Project Summary
Our laboratory seeks to understand—and exploit—the biophysical relationships and logic structures that
allow biocatalytic networks to control complex cellular behaviors. We are broadly interested in (i) the kinetic
and structural features of enzymes that allow them to work together to coordinate nonlinear processes (e.g.,
metabolism, signal processing, and biological display), (ii) the role of natural constraints on biomolecular
diversity (e.g., a limited number of protein folds) in restricting the structures of biocatalytic networks and the
evolutionary trajectories of metabolites, and (iii) the logic structures that allow multi-enzyme systems to control
non-Boolean operations. These interests underlie a programmatic focus on the biosynthesis of targeted,
biologically active molecules. Natural products are a longstanding source of pharmaceuticals and medicinal
preparations. These molecules—perhaps, as a result of their biological origin—tend to exhibit favorable
pharmacological properties (e.g., bioavailability and “metabolite-likeness”) and can exert a striking variety of
therapeutic effects (e.g., analgesic, antiviral, antineoplastic, anti-inflammatory, cytotoxic, immunosuppressive,
and immunostimulatory). Recent advances in synthetic biology have supplied new approaches for the efficient
biosynthesis and functionalization of known, pharmaceutically relevant natural products; complementary
methods for the discovery and optimization new products with specific therapeutically relevant activities,
however, remain poorly developed. This program develops an experimental framework for using a therapeutic
objective (e.g., the inhibition of a human drug target) as a genetically encoded constraint to guide molecular
biosynthesis in microbial hosts. It departs from contemporary efforts to use microorganisms for the synthesis of
known, pharmaceutically relevant natural products by using them, instead, to build new biologically active
molecules. In an abstract sense, it describes a kind of biological computation (i.e., the microbial assembly of
molecular solutions to genetically encoded design challenges). Over the next five years, we will develop
selective inhibitors and activators of protein tyrosine phosphatases (PTPs). These enzymes contribute to an
enormous number of disease (e.g., diabetes, obesity, cancer, Alzheimer's disease, autoimmunity, and heart
disease) but lack targeted therapeutics of any kind. The resulting molecules will supply an important source of
both (i) chemical probes for studying PTP-mediated signaling events and (ii) starting points for the
development of PTP-targeted therapeutics. This work builds toward our long-term goal of using engineered
microorganisms to guide the discovery, biosynthesis, and evolution of new small-molecule pharmaceuticals.