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The 7 Habits of Highly Ineffective Researchers

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"Why Can't We Engineer Drugs on a Computer? And What Can Be Done About It?"

Michael Shirts, Associate Professor, Department of Chemical Engineering, University of Virginia

Abstract:
The design of airplanes, bridges, chemical plants, and computer chips is aided significantly by modern computational tools. Design of novel molecular entities, however, is done primarily by trial-and-error. A prime example is the pharmaceutical industry, where the complexity of biomolecular interactions has greatly limited our ability to model and design effective small molecule drugs. This means drug design has remained somewhat of a black art, relying on many ad hoc assumptions and on the intuitive insights of experienced medicinal chemists.

What are the barriers that must be overcome in order to model drug-ligand binding affinities, solubilities, partitioning into delivery formulations and polymorph stabilities effectively? Is there a hope to change the process of designing drugs with high affinities and a specific mode of action from a trial-and-error art to a nanoscale engineering process using high-quality, reliable modeling? And finally, what other macromolecular machinery could we build to carry out separations or controlled reactions if we can model non covalent interactions at the level necessary to design drugs?

I will discuss research in our group working toward the goal of modeling noncovalent interactions sufficiently reliable and efficient to have a place in the pharmaceutical workflow.

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"Lava Lamps, Hopscotch and Enzymes: A Toolbox for Chemical Engineering at the Microscale"

Victor Ugaz, Associate Professor, Artie McFerrin Department of Chemical Engineering, Texas A&M University

Abstract:
I will describe recent work in our research group aimed at harnessing fundamental transport phenomena at the microscale in ways that can help enable the development of rapid portable bioanalysis systems. First, I will introduce a novel method to actuate DNA replication via the polymerase chain reaction (PCR) by exploiting thermally driven natural convection. This implementation offers advantages including an inherently simple design (similar to a lava lamp) and minimal electrical power consumption (important for portable applications). We have probed the 3-D velocity and temperature distributions inside microscale convective reactors, and unexpectedly discovered a subset of complex flow trajectories where extremely rapid DNA replication rates are achievable due to the onset of chaotic advection. These surprisingly complex 3D flows are also able to function as highly efficient conveyors capable of continually shuttling molecular species from the bulk fluid to targeted locations on the solid boundaries, suggesting a new mechanism to explain emergence of complex biomacromolecules from dilute organic precursors in the prebiotic milieu—a key unanswered question in the origin of life.

Next, I will describe how the inherently disordered dynamics governing macromolecular transport in confined surroundings, conventionally suppressed as an undesirable noisy background, can paradoxically be precisely controlled. This ability lays a foundation for an entropic force microscope, a sensitive probe of nanoscale biomolecular conformation capable of resolving previously unseen details about DNA-protein binding interactions at size scales below the limits of conventional techniques. Finally, I will show how specific biochemical interactions between an enzyme and a biodegradable substrate can be harnessed to execute precise flow-actuated micromachining. This novel approach makes it possible to construct a microfluidic-based filtration device capable of performing simultaneous size-based isolation and enrichment of cells from whole blood. The underlying inertial flow phenomena are strongest at high flow rates, making our design ideally suited for high-throughput processing of large sample volumes.

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"Nanomaterial Heterostructures for Electronic and Energy Technologies"

Mark C. Hersam, Professor, Department of Materials Science and Engineering, Northwestern University

Abstract:
Improvements in nanomaterial purity have yielded corresponding enhancements in the performance of electronic, optoelectronic, sensing, and energy technologies. However, as purities approach 100%, other strategies are required to achieve further improvements in device performance.

Toward this end, our laboratory has focused on the integration of disparate nanomaterials into heterostructures with well-defined interfaces. For example, organic self-assembled monolayers on graphene act as effective seeding layers for atomic layer deposited (ALD) dielectrics, resulting in metal-oxide-graphene capacitors with wafer-scale reliability and uniformity comparable to ALD dielectrics on silicon.

Similarly, the traditional trade-off between on/off ratio and mobility in semiconducting carbon nanotube (CNT) thin-film transistors (TFTs) is overcome by replacing conventional inorganic gate dielectrics with hybrid organic-inorganic self-assembled nanodielectrics, yielding on/off ratios approaching 106 while concurrently achieving mobilities of ~150 cm2/V-s. By utilizing unconventional gate electrode materials (e.g., Ni), the threshold voltage of semiconducting CNT TFTs can be further tuned, thus enabling the realization of CNT CMOS logic gates with sub-nanowatt static power dissipation and full rail-to-rail voltage swing.

Finally, p-type semiconducting CNT thin films are integrated with n-type single-layer MoS2 to form p-n heterojunction diodes. The atomically thin nature of single-layer MoS2 implies that an applied gate bias can electrostatically modulate both sides of the p-n heterojunction concurrently, thereby providing 5 orders of magnitude gate-tunability over the diode rectification ratio in addition to unprecedented anti-ambipolar behavior when operated as a three-terminal device.

Overall, this work establishes that nanomaterial applications can be substantially enhanced and diversified into new areas through precise integration into heterostructure devices. 

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"Design of Microbial Consortia for Industrial Biotechnology"

Paul Barton, Professor, Department of Chemical Engineering, Massachusetts Institute of Technology (MIT)

Abstract:
Large-scale production using microorganisms has long been recognized as a promising source for sustainable fuels and chemicals. However, monocultures optimized for high metabolic production in a sterile laboratory environment are often not economical at production scale due to high costs of capital and substrates, lack of resilience and stability of the culture, etc.

On the other hand, most microorganisms in natural environments do not live in isolation, but exist as part of complex, dynamically changing, microbial consortia. These natural consortia exhibit high productivity combined with high resilience to invasion and can process a wide range of readily available substrates. Hence, synthesis of artificial biological process systems based on microbial consortia seems a promising approach to low cost sustainable production of fuels and chemicals.

Nevertheless, it remains a great challenge to realize such multispecies cultures in industrial applications. Using algal production of fuels and chemicals as an illustrative example, we outline a roadmap towards the quantitative design and optimization of low cost resilient artificial ecologies based on microbial consortia.

To address this challenge, multi-scale models are proposed, which integrate metabolic information available from high-throughput experiments with the ecological scale of the interactions between multiple species and the process scale of bioreactors. These models are formulated as dynamic systems with optimization problems embedded, and progress towards numerical tools for simulation, sensitivity analysis and optimization will be reported.

The long-term goal is a quantitative approach that will enable chemical engineers to design artificial ecologies for a desired purpose in much the same manner as a traditional chemical process.

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"Life Skills for Professional Success: An Alumni Panel Discussion"

Featuring:

• John Richardson, Staff Engineer, Shell Oil Co.
• Anjali Kumar, Vice President of Nonclinical R&D and Scientific Affairs, Flexion Therapeutics
• Jason Hicks, Assistant Professor, Department of Chemical and Biomolecular Engineering, University of Notre Dame

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"Controlling Selectivity in Heterogeneous Catalysis With Organic Monolayers"

Will Medlin, Professor, Department of Chemical and Biological Engineering, University of Colorado

Abstract:
Performing selective reactions of compounds with multiple functional groups is a challenging objective, since each functional group can potentially adsorb and react on a catalytic surface. Addressing this problem is important both in conventional production of chemicals and for the conversion of biomass to chemicals and fuels.

Our group has investigated several techniques for aligning multifunctional molecules above metal surfaces to promote selective reaction of a particular functional group. One approach involves the modification of supported metal catalysts with organic ligands such as organothiols.

Organothiols can be deposited on metal surfaces to form organized self-assembled monolayers (SAMs) that may cause reactants to adopt particular orientations above the metal surface, altering selectivity. Several mechanisms by which SAMs can improve selectivity have been identified. For example, SAM coatings can be used to tune the reactivity of the underlying metal surface sites.

Furthermore, the organic function of SAM coatings can be tuned to control non-covalent interactions in the near-surface environment. The utility of these mechanisms for selectivity control will be illustrated for reaction chemistries important in biorefining and production of valuable chemicals. Some alternative directions for achieving surface and near-surface control will also be discussed.

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"Engineering the Beta Roll Peptide to Participate in Useful Biomolecular Interactions"

Scott Banta, Associate Professor, Department of Chemical Engineering, Columbia University

Abstract:
For the last several years we have been exploring the beta roll forming repeats-in-toxin (RTX) peptide as a unique scaffold for protein engineering studies as it has the useful feature of being intrinsically disordered in the absence of calcium, and it folds into a well-defined 3-D structure in the presence of calcium.

We have extensively characterized this conformational change using a variety of techniques. We have explored the capping requirements for the scaffold, we have made synthetic peptides with a repeated consensus sequence, and we have concatenated beta rolls together to explore how this impacts the folding of the peptide. We have also immobilized the peptides to explore their functionality when tethered.

Now we have begun to engineer the beta roll peptide for useful functional applications. In the first line of work, we have engineered one face of the beta roll with leucine side chains. This enables the beta roll to dimerize in the presence of calcium and we have shown that this can serve as a stimulus-responsive cross-linking domain for use in protein hydrogel formation. We have also shown that a consensus sequence of beta roll domains reversibly precipitates in response to calcium and we have explored this as a novel protein purification tag that is more useful than the commonly used elastin-like peptide sequences.

Finally, we have been working to engineer beta roll mutants with affinity for different target proteins using a variety of selection techniques. We have already produced a mutant beta roll with calcium-dependent affinity for lysozyme and we are in the process of expanding this approach. The most recent results of these efforts will also be presented.

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"Catalysis on and in Biomolecular Surfaces"

M.G. Finn, Chair, Georgia Tech School of Chemistry and Biochemistry

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"Ion Sorption, Diffusion and Transport in Polymer Membranes"

Benny Freeman, Professor, McKetta Department of Chemical Engineering, University of Texas-Austin

Abstract:

Charged polymeric materials are widely used for water purification applications involving control of water and ion transport, such as reverse osmosis and electrodialysis.  Efforts are also underway worldwide to harness separation properties of such materials for energy generation in related applications such as reverse electrodialysis and pressure retarded osmosis.  Additional applications, such as energy recovery ventilation and capacitive deionization, rely on polymer membranes to control transport rates of water, ions, or both.  Improving membranes for such processes would benefit from more complete fundamental understanding of the relation between membrane structure and ion sorption, diffusion and transport properties in both cation and anion exchange membrane materials. Ion-exchange membranes often contain strongly acidic or basic functional groups that render the materials hydrophilic, but the presence of such charged groups also has a substantial impact on ion (and water) transport properties through the polymer.

We are exploring the influence of polymer backbone structure, charge density, and water content on ion transport properties.  Results from some of these studies will be presented, focusing on transport of salt, primarily NaCl, through various neutral, positively charged and negatively charged membranes via concentration gradient driven transport (i.e., ion permeability) and field driven transport (i.e., electrical conductivity).  Our long-term goal is to develop and validate a common framework to interpret data from both electrically driven and concentration gradient driven mass transport in such polymers and to use it to establish structure/property relations leading to rational design of membranes with improved performance.

Ion sorption and permeability data were used to extract information about salt diffusion coefficients in charged membranes.  Concentrations of both counter-ions and co-ions in the polymers were measured via desorption followed by ion chromatography or flame atomic absorption spectroscopy.  Salt permeability, sorption and electrical conductivity data were combined to determine individual ion diffusion coefficients in neutral, cation exchange and anion exchange materials. The use of models to correlate and, in some cases, predict the experimental data is discussed.

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“Targeted Design and Synthesis of New Catalysts for Cleaner Energy Processes”

Jason Hicks, Assistant Professor, Department of Chemical and Biomolecular Engineering, University of Notre Dame

Abstract:

As petroleum resources decrease and the desire for cleaner, more sustainable energy production increases, technologies capable of utilizing alternative feedstocks to produce current types of liquid transportation fuels and chemicals will become vitally important.   Research in the Hicks group has focused on the design and synthesis of catalysts with tunable and/or controllable chemical, structural, and surface properties to generate new materials that effectively and efficiently upgrade various renewable and petroleum-based feedstocks to liquid fuels and chemicals. This presentation will highlight our work synthesizing silica- and polymer tethered catalysts, Ce-incorporated zeolites, bimetallic transition metal phosphide catalysts, and metal-organic framework catalysts for a variety of important reactions: CO2 reduction, ketonization of carboxylic acids, and biomass deoxygenation. Particular focus will be given to discussion of the relationships between catalyst structures and properties through detailed characterization and reactivity studies of these well-defined heterogeneous catalysts. 

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"Advancing Cancer Immunotherapy One Cell at a Time"

Navin Varadarajan, Assistant Professor, Department of Chemical and Biomolecular Engineering, University of Houston

Abstract:
Tumors are a complex mixture of tumor and host cells that have acquired the ability to proliferate and overcome programmed cell death, suppress the host immune response, and induce growth of blood vessels to sustain growth and promote metastasis.

The significance of the immune system in eliminating/suppressing the malignant cells and the ability of tumor cells and the surrounding host cells to co-opt mechanisms of immunosuppresion to enable survival is well documented. The objective of immunotherapy is to harness this specific immune response to not only enable an immediate and potent anti-tumor response but also provide lasting immunity, through the establishment of memory.

Indeed, immunotherapy infusing antibodies, vaccines, and cells has emerged as a very effective approach for the treatment of human malignancies, including ones refractory to conventional treatment regimens. Clinical trials have revealed the advantages of many immune-based therapies, including defined mechanisms of action, reduced deleterious off-target effects, and lower toxicities than conventional approaches. Immune-based therapies, such as allogeneic hematopoietic stem-cell transplantation (HSCT) and monoclonal antibodies are now considered the standard-of-care for many malignancies.

The engineering of either antibodies that aim to modulate the immune-system, or genetically modified immune cells, has enabled new challenges in the design and manufacture of these products, and in determining potency.

I will discuss single-cell technology platforms and molecular engineering approaches that we have developed to address these problems, and how these are being implemented to improve the efficacy of cancer immunotherapy.