The formation of the central nervous system is a remarkable process that starts with the generation of and interaction between diverse cell types. Using single-cell profiling that captures cell identity and cell states within a complex tissue, our work seeks to unveil the series of rules underlying the extraordinary cellular diversity and human brain organization. By applying our knowledge of development, we recreate 2D and 3D in vitro systems to recapitulate key events during human brain development. These systems promise to uncover the principles of cell diversification and create a platform for stem cell-based disease investigation.

Our team aims to translate genetic discoveries from human studies into actionable biological hypotheses and provide new insights into the causal chain of events that result in neurological and psychiatric disease conditions. Together with the Seaver Autism Center at Mount Sinai, we apply human stem cell-based and mouse model systems and use multidisciplinary approaches, including CRISPR gene editing, electrophysiology, single-cell sequencing, and high-resolution imaging, to learn how the disease-associated genetic variation impairs neuronal properties and circuit activities. We also employ brain organoids combined with live-imaging and single-cell profiling to study the early molecular and cellular events, such as cell proliferation, migration, and differentiation impaired by disease-risk variants identified in recent large-scale genomic studies.

Disorders of the brain affect nearly one-fifth of the world’s population. Although genome-wide association studies (GWAS) have identified many genetic variants strongly linked to neurological and psychiatric disorders, functional interpretation is challenging. Most heritable common disease risk distributes to non-coding regions and appears to be particularly enriched in enhancers (classically defined as cis-acting DNA sequences that can increase the transcription of genes) that are specific to disease-relevant cell types. However, only a handful of the enhancers nominated via biochemical annotations have been validated and confidently linked to their target genes. We use innovative multidisciplinary approaches built upon stem cell technology to unravel the functions of non-coding sequences in disease-relevant neuronal types. This work promises an exploration of the biological functions of non-coding regions containing disease risk variants and helps bridge the gap between human genetics and experimental biology.