We develop new approaches to interrogate and engineer biochemical networks (natural and synthetic). We are particularly focused on the application of these approaches to problems in energy and human health.
Kinetic and Molecular Determinants of Flux in Biosynthetic Pathways
In biosynthetic pathways for renewable fuels and chemicals, adjustments to metabolism are typically made through enhanced or attenuated expression of native and non-native enzymes. Pathways assembled from enzymes with mismatched kinetics, promiscuous activities, and/or nonequivalent environmental sensitivities (e.g., pH optima), however, can lead to the accumulation of toxic intermediates, the generation of undesirable final products, and reductions in titer. Future efforts to enhance yields or to tune product profiles in biosynthetic pathways will require strategies for (i) building control systems that adjust enzyme expression levels in response to toxic intermediates and for (ii) altering the activities and/or substrate specificities of pathway enzymes. We are working on (i) and (ii).
Controlling Spatial Regulation in Intracellular Signaling Networks
The reaction networks that govern signal transduction, gene regulation, and metabolism in living cells are spatially and temporally complex. A chemical reaction in one region of a cell (e.g. within the endoplasmic reticulum, at the plasma membrane, within an endosome) may proceed with a vastly different rate than the same reaction elsewhere. An understanding of the mechanisms by which networks of chemical reactions influence cellular behavior requires not only knowledge of which biochemical species interact, and of the products that result, but also an understanding of where species interact and of how their interaction locations influence process outcomes. We are developing an approach to examine the outcomes associated with spatially localized biochemical events, and we are using insights thus gained to control—and to restore—cellular function.
Evolving Functional Small Molecules
Nature is replete with functional small molecules (e.g., the compounds that give flowers their color or honey its flavor); for thousands of years, humans used these molecules as dyes, fragrances, flavorings, and medicines. Unfortunately, the useful properties of such natural products—their color, their smell, their affinity for a receptor—are difficult to design (or to recreate in synthetic analogs). We are developing methods to "evolve" new functional small molecules.