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Director of Crystallography
BioDot-to-dot on an electron density map, the molecular bricks that sustain life - proteins, nucleic acids, polymers, and their ligands, inhibitors, and co-factors - all initially invisible to the naked eye, come alive on-screen. Connecting these molecules to what they do in life inspires research and development. At the Macromolecular Structure Knowledge Center (MSKC) you will find a platform to explore, expand, and enrich our understanding on how natural processes and technology work at the level of the atom.
Associate Professor of Bioengineering and of Medicine (Microbiology and Immunology)
Current Research and Scholarly InterestsThe human microbiome is linked to a range of phenotypes in the host, but it remains difficult to test causality and explore the mechanisms of these interactions. Our lab focuses on two research areas that share a common goal of studying host-microbiota interactions at the level of molecular mechanism:
1) Technology development. Much of what we know about biology has been learned by deleting individual genes from mice, worms, flies and yeast. The ability to do single-strain and single-gene deletion in the microbiome would be transformative but does not yet exist. We are developing technology in three areas to make this possible:
Synthetic ecology: There is a pressing need for model systems for the microbiome that are defined, but of an order of complexity that approaches the native state. Key experiments in the field often show that a host phenotype can be transferred to a germ-free mouse via fecal transplant. If these phenomena could be recapitulated with a defined, high-complexity community, then reductionist experiments to probe mechanism would be possible. We are developing the technology required to build highly complex defined communities (100-200 bacterial species), make them stable upon transplantation into mice, and probe their function in vitro and in vivo.
Genetics: It is difficult to probe mechanism without genetics, and genetic tools exist for only ~10% of the bacterial species in the gut and skin microbiome. We are developing technologies that will make it possible to delete and insert genes, and build mutant libraries, in many of the most common bacterial strains in the gut and skin microbiome.
Computation: In previous work from the lab, we have developed computational algorithms that identify small-molecule-producing genes in bacterial genomes. In current work, we are devising algorithms for genome mining that are specific to the microbiome, and new tools for predicting the chemical structures of small molecules from untargeted metabolomics data.
2) Molecular mechanisms. Many of the early findings in microbiome research are correlative or associative. We are applying the tools described above to explore the mechanisms underlying these phenomena:
Small molecules: Our lab has had a long-standing interest in small molecules from the microbiota. These include: 1) host-derived molecules metabolized by the microbiome, like bile acids; 2) characteristic components of the bacterial membrane and cell wall, including LPS and capsular polysaccharides; and 3) hundreds of other diffusible small molecules (e.g., the products of polysaccharide and amino acid metabolism) that are present in the bloodstream at high concentrations. Our work in this area seeks to establish the mechanisms by which these molecules modulate host biology, especially by deleting them one at a time in the background of a complex community; and to discover new microbiome-derived metabolites present in the bloodstream and host tissues.
Ecology of complex communities: Synthetic ecology at the 100+ strain scale is entirely unexplored, and the emergent properties of complex communities are not well understood. Our work in this area seeks to understand basic principles outlined by the following questions: How many meaningful interactions exist in a community of hundreds of strains? What constitutes a niche, molecularly and spatially, and how do strains map to niches? What are the molecular correlates of stability, and how does a community reconfigure in response to a perturbation? How rare or common are stable states, and how predictable is the process by which a consortium will evolve toward a stable state? To what extent do priority effects (early colonists and events) determine the outcome of ecosystem development? Can the results of ecosystem competition be predicted or engineered?
Assistant Professor of Bioengineering and of Genetics
Current Research and Scholarly InterestsThe Fordyce Lab is focused on developing new instrumentation and assays for making quantitative, systems-scale biophysical measurements of molecular interactions. Current research in the lab is focused on three main platforms: (1) arrays of valved reaction chambers for high-throughput protein expression and characterization, (2) spectrally encoded beads for multiplexed bioassays, and (3) sortable droplets and microwells for single-cell assays.
Donald Kennedy Chair in the School of Humanities and Sciences and Professor of Genetics
Current Research and Scholarly InterestsThe long term goal of our research is to understand how proteins fold in living cells. My lab uses a multidisciplinary approach to address fundamental questions about molecular chaperones, protein folding and degradation. In addition to basic mechanistic principles, we aim to define how impairment of cellular folding and quality control are linked to disease, including cancer and neurodegenerative diseases and examine whether reengineering chaperone networks can provide therapeutic strategies.
Fletcher Jones Professor in the School of Engineering
BioThe processing of complex liquids (polymers, suspensions, emulsions, biological fluids) alters their microstructure through orientation and deformation of their constitutive elements. In the case of polymeric liquids, it is of interest to obtain in situ measurements of segmental orientation and optical methods have proven to be an excellent means of acquiring this information. Research in our laboratory has resulted in a number of techniques in optical rheometry such as high-speed polarimetry (birefringence and dichroism) and various microscopy methods (fluorescence, phase contrast, and atomic force microscopy).
The microstructure of polymeric and other complex materials also cause them to have interesting physical properties and respond to different flow conditions in unusual manners. In our laboratory, we are equipped with instruments that are able to characterize these materials such as shear rheometer, capillary break up extensional rheometer, and 2D extensional rheometer. Then, the response of these materials to different flow conditions can be visualized and analyzed in detail using high speed imaging devices at up to 2,000 frames per second.
There are numerous processes encountered in nature and industry where the deformation of fluid-fluid interfaces is of central importance. Examples from nature include deformation of the red blood cell in small capillaries, cell division and structure and composition of the tear film. Industrial applications include the processing of emulsions and foams, and the atomization of droplets in ink-jet printing. In our laboratory, fundamental research is in progress to understand the orientation and deformation of monolayers at the molecular level. These experiments employ state of the art optical methods such as polarization modulated dichroism, fluorescence microscopy, and Brewster angle microscopy to obtain in situ measurements of polymer films and small molecule amphiphile monolayers subject to flow. Langmuir troughs are used as the experimental platform so that the thermodynamic state of the monolayers can be systematically controlled. For the first time, well characterized, homogeneous surface flows have been developed, and real time measurements of molecular and microdomain orientation have been obtained. These microstructural experiments are complemented by measurements of the macroscopic, mechanical properties of the films.
Assistant Professor of Chemical Engineering
Current Research and Scholarly InterestsHow do we design biological systems as “smart medicine” that sense patients’ states, process the information, and respond accordingly? To realize this vision, we will tackle fundamental challenges across different levels of complexity, such as (1) protein components that minimize their crosstalk with human cells and immunogenicity, (2) biomolecular circuits that function robustly in different cells and are easy to deliver, (3) multicellular consortia that communicate through scalable channels, and (4) therapeutic modules that interface with physiological inputs/outputs. Our engineering targets include biomolecules, molecular circuits, viruses, and cells, and our approach combines quantitative experimental analysis with computational simulation. The molecular tools we build will be applied to diverse fields such as neurobiology and cancer therapy.