Neuropsychiatric and neurodevelopmental disorders are highly prevalent with tremendous unmet medical need worldwide, yet little is known about the underlying molecular pathologies compared to other major disease burdens. Complexities of the brain, coupled with lack of access to disease-affected tissue and poor model systems, have stalled both basic research and drug discovery efforts. Genome-wide analyses from large patient cohorts have recently uncovered a substantial number of genetic variants that predispose individuals to Schizophrenia, Autism and Bipolar disorder. Simultaneous advances in genome-engineering and human stem cell biology now provide the field with a unique opportunity to investigate the molecular and cellular underpinnings of mental illness.
In collaboration with the Stanley Center for Psychiatric Research at the Broad Institute, we are investigating mechanisms by which implicated variants impact neurons to cause dysfunction. By engineering human pluripotent stem cells (hPSCs) to contain different combinations of genetic variants, and then differentiating these cells into diverse neuronal subtypes, we are in a position to interrogate molecular, cellular and circuit level questions at unprecedented scale. This approach integrates the emerging genetics of mental illness with neurobiological mechanism, which we ultimately hope to leverage for the development of novel therapies for these devastating conditions.