and save more lives together.
The researchers’ invitation to take their code is also a gauntlet.
They’re challenging others to come beat them at their own game and help hone a formidable software tool for the greater good. Not only the labor but also the fruits will remain openly accessible to benefit the treatment of patients as best possible.
“We don’t want to hold the code or data for ourselves or make profits with this,” said John McDonald, the director of Georgia Tech’s Integrated Cancer Research Center. “We want to keep this wide open so it will spread.”
Researchers wanting to participate can follow this link to a new study published on October 26, 2017, in the journal PLOS One. There they will find links to download the software from GitHub and to access the code.
They’ll start out with a current program that has been about 85% accurate in assessing treatment effectiveness of nine drugs across the genetic data of 273 cancer patients. The study by McDonald and collaborator Fredrik Vannberg details how and why.
“Nine drugs are in the published study, but we’ve actually run about 120 drugs through the program all total,” said Vannberg, an assistant professor in Georgia Tech’s School of Biological Sciences.
The program uses proven machine learning mechanisms and also normalizes data. The latter allows the machine learning to work with data from varying sources by making them compatible.
And the researchers have reduced human bias about which data are important for predicting outcomes.
“It’s much more effective to put in loads of raw data and let the algorithm sort it out,” McDonald said. “It’s looking for correlations, not causes, so it’s not good to preselect data for what you suspect are most relevant.”
One big bias the researchers tossed out was a concentration only on gene expression data pertaining to the specific type of cancer they were aiming to treat.
“It turns out that it’s better to give the program data from a broad diversity of cancers, and that will actually later give a better prediction of drug effectiveness for a specific cancer like breast cancer,” Vannberg said.
“On a molecular level, some breast cancers, for example, are going to be more similar to some ovarian cancers than to other breast cancers,” McDonald said. “We just let the algorithm work with about everything we had, and we got high accuracy.”
The researchers also want the project to pool large amounts of anonymous patient treatment success and failure data, which will help the program optimize predictions for everyone’s benefit. But that doesn’t mean some companies can’t benefit, too.
“If a company comes along and makes profits while using the program to help patients, that’s fine, and there’s no obligation to give back to the project,” said McDonald, who is also a professor in Georgia Tech’s School of Biological Sciences. “Others may just take if they so please.”
But hopefully, most players will catch the spirit of kindness.
“With our project, we’re advertising that sharing should be what everybody does,” Vannberg said. “This can be a win for everybody, but really it’s a win for the cancer patients.”
Also READ: Basic premise in targeted cancer treatments wrong 60% of the time
Georgia Tech researchers Cai Huang and Roman Mezencev coauthored the study. The research was funded by the Rising Tide Foundation.
]]>Writer and Media Relations Contact: Ben Brumfield (404-660-1408)
]]>“If you’re going to start making medical predictions, you have to be careful,” said Dahlman. “Most people are not equipped to interpret statistics correctly, which can lead to negative predicting and ethical dilemmas. In a few years, genetic counselors will be in high demand so folks can make better decisions about their health.”
Dahlman is fascinated by genetics, citing gene therapy as the most interesting field in the world. And it’s a field that he is revolutionizing through his research. Gene therapy is an experimental technique that uses genes to treat or prevent diseases, including hemophilia, Parkinson’s, cancer and HIV. It can help manage a number of diseases by leveraging genes instead of drugs or surgery. Although gene therapy shows promise, there are still risks involved, including unwanted immune system reactions or the risk of the wrong cells being targeted. That’s where Dahlman’s research comes in.
Dahlman’s lab focuses on drug delivery vehicles, which are nanoparticles. The nanoparticle delivers gene therapies to the right place in the body to fight disease. It’s critical that the gene therapies only target the unhealthy cells to avoid damaging healthy ones. Dahlman is laser focused on ensuring the nanoparticles know what paths to take to reach the correct organ to start the healing process.
“The issue with genetically-engineered drugs is that they don’t work unless they get to the right cell in the body,” said Dahlman. “You can have the world’s best genetic drug that's going to fix a tumor or eradicate plaque, but it’s not going to be effective unless it travels to the right organ. In my lab, we design different nanoparticles to deliver the genetically-engineered drugs to the correct location.”
Dahlman is redefining the field of genetic therapy with a testing system he invented called FIND (Fast Identifiable Nanoparticle Delivery). During the course of identifying effective nanoparticles for drug delivery, thousands of nanoparticles must be tested, which presents scalability issues. Mice must be used for the tests because a cell plate isn’t going to replicate organs in the human body. But ethically, researchers cannot inject thousands of mice for an experiment of this magnitude. So Dahlman developed a testing system that leverages DNA barcodes (a stand-in for the actual drugs) to label each nanoparticle. Once those are injected, researchers can see where the barcodes went in the mouse. For example, if a significant number of barcodes numbered 30 all went to the heart, Dahlman can deduce that the nanoparticle represented by barcode 30 is best suited for that organ.
“The barcode system is redefining our field because we are now able to do several really important things that we couldn’t before,” said Dahlman. “First, we can test thousands of nanoparticles at once, which has been a pipedream in our field forever. Second, we can now study the biology of drug delivery, understanding which genes affect how well a drug will work. And third, we can apply big data and artificial intelligence to drug delivery for the first time. With thousands of nanoparticles being tested at once, we can mine giant data sets for bioinformatics.”
Dahlman’s research and barcoding system has universal implications; he is designing testing systems that everyone can use. Labs across the country can leverage FIND to accelerate their studies. If the technology is used by more labs, Dahlman believes it will increase the rate that gene therapies are developed, advancing the entire field.
Non-liver gene therapy delivery is one of the biggest challenges today that Dahlman hopes to contribute to with his work. The liver has been easier to target with gene therapy because of its filtration system; larger blood vessels let the nanoparticles pass more easily into the organ. Diseases such as hepatitis and cirrhosis have responded well to gene therapies.
“All types of drug therapies have to be delivered,” said Dahlman. “Our field has had the best success with the liver, with 15 clinical trials already successfully running using the same nanoparticle delivery mechanism. The liver is responding extremely well to these therapies, and we are healing livers and curing people. The next frontier will be organs other than the liver, like the heart and brain with tighter blood vessel systems.”
After 12 months, Dahlman’s lab is coming into its own with nine graduate students and four undergraduates working in the lab. Much of the energy and excitement in Dahlman’s lab come from the fact that he is a young professor. He’s only 30 and easily relates to the students in his lab. Dahlman’s had great experiences with faculty members too and describes senior faculty as extremely helpful and supportive.
“I’ve gotten carded at two different faculty events, and I’ve been mistaken as a student more times than I can count!” said Dahlman. “But there haven’t been any challenges here with being a young faculty member. That was one thing that really attracted me to Tech – the young faculty seemed truly happy here.”
Dahlman’s personal and professional goal is to be working on high risk, innovative science for as long as possible. He never wants to be in a rut, and he wants to have the courage to pursue interesting and risky science even if lower risk work is safer. In his lab, his goal is to produce great students. In 20 years, he wants to see his students as leaders in the field.
“I want people to say, ‘That person went through the Dahlman lab, we have to hire them,’” said Dahlman. “That’s what I want for my students, and I think we can get there.”
By Georgia Parmelee
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The researchers aim to identify metabolic features in head and neck cancers that are predictive of tumor response to a new chemotherapeutic drug, ß-lapachone, currently in clinical trial at the University of Texas-Southwestern (UTSW). Fellow leaders of the project are David Boothman, Ph.D., from the UTSW Medical Center and Cristina Furdui, Ph.D., from the Wake Forest School of Medicine.
Joshua Lewis, an Emory M.D./BME Bioinformatics Ph.D. student in Kemp’s lab, developed a genome-wide model of metabolism in head and neck cancer that explained why the cytotoxicity to ß-lapachone differed between radiation-sensitive and radiation-resistant cancer cells.
The research team identified new molecular targets for enhancing cell death with the drug—validating the results with a 332 gene RNAi screen. The modeling analysis suggests that the radiation-resistant cells rerouted metabolism and altered the enzymatic cycling of ß-lapachone, rendering them more susceptible to the chemotherapy.
“I’ve learned through this project how devastating head and neck cancer (HNC) is for patients, and the incidence of HNC is particularly high here in the Southeast compared to the rest of the US,” said Kemp, a researcher with the Petit Institute for Bioengineering and Bioscience at Georgia Tech.
“There are very few FDA-approved drugs for HNC and the survival rate for the late-stage cancer patients we are examining has been relatively stagnant for the past three decades," Kemp added. “Our goals are to develop computational models that factor in patient-to-patient variability in HNC metabolism and use these tools to predict who will respond well to the new ß-lapachone therapies.”
Head and neck cancers include cancers of the larynx (voice box), throat, lips, mouth, nose, and salivary glands.
As part of the award, the researchers will join and participate in the NCI Cancer Systems Biology Consortium. The multidisciplinary Cancer Systems Biology Consortium, funded by the National Cancer Institute, aims to tackle the most perplexing issues in cancer to increase our understanding of tumor biology, treatment options, and patient outcomes.
Media Contact:
Walter Rich
Communications Manager
Wallace H. Coulter Department of Biomedical Engineering
It’s a scattered and somewhat inconsistent revolution, however, as some regions with adequate resources set the pace for discovery, while others are left virtually stranded. Such is the case on the African continent, where many countries are being left behind, a situation that has the potential of widening global and ethnic inequalities in health and economic well-being.
Fortunately, though, a collection of individuals and institutions, including the Georgia Institute of Technology, are responding to the challenge and working to bridge the genomic divide. It’s the kind of bridge-building that King Jordan, a researcher with the Petit Institute for Bioengineering and Bioscience, has grown accustomed to. His lab, and the Bioinformatics Graduate Program that Jordan directs, have been deeply engaged in biotechnology capacity-building efforts in Latin America for close to a decade.
“We’re leveraging bioinformatics and genomics technologies to facilitate public health and to stimulate economic development overseas,” says Jordan, associate professor in the School of Biological Sciences, who cites the Georgia Tech strategic vision plan laid out in 2010, specifically goal number four, which involves expanding Tech’s global footprint and influence.
“That is done in two ways,” says Jordan. “One is by bringing the world to Georgia Tech and training more globally-engaged students. The other way is to project Georgia Tech’s reach out to the world, and we’re doing both.”
And now it’s happening in Africa, with the recent announcement that Jordan and one of his former grad students, Daudi Jjingo, have been awarded a five-year, $1.3 million grant as part of the NIH’s Human Heredity and Health in Africa (H3Africa) Initiative. H3Africa aims to elucidate Africa’s human genetic diversity (the highest on the planet) and thus one with a high potential of revealing more varied ways in which the human genome interacts with diseases and other environmental pertubations.
The plan is to use the award to support two trajectories, according to Jjingo, who earned his PhD as a Fulbright fellow in Jordan’s research team at Georgia Tech in 2013 and returned to his home country, Uganda, where he is a faculty researcher at Makerere University in Kampala.
“First we want to focus on building a computing and physical infrastructure, and secondly, we want to actually start a bioinformatics program,” says Jjingo. “The idea is to build a sustainable bioinformatics program.”
There is a lot of clinical research happening now in Africa, Uganda in particular, Jjingo says, and researchers currently lack the bioinformatics resources to adequately analyze all of that data.
“So the vision is, at the end of five years we’ll have this program established, well-staffed, with students graduating,” Jjingo says. “Having talented students who graduate creates the infrastructure – it builds the right recipe to build a research center, which means we can move beyond academia and provide bioinformatics consulting services for industry and others.” Their bioinformatics consulting efforts will be modeled after the Applied Bioinformatics Laboratory (ABiL), a public-private partnership between the Jordan lab at Georgia Tech and the company IHRC Inc., which provides bioinformatics analysis services and training to industry and non-profit clients.
The program in Uganda will begin, Jjingo says, “with about five Masters students and a couple of PhD students, and the plan is that one of them will spend a year at Georgia Tech – from my own experience, I know the huge value you can get by spending a short time there, learning from a mature research environment and ecosystem. And Georgia Tech personnel will come here to Uganda, to conduct short seminars, and so forth. So we’re talking about an exchange of human resources.”
Jordan adds, “one thing we know that is implicit in the notion of mentoring a grad student is the idea of collaborative research. So when you have a graduate student that serves as the fulcrum between two institutions, it provides a great opportunity build bridges. My hope is that those students will engage in collaborative research that will allow for deeper connections between Georgia Tech and Makerere University.”
CONTACT:
Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience
Headlines, of late, have touted the successes of targeted gene-based cancer therapies, such as immunotherapies, but, unfortunately, also their failures.
Broad inadequacies in a widespread biological concept that affects cancer research could be significantly deflecting the aim of such targeted drugs, according to a new study. A team exploring genetic mechanisms in cancer at the Georgia Institute of Technology has found evidence that a prevailing concept about how cells produce protein molecules, particularly when applied to cancer, could be erroneous as much as two-thirds of the time.
Prior studies by other researchers have also critiqued this concept about the pathway leading from genetic code to proteins, but this new study, led by cancer researcher John McDonald, has employed rare analytical technology to explore it in unparalleled detail. The study also turned up novel evidence for regulating mechanisms that could account for the prevailing concept’s apparent shortcomings.
The concept stems from common knowledge about the assembly line inside cells that produces protein molecules. It starts with code in DNA, which is transcribed to messenger RNA, then translated into protein molecules, the cell’s building blocks.
That model seems to have left the impression that cellular protein production works analogously to an old-style factory production line: That the amount of a messenger RNA encoded by DNA on the front end translates directly into the amount of a corresponding protein produced on the back end. That idea is at the core of how gene-based cancer drug developers choose their targets.
To put that assumed congruence between RNA production and protein production to the test, the researchers examined -- in ovarian cancer cells donated by a patient -- 4,436 genes, their subsequently transcribed messenger RNA, and the resulting proteins. The assumption, that proverbial factory orders passed down the DNA-RNA line determine in a straightforward manner the amount of a protein being produced, proved incorrect 62 percent of the time.
“The messenger RNA-protein connection is important because proteins are usually the targets of gene-based cancer therapies,” McDonald said. “And drug developers typically measure messenger RNA levels thinking they will tell them what the protein levels are.” But the significant variations in ratios of messenger RNA to protein that the researchers found make the common method of targeting proteins via RNA seem much less than optimal.
McDonald, Mengnan Zhang and Ronghu Wu published their results on August 15, 2017 in the journal Scientific Reports. The work was funded by the Ovarian Cancer Institute, The Deborah Nash Endowment, Atlanta’s Northside Hospital and the National Science Foundation. The spectrophotometric technology needed to closely identify a high number of proteins is not widespread and is quite costly but is available in Wu’s lab at Georgia Tech.
Whereas many studies look at normal tissue versus cancerous tissue, this new study focused on cancer progression, or metastasis, which is what usually makes cancer deadly. The researchers looked at primary tumor tissue and also metastatic tissue.
“The idea that any change in RNA level in cancerous development flows all the way up to the protein level could be leading to drug targeting errors,” said McDonald, who heads Georgia Tech’s Integrated Cancer Research Center. Drug developers often look for oddly high messenger RNA levels in a cancer then go after what they believe must be the resulting oddly high levels of a corresponding protein.
Taking messenger RNA as a protein level indicator could actually work some of the time. In the McDonald team’s latest experiment, in 38 percent of the cases, the rise of RNA levels in cancerous cells did indeed reflect a comparable rise of protein levels. But in the rest of cases, they did not.
“So, there are going to be many instances where if you’re predicting what to give therapeutically to a patient based on RNA, your prescription could easily be incorrect,” McDonald said. “Drug developers could be aiming at targets that aren’t there and also not shooting for targets that are there.”
The analogy of a factory producing building materials can help illustrate what goes wrong in a cancerous cell, and also help describe the study’s new insights into protein production. To complete the metaphor: The materials produced are used in the construction of the factory’s own building, that is, the cell’s own structures.
In cancer cells, a mutation makes protein production go awry usually not by deforming proteins but by overproducing them. “A lot of mutations in cancer are mutations in production levels. The proteins are being overexpressed,” said McDonald, who is also a professor in Georgia Tech’s School of Biological Sciences.
A bad factory order can lead to the production of too much of a good material and then force it into the structures of the cell, distorting it. The question is: Where in the production line do bad factory orders appear?
According to the new study, the answer is less straightforward than previously thought.
The orders don’t all appear on the front end of the assembly line with DNA over-transcribing messenger RNA. Additionally, some mutations that do over-transcribe messenger RNA on the front end are tamped down or canceled by regulating mechanisms further down the line, and may never end up boosting protein levels on the back end.
Regulating mechanisms also appear to be making other messenger RNA, transcribed in normal amounts, unexpectedly crank out inordinate levels of proteins.
At the heart of those regulating systems, another RNA called micro RNA may be micromanaging how much, or little, of a protein is actually produced in the end.
“We have evidence that micro RNAs may be responsible for the non-correlation between the proteins and the RNA, and that’s completely novel,” McDonald said. “It’s an emerging area of research.”
Micro RNA, or miRNA, is an extremely short strand of RNA.
McDonald would like to see tissues from more cancer patients undergo similar testing. “Right now, with just one patient, the data is limited, but I also really think it shows that the phenomenon is real,” McDonald said.
“Many past studies have looked at one particular protein and a particular gene, or a particular handful. We looked at more than 4,000,” McDonald said. “What that brings up is that the phenomenon is probably not isolated but instead genome-wide.”
The study’s authors would also like to see currently less accessible, advanced protein detecting technology become more widely available to biomolecular researchers, especially in the field of cancer drug development. “Targeted gene therapy is a good idea, but you need the full knowledge of whether it’s affecting the protein level,” McDonald said.
He pointed out that no one is at fault for the possible incompleteness of commonly held concepts about protein production.
As science progresses, it naturally illuminates new details, and formerly useful ideas need updating. With the existence of new technologies, it may be time to flesh out this particular concept for the sake of cancer research progress.
Also READ: Punching Cancer With RNA Knuckles – with John McDonald
The research was supported by grants from the Ovarian Cancer Institute, The Deborah Nash Endowment Fund, Northside Hospital (Atlanta), and the National Science Foundation (CHE-452 1454501). Cancer tissues from ovary and omental sites were collected from a cancer patient at Northside Hospital with informed consent under Georgia Institute of Technology Institutional Review Board protocols (H14337). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of those agencies.
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]]>Overall, the news from the study is good. Evolution appears, through the ages, to have weeded out genetic influences that promote disease, while promulgating influences that protect from disease. But there's also a hint of bad news for us modern folks. That generally healthy trend might have reversed in the last 500 to 1,000 years.
So, who appears to have had the healthier genes? The “cavemen?” We moderns? And who was more genetically susceptible to mental illness?
READ about our genomic health heritage here, and meet our Copper Age ancestor, the “Iceman.”
]]>Known as Dry Ion Localization and Locomotion (DRILL), the new device creates a swirling flow that can separate electrospray droplets depending on their size. In this application, one of many potential uses for DRILL, the smaller droplets are directed to enter the mass spectrometer, while the larger ones – which still contain solvent – remain in the vortex flow until the solvent evaporates. Removing the solvent allows analysis of additional ions that may be lost in current techniques and reduces the chemical “noise” that inhibits selectivity of the mass spectrometer.
“A major challenge for detecting small quantities of biomolecules using mass spectrometry technology is that we can’t see everything that is actually in the sample,” said Matthew Torres, an assistant professor in Georgia Tech’s School of Biological Sciences. “The DRILL device provides a new way to solve that problem by increasing the number of ions we can get into the mass spec instrument so we can productively detect them. The ions are there now, but not necessarily in a form that the mass spec can handle.”
Developed by researchers at the Georgia Institute of Technology with support from North Carolina State University, DRILL can be added to existing electrospray ionization mass spectrometers without modifying them.
“The principle is to make the droplets rotate and use inertia to separate them out by size,” explained Andrei Fedorov, a professor in Georgia Tech’s Woodruff School of Mechanical Engineering. “We want the droplets to stay in the flow long enough to remove the solvent. In practice, smaller droplets remain in the center, where they are can be removed first for analysis, while the larger ones remain on the edge of the flow until they are dried.”
The key idea of DRILL is based on Fedorov’s 2007 invention “Confining/Focusing Vortex Flow Transmission Structure, Mass Spectrometry Systems, and Methods of Transmitting Particles, Droplets, and Ions." (US Patent No. 7,595,487). In the past three years, the DRILL device has been developed with support from the National Institute of General Medical Sciences of the National Institutes of Health, and its latest version was described June 14 in the American Chemical Society journal Analytical Chemistry.
In electrospray ionization (ESI), an electric potential is applied to a solution inside a capillary, producing a strong electric field at the spray capillary tip. That leads to the expulsion of an aerosol containing charged droplets that carry the molecules to be analyzed. The ejected droplets then break up into smaller droplets, creating a plume that expands spatially beyond the inlet intake capacity of the mass spectrometer, resulting in sample loss. The DRILL device provides an effective interface for collection and transmission of charged analytes from ionization sources, such as ESI, to detection devices, such as mass spectrometers, resulting in significantly improved detection capability.
As much as 80 to 90 percent of large biopolymers (proteins, peptides, and DNA) are currently lost to analysis using existing ESI-MS techniques, which have grown in importance to the life sciences community. Capturing all of the biopolymers could lead to new discoveries, said Torres, whose lab studies post-translational changes in proteins. By allowing analysis of large biomolecules, DRILL could facilitate top-down proteomics in which complete protein molecules could be studied without the need to enzymatically break them up into smaller pieces before MS analysis.
“This could allow us to see combinatorial modifications that exist on a single protein molecule,” said Torres. “It’s very important for us to understand how proteins communicate with one another, and DRILL may allow us to do that by more effectively removing the solvent from these types of samples.”
The Georgia Tech researchers are using DRILL in their lab to interface between liquid chromatography and the ESI-MS instrument. Multiple electrodes and inlet/outlet ports enable precise control over the flow generation and guiding electric field inside the DRILL, so the device can be configured for a variety of uses, Fedorov noted. In a general sense, DRILL adds a new approach for manipulating the trajectory of charged droplets, which, when combined with hydrodynamic drag forces and electric field forces, provides a rich range of possible operational modes.
DRILL can improve the signal-to-noise ratio by a factor of 10 in the detection of angiotensin I, a peptide hormone, and boost the sensitivity for angiotensin II ten-fold to picomole levels. DRILL demonstrated improved signal strength – up to 700-fold – for eight of nine peptides included in a test extract of biological tissue.
DRILL could potentially allow the study of entire cell contents, analyzing thousands of different molecule types simultaneously. That could allow researchers to see how these molecules change over time to detect problems in chemical pathways and to determine why drugs work in some people and not others.
“This could be a huge advance for biologists and others who are interested in protein biochemistry and cell biology because it enhances the sensitivity of the analytical technical and overcomes a major hurdle in studying large biological molecules,” Torres added. “We expect to be able to see things we haven’t been able to see before.”
The Georgia Tech researchers have been collaborating with David Muddiman, a professor in the Department of Chemistry at North Carolina State University, on developing DRILL and its analytical characterization using state-of-the-art mass spectrometry experiments. A unique contribution of the North Carolina State University researchers is in using a powerful statistical method called “design of experiments” to guide the multi-parameter optimization of the DRILL device, resulting in identification of a sweet spot for optimal operation.
Fedorov and Torres hope to expand use of the DRILL device beyond Georgia Tech laboratories and further enhance its design. Among the near-term improvements planned is the addition of internal heating to accelerate the removal of solvent. “We see many additional improvements that will allow DRILL to further enhance the ESI-MS process,” said Fedorov. “We plan to continue evolving it as more labs start to use the device.”
In addition to those already named, the paper’s co-authors include Peter A. Kottke, Jung Y. Lee and Alex P. Jonke from Georgia Tech and Chinthaka A. Seneviratne and Elizabeth S. Hecht from North Carolina State University.
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM112662. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CITATION: Peter A. Kottke, et al., “DRILL: An ESI-MS interface for improved sensitivity via inertial droplet sorting and electrohydrodynamic focusing in a swirling flow,” (Analytical Chemistry, 2017). http://dx.doi.org/10.1021/acs.analchem.7b01555.
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]]>The technique, which has been validated against a drug-resistant bacterial strain, identifies compounds that target two or more receptor sites on proteins that inhibit a key cellular function. To obtain resistance to drug compounds developed with the technique, the microbes would have to simultaneously develop mutations in all the receptor pockets targeted by the drug – a challenge much more significant than developing resistance in a single receptor site.
Researchers from the Georgia Institute of Technology and Harvard University believe the technique could provide a new general approach for battling drug resistance that may potentially also be applied to cancer cells and viruses which also develop drug resistance. The research, supported by the National Institutes of Health, was reported May 19 in the journal ACS Chemical Biology.
“We have developed an entirely novel mechanism for increasing antibiotic effectiveness,” said Jeffrey Skolnick, director of Georgia Tech’s Center for the Study of Systems Biology and a Georgia Research Alliance Eminent Scholar in Computational Systems Biology “The problem of emerging antibiotic resistance is a major health care crisis, and we think this approach could allow the rapid design of new classes of molecules that would be able to maintain their effectiveness longer, allowing us to stay one step ahead of the bugs.”
Antibiotic resistance often develops when proteins – often enzymes – mutate the receptor pockets that allow the drugs to bind to the protein. Bacterial populations often include individuals that have these mutations randomly, and when antibiotics kill off the susceptible cells, the population of those with the specific mutation grows. In order to control these resistant bacteria, doctors must employ a drug compound that targets a different receptor or different binding site on a key bacterial protein.
The technique identified three classes of inhibitor drugs that targeted both primary and secondary receptor pockets on the dihydrofolate reductase (DHFR) enzyme in a drug-resistant strain of Escherichia coli (E. coli). DHFR is necessary for the synthesis of important cellular building blocks, and is a classical target for antibiotics. Without production of these compounds, bacteria cannot reproduce.
Using their algorithm, Skolnick and his Georgia Tech collaborators identified 10 potentially useful drug compounds and prioritized compounds from the three categories – stilbenoid, deoxybenzoin and chalcone family of compounds – for their ability to target a secondary receptor pocket. Interestingly, one of the molecules was resveratrol which is found in red wine and which has been reported to have anti-aging and anti-cancer effects. In the laboratory, the researchers confirmed that the commercially available compounds could indeed bind with DHFR.
But the real test was whether the compounds would work on living bacteria. To evaluate that, the Georgia Tech researchers worked with Eugene Shakhnovich, a professor in the Department of Chemistry and Chemical Biology at Harvard University. Shakhnovich and his colleagues confirmed that the drug compounds shut down the production of folates in the drug-resistant E. coli, dramatically slowing the growth of the bacterium. They also showed that the addition of folates to the bacterial population allowed the bugs to survive despite treatment by the DHFR-inhibiting drugs.
“We tested the compounds in vitro with purified variants of the enzyme,” Shakhnovich said. “We engineered E. coli strains that carry escape mutations in the folA locus – which encodes DHFR – on their chromosomes and proved that the newly-found compounds effectively inhibit growth in both wild-type and escape mutant strains of DHFR, albeit at high concentrations.”
Because it is a relatively small protein with well-defined biophysical properties, DHFR “represents a desirable model to explore the genotype-phenotype relationship between biophysical properties of the enzyme and the fitness and evolution of a microorganism,” Shakhnovich added.
As a next step, Skolnick would like to test the principle on other proteins essential to other microorganisms to see if two or more binding pockets can be targeted. That could require development of new therapeutic molecules able to attack the microbial targets. Ultimately, the technique could be used to shut down other avenues of antibiotic resistance, including the ability of cells to break down drugs or eject them before they can bind.
If the technique proves successful in other laboratory studies, testing with an animal model would be necessary to determine whether it can be beneficial in living organisms.
DHFR has been targeted for anti-cancer drugs, and Skolnick is hopeful that the two-receptor technique may prove useful in developing new chemotherapy agents that could fight off the resistance that often renders them useless.
Skolnick believes the approach may help scientists stay ahead of bacterial resistance by providing a technique to rapidly develop new drugs. The compounds would be used in combination therapies to further guard against development of resistance.
“We are always going to be at war with microbes,” he said. “The bacterial system is going to evolve to respond to new antibiotics, so we have to keep targeting something else so the system never gets to evolve resistance. It’s likely that we’ll need to use combination therapies that use multiple drugs to eliminate the development of resistance.”
This project was funded by 1R35GM118039 and 1RO1068670 (to Shakhnovich) of the Division of General Medical Sciences of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CITATION: Bharath Srinivasan, Joa?o V. Rodrigues, Sam Tonddast-Navaei, Eugene Shakhnovich, and Jeffrey Skolnick, “Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants,” (ACS Chemical Biology, 2017) http://dx.doi.org/10.1021/acschembio.7b00175
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]]>Mitochondrial replacement (MR) therapy combines the nuclear DNA from the mother with healthy mitochondria from a donor egg to create a healthy new egg that can be fertilized with the father’s sperm, thereby yielding a “three-person baby.” Last year, the world’s first three-person baby resulting from this method was delivered by U.S. doctors in Mexico, where there are no laws prohibiting the procedure.
The healthy newborn got about 0.1 percent of his DNA from the donor, and the vast majority of his genetic code – specifying eye color, hair, etc. – from his mom and dad.
Mitochondrial DNA comprises just a small percentage of our total DNA, containing just 37 of the 20,000 to 25,000 protein-coding genes in our body. And while nuclear DNA comes from both parents, “our mitochondrial DNA comes directly from our mothers, so my mitochondrial genome will be exactly like my mother’s, yours will be like your mother’s, and so on,” says Lavanya Rishishwar, former grad student in the lab of Petit Institute researcher King Jordan and team lead for Applied Bioinformatics Laboratory (ABiL, a public-private partnership between Georgia Tech and IHRC Inc.).
While the method hasn’t been green lighted in the U.S. yet, the United Kingdom gave the go-ahead for MR therapy in December. This announcement came in the wake of concerns about the safety of MR therapy that were raised by evolutionary biologists, who argue that nuclear and mitochondrial genomes evolved concurrently, and therefore mitochondria from one person or population may not be compatible with nuclear material from another.
In support of the evolutionary biologists’ nuclear-mitochondrial mismatch hypothesis, a number of previous studies on model organisms have provided evidence for incompatibility between nuclear and mitochondrial genomes from divergent populations of the same species. But a recent study by Jordan and Rishishwar published in BMC Genomics lays those fears to rest.
“The alarm was raised based on work that was done on model systems,” says Jordan, associate professor in the School of Biological Sciences and director of the Bioinformatics Graduate Program. “They didn’t work with humans, they worked with fruit flies, with mice, and those experiments resulted in a host of different problems for the resulting offspring. The key is, those were artificial experiments. Meanwhile, there’s been an ongoing natural experiment that has been conducted over millennia in human populations.”
So Jordan and Rishishwar tested the nuclear-mitochondrial mismatch hypothesis for humans by observing the source: humanity. They used data from the 1,000 Genomes Project and the Human Genome Diversity Project, studying the incidents of nuclear- mitochondrial DNA mismatch seen in more than 3,500 people from about 60 populations on five continents.
“We’ve been working for some years on human population genomics and remain interested in admixed American populations,” Jordan says. “The trajectory of modern human evolution for the past 50,000 to 100,000 years starts with the journey out of Africa, followed by a long period when populations were geographically isolated for the most part. During that time, human populations genetically diverged since they were physically isolated.”
But over the past 500 years or so, since Columbus came to the new world from Europe, “that process of isolation and divergence got flipped upside down,” Jordan notes. “Over a very short evolutionary time, you had populations from the Americas, Europe, and shortly thereafter, Africa because of the transatlantic slave trade, that were all brought together.”
Hence, in the Americas we’ve seen the creation of genome sequences that are evolutionarily novel in the history of humanity, in that they contain combinations of variants that had never existed together before. Jordan and his team have been studying this for a while, and understood that healthy individuals can bear combinations of variants that had different ancestral sources within the same genomic background.
“We knew that at a very intuitive level because of our own research,” says Jordan, who stumbled on a paper in Nature expressing the grave concerns of evolutionary biologists and thought, “instead of relying on artificial experiment systems, why don’t we just try to read the results of this long, ongoing experiment of human evolution and see what it tells us.”
They found that even people with very similar nuclear DNA (nDNA) genomes can have highly divergent mitochondrial DNA (mtDNA) and vice versa. Ultimately, their results showed that mitochondrial and nuclear genomes from divergent human populations can co-exist in healthy individuals, indicating that mismatched nDNA-mtDNA combinations are basically harmless and not likely to jeopardize the safety of MR therapy.
“We tend to think that the story of our evolution is the story of migration, physical isolation, and genetic diversification,” Jordan says. “But all throughout that process, there was admixture along the way. It’s not like there was a linear, onward march. It confirms and underscores the fact that humans are a relatively evolutionarily young species, and from the genetic perspective, there is complete compatibility between human populations.”
]]>But that disposable payload, which can include mRNAs and proteins, can be picked up by other cells, which means that exosomes play an important role as messengers, helping to carry out the critical cell-to-cell communication that multicellular organisms depend on for survival.
Not only can exosomes communicate and provide transport over long distances – they also happen to be in the ideal size range for lymphatic transport, a concept that has long captivated Brandon Dixon and Fred Vannberg, researchers in the Petit Institute for Bioengineering and Bioscience, and others interested in the future of the lymphatic targeted drug delivery systems.
Last year, Dixon and Vannberg collaborated on a groundbreaking research paper in the Nature journal, Scientific Reports, entitled, “Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node.” Their results suggested that exosomes facilitate the rapid exchange of infection-specific information from peripheral tissue to the lymph node, essentially priming the node for an effective innate immune response.
Their latest paper, “TLR-exosomes exhibit distinct kinetics and effector function,” published recently in the same journal (Scientific Reports, March 2017), digs deeper, making a striking new discovery along the way: Exosomes move with what looks like an increased sense of urgency depending on their payload.
“Not only do we find out that these exosomes can inform the node of what kind of specific immune response to initiate – is it viral, or a bacterial infection? It’s that specific – but we found out the uptake of exosomes from viral-infected cells was different from the control exosomes,” says Vannberg, an assistant professor in the School of Biological Sciences.
“They move much faster,” notes Dixon, associate professor in the Woodruff School of Mechanical Engineering. “It was really dramatic. Their uptake to the node was a lot quicker when they contained pathogen information. This is a completely novel finding. Something on the surface of the exosomes has to be communicating with the micro-environment to enhance lymphatic transport, but we really don’t know why this happens yet.”
The researchers demonstrated the enhanced (if unexpected) trafficking of pathogenic-stimulated exosomes, which also have an inclination to recruit infection-fighting neutrophils (white blood cells) along the way.
So after encountering, say, a virus on a peripheral tissue, the exosome acts in a couple of ways, sending the information rapidly across long distances to the lymph node, then bringing the molecular cavalry.
The lead author of the latest paper was biology Ph.D. candidate Swetha Srinivasan, who was lead author on the last paper and is co-advised by Dixon and Vannberg. Other authors included grad students James Moore and Shashidhar Ravishankar, and undergrads Michelle Su and Pamelasara Head.
The researchers say having cutting-edge core facilities close at hand, within the Petit Institute, was critical to the work (giving a shout-out to research scientist Shweta Biliya, for her management of the High Throughput DNA Sequencing Core in the acknowledgements section of the paper).
The team’s work, partially funded by an interdisciplinary Petit Institute seed grant, produced important findings on the road to targeted therapy. But the findings lead to the inevitable sequel.
“In the next chapter, we’ll talk about immunotherapy,” Dixon says. “These results suggest we can go beyond targeting and enhance the transportation itself. Whether that is a way to improve, say, vaccine efficacy or drug delivery to the lymph nodes for tumor therapy remains to be seen. But those are the avenues where these results can have important implications.”
LINKS:
“TLR-exosomes exhibit distinct kinetics and effector function”
Laboratory of Lymphatic Biology and Bioengineering
CONTACT:
Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience
Plenty, because microbes respond, adapt, and evolve faster than other organisms. Scientists can discover how microorganisms will change because of global warming more quickly than is possible for complex organisms. Understanding how microbes respond to climate change will help predict its effects on other forms of life, including humans.
Yet our understanding of microbes’ complex functions in ecosystems and their interaction with a warming planet is incomplete. Filling the knowledge gaps is crucial, says a report just released by the American Academy of Microbiology and the American Geophysical Union. The report, based on a workshop of experts, underscores the importance of microbes in ecosystems buffeted by climate change and identifies priorities for future study.
In addressing climate change, it’s important to understand the importance of microbes in ecosystems, says Joel E. Kostka, a professor in the School of Biological Sciences and the School of Earth and Atmospheric Sciences. He was invited to the workshop for his expertise on microbes in terrestrial polar environments. Despite their size, microorganisms provide critical services to ecosystems, Kostka says. “Through activities that produce or consume greenhouse gases, microbes intimately impact Earth’s climate.”
Microbes are the decomposers, breaking down organic matter and recycling nutrients, Kostka says. “Literally, the clean air we breathe and the food we eat depend upon carbon and nutrient cycling – ecosystem services provided by microbes.”
However, the processes microbes mediate are complex and need to be better understood, Kostka says, “so we can make accurate predictions of how ecosystems will respond to climate change.”
One example of that complexity is plant-microbe interactions. Thousands of microbial species make up plant microbiomes – microbes that live inside or on plants. Microbiomes help plants grow better through nutrient acquisition among many functions. Conversely, microbes process organic matter produced by plants. How microbial communities will change due to Earth’s warming will depend on how plants respond and vice versa, Kostka says. To understand the effect of climate change on ecosystems, we have to know how plants and microbiomes interact or communicate.
Also highlighted by the workshop, Kostka says, is the need for communication across scientific disciplines. “I found myself informing the chemists on the latest information we have on microbes and microbial activity in wetlands, for example.”
The report is intended for the public, educators, and the broader science community, Kostka says. “I would hope that it represents a call to action for better understanding of microbiomes in the environment.”
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By all indications, Redding is the guardian angel every graduate student, as well as graduate program director, wishes for. She is a student advocate, faculty partner, problem solver, go-to person, administrator par excellence. Especially to international students, Redding is the comforting reassurance that whatever vexing problems arise in their educational journey, a suitable solution will be found.
Students and faculty alike sing high praises of Redding.
“Lisa Redding is an exemplary advisor, but an even better person,” says a former M.S. Bioinformatics student. “She is consistently going above and beyond for all students and is always informative, respectful, and just delightful to be around.”
“Lisa embodies the spirit of a graduate academic advisor,” says another former M.S. Bioinformatics student. “She radiates a certain quality of happiness and confidence that made me feel secure in my decision to attend Georgia Tech and confident in my first days in the program.”
“Georgia Tech staff have a remarkable sense of service for members of the academic community. Lisa is an outstanding example of that spirit,” say nine QBios students in a nomination letter. “She showed genuine interest in our lives and would always ask if there were ways she could be helping.”
Redding “has been the highest performing ... member of staff I have had the pleasure to work with at this great and well-run institute,” says Jung H. Choi, a 30-year faculty member, an associate professor in the School of Biological Sciences, and the director of the Professional M.S. Bioinformatics Program.
Redding’s cheerful disposition puts students at ease and helps them focus on their work rather than unduly worrying about paperwork, says I. King Jordan, an associate professor in the School of Biological Sciences and the director of the Bioinformatics Graduate Program.
“She is available to students, responsive to their needs, as well as introspective and thoughtful in trying to bridge the gap between student perceptions and program administration,” says Joshua S. Weitz, a professor in the School of Biological Sciences and the director of QBios. “She has been a tremendous asset in recruitment and in student satisfaction.”
“It is a privilege to work with the graduate students and faculty in the Bioinformatics and QBioS programs,” Redding says. “I am honored to be recognized for my service.”
]]>"The Discovery Files" recently highlighted the work of Brian Hammer, Will Ratcliff, Samuel Brown, and Peter Yunker in a 90-second radio feature titled "A Gut Reaction." The podcast is based on a paper published on Feb. 6, 2017, in the journal Nature Communications.
The researchers used math and physics equations to find patterns and consistency in how two competing armies of cholera bacteria attack each other. The work could someday help scientists develop targeted therapies using engineered microbes that could kill infectious, harmful bacteria while sparing helpful ones.
NSF, which helped fund the research, creates a weekly audio report on the latest scientific research. "The Discovery Files" airs on radio stations throughout the U.S.
You can listen to "A Gut Reaction" here.
Hammer and Brown are associate professors in the School of Biological Sciences. Ratcliff and Yunker are assistant professors, respectively, in the School of Biological Sciences and the School of Physics.
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Beyond the financial drain, textbooks are often bloated with information that will not and cannot be covered during the one or two semesters they are intended to be used. For students and professors alike, there’s got to be a better way.
Ever inventive and industrious, academics in the School of Biological Sciences have found a solution: replace textbooks with custom-built websites.
Over the past several years, Jung Choi, an associate professor, and academic professionals Shana Kerr and Chrissy Spencer have been working toward a textbook-free biology classroom. Their efforts have been supported by a grant from an anonymous alumnus and by a USG Board of Regents Affordable Learning grant.
Choi took the first steps in 2010, when he got fed up with how topics are presented in textbooks. “The only way I was going to get something I liked,” he says, “was to write it myself.”
“Textbooks organize materials in a way that doesn’t necessarily fit the way we think about biology,” Spencer says.
Custom websites dispel the dread of textbooks. First, they drastically reduce the cost. Students taking these courses will only pay a small subscription fee to the website used for homework problems.
Next, they offer significant modularity. Professors can tweak and update information to suit their needs. Already complete is the website for Biology 1510, the first semester of introductory biology. “It’s a living document,” Kerr says. “We make changes as we go along.”
Also available, but not yet complete, are websites for Biology 1520, the second semester of introductory biology, as well as the new non-major course The Biology of Sex and Death. “These two websites are less polished,” Spencer says. “Our ultimate goal over the summer is to get them to the level of 1510.”
Finally, in contrast to textbooks’ information overload, custom websites eschew the excessive detail that students do not need. Such streamlining has no adverse effect on student learning, the professors say. “There is not one single member of our faculty who knows everything in an introductory textbook,” Choi says. “And we’re not going to ask our students to know everything.”
From the feedback they have received, Choi, Kerr, and Spencer are confident that students welcome the switch. Quantitative analyses of students’ performance show no significant difference in performance between students using the textbook and those using the website. Additionally, students showed improvement in learning certain topics that are not adequately covered by textbooks. Results have been presented at local and national conferences.
To disseminate their methods and resources, Choi, Kerr, and Spencer have made the biology course websites available to anyone. Everything can be reused and repurposed by teachers at other universities and schools freely, as long as credit is properly attributed.
The professors hope their example will lead others at Tech to adopt their methods. “We would love for people to be on board with this idea,” Spencer says. “We think teaching things in this way makes a whole lot of sense.”
Despite the tremendous progress, a minor issue remains: how to refer to these textbooks in the form of websites? Choi, Kerr, and Spencer have not yet settled on a moniker.
How about “the Matrix”?
Nathanael Levinson
Contributing Writer
College of Sciences
This groundbreaking work is the result of the Crohn’s & Colitis Foundation’s “RISK Stratification” study, the largest new-onset study completed on pediatric Crohn’s disease patients. It is a multicenter research initiative that consists of 25 U.S. institutions and three from Canada and a cohort of 1,112 CD children enrolled at diagnosis, of which 913 were included in the published study. Of the 28 research sites, four are located in Atlanta - Emory University, Georgia Institute of Technology, Children’s Healthcare of Atlanta, and the Children’s Center for Digestive Health Care. The goal of this research was to identify measurable indicators of the two most common complications in pediatric Crohn’s disease that require surgery - stricturing and penetrating disease.
Stricturing, also referred to as fibrostenosis, is characterized by a build-up of fibrotic scar tissue which leads to thickening of the intestinal wall and narrowing of the intestinal passage. Penetrating disease is the result of sustained inflammation that spreads beyond the intestinal wall resulting in the creation of fistulas, abnormal connections between the intestine and other organs. Penetrating complications can also lead to the formation of abscesses at the sites of fistulas.
“Twenty five percent of patients with Crohn’s disease account for 80 percent of complications, hospitalizations, surgery and health care costs. The aim of RISK is to preemptively identify those 25 percent of patients at diagnosis,” Subra Kugathasan, M.D., Emory University, principal investigator and lead author of the paper. “Through the study of baseline gene expression, immune reactivity, and intestinal bacteria, we have identified distinct biological signatures capable of predicting stricturing and penetrating disease, at diagnosis. After analyzing millions of biological and clinical data points, RISK has generated a composite risk stratification model.”
"Stricturing and penetrating disease account for substantial morbidity in both pediatric and adult patients with Crohn’s disease, but there are no validated models to predict risk and the effect of treatment," said Caren Heller, M.D., chief scientific officer of the Foundation.
RISK study researchers looked at intestinal gene expression levels to identify risk factor genes whose levels are altered (increased or decreased) at enrollment, and identified distinct biological gene expression signatures at baseline that could distinguish children who will develop strictures form those who develop fistulas or abscesses, without the confounding effects of treatment on gene expression. Therefore, these genetic signatures together with other biological and clinical variables they evaluated could be used as predictors of complications and treatment outcomes at diagnosis.
"Importantly, the functional nature of these genetic signatures is consistent with the clinical presentation of the complications," said Ted Denson, M.D., Cincinnati Children's Hospital, co-principal investigator and lead author of the paper. "This means that while patients who develop fibrostenosis exhibit, at diagnosis, increased levels of several genes involved in the fibrosis process, patients who develop penetrating disease have increased levels of genes involved in the inflammatory response."
In addition to providing predictive biological signatures for development of complications, the RISK study also found that patients who receive early anti-TNFa biologic treatment, within three months of diagnosis, were less likely to develop penetrating complications. However, patients with stricturing complications were poorly responsive to early intervention with biologics. These data support the utility of risk stratification of pediatric Crohn’s disease patients at diagnosis, and may guide early tailored use of anti-TNFa therapy. The data also highlight the unmet medical need to find new treatment options for children likely to develop strictures.
“These discoveries are great steps toward precision medicine in the treatment of pediatric Crohn's disease,” said Andrés Hurtado-Lorenzo, Ph.D., Director of Translational Research of the Foundation. “In the coming years, we plan to translate these findings into a risk diagnostic tool that could use these biological signatures as biomarkers to predict risk of complications and to help clinicians make therapeutic decisions at diagnosis.”
The Foundation has made significant investments in support of pediatric IBD research through the PRO-KIIDS network, an umbrella for clinics participating in pediatric IBD research. Although many projects are expected to arise from this network the Risk Stratification has been the flagship study.
“Pediatric patients are the fastest growing group of the IBD population. Under the auspices of the PRO-KIIDS network, every major pediatric IBD center in the country is touched by our work or funding,” said Michael Osso, President and CEO of the Foundation. “Through the network, and the results of the RISK study, we are furthering research that will significantly lower the treatment burden on kids, and help minimize side effects on the quality of life surrounding the most vulnerable of patients.”
As part of the study, Georgia Tech postdoctoral researcher Urko Marigorta analyzed RNAseq gene expression data from biopsies provided by Cincinnati Children's Hospital. The work identified dozens of pathways that are differentially expressed in complicated disease, and showed that immune activity is more disrupted in penetrating disease while extracellular matrix is more involved in stricturing disease. Inclusion of these profiles in a statistical model with the serological and classical markers improved the predictive accuracy of the model significantly.
“We performed statistical and bioinformatic analyses of the genomic data which led to enhanced discrimination of which patients are likely to progress to complicated disease,” said Greg Gibson, a professor in the Georgia Tech School of Biological Sciences and one of the paper’s co-authors. “The involvement of TNF-alpha signaling in progression to stricturing disease is consistent with the overall finding that these are the patients who respond to TNF-alpha therapy.”
This seminal work and its discovery represent over $10 million investment by the Crohn’s & Colitis Foundation, nearly 10 years of work, and collaborative team effort. Dr. Thomas Walters from the Hospital for Sick Kids, Canada shares lead authorship with Drs. Kugathasan and Denson. In addition, Dr. Jeffrey Hyams (Connecticut Children’s Medical Center), and Dr. Marla Dubinsky (Mount Sinai Hospital, New York) share authorship.
About the RISK Stratification Study
The RISK Stratification Study enrolled 1,800 patients from 28 clinics, with a focus on 913 children with Crohn’s disease enrolled at diagnosis and complication-free following 90 days after diagnosis. This 36-month prospective inception cohort study included well documented clinical, demographic, and biological sample collection every six months on all patients for three years with continuing follow up for five years.
About the Crohn's & Colitis Foundation
The Crohn's & Colitis Foundation is the largest non-profit, voluntary, health organization dedicated to finding cures for inflammatory bowel diseases (IBD). The Foundation’s mission is to cure Crohn's disease and ulcerative colitis, and to improve the quality of life of children and adults who suffer from these diseases. The Foundation works to fulfill its mission by funding research; providing educational resources for patients and their families, medical professionals, and the public; and furnishing supportive services for those afflicted with IBD. For more information visit www.crohnscolitsfoundation.org.
- Written by Crohn’s & Colitis Foundation
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]]>What attracted you to study in Georgia Tech? How did Georgia Tech meet your expectations?
The main reason was my advisor, Dr. Kostas Konstantinidis. I read some of his work while I was an undergraduate and was fascinated by his research. While studying for my master’s degree, I had the privilege of visiting his lab for two weeks. During this period, I became convinced that I wanted to work in microbial ecology, and he offered to receive me as a Ph.D. student. Once I started the program, I quickly realized that Georgia Tech exceeded my expectations, offering a far richer campus life than I had anticipated.
What is the most important thing you learned while at Georgia Tech?
Balancing work and academic life with other activities. I became involved in social dancing, a hobby I’ve cultivated and enjoyed for over three years now, learning salsa, bachata, zouk, and tango. I discovered in Georgia Tech the importance of this balance in carrying out a productive and happy academic life.
What surprised you the most at Georgia Tech? What disappointed you the most?
I was surprised by the variety of cultural activities. Having a stereotypical image of a technology institute in mind, I was pleasantly surprised by poetry recitals, concerts, dance and theater performances, and many more activities on campus. After the success of the BVN Youth Poetry Slam semifinals at Georgia Tech in summer 2015, it was a disappointment that Tech didn’t continue to build on promoting slam poetry.
Which professor(s) or class(es) made a big impact on you? Why?
Certainly my advisor, Dr. Konstantinidis. Not only did I learn about microbial ecology from him, but also his frequent encouragement to critically discuss ideas has prepared me for scholastic discussion outside of Tech.
What is your most vivid memory of your time at Georgia Tech?
I cherish with particular warmth my memories of the Salsa Club, first as a regular member and later as a board member and an instructor.
On the basis of your experience, what advice would you give to incoming new graduate students at Georgia Tech?
Learn to say no and value your free time.
Learning to say no is hard, but as graduate students we often get bombarded with options and our first instinct is to try and cover them all. Some diversity in research topics is highly desirable, but it’s important to find a balance in which, at the end, a consistent story can be told in the dissertation.
Another area in which balance is hard to find is time management. We tend to err on the side of too much academic involvement and little or no personal life. Hobbies are important, they keep us healthy, happy, and productive, and it’s our own job to cultivate them and devote some time to them.
What feedback would you give to Georgia Tech leaders, faculty, and/or staff to improve the Georgia Tech experience for future students?
I would encourage more curricular freedom for graduate students. I was fortunate enough to be in the Ph.D. in Bioinformatics, a program with great latitude on the courses I could (or should) take. And yet, even in this program, I was never presented with the possibility of attending classes outside of the main program areas, while most advisors explicitly discourage this. For example, Georgia Tech offers very interesting courses in the humanities that are never mentioned to graduate students in the sciences or engineering.
Where are you headed after graduation? How did your Georgia Tech education prepare you for this next step?
I’ll stay in Georgia Tech for a short-term postdoctoral position in the School of Civil and Environmental Engineering. I plan on continuing in an academic career, for which Georgia Tech has prepared me with valuable practical experience in research, collaborations with faculty and students from other laboratories, and proposals of novel research ideas and projects.
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But what if your diagnosis and treatment could be further informed by the experience of millions of other patients, including those who not only had similar symptoms, but perhaps also were your age, gender, ethnicity — and with similar medical history? That’s among the benefits coming soon from health analytics and informatics.
Using massive data sets, machine learning, and high-performance computing, health analytics and informatics is drawing us closer to the holy grail of health care: precision medicine, which promises diagnosis and treatment tailored to individual patients. The information, including findings from the latest peer-reviewed studies, will arrive on the desktops and mobile devices of clinicians in health care facilities large and small through a new generation of decision-support systems.
“There are massive implications over the coming decade for how informatics will change the way care is delivered, and probably more so for how care is experienced by patients,” said Jon Duke, M.D., director of Georgia Tech’s Center for Health Analytics and Informatics. “By providing data both behind the scenes and as part of efforts to change behavior, informatics is facilitating our ability to understand patients at smaller population levels. This will allow us to focus our diagnostic paths and treatments much better than we could before.”
At Georgia Tech, health informatics researchers are partnering with both public- and private-sector organizations to develop and apply transformative technology that will connect incompatible systems and analyze vast data sets. This technology also will help clinicians track the latest research, potentially shortening the time required to move health care advances into practice.
“Our goal is to be directly involved with that health care transformation and to be one of the contributors focusing on what technology can do well,” said Steve Rushing, senior strategic advisor for health extension services at Georgia Tech. “Technology has to be leveraged in a way that will meet the goals of improving the quality of care, bettering the patient experience, and addressing the rising cost of health care.”
Georgia Tech’s health informatics effort combines academic researchers in computing and the biosciences, practitioners familiar with the challenges of the medical community, extension personnel who understand the issues private companies face, and engineers and data scientists with expertise in building and operating secure networks tapping massive databases.
“It takes all of these components to really make a difference in an area as complex as health informatics,” said Margaret Wagner Dahl, Georgia Tech’s associate vice president for information technology and analytics. “This integrated approach allows us to add value to collaborators as diverse as pharmaceutical companies, health care providers, large private employers, and federal agencies.”
See the complete article from Research Horizons magazine.
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]]>With a novel targeted therapy researchers at the Georgia Institute of Technology have purged ovarian tumors in limited, in vivo tests in mice. “The dramatic effect we see is the massive reduction or complete eradication of the tumor, when the ‘nanohydrogel’ treatment is given in combination with existing chemotherapy,” said chief researcher John McDonald.
That nanohydrogel, a type of nanoparticle, is a minute gel pellet that honed in on malignant cells with a payload of an RNA strand. The RNA entered the cell, where it knocked down a protein gone awry that is involved in many forms of cancer.
In trials on mice, it put the brakes on ovarian cancer growth and broke down resistance to chemotherapy. That allowed a common chemotherapy drug, cisplatin, to drastically reduce or eliminate large carcinomas, with very similar speed and manner. The successful results treating four mice with the combination of siRNA and cisplatin showed little variance.
Chink in the armor
The therapeutic short interfering RNA (siRNA) developed by McDonald and Georgia Tech researchers Minati Satpathy and Roman Mezencev, thwarted cancer-causing overproduction of cell structures called epidermal growth factor receptors (EGFRs), which extend out of the wall of certain cell types. EGFR overproduction is associated with aggressive cancers.
The researchers from Georgia Tech’s School of Biological Sciences published their results on Monday, November 7, 2016, in the journal Scientific Reports. Research was funded by the National Institutes of Health’s IMAT Program, the Ovarian Cancer Institute, the Deborah Nash Endowment Fund, the Curci Foundation and the Markel Foundation.
The new treatment has not been tested on humans, and research would be required by science and by law to demonstrate consistent results – efficacy – among other things, before preliminary human trials could become possible.
The current in vivo success strengthens the idea that knocking out EGFR at the RNA level may be a worthy goal to explore in the fight against carcinomas in general. The same patented nanohydrogel packed with other types of therapeutic RNA is currently being tested for the treatment of other types cancers.
Helper turned killer
EGFRs are receptors found in epithelial cells, which line organs throughout the body: Lungs, mouth, throat, intestines and others. In women, it also lines reproductive organs: Ovaries, uterus and cervix.
They are long proteins that poke through the cell membrane, connecting the cell’s interior with the outside. They look like squiggly worms with tiny mouths on the outside that take up a messenger protein.
In a healthy cell, those messenger molecules cause EGFRs to trigger long chains of biochemical reactions that lead to the activation of genes involved in a variety of cellular functions. In carcinoma cells, the number of EGFRs present typically skyrockets.
“In many cancers, EGFR is overexpressed,” said McDonald, who heads Georgia Tech's Integrated Cancer Research Center. “The problem is that because of this overexpression, many cellular functions, including cell replication and resistance to certain chemotherapy drugs, are dramatically cranked up.”
The cell goes haywire, metabolizes too much sugar, divides too much, and resists chemotherapy. The cancer grows into a tumor and can spread through the body.
An overabundance of EGFRs found in a biopsy is usually a sign that cancer patient prognosis is poor. “In 70 percent of ovarian cancer patients, EGFR is overexpressed at very high levels,” McDonald said.
Cell suicide: apoptosis
EGFR overexpression also makes cancer cells resistant to chemotherapy by thwarting a natural defense mechanism.
“The platinum-based chemotherapies used to treat ovarian cancers cause DNA damage, which switches on apoptosis,” McDonald said. Apoptosis is cell suicide. When cells can’t repair DNA damage, they’re programmed to kill themselves to keep the damaged cells from spreading.
The primary chemotherapy used to treat ovarian cancer works by coaxing cancer cells to trigger the suicide program, but having too many epidermal growth factor receptors gets in the way.
“EGFR overexpression hinders apoptosis; they won’t die. By knocking down EGFR, we make the cell hypersensitive to the drug. Apoptosis is reactivated,” McDonald said.
Existing EGFR targeted drugs called tyrosine-kinase inhibitors disrupt an EGFR function, but their success in treating ovarian cancer has been limited. “Clinicians have tried EGFR inhibitors to treat ovarian cancers for some years, and they only get about 20% of patients responding to it,” McDonald said. “Apparently, the particular EGFR function inhibited by these drugs is not critical to ovarian cancer.”
Guided brass knuckles
The short interfering (si) RNA designed by the Georgia Tech researchers attacks the cancer much closer to its root.
To make the protein for EGFR, RNA has to transfer its genetic code from DNA. The researchers’ siRNA binds to the cell’s RNA and stops it from working.
“We’re knocking down EGFR at the RNA level,” he said. “Since EGFR is multi-functional, it’s not exactly clear which malfunctions contribute to ovarian cancer growth. By completely knocking out its production in ovarian cancer cells, all EGFR functions are blocked.”
The nanohydrogel that delivers the siRNA to the cancer cells is a colloid ball of a common, compact organic molecule and about 98 percent water. Another molecule is added to the surface of the nanohydrogel as a guide. It makes the pellets adhere to the cancer cells like sticky cluster bombs.
Cancerous tissue may also be aiding the nanohydrogel in targeting it. “When you get into a tumor, there are a lot of blood vessels, and many are broken,” McDonald said. “This may help the nanoparticles get passively trapped in the neighborhood of tumorous tissues.”
In the in vivo trials, the siRNA, which contained a fluorescent tag, allowed researchers to observe nanoparticles successfully honing in on the cancer cells.
Fortuitous victory
“We originally selected to target the EGFR gene because its activity is easily measured, and we wanted to use it simply as an indicator that our nanoparticle siRNA delivery system was working,” McDonald said. “The fact that the EGFR knockdown so dramatically sensitized the cells to standard chemotherapy came as a bit of a surprise.”
At first, his team observed how the tumors responded to chemotherapy alone. Then they combined it with the nanoparticle treatment.
“When we gave the chemotherapy alone, the response was moderate, but with the addition of the nanoparticles, the tumor was either significantly reduced or completely gone,” McDonald said.
But he tempered enthusiasm with caution. “Further work will be required to see if the treatment completely destroyed every trace of cancer cells in the tumors that disappeared, or if future recurrence is possible.”
If the researchers’ continuing studies further prove to be consistent, the combination of the nanohydrogel with other therapeutic RNAs could represent a significant advancement in the treatment of a wide spectrum of cancers.
Georgia Tech’s Lijuan Wang and Dr. Benedict Benigno from Atlanta’s Northside Hospital coauthored the paper. Research was funded by the National Institutes of Health’s Program for Innovative Molecular Analysis Technologies Program (grant 1R21CA155479-01), the Ovarian Cancer Institute at Northside Hospital, the Deborah Nash Endowment Fund, the Curci Foundation, and the Markel Foundation. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the sponsoring agencies.
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]]>Researchers from the Georgia Institute of Technology and the U.S. Centers for Disease Control and Prevention (CDC) recently compared the new methodology against traditional culture-based methods with samples from two severe outbreaks of Salmonella, a common foodborne pathogen. The metagenomics approach – which relies on DNA sequencing and bioinformatics analysis of the resulting sequencing data -- not only correctly identified the bacterial culprit, but also found a possible coinfection with a second important pathogen, Staphylococcus.
Widespread use of the new shotgun metagenomics methodology could improve real-time disease surveillance, provide a better quantitative picture of pathogen abundance and help scientists and doctors understand the response of the body’s natural microbiome. Supported by the CDC and the National Science Foundation, the research was reported November 23 in the journal Applied and Environmental Microbiology.
“When we receive the samples, we can move directly to characterizing them by sequencing the genomes of the microbes that are in the sample without waiting for conventional culturing techniques,” explained Kostas Konstantinidis, the Carlton Wilder Associate Professor in the Georgia Tech School of Civil and Environmental Engineering. “Using computational analysis, we can then say what the pathogen is and identify the variant, its virulence factors, even what antibiotic might be effective against it. That can usually be done in a single day.”
Conventional techniques used for identifying foodborne bacteria involve culturing the microbes to increase the numbers necessary for detection. This takes time, as long as two or three days, and some bacteria don’t grow on traditional culture media and could be missed. Polymerase chain reaction (PCR) can also be used to identify pathogenic bacteria, but it also relies on isolating the unknown microbes from a culture.
Metagenomics technology has already been used to analyze the microbial content of everything from lake ecosystems to drinking water in pipes. The evaluation of samples from separate bacterial outbreaks in Alabama and Colorado is one of the very first applications of the methodology for diagnosing foodborne bacteria.
“Stool samples are very complex and contain lots of different DNA from humans, healthy bacteria, and the food you ate,” explained Andrew Huang, Ph.D., a microbiologist/ bioinformatician in CDC’s Enteric Diseases Laboratory Branch. “The process of generating the DNA fingerprint of the bacteria directly from a sick patient’s stool is like finding a needle in a haystack of all kinds of DNA. Because of this, the use of metagenomics for disease detection is in the early stages of research and development. However, this study shows the potential to use stools from healthy and sick people directly to determine who is involved in an outbreak, which will revolutionize the way we detect and monitor for foodborne disease in the future.”
Metagenomics identifies the microbes present by sequencing all of the DNA present in a sample and comparing the genomic data to a database of known microbes. In addition to identifying the bacteria present in the samples, the methodology can also measure the relative abundance of each microbial species and their virulence potential, among other things.
“Currently, the most advanced DNA fingerprinting method, whole genome sequencing, requires first pulling out, or isolating in a pure culture, the bacteria that made a person sick to generate a fingerprint,” said Huang, who co-leads a group working on culture independent and metagenomics subtyping. “Metagenomics differs from whole genome sequencing because it could allow us to sequence all the DNA in a patient’s sample. It could allow us to skip the isolation steps and go directly from a stool sample to a highly detailed DNA fingerprint of the bacteria that made you sick. This method saves time and provides more detail that could be helpful for diagnosing a patient and identifying an outbreak.”
In the two 2013 outbreaks investigated, the traditional diagnostic technique and the metagenomics methodology arrived at the same answers, but the metagenomics data provided specific information about the bacterial phenotype involved and identified a secondary Staphylococcus aureus pathogen present in two of the samples tested. Knowing the specific phenotype can help in pinpointing the origins of an outbreak, while information about the secondary infection may help explain related factors such as the severity of the infection.
Scientists were also able to rule out one species – Escherichia coli (or E. coli) – because the variant present was not of a virulent type. Variants of this bacteria are present naturally in the gut microbiome (called "commensal E. coli") while other variants are notorious enteric pathogens. Metagenomics showed the abundant E. coli population in the outbreak samples was probably commensal, and its growth may have been accelerated when conditions became more favorable during the Salmonella infection. In the two cases evaluated, scientists were able to determine that although the symptoms were similar, the outbreaks were caused by different variants of Salmonella and therefore were probably not connected.
As many as half of foodborne disease outbreaks are never attributed to a source. Those outbreaks may be caused by new infectious agents, or by microbes not commonly seen in food. The metagenomic methodology could help identify unknown microbes, potentially providing advance warning of new outbreaks.
“Without going through culture methods, we are able to see all of the microbes that are in the sample,” Konstantinidis said. “We can get this information in a day or so, which is quite important in selecting the right antibiotic to combat the infection, controlling the outbreak and working with food producers to recall items that caused the outbreak. The sooner we have the answer, the better.”
Though the study confirmed the benefits expected, two challenges must be addressed before the new approach can go into widespread use, Konstantinidis said.
The first is the cost, which can be significantly higher than traditional approaches, suggesting the metagenomics test might be used first in complicated cases. The second challenge is in removing human DNA from the samples. All DNA must be sequenced, but the human DNA can account for as much as 99 percent of the genomic data, so removing it from consideration could accelerate the analysis.
CITATION: Andrew D. Huang, Chengwei Luo, Angela Pena-Gonzalez, Michael R. Weigand, Cheryl Tarr, and Konstantinos T. Konstantinidis, “Metagenomics of Two Severe Foodborne Outbreaks Provides Diagnostic Signatures and Signs of Coinfection Not Attainable by Traditional Methods," (Applied and Environmental Microbiology, 2016) http://dx.doi.org/ doi:10.1128/AEM.02577-16
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]]>A recent study published in the Proceedings of the National Academy of Sciences analyzed the viral content of the human gut (Manrique et al., PNAS, 2016). The research focused on a particular kind of virus called bacteriophage, which only infect bacterial cells and do not infect human cells. Manrique and colleagues found that healthy individuals had a “core” group of bacteriophage. In addition, they found that these core bacteriophage were less frequently found in individuals with gastrointestinal disease. This novel finding reveals a potential link between the viruses in our gut and our health.
Joshua Weitz, a professor in the School of Biological Sciences explains the findings:
Yogurt is a breakfast staple. In my family, we pack single-serve yogurt containers with our kids’ lunches and eat “stinky” cheese. In doing so we are also serving our children bacteria. Intentionally. Yogurt and cheese are examples of “living” food. The living component are cultures of bacteria.
As any shopper knows, the marketing of yogurt is tied not just to its taste but to its health benefits. The active bacteria in yogurt differ among company and brands. Irrespective of the brand-name, the active bacteria are nearly all close relatives of “lactic acid bacteria”. Lactic acid bacteria take the sugars in milk, break them down, and release lactic acid. That lactic acid and other byproducts give yogurt its distinctly sour taste.
The idea that eating more bacteria could be good for you reflects a paradigm shift in the scientific attitude towards microbes and health. Bacteria can make us sick. But, many bacteria keep us healthy. We could not go about our daily routine without them. These bacteria constitute part of our “microbiome” – that is the world of bacteria that lives in and on us. Yet, despite the changing attitudes towards bacteria, there has not been a similar paradigm shift with respect to viruses. I have yet to see a yogurt offered with extra viruses. I would imagine it would not be a sales hit… Or would it?
The study of Manrique and colleagues identified a core “virome” correlated to human health. But we still do not know if there is a causative link between the two, e.g., do bacteriophage in the human virome infect components of the healthy human microbiome and/or do they infect otherwise harmful pathogens? Future research will be needed to tease apart these relationships. But one thing is clear: consumers may eventually need to consider the health benefits of viruses and bacteria when thinking about maintaining or improving their health.
]]>Director of Communications
College of Sciences
]]>Oceanic dead zones are natural laboratories for exploring biological diversity. In a study published this year in the journal Nature, scientists at Georgia Tech discovered new species of the world's most abundant organism group, a bacterial clade called SAR11, which have adapted to life in dead zones by acquiring genes necessary to breath the chemical nitrate. Other work by Tech scientists shows that dead zones in the Pacific, which contain the largest pools of the greenhouse gas methane (CH4) in the open ocean, support microbes adapted to consume methane, potentially through a process that requires these microbes to make their own oxygen. Research on dead zones is challenging scientists to devise new tools to collect and manipulate ocean microbes while maintaining the exact environmental conditions the cells experience in nature. Frank Stewart, of the School of Biological Sciences, explains:
The oceans are losing oxygen. A poignant example is the "dead zone" that forms each summer in the Gulf of Mexico. Each spring, fertilizers from farms and lawns wash into the rivers feeding the Gulf. This influx of nutrients, primarily nitrogen and phosphorus from the Mississippi River, fuels expansive blooms of photosynthetic algae near the river mouths. When these algae die, they are eaten by single-celled microbes (bacteria) that consume oxygen during growth. If oxygen removal exceeds replenishment, as occurs in the Gulf during high microbial growth in the calm of summer, seawater oxygen levels can fall nearly to zero, creating a "dead zone" devoid of larger marine life. Dead zones like those in the Gulf can span thousands of square miles and, by altering the distributions of animals such as shrimp and fish, compromise the health of the ocean's most productive and biodiverse ecosystems.
But not all life deplores a dead zone. Indeed, thousands of microbial species thrive under the low-oxygen conditions of the dead zone, occurring at densities of millions of cells per milliliter (~1/5 of a teaspoon). These microbes employ a wide spectrum of biochemical solutions to life without oxygen, many of which remain poorly understood but are critical for ocean processes. For example, many of the microbes responsible for controlling the bioavailability of nitrogen, an essential component of proteins and DNA, grow only under low-oxygen conditions by using nitrogen-containing compounds, such as nitrite (NO2-), in place of oxygen. In metabolizing such compounds, these microbes produce nitrogen-containing gases, including the potent greenhouse gas nitrous oxide (N2O).
Studies of dead zone microbes are transforming our knowledge of ocean ecosystems. By collecting water at different depths through a dead zone, researchers can sample microbes exposed to vastly different oxygen and chemical conditions, thereby testing predictions of how ecosystem-level processes, such as the cycling of nutrients or greenhouse gases, may change as human activities influence ocean parameters.
Dead zones, in addition to exerting critical effects on the function of marine ecosystems, are breathing life into a broader understanding of microbes in the oceans.
]]>Director of Communications
College of Sciences
]]>With the realization now that there are more than 200 types and subtypes of cancer, the battle plan has evolved from a one-size-fits-all strategy to a data-driven, more personalized approach, which means the army of researchers and clinicians devoted to fighting cancer also has evolved.
“We’re seeing the emergence of the new cancer biology,” says John McDonald, director of the Integrated Cancer Research Center (ICRC) at the Georgia Institute of Technology. “It’s actually being driven now by technologies and expertise that lie outside the traditional framework of cancer biology. That’s why I think you’re probably going to see major breakthroughs in cancer research coming out of places like Georgia Tech and M.I.T., as opposed to traditional medical schools.”
Advances in genomics and high throughput sequencing have generated massive amounts of data, “and it’s opened up the field to people that were not trained as cancer biologists, but have the necessary skillsets for the analysis of all this new, big data,” says McDonald, a faculty researcher with the Petit Institute for Bioengineering and Bioscience and professor in the School of Biological Sciences, who has definitely seen his share of breakthroughs in his own recent research focused on ovarian cancer.
The cancer biology that McDonald knew when he was a college student has moved from an era of specialization into an era of multidisciplinary research, in which researchers from a wide range of areas now work together on common projects.
“Twenty five years ago, these people probably wouldn’t have spoken to each other because they didn’t have any common interests,” says McDonald. “I was like a kid in a candy store when we first came to Georgia Tech, and it still feels like that – the idea of being in a place where all of this expertise and creativity exist. Cancer research is not a one-person endeavor. It’s all about collaboration.”
And McDonald has plenty of collaborators within and beyond the ICRC, which occupies a busy space where molecular biology, computational science, engineering and nanotechnology converge. Together, these scientists and engineers are developing next generation cancer diagnostics and therapeutics.
Family Affair
Fatih Sarioglu trained as an electrical engineer in his native Turkey and later at Stanford University, developing particular expertise in microsystems and nanosystems, developing sensitive, small-scale devices to look at atoms. After earning his Ph.D., he says, “I wondered how I could use these skills to benefit humanity.”
Sarioglu, assistant professor in the School of Electrical and Computer Engineering and a Petit Institute faculty researcher, he spent three years as a post-doc at Massachusetts General Hospital and Harvard Medical School, learning about cancer. He found his opportunity, “to give biologists and biomedical scientists and clinicians capabilities they don’t have.”
There was a personal reason for Sarioglu’s interest in cancer, as well. The disease took the life of two grandparents. But he was particularly motivated when his mother-in-law was diagnosed, back in Turkey, with late-stage brain cancer.
“It was devastating. I knew life expectancy was about four or five months,” says Sarioglu. “But their diagnosis was based purely on the pathology, a biopsy slice.”
He asked a colleague at Mass General, David Lewis, one of the world’s top pathologists, for another opinion. Lewis’ conclusions were vastly different. The cancer was benign, operable, and Sagioglu’s mother-in-law is alive and well.
“It showed me that we still have to improve how we diagnose cancer,” says Sarioglu, whose lab develops microfluidic chips that can isolate tumor cells out of billions of other cells. At Mass General, he worked on a device that captures clumps of tumor cells before metastasis, preventing the spread of cancer.
He’s continued that work since arriving at Georgia Tech in 2014, developing microchip technology that analyzes cells accurately and at very high speeds. Essentially, it is a better way to find the needle in the haystack, a minimally invasive way to diagnose cancer, liquid biopsy.
“The possibilities are endless, really,” says Sarioglu, who counts McDonald and Fred Vannberg (an expert in DNA sequencing who specializes in the molecular analysis of cancer) among his research collaborators. “The technology is applicable to all types of cancer.”
Doing Better
The primary tumor is rarely the killer in cancer. Nine times out of 10, cancer kills because it spreads to other parts of the body. So when a patient gets a cancer diagnosis, one of his first questions is, “has it metastasized?”
“You can obviously appreciate the anxiety. The physician and patient wonder the same exact thing. That’s the first question,” says Stanislav Emelianov, professor in the Georgia Tech/Emory Wallace H. Coulter Department of Biomedical Engineering (BME), a Georgia Research Alliance Eminent Scholar and the Joseph M. Pettit Chair in School of Electrical and Computer Engineering.
“Then there are more questions. What is the prognosis, the treatment, how do I deal with this – a lot of questions that can be better answered if we know the answer to the first question,” says Emelianov, whose team designs ultrasound imaging devices and algorithms, and has embarked on a project supported by a grant from the Breast Cancer Research Foundation to use light and sound and a non-radioactive molecularly targeted contrast agent, to answer that anxious first question.
The traditional approach has been to inject radioactive material and tracking that, then biopsy, which involves incision of the skin to expose the lymph node and taking pieces out to look for cancer.
“It is accurate, but it is also invasive, complicated and uses radioactive material,” Emelianov says. “We can do better.”
Emelianov speculates that in the future, we may be able to “weaponize” these contrast agents to actually kill cancer cells. Meanwhile, his team also is using its advanced imaging technology in collaboration with colleagues at Emory University’s Winship Cancer Center, to diagnose thyroid cancer and differentiate between malignant and benign tumors.
Tech’s Cancer Army
There are more than 40 faculty researchers at Georgia Tech who are members of the ICRC. They come from 12 different departments or schools. And there are an additional 16 researchers from academic and medical institutions that are affiliate members. It’s a diverse intellectual force that is giving Georgia Tech its own identity in cancer research.
“We can be a major player in cancer,” says McDonald. “How many medical schools have this breadth of expertise?”
He’s talking about young researchers like Susan Thomas, awarded Georgia Tech’s first grant from Susan G. Komen (breast cancer research foundation), supporting her work in immunotherapy for breast cancer; and Manu Platt, whose lab developed a new technique to give patients and oncologists more personalized information for choosing breast cancer treatment options.
And he’s referring to computer scientists like Constantine Dovrolis, who has spent the last few years investigating a phenomenon called “the hourglass effect” that is present in both technological and natural systems. He’s adapting what he learned studying embryogenesis with Georgia Tech biologist (and Petit Institute researcher) Soojin Yi to his collaboration with McDonald in cancer research.
He’s also thinking of BME-based researchers James Dahlman and William Lam.
Dahlman, an assistant professor who came to Georgia Tech earlier this year, works on cancer in two ways. Focusing extensively on primary lung tumors as well as lung metastasis, his team works on delivering genetic drugs to tumors.
“We have changed their gene expression, and either slowed tumor growth or caused established tumors to recede,” says Dahlman, an expert in gene editing. “In some cases, we have delivered multiple therapeutic RNAs to tumors, so that tumor cells are hit with a genetic ‘one-two’ punch that affects multiple cancer causing genes.”
His lab also creates tools to understand how cancer genes cause tumor resistance, studying how combinations of genes influence tumor growth, “because cancer is such a complicated disease and the genetics of cancer are notoriously difficult to understand,” Dahlman says. “It’s driven by many genes working together at once.”
For Lam, the war on cancer is waged in a lab and on the front lines, in a clinical setting. In addition to being a biomedical engineer, he’s also a pediatric hematologist-oncologist who treats patients at Children’s Healthcare of Atlanta.
His Ph.D. was actually focused on the biophysics of childhood leukemia, and his research in this area has focused on a small percentage of patients who develop leukostasis (stroke-like symptoms and lung failure).
“We always thought it was due to the biophysical properties of leukemia cells, which become big and sticky and jam up the plumbing of our blood vessels in our brain and lungs, which happen to have the smallest blood vessels,” says Lam, who is collaborating with Todd Sulchek, associate professor in mechanical engineering and a Petit Institute researcher.
“We’re combining some of Todd’s microfluidic technologies and our microfluidic technologies, to develop more high throughput ways to address this issue,” says Lam.
He’s also collaborating with the lab of BME professor Krish Roy on developing a ‘lymphoma on the chip’ model, to study how new cell therapies can directly affect the killing of cancer cells, as a way to determine whether those therapies have what it takes to work in the patient.
It’s all part of the multidisciplinary, “basement to bench to bedside” approach that Lam’s lab, with its connections to Georgia Tech, Emory University and Children’s Healthcare, has become known for.
“Within our lab, we’re certainly interested in technology development,” Lam says. “But then, we’re also interested in the assessment of the technology and, ultimately, directly translating that to the patient. Our lab lives in that entire space.”
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“This endeavor was uniquely made possible by the anonymous sample donors and the collaboration effort of nearly 100 researchers from 74 different research groups from all over the World,” Metspalu said.
The lab of Joseph Lachance in the School of Biological Sciences at Georgia Institute of Technology is one of these research groups. “By studying a global panel of individuals, we are able to identify genetic variants that are shared among different subsets of humanity and decipher our evolutionary past,” Lachance said.
The high geographic coverage of the samples permitted the researchers to study many aspects of genetic and phenotypic differences between individuals and populations using a common spatial framework. Researchers found that the sharpest genetic gradient in Eurasia separates East and West Eurasians. This barrier runs roughly along the Ural Mountains in the north, opens in the Steppe belt connecting Central Asia to South Siberia, and becomes strong again on the Tibetan plateau, elongating south toward the Indian Ocean while separating South and Southeast Asia.
In addition to increasing our understanding of the challenges that humans faced when settling down in ever-changing environments, the deluge of freely available data will serve as future starting point to further studies on the genetic history of modern and ancient human populations.
]]>Director of Communications
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]]>The National Institutes of Health made the award as part of an $11.1 million total investment in research funds slated for five institutions, including Georgia Tech. The researchers’ work could increase understanding of the causes of diabetes, Crohn’s disease, rheumatoid arthritis, forms of heart disease, and more afflictions where inflammation is at issue, and where there may be a connection to autoimmunity.
"We know that hundreds of genes impact autoimmunity, but the challenge is to narrow down the actual DNA sequence changes that have an impact. This grant combines our statistical genetics expertise with evolutionary genetics and genome editing by collaborators,” said Greg Gibson, a professor at Georgia Tech’s School of Biological Sciences.
In its research, Georgia Tech will work together with Rice University in Houston and Temple University in Philadelphia. Gibson's researchers will handle statistical analysis and interpretation; Rice's scientists will carry out gene editing, and evolutionary geneticists at Temple will contribute insights on which gene sites should or should not be variable in the human genome.
Our cells work together with masses of microbes that are an integral part of the human body, but the immune systems of people with related diseases can attack the microbes and healthy human cells, and lead to inflammation. “Lymphocytes, for example, could be attacking the body,” Gibson said.
“We’re looking at genes that regulate the immune system,” he said. “They’ve all got subtle effects. What counts is that they all work together. We’re looking for sections of genetic code that work a little oddly.”
Researchers will put data through algorithms to better identify genetic variants in sections of the human genome that do not encode proteins, but have regulatory functions, the NIH said in a news release. These are sections of DNA that, for example, turn encoding genes on and off.
They have been lesser studied but are known to be critical and could provide new information on yet undiscovered pathways composed of multiple faint characteristics that add up to disease.
"Taken alone, some small characteristic may appear indistinct, and at the same time, it’s really hard to read how a big group of them work in total,” Gibson said. “But their cumulative effect is dramatic, and unfortunate.”
Recent genomic research methods have compared the complete genomes of patients with diseases to those without them, leading to thousands of statistical hints. Now new data and interpretive approaches are needed to effectively sift through these to see the foundations of diseases, or make predictions of who is most at risk, and what people can do to reduce the risk.
The NIH hopes statistical methods will allow prediction of possible effects some variants have on susceptibility to disease and on drug response. The funding comes from the NIH’s National Human Genome Research Institute (NHGRI)'s Non-Coding Variants Program, and the National Cancer Institute (NCI).
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]]>Now researchers at the Georgia Institute of Technology have made it more likely that ancestral genes, along with ancestral proteins, can be confidently identified and reconstructed. They have benchmarked a vital tool that would seem nearly impossible to benchmark. The newly won confidence in the tool could also help scientists compute ancient gene sequences and use them to synthesize better proteins to battle diseases.
For some 20 years, scientists have used algorithms to compute their way hundreds of millions of years back into the evolutionary past. Starting with present-day gene sequences, they perform what’s called ancestral sequence reconstruction (ASR) to determine past mutations and figure out the genes’ primal forerunners.
“With the help of ASR, we can now actually build those ancient genes in the laboratory and express their encoded ancient proteins,” said Eric Gaucher, an associate professor at Georgia Tech’s School of Biological Sciences. In a separate project, his lab is computing ancient proteins that were very effective in blood clotting 80 million years ago, in hopes of using them to fight hemophilia today.
That protein comes from a common ancestor humans share with rats.
But ASR algorithms have faced logical criticism. Species based on those primal genes are long extinct, and scientists can’t travel back in time to observe mutations that have happened since. So, how can anyone find any physical benchmark to verify and gauge ASR?
A team of researchers led by Gaucher did it by building an evolutionary framework out of myriad mutations. Then they benchmarked ASR algorithms against it – no time machine required. Their results have shored up confidence that the widely used algorithms are working as they should.
“Most of them did a very good job – 98% accurate,” Gaucher said of contemporary algorithms’ ability to compute ancient gene sequences. Their determination of proteins encoded by those sequences was virtually perfect.
Gaucher, research coordinator Ryan Randall and undergraduate student Caelan Radford published their results on Thursday, September 15, 2016, in the journal Nature Communications. Their research has been funded by the NASA Exobiology program, E.I. du Pont de Nemours and Company (DuPont) and the National Science Foundation.
Ancestral sequence reconstruction is like making a family tree for genes.
The many twigs and branches at the treetop would be sequences from species alive today. Shimmying down the tree, called a phylogeny in genetics, you would find their common ancestors, millions of years old, in the lower branches.
There’s a caveat; none of the lower branches exist any longer. They vanished in the extinction of the species bearing those genetic sequences.
ASR computes them back into place using algorithms based on scientific models of evolution. It’s like replacing missing branches with holographic duplicates.
The accuracy of those evolutionary models has been a historic sticking point. And doubts about the algorithms based on them linger in some circles that hold on to an old, tried-and-true algorithm.
So, Gaucher and researcher coordinator Randall pitted the contemporary model-based, or “maximum likelihood,” algorithms in a race against the generic, or “parsimony,” algorithm.
“Parsimony follows the simplest notion of evolution, which is that very little mutation occurs,” Randall said. The models behind contemporary “maximum likelihood” algorithms, by contrast, are laced with filigree, data-packed details.
For the race, Randall made a track of sorts by putting a gene sequence that made a single protein through multiple mutations to construct a real-life phylogeny. She used methods that closely mimicked natural evolution, but that were much, much faster.
In cells, enzymes called polymerases aid in DNA duplication. They work very efficiently, but their rare mistakes are the most common source of mutations, and Randall took her lead from this.
“We used a polymerase that is error-prone to speed up mutations, and speed up evolution,” she said.
The genes used at the starting point of the lab evolution made a protein that fluoresced red when placed in bacteria. As significant mutations arose, the proteins began changing color. Bacteria containing green fluorescing proteins popped up among the red ones.
Randall divided bacteria with major mutations into new groups, creating branches in the phylogeny, as she went. Many mutations produced new colors – yellow, orange, blue, pink – and Randall ended up with a gene family tree in rainbow colors.
The colors reflected not only new gene sequences but also new phenotypes – the actual proteins they produced, the organism’s working molecules.
“What counts is phenotype,” Gaucher said. “When you analyze DNA strictly by itself, it ignores the context, in which that DNA is connected to phenotype,” he said.
DNA can mutate and still encode the same amino acids, protein’s component parts. Then the mutation has no real effect. But when mutations cause DNA to encode different amino acids, they’re more significant.
A worthy test of ancestral sequence reconstruction algorithms must therefore include phenotype. And Randall took this into account when she selected mutated proteins.
“I selected for variants to purposely make it hard on the algorithms to infer the phenotypes,” she said. The race ensued, and the algorithms got limited information to infer the evolutionary tree’s many dozens of past mutations.
Though the tried-and-true parsimony algorithm performed well, maximum likelihood performed better. “Even though it got the same number of residues (DNA sequences) wrong as parsimony, the incorrectly inferred sequences were still more likely to encode the right phenotypes,” said undergraduate student Caelan Radford, who analyzed the experiment’s statistics.
The margin of error was so tiny that it would not interfere in the determination of past species.
The experiment’s outcome was not too surprising, because prior simulations had predicted it. But the researchers wanted the scientific community to have physical proof that feels trustier than proof from a computer. “It’s a computer algorithm. It will do what you will tell it to do,” Gaucher said.
Doubts about ancestral sequence reconstruction -- and maximum likelihood algorithms in particular -- go far back. The idea of performing ASR first came up in 1963, but it didn’t get started until the 1990s, and back then, researchers battled fervently over wide-ranging methods.
“People would come up with the craziest notion as to why one model was best,” Gaucher said. “They’d say, ‘Well, if I simulate this weird mode of evolution along these branches here, my algorithm will work better than your algorithm.’”
The parsimony algorithm was a way of reigning in the chaos that grew out of a lack of data in evolutionary models at the time. “When the model is wrong, ‘maximum likelihood’ fails miserably,” Gaucher said.
But, now, a host of data and analysis give scientists a great picture of how evolution works (and it’s not a parsimony principle): For ages, nothing moves, then change bursts forth, then things stabilize again.
“You get this quick evolution, so lots of stuff works and lots of stuff fails, and the stuff that works then goes on and kind of maintains its status and doesn’t change,” Gaucher said. By confirming the high accuracy of the algorithms, the Georgia Tech team has also corroborated the validity of current evolutionary science they’re based on.
Kelsey Roof and Divya Natarajan of Georgia Tech coauthored the paper. Research was funded the NASA Exobiology program (grant number NNX12AI10G), DuPont (Young Professor Award) and the National Science Foundation (grant number 1145698). Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the sponsoring agencies.
Read more exciting science and technology research news at Research Horizons
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]]>In addition to being a founding father of the United States, Franklin also was a scientist, so he’d probably be interested in the Bioinformatics Graduate Program at the Georgia Institute of Technology, where another kind of certainty has been in play.
For the last five years every graduate of the program found the work they wanted – a 100-percent job placement rate. Well, almost. It turns out, there’s a tiny wrinkle in that impeccable run of success, according to program director King Jordan.
“It’s a lofty claim, to be sure, that we’ve been at 100 percent for years,” says Jordan, researcher at the Petit Institute for Bioengineering and Bioscience and associate professor in the School of Biological Sciences. “But there is one person we know for sure that isn’t working right now. He isn’t sure what he wants to do yet. That’s why he isn’t employed.”
Yet.
For now, 99-plus percent will do. It’s a high success rate, 10 years in the making, since Jordan arrived at Georgia Tech to help develop the bioinformatics curriculum and grow the program.
“The program didn’t have the best record at the time; some of our graduating students were struggling to find employment,” says Jordan, who came to Georgia Tech from the National Center for Biotechnology Information at NIH.
Jordan and his colleagues revamped the curriculum, emphasizing active learning and practical skills. “We made the program more project oriented,” he says.
One of the first courses, and part of the core curriculum, is programming for bioinformatics. It’s taught largely by Ph.D. students and is a fundamental first-step, designed to bring everyone up to the same speed on the primary tool of the trade – the computer.
“Bioinformatics lies at the intersection of biology and computer science,” Jordan says. “So we have a diverse cross-section of students. At one end are straight biologists, like me. At the other end, we have the programmers.”
Students are given coding assignments every week, and every assignment is grounded in the actual analysis of data.
The computational genomics course takes data analysis up to another level. Students are charged with analyzing sets of genomic sequences from microbial pathogens for the Centers for Disease Control and Prevention (CDC).
The relationship between the CDC and the Bioinformatics Graduate Program has had far-reaching impact. Jordan and a team of graduate students worked closely with CDC to develop computational tools for microbial genome analysis that helped trace the source of listeria outbreaks in Colorado and an E. coli outbreak in Europe.
“Students are producing products and technology that is being used by the CDC to address real world public health challenges,” says Jordan, whose team developed and teaches the course in collaboration with the CDC.
The tools needed for a course like computational genomics keep changing, so students are expected to stay abreast of an ever-shifting technological landscape, which is moving the science briskly forward. Think about it. The Human Genome Project, completed in 2003, took 10 years and $3 billion to sequence one genome – something that can be done in a day for about a thousand dollars now.
“If I teach you how to use program X today, by next year it will probably be obsolete,” Jordan says.
Consequently, students are presented with the project goals and the different technical options, and then asked to evaluate which computer programs (which tools, which options) to use in their analysis.
“Mostly, they wind up using a combination of programs,” Jordan says. “It’s cliché, but it’s like teaching them how to fish, how to acquire and evaluate the technology to complete the project.”
While the Georgia Tech curriculum and deep-dive project experience has been an obvious selling point for the job seekers, the market for their services has expanded as well.
“There’s more demand in the market than we can meet,” says Jordan.
The Georgia Tech Bioinformatics Program is trying to help meet the demand by adding more students – this fall’s incoming class of 52 students (40 master’s, 12 PhD) is the biggest in the program’s history, and as usual, they come from a range of backgrounds.
So, what are all of these students doing after they graduate?
For one thing, they’re working in university and research institute labs. Biology is becoming a ‘big data’ science as biologists are generating massive data sets in the era of high-throughput experimentation techniques. Consequently, biologists today need people who are competent in the skills and tools used to analyze those huge data sets.
“The technological revolution in DNA sequencing, which has vastly outpaced increases in computing speed over the last decade, is fundamentally transforming biological sciences in nearly all disciplines,” explains Jung Choi, associate professor in the School of Biological Sciences, and director of the Professional Science Masters (M.S.) track in the bioinformatics program. Jordan directs the Ph.D. track.
“The explosion of big data in biological sciences created a shortfall in people trained to manage and make sense of the data in the context of biology,” Choi adds. “Bioinformatics, genomics, and computational biology are among the most rapidly advancing fields. In a research setting, our students learn how to evaluate and adapt the best new tools and methods that emerge every year.”
Bioinformatics grads are finding their way into government labs – once again, the CDC has come up big, hiring seven bioinformatics grads from the past two classes. And they’re also going into the private sector.
“Within biotech are two big sectors that are frequent employers of our graduates,” says Jordan. “The pharmaceutical industry and the agriculture industry.”
Then there is another route some students are choosing as a result of the research-intensive nature of the bioinformatics program. About a quarter of the Master’s students choose to continue their education and enter Ph.D. programs.
“M.S. students can go right away to pharmaceutical companies and make big bucks, but some who are exposed to research are becoming passionate about that, so they decide to go on and pursue the Ph.D.,” Jordan says. “That’s what I call an unanticipated benefit of our revamped focus.”
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But he says that all changed around 2000, near the conclusion of the Human Genome Project, which utilized an integrated, cross-disciplinary approach to transform biology, leading to the launch of ‘systems biology.’
“Then, all of a sudden, we came out of the shadows,” says Voit, a professor in the Wallace H. Coulter Department of Biomedical Engineering (BME) and a researcher in the Petit Institute for Bioengineering and Bioscience.
“Talk about a tipping point,” says Voit, also a Georgia Research Alliance Eminent Scholar in Systems Biology. “That was the Human Genome Project. Until then, nobody even wanted to talk with people like me. ”
Probably, it’s because they wouldn’t have known what to talk about.
“The field was very, very underdeveloped,” says Voit, who has spent a good part of his career trying to explain what systems biology is, becoming an internationally recognized leader in the field and an authoritative spokesperson as the author of five books on the subject.
His textbook, A First Course in Systems Biology, is required reading for BME students at the Georgia Institute of Technology. While that book has been hailed as one of the best in the field, a powerful introduction to systems biology, it isn’t exactly light reading, and the target audience is limited.
“There aren’t a lot of people looking for systems biology books in the book store, and what they do find is incomprehensible,” said Voit, who decided to write something that would appeal to a larger audience, partly because, “it started to bother me that not even my own family and friends would read my books.”
Systems biology is, basically, a holistic, but rigorously anchored approach to biological research; the study of whole systems (molecules, cells, organisms or entire species), utilizing technologies like genomics, molecular analysis and proteomics and, importantly, mathematical and computational models.
“Most books in the field use heavy, heavy math. I wanted to write a systems biology book without equations,” says Voit.
The result is the recently published The Inner Workings of Life: Vignettes in Systems Biology. The reader doesn’t have to dive very deep before realizing that this is not your average science book.
The front of the book has an ‘Appetizer,’ instead of a ‘Preface or ‘Foreword.’ The chapters have provocative titles like, “I’d rather be fishin’” and “Close only counts in horseshoes and hand grenades,” and “Love thyself and fight all others.”
Voit is obviously having fun and manages to commiserate with the reader while sharing his knowledge with this new book. For instance, he lightheardedly mocks the overuse of some jargon within his field (there’s a whole chapter, most of it tongue-in-cheek while also managing to be explanatory, on the nearly ubiquitous suffix “-omics”), but then he includes a helpful, informative section called “Gentle Jargon” near the back of the book.
Basically, The Inner Works of Life is Voit’s way of explaining himself and his work and the field he works within, to people who pay the freight.
“The taxpayer is paying for this research we’re doing, and if he or she is interested in what we’re doing, he or she should have the opportunity to learn more about it, without needing an advanced degree,” Voit says. “This is rather complicated stuff, especially the technical aspects, but one should be able to write about what is happening out there in systems biology in an easy-to-understand way. You can write what the challenges are, what the promise is, why we are doing what we do. All of that was a good reason to write this book.”
It’s the first of its kind – a systems biology book that is accessible to the general reading public. Voit was probably the perfect fit for this kind of groundbreaking. He was the first person in the 630-year history of the University of Cologne (in his native Germany) to major in biology with a minor in mathematics.
“They laughed at me then because, at the time, the thinking was that biology is too complicated to use math,” he says. “Now we know that biology is too complicated not to use math.”
But there are no equations in Voit’s new book. He relies on facts, narrative, wit, and the occasional metaphor to help define a field of research that is still defining itself, populated by researchers who are finally out of the shadows. Voit thinks of these system biologists, who are working in a realm that is central to all areas of biology and medicine, as master Sudoku players.
“Trying to figure out how the multitudinous parts in cells work together to create something as incredible as a brain is very attractive to us,” he says. “We are fully aware that we will not solve the whole puzzle in our lifetimes, but nature is modular, and every systems biologist hopes to solve a large sub-puzzle, or at least a few smaller puzzles. The intellectual challenge is the enormous complexity of every cell and organism, which requires us to invent new tools and methods, and that’s what systems biology is all about.”
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The three Regents Professors are:
The new Regents Researcher is:
“Georgia Tech is incredibly proud to have some of the world’s best and brightest scholars, and we congratulate these faculty members on their new appointments,” said Rafael L. Bras, provost and executive vice president for Academic Affairs and the K. Harrison Brown Family Chair. “This new distinction is a testament to their continued commitment to excellence in teaching, research, and scholarship.”
Each year, academic deans may nominate two academic faculty members for the Regents Professor title and one research faculty member for the Regents Researcher title. Georgia Tech Research Institute (GTRI) may nominate two research faculty members for Regents Researcher. The titles are awarded upon approval of the chancellor and the Committee on Academic affairs only with unanimous recommendation of the president, the chief academic officer, the appropriate academic dean, and three other faculty members.
“The contributions of these faculty members make a lasting impact on the research and education enterprise here at Georgia Tech,” said Steve Cross, executive vice president for Research. “That impact also bolsters the Institute’s goals to serve as a driver of economic vitality in Atlanta, the state of Georgia, and beyond.”
The Board of Regents is the University System of Georgia governing body.
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]]>In schizophrenia, the matrix is sharply jarred, debilitating the mind and triggering hallucinations. Now, researchers at the Georgia Institute of Technology have created an interactive model of that matrix to fast-track research and treatment of the tormenting disorder.
Working memory disruptions paralyze the mental coherence of schizophrenia sufferers, yet there is a stark lack of medical treatment for it. Researchers Zhen Qi and Eberhard Voit hope their new, very accurate computational simulator built around this symptom will help change that to curb anquish for many patients.
Learn more about the simulator, which puts this brain dysfunction into a virtual setting.
]]>Bader, a renowned HPC expert, leads several initiatives and projects that connect to the NSCI’s core objectives. He attended the invitation-only meeting to offer his insights on the country’s current standing in HPC.
“From improving health care to protecting our nation against a cyberattack, the United States must invest in high-performance computing,” said Bader. “Maintaining a competitive advantage in HPC requires strategic investment and coordination across government, industry, and academia. Georgia Tech is a key university where we can make significant leaps in solving tomorrow’s computational and big data challenges.”
The goal of the NSCI is to advance core technologies in order to solve difficult computational problems, and foster increased collaboration between the public and private sectors. It will enable new analytic methods requiring more extensive computer processing, such as emerging techniques that allow artificial intelligence to learn new skills from large number sets.
There are also national security benefits, including using modeling and simulation to design vehicles resistant to improvised explosive devices (IEDs). This coordinated national HPC strategy draws on the strengths of departments and agencies to move the federal government into a position that sharpens, develops, and streamlines a wide range of new 21st century applications.
For additional information about David Bader or the National Strategic Computing Initiative, please use the links provided.
]]>Communications Assistant
]]>Though it can’t think – much less think twice -- about anything, the laboratory worm underwent a surprising mutation that made it prioritize the survival of adults over creating abundant offspring. Researchers noticed the sweeping change in behavior, and the mutation, after LSJ2 had faced hardship for 50 years.
Such so-called life history trade-offs have been described in many living things from mice to elephants, but now, for the first known time, researchers at the Georgia Institute of Technology have pinned some to a specific mutation.
“This is a great hint at how life history trade-offs could be regulated genetically,” said lead researcher Patrick McGrath, an assistant professor in Georgia Tech’s School of Biological Sciences.
The researchers confirmed the link in LSJ2, a strain of the C. elegans species, by duplicating the mutation in another strain, which reproduced the mutation’s effects to a very high degree.
The researchers published their results in the journal PLOS Genetics on Thursday, July 28, 2016. Their work has been funded by the National Institutes of Health and the Ellison Medical Foundation.
The mutation in the LSJ2 strain amounted to a small deletion in its DNA. As a result, a large protein changed by a meager 10 of its roughly 3,000 amino acids.
But that triggered a huge behavioral overhaul that boosted lifespan and slowed down reproduction. The contrast between the minor genetic tweak and its transformative ramifications might compare well with a toddler knocking loose an avalanche with a snowball.
The new discovery also has a tangential connection to human genetics. The roundworm shares with us the NURF-1 gene, on which the mutation occurred. And an associated human protein is involved in, among other things, reproduction.
All at once, LSJ2 did a lot of peculiar things, and that got the attention of McGrath and his team. And that’s what the lab roundworms are there for.
Since 1951, generations of scientists have been speeding up the evolution of lab-bound C. elegans by forcing the microscopic species of roundworms to adapt to new, mostly stressful, conditions. Then, when researchers have noticed changes, they’ve worked to trace them to the animals’ genes.
McGrath points to a thin, glass slide standing vertically under a light with tubules of fluid connected to it. Inside the slide, is a different lab strain of C. elegans.
“We’re raising those in fluid with gravity pulling them down to see if mutations will give them the ability to swim,” McGrath said.
In the case of LSJ2, researchers came up with a different challenge to accelerate its evolution. They fed it bland food for 50 years.
“It’s a diet of watery soy extract with some beef liver extract,” said Wen Xu, a graduate student who researches with McGrath. Sounds yucky enough to humans, but to the roundworm, it's worse. It equates to a regimen of bread and water.
Mutations eventually took hold to promote LSJ2’s survival in the scanty broth, and they were head-turning.
“The stark thing that we noticed first was the propensity to no longer enter the state called dauer,” McGrath said. It’s a kind of hyper-hibernation. “Dauer is something most C. elegans do to extend their lives, but LSJ2 did not. And it lived longer in spite of it.”
Then the list of anomalies grew, and grew.
“We found that almost everything was affected – when they started reproducing, how many offspring they made, how long they lived,” McGrath said. Some even survived exposure to drugs and heavy metals.
“Eventually we realized that the worms were prioritizing individual survival over reproductive rate.”
In many species, sex dries up when food is scarce, resulting in fewer progeny to compete for it. In addition, many organisms are well-equipped to manage their energies to survive dearth.
But C. elegans LSJ2 had to mutate into those abilities, and so many mutation-based behavioral changes all at once is uncommon.
“What you usually find is mutations that play narrow, very specific roles,” McGrath said. “They only affect egg laying, or they only affect life span, or they only affect dauer formation."
McGrath and Xu went sleuthing for DNA alterations by mapping quantitative trait loci, which matches up changes in characteristics to genetic changes. They dug in for a long investigation, anticipating multiple suspects among LSJ2’s many mutations.
“There were hundreds of genetic differences between roundworm strain LSJ2 and the one we were comparing it to,” McGrath said.
The comparison laboratory strain is called N2, and it has led a pampered existence with a diet of E. coli -- optimal food for C. elegans. (Both the E. coli and the roundworms are strains that are not harmful to humans.)
So, N2 hadn’t been pushed to mutate so much. In addition, to avoid confusion in their research results, the researchers reset some of the mutations N2 did happen to undergo.
The comparison led to swift evidence in LSJ2. “Every single time, it pointed us to the same genetic region on the right arm of chromosome 2,” McGrath said. C. elegans has six chromosomes.
“There were only five genes that were candidates. One of the mutations was a smoking gun -- a 60-base-pair deletion just at the end of the NURF-1 gene.”
NURF-1 has the function of remodeling chromatin, which pairs DNA with proteins to wrap them into chromosomes. The resulting configurations strongly influence which genes are expressed. It appears the tiny mutation in the remodeling gene may have led to a massive change in the expression of other genes.
There are missing pieces needed to understand the pathway from the mutated gene to the massive real-life changes, and the researchers are working to fill them in.
To confirm the mutation as the trigger of the changes, Xu deployed a CRISPR Cas9 gene editor into N2 worms to make the deletion that LSJ2 had received via mutation, and the results left little doubt.
“It had a lot of the same effects – longer life, dauer formation,” Xu said. “The main difference was the reduction of reproduction rates. It was only about half as much in the comparison worm that got the gene editing.”
By the way, as sex goes, C. elegans are mostly hermaphrodites that produce eggs and their own sperm to fertilize them with. But there are also males that copulate with the hermaphrodites to add new sperm and with it genetic diversity.
Edward E. Large, Yuehui Zhao and Lijiang Long from Georgia Tech; Shannon Brady and Erik Andersen from Northwestern University, and Rebecca Butcher from the University of Florida coauthored the paper. Research was sponsored by grants from the National Institutes of Health (numbers R21AG050304 and R01GM114170) and by an Ellison Medical Foundation New Scholar in Aging grant.
]]>Science synopsis: Possible regulator gene for life history trade-offs found via pleiotropic NURF-1 mutation in C. elegans; confirmed with CRISPR Cas9
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]]>IDEaS is jointly led by Co-Executive Directors Srinivas Aluru and Dana Randall, both professors in the College of Computing, and includes researchers and faculty that span all six colleges, creating critical interdisciplinary research opportunities, and positioning Georgia Tech at the forefront of big data solutions.
“As Georgia Tech becomes more visible as a thought leader in data science and engineering, the big idea for IDEaS is to provide the coordination and expertise necessary to link researchers across the Institute, strengthening our position in big data,” said Steve Cross, executive vice president for Research. “Doing so better equips them to take on important and complex problems. It creates meaningful partnerships and accessible resources, and educates future data science leaders. It also addresses long-standing challenges in the world of big data, creating critical push points through the innovation stage, enabling and accelerating the adoption process.”
Data-driven research is becoming commonplace in many fields of science and engineering, with devices, sensors, and scientific instruments collecting enormous amounts of data that must be analyzed with both discipline-specific knowledge and data science skills. The need to forge partnerships and unify resources in this area is widely recognized, as the National Science Foundation recently established four Regional Innovation Hubs. Aluru co-leads one of these, the South Big Data Hub, that unites partners across 16 Southern states and Washington, D.C.
“The IRI will link research centers and efforts horizontally in foundational areas such as machine learning, high-performance computing, and algorithms,” said Aluru. “It will also drive research within disciplines such as precision medicine, materials science, energy, and smart cities, giving researchers what they need to innovate and pursue challenges on a much bigger scale.”
IDEaS will facilitate new ventures and industrial collaboration between Technology Square’s recently announced Coda building research neighborhoods, providing a unique opportunity for academia to rub shoulders with industry, and be an asset to other premier education, research, and public-serving institutions in Georgia, particularly Emory University and the Centers for Disease Control. It will also collaborate with several stakeholders in the State of Georgia, including the Technology Association of Georgia, and the Georgia Manufacturing Extension Partnership, and serve as an incubator for economic development opportunities.
“Data is a critical part of research and applications everywhere,” said Randall. “Despite impressive advances, many in research and industry remain ill-equipped to derive the most benefits from data. IDEaS exists to change that.”
]]>If the miRNA molecules can be delivered to cells in the human body – potentially with nanoparticles – the technique might one day be used to battle the chemotherapy resistance that often develops during cancer treatment. A research team at the Georgia Institute of Technology identified the miRNA used in the research with a computer algorithm that compared the ability of different miRNAs to control the more than 500 genes that were up-regulated in drug-resistant cancer cells.
The study was reported May 27 in the Nature Publishing Group journal Cancer Gene Therapy.
“We were specifically interested in what role miRNAs might play in developing drug resistance in these cancer cells,” said John McDonald, a professor in Georgia Tech’s School of Biology and director of its Integrated Cancer Research Center. “By increasing the levels of the miRNA governing the suite of genes we identified, we increased the cells’ drug sensitivity back to what the baseline had been, essentially undoing the resistance. This would suggest that for patients developing chemotherapy resistance, we might one day be able to use miRNAs to restore the sensitivity of the cancer cells to the drugs.”
MicroRNAs are small non-coding molecules that function in RNA silencing and post-transcriptional regulation of gene expression. The miRNAs operate via base-pairing with complementary sequences within messenger RNA (mRNA) molecules, silencing the mRNA molecules that control the expression of certain proteins.
Roman Mezencev, a senior research scientist in the McDonald lab, began by exposing a line of pancreatic cancer cells (BxPC3) to increasing levels of the chemotherapy drug cisplatin. After each in vitro treatment, surviving cells were allowed to proliferate before being exposed to a higher level of the drug. After approximately a year and 20 treatment cycles, the resulting cell line had a resistance to cisplatin that was 15 times greater than that of the original cancer cells.
The next step was to study the genetic changes associated with the resistance, comparing levels of more than 2,000 miRNAs in the cisplatin-resistant line to the original cell line that had not been exposed to the drug. Using a hidden Markov model (HMM) algorithm, they found 57 miRNAs that were either up-regulated or down-regulated, and identified miR-374b as the molecule most likely to be controlling the genes that govern chemotherapy resistance.
While previous work by other researchers has shown that miRNAs can provide a mechanism for the development of drug resistance, the Georgia Tech team took the findings a step farther by increasing the expression of miR-374b. When they did, they found that the cells previously resistant to the cisplatin were again sensitive to the drug – almost back to their original levels.
Techniques to control protein expression are already being used in cancer therapy, but McDonald believes there may be benefits in targeting the activity higher up in the process – at the RNA level. Studies by the Georgia Tech team and by other researchers clearly show an association between chemotherapy resistance and changes in levels of certain miRNAs.
“Molecular evolution is a highly efficient process,” McDonald said. “Our evidence suggests that many of the genes regulated by a single microRNA are involved in coordinated cellular functions – in this case, drug resistance. We believe that microRNAs might be particularly good cancer therapeutic agents because when we manipulate them, we are manipulating suites of functionally coordinated genes.”
A next step will be to study the effects of manipulating miRNA levels in animal cancer models. The McDonald research team is currently pursuing this possibility by inserting the microRNAs into tumors using nanoscale hydrogels developed by Andrew Lyon, former chair of Georgia Tech’s School of Chemistry and Biochemistry.
McDonald says the study confirms the role of miR-374b in creating resistance, though he says there could be other microRNA molecules involved, as well.
“These cells have acquired resistance to the drug, and we have found a microRNA that seems to be playing a major role,” he said. “We have shown that we can bring sensitivity to drugs back by restoring levels of miR374b, but there may be other miRNAs that will work equally as well. Just as there are multiple pathways to establish cancer and chemoresistance, there may be multiple pathways to restore chemosensitivity, as well.”
If cancer could one day be treated using miRNAs, it’s likely to be a continuing battle rather than a decisive victory, McDonald said. Cancer cells are very resourceful, and will likely find a new genetic route to resistance if one pathway is destroyed. That could require use of a different miRNA to reverse resistance.
While the miRNA research isn’t likely to provide a “magic bullet” for cancer, it does show the possible role of these tiny RNA molecules in controlling a broad class of bodily processes.
“There is growing evidence that this class of small regulatory RNAs may be involved in many processes ranging from evolution to heart disease,” he said. “MiRNAs are emerging as important players in cancer in general. Here, we are focusing on just one particular aspect of it.”
In addition to those already mentioned, the research team included R. Schreiber and L.V. Matyunina, both from Georgia Tech. In addition Schreiber is affiliated with the Faculdade de Ciências Médicas – UNICAMP in Brazil. The work was supported by funds from the Deborah Nash Endowment and the Mark Light Fellowship.
CITATION: R. Schreiber, et al., “Evidence for the role of microRNA 374b in acquired cisplatin resistance in pancreatic cancer cells,” (Cancer Gene Therapy, 2016). http://dx.doi.org/10.1038/cgt.2016.23
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]]>Researchers at the Georgia Institute of Technology used high-throughput screening techniques to study the effects of titanium dioxide nanoparticles on the expression of 84 genes related to cellular oxidative stress. Their work found that six genes, four of them from a single gene family, were affected by a 24-hour exposure to the nanoparticles.
The effect was seen in two different kinds of cells exposed to the nanoparticles: human HeLa cancer cells commonly used in research, and a line of monkey kidney cells. Polystyrene nanoparticles similar in size and surface electrical charge to the titanium dioxide nanoparticles did not produce a similar effect on gene expression.
“This is important because every standard measure of cell health shows that cells are not affected by these titanium dioxide nanoparticles,” said Christine Payne, an associate professor in Georgia Tech’s School of Chemistry and Biochemistry. “Our results show that there is a more subtle change in oxidative stress that could be damaging to cells or lead to long-term changes. This suggests that other nanoparticles should be screened for similar low-level effects.”
The research was reported online May 6 in the Journal of Physical Chemistry C. The work was supported by the National Institutes of Health (NIH) through the HERCULES Center at Emory University, and by a Vasser Woolley Fellowship.
Titanium dioxide nanoparticles help make powdered donuts white, protect skin from the sun’s rays and reflect light in painted surfaces. In concentrations commonly used, they are considered non-toxic, though several other studies have raised concern about potential effects on gene expression that may not directly impact the short-term health of cells.
To determine whether the nanoparticles could affect genes involved in managing oxidative stress in cells, Payne and colleague Melissa Kemp – an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University – designed a study to broadly evaluate the nanoparticle’s impact on the two cell lines.
Working with graduate students Sabiha Runa and Dipesh Khanal, they separately incubated HeLa cells and monkey kidney cells with titanium oxide at levels 100 times less than the minimum concentration known to initiate effects on cell health. After incubating the cells for 24 hours with the TiO2, the cells were lysed and their contents analyzed using both PCR and Western Blot techniques to study the expression of 84 genes associated with the cells’ ability to address oxidative processes.
Payne and Kemp were surprised to find changes in the expression of six genes, including four from the peroxiredoxin family of enzymes that helps cells degrade hydrogen peroxide, a byproduct of cellular oxidation processes. Too much hydrogen peroxide can create oxidative stress which can damage DNA and other molecules.
The effect measured was significant – changes of about 50 percent in enzyme expression compared to cells that had not been incubated with nanoparticles. The tests were conducted in triplicate and produced similar results each time.
“One thing that was really surprising was that this whole family of proteins was affected, though some were up-regulated and some were down-regulated,” Kemp said. “These were all related proteins, so the question is why they would respond differently to the presence of the nanoparticles.”
The researchers aren’t sure how the nanoparticles bind with the cells, but they suspect it may involve the protein corona that surrounds the particles. The corona is made up of serum proteins that normally serve as food for the cells, but adsorb to the nanoparticles in the culture medium. The corona proteins have a protective effect on the cells, but may also serve as a way for the nanoparticles to bind to cell receptors.
Titanium dioxide is well known for its photo-catalytic effects under ultraviolet light, but the researchers don’t think that’s in play here because their culturing was done in ambient light – or in the dark. The individual nanoparticles had diameters of about 21 nanometers, but in cell culture formed much larger aggregates.
In future work, Payne and Kemp hope to learn more about the interaction, including where the enzyme-producing proteins are located in the cells. For that, they may use HyPer-Tau, a reporter protein they developed to track the location of hydrogen peroxide within cells.
The research suggests a re-evaluation may be necessary for other nanoparticles that could create subtle effects even though they’ve been deemed safe.
“Earlier work had suggested that nanoparticles can lead to oxidative stress, but nobody had really looked at this level and at so many different proteins at the same time,” Payne said. “Our research looked at such low concentrations that it does raise questions about what else might be affected. We looked specifically at oxidative stress, but there may be other genes that are affected, too.”
Those subtle differences may matter when they’re added to other factors.
“Oxidative stress is implicated in all kinds of inflammatory and immune responses,” Kemp noted. “While the titanium dioxide alone may just be modulating the expression levels of this family of proteins, if that is happening at the same time you have other types of oxidative stress for different reasons, then you may have a cumulative effect.”
Seed funding for the research came from the HERCULES: Exposome Research Center (NIEHS: P30 ES019776) at the Rollins School of Public Health, Emory University, NIH grant DP2OD006483-01 and a Vasser Woolley Faculty Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CITATION: Sabiha Runa, Dipesh Khanal, Melissa L. Kemp, Christine K. Payne, “TiO2 Nanoparticles Alter the Expression of Peroxiredoxin Anti-Oxidant Genes,” (Journal of Physical Chemistry C, 2016). http://dx.doi.org/10.1021/acs.jpcc.6b01939.
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]]>These tiny vesicles (smaller than red blood cells), discovered about 35 years ago, were initially thought of as little dumpsters for unwanted cellular material. But further study of exosomes demonstrated their role as long-distance couriers with specific messages to carry – they can transfer biomolecules (proteins, lipids, genetic material) that impact recipient cells’ functionality in a variety of physiologic and disease processes.
It also turns out that exosomes are in the ideal size range for lymphatic transport, and this is what really interests Brandon Dixon, faculty researcher in the Petit Institute for Bioengineering and Bioscience.
Dixon, whose research focuses on lymphatic function, attended a presentation by fellow Petit Institute researcher Fred Vannberg several years ago. Vannberg’s lab uses computer algorithms and genomics to investigate infectious diseases, and this includes the role of exosomes during infection. His presentation that day described the characteristics of exosomes, which when released in the periphery are too big to be taken up by blood vessels, but just right for lymphatic transport.
“When Fred told me that, I thought that here was a mechanism that seems to have been made to target lymphatics,” says Dixon, associate professor in the Woodruff School of Mechanical Engineering, who leads the Laboratory of Lymphatic Biology and Bioengineering (LLBB). “Exosomes are the perfect size when we think of creating contrast agents or drug delivery particles that we want to use to target lymphathics.”
So, utilizing a Petit Institute seed grant, Dixon and Vannberg brought their distinct skills together to produce a groundbreaking research paper, “Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node,” published last month in the Nature journal, Scientific Reports.
“Lymphatic vessels provide an extremely rapid route for delivery of exosomes from the tissue to the draining lymph node,” Dixon says. “Lymphatic transport has been implied in previous publications, but this is the first demonstration of immediate lymphatic transport, a feat we achieved using our non-invasive near-infrared imaging technology and fluorescently labeled exosomes.”
Their results suggest that exosome transfer via lymphatic flow (from the periphery to the lymph node) could enable a rapid exchange of infection-specific information that precedes the arrival of migrating cells, priming the node for a more effective innate immune response, or “a first warning response during infection,” Dixon explains.
“What’s exciting about this research is, we’re kind of finding out what is happening as part of the real-time response to infection, with the innate immune system being activated in a particular way by these particles,” adds Vannberg, assistant professor in the School of Biology. “And that helps guide what’s going to happen a few days later with the adaptive immune response.”
In previous research, Vannberg has tried to quantitate the body’s ability to fight infection, focusing on tuberculosis and leprosy. He became especially interested in exosomes’ role in our immune system’s ability to detect and fight disease after reading the research of Notre Dame researcher Jeff Schorey, who identified exosomes as ideal for diagnostic development.
The collaboration between Vannberg and Dixon is like a research laboratory version of a Marvel super hero saga – individuals combining disparate skills (‘super powers’ in the movie version) to achieve a common goal. Or, as Vannberg says, “this paper helps highlight both of our areas of expertise – mine in terms of genomics and infectious diseases, while Brandon is known worldwide for his work in lymphatic biology and his understanding of kinetics.”
Dixon’s lab was able to determine how fast the particles got delivered to the node – “within a few minutes,” Dixon says. “Until now, we really had no appreciation of the time scale.”
Lead author on the paper was biology grad student Swetha Srinivasan, who is co-advised by Dixon and Vannberg. They designed the experiments and she carried out the experimental work, while all three analyzed the data, wrote and reviewed the manuscript. Their published research illustrates a potentially efficient pathway for targeted therapeutics, somewhere down the line.
“We believe this work has far-reaching implications on how biological systems – like pathogens, immune cells and cancer cells – could utilize lymphatic transport of exosomes to rapidly manipulate the lymph node environment,” Dixon says.
An upcoming paper will help determine what actually happens when exosomes arrive in the lymph node.
“We’re interested in understanding the immune consequences of exosomes in the context of infection and immunity,” Vannberg says. “Further research will help explain how these particles can stimulate a quick response and also inform the adaptive response.”
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The research produced what may be the largest dynamic model of microbial species interactions ever created. Analyzing long-term data from Lake Mendota near Madison, Wisconsin, a Georgia Tech research team identified and modeled interactions among 14 sub-communities, that is, collections of different species that become dominant at specific times of the year. Key environmental factors affecting these sub-communities included water temperature and the levels of two nutrient classes: ammonia/phosphorus and nitrates/nitrites. The effects of these factors on the individual species were, in general, more pronounced than those of species-species interactions.
Beyond understanding what’s happening in aquatic microbial environments, the model might also be used to study other microbial populations – perhaps even human microbiomes. The research was reported on March 24 in the journal Systems Biology and Applications, a Nature partner journal. The work was sponsored by the National Science Foundation’s Dimensions of Biodiversity program.
“Ultimately, we want to understand why some microbial populations are declining and why some are increasing at certain times of the year,” said Eberhard Voit, the paper’s corresponding author and The David D. Flanagan Chair Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “We want to know why these populations are changing – whether it is because of environmental conditions alone, or interactions between the different species. Importantly, we also look at the temporal development: how interactions change over time.”
Because of the large number of different microorganisms involved, creating such a model was a monumental task. To make it more manageable, the researchers segmented the most abundant species into groups that had significant interactions at specific times of the year. Georgia Tech Research Scientist Phuongan Dam created 14 such categories or sub-communities – corresponding to roughly one per month – and mapped the relationships between them during different times of the year. Two of the 14 groups had two population peaks per year.
“The exciting part about this work is that we are now able to model hundreds of species,” said Kostas Konstantinidis, a co-author on the paper and the Carlton S. Wilder associate professor in Georgia Tech’s School of Civil and Environmental Engineering. “The ability to dynamically model microbial communities containing hundreds or even thousands of species as those interactions change over time or after environmental perturbations will have numerous implications and applications for other research areas.”
In the past, researchers have created static models of interactions between large numbers of microorganisms, but those provided only snapshots in time and couldn’t be used to model interactions as they change throughout the year. Scientists might want to know, for example, what would happen if a community lost one species, if a flood of nutrients hit the lake or if the temperature rose.
As with many communities, the lake includes organisms from different species and families that are highly interconnected, playing a variety of interrelated roles, such as fixing nitrogen, carrying out photosynthesis, degrading pollutants and providing metabolic services used by other organisms. Information about the microbes came from a long-term data set compiled by other scientists who study the lake on a regular basis.
Voit, a bio-mathematician, said the model, although itself nonlinear, uses algorithms based on linear regression, which can be analyzed using standard computer clusters. Using their 14 sub-communities, the researchers found 196 interactions that could describe the species interactions – a far easier task than analyzing the 300 million potential interactions between the full 18,642 species in the lake. Reducing the number of potential interactions was possible only due to the strategy of defining sub-communities and a clever modeling approach.
The researchers initially tried to organize the microbes into genetically related organisms, but that strategy failed.
“At any time of the year, the lake needs species that can do certain tasks,” said Voit. “Closely-related species tend to play essentially the same roles, so that putting them all together into the same group results in having many organisms doing the same things – but not executing other tasks that are needed at a specific time. By looking at the 14 sub-communities, we were able to get a smorgasbord of every task that needed to be done using different combinations of the microorganisms at each time.”
By looking at sub-communities present at specific times of the year, the research team was able to study interactions that occurred naturally – and avoided having to study interactions that rarely took place. The model examines interactions at two levels: among the 14 sub-communities, and between the sub-communities and individual species.
The research depended heavily on metagenomics, the use of genomic analysis to identify the microorganisms present. Only 1 percent of microbial species can be cultured in the laboratory, but metagenomics allows scientists to obtain the complete inventory of species present by identifying specific sections of their DNA. Because they are not fully characterized species, the components of genomic data are termed “operational taxonomic units” (OTUs), which the team used as a "proxy" for species.
The next step in the research will be to complete a similar study of Lake Lanier, located north of Atlanta. In addition to the information studied for Lake Mendota, that study will gather data about the enzymatic and metabolic activities of the microorganism communities. Lake Lanier feeds the Chattahoochee River and a series of other lakes, and the researchers hope to study the entire river system to assess how different environments and human activities affect the microbial populations.
The work could lead to a better understanding of what interactions are necessary for a healthy lake, which may help scientists determine what might be needed to address problems in sick lakes. The modeling technique might also help scientists with other complex microbial systems.
“Our work right now is with the lake community, but the methods could be applicable to other microbial communities, including the human microbiome,” said Konstantinidis. “As with sick lakes, understanding what is healthy might one day allow scientists to diagnose microbiome-related disease conditions and address them by adjusting the populations of different microorganism sub-communities.”
This material is based upon work supported by the National Science Foundation under Grant No. DEB-1241046. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.
CITATION: Phuongan Dam, Luis L. Fonseca, Konstantinos T. Konstantinidis and Eberhard O. Voit, “Dynamic models of the complex microbial metapopulation of Lake Mendota,” (Nature Partner Journal Systems Biology and Applications, 2016). http://dx.doi.org/10.1038/npjsba.2016.7
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]]>A new study of more than 50 samples of Vibrio cholerae isolated from both patients and the environment demonstrates the diversity and resourcefulness of the organism. In the environment, the cholera bacterium is commonly found attached to chitin, a complex sugar used by aquatic creatures such as crabs and zooplankton to form protective shells. In the wild, most strains of cholera can degrade the shells for use as food, and the new study showed how the presence of chitin can signal the bacteria – which have receptors for the material – to produce behaviors very different from those seen in human disease.
Among the cholera strains studied, less than a quarter were able to take up DNA from other sources. Almost all of the samples taken from the environment were able to kill other bacteria – a phenomenon called “bacterial dueling” – but just 14 percent of the bacterial pathogen strains isolated from humans had that capability.
“It’s a dog-eat-dog world out there even for bacteria,” said Brian Hammer, an associate professor in the School of Biology at the Georgia Institute of Technology. “Bacteria such as Vibrio cholerae sense and respond to their surroundings, and they use that information to turn on and off the genes that benefit them in the specific environments in which they find themselves.”
The research, supported by the National Science Foundation and the Gordon and Betty Moore Foundation, provides information that could lead to development of better therapeutic agents against the disease, which is found in densely-populated areas with limited sanitation and clean water. The research was done with assistance from the Centers for Disease Control and Prevention (CDC), and was reported online March 4 in the journal Applied and Environmental Microbiology.
In humans, the cholera bacteria produce a diarrheal disease that can kill untreated patients in just a few hours. The deadly effects of the disease, however, are actually caused by a virus that infects the Vibrio cholerae strains found in humans. The toxin carried by the virus helps spread the disease among humans, but cholera strains quickly lose the virus and adapt other competitive mechanisms in the environment.
To study how cholera regulates these adaptations, Georgia Tech graduate student Eryn Bernardy obtained nearly 100 samples of cholera bacteria from a variety of sources globally, including one originally isolated from a 1910 Saudi Arabian outbreak of the disease. She then studied 53 of the samples for their ability to (1) degrade chitin, (2) take up DNA from the environment, and (3) kill other bacteria by poking them with a poisoned spear.
Colonies of each strain were grown in petri plates containing chitin material. The strains able to digest the material produced a clear ring showing that they had broken down the chitin in the agar growth medium. Only three of the cholera colonies failed to degrade the chitin.
To study their ability to take up DNA, bacterial cells were grown on crab shells, then exposed to raw DNA containing a gene for antibiotic resistance. The cells were scraped off the shells and placed onto agar plates containing an antibiotic that would normally kill the bacteria. Colonies that survived showed they had taken up the genetic material.
To study their ability to compete with other bacteria, each cholera strain was placed into contact with a billion or so E. coli cells on petri plates. After a few hours in contact, the researchers counted the number of E. coli remaining. Some cholera strains were able to kill nearly all of the E. coli cells, reducing their numbers to a few hundred thousand.
“We found a very sharp difference between the clinical isolates and the environmental isolates,” Hammer said. “For example, most of the isolates that came out of patients either couldn’t kill other bacteria, or were carefully controlling that behavior. Patient isolates have a very different way of competing inside the human body. They use the virus-encoded toxin to cause the diarrheal disease and remove their competitors from the intestine.”
With help from CDC scientists, the researchers correlated the behavior of each strain with their unique DNA sequences. They also examined the strains for the presence of the toxin used to cause disease.
To deduce the rules governing the bacterium’s behavior, Hammer and his lab have been studying cholera for the last 15 years, starting with a single strain first isolated in Peru in the early 1990s. When a cholera outbreak began in Haiti after the 2010 earthquake, his lab worked with the CDC to isolate these new strains. In further study, Hammer was surprised to find that the 2010 Haitian strains were less capable than the 1991 Peruvian variety.
“We were very surprised to find that most of the Haiti strains did not behave like the one we had been studying for years,” he said. “This was a reminder to us that we needed to embrace the diversity of the organisms we’ve been studying. We thought this would be an opportune time to start looking at how diverse Vibrio cholerae really is.”
Hammer compared the diversity of the cholera strains to the diversity of humans, who increasingly receive personalized health care.
“In humans, one size doesn’t fit all for patient care,” he said. “For cholera, the behavior is personalized for each strain. Understanding this will be useful in the development of future therapeutics, and we’re hopeful that knowing how these bacteria interact with other organisms in complex communities will lead us to things that can truly benefit humans.”
In addition to those already mentioned, the study included Maryann A. Turnsek and Cheryl L. Tarr from the CDC. Georgia Tech undergraduate Sarah K. Wilson from the Hammer lab, another author on the paper, is now a Ph.D. student at the University of Wisconsin-Madison.
This material is based upon work supported by the Gordon and Betty Moore Foundation and National Science Foundation Grant No. 1149925. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation or the Moore Foundation.
CITATION: Eryn E. Bernardy, et al., “Diversity of Clinical and Environmental Isolates of Vibrio cholerae in Natural Transformation and Contact-Dependent Bacterial Killing Indicative of Type VI Secretion System Activity,” (Applied and Environmental Microbiology, 2016). http://dx.doi.org/10.1128/AEM.00351-16.
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]]>Dr. Joseph Lachance is leading the effort at Georgia Institute of Technology. His lab will use their expertise in population genetics and computational biology to focus on the evolutionary genomics of prostate cancer in African populations. “It is important to know which populations and ancestries have a genetic predisposition to prostate cancer, and to understand whether these health disparities are due to natural selection or neutral evolution,” said Lachance.
The five-year study, funded by the National Cancer Institute, is being led by principal investigator Timothy Rebbeck, PhD, professor of Medical Oncology, Dana-Farber Cancer Institute and professor of Cancer Epidemiology at Harvard TH Chan School of Public Health.“Aggressive prostate cancer is the form of the disease that is the most important to control. African descent men, including African Americans, seem to have biologically more aggressive forms of prostate cancer than other groups. By studying African descent men, we may also learn about aggressive prostate cancer so that we can better prevent and treat the disease,” said Rebbeck.
The participating centers are part of a consortium, Men of African Descent and Carcinoma of the Prostate, and include: Dana-Farber Cancer Institute. Boston, Massachusetts; 37 Military Hospital, Accra, Ghana; Albert Einstein College of Medicine, Bronx, New York; Center for Proteomic & Genomic Research and Clinical Laboratory Services, Cape Town, South Africa; Georgia Institute of Technology, Atlanta, Georgia; Hȏpital Général de Grand Yoff, , Dakar, Senegal; Korle-Bu Hospital, Accra Ghana; National Health Laboratory Services, Johannesburg, South Africa; NIH/NCI, Bethesda, Maryland; Stanford Cancer Institute, Stanford, California; Stellenbosch University, Cape Town, South Africa; University College Hospital, Ibadan, Nigeria.
The grant is funded by the NCI, grant number U01-CA184374.
]]>A paper published March 11 in the journal Applied and Environmental Microbiology describes microbial communities found in shower hoses at a major U.S. hospital. The study documented bacteria – and related genes – using cutting-edge metagenomic techniques that allow the characterization of organisms that cannot be detected using traditional culture-based microbiology assays.
Researchers from the U.S. Environmental Protection Agency and the Georgia Institute of Technology collaborated to study these biofilm communities, but can’t say yet if these bacteria pose a threat to hospital patients. But because some of the genes could indicate pathogenic characteristics – such as resistance to antibiotics – the researchers want to learn more about the potential health implications, and whether other buildings house similar biofilms. Antibiotic resistance is a public health emerging priority identified by the World Health Organization, which in 2015 released a global action plan to address the problem.
“We can say confidently that if pathogens are in there, they are not there in very high abundance,” said Kostas Konstantinidis, an associate professor in the School of Civil and Environmental Engineering at Georgia Tech. “But the organisms that we detected as abundant in these biofilms appear to have characteristics that could be of interest because they are related to some bacteria that are opportunistic pathogens that could pose a threat, especially to immunocompromised hospital patients”
The study began by culturing bacteria from 40 shower hoses removed from individual hospital rooms by EPA researchers. Nucleic acid was extracted from five of the shower hoses and processed using next-generation sequencing technology. The sequencing data was sent to Georgia Tech, where doctoral student Maria Juliana Soto-Girón matched the sequences against known bacteria – and genes that have known effects, such as virulence and antibiotic resistance.
The microbiome study found an abundant population of bacteria that the researchers believe are novel “Mycobacterium-like” species not described previously, closely related to Mycobacterium rhodesiae and Mycobacterium tusciae. Traditional culture-based methods instead identified organisms affiliated with Proteobacteria – such as members of the genera Sphingomonas, Blastomonas and Porphyrobacter – as the most abundant.
The biofilm communities harbored genes related to disinfectant tolerance, which constituted 2.3 percent of the total annotated proteins – and a lower abundance of virulence determinants related to colonization and evasion of the host immune system. Additionally, genes potentially conferring resistance to beta-lactam, aminoglycoside, amphenicol and quinolone antibiotics were identified. The frequency of these genes was higher than the frequency found in Lake Lanier, a natural freshwater ecosystem that has been studied by the Georgia Tech research team, suggesting that the drinking water pipe environments merit closer attention.
The research grew out of an EPA research project to understand the issues of drinking water systems and building microbiomes – the collection of microbes found in such structures. While biofilms are common in building water pipes, this study generated the most metagenomic data so far for the organisms living in these water systems. Additionally, the researchers analyzed 94 partial genomes of isolated biofilm bacteria, including some that had not been reported before, though they are related to previously-characterized microorganisms.
Though well-known pathogens weren’t seen in abundance, the presence of genes for antibiotic resistance, resistance to water disinfectants and virulence raises concerns because bacteria can share such genes to potentially become more significant health threats.
“If they have a core of genes, they may be receptive to acquiring other genes that will render these microorganisms more problematic," said Jorge Santo Domingo, a microbial ecologist with the EPA’s Office of Research and Development in Cincinnati. “These organisms are very good at living in difficult environmental conditions with limited carbon sources, so fighting them could become a challenging proposition. We don’t know if they constitute a problem, but we certainly want to find out.”
The analysis of material taken from the shower hoses is only a preliminary study, and much more research will be needed. Santo Domingo compared the findings to a “check engine” light in an automobile. The warning doesn’t necessarily indicate an immediate problem, though it does show that attention – and potential action – may be required.
“Some of the identified genes are the kind that we’d want to keep an eye on,” he explained. “We would like to conduct more studies to gather data on the dynamics of these bacterial groups, but the fact that these genes are present indicates that more studies should be done.”
The potential clinical significance of the bacteria needs to studied, and any public health impacts understood, he added. Other questions include whether similar biofilms would be found in other hospitals, whether biofilms differ among facilities, how monitoring should be done – and whether shower heads and hoses should be replaced on a regular basis.
The work could also provide a foundation for new research into the types of water disinfection used in hospitals. The chlorine compounds used in public drinking water may not provide sufficient protection for water supplies in these facilities. The sequencing data and bioinformatics analyses will help identify genetic markers that could be used to monitor these genes and determine their public health relevance.
While Konstantinidis and his research group have been studying microbes in natural ecosystems such as Lake Lanier in Georgia, this represents their first metagenome analysis of microbial communities in the built environment. They are hopeful that the technique, which is still in the research and development stage, can help understand issues involving microbial populations and their virulence potential in buildings where humans spend most of their time.
“Metagenomics gives you a more complete and quantitative picture of what microorganisms are there and how abundant they are,” he said. “This shows that traditional culture methods are limited in what they can detect, and that they can often provide a biased look at what is there.”
In addition to those already mentioned, the paper’s authors included Luis Rodriguez and Chengwei Luo from Georgia Tech, Michael Elk and Hodon Ryu from Pegasus, Inc., and Jill Hoelle from the EPA.
CITATION: Maria J. Soto-Girón, et al., “Characterization of biofilms developing on hospital shower hoses and implications for nosocomial infections,” (Applied and Environmental Microbiology, 2016).
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]]>Spawned by their development and application of a custom bioinformatics software tool (called SAPH-ire) 1, the Torres lab discovered a new way in which G protein signaling is regulated by phosphorylation – an enzyme-driven chemical modification of specific amino acid side chains found in most proteins. The newly discovered phospho-regulatory element, like G proteins themselves, is well conserved throughout eukaryotes, which will enable Torres and his lab to investigate how the element functions across diverse organisms such as budding yeast and humans. The National Institutes of Health grant will also provide funding to determine the biochemical mechanism of G protein phosphorylation – including the enzymes that activate the regulatory element in coordination with other cellular processes including cell division and stress. Through these and other approaches, Torres hopes to determine whether his lab has discovered a protein mechanism that is not only fundamental to the process of G protein signaling in all eukaryotes, but also a possible alternative target for pharmaceutical drug therapies.
Dewhurst, H. M., Choudhury, S. & Torres, M. P. Structural Analysis of PTM Hotspots (SAPH-ire)--A Quantitative Informatics Method Enabling the Discovery of Novel Regulatory Elements in Protein Families. Mol. Cell. Proteomics 14, 2285–97 (2015).
]]>Using advanced liquid chromatography and mass spectrometry techniques coupled with machine learning computer algorithms, researchers have identified 16 metabolite compounds that provided unprecedented accuracy in distinguishing 46 women with early-stage ovarian cancer from a control group of 49 women who did not have the disease. Blood samples for the study were collected from a broad geographic area – Canada, Philadelphia and Atlanta.
While the set of biomarkers reported in this study are the most accurate reported thus far for early-stage ovarian cancer, more extensive testing across a larger population will be needed to determine if the high diagnostic accuracy will be maintained across a larger group of women representing a diversity of ethnic and racial groups.
The research was reported November 17 in the journal Scientific Reports, an open access journal from the publishers of Nature.
“This work provides a proof of concept that using an integrated approach combining analytical chemistry and learning algorithms may be a way to identify optimal diagnostic features,” said John McDonald, a professor in the School of Biology at the Georgia Institute of Technology and director of its Integrated Cancer Research Center. “We think our results show great promise and we plan to further validate our findings across much larger samples.”
Ovarian cancer has been difficult to treat because it typically is not diagnosed until after it has metastasized to other areas of the body. Researchers have been seeking a routine screening test that could diagnose the disease in stage one or stage two – when the cancer is confined to the ovaries.
Working with three cancer treatment centers in the U.S. and Canada, the Georgia Tech researchers obtained blood samples from women with stage one and stage two ovarian cancer. They separated out the serum, which contains proteins and metabolites – molecules produced by enzymatic reactions in the body.
The serum samples were analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), which is two instruments joined together to better separate samples into their individual components. Heavier molecules are separated from lighter molecules, and the molecular signatures are determined with enough accuracy to identify the specific compounds. The Georgia Tech researchers decided to look only at the metabolites in their research.
“People have been looking at proteins for diagnosis of ovarian cancer for a couple of decades, and the results have not been very impressive,” said Facundo Fernández, a professor in Georgia Tech’s School of Chemistry and Biochemistry who led the analytical chemistry part of the research. “We decided to look in a different place for molecules that could potentially provide diagnostic capabilities. It’s one of the places that people had really not studied before.”
Samples from each of the 46 cancer patients were divided so they could be analyzed in duplicate. The researchers also looked at serum samples from 49 women who did not have cancer. The work required eliminating unrelated compounds such as caffeine, and molecules that were not present in all the cancer patients.
“We used really high resolution equipment and instrumentation to be able to separate most of the components of the samples,” Fernández explained. “Otherwise, detection of early-stage ovarian cancer is very difficult because you have a lot of confounding factors.”
The chemical work identified about a thousand candidate compounds. That number was reduced to about 255 through the work of research scientist David Gaul, who removed duplicates and unrelated molecules from the collection.
These 255 compounds were then analyzed by a learning algorithm which evaluated the predictive value of each one. Molecules that did not contribute to the predictive accuracy of the screening were eliminated. Ultimately, the algorithm produced a list of 16 molecules that together differentiated cancer patients with extremely high accuracy – greater than 90 percent.
“The algorithm looks at the metabolic features and correlates them with whether the samples were from cancer or control patients,” McDonald explained. “The algorithm has no idea what these compounds are. It is simply looking for the combination of molecules that provides the optimal predictive accuracy. What is encouraging is that many of the diagnostic features identified are metabolites that have been previously implicated in ovarian cancer.”
As a next step, McDonald and Fernández would like to study samples from a larger population that includes significant numbers of different ethnic and racial groups. Those individuals may have different metabolites that could serve as biomarkers for ovarian cancer.
Though sophisticated laboratory equipment was required to identify the 16 molecules, a screening test would not require the same level of sophistication, Fernández said.
“Once you know what these molecules are, the next step would be to set up a clinical assay,” he said. “Mass spectrometry is a common tool in this field. We could use a clinical mass spectrometer to look at only the molecules we are interested in. Moving this to a clinical assay would take work, but I don’t see any technical barriers to doing it.”
The Fernández and McDonald groups have used a similar approach with prostate cancer and plan to explore its utility for detecting other types of cancer.
The research was supported by grants from The Laura Crandall Brown Ovarian Cancer Foundation, The Ovarian Cancer Research Fund, The Ovarian Cancer Institute, Northside Hospital (Atlanta), The Robinson Family Fund, and the Deborah Nash Endowment Fund.
CITATION: David A. Gaul, et al., “Highly-accurate metabolomics detection of early-stage ovarian cancer,” (Scientific Reports, 2015). http://www.dx.doi.org/10.1038/srep16351
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]]>It’s important to examine the fundamental cell biology principles that govern this process, to reach a better understanding of developmental biology and engineering novel multicellular systems, but there are a number of challenges.
Functional micro-tissues derived from pluripotent embryonic stem cell (ESC) aggregates provide novel platforms for experimentation, but clarifying the factors that direct emergent spatial phenotypic patterns remains a hurdle. Computational modeling offers a complementary approach and provides a wealth of spatiotemporal data, but quantitative analysis of simulations and comparison to the experimental data is difficult.
Quantitative descriptions of spatial phenomena across multiple systems and scales would enable unprecedented comparisons of computational simulations with experimental systems and leverage the ability of computational methods to interrogate the mechanisms of multicellular biology.
To address these challenges, a group of researchers from multiple disciplines at the Georgia Institute of Technology have developed an innovative, portable pattern recognition pipeline, the first of its kind.
“There is a lot of biological data available. To some extent, it’s all image data, whether we’re talking about confocal microscopy or two-dimensional images of cells. The field has made significant advances the last 10 or 15 years in terms of quantifying images, but there are still gaping holes in terms of quantifying spatial patterns and how those emerge in cells over time,” says Doug White, lead author of a research paper entitled, “Quantitative multivariate analysis of dynamic multicellular morphogenic trajectories,” published this summer in the journal Integrative Biology (a publication of the Royal Society of Chemistry).
White, a recent Ph.D. graduate from the Wallace H. Coulter Department of Biomedical Engineering, now manages a team using mathematical modeling approaches to understand the guiding principles behind cancer drug design, for Takeda Pharmaceuticals in Boston. The research paper is the result of work he began about three years ago. His Ph.D. was focused on understanding stem cell biology using computational modeling.
“We set out to come up with a method that was portable across multiple system that anybody can use, but still powerful enough to extract meaningful data,” he says.
The pipeline permits entirely new forms of quantitative analysis based upon the fundamental interconnectivity of multicellular networks, which the research team believes could revolutionize the characterization of biologically complex spatiotemporal phenomena. And it’s the first network-based approach currently capable of using single cell information on spatial positioning and cellular states to classify tissue level pattern dynamics.
“The Petit Institute has instruments that measure different images with different resolutions,” says Melissa Kemp, associate professor in the Coulter Department, faculty member of the Petit Institute for Bioengineering and Bioscience, who co-authored the paper and was White’s co-advisor. “This pipeline allows us to take any of those images of multicellular structures and redefines the structure in terms of individual cells. Once you can define those individual entities within the image, you can create these network structures.”
Their innovation is their ability to take a plain image from a microscope and turn it into a network structure, much like LinkedIn or Facebook uses to study social connections. “We can then use newly defined features of those structures as they evolve over time to understand the underlying biology,” Kemp says.
The interdisciplinary team contributing to the research paper includes Petit Institute faculty members Hang Lu (professor and James R. Fair Faculty Fellow in the School of Chemical and Biomolecular Engineering) and Todd Streelman (professor and associate chair for graduate studies in the School of Biology), as well as White’s co-advisor Todd McDevitt, who left Georgia Tech last year to join the Gladstone Institute. Other co-authors were Jonathan Sylvester (postdoctoral fellow in the Streelman lab) and Thomas Levario (graduate student in the Lu lab). All, with the exception of McDevitt, are now based in the new Engineered Biosystems Building in the cell and developmental bioengineering neighborhood.
“We’re excited about how this could be used in other prediction-based studies,” Kemp says.
The nice thing about the technology is its portability across many imaging modalities, according to White, who adds, “The sky is the limit in terms of what this technology is capable of.”
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The current consensus among the vast majority of researchers is that most if not all cancers are caused by a change in or damage to genes, collectively called “mutations.” But research from two Georgia Institute of Technology cancer geneticists may alter the prevailing view.
“With the exception of the few things that we know are related to predisposition, the consensus view now is that cancer is due to ‘de novo’ mutations,” says John McDonald, professor of Biology and director of the Integrated Cancer Research Center (ICRC) at the Petit Institute for Bioengineering and Bioscience.
The term “mutation” is typically used to encompass a broad spectrum on genomic level lesions ranging from small changes in the single letter DNA code (point mutations) to large chromosomal deletions and rearrangements (structural mutations) that can adversely affect the architecture and function of cells.
The explosion in the number of genome sequencing studies carried out over the past several years comparing normal and cancer tissues has generated an abundance of genome databases ripe for computational analyses of the spectrum of mutations associated with cancer.
In a study just reported in the online journal BMC Medical Genomics McDonald and Vinay Mittal (former graduate student in McDonald’s lab, now a bioinformatics scientist with Thermo Fisher Scientific in Michigan) report the results of a detailed analysis of structural mutations associated with ovarian cancer – the deadliest of all gynecological cancers.
Unlike most computational analyses of cancer mutations, the authors not only analyzed the structural variants found in cancer tissues but also those naturally occurring mutations present in the normal tissues of the same patients.
“The results were remarkable in the shear number of structural mutations identified,” says McDonald. They found 4,516 structural mutations in the cancer tissues and 5,518 in the normal tissues.
“Most of the structural variants identified are probably of little functional significance,” says Mittal. “But around 10 percent of the variants identified are ‘gene-fusions’ with the potential to generate hybrid proteins that may contribute significantly to cancer onset and progression.”
In addition to identifying and categorizing all of the structural variants associated with the ovarian cancer patients, Mittal and McDonald went on to determine the extent to which these variants were actually being expressed in the normal and cancer tissues.
While our DNA harbors all of the genetic information in our cells, like a blueprint, not all of this information is transmitted or “expressed” at any given time. Information in DNA must be transmitted to an intermediary RNA molecule before it can result in the manufacture of a functional protein. For example, many of the genes necessary for liver cell function are not expressed in the brain, and vice versa.
The detailed pattern of regulatory controls typical in normal cells is often disrupted in cancer cells. Thus, cancer cells not only contain DNA lesions or mutations not detected in normal cells, they may also display abnormal expression patterns, “genetic information that is silenced in normal cells but abnormally expressed in cancer cells,” says McDonald, who has called cancer, “a disease of misinformation.”
Cells get wrong information, such as being told to rapidly divide when they should be inactive. It could be an error in the cell’s blueprint (a mutation). Or, it could be an error in the flow of information (abnormal expression), a regulation problem, which gets to what may be the most remarkable and unexpected finding of the study, according to McDonald.
“At least some of the functionally significant abnormal gene-fusions expressed in the cancer tissues are also present in normal tissues,” he says. “But they are not being expressed.”
The results of the study underscore the importance of gene regulation in cancer. It raises questions about how and when cancer is due to a de novo mutational event or a mistake in information flow.
“The accumulation of structural variants and other mutations in our cells with the potential to cause cancer may be inevitable as we age, but our cells may naturally strive to suppress the expression of some of this misinformation,” says McDonald. “This suggests that while mutations may be necessary for the onset of most cancers, they my not be sufficient. We need to better understand the regulatory mechanisms that can suppress cancer causing mutations in some individuals and how these mechanisms break down in cancer patients.”
Studies are currently on-going to see if the suppression of cancer causing genetic lesions extends to other classes of mutation and to understand the molecular processes that may underlie the suppression mechanism. The hope is that this work will lead to novel and more effective therapies and treatments for cancer.
The Parker H. Petit Institute for Bioengineering and Bioscience, an internationally recognized hub of multidisciplinary research at the Georgia Institute of Technology, brings engineers, scientists, and clinicians together to solve some of the world’s most complex health challenges. With 17 research centers, more than 170 faculty members, and $24 million in state-of-the-art facilities, the Petit Institute is translating scientific discoveries into game-changing solutions to solve real-world problems.
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Research reported July 15 in the journal Angewandte Chemie International Edition demonstrates that important molecules of contemporary life, known as polypeptides, can be formed simply by mixing amino and hydroxy acids – which are believed to have existed together on the early Earth – then subjecting them to cycles of wet and dry conditions. This simple process, which could have taken place in a puddle drying out in the sun and then reforming with the next rain, works because chemical bonds formed by one compound make bonds easier to form with the other.
The research supports the theory that life could have begun on dry land, perhaps even in the desert, where cycles of nighttime cooling and dew formation are followed by daytime heating and evaporation. Just 20 of these day-night, wet-dry cycles were needed to form a complex mixture of polypeptides in the lab. The process also allowed the breakdown and reassembly of the organic materials to form random sequences that could have led to the formation of the polypeptide chains that were needed for life.
“The simplicity of using hydration-dehydration cycles to drive the kind of chemistry you need for life is really appealing,” said Nicholas Hud, a professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology, and director of the NSF/NASA Center for Chemical Evolution, which is supported by the NSF Centers for Chemical Innovation Program and the NASA Astrobiology Program. “It looks like dry land would have provided a very favorable environment for getting the chemistry necessary for life started.”
Origin-of-life scientists had previously made polypeptides from amino acids by heating them well past the boiling point of water, or by driving polymerization with activating chemicals. But the high temperatures are beyond the point at which most life could survive, and the robust availability of activating chemicals on the early Earth is questionable. The simplicity of the wet-dry cycle therefore makes it attractive to explain how peptides could have formed, Hud added.
The idea for combining chemically similar amino acids and hydroxyl acids was inspired by the demonstration that polyesters are easy to form by repetitive hydration-dehydration cycles and the fact that esters are activated to attack by the amino group of amino acids. The potential importance of this reaction in the earliest stages of life is supported by studies of meteorites, which revealed that both compounds would have been present on the prebiotic Earth.
Hydroxy acids combine to form polyester, better known as a synthetic textile fiber, and that reaction requires less energy than formation of the amide bonds needed to create peptides from amino acids. In the wet-dry cycles, formation of polyester comes first – which then facilitates the more difficult peptide formation, Hud said.
“The ester linkages that we are making in the polyester can serve as an activating agent formed within the solution,” he explained. “Over the course of a very simple chemical evolution, the polymers progress from having hydroxy acids with ester linkages to amino acids with peptide linkages. The hydroxy acids are gradually replaced through the wet and dry cycles because the ester bonds holding them together are not as stable as the peptide bonds.”
Experimentally, graduate student Sheng-Sheng Yu put the amino and hydroxy acid mixtures through 20 wet-dry cycles to produce molecules that are a mixture of polyesters and peptides, containing as many as 14 units. After just three cycles, and at temperatures as low as 65 degrees Celsius, peptides consisting of two and three units began to form. Postdoctoral fellow Jay Forsythe confirmed the chemical structures using NMR mass spectrometry.
“We allowed the peptide bonds to form because the ester bonds lowered the energy barrier that needed to be crossed,” Hud added.
On the early Earth, those cycles could have taken 20 days and nights – or perhaps much longer if the heating and drying cycles corresponded to seasons of the year.
Beyond easily forming the polypeptides, the wet-dry process has an additional advantage. It allows compounds like peptides to be regularly broken apart and reformed, creating new structures with randomly-ordered amino acids. This ability to recycle the amino acids not only conserves organic material that may have been in short supply on the early Earth, but also provides the potential for creating more useful combinations.
A combination of hydroxy and amino acids likely existed in the prebiotic soup of the early Earth, but analyzing such a “messy” reaction was challenging, Hud said. “We were led into this idea that a mixture might work better than separate components,” he explained. “It might have been messy at the start, but it’s easier to get going than a pristine chemical reaction.”
Beyond helping explain how life might have started, the wet-dry cycles could also provide a new way to synthesize polypeptides. Existing techniques produce the chemicals through genetic engineering of microorganisms, or through synthetic organic chemistry. The wet-dry cycling could provide a simpler and more sustainable water-based process for producing these chemicals.
The demonstration of peptide formation opens the door to asking other questions about how life may have gotten going in prebiotic times, said Ramanarayanan Krishnamurthy, a member of the research team and an associate professor of chemistry at the Scripps Research Institute. Future studies will include a look at the sequences formed, whether there are sequences favored by the process, and what sequences might result. The process could ultimately lead to reactions able to continue without the wet-dry cycles.
“If this process were repeated many times, you could grow up a peptide that could acquire a catalytic property because it had reached a certain size and could fold in a certain way,” Krishnamurthy said. “The system could begin to develop certain emergent characteristics and properties that might allow it to self-propagate.”
In addition to those already named, the paper’s authors include Irena Mamajanov, Martha A Grover, and Facundo M. Fernández, all from Georgia Tech.
This research was supported by the NSF Centers for Chemical Innovation Program and the NASA Astrobiology Program under the NSF/NASA Center for Chemical Evolution under grant number CHE-1004570. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NSF or NASA.
CITATION: Jay G. Forsythe, et al., “Ester-Mediated Amide Bond Formation Driven by Wet-Dry Cycles: A Possible Path to Polypeptides on the Prebiotic Earth,” (Angewandte Chemie International Edition, 2015).
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“I’m honored and humbled to receive a committee position within this globally-recognized organization,” Wang said. “Health Informatics is identified as one of the 14 Grand Challenges in the 21st Century by the National Academy of Engineering. I have been devoted to biomedical and health informatics (BHI) research for personalized and predictive medicine since I joined Georgia Tech-Emory BME as a faculty member. This new recognition will allow me to help grow BHI within the IEEE and BME communities to tackle this Grand Challenge.”
In addition to her new position, Wang has been serving as the Biomedical and Health Informatics Technical Committee Chair and will present at the EMBC 2014 Frontiers in Biomedical Engineering Symposium.
Wang’s research centers around translating huge amounts of multi-modality and multi-scale biomedical data acquired by –omic technologies, tissue and histopathological imaging, bedside monitors, and wearable sensors into knowledge that helps physicians make health decisions for each individual, including:
“Through my new position with EMBS, I will have the opportunity to work with biomedical engineers around the world to continually innovate in the field of BHI research for discovery, development, and delivery. The ultimate goal is to use novel technologies to improve human health outcomes and reduce costs at every level.”
IEEE Engineering in Medicine and Biology Society is the world's largest international society of biomedical engineers. The organization is made up of 9,100 members in some 97 countries. EMBS provides its members with access to the people, practices, information, ideas and opinions that are shaping one of the fastest growing fields in science.
Related Links: Wang’s Profile , Wang's Lab
Written by Chris Calleri
]]>Researchers found the risk signature by comparing gene expression profiles in 31 study subjects who died of cardiovascular causes against the profiles of living members of the study group. Twenty-five of the 31 deaths occurred in the group with the high-risk profile, though coronary deaths were also recorded among the lower risk members of the study group. All of the patients studied had coronary artery disease (CAD), and about one in five had suffered a heart attack prior to the study.
Researchers from the Georgia Institute of Technology, Emory University and Princeton University participated in the study, which obtained gene expression profiles from blood samples taken from patients undergoing cardiac catheterization at Emory University clinics in Atlanta. The results were published in the open-access journal Genome Medicine on May 29, 2014.
“We envision that with our gene expression-based marker, plus some biochemical markers, genotype information and family history, we could produce a tiered evaluation of people’s risks of adverse coronary events,” said Gregory Gibson, director of the Center for Integrative Genomics at Georgia Tech and one of the study’s senior authors. “This could lead to a personalized medicine approach for people recovering from heart attack or coronary artery bypass grafting.”
Coronary artery disease is the leading cause of death for both men and women in the United States. Manifested in the narrowing of blood vessels through the buildup of plaque, CAD sets the stage for heart attacks and long-term heart failure.
As many as half of Americans over the age of 50 suffer from CAD to some extent, so the researchers wondered if they could single out those with the highest risk of death. From a cohort of more than 3,000 persons known as the Emory Cardiovascular Biobank (EmCD), they selected two groups of patients for extensive gene expression analysis based on blood samples.
After following the patients for as long as five years, the researchers examined gene expression patterns in a total of 31 persons from the study group who had suffered coronary deaths. Comparing these patterns against those of other study subjects revealed a pattern in which genes affecting inflammation were up-regulated, while genes affecting T-lymphocytes were down-regulated.
The patients studied ranged in age from 51 to 73, were mostly Caucasian, and 65 percent male. Seventy percent of the subjects had significant CAD, and 18 percent were experiencing an acute myocardial infarction when blood samples were taken. Gene expression was analyzed using microarrays and two different normalization procedures to control for technical and biological covariates. Whole genome genotyping was used to support comparative genome-wide association studies of gene expression. Two phases of the study were conducted independently with the two different groups, and produced similar results.
“What’s new in this research is the recognition that this risk pathway exists and that it relates to particular aspects of immune system functions that include T-cell signaling,” said Gibson, who is also a professor in Georgia Tech’s School of Biology. “We went beyond the signature of coronary artery disease to really provide a signature for adverse outcomes in that high-risk population.”
The pattern, said Gibson, doesn’t indicate the causes of the disease. The researchers would now like to expand the study to include a larger group of patients and learn more about what causes the disease. They’d also like to know whether the risks can be reversed through diet, exercise or drug therapy.
Cardiologist Arshed Quyyumi, the paper’s other senior author, directs Emory University’s Clinical Cardiovascular Research Center and created the Biobank five years ago to facilitate cardiovascular research. He says that identifying patients at highest risk could help encourage their compliance with treatment programs, and prioritize introduction of newer therapeutics, such as cholesterol lowering medications like PCSK9 inhibitors.
“A number of patients with CAD are currently not maximally treated,” said Quyyumi, who is a professor in Emory’s School of Medicine. “In those that appear to have been prescribed adequate medication, a significant proportion of subjects are non-compliant with their medications. Thus, knowledge of a high risk genetic profile in a patient can prompt both the patient and physician to maximize currently available medications and improve patient compliance.”
Approximately 15,000 genes are expressed in human blood, but analyzing them is not as daunting as it sounds. Most of the gene expression is correlated, so there may be only a few dozen independent measurements that can be related to disease states, Gibson said. In the study, researchers identified nine “axes” that represented specific biological pathways to disease. Two of them were relevant to the high-risk profile.
Gibson believes identifying the high-risk signatures in CAD patients may lead to opportunities for improving their health.
“Our dream would be a hand-held device that would allow patients to take a droplet of blood, much like diabetics do today, and obtain an evaluation of these transcripts that they could track at home,” he said. “If we can use this information to help people adopt healthier behaviors, it will be very positive.”
In addition to those already mentioned, the co-authors include Jinhee Kim, from the Georgia Tech School of Biology; Nima Ghasemzadeh and Danny Eapen from the Emory University School of Medicine, and John Storey and Neo Christopher Chung from the Lewis-Sigler Institute at Princeton University.
CITATION: Jinhee Kim, Nima Ghasemzadeh, Danny J. Eapen, Neo Christopher Chung, John D. Storey, Arshed A. Quyyumi and Greg Gibson, “Gene expression profiles associated with acute myocardial infarction and risk of cardiovascular death.” (Genome Medicine 2014). http://genomemedicine.com/content/6/5/40.
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]]>When the predator population becomes too large, however, the prey population often plummets, leaving too little food for the predators, whose population also then crashes. This canonical view of predator-prey relationships was first identified by mathematical biologists Alfred Lotka and Vito Volterra in the 1920s and 1930s.
But all bets are off if both the predator and prey species are evolving in even small ways, according to a new study published this week in the journal Proceedings of the National Academy of Sciences. When both species are evolving, the traditional cycle may reverse, allowing predator populations to peak before those of the prey. In fact, it may appear as if the prey are eating the predators.
Researchers at the Georgia Institute of Technology have proposed a theory to explain these co-evolutionary changes. And then, using data collected by other scientists on three predator-prey pairs – mink-muskrat, gyrfalcon-rock ptarmigan and phage-Vibrio cholerae – they show how their theory could explain unexpected population cycles.
The new theory and analysis of these co-evolution cycles could help epidemiologists predict cycles of disease and the virulence of infectious agents, and lead to a better understanding of how population cycles may affect ecosystems. The research was supported by the National Science Foundation and the Burroughs Wellcome Fund.
“Our work shows that co-evolution can yield new and unique behavior at the population scale,” explained Joshua Weitz, an associate professor in the School of Biology at Georgia Tech. “When you include evolution, the classic prey-predator dynamics have a much greater range of possible outcomes. We are not replacing the original theory, but proposing a more general model that opens the door to these new phenomena.”
Evolution is often perceived as an historical event, noted Weitz, who also has a courtesy appointment in the Georgia Tech School of Physics. But organisms are evolving continuously, with certain phenotypes becoming dominant as environmental and other conditions favor them. In organisms such as birds or small mammals, those changes can be manifested in as few as ten generations. In microbial species with brief lifespans, evolutionary changes can happen within days or weeks.
Evolutionary changes can dramatically affect relationships between species, potentially making them more vulnerable or less vulnerable. For instance, if a mutation that confers viral resistance in a species of bacteria becomes dominant, that may change the predator-prey relationship by rendering the bacteria population safe from harm. More generally, co-evolutionary cycles can arise when predator offense is costly and prey defense is effective against low offense predators.
“With predator and prey co-evolution, you can see oscillations in which there are lots of prey around even when there are many predators, or lots of predators around even when there are very few prey,” noted Michael Cortez, a postdoctoral fellow in the Weitz lab and first author of the paper.
“When prey is abundant and there are few predators, it may be because there are many defended prey – prey that the predators can’t eat,” he added. “When there are lots of predators around and few prey, it’s because the prey are very good food sources and the predators are doing quite well.”
In their paper, Weitz and Cortez simulated models in which the evolutionary process was sped up to show how their theory of co-evolution would affect predator-prey population cycles. Speeding up the process allowed them to break the cycle up into smaller segments that could be analyzed in more detail. They then used the earlier observations of the changing abundances of the three pairs of predators and prey -- leveraging data sets collected by other scientists – to show how the models would apply.
“Although the structure of the cycles in these three systems had been noted as unusual by the authors who observed them, there had been, as yet, no unified theoretical framework from which to make sense of such as radical departure from the classic signature of predator-prey interactions,” Weitz said.
Scientists have long studied how the interaction between species affects overall populations in ecosystems. Weitz and Cortez believe their new model will give scientists a broader and more complete picture of the complex process.
“This study identifies how adaptation between two species and interactions between their numbers can result in something different from what you would get if you just had the interaction between the numbers,” said Cortez. “This is something that will show up across many ecological systems. We can now explain broad trends that occur in vastly different systems using a theoretical approach, and the fact that we can identify the mechanism responsible for it is unique to our study.”
This research was supported by the National Science Foundation under Award DMS-1204401, and by the Burroughs Wellcome Fund. Any conclusions or opinions expressed are those of the authors and do not necessarily represent the official views of the sponsoring agencies.
CITATION: Michael H. Cortez and Joshua S. Weitz, “Coevolution Can Reverse Predator-Prey Cycles,” (Proceedings of the National Academy of Sciences, 2014). www.pnas.org/cgi/doi/10.1073/pnas.1317693111
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]]>Researchers have shown that a process called DNA methylation can shield duplicate genes from being removed from the genome during natural selection. The redundant genes survive and are shaped by evolution over time, giving birth to new cellular functions.
“This is the first study to show explicitly how the processes of DNA methylation and duplicate gene evolution are related,” said Soojin Yi, an associate professor in the School of Biology and the Parker H. Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology.
The study was sponsored by the National Science Foundation (NSF) and was scheduled to be published the week of April 7 in the Online Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS).
At least half of the genes in the human genome are duplicates. Duplicate genes are not only redundant, but they can be bad for cells. Most duplicate genes accumulate mutations at high rates, which increases the chance that the extra gene copies will become inactive and lost over time due to natural selection.
The new study found that soon after some duplicate genes form, small hydrocarbons called methyl groups attach to a duplicate gene’s regulatory region and block the gene from turning on.
When a gene is methylated, it is shielded from natural selection, which allows the gene to hang around in the genome long enough for evolution to find a new use for it. Some young duplicate genes are silenced by methylation almost immediately after being formed, the study found.
“What we have done is the first step in the process to show that young gene duplicates seems to be heavily methylated,” Yi said.
The study showed that the average level of DNA methylation on the duplicate gene regulatory region is significantly negatively correlated with evolutionary time. So, younger duplicate genes have high levels of DNA methylation.
For about three-quarters of the duplicate gene pairs studied, the gene in a pair that was more methylated was always more methylated across all 10 human tissues studied, said Thomas Keller, a post-doctoral fellow at Georgia Tech and the study’s first author.
“For the tissues that we examined, there was remarkable consistency in methylation when we looked at duplicate gene pairs,” Keller said.
The computational study constructed a dataset of all human gene duplicates by comparing each sequence against every other sequence in the human genome. DNA methylation data was then obtained for the 10 different human tissues. The researchers used computer models to analyze the links between DNA methylation and gene duplication.
The human brain is one example of a tissue for which gene duplication has been particularly important for its evolution. In future studies, the researchers will examine the link between epigenetic evolution and human brain evolution.
This research is supported by the National Science Foundation (NSF) under award numbers BCS-1317195 and MCB-0950896. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agency.
CITATION: Thomas E. Keller, et al., “DNA Methylation and Evolution of Duplicate Genes.” (PNAS, April 2014). http://www.dx.doi.org/10.1073/pnas.1321420111
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]]>To help coordinate a rapid response to pandemics, a professor at the Georgia Institute of Technology in Atlanta has designed software that combines biological data on the pandemic with demographic data of the at-risk population so that health officials can develop a game plan to limit the pandemic’s spread. The software also combs social media sites for real-time information on the pandemic and activities of the population.
Eva Lee, director of the Center for Operations Research in Medicine and HealthCare at the H. Milton Stewart School of Industrial and Systems Engineering at the Georgia Institute of Technology in Atlanta, talked about her emergency response software at the 2014 AAAS annual meeting in Chicago.
“We have developed a real-time system that will gather the demographics of the region that is being affected, and also pick up on-the-ground-data about who is available and doing what, and about movement of the affected population,” Lee said. “Our work is the first to take demographic information and real-time population behavior and interlace it with the biological information to come up with a decision that health officials can actually use.”
Lee chaired the panel titled “Emergency Response and Community Resilience via Engineering and Computational Advances.”
Lee shared her experience helping federal officials respond to the H1N1 flu in 2009, as well as her experience planning an emergency response to a potential anthrax outbreak. Lee was also involved in coordinating a response to the 2010 earthquake in Haiti, and the decontamination and health screening effort in Japan after the 2011 Fukushima radiological disaster.
Other speakers on the panel include Ronald Eguchi of ImageCat Inc. in Long Beach, Calif, who talked about inventory data capture tools to assess risk from natural disasters. Yasuaki Sakamoto, of Stevens Institute of Technology in Hoboken, N.J., spoke about improving social media for disaster response.
Emergency responders to a pandemic must quickly gather information on the biological agent to assess the characteristics of the pandemic and decide which treatment would be most effective. They also collect data on the risk factors of the individuals in the pandemic, such as the severity of patient’s sickness, and if children or pregnant women are infected.
“The big challenge in a pandemic is how do you use all of this information to determine the best strategy that will give you the minimum number of total infections and mortality rate,” Lee said.
Information from Lee’s systems approach allows health official to determine where to allocate medical resources and personnel in the best way so that operations will be most successful. Through the software developed in her lab at Georgia Tech, officials can determine, for example, how much vaccine to give at-risk populations and how much to give to the general populations to limit the spread of infection and mortality. Officials can also map where to set up medical sites to avoid traffic gridlock and worsening the pandemic as infected patients converge on treatment sites.
“We can do a real-time optimization to tell you exactly what are the sites that you should set up and who should be going where,” Lee said.
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]]>The team will investigate a new hypothesis about how viruses may control the structure and function of microbial communities. The traditional view of viruses is that they negatively impact the fitness of infected hosts. In other words, they are viewed strictly as pathogens, in which the host tries to eliminate the virus. This project will explore an alternative hypothesis: that chronic viral infections contribute positively to host fitness, increasing the success of the virus-host pair by protecting their hosts from infection by even more pathogenic viruses.
In humans, lifespan is a heritable trait, meaning that differences in our genes influence how fast we age. The McGrath lab plans to identify new signaling pathways controlling aging that are preferentially modified by combinations of natural polymorphisms segregating within a population.
The foundation’s New Scholar awards provide support for new investigators to help establish their labs. The award provides funding of $100,000 per year for a four-year period.
New Scholar applications are by invitation only. This is the first year that Georgia Tech has been invited to nominate a candidate to apply.
]]>Previous lab studies suggest that metastasizing cancer cells undergo a major molecular change when they leave the primary tumor – a process called epithelial-to-mesenchymal transition (EMT). As the cells travel from one site to another, they pick up new characteristics. More importantly, they develop a resistance to chemotherapy that is effective on the primary tumor. But confirmation of the EMT process has only taken place in test tubes or in animals.
In a new study, published in the Journal of Ovarian Research, Georgia Tech scientists have direct evidence that EMT takes place in humans, at least in ovarian cancer patients. The findings suggest that doctors should treat patients with a combination of drugs: those that kill cancer cells in primary tumors and drugs that target the unique characteristics of cancer cells spreading through the body.
The researchers looked at matching ovarian and abdominal cancerous tissues in seven patients. Pathologically, the cells looked exactly the same, implying that they simply fell off the primary tumor and spread to the secondary site with no changes. But on the molecular level, the cells were very different. Those in the metastatic site displayed genetic signatures consistent with EMT. The scientists didn’t see the process take place, but they know it happened.
“It’s like noticing that a piece of cake has gone missing from your kitchen and you turn to see your daughter with chocolate on her face,” said John McDonald, director of Georgia Tech’s Integrated Cancer Research Center and lead investigator on the project. “You didn’t see her eat the cake, but the evidence is overwhelming. The gene expression patterns of the metastatic cancers displayed gene expression profiles that unambiguously identified them as having gone through EMT.”
The EMT process is an essential component of embryonic development and allows for reduced cell adhesiveness and increased cell movement.
According to Benedict Benigno, collaborating physician on the paper, CEO of the Ovarian Cancer Institute and director of gynecological oncology at Atlanta’s Northside Hospital, “These results clearly indicate that metastasizing ovarian cancer cells are very different from those comprising the primary tumor and will likely require new types of chemotherapy if we are going to improve the outcome of these patients.”
Ovarian cancer is the most malignant of all gynecological cancers and responsible for more than 14,000 deaths annually in the United States alone. It often reveals no early symptoms and isn’t typically diagnosed until after it spreads.
“Our team is hopeful that, because of the new findings, the substantial body of knowledge that has already been acquired on how to block EMT and reduce metastasis in experimental models may now begin to be applied to humans,” said Georgia Tech graduate student Loukia Lili, co-author of the study.
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In a new study published in the journal mBio, the Centers for Disease Control and Prevention’s Cheryl Tarr and Lee Katz (School of Biology Ph.D. recipient) along with Georgia Tech’s School of Biology Professor Brian Hammer, his student Elena Antonova, and other colleagues, analyzed a set of isolates collected in Haiti at various times and locations since 2010. Genome sequencing of these isolates supports a model in which the outbreak was due to a single point-source introduction of V. cholerae to the island. Further analysis revealed that not only have the Haiti isolates not acquired new genes from the environment, but they are also severely impaired for the ability to undergo horizontal gene transfer, which typically allows bacteria to adapt quickly to new environments. On-going studies are underway to identify the mutation that prevents the Haiti strains from taking up environmental DNA.
The study was published on July 2, 2013 in mBio, the online open access journal from the American Society for Microbiology, and can be found at: http://mbio.asm.org/content/4/4/e00398-13. Funding for Hammer’s work in this study was provided by a grant from the National Science Foundation.
]]>The temporal niches – changes in environmental conditions that occur during specific periods of time – promoted frequency-dependent selection within the bacterial communities and positive growth of new mutants. They played a vital role in allowing diversity among bacterial phenotypes to persist.
The research provides new insights into the factors that promote species coexistence and diversity in natural systems. Understanding the mechanisms governing the origin and maintenance of biodiversity is important to scientists studying the roles of both ecology and evolution in natural systems.
“This study provides the first experimental evidence showing the impact of temporal niche dynamics on biodiversity evolution,” said Lin Jiang, co-author of the paper and an associate professor in the School of Biology at the Georgia Institute of Technology. “Our laboratory results in bacteria can potentially explain the diversity dynamics that have been observed for other organisms over evolutionary time.”
The research, which was supported by the National Science Foundation, was published July 9 in the journal Nature Communications.
In experimental manipulation of the bacterium Pseudomonas fluorescens, the researchers showed that alternating environmental conditions in 24-hour cycles strongly influences biodiversity dynamics by helping to maintain closely-related phenotypes that might otherwise be lost to competition with a dominant phenotype. The experiment followed the bacteria through more than 200 generations over a period of nearly two weeks.
In the laboratory, Jiang and graduate student Jiaqi Tan established communities of the bacterium in test tubes called microcosms. In designing the experiments, they collaborated with Colleen Kelly, a senior research associate in the Department of Zoology at the University of Oxford.
“You begin with one phenotype, and within two days, you might have two or three different phenotypes,” said Jiang. “The system can do this in a matter of days.”
Through a 12-day experimental period, the researchers subjected one group of cultures to 24-hour periods in which they were alternately allowed to grow undisturbed and shaken vigorously. To control for the impact of starting conditions, cultures within those two groups were chosen to begin with a period of static growth, while others began with a period of shaken growth. Finally, groups of control cultures were grown under continuous shaking or continuous static conditions.
During the study, the researchers periodically measured the population sizes of each phenotype present in each culture. Cultures subjected to alternating shaking and static conditions produced the highest level of diversity among the closely-related bacteria, which is often studied because it diversifies so rapidly.
“Static conditions promoted diversification,” Jiang explained. “But the shaking tended to maintain the diversity that had evolved. Both conditions were essential for high biodiversity.”
In experiments, the ancestral bacterial phenotype, which is known as “smooth morph,” quickly diversifies and generates two niche-specialists, known as “wrinkled spreader” and “fuzzy spreader.” Those, in turn, diversify into additional phenotypes. Competition for oxygen in the microcosms in which the bacteria grow is believed to drive the diversification; shaking the microcosms changes the levels of oxygen available to each phenotype. Because different phenotype groups inhabit different sections of the container, the shaking eliminated the preferred niches of some phenotypes.
The diversification in the microcosms experiencing constant shaking was much slower than in static microcosms. In microcosms experiencing temporal niche dynamics – the alternating shaking and non-shaking periods – the diversity increased rapidly and was maintained longer than in the other environments. The researchers found that the two different temporal niche dynamics environments – which differed only in their starting conditions – both produced richer biodiversity than those environments without it.
While the diversification occurred rapidly over a period of four days, the decline in the number of phenotypes due to natural competition took longer. Some of the phenotypes were ultimately excluded through the competitive processes.
“Diversity typically increases with time, then plateaus,” said Jiang. “Without temporal niche, diversity tends to decline. Temporal niche allows a greater diversity to be maintained over time than would be possible otherwise.”
Though the study focused on rapidly diversifying bacteria, the researchers believe it may have broader implications. The general theory of temporal niche dynamics was developed with more complex organisms, such as plants and corals, in mind.
“The mechanisms that promote biodiversity, which we call frequency-dependent selection, are very common in species,” said Tan. “As long as you have a strong intra-species competition within the populations, you are expected to see this frequency-dependent selection. Based on this most common mechanism that we find in this system, there are implications for other ecosystems.”
For the future, the researchers would like to study the effects of combining spatial and temporal niches in evolution.
“From this experiment, we know that temporal niche can maintain biodiversity,” said Tan. “Similarly, we want to manipulate spatial diversity to see if heterogeneity in the spatial scale can affect the maintenance of biodiversity.”
This research was supported by the National Science Foundation under grants DEB-1120281 and DEB-1257858. Any opinions expressed are those of the authors and do not necessarily represent the official views of the National Science Foundation.
CITATION: Jiaqi Tan, Colleen K. Kelly and Lin Jiang, “Temporal niche promotes biodiversity during adaptive radiation,” (Nature Communications, 2013). http://dx.doi.org/10.1038/ncomms3102
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]]>The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. A research group led by the Buck Institute for Research on Aging in collaboration with the Georgia Institute of Technology, conducted the study that pinpoints what is going wrong with the biological clock underlying the limited division of human adult stem cells as they age.
"We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional 'genomic junk'," said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.
Adult stem cells are important because they help keep human tissues healthy by replacing cells that have gotten old or damaged. They're also multipotent, which means that an adult stem cell can grow and replace any number of body cells in the tissue or organ they belong to. However, just as the cells in the liver, or any other organ, can get damaged over time, adult stem cells undergo age-related damage. And when this happens, the body can't replace damaged tissue as well as it once could, leading to a host of diseases and conditions. But if scientists can find a way to keep these adult stem cells young, they could possibly use these cells to repair damaged heart tissue after a heart attack; heal wounds; correct metabolic syndromes; produce insulin for patients with type 1 diabetes; cure arthritis and osteoporosis and regenerate bone.
The team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. They thought so because body cells are known to experience a shortening of the caps found at the ends of chromosomes, known as telomeres. But adult stem cells are known to maintain their telomeres. Much of the damage in aging is widely thought to be a result of losing telomeres. So there must be different mechanisms at play that are key to explaining how aging occurs in these adult stem cells, they thought.
Researchers used adult stem cells from humans and combined experimental techniques with computational approaches to study the changes in the genome associated with aging. They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups.
"We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons," said King Jordan, associate professor in the School of Biology at Georgia Tech.
"Retroransposons were previously thought to be non-functional and were even labeled as 'junk DNA', but accumulating evidence indicates these elements play an important role in genome regulation," he added.
While the young adult stem cells were able to suppress transcriptional activity of these genomic elements and deal with the damage to the DNA, older adult stem cells were not able to scavenge this transcription. New discovery suggests that this event is deleterious for the regenerative ability of stem cells and triggers a process known as cellular senescence.
"By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture," said Lunyak.
"Furthermore, by rewinding the cellular clock in this way, we were not only able to rejuvenate 'aged' human stem cells, but to our surprise we were able to reset them to an earlier developmental stage, by up-regulating the "pluripotency factors" â" the proteins that are critically involved in the self-renewal of undifferentiated embryonic stem cells." she said.
Next the team plans to use further analysis to validate the extent to which the rejuvenated stem cells may be suitable for clinical tissue regenerative applications.
The study was conducted by a team with members from the Buck Institute for Research on Aging, the Georgia Institute of Technology, the University of California, San Diego, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, International Computer Science Institute, Applied Biosystems and Tel-Aviv University.
Citation:
Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human
adult stem cells reinstates self-renewal. Cell Cycle, Volume 10, Issue 17, September 1, 2011
Buck Institute Contact Info
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“Being a mentor is my favorite part of my work,” said Shi. “I have learned so much about student psychology and my own psychology. As scientists, we can neglect the human experience it takes for us all to collaborate. I love thinking of new ways to improve the effectiveness of our communication so we all feel welcomed and valued in our scientific communities.”
In 2022, Shi started a mentorship group, FishStalkers, which grew from five to 20 members in just one semester. Shi’s mentees have been offered competitive co-ops and internships, awarded prestigious fellowships, presented at research symposiums, and more.
Shi provides her techniques for cultivating a positive and productive mentor-mentee connection.
Instill confidence in your mentees. “Student researchers have a lot of helpful ideas,” said Shi. “They attend courses where they learn about the newest software and theories while you are held up in the lab. You need to try and access this information, but it’s not going to happen if you do not instill the confidence in them that their idea is worth your time, and that it’s okay if the idea doesn’t work out because the contribution is valuable.”
Lower the standards you set for yourself. “Most Ph.D. students are perfectionists, and they will put a lot of pressure on themselves in terms of responsibility to a mentee,” said Shi. “You don’t need to be perfect. In fact, if you are perfect around your mentees, you will probably just intimidate them.”
According to Shi, this pressure can deter Ph.D. students from pursuing mentorship.
“A lot of people will place barriers on themselves that they do not know enough, or they don’t have enough ‘good work’ for a mentee,” said Shi. “You will make mistakes as a mentor. You and your mentees as people will solve these miscommunications or issues. This is normal and healthy.”
Humanize yourself. “Mentees often have an idealized perception of what a Ph.D. student is,” said Shi. “I will point out mistakes I have made in my work to students and encourage them to correct me if they have better information. I do not want to feel smart. I want to do good work and that requires criticism from other parties, including my mentees. Our goal is to increase the comfortability of the mentee while maintaining the professional boundary required of your role.”
Facilitate situations where the mentee is empowered. “The important thing I focus on with my students is cross-training,” said Shi. “If one mentee has studied a software, they now become responsible for training other mentees and me. It helps to be intentional in teaching your mentees that knowledge can come from anyone. I think putting knowledge into a hierarchy is overblown and only serves to preserve the status of people at the top rather than allowing for new ideas.”
Align mentor and mentee goals. “Goals should not conflict with one another, but this can happen if the mentor does not plan strategically,” said Shi. “The mentor needs to be transparent with what work the mentee needs to complete and the timeline. The mentor should inform the mentee of the amount of time the mentor has to assist the mentee and the appropriate method for contacting you when you need help. It is always best practice to be as specific with what you want rather than assume some ‘should know’ something.”
Shi has created a mentorship document that outlines her expectations for all new student researchers.
Communicate expectations. “We should communicate with each other the experience that we want from the relationship and work towards that goal,” said Shi. “You should align your students’ projects such that they are working towards something that advances your work. Sometimes, you will have motivated students who want to go off and do their own idea. That shows initiative in the student, but you should be direct with them that straying off into projects unrelated to your current research goals will mean that they will receive less oversight/feedback from you.”
Provide positive feedback. “A lot of us analytical types may forget that we should point out tasks that are proceeding well along with the things that are going up in flames,” said Shi. “Recognizing quality mentee work is vital to them reproducing that quality of work again. They need to know when they have met your standards.”
Provide critical feedback. “You will need to provide critical feedback to the mentee both on work and logistical miscommunications,” said Shi. “Do not shy away from this. If you are uncomfortable with discussing concerns on performance, this is normal, but by ignoring the issue you will deny the mentee from improving in this respect.”
Shi’s procedure for handling performance issues involves gathering the facts, detangling your emotions, defining the solution, and sending them a message.
For logistical, non-research issues, Shi recommends keeping records.
“There is a lot of front-loaded work in creating documentation of expectations, but it really pays off in terms of not dealing with day-to-day logistical questions.”
Understand the student researcher’s mindset. “Student researchers often feel insecure in navigating the lab equipment,” said Shi. “Sometimes, their perfectionism will cause them to ask you a lot of questions because they really want to impress you and do things correctly.”
In these situations, Shi advises mentors to protect their own time while reassuring the mentee in their work. Let them know that you appreciate their effort to do things correctly, but part of research is independence, or let them know that you are unavailable to answer their question and provide a timeline for when they can expect to hear from you.
Take the Tech to Teaching program and try your best! “I highly recommend this [Tech to Teaching] program to any Ph.D. student who has long-term goals of becoming a professor,” said Shi. “I want to emphasize something: you do not need formal training to be a mentor. If you are on the fence, try your best. You will learn the most about being a mentor by being a mentor. Listen to your mentee, balance your commitments, prioritize your time and goals, and you will be fine. There is the perception some people have that you need to mentor in a specific way. I do not agree with this mentality. I believe the scope of mentorship should be negotiated by the mentor and the mentee based on an alignment of goals.”
]]>The 12 projects received a total of $27 million in investment, supporting the use of knowledge learned from studying the Rules of Life — the complex interactions within and between a broad array of living systems across biological scales, and time and space — to tackle pressing societal challenges, including clean water, planet sustainability, carbon capture, biosecurity, and antimicrobial resistance to antibiotics. The Georgia Tech-related projects received a total of $7.7 million.
"The enormous opportunity to apply biological principles to solving the biggest problems of today is one we cannot take lightly," said Susan Marqusee, NSF assistant director for Biological Sciences. "These projects will use life to improve life, including for many underprivileged communities and groups."
The Georgia Tech-led projects include:
The project’s principal investigator is Lily Cheung, assistant professor of ChBE@GT, and the co-principal investigators are Shuichi Takayama, professor of biomedical engineering at Georgia Tech, and William San Martín, assistant professor of global environmental science, technology, and governance at Worcester Polytechnic Institute.
The researchers will address food security through low-cost technology based on biological principles to increase nitrogen content in soils and improve crop production on marginal lands.
The project’s principal investigator is Corey Wilson, professor of ChBE@GT, and the co-principal investigators are Matthew Realff, professor of ChBE@GT, and Christopher Voigt, professor of biological engineering at Massachusetts Institute of Technology.
The researchers will create programmable, biological combination lock methods — "on and off" states — for using synthetic biology safely, containing potentially dangerous organisms and protecting valuable ones.
The project’s principal investigator is Mark Styczynski, professor of ChBE@GT, and the co-principal investigators are Shuichi Takayama, professor of biomedical engineering at Georgia Tech; Brian Hammer, associate professor of biological sciences at Georgia Tech, and Neha Garg, assistant professor of chemistry and biochemistry at Georgia Tech.
The researchers will create synthetic "protocells" enabling the development of a highly sensitive, field deployable analysis system that could be used for many applications such as measuring micronutrient deficiencies in undernourished populations.
]]>Researchers at the Georgia Institute of Technology (Georgia Tech) have received funding to study the concept of using modified strains of probiotic bacteria – that are already part of the human gut microbiome – to stimulate the formation of antibodies against the flu virus in the body’s mucosal membranes. Respiratory viruses like influenza infect the body through mucosal membranes, and the proof-of-concept project will help evaluate whether snippets of influenza proteins – tiny fragments of the virus – could be added to two common bacterial strains to create the antibody response. Antibodies in the mucosal membranes might then complement those created by traditional intramuscular injections to head off flu infection.
The research, supported by the Air Force Research Laboratory (AFRL), will study whether or not the harmless bacteria can be successfully modified to carry snippets of a viral coat protein that could stimulate the desired response in mucosal membranes lining the gut. Beyond reducing influenza infection in the general population, improved protection against the flu could have a significant impact on the U.S. military, which wants to provide the best possible protection for its warfighters to reduce possible impacts on readiness and training from influenza outbreaks.
At Georgia Tech, the project is a collaboration between researchers at the Georgia Tech Research Institute (GTRI) and the Georgia Tech School of Biological Sciences. All of the research at Georgia Tech will be done using BSL-2 facilities designed for this type of study. The award does not include research on animals or humans.
“Ultimately, this could one day make vaccination programs much more effective,” said Michael Farrell, a GTRI principal research scientist. “This isn’t going to be a replacement for flu vaccines as they currently exist, but it could act as an adjuvant – something that’s done in addition to vaccination to increase the overall immune response. To benefit from it, you might take a pill like you do with probiotics now.”
Using Common Probiotic Bacteria as Vehicles
The project will focus on two common probiotic bacteria: Escherichia coli – a gram-negative bacterium better known as E. coli – and Lactococcus lactis, a gram-positive bacterium found in cheese, buttermilk, and other dairy food items. The researchers will attempt to coax the bacteria to express the influenza virus’ Hemagglutinin (HA) receptor protein on their outer cell surface. There, the protein would stimulate an antibody response in the gut mucosal membrane as it passes through the body’s gastrointestinal tract.
“We’re using some well-established probiotic bacteria that have been utilized for dozens of years, are well vetted and safe for humans,” said Brian Hammer, an associate professor in the School of Biological Sciences who specializes in bacterial genetics. “Ultimately, the idea is to use these bacteria as a chassis to create living vaccines, since the body already tolerates them both well.”
Researchers at AFRL and Georgia Tech envision that a single pill or capsule would carry the bacteria into the gastrointestinal tract to provide the necessary antibody stimulation. The bacteria would be modified so they could not reproduce, preventing them from becoming part of the body’s gut microbiome – a diverse collection of bacteria that live in the body and help carry out specific functions, including metabolizing food and modulating the immune system.
“We know the human microbiome is intimately involved in human health and disease, influencing processes in ways that have both positive and negative outcomes for us,” said Richard Agans, senior research biological scientist at the U.S. Air Force School of Aerospace Medicine (USAFSAM). “Recently, we have started to better understand how the microbiome communicates with our bodies and how we can identify, target, and promote the beneficial aspects. Currently, we are working to determine how to utilize these microbial communities to better protect our warfighters as well as the general public.”
Overcoming Challenges of Manipulating Bacteria
Hammer’s lab specializes in manipulating proteins of organisms such as bacteria and viruses to create novel fusions. Among the techniques available is the new CRISPR-Cas, the gene-editing technology that was the subject of a Nobel Prize in 2020, but other more traditional techniques may also be used to get the influenza surface protein where the researchers want it to be.
Among the challenges ahead is that adding a new component to bacterial organisms can be difficult.
“In general, bacteria have evolved with the genetic components they need to survive,” Farrell explained. “If you add something else, they may just kick it out. It’s very hard to find a neutral location in the bacterial genome where we can stably add new functionality. This is especially true for this effort, in which there will be no cointroduction of antimicrobial resistance markers.”
In addition, the probiotic bacteria strains that are widely used in research as model organisms, or “lab rats,” are adapted to living in laboratory conditions. This project, however, will use natural commensal strains that co-exist in humans. That approach may make it even more challenging to add the appropriate material for expressing the viral proteins on the bacteria cell surfaces, Hammer said.
“We used to perceive that genes could be shuffled around in the bacteria without much effect on them, but we’re learning now that location really matters,” he said. “One of the concerns is that tools that work on the ‘lab rat’ versions of these bacteria will not be as readily accepted by these commensals.”
As part of the project, the researchers will have to show that the addition of the protein doesn’t cause instability in the bacteria, and that the modified bacteria generate the correct response when exposed to human immune cells in culture.
Proof of Concept Could Lead to Broader Vaccine Therapies
Beyond its importance to the military, influenza was chosen to study this adjuvant approach because a number of vaccines exist for this virus, and they have been well studied over the years. If this approach works with influenza, the combination of pill and injection might be useful for vaccines against other respiratory viruses.
“If this is ultimately successful, it could be the first foray into showing that these vehicles, these probiotics, could potentially be scaled up for lots of different therapeutic uses,” said Hammer. “By customizing the cargo, this approach could be rapidly adapted to address new and emerging threats that may arise in the future.”
Project Provides Student Opportunity
The two-year project life was chosen because of the expected difficulty – and because another of its goals is to train a master’s degree student in the bacterial modification techniques being utilized.
The Georgia Tech researchers have chosen an underrepresented minority student who holds an undergraduate degree in biology from Kennesaw State University and has worked in a commercial DNA laboratory. Katrina Lancaster will begin work on this project during fall semester, collaborating with both Hammer and Farrell – and the students and other researchers in their labs.
“This student will have excellent opportunities, not only to learn the skills in the lab and take the coursework, but also to develop a rich network of connections, both in the School of Biological Sciences and at GTRI, that will be helpful in moving forward and advancing their career,” Hammer said. “It’s a really beautiful combination of components for this project.”
The project is funded through the AFRL’s Minority Leaders Research Collaboration Program (ML-RCP).
“Partnering with academic institutions, such as GTRI, presents great opportunities for our team to interact and work with top minds in these fields to develop better outcomes for everyone,” Agans said. “We are especially grateful for the opportunity to mentor and provide opportunities for underrepresented students with STEM aspirations. We are excited to work with GTRI in this endeavor and envision this being just the first step.”
USAFSAM is part of the Air Force Research Laboratory’s 711th Human Performance Wing.
Writer: John Toon (john.toon@gtri.gatech.edu)
GTRI Communications
Georgia Tech Research Institute
Atlanta, Georgia
The Georgia Tech Research Institute (GTRI) is the nonprofit, applied research division of the Georgia Institute of Technology (Georgia Tech). Founded in 1934 as the Engineering Experiment Station, GTRI has grown to more than 2,900 employees, supporting eight laboratories in over 20 locations around the country and performing more than $940 million of problem-solving research annually for government and industry. GTRI's renowned researchers combine science, engineering, economics, policy, and technical expertise to solve complex problems for the U.S. federal government, state, and industry.
]]>Michelle Gowdy
Michelle.Gowdy@gtri.gatech.edu
404-407-8060
]]>The research, supported by the Air Force Research Laboratory (AFRL), will study whether or not the harmless bacteria can be successfully modified to carry snippets of a viral coat protein that could stimulate the desired response in mucosal membranes lining the gut. Beyond reducing influenza infection in the general population, improved protection against the flu could have a significant impact on the U.S. military, which wants to provide the best possible protection for its warfighters to reduce possible impacts on readiness and training from influenza outbreaks.
At Georgia Tech, the project is a collaboration between researchers at the Georgia Tech Research Institute (GTRI) and the Georgia Tech School of Biological Sciences. All of the research at Georgia Tech will be done using BSL-2 facilities designed for this type of study. The award does not include research on animals or humans.
“Ultimately, this could one day make vaccination programs much more effective,” said Michael Farrell, a GTRI principal research scientist. “This isn’t going to be a replacement for flu vaccines as they currently exist, but it could act as an adjuvant – something that’s done in addition to vaccination to increase the overall immune response. To benefit from it, you might take a pill like you do with probiotics now.”
Using Common Probiotic Bacteria as Vehicles
The project will focus on two common probiotic bacteria: Escherichia coli – a gram-negative bacterium better known as E. coli – and Lactococcus lactis, a gram-positive bacterium found in cheese, buttermilk, and other dairy food items. The researchers will attempt to coax the bacteria to express the influenza virus’ Hemagglutinin (HA) receptor protein on their outer cell surface. There, the protein would stimulate an antibody response in the gut mucosal membrane as it passes through the body’s gastrointestinal tract.
“We’re using some well-established probiotic bacteria that have been utilized for dozens of years, are well vetted and safe for humans,” said Brian Hammer, an associate professor in the School of Biological Sciences who specializes in bacterial genetics. “Ultimately, the idea is to use these bacteria as a chassis to create living vaccines, since the body already tolerates them both well.”
Researchers at AFRL and Georgia Tech envision that a single pill or capsule would carry the bacteria into the gastrointestinal tract to provide the necessary antibody stimulation. The bacteria would be modified so they could not reproduce, preventing them from becoming part of the body’s gut microbiome – a diverse collection of bacteria that live in the body and help carry out specific functions, including metabolizing food and modulating the immune system.
“We know the human microbiome is intimately involved in human health and disease, influencing processes in ways that have both positive and negative outcomes for us,” said Richard Agans, senior research biological scientist at the U.S. Air Force School of Aerospace Medicine (USAFSAM). “Recently, we have started to better understand how the microbiome communicates with our bodies and how we can identify, target, and promote the beneficial aspects. Currently, we are working to determine how to utilize these microbial communities to better protect our warfighters as well as the general public.”
Overcoming Challenges of Manipulating Bacteria
Hammer’s lab specializes in manipulating proteins of organisms such as bacteria and viruses to create novel fusions. Among the techniques available is the new CRISPR-Cas, the gene-editing technology that was the subject of a Nobel Prize in 2020, but other more traditional techniques may also be used to get the influenza surface protein where the researchers want it to be.
Among the challenges ahead is that adding a new component to bacterial organisms can be difficult.
“In general, bacteria have evolved with the genetic components they need to survive,” Farrell explained. “If you add something else, they may just kick it out. It’s very hard to find a neutral location in the bacterial genome where we can stably add new functionality. This is especially true for this effort, in which there will be no cointroduction of antimicrobial resistance markers.”
In addition, the probiotic bacteria strains that are widely used in research as model organisms, or “lab rats,” are adapted to living in laboratory conditions. This project, however, will use natural commensal strains that co-exist in humans. That approach may make it even more challenging to add the appropriate material for expressing the viral proteins on the bacteria cell surfaces, Hammer said.
“We used to perceive that genes could be shuffled around in the bacteria without much effect on them, but we’re learning now that location really matters,” he said. “One of the concerns is that tools that work on the ‘lab rat’ versions of these bacteria will not be as readily accepted by these commensals.”
As part of the project, the researchers will have to show that the addition of the protein doesn’t cause instability in the bacteria, and that the modified bacteria generate the correct response when exposed to human immune cells in culture.
Proof of Concept Could Lead to Broader Vaccine Therapies
Beyond its importance to the military, influenza was chosen to study this adjuvant approach because a number of vaccines exist for this virus, and they have been well studied over the years. If this approach works with influenza, the combination of pill and injection might be useful for vaccines against other respiratory viruses.
“If this is ultimately successful, it could be the first foray into showing that these vehicles, these probiotics, could potentially be scaled up for lots of different therapeutic uses,” said Hammer. “By customizing the cargo, this approach could be rapidly adapted to address new and emerging threats that may arise in the future.”
Project Provides Student Opportunity
The two-year project life was chosen because of the expected difficulty – and because another of its goals is to train a master’s degree student in the bacterial modification techniques being utilized.
The Georgia Tech researchers have chosen an underrepresented minority student who holds an undergraduate degree in biology from Kennesaw State University and has worked in a commercial DNA laboratory. Katrina Lancaster will begin work on this project during fall semester, collaborating with both Hammer and Farrell – and the students and other researchers in their labs.
“This student will have excellent opportunities, not only to learn the skills in the lab and take the coursework, but also to develop a rich network of connections, both in the School of Biological Sciences and at GTRI, that will be helpful in moving forward and advancing their career,” Hammer said. “It’s a really beautiful combination of components for this project.”
The project is funded through the AFRL’s Minority Leaders Research Collaboration Program (ML-RCP).
“Partnering with academic institutions, such as GTRI, presents great opportunities for our team to interact and work with top minds in these fields to develop better outcomes for everyone,” Agans said. “We are especially grateful for the opportunity to mentor and provide opportunities for underrepresented students with STEM aspirations. We are excited to work with GTRI in this endeavor and envision this being just the first step.”
USAFSAM is part of the Air Force Research Laboratory’s 711th Human Performance Wing.
Writer: John Toon (john.toon@gtri.gatech.edu)
GTRI Communications
Georgia Tech Research Institute
Atlanta, Georgia
This story first appeared in the GTRI newsroom.
]]>While rarely in the news, these ice cage formations, known as methane clathrates, have garnered attention because of their potential to affect climate change. During offshore drilling, methane ice can get stuck in pipes, causing them to freeze and burst. The 2010 Deepwater Horizon oil spill is thought to have been caused by a buildup of methane clathrates.
But until now, the biological process behind how methane gas remains stable under the sea has been almost completely unknown. In a breakthrough study, a cross-disciplinary team of Georgia Tech researchers discovered a previously unknown class of bacterial proteins that play a crucial role in the formation and stability of methane clathrates.
A team led by Jennifer Glass, associate professor in the School of Earth and Atmospheric Sciences, and Raquel Lieberman, professor and Sepcic-Pfeil Chair in the School of Chemistry and Biochemistry, showed that these novel bacterial proteins suppress the growth of methane clathrates as effectively as commercial chemicals currently used in drilling, but are non-toxic, eco-friendly, and scalable. Their study, funded by NASA, informs the search for life in the solar system, and could also increase the safety of transporting natural gas.
The research, published in the journal PNAS Nexus, underscores the importance of fundamental science in studying Earth’s natural biological systems and highlights the benefits of collaboration across disciplines.
“We wanted to understand how these formations were staying stable under the seafloor, and precisely what mechanisms were contributing to their stability,” Glass said. “This is something no one has done before.”
Sifting Through Sediment
The effort started with the team examining a sample of clay-like sediment that Glass acquired from the seafloor off the coast of Oregon.
Glass hypothesized that the sediment would contain proteins that influence the growth of methane clathrate, and that those proteins would resemble well-known antifreeze proteins in fish, which help them survive in cold environments.
But to confirm her hypothesis, Glass and her research team would first have to identify protein candidates out of millions of potential targets contained in the sediment. They would then need to make the proteins in the lab, though there was no understanding of how these proteins might behave. Also, no one had worked with these proteins before.
Glass approached Lieberman, whose lab studies the structure of proteins. The first step was to use DNA sequencing paired with bioinformatics to identify the genes of the proteins contained in the sediment. Dustin Huard, a researcher in Lieberman’s lab and first author of the paper, then prepared candidate proteins that could potentially bind to the methane clathrates. Huard used X-ray crystallography to determine the structure of the proteins.
Creating Seafloor Conditions in the Lab
Huard passed off the protein candidates to Abigail Johnson, a former Ph.D. student in Glass’ lab and co-first author on the paper, who is now a postdoctoral researcher at the University of Georgia. To test the proteins, Johnson formed methane clathrates herself by recreating the high pressure and low temperature of the seafloor in the lab. Johnson worked with Sheng Dai, an associate professor in the School of Civil and Environmental Engineering, to build a unique pressure chamber from scratch.
Johnson placed the proteins in the pressure vessel and adjusted the system to mimic the pressure and temperature conditions required for clathrate formation. By pressurizing the vessel with methane, Johnson forced methane into the droplet, which caused a methane clathrate structure to form.
She then measured the amount of gas that was consumed by the clathrate — an indicator of how quickly and how much clathrate formed — and did so in the presence of the proteins versus no proteins. Johnson found that with the clathrate-binding proteins, less gas was consumed, and the clathrates melted at higher temperatures.
Once the team validated that the proteins affect the formation and stability of methane clathrates, they used Huard's protein crystal structure to carry out molecular dynamics simulations with the help of James (JC) Gumbart, professor in the School of Physics. The simulations allowed the team to identify the specific site where the protein binds to the methane clathrate.
A Surprisingly Novel System
The study unveiled unexpected insights into the structure and function of the proteins. The researchers initially thought the part of the protein that was similar to fish antifreeze proteins would play a role in clathrate binding. Surprisingly, that part of the protein did not play a role, and a wholly different mechanism directed the interactions.
They found that the proteins do not bind to ice, but rather interact with the clathrate structure itself, directing its growth. Specifically, the part of the protein that had similar characteristics to antifreeze proteins was buried in the protein structure, and instead played a role in stabilizing the protein.
The researchers found that the proteins performed better at modifying methane clathrate than any of the antifreeze proteins that had been tested in the past. They also performed just as well as, if not better than, the toxic commercial clathrate inhibitors currently used in drilling that pose serious environmental threats.
Preventing clathrate formation in natural gas pipelines is a billion-dollar industry. If these biodegradable proteins could be used to prevent disastrous natural gas leaks, it would greatly reduce the risk of environmental damage.
“We were so lucky that this actually worked, because even though we chose these proteins based on their similarity to antifreeze proteins, they are completely different,” Johnson said. “They have a similar function in nature, but do so through a completely different biological system, and I think that really excites people.”
Methane clathrates likely exist throughout the solar system — on the subsurface of Mars, for example, and on icy moons in the outer solar system, such as Europa. The team’s findings indicate that if microbes exist on other planetary bodies, they might produce similar biomolecules to retain liquid water in channels in the clathrate that could sustain life.
“We’re still learning so much about the basic systems on our planet,” Huard said. “That’s one of the great things about Georgia Tech — different communities can come together to do really cool, unexpected science. I never thought I would be working on an astrobiology project, but here we are, and we’ve been very successful.”
Citation: Dustin J E Huard, et al. Molecular basis for inhibition of methane clathrate growth by a deep subsurface bacterial protein, PNAS Nexus, Volume 2, Issue 8, August 2023.
DOI: https://doi.org/10.1093/pnasnexus/pgad268
Funding: National Aeronautics & Space Administration, National Science Foundation, National Institutes of Health, American Chemical Society Petroleum Research Fund
Georgia Tech co-authors included Zixing Fan, Ph.D. student, and two undergraduates, Lydia Kenney (now a Ph.D. student at Northwestern University) and Manlin Xu (now a Ph.D. student in the MIT-Woods Hole Oceanographic Institution Joint Program). Ran Drori, associate professor of chemistry at Yeshiva University, also contributed.
]]>Institute Communications
]]>In a new study, Georgia Tech researchers investigated whether 25 rare gene variants known to be associated with inflammatory bowel disease (IBD) play a role in risk for African Americans. While the rare variant associations were recently discovered in individuals of European ancestry, contributing to about 15% of cases, it was unknown if and how those same rare gene variants might affect risk for African Americans.
Led by Greg Gibson, Regents’ Professor and Tom and Marie Patton Chair in the School of Biological Sciences, the study highlights the importance of considering genetic diversity and the mixing of ancestry in genetics research. The findings were published in the journal Genome Medicine.
“Because of major advancements in the last decade, we now know that most diseases are far more complex than we originally thought, in terms of genetics,” said Gibson, who is also director of the Center for Integrative Genomics at Georgia Tech. “Understanding whether genetic differences contribute to health disparities is a major point of focus for current genetics research, and we had an opportunity to test one idea with this study.”
Today, African Americans have a similar prevalence of various types of IBD as European Americans. But progression is often much worse: African Americans are more likely to progress to severe disease requiring colectomies and other major interventions.
Courtney Astore, a Ph.D. student in Gibson’s lab and first author on the paper, wanted to assess whether those same rare variants would have a similar effect on IBD risk in African Americans. In a collaboration with Subra Kugathasan from Emory University and the NIH’s IBD Genetics Consortium, Gibson’s lab had analyzed the complete genome sequences of over 3,000 genomes of African Americans, half with IBD. Astore used that database to conduct her analysis.
She started by plotting the difference in frequency of the rare variants, and quickly realized that there was a significant reduction in prevalence of the variants in African Americans. Through further computations, she estimated that European ancestry variants actually only made a very small contribution to IBD in African Americans (around 44 additional cases per 100,000 people), fourfold less than Americans of European ancestry.
“Prior to our analysis, we suspected that admixture may play a role in the presence of IBD-associated rare variants in African Americans,” Astore said. “When I saw the differences, that was when I realized that there was something important there that we needed to discover.”
Astore then used a method known as chromosome painting, which is a tool for visualizing where each segment of the genome comes from. She showed that the rare variants found in African Americans were almost always located on segments of European ancestry genomes.
In simple terms, the location of the variants indicated that the genes resulted from admixture — a scientific term for mixing of genetic backgrounds throughout ancestry — which enabled Astore to show that the mutations had arisen outside of Africa, and only began to appear in people of African ancestry over the last dozen generations.
To conclude the study, Gibson and Astore assessed the presence of other rare variants associated with a dozen other diseases, which similarly confirmed that the presence of the variants contributes to African Americans generally through admixture.
The findings are important for several reasons. First, they highlight the value of considering genetic diversity and admixture in all genetics research, and especially when investigating rare variants and their associations with complex disease. While they showed that the European variants were rare in African Americans, there are almost certainly rare variants that contribute to IBD in African Americans that have yet to be discovered and may point to biological mechanisms.
“Doing more genetic studies on diverse populations, and especially those that have admixture, is going to be pivotal for therapeutic discovery,” Astore said.
Precision medicine will eventually be tailored to a person’s genome, which means that in some cases knowing the identity of rare variants will help guide therapy. If that is the case, knowing the context of ancestry will be beneficial. It also means that if more research on diverse ancestry groups isn’t done, then new treatments might not be effective for all people. The team also emphasizes that genetics is not the only factor contributing to risk for complex diseases like IBD, and their study simply highlights that it cannot be assumed that genetic discoveries are risk factors for all people.
“Our study emphasizes that in order to move in the direction of greater health equity, it is absolutely crucial to do large-scale genetic sequencing for African Americans and all ancestry groups,” Gibson said. “We hope our work will encourage more research on both social determinants of health and the genetics of IBD across ancestries.”
Note: The IBD Genetics Consortium, of which Gibson is a part, organized the cohort of African Americans with IBD, and their samples were gathered at institutes across the country, including Emory University, Johns Hopkins University, Rutgers University, Cedars Sinai Los Angeles, and Mt. Sinai New York.
Funding: National Institutes of Health
DOI: https://doi.org/10.1186/s13073-023-01244-w
]]>John McDonald, professor emeritus in the School of Biological Sciences, founding director of the ICRC, and the study’s corresponding author, explains that the new test’s accuracy is better in detecting ovarian cancer than existing tests for women clinically classified as normal, with a particular improvement in detecting early-stage ovarian disease in that cohort.
The team’s results and methodologies are detailed in a new paper, “A Personalized Probabilistic Approach to Ovarian Cancer Diagnostics,” published in the March 2024 online issue of the medical journal Gynecologic Oncology. Based on their computer models, the researchers have developed what they believe will be a more clinically useful approach to ovarian cancer diagnosis — whereby a patient’s individual metabolic profile can be used to assign a more accurate probability of the presence or absence of the disease.
“This personalized, probabilistic approach to cancer diagnostics is more clinically informative and accurate than traditional binary (yes/no) tests,” McDonald says. “It represents a promising new direction in the early detection of ovarian cancer, and perhaps other cancers as well.”
The study co-authors also include Dongjo Ban, a Bioinformatics Ph.D. student in McDonald’s lab; Research Scientists Stephen N. Housley, Lilya V. Matyunina, and L.DeEtte (Walker) McDonald; Regents’ Professor Jeffrey Skolnick, who also serves as Mary and Maisie Gibson Chair in the School of Biological Sciences and Georgia Research Alliance Eminent Scholar in Computational Systems Biology; and two collaborating physicians: University of North Carolina Professor Victoria L. Bae-Jump and Ovarian Cancer Institute of Atlanta Founder and Chief Executive Officer Benedict B. Benigno. Members of the research team are forming a startup to transfer and commercialize the technology, and plan to seek requisite trials and FDA approval for the test.
Silent killer
Ovarian cancer is often referred to as the silent killer because the disease is typically asymptomatic when it first arises — and is usually not detected until later stages of development, when it is difficult to treat.
McDonald explains that while the average five-year survival rate for late-stage ovarian cancer patients, even after treatment, is around 31 percent — but that if ovarian cancer is detected and treated early, the average five-year survival rate is more than 90 percent.
“Clearly, there is a tremendous need for an accurate early diagnostic test for this insidious disease,” McDonald says.
And although development of an early detection test for ovarian cancer has been vigorously pursued for more than three decades, the development of early, accurate diagnostic tests has proven elusive. Because cancer begins on the molecular level, McDonald explains, there are multiple possible pathways capable of leading to even the same cancer type.
“Because of this high-level molecular heterogeneity among patients, the identification of a single universal diagnostic biomarker of ovarian cancer has not been possible,” McDonald says. “For this reason, we opted to use a branch of artificial intelligence — machine learning — to develop an alternative probabilistic approach to the challenge of ovarian cancer diagnostics.”
Metabolic profiles
Georgia Tech co-author Dongjo Ban, whose thesis research contributed to the study, explains that “because end-point changes on the metabolic level are known to be reflective of underlying changes operating collectively on multiple molecular levels, we chose metabolic profiles as the backbone of our analysis.”
“The set of human metabolites is a collective measure of the health of cells,” adds coauthor Jeffrey Skolnick, “and by not arbitrary choosing any subset in advance, one lets the artificial intelligence figure out which are the key players for a given individual.”
Mass spectrometry can identify the presence of metabolites in the blood by detecting their mass and charge signatures. However, Ban says, the precise chemical makeup of a metabolite requires much more extensive characterization.
Ban explains that because the precise chemical composition of less than seven percent of the metabolites circulating in human blood have, thus far, been chemically characterized, it is currently impossible to accurately pinpoint the specific molecular processes contributing to an individual's metabolic profile.
However, the research team recognized that, even without knowing the precise chemical make-up of each individual metabolite, the mere presence of different metabolites in the blood of different individuals, as detected by mass spectrometry, can be incorporated as features in the building of accurate machine learning-based predictive models (similar to the use of individual facial features in the building of facial pattern recognition algorithms).
“Thousands of metabolites are known to be circulating in the human bloodstream, and they can be readily and accurately detected by mass spectrometry and combined with machine learning to establish an accurate ovarian cancer diagnostic,” Ban says.
A new probabilistic approach
The researchers developed their integrative approach by combining metabolomic profiles and machine learning-based classifiers to establish a diagnostic test with 93 percent accuracy when tested on 564 women from Georgia, North Carolina, Philadelphia and Western Canada. 431 of the study participants were active ovarian cancer patients, and while the remaining 133 women in the study did not have ovarian cancer.
Further studies have been initiated to study the possibility that the test is able to detect very early-stage disease in women displaying no clinical symptoms, McDonald says.
McDonald anticipates a clinical future where a person with a metabolic profile that falls within a score range that makes cancer highly unlikely would only require yearly monitoring. But someone with a metabolic score that lies in a range where a majority (say, 90%) have previously been diagnosed with ovarian cancer would likely be monitored more frequently — or perhaps immediately referred for advanced screening.
Citation: https://doi.org/10.1016/j.ygyno.2023.12.030
Funding
This research was funded by the Ovarian Cancer Institute (Atlanta), the Laura Crandall Brown Foundation, the Deborah Nash Endowment Fund, Northside Hospital (Atlanta), and the Mark Light Integrated Cancer Research Student Fellowship.
Disclosure
Study co-authors John McDonald, Stephen N. Housley, Jeffrey Skolnick, and Benedict B. Benigno are the co-founders of MyOncoDx, Inc., formed to support further research, technology transfer, and commercialization for the team’s new clinical tool for the diagnosis of ovarian cancer.
]]>Editor: Jess Hunt-Ralston
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