A new technique for studying the structure of the RSV virion and the activity of RSV in living cells could help researchers unlock the secrets of the virus, including how it enters cells, how it replicates, how many genomes it inserts into its hosts – and perhaps why certain lung cells escape the infection relatively unscathed. That could provide scientists information they need to develop new antiviral drugs and perhaps even a vaccine to prevent severe RSV infections.

“We want to develop tools that would allow us to get at how the virus really works,” said Philip Santangelo, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “We really need to be able to follow the infection in a single living cell without affecting how the virus infects its hosts, and this technology should allow us to do that.”

The research was supported by the National Institutes of Health’s National Institute of General Medical Sciences and published online ahead of print in the journal ACS Nano on December 30, 2013. While RSV will be the first target for the work, the researchers believe the imaging technique they developed could be used to study other RNA viruses, including influenza and Ebola.

“We’ve shown that we can tag the genome using our probes,” explained Santangelo. “What we’ve learned from this is that the genome does get incorporated into the virion, and that the virus particles created are infectious. We were able to characterize some aspects of the virus particle itself at super-resolution, down to 20 nanometers, using direct stochastic optical reconstruction microscopy (dSTORM) imaging.”

RSV can be difficult to study. For one thing, the infectious particle can take different forms, ranging from 10-micron filaments to ordinary spheres. The virus can insert more than one genome into the host cells and the RNA orientation and structure are disordered, which makes it difficult to characterize.

The research team, which included scientists from Vanderbilt University and Emory University, used a probe technology that quickly attaches to RNA within cells. The probe uses multiple fluorophores to indicate the presence of the viral RNA, allowing the researchers to see where it goes in host cells – and to watch as infectious particles leave the cells to spread the infection.

“Being able to see the genome and the progeny RNA that comes from the genome with the probes we use really give us much more insight into the replication cycle,” Santangelo said. “This gives us much more information about what the virus is really doing. If we can visualize the entry, assembly and replication of the virus, that would allow us to decide what to go after to fight the virus.”

The research depended on a new method for labelling RNA viruses using multiply-labeled tetravalent RNA imaging probes (MTRIPS). The probes consist of a chimeric combination of DNA and RNA oligonucleotide labeled internally with fluorophores tetravelently complexed to neutravidin. The chimeric combination was used to help the probes evade cellular defenses.

“There are lots of sensors in the cell that look for foreign RNA and foreign DNA, but to the cell, this probe doesn’t look like anything,” Santangelo explained. “The cell doesn’t see the nucleic acid as foreign.”

Introduced into cells, the probes quickly diffuse through a cell infected with RSV and bind to the virus’s RNA. Though binding tightly, the probe doesn’t affect the normal activities of the virus and allows researchers to follow the activity for days using standard microscopy techniques. The MTRIPS can be used to complement other probe technology, such as GFP and gold nanoparticles.

Work done by graduate student Eric Alonas to concentrate the virus was essential to the project, Santangelo said. The concentration had to be done without adversely affecting the infectivity of the virus, which would have impacted its ability to enter host cells.

“It took quite a bit of work to get the right techniques to concentrate the RSV,” he said. “Now we can make lots of infectious virus that’s labelled and can be stored so we can use it when we want to.”

To study the infection’s progress in individual cells, the researchers faced another challenge: living cells move around, and following them complicates the research. To address that movement, the laboratory of Thomas Barker – also in the Coulter Department – used micro-patterned fibronectin on glass to create 50-micron “islands” that contained the cells during the study.

Among the mysteries that the researchers would like to tackle is why certain lung cells are severely infected – while others appear to escape ill effects.

“If you look at a field of cells, you see huge differences from cell to cell, and that is something that’s not understood at all,” Santangelo said. “If we can figure out why some cells are exploding with virus while others are not, perhaps we can figure out a way to help the bad ones look more like the good ones.”

In addition to those already mentioned, the research team included James Crowe, professor of pediatrics at Vanderbilt University; Elizabeth Wright, assistant professor in the School of Medicine at Emory University; Daryll Vanover, Jeenah Jung, Chiara Zurla, Jonathan Kirschman, Vincent Fiore, and Alison Douglas from the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University; Aaron Lifland and Manasa Gudheti from Vutara Inc. in Salt Lake City, and Hong Yi from the Emory University School of Medicine.

One of the challenges of studying RSV is maintaining its activity in the laboratory setting – a problem parents of young children don’t share.

“When you handle this virus in the lab, you have to always be careful about it losing infectivity,” Santangelo noted. “But if you take a room full of children who have not been infected and let one infected child into the room, 15 minutes later all of the children will be infected.”

The research described here was supported by the National Institute of General Medical Sciences of the National Institutes of Health under contract R01 GM094198-01. Any conclusions or opinions expressed are those of the authors and do not necessarily represent the official views of the NIH.

CITATION: Eric Alonas, et al., “Combining Single RNA Sensitive Probes with Subdiffraction-Limited and Live-Cell Imaging Enables the Characterization of Virus Dynamics in Cells,” (ACS Nano, December 2013). (http://dx.doi.org/10.1021/nn405998v).

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Writer: John Toon

Today, genetic information is stored in DNA. RNA is created from DNA to put that information into action. RNA can direct the creation of proteins and perform other essential functions of life that DNA can’t do. RNA’s versatility is one reason that scientists think this polymer came first, with DNA evolving later as a better way to store genetic information for the long haul. But like DNA, RNA also could be a product of evolution, scientists theorize.

Chemists at the Georgia Institute of Technology have shown how molecules that may have been present on early Earth can self-assemble into structures that could represent a starting point of RNA. The spontaneous formation of RNA building blocks is seen as a crucial step in the origin of life, but one that scientists have struggled with for decades.

“In our study, we demonstrate a reaction that we see as important for the formation of the earliest RNA-like molecules,” said Nicholas Hud, professor of Chemistry and Biochemistry at Georgia Tech, where he’s also the director of the Center for Chemical Evolution.

The study was published Dec. 14 online in the Journal of the American Chemical Society. The research was funded by the National Science Foundation and NASA.

RNA is perfect for the roles it plays in life today, Hud said, but chemically it’s extraordinarily difficult to make. This suggests that RNA evolved from simpler chemical couplings. As life became more chemically complex and enzymes were born, evolutionary pressures would have driven pre-RNA into the more refined modern RNA.

RNA is made of three chemical components: the sugar ribose, the bases and phosphate. A ribose-base-phosphate unit links together with other ribose-base-phosphate units to form an RNA polymer. Figuring out how the bond between the bases and ribose first formed has been a difficult problem to address in the origins of life field, Hud said.

In the study, Hud’s team investigated bases that are chemically related to the bases of modern RNA, but that might be able to spontaneously bond with ribose and assemble with other bases through the same interactions that enable DNA and RNA to store information. They homed in on a molecule called triaminopyrimidine (TAP).

The researchers mixed TAP with ribose under conditions meant to mimic a drying pond on early Earth. TAP and ribose reacted together in high yield, with up to 80 percent of TAP being converted into nucleosides, which is the name for the ribose-base unit of RNA. Previous attempts to form a ribose-base bond with the current RNA bases in similar reactions had either failed or produced nucleosides in very low yields.

“This study is important in showing a feasible step for how we get the start of an RNA-like molecule, but also how the building blocks of the first RNA-like polymers could have found each other and self-assembled in what would have been a very complex mixture of chemicals,” Hud said.

The researchers demonstrated this property of the TAP nucleosides by adding another molecule to their reaction mixture, called cyanuric acid, which is known to interact with TAP. Even in the unpurified reaction mixture, noncovalent polymers formed with thousands of paired nucleosides.

“It is amazing that these nucleosides and bases actually assemble on their own, as life today requires complex enzymes to bring together RNA building blocks and to spatially order them prior to polymerization,”said Brian Cafferty, a graduate student at Georgia Tech and co-author of the study

The study demonstrated one possible way that the building blocks for an ancestor of RNA could have come together on early Earth. TAP is an intriguing candidate for one of the first bases that eventually led to modern RNA molecules, but there are certainly others, Hud said.
Future work, in Hud’s lab and by other laboratories in the Center for Chemical Evolution, will investigate the origins of RNA’s phosphate backbone, as well as other pathways toward modern RNA.

“We’re looking for a simple, robust chemistry that can explain the earliest origin of RNA or its ancestor,” Hud said.

This research is supported by the National Science Foundation (NSF) Center for Chemical Evolution under award number CHE-1004570, and the NASA Exobiology Program under award number NNX13AIO2G. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

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Writer: Brett Israel

Election as a fellow of AAAS, the world’s largest general scientific society, is an honor bestowed upon members by their peers. Fellows are recognized for meritorious efforts to advance science or its applications.

New fellows include:

• School of Interactive Computing Professor Henrik Christensen, cited “for contributions to applied estimation methods in mapping, robot localization, visual tracking and recognition, as well as national-level leadership of the robotics community.”
• School of Biology Professor Mark Hay, cited “for distinguished contributions in ecology, particularly for developing marine chemical ecology and for elucidating how chemical cues and signals structure populations, communities, and ecosystems.”
• School of Chemical and Biomolecular Engineering Professor Hang Lu, cited “for distinguished contributions to the field of engineering systems for high-throughput quantitative and systems biology, particularly for microfluidics, automation, image-based science, and phenomics.”
• School of Aerospace Engineering Professor Suresh Menon, cited “for distinguished and innovative contributions to the field of multi-scale computational simulation and modeling of turbulent combustion in power and propulsion systems.”

Collaboration doesn’t just come easy for him. It is at the very foundation of his research approach when it comes to understanding cancer. McDonald, then, was a natural choice among faculty members who will relocate to the Engineered Biosystems Building (EBB) when it opens in 2015. Campaign Georgia Tech has been instrumental in raising money for the building.

“I’m convinced that the effective treatment of complex diseases like cancer will require an understanding of the interactive relationships that underlie cell function,” McDonald said. “I am excited about the prospect of working with other researchers committed to a ‘systems’ approach to better understand the basis of cancer onset and progression.”

The EBB was conceptualized and designed, and will be constructed, according to one fundamental tenet — that understanding and fighting multifaceted disease requires a new way of doing things; that new insights emerge not from the solitary confines of one laboratory or one discipline but from shared resources, spaces, and expertise.

The collaborative spaces within the facility are decidedly intentional and planned. The five-story, 200,000-square-foot building will house faculty members and other researchers in three research neighborhoods: chemical biology, cell and developmental bioengineering, and systems biology. Within each neighborhood, scientists and engineers from many different disciplines will share lab, office, and communal spaces, making it possible for them to share ideas, perspectives, and resources in an entirely new way.

For many years, McDonald has taken a collaborative approach to cancer research, working with faculty in chemistry and computer science to develop new, highly accurate diagnostic tests for ovarian and prostate cancer, and partnering with biomedical engineers, chemists, and biologists in cell therapies and personalized cancer medicine. Once the EBB is operational, collaboration will drive its every function and use, which will help accelerate the pace of discovery.

“We are not striving to compete with cancer centers like MD Anderson,” explained McDonald. “We are complementing their efforts by developing these unique integrative approaches, and this building will greatly enhance our ability to do that.”

For more about Campaign Georgia Tech, click here.

Editor’s Note: This article is part of a monthly series that focuses on Campaign Georgia Tech.

The K99/R00 Pathway to Independence Award is an award given by NIH to postdoctoral scientists to support their transition into an independent faculty appointment. This award provides support for a one- to two-year postdoctoral mentored phase and a successive three-year independent phase as a principal investigator. The main objective of this grant is to support promising scientists in the early stages of their career and accelerate their transition to an independent research position.

This competitive award is one of the few available for non-U.S. citizens and is a great complement for prospective faculty candidates. Current faculty members of the Georgia Tech community who have won this award include Dr. Brandon Dixon (Mechanical Engineering) and Dr. Matthew Torres (Biology).

After completing undergraduate studies in chemical engineering at Monterrey Institute of Technology (ITESM) and working in industry for a couple of years, Adriana moved to the United States from her native Mexico to pursue a graduate degree at Georgia Tech. She completed her Ph.D. in chemical and biomolecular engineering under the supervision of Dr. Sven Behrens, working on stimulus-responsive microcapsules and emulsions. She is now a postdoctoral fellow in Dr. Hang Lu’s lab, where she and others work on integrated engineering systems to perform high-throughput experiments with the nematode C. elegans to answer biological questions that cannot be addressed with conventional methods. Tools developed in the Lu lab, including microfluidics, machine learning and hardware automation, allow unbiased quantitative multidimensional characterization of micron-sized synaptic sites in large animal populations.

In the study, individuals with paralysis were able to use a tongue-controlled technology to access computers and execute commands for their wheelchairs at speeds that were significantly faster than those recorded in sip-and-puff wheelchairs, but with equal accuracy. This study is the first to show that the wireless and wearable Tongue Drive System outperforms sip-and-puff in controlling wheelchairs. Sip-and-puff is the most popular assistive technology for controlling a wheelchair.

The Tongue Drive System is controlled by the position of the user’s tongue. A magnetic tongue stud lets them use their tongue as a joystick to drive the wheelchair. Sensors in the tongue stud relay the tongue’s position to a headset, which then executes up to six commands based on the tongue position.

The Tongue Drive System holds promise for patients who have lost the use of their arms and legs, a condition known as tetraplegia or quadriplegia.

“It’s really easy to understand what the Tongue Drive System can do and what it is good for,” said Maysam Ghovanloo, an associate professor in the School of Electrical and Computer Engineering at the Georgia Institute of Technology, and a study co-author and principal investigator. “Now, we have solid proof that people with disabilities can potentially benefit from it.”

The study was published on Nov. 27 in the journal Science Translational Medicine. The National Institute of Biomedical Imaging and Bioengineering and the National Science Foundation funded the research. Scientists from Shepherd Center in Atlanta, and the Rehabilitation Institute of Chicago and the Northwestern University Feinberg School of Medicine in Chicago were also involved in the study. Jeonghee Kim and Hangue Park, who are working on the Tongue Drive System as graduate students at Georgia Tech, are co-authors of the study.

“The Tongue Drive System is a novel technology that empowers people with disability to achieve maximum independence at home and in the community by enabling them to drive a power wheelchair and control their environment in a smoother and more intuitive way,” said

Northwestern co-lead investigator Elliot Roth, M.D, chair of physical medicine and rehabilitation at Feinberg and the medical director of the patient recovery unit at Rehabilitation Institute of Chicago. “The opportunity to use this high-tech innovation to improve the quality of life among people with mobility limitations is very exciting.”

The research team had subjects complete a set of tasks commonly used in similar clinical trials. Subjects in the trials were either able-bodied or people with tetraplegia.

“By the end of the trials, everybody preferred the Tongue Drive System over their current assistive technology,” said Joy Bruce, manager of Shepherd Center’s Spinal Cord Injury Lab and co-author of the study. “It allows them to engage their environment in a way that is otherwise not possible for them.”

Researchers compared how able-bodied subjects were able to execute commands either with the Tongue Drive System or with a keypad and mouse. For example, targets randomly appeared on a computer screen and the subjects had to move the cursor to click on the target. Scientists are able to calculate how much information is transferred from a person’s brain to the computer as they perform a point-and-click task. The performance gap narrowed throughout the trial between the keypad and mouse and the Tongue Drive System.

For the first time, the research team showed that people with tetraplegia can maneuver a wheelchair better with the Tongue Drive System than with the sip-and-puff system. On average, the performance of 11 subjects with tetraplegia using the Tongue Drive System was three times faster than their performance with the sip-and-puff system, but with the same level of accuracy, even though more than half of the patients had years of daily experience with sip-and-puff technology.

“That was a very exciting finding,” Ghovanloo said. “It attests to how quickly and accurately you can move your tongue.”

The idea for piercing the tongue with the magnet was the inspiration of Anne Laumann, M.D., professor of dermatology at Feinberg and a lead investigator of the Northwestern trial. She had read about an early stage of Tongue Drive System using a glued-on tongue magnet. The problem was the magnet fell off after a few hours and aspiration of the loose magnet was a real danger to these users.

“Tongue piercing put to medical use — who would have thought it? It is needed and it works!” Laumann said.

The experiments were repeated over five weeks for the able-bodied test group, and over six weeks for the tetraplegic group. All of the subjects with tetraplegia were able to complete the trial, which Ghovanloo called an “exciting” and “major finding.”

The tetraplegic group was using the Tongue Drive System just one day each week, but their improvement in performance was dramatic.

“We saw a huge, very significant improvement in their performance from session one to session two,” Ghovanloo said. “That’s an indicator of how quickly people learn this.”

Experiments on the Tongue Drive System to date have been done in the lab or hospital. In future studies, scientists will test how the Tongue Drive System performs outside of the controlled clinical environment. The research team hopes to test how patients maneuver with the Tongue Drive System in their homes and other environments.

The Tongue Drive System isn’t quite ready for commercialization, but Ghovanloo’s startup company, Bionic Sciences, is working with Georgia Tech to move the technology forward.
Ghovanloo is the foundering director of the GT-Bionics Laboratory, where his team is experimenting with other devices to improve the quality of life for individuals with disability.

“All of my projects are related to helping people with disabilities using the latest and greatest technologies,” Ghovanloo said. “That’s my goal in my professional life.”

DiSanto hopes that the one day he’ll be able to use a tongue-powered wheelchair outside of the hospital, which would help him gain some independence he lost after his diving accident.

"The Tongue Drive System will greatly increase my quality of life when I can start using it everywhere I go,” DiSanto said. “With the sip-and-puff system, there is always a straw in front of my face. With the Tongue Drive, people can see you, not just your adaptive equipment."

This research is supported by the National Institute of Biomedical Imaging and Bioengineering under award number 1RC1EB010915, and by the National Science Foundation under awards CBET-0828882 and IIS-0803184. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

Dr. Ghovanloo's company, Bionic Sciences, is negotiating with the Georgia Tech Research Corporation for a license to the technologies discussed in this article. If the license is executed, the results of his research on the Tongue Drive System could affect his personal financial status. Dr. Ghovanloo's Conflict of Interest has been reviewed and approved by Georgia Tech in accordance with its conflict of interest policies.

CITATION: J Kim, et al “The Tongue Enables Computer and Wheelchair Control for People with Spinal Cord Injury,” (Science Translational Medicine, 2013). http://dx.doi.org/ 10.1126/scitranslmed.3006296

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Writer: Brett Israel

 A research team is attempting to engineer an injectable therapy for the shoulder’s supraspinatus tendon, a rotator cuff tendon that is commonly torn in sports. When the tendon is damaged, the body makes things worse by activating enzymes that further break down the tendon. The scientists hope to develop an injectable compound that would deliver an inhibitor capable of blocking these enzymes, thereby reducing the severity of the injury or even healing the tissue.

“Normally people focus on treating tendon injuries after the tear has occurred, but we’re focusing on a much earlier stage in the disease,” said Johnna Temenoff, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “This is the first time that an injectable therapy specifically designed to interact with tissue at an early disease state has been attempted for this particular tendon injury.”

Temenoff’s work is supported by a $1 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) for five years of research, which began in September 2013. Collaborating on the research is Manu Platt, an assistant professor in the same department. Temenoff’s previous work on tendon injuries, which focused on quarterbacks in football, was sponsored by the NFL Charities.

Shoulder tendon injuries are common overuse injuries for athletes and also for industrial workers whose repetitive overhead motion put them at risk. The rotator cuff is a collation of four tendons, and the tendons are made of collagen. Overuse of the tendons damages the collagen, and people feel stiff and sore in their shoulders as the area becomes weaker.

Once a tendon is damaged, the body accelerates the damage by activating enzymes that eat at the tendon, worsening the condition over time.

“The interesting thing about this disease is that we don’t know exactly what causes it,” Temenoff said. “We’re studying enzymes that are known to chew up the collagen, and we’re looking at then delivering inhibitors to those enzymes in a local injection in the tendon to try to stop the degradation.”

In their research, the team will use an animal model to characterize when these collagen-destroying enzymes are the most active. This will give researchers a good idea of when to inject inhibitors.

So that patients won’t need multiple shots, the scientists are working on a drug delivery material that will release the inhibitors over time once inside the body. One idea is to control the interactions between the inhibitors and small amounts of the blood thinner heparin. The team will also study the histology and mechanics of the tendons after healing.

Temenoff said that the injectable therapy could, in theory, work on other kinds of tendon injuries, not just in the shoulder.

“We’re studying the disease in the shoulder, but it’s the same disease that causes tennis elbow, Achilles injuries, and jumper’s knee,” Temenoff said. “It’s the same process, just in different tendons in the body.”

This research is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under award1R01AR063692-01A1. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of NIAMS.

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Writer: Brett Israel

McDevitt is an associate professor in the Coulter Department, a Petit Faculty Fellow in the Petit Institute for Bioengineering and Bioscience, and director of the Stem Cell Engineering Center at Georgia Tech. The objective of McDevitt’s research program is to develop enabling technologies for the directed differentiation of stem cells for regenerative medicine, disease models, and diagnostic applications. Much of his research focuses on the application of technologies to engineer stem cell fate, on stem cell bioprocessing and on engineering regenerative therapies from stem cells. McDevitt has garnered more than $9 million in funding, including a Transformative R01 award from the NIH and an NSF IGERT on Stem Cell Biomanufacturing. He received the 2010 Society for Biomaterials Young Investigator Award, a New Investigator Award from the American Heart Association and was recognized as one of the “40 Under 40” by Georgia Trend magazine. McDevitt graduated cum laude from Duke University, with a B.S.E. and a double major in Biomedical and Electrical Engineering. He received his Ph.D. in 2001 in Bioengineering from the University of Washington, where he worked for Patrick S. Stayton, and where he conducted post-doctoral research in the pathology laboratory of Charles E. Murry. 

Roy joined the Coulter Department this summer as professor and is currently the director of the Center for Immunoengineering.  He is an elected Fellow of the American Institute for Medical and Biological Engineering (AIMBE) and a Fellow of the Biomedical Engineering Society (BMES). He received his B.S. from the Indian Institute of Technology, M.S. from Boston University and his Ph.D. in Biomedical Engineering from Johns Hopkins University. Following his Ph.D., he joined a start-up biotechnology company, Zycos Inc., where he served as a senior scientist in drug delivery research.  He joined The University of Texas at Austin in 2002, where most recently he was professor of Biomedical Engineering. He also served as the director of the graduate program and as associate chair for education and outreach. His research interests are in the areas of immunoengineering with particular focus on material-directed cells signaling and immune cell generation and controlled drug and vaccine delivery technologies with applications in cancer and immunotherapies.  Roy has received the Young Investigator Awards from The Society for Biomaterials (SFB) and the Controlled Release Society (CRS). He has been extensively funded by NIH, NSF, the Coulter Foundation, the Whitaker Foundation and the Cancer Prevention And Research Institute of Texas, among others. He serves as a member of the editorial boards for the Journal of Controlled Release and the European Journal of Pharmaceutics and Biopharmaceutics.

Georgia Tech and Emory created the joint department of biomedical engineering in the fall of 1997. The collaborative relationship blends the expertise of medical researchers at the Emory University School of Medicine with that of the engineering faculty at Georgia Tech, and is the first of its kind between a public and private institution. The collaboration has resulted in a biomedical engineering program that consistently ranks among the top five in the nation by U.S. News & World Report.

People with long-term disabilities and chronic conditions will encounter a unique set of challenges as they get older. But that doesn’t mean they can’t age successfully and safely.

The Georgia Institute of Technology has received a five-year $4.6 million grant to increase understanding of the aging process for people with disabilities and use data gleaned from the study to develop technologies that will benefit them and others.

The grant from the National Institute on Disability and Rehabilitation Research in the Department of Education will support the interdisciplinary Center on Technologies to Support Successful Aging with Disability (RERC TechSAge).

“This will serve as a major catalyst for understanding the issues at work as well as developing technologies to be used in homes and our communities,” said Professor Jon Sanford, the lead principal investigator who is also director of the Center for Assistive Technology and Environmental Access (CATEA). “We are focusing on certain groups but this will be useful for all of society.”

The project classifies disabilities as low vision or blind; deaf or hard of hearing; and mobility limitation, such as using a wheelchair or walker. It focuses primarily on adults 50 and older.

“This is an emerging population and we aim to get a full understanding of their different needs,” said Professor Wendy Rogers, a co-principal investigator.

Researchers will assess needs as they relate to work, home, transportation and health care, said Rogers, who leads Georgia Tech’s Human Factors and Aging Laboratory. They will conduct surveys, hold structured interviews and observe participants in different settings.

Technology projects will build on these data. Researchers expect robots will remotely monitor and perform tasks for individuals with disabilities as they age.

Tracy Mitzner, the other co-principal investigator and associate director of the Human Factors and Aging Laboratory, will investigate how telerobotics can support older adults with disabilities by allowing them to remain active and improve their physical strength. It would also help aging adults remain social, Mitzner said.

Another project is expected to result in open source software and hardware that enables robots to better assist people with disabilities as they age, said Charlie Kemp, director of the Healthcare Robotics Lab at Georgia Tech.

Kemp’s project will continue his collaboration with Henry and Jane Evans. Henry Evans lives with quadriplegia. Their original collaboration as part of the Robots for Humanity project resulted in Evans briefly using a mobile robot to shave and scratch his face, pull a blanket over himself and perform other tasks.

In all, the vast project will rely on expertise from multiple research centers at Georgia Tech. In addition to CATEA, the School of Psychology and the Healthcare Robotics Lab, those involved include: the Institute for People and Technology, Aware Home Research Initiative, School of Industrial Design, Center for Geographic Information Systems, Alternative Media Access Center, Interactive Media Technology Center, Human-Centered Computing, the Wallace H. Coulter Department of Biomedical Engineering and the Georgia Tech Research Institute.

Researchers from the Emory Center for Health in Aging and the University of South Carolina will also participate.

Research into the stiffness of diseased cells is lacking, in part due to limits in technology. Researchers have developed a new technology to sort human cells according to their stiffness, which might one day help doctors identify certain diseases in patients, according to a new study.

The research team, from the Georgia Institute of Technology, hopes that their technology might one day aid doctors in the field to rapidly and more accurately diagnose disease.

The new technology is being tested in a small device, about 1 inch wide by 1.5 inches long. Cells are injected into a microfluidic channel on one side of the device. As the cells move through the channel, they are forced to squeeze over a series of ridges that are fabricated at an angle to the channel. If the cells are very flexible, they will easily squeeze over the ridges and follow the fluid stream. But if the cells are stiffer, when they hit a ridge, they will slide along the angled ridge before squeezing over, causing the cells to move to one side, separating them from the softer cells. These ridges eventually separate a single stream of cells into two streams depending on the cells’ stiffness, which in some cases can be an indicator of a disease.

“If you imagine a microfluidic channel that is focusing a stream of cells, you’ll push the cells in different directions based on their mechanical properties,” said study co-author Todd Sulchek, an assistant professor in the George W. Woodruff School of Mechanical Engineering at Georgia Tech. Sulchek specializes in studying the mechanical properties of cells.

The new research was published Oct. 16 in the journal PLOS ONE. The research was sponsored by the National Science Foundation. The researchers also have a patent on this technology.

“There are no real techniques to sort cells by stiffness right now in large numbers,” said Alexander Alexeev, an assistant professor in Georgia Tech’s George W. Woodruff School of Mechanical Engineering. Alexeev is an expert in fluid mechanics and a co-author on the study

A few other research groups are working on microfluidic approaches to sorting cells by stiffness, but Sulchek and Alexeev believe their technology will be quite sensitive.

“There are several microfluidic approaches, but there’s not a real device yet,” Alexeev said. “The main problem is how to sort cells very rapidly because if we are looking at cancer cells, there are very, very few of them. So we need to look at thousands of millions of cells to capture maybe a hundred cancer cells.”

Their technology can sort cells at speeds similar to other cell sorting devices, such as a fluorescently activated cell sorter machine, which is a commonly device used in research labs.
To show that their device can successfully sort cells based on stiffness, the researchers made some cells artificially soft, then labeled them with a different color so they could find them later. After running the cells through their device and analyzing the separated cells by color, they found that the artificially soft cells were separated from the other cells. Then the researchers used atomic force microscopy to probe the cells’ mechanical properties to make sure they were actually different.

“We show that we separate by stiffness, not by other factors,” Sulchek said.

The researchers tested four different commercially available cell lines. White blood cells sort by stiffness particularly well, the researchers reported.

The research team will now work on using their device to separate cancer cells, malaria-infected cells, and sickle cells, and to sort stem cells.

“We’re assured the device is very sensitive to say that the soft cells are all soft, but what we don’t know is whether all the disease cells are soft,” Sulchek said.

Aside from testing for disease, the cell stiffness sorter could also be used in as a method for purifying and enriching an undifferentiated stem cell population from the differentiated cells, which would be useful for laboratory scientists.

“This is also a useful tool for just basic research and understanding what the effect of specific disease is on cell mechanics,” Alexeev said.

Gonghao Wang, a PhD student in Sulchek’s lab, is the first author of the study.

This research is supported by the National Science Foundation under award CBET-0932510. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

CITATION: G Wang, et al., “Stiffness Dependent Separation of Cells in a Microfluidic Device,” (PLOS ONE, 2013). http://dx.plos.org/10.1371/journal.pone.0075901

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Writer: Brett Israel

Nearly 300 colleges and universities from around the world registered a team and participated in this competition. Teams designed and employed standard biological parts in order to carry out a designated function within living cells. Early in October, the Georgia Tech iGEM team was awarded a gold medal at the North American regional jamboree. The team will now advance to the world championship. Out of the 65 registered teams in North America, only 13 undergraduate teams received a gold medal and advanced to the world competition.

The Georgia Tech iGEM team consists of seven undergraduate students: Tilak Balavijayan, Rachael Blackstone, Spencer Cooper, Haoli Du, Casey Haynes, Jack Jenkins, and Jessica Siemer. The team was assembled in the summer of 2013 and has been working towards expressing human integrin sensors on the surface of E. coli cells, a feat that has not yet been accomplished. The team is advised by Anton Bryksin, Vince Fiore, and Haylee Bachman, lab space was provided by Thomas Barker in the Biomedical Engineering Department at Georgia Tech and partial financial support by the Parker H. Petit Institute for Bioengineering and Bioscience.

The International Genetically Engineered Machine competition (iGEM) is the premiere undergraduate Synthetic Biology competition. Student teams are given a kit of biological parts at the beginning of the summer from the Registry of Standard Biological Parts. Working at their own schools over the summer, they use these parts and new parts of their own design to build biological systems and operate them in living cells. This project design and competition format is an exceptionally motivating and effective teaching method. The iGEM Jamboree is the largest annual gathering of synthetic biologists.

• Graduate student mentors receive $750 for travel
• Great CV builder, most employers prefer PhD’s with management experience
• Labs receive $2,000 for materials and supplies

For complete Petit Mentor program information, visit website

Project submission deadline Friday, October 25, 2013

Understanding how the shape of nanoparticles affects their transport into cells could be a major boost for the field of nanomedicine by helping scientists to design better therapies for various diseases, such as improving the efficacy and reducing side effects of cancer drugs.

In addition to nanoparticle geometry, the researchers also discovered that different types of cells have different mechanisms to pull in nanoparticles of different sizes, which was previously unknown. The research team also used theoretical models to identify the physical parameters that cells use when taking in nanoparticles.

“This research identified some very novel yet fundamental aspects in which cells interact with the shape of nanoparticles,” said Krishnendu Roy, who recently joined the Wallace H. Coulter

Department of Biomedical Engineering at Georgia Tech and Emory University. Roy conducted this research at The University of Texas at Austin in collaboration with Profs. S. V. Sreenivasan and Li Shi, but is continuing the work at Georgia Tech.

The study was scheduled to be published the week of Oct. 7 in the early online edition of the journal Proceedings of the National Academy of Sciences. The work was sponsored by the National Science Foundation and the National Institutes of Health.

Roy’s team used a unique approach to making the differently shaped nanoparticles. The researchers adapted an imprinting technology used in the semiconductor industry and rigged it to work with biological molecules, Roy said. This imprinting technique, which they developed at UT-Austin, works like a cookie cutter but on the nanoscale. Drugs are mixed with a polymer solution and dispensed on a silicon wafer. Then a shape is imprinted onto the polymer-drug mixture using a quartz template. The material is then solidified using UV light. Whatever the cookie cutter’s template – triangle, rod, disc – a nanoparticle with that shape is produced.

Another key feature of the nanoparticles is that they are negatively charged and are hydrophilic, attributes that make them relevant for clinical use in drug delivery.

“We have exquisite control over the shapes and sizes,” said Roy, who is a Wallace H. Coulter Distinguished Faculty Fellow.

His team then used particles of various shapes and sizes to see how different kinds of cultured mammalian cells would respond to them. The materials and surface charges of the particles were all the same, only the shapes differed.

Roy’s team was not expecting cells to prefer discs over rods. They found that in cell culture, unlike spherical nanoparticles, larger sized discs and rods are taken up more efficiently, a finding that was also unexpected. When they ran theoretical calculations they found that the energy required by a cell membrane to deform and wrap around a nanoparticle is lower for discs than rods and that gravitational forces and surface properties play a significant role in nanoparticle uptake in cells.

“The reason this has been unexplored is that we did not have the tools to make these precisely-shaped nanoparticles,” Roy said. “Only in the past seven or eight years have there been a few groups that have come up with these tools to make polymer particles of various sizes and shapes, especially in the nanoscale.”

Cells take in nanoparticles through a process called endocytosis, but depending on the shape and cell-type, specific uptake pathways are triggered, the team discovered. Some cells rely on proteins in their membranes called caveolin; others use a different membrane protein, known as clathrin.

Understanding how cells respond to the shapes of nanoparticles is important not just for drug delivery, but also for understanding the toxicity of nanomaterials used in consumer products. Roy’s new work provides another piece to solving this puzzle. 

“People are making different nanoscale stuff with various materials without fundamentally understanding their interactions with cells,” Roy said.

In future work at Georgia Tech, Roy’s lab would like to investigate how the shapes of nanomaterials affect their transport and function in animal models. This will give researchers a better idea how the particles move into tumors, pass across mucosal surfaces and distribute into organs, and ultimately aid in clinical therapies.

“99.9 percent of our work is still to be done, which we want to continue to do here at Tech in collaboration with researchers at UT,” Roy said.

Other researchers on the study include Rachit Agarwal, the lead author who is now a post-doctoral fellow at Georgia Tech, as well as Vikramjit Singh, Patrick Jurney, Li Shi and S.V. Sreenivasan, all of whom were at The University of Texas at Austin

This research is supported by the National Science Foundation under award CMMI0900715, and by the National Institutes of Health under award EB008835. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

CITATION: R. Agarwal, et al., “Mammalian Cells Preferentially Internalize Hydrogel Nanodiscs over Nanorods and Use Shape-Specific Uptake Mechanisms,” (Proceedings of the National Academy of Sciences, 2013). http://www.pnas.org/cgi/doi/10.1073/pnas.1305000110.

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Writer: Brett Israel

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• Sophomores and above with a GPA of 3.0 or better. Students with freshman standing considered
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To be considered for these summer internship opportunities, interested GT candidates should FIRST submit their applications online to specific internship openings and then forward a resume directly to Colly Mitchell at Georgia Tech indicating to which openings have been applied.

Lymphedema develops when the body fails to circulate lymphatic fluid, a mixture of immune cells, proteins, and lipids. This fluid builds up in the arms, legs and genitals — sometimes causing extreme swelling and permanent remodeling of the tissue. The mechanisms involved in the progression of the disease are unclear, so professor J. Brandon Dixon’s lab will use an engineering approach to studying the disease. This innovative methodology could lead to new technologies to test and treat lymphatic disease.

Solving this biological problem with engineering is an ideal strategy, Dixon said, because the lymphatic system is an engineered system — essentially a very complicated network of pumps. In a healthy person, the lymphatic system pumps the lymphatic fluid around the body, draining excess fluid from tissues and returning it to the circulation. Understanding the details of how the system works, and what goes wrong when it fails during lymphedema, requires engineering expertise.

“I really think the reason we’re so far behind in lymphatic research compared to vascular research is technology,” said Dixon, an assistant professor in the Georgia Tech School of Mechanical Engineering. “You can go to the most advanced lymphedema center in the world and it’s still difficult to say how well your lymphatic system is working.”

Dixon’s lab is located in Georgia Tech’s Parker H. Petit Institute for Bioengineering and Bioscience, a unique collaborative unit of experts from engineering and the life sciences. He’s one of only a handful of engineers in the world that study the mechanical forces at work in lymphedema.

The lymphatic system is difficult to see and access, but Dixon’s expertise lies in developing engineering technologies such as imaging and recreating the lymphatic environment in the lab. His lab has pioneered technologies to manipulate the micromechanical environment on cells and in isolated vessels.

By teasing apart the workings of the lymphatic system, Dixon’s research could lead to diagnostic technologies that measure how well the lymphatic system is functioning, and also to therapies that manipulate the system and stop the painful swelling that occurs during lymphedema.

For the past 30 years, little progress has been made in treating lymphedema. Patients are treated with compression wraps to limit painful swelling.

Limited research on the prevalence of lymphedema suggests that between 20 and 60 percent of post-mastectomy breast cancer patients develop the disease. One in six women will get breast cancer, estimates suggest. Worldwide, lymphedema affects more than 100 million people. In undeveloped countries, parasites can cause a severe form of lymphedema-related swelling known as filariasis.

Scientists cannot yet say what causes lymphedema in post-mastectomy breast cancer patients, nor can they assign a patient-specific risk of developing the disease. And since lymphedema can arise as long as six years after surgery, determining cause and effect is difficult. The later the onset, the more likely patients are to report the swelling to their general practitioner and not their cancer surgeon. This uneven reporting makes it hard to measure the burden that lymphedema places on the healthcare system.

“It’s hard to measure the cost of lymphedema,” Dixon said. “It’s not like a stroke where there’s an obvious event that occurs and a rate of death. People don’t die of lymphedema, per se.”

Long-term lymphedema-related swelling is not from the fluid itself, but from actual growth of the affected limb through fibrosis and the deposition of fats. Scientists don’t yet understand what causes this. Dixon’s hypothesis is that something happens during breast cancer surgery that changes the mechanical forces on lymphatic vessels that impairs their ability to pump this fat-containing fluid.

“If the pump doesn’t work, it’s like a feedback loop,” Dixon said. “You get accumulation of fluid and other remodeling of the tissue, which in turn leads to greater lymphatic failure”

To test the hypothesis, Dixon’s lab will mechanically perturb lymphatic vessels in isolated vessels, and cells. They’ll stretch them and ramp up the fluid flow rates across them and observe changes in vessels function and remodeling. Clues about how the vessels work might be found in genes that are switched on and off, changes in pump rate, buildup of extracellular matrix, and other biological abnormalities.

In another experiment, the lab will use animal models to explore what happens to the lymphatic vessels after breast cancer surgery. The researchers plan to destroy one lymphatic vessel and observe what happens to the system as it tries to compensate for the loss.

Data from the experiments will feed a mathematical model of the growth and remodeling of lymphatic vessels, which is under development by Dixon’s collaborator on the project, Rudolph Gleason, an associate professor in Georgia Tech’s Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

Also collaborating on the project is Mari Muthuchamy, a professor of medical physiology at the Texas A&M Health Science Center in College Station, Texas.

This research is supported by the National Institutes of Health under award R01HL113061. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the NIH.

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Writer: Brett Israel

When chromosomes experience double-strand breaks due to oxidation, ionizing radiation, replication errors and certain metabolic products, cells utilize their genetically similar chromosomes to patch the gaps via a mechanism that involves both ends of the broken molecules. To repair a broken chromosome that lost one end, a unique configuration of the DNA replication machinery is deployed as a desperation strategy to allow cells to survive, the researchers discovered.

The collaborative work of graduate students working under Anna Malkova, associate professor of biology at Indiana University-Purdue University Indianapolis (IUPUI) and Kirill Lobachev, associate professor of biology at the Georgia Institute of Technology, was critical in the advancement of the project. The group’s research was scheduled to be published Sept. 11 in the online edition of the journal Nature, with two graduate students, Sreejith Ramakrishnan of IUPUI, and Natalie Saini of Georgia Tech, as first authors. Other collaborators include James Haber of Brandeis University and Grzegorz Ira of the Baylor College of Medicine.

“Previously we have shown that the rate of mutations introduced by break-induced replication is 1,000 times higher as compared to the normal way that DNA is made naturally, but we never understood why,” Malkova said.

Lobachev’s lab used cutting-edge analysis techniques and equipment available at only a handful of labs around the world. This allowed the researchers to see inside yeast cells and freeze the break-induced DNA repair process at different times. They found that this mode of DNA repair doesn’t rely on the traditional replication fork — a Y-shaped region of a replicating DNA molecule — but instead uses a bubble-like structure to synthesize long stretches of missing DNA. This bubble structure copies DNA in a manner not seen before in eukaryotic cells.

Traditional DNA synthesis, performed during the S-phase of the cell cycle, is done in semi-conservative manner as shown by Matthew Meselson and Franklin Stahl in 1958 shortly after the discovery of the DNA structure. They found that two new double helices of DNA are produced from a single DNA double helix, with each new double helix containing one original strand of DNA and one new strand.

“We demonstrated that break-induced replication differs from S-phase DNA replication as it is carried out by a migrating bubble instead of a normal replication fork and leads to conservative DNA synthesis promoting highly increased mutagenesis,” Malkova said.

This desperation replication triggers “bursts of genetic instability” and could be a contributing factor in tumor formation.

“From the point of view of the cell, the whole idea is to survive, and this is a way for them to survive a potentially lethal event, but it comes at a cost,” Lobachev said. “Potentially, it’s a textbook discovery.”

During break-induced replication, one broken end of DNA is paired with an identical DNA sequence on its partner chromosome. Replication that proceeds in an unusual bubble-like mode then copies hundreds of kilobases of DNA from the donor DNA through the telomere at the ends of chromosomes.

“Surprisingly, this is a way of synthesizing DNA in a very robust manner,” Saini said. “The synthesis can take place and cover the whole arm of the chromosome, so it’s not just some short patches of synthesis.”

The bubble-like mode of DNA replication can operate in non-dividing cells, which is the state of most of the body’s cells, making this kind of replication a potential route for cancer formation.

“Importantly, the break-induced replication bubble has a long tail of single-stranded DNA, which promotes mutations,” Ramakrishnan said.

The single-stranded tail might be responsible for the high mutation-rate because it can accumulate mutations by escaping the other repair mechanisms that quickly detect and correct errors in DNA synthesis.

“When it comes to cancer, other diseases and even evolution, what seems to be happening are bursts of instability, and the mechanisms promoting such bursts were unclear,” Malkova said.

The molecular mechanism of break-induced replication unraveled by the new study provides one explanation for the generation of mutations.

This research is supported by the National Institutes of Health under awards RO1GM082950, RO1GM084242, RO3ES016434, GM76020, and by the National Science Foundation under award MCB-0818122. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the NIH or NSF.

CITATION: N. Saini, et al., “Migrating bubble during break-induced replication drives conservative DNA synthesis,” (Nature, 2013). http://dx.doi.org/10.1038/nature12584

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The researchers determined the structure of BamA, a key component of the cellular machinery that controls insertion of beta-barrel proteins into the outer membranes of Gram-negative bacteria, organisms that cause a range of respiratory, gastrointestinal, urinary and other infections.

Beta-barrel membrane proteins transport substrates ranging from small molecules to large proteins into and out of the Gram-negative bacteria. These transport proteins help maintain the structure and composition of the outer membrane. Responsible for the virulence of pathogenic strains, the proteins are also essential to the viability of the bacteria – making them of interest for the development of new therapeutics.

“Because BamA is required for viability in all Gram-negative bacteria, it is a promising candidate for vaccines and drugs targeting bacterial infections,” said Susan Buchanan, a senior investigator in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH) in Bethesda, Md. “Knowing the structure and understanding how BamA works will likely help advance vaccine and drug design, and could result in novel antibiotics.”

The research team solved BamA structures from two bacteria: Neisseria gonorrhoeae and Haemophilus ducreyi. Buchanan, the paper’s principal author, said several biotechnology companies are already interested in understanding the structure of the protein and how it functions.  

The team reported its findings September 1 in the journal Nature. The research was led by NIH scientists and included researchers from the Georgia Institute of Technology, Monash University in Australia and Diamond Light Source in the United Kingdom.

“Learning how individual amino acid residues are organized into three-dimensional protein structures helps us understand features that are not apparent by any other type of analysis,” Buchanan said. “With a crystal structure, we essentially have a snapshot of what the protein looks like in 3D, which is a huge advantage in determining how a particular protein functions and in designing therapeutics.”

Once they had determined the three-dimensional structure of the protein, the researchers still needed to understand how the BamA-mediated insertion mechanism worked. To develop clues to the protein’s function, a Georgia Tech researcher carried out molecular dynamics simulations to provide a hypothesis that could be tested experimentally.

“When we looked at the structure, it wasn’t obvious to us how BamA helps proteins insert into the membrane,” said J.C. Gumbart, an assistant professor in the Georgia Tech School of Physics. “What my simulations revealed is that the barrel spontaneously opens and closes laterally to the membrane. We could actually see the opening of the barrel in the simulations, and based on that, came up with a hypothesis for how it could assist insertion of proteins into the outer membrane of the bacteria.”

For example, the crystalline structure of the protein showed that one side of the membrane-spanning beta-barrel domain is shorter than the other side, a feature that, according to the simulations, compresses the lipid bilayer and locally destabilizes the lipids in that region. The structure provides a potential route for inserting newly-synthesized outer-membrane proteins.

In conducting the simulations, Gumbart used the special-purpose Anton supercomputer at the Pittsburgh Supercomputing Center. The machine, developed by D.E. Shaw Research, allows simulations to attain microsecond-per-day computation rates, which was essential because the BamA simulations needed to be unusually long for researchers to observe its conformational flexibility.

The simulations will next have to be validated by experimental research, which could provide additional information about how the membrane proteins are inserted. In turn, that may lead to further simulations and additional experiments.

“Simulations and experiments often work hand-in-hand to attack very difficult problems,” Gumbart said. “We can have a give-and-take in which I make a prediction based on the simulations, and the other members of the team work to verify it experimentally.”

The new work adds significantly to the understanding of how BamA proteins operate in Gram-negative bacteria.

“Gram-negative bacteria have an unusual outer membrane that differs from other species and had not been well studied before,” Gumbart noted. “Many people are aware of the protein folding problem generally, but fewer people know about the membrane protein issues. This is a really distinct, but critical biophysical question that we need to address to better understand how these bacteria function.”

Ultimately, the work may lead to new approaches for addressing the challenge posed by bacterial resistance to existing drugs.

“We need completely new thinking about antimicrobials and antibacterial agents to get ideas on how better to kill these bacteria,” Gumbart added. “Any time you develop a better understanding of how a process works in a cell, you can begin to predict ways to interfere with that process. Inserting proteins into the outer membranes of bacteria is one of the most fundamental processes taking place in these microorganisms, so it offers a significant target for therapeutic development.”

In addition to those already mentioned, the paper’s authors included Nicholas Noinaj, Adam J. Kuszak, Hoshing Chang and Nicole C. Easley from the NIH; Petra Lukacik from Diamond Light Source, and Trevor Lithgow from Monash University.

CITATION: Nicholas Noinaj, et al., “Structural insight into the biogenesis of beta-barrel membrane proteins,” (Nature 2013). http://dx.doi.org/10.1038/nature12521

The research was supported by the NIDDK Intramural Research Program of the National Institutes of Health (NIH) and by NIH grants K22-AI100927 and R01-GM067887. The opinions and conclusions are those of the authors and do not necessary reflect the official views of the NIH.

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Writer: John Toon

“A bunch of numbers and computer commands,” was her best guess. Eight weeks later, she had recognized the power of computing and could “make the computer do what I want.” What made the difference is a coding program developed at the Georgia Institute of Technology.

EarSketch is one of several Georgia Tech initiatives that researchers and staff members are making available to K-12 students around the state and the country. From the Nerdy Derby to online lessons and underwater tours, every program uses creative and different tactics. But the goal of each is the same: to get more students interested in science, technology, engineering and mathematics (STEM) fields. Many are designed to provide STEM outreach with a focus on minorities and underserved students.

Serving the State

Though it doesn’t have an education college, Georgia Tech is one of the state’s leaders as Georgia attempts to increase the number of STEM students, expand its future workforce and drive the economy. For 25 years, the Institute’s Center for Education Integrating Science, Mathematics and Computing (CEISMC) has connected Georgia Tech with educational groups, schools, corporations and opinion leaders around the state and nation. The 48-member staff has two key initiatives for students: STEM awareness and preparation.

“Many K-12 children have never seen a scientist. Some have never seen a lab,” said CEISMC Director Richard Millman. “For children to decide if they want to pursue STEM fields, they must first be introduced to the field in a way that intrigues them. Thanks to many of the faculty of Georgia Tech, the excitement of research can be brought to the K-12 schools.”

CEISMC also focuses on STEM teacher professional development using content enrichment initiatives, including initiatives funded by the federal government’s Race to the Top program.

Similarly, the Georgia Tech Research Institute (GTRI) – Georgia Tech’s applied research organization – has made STEM a top priority. As part of its core mission, GTRI is helping educate the leaders of a technologically driven world.

“Our team will continue to bring excitement, vitality and good science to classrooms across the state,” said GTRI Director and Georgia Tech Vice President Robert McGrath. “At the same time, we will concentrate our resources, attempting to have direct and significant impact on the future careers and livelihoods of targeted groups of students. My hope and experience suggests that such notable impact can and will be contagious.”

Discovering the World

Principal research engineer Jud Ready is growing nanotubes in his lab at GTRI’s Baker Building. Approximately 30 high school students are watching his every move, some even suggesting which gases to use during the experiment. Ready can see their wide eyes and amazed looks as the nanotubes grow. He answers their questions and offers others in return. But there are no students with him in the lab. They are 66 miles away at Jasper County High School.

Ready is teaching a lesson, using videoconferencing technology, as part of GTRI’s Direct-to-Discovery (D2D) program. The five-year-old initiative connects Georgia Tech researchers with Georgia’s K-12 schools using high-speed Internet connections and high-definition, real-time video, allowing students to participate in research as it happens.

“I was introduced to science in the second grade during a field trip to the University of North Carolina at Chapel Hill. I watched the scientists shatter flowers using liquid nitrogen,” said Ready, who regularly leads D2D lessons. “Every student should have the opportunity to discover and explore their own personal interests.”

Later in the lesson, Ready places the nanotubes under his scanning electron microscope, giving the students a glimpse of something impossible to replicate in their regular classroom.

Jasper County is the latest high school to participate in D2D. Earlier lessons have taken place with Barrow and Ware County schools, where students have peered underwater at the Georgia Aquarium and controlled telescopes in Australia to see the stars.

“Due to economics and distance, our students don’t have the chance to regularly attend or engage with museums, aquariums or labs for educational opportunities,” said Joseph Barrow, superintendent of Ware County Schools. “We saw D2D as a golden opportunity to figuratively tear down the brick and mortar walls of our system and to literally bring the world to our students.”

Because of D2D’s flexibility, Georgia Tech researchers don’t participate in every lecture. Sometimes schools use the technology to create their own opportunities. For instance, one of Ware County’s elementary schools connected with former First Lady Barbara Bush, who read students a story and spoke about the importance of reading. A high school class has connected with NASA’s Goddard Space Flight Center.

“It takes three to five years to develop a textbook, which is then used in a classroom for about 10 years,” said Jeff Evans, a GTRI principal research engineer and one of the D2D leaders. “By the time some students read it in the book, the technology is already obsolete. Direct to Discovery is an evolutionary leap beyond a textbook, and exposes students to the technologies of today and tomorrow.”

Mentoring the Next Generation

Studies show that students who do not perform well in algebra have limited career options in the science, technology, engineering and mathematics fields.

To help students pass through what educators call the algebra “gateway,” Georgia Tech offers All Kids Count in Atlanta. The math-tutoring program is available to students at Centennial Place Elementary School, as well as the B.E.S.T. Academy Middle and High Schools and Coretta Scott King Middle and High Schools – both of which are single gendered, African-American schools.

Each week, Georgia Tech work-study students work one-on-one with students in need of remedial help or assistance preparing for school and statewide, standardized tests. All Kids Count mentors also increase student interest in STEM by facilitating hands-on science activities and teaching students about technology through blogging, computer programming and other activities.

All Kids Count in Atlanta is just one of a plethora of mentoring programs offered by Georgia Tech.

The Pathways into STEM Program, another partnership between CEISMC and the Atlanta Public Schools, provides mentors to students at the B.E.S.T. Academy High School and Coretta Scott King High School.

Pathways mentors are AmeriCorps members who are in the schools between 12 and 40 hours per week. They help students not only develop their math and science skills, but also prepare them for the college and scholarship application processes.

“Most of these students are the first in their families to pursue college and they don’t know what is required or how the process works,” said Taneisha Lee, director of the Pathways Program. “Having a strong support system and information early on is very important for students to be successful.”

Indeed, the Pathways Program has made a significant impact. Over the last four years, nearly 90 percent of students who participated in Pathways went on to attend a two- or four-year college or university, and nearly half of the students pursued STEM degrees.

The Pathways Program has been so successful that CEISMC expanded it into Gwinnett County’s Lilburn and Radloff Middle Schools and Meadowcreek High School. It has also been incorporated into GoSTEM, a larger initiative that targets the Latino K-12 population in Gwinnett County.

Enhancing Outreach to Hispanics

Currently only 2 percent of Hispanics are employed in the STEM fields compared to 6 percent of whites and 15 percent of Asians, according to a recent report by the U.S. Department of Commerce’s Economic & Statistics Administration. Regardless of race or origin, higher education is a gateway to high-quality, high-paying STEM jobs, the report found.

That’s why Georgia Tech is partnering with the Gwinnett County School System on a new initiative called GoSTEM that aims to enhance the K-12 STEM educational experience for Latinos, as well as strengthen the pipeline of Hispanic students pursuing STEM degrees in college.

Funded by The Goizueta Foundation, GoSTEM is a community-focused program that brings resources for students, families and teachers to address the factors that impede Latino students from going into STEM fields. GoSTEM tries to reach students early on in elementary school and continues support through middle and high school.

The program provides schools-based math, science and engineering college preparation programs conducted by Georgia Tech mentors, extracurricular activities such as robotic competitions and community service projects, as well as summer camps. Pathways to College, which is part of the Pathways Program, also helps Latino high school students with their college application process and provides them with STEM career information and resources.

“We want to get students interested in STEM careers and give them the tools they need to pursue their dreams,” said Diley Hernandez, GoSTEM program director. “This is a good step in preparing them for the future and opening their eyes to the array of opportunities and choices ahead of them.”

GoSTEM also conducts a variety of community-wide events and campus tours to empower Latino parents and guardians, and provide them with information on how to guide their students to college and possibly a STEM career. For K-12 teachers, GoSTEM offers fellowships for CEISMC’s Georgia Intern Fellowships for Teachers (GIFT) to help them develop and implement a STEM curriculum through a summer internship at Georgia Tech.

GoSTEM is currently being offered at one cluster of Gwinnett County Public Schools including six elementary schools, two middle schools and one high school. Hernandez plans to expand the reach of the community-wide programs in the years ahead.

Engaging African-Americans in Biomedical Engineering

Fewer than 3 percent of Ph.D.s are awarded to African-Americans. Georgia Tech is working to change that statistic.

To increase the number of under-represented minorities in STEM fields, Manu Platt, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and Professor Emeritus Robert Nerem, have created Project ENGAGE (Engaging New Generations at Georgia Tech through Engineering).

The program is a partnership between Georgia Tech and two single-gendered African-American public schools – the all-male Benjamin Carson B.E.S.T Academy and the all-female Coretta Scott King Young Women’s Leadership Academy. It aims to introduce rising juniors and seniors to biomedical engineering by providing a hands-on experience in a research lab.

The first cohort of students, six from each school, began their research fellowship at Georgia Tech in June 2013. During the summer, they will work 40 hours per week and they will continue on throughout the school year dedicating 15 to 20 hours per week.

The fellowship kicks off with a four-week biology boot camp, developed and taught by three high school teachers who spent last summer in Georgia Tech’s biomedical labs learning the fundamentals. After the boot camp, the student fellows move into the lab where they are mentored by either a Ph.D. candidate or a postdoctoral researcher. The goal is for each student to present his or her project at a science fair before the end of the school year.

Project ENGAGE is more than just the research fellowship. Ph.D. candidates and postdoctoral scholars regularly visit B.E.S.T. and Coretta Scott King high schools to introduce biomedical engineering topics and discuss their research goals. The teens are also invited to visit Platt’s lab at Georgia Tech throughout the year, either in person or virtually via high-bandwidth video conferencing developed by the Georgia Tech Research Institute (GTRI).

“The more barriers we remove between these students and research universities, the more likely they will feel that they, too, deserve to be on campus and can be just as successful,” Platt said.

Project ENGAGE, which also includes mentoring partnerships with CEISMC and may expand even further, is supported by the National Science Foundation through the Emergent Behaviors of Integrated Cellular Systems Science and Technology Center.

Manufacturing a Better Future

Bringing manufacturing back to the United States could create new high-quality jobs for Americans. Georgia Tech is helping ensure that the next generation has the interest and skills necessary to fill those positions.

With the help of a $7.3 million grant from the National Science Foundation, Georgia Tech and the Griffin-Spalding County School System have teamed up to bring manufacturing technologies to middle and high school students in this low-income and highly diverse school district.

The five-year initiative – led by Georgia Tech’s George W. Woodruff School of Mechanical Engineering in collaboration with CEISMC – is bringing advanced manufacturing learning experiences, such as creating items using rapid prototyping and 3-D printers – to Griffin-Spalding County students in the 6th through 9th grades.

Called Advanced Manufacturing and Prototyping Integrated to Unlock Potential (AMP-IT-UP), the program allows students to learn about manufacturing by exploring their creativity and creating a physical solution to an engineering challenge using the engineering design process and both traditional and advanced manufacturing tools.

“With AMP-IT-UP we hope to inspire all students to connect with STEM fields,” said CEISMC associate director and AMP-IT-UP program director Marion Usselman. “In particular, we want to catch those students who might be our future creative innovators but who are at risk of falling through the cracks in our current book and test-driven education.”

Student classroom experiences are broadened by extracurricular clubs and competitions provided through the project. Georgia Tech faculty and students are mentoring Griffin-Spalding students in clubs such as the Junior Makers Club and robotic competitions including FIRST LEGO League and FIRST Robotics. Griffin-Spalding students have also been invited to campus for events such as the Nerdy Derby and the InVenture Prize.

“It’s about creating students who are aware, who are capable and who are enthusiastic about engineering, math, science and its role in the future advancement of our country,” said CEISMC Program Director and AMP-IT-UP co-principal investigator Jeff Rosen.

Additionally, through AMP-IT-UP, Georgia Tech faculty will investigate how the program affects academic engagement, content understanding and student persistence in the field. Georgia Tech and the school system have been awarded $2.9 million for the first two years of the grant, with another $4.3 million to follow in 2014.

Coding for All

At Lanier High School, Candela Rojas has created a 30-second, computerized remix of beats and samples despite knowing nothing about computer programming six weeks prior. On a recent morning, the girl who has loved music for years and fell in love with coding in days was sharing headphones with one of the biggest names in hip hop. Gimel “Young Guru” Keaton, the computer engineering wizard behind 10 albums for superstar Shawn “Jay-Z” Carter, offers advice and encouragement.

Young Guru approached Georgia Tech in 2012 with a goal of selling students on the impact of music, computers and technology. Within months, he was contributing original beats and loops to EarSketch, an NSF-funded initiative that was developed by researchers Jason Freeman and Brian Magerko. The duo built EarSketch with the intent of using musical remixes to introduce high school students – especially minorities and young women – to the world of computer programming. The software utilizes the Python programming language and Reaper, a digital audio workstation program similar to those used in recording studios.

“We think that we can get students more motivated to enter computer science careers by placing introductory computing education into a really interesting, fun context,” said Freeman, an associate professor in the Georgia Tech School of Music. “Instead of writing programs that sort lists or crunch numbers, students learn all of these skills while making music.”

Lanier High became the first high school to try it when 75 freshmen in its Center for Design and Technology gave EarSketch an eight-week test run this winter. Thirty five percent of the class is female.

Mike Reilly, a former computer programmer who became a teacher several years ago, worked with Georgia Tech to implement the course. A year ago, three of his freshmen chose to continue coding classes as sophomores. He thinks 25 of this year’s freshmen will sign up.

“Our students now see computer programming as a skill set, rather than something that is hard to understand,” Reilly says. “At a minimum, this project is teaching them to respect and recognize the power of coding.”

Discussions are underway to expand EarSketch to other metro Atlanta schools. The curriculum and software are available for download on the project’s website and available to teachers across the nation.

“By leveraging the collaborative nature of remix composition and musically oriented computer programming, EarSketch may provide a successful alternative to the cultural issues that computer games have in the engagement of minorities,” said Magerko, an assistant professor in the School of Literature, Media and Communication.

It has already had an impact on Brie Edwards. Like most students, the African-American girl was lost on the first day of class.

“I wasn’t sure I could do it,” Brie admitted. “But the more I practiced, the easier it became and the more I enjoyed it. Now I don’t want to leave the computer. I know that I’ll study programming in college.”

This article originally appeared in the Spring-Summer 2013 issue of Research Horizons, Georgia Tech’s research magazine.

Projects described in this article were supported by the National Science Foundation (NSF) under award numbers DUE-1238089 and CNS-1138649. Any opinions expressed are those of the principal investigators and may not necessarily represent the official views of the NSF.

Writers: Liz Klipp and Jason Maderer, Institute Communications

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.

The image was created with an atomic force microscope and a process called ThermoChemical NanoLithography (TCNL). Going pixel by pixel, the Georgia Tech team positioned a heated cantilever at the substrate surface to create a series of confined nanoscale chemical reactions. By varying only the heat at each location, Ph.D. Candidate Keith Carroll controlled the number of new molecules that were created. The greater the heat, the greater the local concentration. More heat produced the lighter shades of gray, as seen on the Mini Lisa’s forehead and hands. Less heat produced the darker shades in her dress and hair seen when the molecular canvas is visualized using fluorescent dye. Each pixel is spaced by 125 nanometers.

“By tuning the temperature, our team manipulated chemical reactions to yield variations in the molecular concentrations on the nanoscale,” said Jennifer Curtis, an associate professor in the School of Physics and the study’s lead author. “The spatial confinement of these reactions provides the precision required to generate complex chemical images like the Mini Lisa.”

Production of chemical concentration gradients and variations on the sub-micrometer scale are difficult to achieve with other techniques, despite a wide range of applications the process could allow. The Georgia Tech TCNL research collaboration, which includes associate professor Elisa Riedo and Regents Professor Seth Marder, produced chemical gradients of amine groups, but expects that the process could be extended for use with other materials. 

“We envision TCNL will be capable of patterning gradients of other physical or chemical properties, such as conductivity of graphene,” Curtis said. “This technique should enable a wide range of previously inaccessible experiments and applications in fields as diverse as nanoelectronics, optoelectronics and bioengineering.”

Another advantage, according to Curtis, is that atomic force microscopes are fairly common and the thermal control is relatively straightforward, making the approach accessible to both academic and industrial laboratories.  To facilitate their vision of nano-manufacturing devices with TCNL, the Georgia Tech team has recently integrated nanoarrays of five thermal cantilevers to accelerate the pace of production. Because the technique provides high spatial resolutions at a speed faster than other existing methods, even with a single cantilever, Curtis is hopeful that TCNL will provide the option of nanoscale printing integrated with the fabrication of large quantities of surfaces or everyday materials whose dimensions are more than one billion times larger than the TCNL features themselves.

The paper, Fabricating Nanoscale Chemical Gradients with ThermoChemical NanoLithography, is published online by the journal Langmuir.

This research was funded by the National Science Foundation (PHYS-0849497, DMR-0120967, DMR-0820382 and CMMI-1100290). The findings and conclusions are those of the authors and do not necessarily represent the official views of the NSF. This material is based upon work supported by the Department of Energy (Office of Basic Energy Services) under award number DE-FG02-06ER46293. This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness or usefulness of any information, apparatus, product or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process or service by trade name, trademark, manufacturer or otherwise does not necessarily constitute or imply its endorsement, recommendation or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof.

By feeding stem cells tiny particles made of magnetized iron oxide, scientists at Emory University and the Georgia Institute of Technology can then use magnets to attract the cells to a particular location in the body after intravenous injection.

The results are published online in the journal Small and will appear in an upcoming issue.

The paper was a result of collaboration between the laboratories of W. Robert Taylor of Emory, and Gang Bao of Georgia Tech. Taylor is professor of medicine and biomedical engineering and director of the Division of Cardiology at Emory University School of Medicine. Bao is professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. Co-first authors of the paper are postdoctoral fellows Natalia Landazuri and Sheng Tong. Landazuri is now at the Karolinska Institute in Sweden.

The type of cells used in the study, mesenchymal stem cells, are not embryonic stem cells. Mesenchymal stem cells can be readily obtained from adult tissues such as bone marrow or fat. They are capable of becoming bone, fat and cartilage cells, but not other types of cell such as muscle or brain. They secrete a variety of nourishing and anti-inflammatory factors, which could make them valuable tools for treating conditions such as cardiovascular disease or autoimmune disorders.

Magnetized iron oxide nanoparticles are already FDA-approved for diagnostic purposes with magnetic resonance imaging (MRI). Other scientists have tried to load stem cells with similar particles, but found that the coating on the particles was toxic or changed the cells’ properties. The nanoparticles used in this study have a polyethylene glycol coating that protects the cell from damage. Another unique feature is that the Emory/Georgia Tech team used a magnetic field to push the particles into the cells, rather than chemical agents used previously.

“We were able to load the cells with a lot of these nanoparticles and we showed clearly that the cells were not harmed,” Taylor said. “The coating is unique and thus there was no change in viability and perhaps even more importantly, we didn’t see any change in the characteristics of the stem cells, such as their capacity to differentiate. This was essentially a proof of principle experiment. Ultimately, we would target these to a particular limb, an abnormal blood vessel or even the heart.”

The particles are coated with the nontoxic polymer polyethylene glycol, and have an iron oxide core that is about 15 nanometers across. For comparison, a DNA molecule is two nanometers wide and a single influenza virus is at least 100 nanometers wide.

The particles appear to become stuck in cells’ lysosomes, which are parts of the cell that break down waste. The particles stay put for at least a week and leakage cannot be detected. The scientists measured the iron content in the cells once they were loaded up and determined that each cell absorbed roughly 1.5 million particles.

Once cells were loaded with iron oxide particles, the Emory/Georgia Tech team tested the ability of magnets to nudge the cells both in cell culture and in living animals. In mice, a bar-shaped rare earth magnet could attract injected stem cells to the tail. The magnet was applied to the part of the tail close to the body while the cells were being injected. Normally most of the mesenchymal stem cells would become deposited in the lungs or the liver.

To track where the cells went inside the mice, the scientists labeled the cells with a fluorescent dye. They calculated that the bar magnet made the stem cells six times more abundant in the tail. In addition, the iron oxide particles themselves could potentially be used to follow cells’ progress through the body.

“Next, we plan to focus on therapeutic applications in animal models where we will use magnets to direct these cells to the precise site need to affect repair and regeneration of new blood vessels,” Taylor said.

The research was supported by the National Heart Lung and Blood Institute’s Program of Excellence in Nanotechnology (HHSN268201000043C).

Reference: N. Landazuri, S. Tong, J. Suo, G. Joseph, D. Weiss, D.J. Sutcliffe, D.P. Giddens, G. Bao and W.R. Taylor. Magnetic targeting of human mesenchymal stem cells with internalized superparamagnetic iron oxide nanoparticles. Small, early view (2013)

Media Relations Contacts: Emory University – Quinn Eastman (404-727-7829) (qeastma@emory.edu); Georgia Tech – John Toon (404-894-6986) (jtoon@gatech.edu).
Writer: Quinn Eastman

“That’s the beauty of this class, not only is the topic of stem cell engineering unique, but thanks to video conferencing technology, Georgia Tech students can now take a class with their peers from across the country,” said McDevitt, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering.

Stem Cell Engineering (BMED 8813) has been offered since the spring of 2011 and was created by McDevitt as a way to educate graduate students about a research area that is becoming increasingly popular.

Including the 10 students at Tech, there are 39 students enrolled in this semester’s course. Aside from Tech, they are located at Washington University, the Massachusetts Institute of Technology, Boston University, University of California, Merced, and the University of Wisconsin. And although this is a graduate-level course, undergraduates can take the course with McDevitt’s permission.

So what can students expect during a week of classes? On Tuesdays, students from all of the participating campuses hear a lecture via the video conferencing system on a stem cell engineering topic — think everything from stem cell biology basics to stem cell biomanufacturing.

When the class meets on Thursdays, two students (at each location) typically lead a 50-minute discussion on a recently published journal article related to the lecture topic to their in-person peers.

Then, for the remainder of class, the Tech group video conferences with the students at other locations to discuss the key points brought up by each local group.

“It’s very helpful to have the perspective of students and faculty from other universities,”  said Jenna Wilson, a Ph.D. student in the bioengineering program who is a former student of the course turned teaching assistant. “Because people at other universities have different areas of research expertise, they can provide greater insight into aspects of the stem cell engineering field and pose interesting questions for discussion.”

Wilson also appreciated the small class size and discussion format of the course.

“Both aspects allow for great conversations with other students and some of the leading faculty in the stem cell engineering field,” she added. “Even though the class is broadcast across six universities, it's still a small group where you can feel comfortable sharing ideas and opinions.”

The course is typically offered during spring semester. For more information, email McDevitt .

Researchers are now reporting advances in these areas by using gelatin-based microparticles to deliver growth factors to specific areas of embryoid bodies, aggregates of differentiating stem cells. The localized delivery technique provides spatial control of cell differentiation within the cultures, potentially enabling the creation of complex three-dimensional tissues. The local control also dramatically reduces the amount of growth factor required, an important cost consideration for manufacturing stem cells for therapeutic applications.

The microparticle technique, which was demonstrated in pluripotent mouse embryonic cells, also offers better control over the kinetics of cell differentiation by delivering molecules that can either promote or inhibit the process. Based on research sponsored by the National Institutes of Health and the National Science Foundation, the developments were reported online July 1 in the journal Biomaterials and were presented at the 11th Annual International Society for Stem Cell Research meeting held in Boston June 12-15, 2013 .

“By trapping these growth factors within microparticle materials first, we are concentrating the signal they provide to the stem cells,” said Todd McDevitt, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “We can then put the microparticle materials physically inside the multicellular aggregate system that we use for differentiation of the stem cells. We have good evidence that this technique can work, and that we can use it to provide advantages in several different areas.”

The differentiation of stem cells is largely controlled by external cues, including morphogenic growth factors, in the three-dimensional environment that surrounds the cells. Most stem cell researchers currently deliver the growth factors into liquid solutions surrounding the stem cell cultures with a goal of creating homogenous cultures of cells. Delivering the growth factors from microparticles, however, provides better control of the spatial and temporal presentation of the molecules that govern the growth and differentiation of the stem cells, potentially allowing formation of heterogeneous structures formed from different cells.

Groups of stem cells stick together as they develop, forming multicellular aggregates that form spheroids as they grow. The researchers took advantage of that by driving microparticles containing growth factor BMP4 or noggin – which inhibits BMP4 signaling – into layers of stem cells using centrifugation. When the cell aggregates formed, the microparticles became trapped inside.

The researchers used confocal imaging and flow cytometry to observe the differentiation process and found that growth factors in the microparticles directed the cells toward mesoderm and ectoderm tissues just as they do in solution-based techniques. But because the BMP4 and noggin molecules were directly in contact with the cells, much less growth factor was needed to spur the differentiation – approximately 12 times less than what would be required by conventional solution-based techniques.

“One of the major advantages, in a practical sense, is that we are using much less growth factor,” said McDevitt, who is also director of the Stem Cell Engineering Center at Georgia Tech. “From a bioprocessing standpoint, a lot of the cost involved in making stem cell products is related to the cost of the molecules that must be added to make the stem cells differentiate.”

Beyond more focused signaling, the microparticles also provided a localized control not available through any other technique. That allowed the researchers to create spatial differences in the aggregates – a possible first step toward forming more complex structures with different tissue types such as vasculature and stromal cells.

“To build tissues, we need to be able to take stem cells and use them to make many different cell types which are grouped together in particular spatial patterns,” explained Andres M. Bratt-Leal, the paper’s first author and a former graduate student in McDevitt’s lab. “This spatial patterning is what gives tissues the ability to perform higher order functions.”

After creating stem cell aggregates with microparticles containing different growth factors, the researchers observed a hemispherical organization of cells for several days, with the different cells remaining spatially segregated.

“We can see the microparticles had effects on one population that were different from the population that didn’t have the particles,” McDevitt said. “This may allow us to emulate aspects of how development occurs. We can ask questions about how tissues are naturally patterned. With this material incorporation, we have the ability to better control the environment in which these cells develop.”

The microparticles could also provide better control over the kinetics of cell differentiation. Including different amounts of molecules – one the growth factor and the other its antagonist – could vary the rate at which the stem cell differentiation proceeds.

While the research reported in this paper manipulated pluripotent mouse cells, the researchers have moved ahead in performing similar studies with human stem cells and achieved comparable types of results with the microparticle delivery approaches.

The developments not only help move stem cell technologies closer to the clinic, but also provide a new tool for research.

“Our findings will provide a significant new tool for tissue engineering, bioprocessing of stem cells and also for better studying early development processes such as axis formation in embryos,” said Bratt-Leal. “During development, particular tissues are formed by gradients of signaling molecules. We can now better mimic these signal gradients using our system.”

In addition to those already mentioned, the research team also included Anh H. Nguyen, Katy A. Hammersmith and Ankur Singh, all associated with Georgia Tech and Emory University when the research was conducted.

This research was supported by the National Institutes of Health (NIH) through award GM088291 and the National Science Foundation (NSF) through award CBET 0651739. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the NIH or NSF.

CITATION: Andres M. Bratt-Leal, Anh H. Nguyen, Katy A. Hammersmith, Ankur Singh and Todd C. McDevitt, “A Microparticle Approach to Morphogen Delivery within Pluripotent Stem Cell Aggregates,” Biomaterials, 2013). http://dx.doi.org/10.1016/j.biomaterials.2013.05.079

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Ramaswamy kicked off his visit with a seminar for students and faculty: “Setting the Table for a Hotter, Flatter, More Crowded Earth.” He described the research outlook for the USDA and how Georgia Tech researchers are uniquely poised to tackle grand challenges like feeding a growing population in light of dwindling resources such as land and water. This and other major challenges will require multi-faceted approaches and expertise ranging from engineering and cybersecurity to social sciences. His presentation is available here.

Ramaswamy toured Georgia Tech’s Agricultural Technology Research Program and met with EVP for Research Stephen Cross. The visit closed with a multidisciplinary research roundtable, including bioenergy researcher and professor Art Ragauskas (School of Chemistry and Biochemistry); sphingolipid researcher and professor Al Merrill (School of Biology); and aquaponics researcher Steven Van Ginkel (School of Civil and Environmental Engineering).

Most swimming creatures rely on an undulating pattern of body movement to propel themselves through fluids. Though differences in body flexibility may lead to different swimming styles, scientists have found “neuromechanical phase lags” in nearly all swimmers. These lags are characterized by a wave of muscle activation that travels faster down the body than the wave of body curvature.

A study of the sandfish lizard – which “swims” through sand – led to development of the new model, which researchers believe could also be used to study other swimming animals. Beyond assisting the study of locomotion in a wide range of animals, the findings could also help researchers design efficient swimming robots.

“A graduate student in our group, Yang Ding, who is now at the University of Southern California, was able to develop a theory that could explain the kinematics of how this animal swims as well as the timing of the nervous system control signals,” said Daniel Goldman, an associate professor in the School of Physics at the Georgia Institute of Technology. “For animals swimming in fluids using an undulating movement, there are basic physical constraints on how they must activate their muscles. We think we have uncovered an important mechanism that governs this kind of swimming.”

The research was reported June 3 in the early edition of the journal Proceedings of the National Academy of Sciences. It was sponsored by the National Science Foundation’s Physics of Living Systems program, the Micro Autonomous Systems and Technology (MAST) program of the Army Research Office, and the Burroughs Wellcome Fund.

Undulatory locomotion is a gait in which thrust is produced in the opposite direction from a traveling wave of body bending. Because it is so commonly used by animals, this mode of locomotion has been widely used for studying the neuromechanical principles of movement.

Sarah Sharpe, the paper’s second author and a graduate student in Georgia Tech’s Interdisciplinary Bioengineering Program, led laboratory experiments studying undulatory swimming in sandfish lizards. She used X-ray imaging to visualize how the animals swam through sand that was composed of tiny glass spheres.

At the same time their swimming movements were being tracked, a set of four hair-thin electrodes implanted in the lizards’ bodies were providing information on when their muscles were activated. The two information sources allowed the researchers to compare the electrical muscle activity to the lizards’ body motion.

“The lizards propagate a wave of muscle activations, contracting the muscles close to their heads first, then the muscles at the midpoint of their body, then their tail,” said Sharpe. “They send a wave of muscle of contraction down their bodies, which creates a wave of curvature that allows them to swim. This wave of activation travels faster than the wave of curvature down the body, resulting in different timing relationships, known as phase differences, between muscle contracts and bending along the body.”

Sand acts like a frictional fluid as the sandfish swims through it. However, a sandfish swimming through sand is simpler to model than a fish swimming through water because the sand lacks the vortices and other complex behavior of water – and the friction of the sand eliminates inertia.

“Theoretically, it is difficult to calculate all of the forces acting on a fish or an eel swimming in a real fluid,” said Goldman. “But for a sandfish, you can calculate pretty much everything.”
The relative simplicity of the system allowed the research team – which also included Georgia Tech professor Kurt Wiesenfeld – to develop a simple model showing how the muscle activation relates to motion. The model showed that combining synchronized torques from distant points in the lizards’ bodies with local traveling torques is what creates the neuromechanical phase lag.

“This is one of the simplest, if not the simplest, models of swimming that reproduces the neuromechanical phase lag phenomenon,” Sharpe said. “All we really had to pay attention to was the external forces acting on an animal’s body. We realized that this timing relationship would emerge for any undulatory animal with distributed forces along its body. Understanding this concept can be used as the foundation to begin understanding timing patterns in all other swimmers.”

The sandfish swims using a simple single-period sinusoidal wave with constant amplitude. A key finding that facilitated the model’s development was that the sandfish’s body is extremely flexible, allowing internal forces – body stiffness – to be ignored.

“This animal turns out to be like a little limp noodle,” said Goldman. “Having that result in the theory makes everything else pop out.”

The model shows that the waveform used by the sandfish should allow it to swim the farthest with the least expenditure of energy. Swimming robots adopting the same waveform should therefore be able to maximize their range.

Goldman and his colleagues have been studying the sandfish, a native of the northern African desert, for more than six years.

“Sandfish are among the champions of all sand diggers, swimmers and burrowers,” said Goldman. “This lizard has provided us with an interesting entry point into swimming because its environment is surprisingly simple and behavior is simple. It turns out that this little sand-dweller may be able to tell us things about swimming more generally.”

This research has been supported by the National Science Foundation Physics of Living Systems (PoLS) under grants PHY-0749991 and PHY-1150760, by the U.S. Army Research Laboratory’s (ARL) Micro Autonomous Systems and Technology (MAST) Program under cooperative agreement W911NF-11-1-0514, and by the Burroughs Wellcome Fund Career Award. Any conclusions are those of the authors and do not necessarily represent the official views of the NSF or ARL.

CITATION: Yang Ding, Sarah Sharpe, Kurt Wiesenfeld and Daniel Goldman, “Emergence of the advancing neuromechanical phase in resistive force dominated medium,” (Proceedings of the National Academy of Sciences, 2013).

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The group spent the morning highlighting NIH funded research. Scientists representing Georgia Tech included Robert Guldberg, Ph.D., executive director of the Petit Institute for Bioengineering and Bioscience and professor in mechanical engineering, who spoke to Collins about the Regenerative Engineering and Medicine Center, a partnership between Emory University and Georgia Tech focused on endogenous repair and healing of nerves, bone, metabolic and cardiac applications. 

Todd McDevitt, Ph.D., director of the Stem Cell Engineering Center and associate professor in biomedical engineering at Georgia Tech, presented four projects funded with NIH dollars, including wound healing studies from a “Transformative Research Award,” a program developed to fund “high-risk, high-reward” science under the NIH’s Common Fund.

“Given that Dr. Collins recently dedicated a blog post on the ongoing research of Andrés García, Todd McDevitt, Hang Lu and Steve Stice from UGA, we were excited to share the great work being done in regenerative medicine and in stem cells,” explained Stephen Cross, Ph.D., executive vice president for research. “Bob and Todd were able to present ongoing NIH funded work for which Dr. Collins expressed both admiration and strong support.” 

Later that morning, administration from each university traveled to the Centers for Disease Control and Prevention, where they were joined by representatives from Clark Atlanta University, Georgia Regents University, Georgia Southern University and Mercer University for further discussions with Congressman Jack Kingston, Collins and Tom Frieden, M.D., M.P.H, director for the Center for Disease Control.  Each representative highlighted their NIH and/or CDC funded research as well as shared concerns regarding sequestration impacts on each university’s budget and ultimately the state’s economy.  Representatives also provided Collins and Frieden with suggestions on specific grant programs and reporting, peer review processes and programs aimed at diversifying the healthcare workforce.    

Due to the sequestration, the NIH’s budget will fall by $1.71 billion in 2013, which represents a 5% decrease.  As a result, NIH expects to fund 703 fewer new and competing research grants this year.

This decline in funding will have an impact on our Georgia universities, including Georgia Tech, which was awarded $41.3 million from the NIH in 2012.  NIH estimates that every $1 in NIH funding generates $2.21 in local economic growth.

As for how these cuts will affect individual research labs, that may not be known for some time. However, Collins is already seeking anecdotes of the sequestration’s impact via a twitter discussion using the hashtag #NIHSequesterImpact. 

Georgia Tech has created a sequestration information webpage, which includes the latest updates from Georgia Tech and many of its federal search sponsors. http://tlw-proxy.gatech.edu/research/faculty-and-staff-resources/sequestration-updates

The HERCULES Center is funded by the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health as an Environmental Health Sciences Core Center. This NIEHS initiative is designed to establish leadership and support for programs of excellence in environmental health sciences by providing scientific guidance, technology and career development opportunities for promising investigators.

The exposome is a relatively new concept that incorporates all of the exposures encountered by humans. It is proposed to be the environmental equivalent of the human genome and includes lifetime exposures to environmental pollutants in food, water, physical activity, medications, homes and daily stressors. Exposome research looks at the holistic view of the human body’s exposures, how the body responds to those exposures, and their combined effects.

“HERCULES is more than an acronym,” explains Gary W. Miller, PhD, professor and associate dean for research at the Rollins School of Public Health, and director of the HERCULES Center. “Sequencing of the human genome project was a Herculean task, and determining the impact of the complex exposures we face throughout our lives represents a similarly difficult challenge. The exposome itself represents all of the external forces that act upon us. We know that measuring the exposome will be extremely difficult, but very worthwhile.”

Scientists believe that when coupled with a growing understanding of genetics, the exposome will help uncover the causes of many complex disorders, such as autism, asthma and Alzheimer’s disease.

Based at Emory’s School of Public Health, the HERCULES Center comprises 38 investigators from both Emory and Georgia Tech. The center aims to promote the importance of the environment at a level equivalent to that of genetics.

A key feature of the HERCULES Center is the Systems Biology Core headed by Eberhard Voit, PhD, in the Department of Biomedical Engineering at Georgia Institute of Technology. Voit is a Georgia Research Alliance Eminent Scholar. The Systems Biology Core will provide expertise in computational approaches used to analyze and integrate large datasets.

“Assessing the enormous complexity of the exposome means entering uncharted territory and a unique opportunity for exploring and applying concepts and computational technologies that are just emerging in the nascent field of systems biology,” says Voit, who is also the David D. Flanagan Chair in the biomedical engineering department. “We are very excited that Georgia Tech and Emory will venture into this new field together to learn and gain a greatly improved understanding of health and disease.”

“This is such exciting news for us all,” explains Paige Tolbert, PhD, chair of Environmental Health at Rollins School of Public Health and deputy director of the HERCULES Center. “This is a terrific development for the department, the school, the university and our bridge with Georgia Tech and beyond.”

The HERCULES Center aims to promote the concept of the human exposome project on both a national and international level and welcomes research outside of Emory and Georgia Tech.

The doughnut-shaped droplets, a shape known as toroidal, are formed from two dissimilar liquids using a simple rotating stage and an injection needle. About a millimeter in overall size, the droplets are produced individually, their shapes maintained by a surrounding springy material made of polymers. Droplets in this toroidal shape made of a liquid crystal – the same type of material used in laptop displays – may have properties very different from those of spherical droplets made from the same material.

While researchers at the Georgia Institute of Technology don’t have a specific application for the doughnut-shaped droplets yet, they believe the novel structures offer opportunities to study many interesting problems, from looking at the properties of ordered materials within these confined spaces to studying how geometry affects how cells behave.

“Our experiments provide a fresh approach to the way that people have been looking at these kinds of problems, which is mainly theoretical. We are doing experiments with toroids whose geometry can be precisely controlled in the lab,” said Alberto Fernandez-Nieves, an assistant professor in the Georgia Tech School of Physics. “This work opens up a new way to experimentally look at problems that nobody has been able to study before. The properties of toroidal surfaces are very different, from a general point of view, from those of spherical surfaces.”

Development of these “stable nematic droplets with handles” was described May 20 in the early edition of the journal Proceedings of the National Academy of Sciences (PNAS). The research has been sponsored by the National Science Foundation (NSF), and also involves researchers at the Lorentz Institute for Theoretical Physics at Leiden University in The Netherlands and at York University in the United Kingdom.

Droplets normally form spherical shapes to minimize the surface area required to contain a given volume of liquid. Though they appear to be simple, when an ordered material like a crystal or a liquid crystal lives on the surface of a sphere, it provides interesting challenges to mathematicians and theoretical physicists.

A physicist who focuses on soft condensed matter, Fernandez-Nieves had long been interested in the theoretical aspects of curved surfaces. Working with graduate research assistant Ekapop Pairam and postdoctoral fellow Jayalakshmi Vallamkondu, he wanted to extend the theoretical studies into the experimental world for a system of toroidal shapes.

But could doughnut-shaped droplets be made in the lab?

The partial answer came from churros Fernandez-Nieves ate as a child growing up in Spain. These “Spanish doughnuts” – actually spirals – are made by injecting dough into hot oil while the dough is spun and fried.

In the lab at a much smaller size scale, the researchers found they could use a similar process with two immiscible liquids such as glycerine or water and oil, a needle and a magnetically-controlled rotating stage. A droplet of glycerine is injected into the rotating stage containing the oil. In certain conditions, a jet forms at the needle, which closes up into a torus because of the imposed rotation.

“You can control the two relevant curvatures of the torus,” explained Fernandez-Nieves. “You can control how large it is because you can move the needle with respect to the rotation axis. You can also infuse more volume to make the torus thicker.”

If the stage is then turned off, however, the drop of glycerine quickly loses its doughnut shape as surface tension forces it to become a traditional spherical droplet. To maintain the toroidal shape, Fernandez-Nieves and his collaborators replace the surrounding oil with a springy polymeric material; the springy character of this material provides a force that can overcome surface tension forces.

“When you are making the toroid, the forces on the needle are large enough that the surrounding material behaves as a fluid,” he explained.  “Once you stop, the elasticity of the outside fluid overcomes surface tension and that freezes the structure in place.”

The researchers have been using the doughnut shapes to study how liquid crystal materials, which are well known for their applications in laptop displays, organize inside the torus. These materials have degrees of order beyond those of simple liquids such as water. For these materials, the toroidal shape provides a new set of study opportunities from both theoretical and experimental perspectives.

“This changes how you think about a liquid inside a container,” said Fernandez-Nieves. “The materials will still adopt the shape of the container, but its energy will be different depending on the shape. The materials feel distortions and will try to minimize them. In a given shape, the molecules in these materials will rearrange themselves to minimize these distortions.”

Among the surprises is that the nematic droplets created with toroidal shapes become chiral, that is, they adopt a certain twisting direction and break their mirror symmetry.

“In our case, the materials we are using are not chiral under normal circumstances,” he noted. “This was a surprise to us, and it has to do with how we are confining the molecules.”

Beyond looking at the dynamics of creating the droplets and how ordered materials behave when the torus transforms into a sphere, Fernandez-Nieves and colleagues are also exploring potential biological applications, applying electrical fields to the droplets, and sharing the unique structures with scientists at other institutions.

“This is the first time that stable nematic droplets have been generated with handles, and we have exploited that to look at the nematic organization inside those spaces,” said Fernandez-Nieves. “Our experiments open up a versatile new approach for generating handled droplets made of an ordered material that can self-assemble into interesting and unexpected structures when confined to these non-spherical spaces. Now that theoreticians realize we can generate and study these systems, there may be much more development in this area.”

In addition to those already mentioned, the paper’s authors included V. Koning, B.C. van Zuiden and V. Vitelli from Leiden University, M.A. Bates from the University of York in the United Kingdom, and P.W. Ellis from Georgia Tech.

The research described here has been sponsored by the National Science Foundation under CAREER award DMR-0847304. The findings and conclusions are those of the authors and do not necessarily represent the official views of the National Science Foundation.

CITATION: E. Pairam, et al., “Stable nematic droplets with handles,” (Proceedings of the National Academy of Sciences, 2013)

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• Watch a YouTube video of this project.

By studying fire ants in the laboratory using video tracking equipment and X-ray computed tomography, researchers have uncovered fundamental principles of locomotion that robot teams could one day use to travel quickly and easily through underground tunnels. Among the principles is building tunnel environments that assist in moving around by limiting slips and falls, and by reducing the need for complex neural processing.

Among the study’s surprises was the first observation that ants in confined spaces use their antennae for locomotion as well as for sensing the environment.

“Our hypothesis is that the ants are creating their environment in just the right way to allow them to move up and down rapidly with a minimal amount of neural control,” said Daniel Goldman, an associate professor in the School of Physics at the Georgia Institute of Technology, and one of the paper’s co-authors. “The environment allows the ants to make missteps and not suffer for them. These ants can teach us some remarkably effective tricks for maneuvering in subterranean environments.”

The research was reported May 20 in the early edition of the journal Proceedings of the National Academy of Sciences. The work was sponsored by the National Science Foundation’s Physics of Living Systems program.

In a series of studies carried out by graduate research assistant Nick Gravish, groups of fire ants (Solenopsis invicta) were placed into tubes of soil and allowed to dig tunnels for 20 hours. To simulate a range of environmental conditions, Gravish and postdoctoral fellow Daria Monaenkova varied the size of the soil particles from 50 microns on up to 600 microns, and also altered the moisture content from 1 to 20 percent.

While the variations in particle size and moisture content did produce changes in the volume of tunnels produced and the depth that the ants dug, the diameters of the tunnels remained constant – and comparable to the length of the creatures’ own bodies: about 3.5 millimeters.

“Independent of whether the soil particles were as large as the animals’ heads or whether they were fine powder, or whether the soil was damp or contained very little moisture, the tunnel size was always the same within a tight range,” said Goldman. “The size of the tunnels appears to be a design principle used by the ants, something that they were controlling for.”

Gravish believes such a scaling effect allows the ants to make best use of their antennae, limbs and body to rapidly ascend and descend in the tunnels by interacting with the walls and limiting the range of possible missteps.

“In these subterranean environments where their leg motions are certainly hindered, we see that the speeds at which these ants can run are the same,” he said. “The tunnel size seems to have little, if any, effect on locomotion as defined by speed.”

The researchers used X-ray computed tomography to study tunnels the ants built in the test chambers, gathering 168 observations. They also used video tracking equipment to collect data on ants moving through tunnels made between two clear plates – much like “ant farms” sold for children – and through a maze of glass tubes of differing diameters.

The maze was mounted on an air piston that was periodically fired, dropping the maze with a force of as much as 27 times that of gravity. The sudden movement caused about half of the ants in the tubes to lose their footing and begin to fall. That led to one of the study’s most surprising findings: the creatures used their antennae to help grab onto the tube walls as they fell.

“A lot of us who have studied social insects for a long time have never seen antennae used in that way,” said Michael Goodisman, a professor in the Georgia Tech School of Biology and one of the paper’s other co-authors. “It’s incredible that they catch themselves with their antennae. This is an adaptive behavior that we never would have expected.”

By analyzing ants falling in the glass tubes, the researchers determined that the tube diameter played a key role in whether the animals could arrest their fall.

In future studies, the researchers plan to explore how the ants excavate their tunnel networks, which involves moving massive amounts of soil. That soil is the source of the large mounds for which fire ants are known.

While the research focused on understanding the principles behind how ants move in confined spaces, the results could have implications for future teams of small robots.

“The problems that the ants face are the same kinds of problems that a digging robot working in a confined space would potentially face – the need for rapid movement, stability and safety – all with limited sensing and brain power,” said Goodisman. “If we want to build machines that dig, we can build in controls like these ants have.”  

Why use fire ants for studying underground locomotion?

“These animals dig virtually non-stop, and they are good, repeatable study subjects,” Goodisman explained. “And they are very convenient for us to study. We can go outside the laboratory door and collect them virtually anywhere.”

The research described here has been sponsored by the National Science Foundation (NSF) under grant POLS 095765, and by the Burroughs Wellcome Fund. The findings and conclusions are those of the authors and do not necessarily represent the official views of the NSF.

CITATION: Nick Gravish, et al., “Climbing, falling and jamming during ant locomotion in confined environments,” (Proceedings of the National Academy of Sciences, 2013).

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Grand Challenges Explorations (GCE) funds individuals worldwide to explore ideas that can break the mold in how we solve persistent global health and development challenges. Dixon’s project is one of the Grand Challenges Explorations Round 10 grants announced May 21 by the Bill & Melinda Gates Foundation. 

To receive funding, Dixon and other Grand Challenges Explorations Round 10 winners demonstrated in a two-page online application a bold idea in one of four critical global heath and development topic areas that included agriculture development, neglected tropical diseases and communications.

The grant will fund development of a tissue-engineered model of the human lymphatic system that will support laboratory research into lymphatic filariasis, a parasitic disease known to cause elephantiasis. According to the World Health Organization, the mosquito-borne disease affects more than 120 million persons in tropical areas of the world, and can cause severe disfigurement. The parasitic worms that cause lymphatic filariasis are difficult to study because the most common species of the parasite can survive only in humans. While less common species can be maintained in felines or gerbils, they are challenging to culture long-term outside the host. The model that Dixon plans to develop would use human cells housed within fabricated microfluidic devices to closely simulate the environment where the adult worms live within their hosts, allowing the parasites to be studied longer term in vitro.

“We would use this human lymphatic environment on a microfluidic chip to study the progression of the disease and the communication between the host and the parasite,” explained Dixon, who is also a member of Georgia Tech’s Institute for Bioengineering and Bioscience. “We could also scale this up to evaluate new pharmaceutical compounds that could potentially target the worm.”

The microfluidic system will include human lymphatic endothelial cells, which are the primary cell type in contact with the worms in the body. Researchers will also include human dermal fibroblasts – an important cell type in the skin where the mosquito first delivers the parasitic infection – and the immune cells that fight infection long-term. Beyond creating the cellular environment needed to support the worms, the researchers will also design a matrix to house the living cells, determine which hormones and nutrients are needed, and establish appropriate fluid flow rates for the microfluidic devices to recreate the hydrodynamic forces the worms encounter in the body. The devices will be integrated into an optical platform that would allow researchers to quantify the activity of the worms over extended periods of time using automated image analysis algorithms.

Beyond studying lymphatic filariasis, Dixon believes a lymphatic system on a chip could ultimately support broader areas of research into disorders of this bodily system. The human lymphatic system has historically been underappreciated and is challenging to study because it is difficult to image, the vessels involved are small and the flow rates are very low compared to blood vasculature.

About Grand Challenges Explorations
Grand Challenges Explorations is a $100 million initiative funded by the Bill & Melinda Gates Foundation. Launched in 2008, over 800 people in more than 50 countries have received Grand Challenges Explorations grants. The grant program is open to anyone from any discipline and from any organization. The initiative uses an agile, accelerated grant-making process with short two-page online applications and no preliminary data required. Initial grants of $100,000 are awarded two times a year. Successful projects have the opportunity to receive a follow-on grant of up to $1 million.

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Studying a set of artificial proteins and comparing them to natural proteins, researchers at the Georgia Institute of Technology have concluded that there may be no more than about 500 unique protein pocket configurations that serve as binding sites for small molecule ligands. Therefore, the likelihood that a molecule intended for one protein target will also bind with an unintended target is significant, said Jeffrey Skolnick, a professor in the School of Biology at Georgia Tech.

“Our study provides a rationalization for why a lot of drugs have significant side effects – because that is intrinsic to the process,” said Skolnick. “There are only a relatively small number of different ligand binding pockets. The likelihood of having geometry in an amino acid composition that will bind the same ligand turns out to be much higher than anyone would have anticipated. This means that the idea that a small molecule could have just one protein target can’t be supported.”

Research on the binding pockets was published May 20 in the early edition of the journal Proceedings of the National Academy of Sciences. The research was supported by the National Institutes of Health (NIH).

Skolnick and collaborator Mu Gao have been studying the effects of physics on the activity of protein binding, and contrasting the original conditions created by the folding of amino acid residues against the role played by evolution in optimizing the process.

“The basic physics of the system provides the mechanism for molecules to bind to proteins,” said Skolnick, who is director of the Center for the Study of Systems Biology at Georgia Tech. “You don’t need evolution to have a system that works on at least a low level. In other words, proteins are inherently capable of engaging in biochemical function without evolution’s selection. Beyond unintended drug effects, this has a lot of implications for the biochemical component of the origins of life.”

Binding pockets on proteins are formed by the underlying secondary structure of the amino acids, which is directed by hydrogen bonding in the chemistry. That allows formation of similar pockets on many different proteins, even those that are not directly related to one another.

“You could have the same or very similar pockets on the same protein, the same pockets on similar proteins, and the same pockets on completely dissimilar proteins that have no evolutionary relationship. In proteins that are related evolutionarily or that have similar structures, you could have very dissimilar pockets,” said Skolnick, who is also a Georgia Research Alliance Eminent Scholar. “This helps explain why we see unintended effects of drugs, and opens up a new paradigm for how one has to think about discovering drugs.”

The implications of this “biochemical noise” for the drug discovery process could be significant. To counter the impact of unintended effects, drug developers will need to know more about the available pockets so they can avoid affecting binding locations that are also located on proteins critical to life processes. If the inevitable unintended binding takes place on less critical proteins, the side effects may be less severe.

In addition, drug development could also move to a higher level, examining the switches that modulate the activity of proteins beyond binding sites. That may require a different approach to drug development.

“The strategy for minimizing side effects and maximizing positive effects may have to operate at a higher level,” Skolnick said. “You are never going to be able to design unintended binding effects away. But you can minimize the undesirable effects to some extent.”

In their study, Skolnick and Gao used computer simulations to produce a series of artificial proteins that were folded according the laws of physics, but not optimized for function. Using an algorithm that compares pairs of pockets and assesses the statistical significance of their structural overlap, they analyzed the similarity between the binding pockets in the artificial proteins and the pockets on a series of native proteins. The artificial pockets all had corresponding pockets on the natural proteins, suggesting that the simple physics of folding has been a major factor in development of the pockets.

“This is how life, at least the biochemistry of life, could have gotten started,” said Skolnick. “Evolution would have optimized the functions, but you don’t need that to get started at a low level of efficiency. If you had a soup of our artificial proteins, even with no selection you could at least do low-level biochemistry.”

Though the basic biochemistry of life was made possible by simple physics, optimizing the binding process to allow the efficiencies seen in modern organisms would have required evolutionary selection.

“This is the first time that it has been shown that side effects of drugs are an inherent, fundamental property of proteins rather than a property that can be controlled for in the design,” Skolnick added. “The physics involved is more important than had been generally appreciated.

Research reported in this news release was supported by the Institute of General Medical Sciences of the National Institutes of Health (NIH) under award number GM48835. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

CITATION: Jeffrey Skolnick and Mu Gao, “Interplay of physics and evolution in the likely origin of protein biochemical function,” (Proceedings of the National Academy of Sciences, 2013).

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The study shows that RNA is capable of catalyzing electron transfer under conditions similar to those of the early Earth. Because electron transfer, the moving of an electron from one chemical species to another, is involved in many biological processes – including photosynthesis, respiration and the reduction of RNA to DNA – the study’s findings suggest that complex biochemical transformations may have been possible when life began.

There is considerable evidence that the evolution of life passed through an early stage when RNA played a more central role, before DNA and coded proteins appeared. During that time, more than 3 billion years ago, the environment lacked oxygen but had an abundance of soluble iron.

“Our study shows that when RNA teams up with iron in an oxygen-free environment, RNA displays the powerful ability to catalyze single electron transfer, a process involved in the most sophisticated biochemistry, yet previously uncharacterized for RNA,” said Loren Williams, a professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology.

The results of the study were published online on May 19, 2013, in the journal Nature Chemistry. The study was sponsored by the NASA Astrobiology Institute, which established the Center for Ribosomal Origins and Evolution (Ribo Evo) at Georgia Tech.

Free oxygen gas was almost nonexistent in the Earth’s atmosphere more than 3 billion years ago. When free oxygen began entering the environment as a product of photosynthesis, it turned the earth’s iron to rust, forming massive banded iron formations that are still mined today. The free oxygen produced by advanced organisms caused iron to be toxic, even though it was – and still is – a requirement for life. Williams believes the environmental transition caused a slow shift from the use of iron to magnesium for RNA binding, folding and catalysis.

Williams and Georgia Tech School of Chemistry and Biochemistry postdoctoral fellow Chiaolong Hsiao used a standard peroxidase assay to detect electron transfer in solutions of RNA and either the iron ion, Fe2+, or magnesium ion, Mg2+. For 10 different types of RNA, the researchers observed catalysis of single electron transfer in the presence of iron and absence of oxygen. They found that two of the most abundant and ancient types of RNA, the 23S ribosomal RNA and transfer RNA, catalyzed electron transfer more efficiently than other types of RNA. However, none of the RNA and magnesium solutions catalyzed single electron transfer in the oxygen-free environment.

“Our findings suggest that the catalytic competence of RNA may have been greater in early Earth conditions than in present conditions, and our experiments may have revived a latent function of RNA,” added Williams, who is also director of the Ribo Evo Center.

This new study expands on research published in May 2012 in the journal PLoS ONE. In the previous work, Williams led a team that used experiments and numerical calculations to show that iron, in the absence of oxygen, could substitute for magnesium in RNA binding, folding and catalysis. The researchers found that RNA’s shape and folding structure remained the same and its functional activity increased when magnesium was replaced by iron in an oxygen-free environment.

In future studies, the researchers plan to investigate whether other unique functions may have been conferred on RNA through interaction with a variety of metals available on the early Earth.

In addition to Williams and Hsiao, Georgia Tech School of Biology professors Roger Wartell and Stephen Harvey, and Georgia Tech School of Chemistry and Biochemistry professor Nicholas Hud, also contributed to this work as co-principal investigators in the Ribo Evo Center at Georgia Tech.

This work was supported by NASA (Award No. NNA09DA78A). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of NASA.

CITATION: Chiaolong Hsiao, et al., “RNA with iron(II) as a cofactor catalyses electron transfer,” (Nature Chemistry, 2013). http://dx.doi.org/10.1038/nchem.1649

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Georgia Tech engineers and Emory University clinicians have successfully engrafted insulin-producing cells into a diabetic mouse model, reversing diabetic symptoms in the animal in as little as 10 days.

The research team engineered a biomaterial to protect the cluster of insulin-producing cells – donor pancreatic islets – during injection. The material also contains proteins to foster blood vessel formation that allow the cells to successfully graft, survive and function within the body.

“It’s very promising,” said Andrés Garcia, Georgia Tech professor of mechanical engineering. “There is a lot of excitement because not only can we get the islets to survive and function, but we can also cure diabetes with fewer islets than are normally needed.”

The research article – a partnership with Emory’s Dr. Robert Taylor and Dr. Peter Thule that was funded in part by the JDRF, the leading global organization funding Type 1 diabetes research – will be published in the June issue of the journal Biomaterials.

Organizations such as JDRF are dedicated to finding a cure for Type 1 diabetes, a chronic disease that occurs when the pancreas produces little or no insulin, a hormone that allows the transport of sugar and other nutrients into tissues where they are converted to energy needed for daily life.

Pancreatic islet transplantation re-emerged as a promising therapy in the late 1990s. Patients with diabetes typically find it difficult to comply with multiple daily insulin injections, which only partially improve long-term outcomes. Successful islet transplantation would remove the need for patients to administer insulin. While islet transplantation trials have had some success, and control of glucose levels is often improved, diabetic symptoms have returned in most patients and they have had to revert to using some insulin.

Unsuccessful transplants can be attributed to several factors, researchers say. The current technique of injecting islets directly into the blood vessels in the liver causes approximately half of the cells to die due to exposure to blood clotting reactions. Also, the islets – metabolically active cells that require significant blood flow – have problems hooking up to blood vessels once in the body and die off over time.

Georgia Tech and Emory researchers engineered a hydrogel, a material compatible with biological tissues that is a promising therapeutic delivery vehicle. This water-swollen, cross-linked polymer surrounds the insulin-producing cells and protects them during injection. The hydrogel containing the islets was delivered to a new injection site on the outside of the small intestine, thus avoiding direct injection into the blood stream.

Once in the body, the hydrogel degrades in a controlled fashion to release a growth factor protein that promotes blood vessel formation and connection of the transplanted islets to these new vessels. In the study, the blood vessels effectively grew into the biomaterial and successfully connected to the insulin-producing cells.

Four weeks after the transplantation, diabetic mice treated with the hydrogel had normal glucose levels, and the delivered islets were alive and vascularized to the same extent as islets in a healthy mouse pancreas. The technique also required fewer islets than previous transplantation attempts, which may allow doctors to treat more patients with limited donor samples. Currently, donor cells from two to three cadavers are needed for one patient.

While the new biomaterial and injection technique is promising, the study used genetically identical mice and therefore did not address immune rejection issues common to human applications. The research team has funding from JDRF to study whether an immune barrier they created will allow the cells to be accepted in genetically different mice models. If successful, the trials could move to larger animals.

 “We broke up our strategy into two steps,” said Garcia, a member of Georgia Tech's Petit Institute for Bioengineering and Bioscience. “We have shown that when delivered in the material we engineered, the islets will survive and graft. Now we must address immune acceptance issues.”

Most people with Type 1 diabetes currently manage their blood glucose levels with multiple daily insulin injections or by using an insulin pump. But insulin therapy has limitations. It requires careful measurement of blood glucose levels, accurate dosage calculations and regular compliance to be effective.

This work was also funded by the Regenerative Engineering and Medicine Center at Georgia Tech and Emory, and the Atlanta Clinical and Translation Science Institute under PHS grant UL RR025008 from the Clinical and Translational Science Award Program.

The Center for Pediatric Healthcare Technology Innovation at Georgia Tech, the Department of Veterans Affairs Merit Review Program and the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases (Grant R01 DK076801-01) helped fund the project as well. 

CITATION: Edward A. Phelps, Devon M. Headen, W. Robert Taylor, Peter M. Thule and Andrés J. Garcia. Vasculogenic Bio-Synthetic Hydrogel for Enchancement of Pancreatic Islet Engraftment and Function in Type 1 Diabetes, Biomaterials, June 2013, Pages 4602-4611.

Those behavioral differences likely arise from a complex region of the brain known as the telencephalon, which governs communication, emotion, movement and memory in vertebrates – including humans, where a major portion of the telencephalon is known as the cerebral cortex. A study published this week in the journal Nature Communications shows how the strength and timing of competing molecular signals during brain development has generated natural and presumably adaptive differences in the telencephalon much earlier than scientists had previously believed.

In the study, researchers first identified key differences in gene expression between rock- and sand-dweller brains during development, and then used small molecules to manipulate developmental pathways to mimic natural diversity.

“We have shown that the evolutionary changes in the brains of these fishes occur really early in development,” said Todd Streelman, an associate professor in the School of Biology and the Petit Institute for Bioengineering and Biosciences at the Georgia Institute of Technology. “It’s generally been thought that early development of the brain must be strongly buffered against change. Our data suggest that rock-dweller brains differ from sand-dweller brains – before there is a brain.”

For humans, the research could lead scientists to look for subtle changes in brain structures earlier in the development process. This could provide a better understanding of how disorders such as autism and schizophrenia could arise during very early brain development.

The research was supported by the National Science Foundation and published online April 23 by the journal.

“We want to understand how the telencephalon evolves by looking at genetics and developmental pathways in closely-related species from natural populations,” said Jonathan Sylvester, a postdoctoral researcher in the Georgia Tech School of Biology and lead author of the paper. “Adult cichlids have a tremendous amount of variation within the telencephalon, and we investigated the timing and cause of these differences. Unlike many previous studies in laboratory model organisms that focus on large, qualitative effects from knocking out single genes, we demonstrated that brain diversity evolves through quantitative tuning of multiple pathways.”

In examining the fish from embryos to adulthood, the researchers found that the mbuna, or rock-dwellers, tended to exhibit a larger ventral portion of the telencephalon, called the subpallium – while the sand-dwellers tended to have a larger version of the dorsal structure known as the pallium. These structures seem to have evolved differently over time to meet the behavioral and ecological needs of the fishes. The team showed that early variation in the activity of developmental signals expressed as complementary dorsal-ventral gradients, known technically as “Wingless” and “Hedgehog,” are involved in creating those differences during the neural plate stage, as a single sheet of neural tissue folds to form the neural tube.  

To specifically manipulate those two pathways, Sylvester removed clutches of between 20 and 40 eggs from brooding female cichlids, which normally incubate fertilized eggs in their mouths. At about 36 to 48 hours after fertilization, groups of eggs were exposed to small-molecule chemicals that either strengthened or weakened the Hedgehog signal, or strengthened or weakened the Wingless signal. The chemical treatment came while the structures that would become the brain were little more than a sheet of cells. After treatment, water containing the chemicals was replaced with fresh water, and the embryos were allowed to continue their development.

“We were able to artificially manipulate these pathways in a way that we think evolution might have worked to shift the process of rock-dweller telencephalon development to sand-dweller development, and vice-versa. Treatment with small molecules allows us incredible temporal and dose precision in manipulating natural development,” Sylvester explained. “We then followed the development of the embryos until we were able to measure the anatomical structures – the size of the pallium and subpallium – to see that we had transformed one to the other.”

The two different brain regions, the dorsal pallium and ventral subpallium, give rise to excitatory and inhibitory neurons in the forebrain. Altering the relative sizes of these regions might change the balance between these neuronal types, ultimately producing behavioral changes in the adult fish.

“Evolution has fine-tuned some of these developmental mechanisms to produce diversity,” Streelman said. “In this study, we have figured out which ones.”

The researchers studied six different species of East African cichlids, and also worked with collaborators at King’s College in London to apply similar techniques in the zebrafish.

As a next step, the researchers would like to follow the embryos through to adulthood to see if the changes seen in embryonic and juvenile brain structures actually do change behavior of adults. It’s possible, said Streelman, that later developmental events could compensate for the early differences.

The results could be of interest to scientists investigating human neurological disorders that result from an imbalance between excitatory and inhibitory neurons. Those disorders include autism and schizophrenia. “We think it is particularly interesting that there may be some adaptive variation in the natural proportions of excitatory versus inhibitory neurons in the species we study, correlated with their natural behavioral differences,” said Streelman.

In addition to the researchers already mentioned, the study included undergraduate coauthors Constance Rich and Chuyong Yi from Georgia Tech, and Joao Peres and Corinne Houart from King’s College in London. Rich is presently in the neuroscience PhD program at the University of Cambridge.

This research was supported by the National Science Foundation (NSF) under grants IOS 0922964 and IOS 1146275. The findings and conclusions are those of the authors and do not necessarily represent the official views of the NSF.

CITATION: Sylvester, J.B., et al., “Competing Signals Drive Telencephalon Diversity,” (Nature Communications, 2013).

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Both the baby turtles and FlipperBot run into trouble under the same conditions: traversing granular media disturbed by previous steps. Information from the robot research helped scientists understand why some of the hatchlings they studied experienced trouble, creating a unique feedback loop from animal to robot – and back to animal.

The research could help robot designers better understand locomotion on complex surfaces and lead biologists to a clearer picture of how sea turtles and other animals like mudskippers use their flippers. The research could also help explain how animals evolved limbs – including flippers – for walking on land.

The research was published April 24 in the journal Bioinspiration & Biomimetics. The work was supported by the National Science Foundation, the U.S. Army Research Laboratory’s Micro Autonomous Systems and Technology (MAST) Program, the U.S. Army Research Office, and the Burroughs Wellcome Fund.

“We are looking at different ways that robots can move about on sand,” said Daniel Goldman, an associate professor in the School of Physics at the Georgia Institute of Technology. “We wanted to make a systematic study of what makes flippers useful or effective. We’ve learned that the flow of the materials plays a large role in the strategy that can be used by either animals or robots.”

The research began in 2010 with a six-week study of hatchling loggerhead sea turtles emerging at night from nests on Jekyll Island, one of Georgia’s coastal islands. The research was done in collaboration with the Georgia Sea Turtle Center.

Nicole Mazouchova, then a graduate student in the Georgia Tech School of Biology, studied the baby turtles using a trackway filled with beach sand and housed in a truck parked near the beach. She recorded kinematic and biomechanical data as the turtles moved in darkness toward an LED light that simulated the moon.

Mazouchova and Goldman studied data from the 25 hatchlings, and were surprised to learn that they managed to maintain their speed regardless of the surface on which they were running.

“On soft sand, the animals move their limbs in such a way that they don’t create a yielding of the material on which they’re walking,” said Goldman. “That means the material doesn’t flow around the limbs and they don’t slip. The surprising thing to us was that the turtles had comparable performance when they were running on hard ground or soft sand.”

The key to maintaining performance seemed to be the ability of the hatchlings to control their wrists, allowing them to change how they used their flippers under different sand conditions.

“On hard ground, their wrists locked in place, and they pivoted about a fixed arm,” Goldman explained. “On soft sand, they put their flippers into the sand and the wrist would bend as they moved forward. We decided to investigate this using a robot model.”

That led to development of FlipperBot, with assistance from Paul Umbanhowar, a research associate professor at Northwestern University. The robot measures about 19 centimeters in length, weighs about 970 grams, and has two flippers driven by servo-motors. Like the turtles, the robot has flexible wrists that allow variations in its movement. To move through a track bed filled with poppy seeds that simulate sand, the robot lifts its flippers up, drops them into the seeds, then moves the flippers backward to propel itself.

Mazouchova, now a Ph.D. student at Temple University, studied many variations of gait and wrist position and found that the free-moving mechanical wrist also provided an advantage to the robot.

“In the robot, the free wrist does provide some advantage,” said Goldman. “For the most part, the wrist confers advantage for moving forward without slipping. The wrist flexibility minimizes material yielding, which disturbs less ground. The flexible wrist also allows both the robot and turtles to maintain a high angle of attack for their bodies, which reduces performance-impeding drag from belly friction.”

The researchers also noted that the robot often failed when limbs encountered material that the same limbs had already disturbed. That led them to re-examine the data collected on the hatchling turtles, some of which had also experienced difficulty walking across the soft sand.

“When we saw the turtles moving poorly, they appeared to be suffering from the same failure mode that we saw in the robot,” Goldman explained. “When they interacted with materials that had been previously disturbed, they tended to lose performance.”

Mazouchova and Goldman then worked with Umbanhowar to model the robot’s performance in an effort to predict how the turtle hatchlings should respond to different conditions. The predictions closely matched what was actually observed, closing the loop between robot and animal.

“The robot study allowed us to test how principles applied to the animals,” Goldman said.

While the results may not directly improve robot designs, what the researchers learned should contribute to a better understanding of the principles governing movement using flippers. That would be useful to the designers of robots that must swim through water and walk on land.

“A multi-modal robot might need to use paddles for swimming in water, but it might also need to walk in an effective way on the beach,” Goldman said. “This work can provide fundamental information on what makes flippers good or bad. This information could give robot designers clues to appendage designs and control techniques for robots moving in these environments.”

The research could ultimately provide clues to how turtles evolved to walk on land with appendages designed for swimming.

“To understand the mechanics of how the first terrestrial animals moved, you have to understand how their flipper-like limbs interacted with complex, yielding substrates like mud flats,” said Goldman. “We don’t have solid results on the evolutionary questions yet, but this certainly points to a way that we could address these issues.”

This research has been supported by the National Science Foundation under grant CMMI-0825480 and the Physics of Living Systems PoLS program, the U.S. Army Research Laboratory’s (ARL) Micro Autonomous Systems and Technology (MAST) Program under cooperative agreement W911NF-08-2-0004, the U.S. Army Research Office (ARO) and the Burroughs Wellcome Fund Career Award. Any conclusions are those of the authors and do not necessarily represent the official views of the NSF, ARL or ARO.

CITATION: Nicole Mazouchova, Paul B. Umbanhowar and Daniel I. Goldman, “Flipper-driven terrestrial locomotion of a sea turtle-inspired robot, (Bioinspiration & Biomimetics, 2013).

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