Benjamin F. Cravatt

Our research group aims to understand the roles that proteins play in human physiological and pathological processes and to use this knowledge to identify novel therapeutic targets and drugs to treat disease. To achieve these goals, we develop and apply new technologies that bridge the fields of chemistry and biology, ascribing to the philosophy that the most significant biomedical problems require creative multidisciplinary approaches for their solution. Our technological innovations address fundamental challenges in human physiology and disease that are beyond the scope of contemporary methods. For instance, enzymes are tightly regulated by post-translational events in vivo, meaning that their activity may not correlate with expression as measured by standard genomic and proteomic approaches. Considering that it is an enzyme's activity, rather than abundance that ultimately dictates its role in cell physiology and pathology, we have introduced a set of proteomic technologies that directly measures this parameter. These activity-based protein profiling (ABPP) methods exploit the power of chemistry to engender new tools and assays for the global analysis of enzyme activities. The enzyme activity profiles generated by ABPP constitute unique molecular portraits of cells and tissues that illuminate how metabolic and signaling networks are regulated in vivo. Additionally, by evaluating enzymes based on functional properties rather than mere abundance, ABPP acquires high-content proteomic information that is enriched in novel markers and targets for the diagnosis and treatment of human disease. We have also shown that ABPP can serve as a near-universal assay for the discovery of small-molecule inhibitors or ligands of proteins directly in native biological systems and, through doing so, greatly expand the scope of proteins that can be targeted by chemical probes and drugs.

We complement these efforts in technology development with focused studies on individual proteins. With particular interests in the nervous system and cancer, we select proteins, such as the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), for detailed investigation using a range of chemical, biochemical, genetic, and pharmacological techniques. This multidisciplinary approach ensures that we generate all of the tools and models required to assign molecular, cellular, and physiological functions to enzymes and, as an important corollary, assess their suitability as therapeutic targets. Notably, these basic discovery projects both benefit from and provide a fertile testing ground for our technological innovations. Thus, through the integration of two complementary research programs, one dedicated to methods development for chemical proteomics, and the other to the characterization of key proteins and pathways, our group achieves a unique balance that cultivates the creation and rapid implementation of cutting-edge technologies for the advancement of basic and translational science.