Learning from Human Genetics

The Broad Institute, funded by the Helmsley Charitable Trust, is working to identify novel small molecules with the potential to offer breakthroughs in therapy for Type 1 Diabetes (T1D) and Crohn’s disease (CD). Key challenges in developing novel therapeutics for such complex diseases include: (1) knowing which targets to modulate to achieve clinical benefit, and (2) having methods to modulate these targets with small molecules, even if not classical “druggable” targets.

Progress in human genetics is locating the genes that play a causal role in vivo in T1D and CD. Progress in high-throughput cell biology and genomics is making it possible to take such lists of genes and identify the smaller set of biological and cellular processes that they modulate. Progress in chemical biology is creating a path from knowledge of causal processes to small-molecule therapeutics.

These three advances have not yet been combined systematically to understand, prevent and treat T1D and CD. Our project - a collaboration led by Ramnik Xavier, David Altshuler, and Stuart Schreiber - aims to illuminate the functional roles of genes underlying T1D and CD pathogenesis and to reverse pathways that contribute to disease pathogenesis with small molecules, initially in cellular and animal models but with a focus on enabling human clinical investigation of T1D and CD.