BIOTECHNOLOGY TRAINING PROGRAM
Reginald Avery - Olsen Lab and Khademhosseini Lab
Hemorrhagic shock is a leading cause of death after penetrating injury on the battlefield. Current hemostats utilized in battlefield situations are limited to topical wounds and are not designed for treating internal wounds. One of the possible approaches to develop hemostatic agents for combat scenarios is to develop injectable, self-healing biomaterials that promote hemostasis. An agent with these features has the potential to significantly increase soldier survival after injury. To this end, we are developing shear-thinning hydrogels that have pro-coagulant properties and are stable in physiological environments. Further development will focus on improving the hydrogel's hemostatic properties with pro-coagulant/anti-fibrinolytic molecules and localizing the activity of the hemostat to the injury site.
Irene M. Brockman - Prather Research Group
Research Project: Controlled protein degradation for development of metabolite valves
A variety of gene knockout and genetic control strategies have been used to redirect flux into heterologous biosynthetic pathways in microorganisms. However, for many pathways, the ideal targets for control are part of the central carbon metabolism of the host, and downregulation of these enzymes may result in poor growth on the desired substrate. My research is focused on strategies for dynamically modulating the abundance of key enzymes within the host cell, allowing for switching between growth and production modes as flux is directed away from central metabolism. I am especially interested in targeted protein degradation, since it allows enzymes to be rapidly depleted even under conditions of slow growth.
Robert Citorik - Lu Lab
I am working in Dr. Timothy Lu's laboratory as part of the MIT Synthetic Biology Center. After getting a B.S. in microbiology and spending a few years researching bacterial pathogens at MGH, I found myself excited to enter the rapidly growing field of synthetic biology and apply it to infectious diseases. One of the largest problems we face today is the emergence and expansion of highly resistant microbes that are capable of causing disease while confounding many or all available antibiotic treatments. Both the nature and importance of this problem warrant exploration of alternative treatment strategies. My current research involves working with new tools in genomic editing to specifically target resistant populations for modification or elimination.
Christi Dionne Cook - Griffith Lab
Research Project: I am interested in characterizing rare cell populations in the peritoneal cavity of endometriosis patients. My research involves developing better quantitative models to characterize the dynamics of endometrial cell proliferation and invasion, using a combination of biomaterials scaffolds, high throughput imaging, and computational analysis.
Amanda Daigle - Fraenkel Lab
We are developing systems biology approaches to research on human disease. Current technology enables us to get data across entire cellular systems, such as the genome and proteome. Combining and effectively using these technologies to advance the search for novel therapies for human disease is an important challenge. I am approaching this challenge by developing computational models for analyzing these large data sets, and pulling important and actionable data out of them.
Adam Freedman - Thompson Laboratory
Research Project: I am interested in biochemical processes that utilize microbial conversions of byproduct wastes or greenhouse gases to produce clean fuels, useful biodegradable materials and aid in effective carbon management. My interests lie most directly at the point where microbiology, genetic engineering and sustainable energy converge, as I will explore the potential for introducing biofuel-producing genes into various bacterial species.
Furthermore, I am interested in how microbes affect the geochemistry of deep subsurface environments after injection of high-pressure CO2. To that end, I am researching the extent to which microbes catalyze biomineralization under high-pressure CO2 conditions, a process that has the potential to reduce CO2 migration/leakage and improve the sealing capacity of reservoirs targeted for geologic carbon sequestration.
Matt Glassman - The Olsen Laboratory
Research Project: Hydrogels are an exciting platform technology for biomedical solutions in many high impact areas, from managing chronic ailments such as rheumatoid arthritis and osteoporosis, to treating acute conditions such as hemorrhaging and cancer. Precisely engineered injectable hydrogels could enable minimally-invasive surgical implantation for improved control in the delivery molecular and/or cellular cargo within bioactive, degradable scaffolds. We are developing new methods for engineering shear thinning hydrogels that can be thermoresponsively strengthened post-injection to yield tough implants that can bear significant physiological loads. By utilizing artificially-engineered proteins conjugated to designer polymers, we are synthesizing biomaterials that are finely tuned for protecting and communicating with encapsulated cells, integrating with host tissues at the target site, and executing predefined programs for nanostructure formation and controlled release. Fundamental studies on the structure and mechanics of double physical network hydrogels (which consist of two independent, reversibly-associating networks) will enable the development of enhanced materials to meet clinical demands.
Nicole Kavanaugh - Ribbeck Laboratory
Research Project: My primary research focus is understanding the interactions between pathogenic microbes and mucus. Mucus is an important biological barrier inside the human body that functions to keep harmful microbes from causing infections. I hope to understand the mechanisms by which mucus provides this protection in order to develop new anti-infection strategies.
Jennifer E. Kay - Engelward Laboratory
Research Project: My research is on DNA damage and repair with a focus on homologous recombination. We are especially interested in the role of the repair gene Brca2 in HR. In vitro, I induce double strand breaks in cells of various genotypes, then measure their repair capacity. In vivo, I have investigate the role of gut infections on DNA damage, inflammation and cancer in other organs.
Ryan Kelly - Wittrup Laboratory
Structure and Sequence Determinants of Nonspecificity and Aggregation of Therapeutic Antibodies
While high throughput methods such as phage and yeast display are frequently able to isolate high affinity antibodies against clinical targets, many of these antibodies fail in clinical stages due to poor pharmacokinetics and pharmacodynamics. Correcting these problems is an inexact science, costing significant time and money and often leading to promising drugs being abandoned altogether. It is my goal to first develop a high throughput assay to detect poor developability at an early stage, and then use this assay to determine the sequence and structure determinants of aggregation and nonspecificity.
Alexandria D. Liang - Lippard Research Group
Research Project: Ali works on protein-protein dynamics, electron transfer and proton transfer within the multicomponent protein toluene/o-xylene monooxygenase.
Surin Mong - Pentelute Laboratory
Cytosolic delivery of DARPin scaffold variants to perturb protein-protein interactions
Protein-protein interactions are essential for biological function of living systems. However, their large surface area often makes it difficult for small molecules to bind and disrupt such interactions for investigative or therapeutic purposes. Alternatives to small molecules include engineered protein scaffolds that possess the high affinity and selective binding capabilities of an antibody. Using chemistry I aim to enhance one such class of scaffold, Designed Ankyrin Repeat Proteins (DARPins), such that they may be used to perturb intracellular protein-protein interactions. In order to modify DARPins at will, I will demonstrate their efficient and total synthesis using instrumentation that allows for extremely rapid peptide synthesis. Cytosolic delivery of chemically enhanced DARPins will be achieved through a novel delivery platform that hijacks the natural mechanism of anthrax toxin translocation.
Nicholas Mozdzierz - Love Laboratory
While various eukaryotic hosts have been used to successfully produce certain recombinant human proteins for nearly 40 years, each has drawbacks that preclude complete expression optimization. Mammalian platforms such as CHO cells offer the benefit of fully human post-translational modifications, and therefore essentially guarantee that recombinant proteins will attain the correct tertiary structure. Processes employing these cell lines, however, are plagued by exorbitant media costs, intensive purification steps, and low product yields. Conversely, the yeast species S. cerevisiae and P. pastoris are readily cultured to high cell densities using inexpensive media, and are capable of secreting heterologous proteins at relatively high purity.
My efforts will thus center on exploiting the P. pastoris expression system to produce heterologous proteins of general medical value at high titers. In the near term, my objective will be the transformation and validation of distinct P. pastoris strains capable of secreting bioactive forms of recombinant human interferon α-2b (IFNα
2b), recombinant human growth hormone (rhGH), and trypsin. Subsequently, building off of expertise previously acquired by the Love Lab, multiple rounds of random mutagenesis and single-cell sub-nanoliter well screening will be used to identify high-secreting mutants of the aforementioned strains that grow optimally in the microbioreactor arrays developed by Prof. Rajeev Ram in the MIT Department of Electrical Engineering and Computer Science. Leveraging the knowledge that I gained while working at Regeneron, RNA-seq experiments will be performed with the assistance of the Broad Institute to elucidate the mechanisms behind improved secretion.
Raven Reddy - White Laboratory
Despite our rapidly advancing understanding of many facets of cancer, metastasis persists as one of the most clinically important questions to address. Recent work has been able to isolate the tumor cells that have the highest propensity to break away from the primary tumor and form metastases. Genetic analysis of these cells suggests that their invasive potential arises from a sensitized motility pathway. However, the mechanism by which they process signals from their environment differently than their non-metastatic counterparts has yet to be elucidated. My work aims to analyze the phosphoproteome using mass spectrometry to determine how signals are initiated and propagated through these two systems that ultimately produce the different observed behaviors.
Sarah Schrier - Lauffenburger Research Group
Research Project: Application of Modeling Techniques to Study Intercellular Signaling
Immune cells communicate to mount a response, often through the secretion of various cytokines or chemokines. Responses can be dynamic and involve the cooperation of many cell types. My project aims to further develop tools used to study intracellular signaling cascades to understand cell-cell communication, including both intracellular signals and their extracellular responses, with a particular focus on immunology and inflammation.
Rathi Srinivas - Doyle Group
Research Project: Encoded Hydrogel Microparticles for High Throughput and Multiplexed Biomolecule Detection
Robust biomolecule detection platforms are crucial in order to characterize disease states and advabce medical diagnostic tools. My work is focused on developing a novel microfluidic hydrogel-based system to understand protein and nucleic acid profiles in biologically complex media such as cell cultures and blood serum. Compared to a solid substrate, the three-dimensional and flexible scaffold of a hydrogel is more favorable for biological interactions and often offers higher sensitivity. Meanwhile, microfluidic synthesis and analysis techniques allow for rapid, high-throughput, and multiplexed quantification.
Mark M. Stevens - Manalis Laboratory
Research Project: Utilizing high precision mass sensing to directly measure cell response to nutrient depletion and cellular nutrient requirements
Despite exciting research targeting therapies to the metabolic changes seen in cancer cells, understanding metabolism well enough to take advantage of these differences remains a major challenge in cancer research. Still little is known about why these changes take place, what the basic metabolic requirements necessary for growth are, or how cells respond to changes in their metabolic microenvironment. In an effort to gain new insight into these questions, I am applying the femptogram-precision suspended microchannel mass sensor (SMR) to monitor cell growth and metabolism from the perspective of cell mass. With high temporal resolution, I am able to observe cell growth response to changes in its metabolic environment in real-time, and hope to elucidate some of the underlying mechanisms driving these response phenotypes.
Austin L. Travis - Imperiali Group
Research Project: Gram-negative bacteria have historically proven to be a challenging target for antibiotic development due to phentotypic difficulties as well as the continuing struggle with antibiotic resistance. A new paradigm of targeting virulence factors such as protein glycosylation rather than survival functions could present a key new indication for the discovery of novel antimicrobial agents. Additionally such a chemical tool would prove to be invaluable for studying the host-pathogen interaction in real time. A fragment-based drug discovery approach relying on chemical synthesis, x-ray crystallography, and several biological activity assays is being undertaken in order to develop a small molecule inhibitor of N-linked protein glycosylation.
Elizabeth Wittenborn - Drennan Research & Education Laboratory
My research in the Drennan Lab is focused on the structural characterization of key enzymes in the Wood-Ljungdahl pathway of carbon fixation. Through this pathway, two molecules of CO2 are ultimately incorporated into acetyl-coenzyme A (acetyl-CoA), an important building block in cellular metabolism. In the model acetogenic organism Moorella thermoacetica, the final step in the pathway is carried out by the enzyme carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS). As the name implies, CODH/ACS is a bifunctional enzyme that catalyzes two distinct reactions at two different active sites. At the first active site, called the C-cluster, CO2 is reduced to CO. This CO is then directed through a gas channel that runs the length of the enzyme to the second active site, the A-cluster. At the A-cluster, CO is methylated, forming an acetyl moiety, which is then combined with coenzyme A to make acetyl-CoA.
Due to its ability to perform difficult 1-carbon chemistry, CODH/ACS plays a significant role in the global carbon cycle. A more thorough mechanistic and structural understanding of CODH/ACS could aid in the development of biomimetic catalysts that are able to remove both CO2 and CO from the environment.
Boyang Zhao - Lauffenburger Research Group and The Hemann Lab
Research Project: Recent high-resolution sequencing studies have revealed substantial intra-tumor heterogeneity in patients. This poses considerable challenges on the development of treatment strategies to eradicate all tumor subclones. Using an integrated approach of computational modeling and experimentation in the Eµ-myc lymphoma mouse model, we aim to investigate in vitro and in vivo how cancer therapies influence the clonal architecture and to develop therapeutic strategies for minimizing drug resistance.
Eric Zhu - Wittrup Laboratory
Research Project: Developing immunotherapies against tumors and elucidating mechanisms of the resulting immune response
Antibodies targeting tumor antigens and cytokine therapies have shown great clinical efficacy in treating tumors, but the underlying immunological mechanisms for their anti-tumor action remain unclear. Recent evidence suggests that combinations of these therapies can generate a potent host response against tumor challenge that requires both the innate and adaptive immune systems. I hope to elucidate the temporal mechanisms involved in this anti-tumor response and through this understanding develop additional agents to create more effective and long-lived treatments against tumors.