On behalf of the many former and current lab members and collaborators who conducted the work, I am incredibly grateful to receive the 2026 Joseph Altman Award in Developmental Neuroscience from the Japan Neuroscience Society. Our stem cell research relies on teamwork to bridge the fields of genetics and neuroscience to inform human brain development and disease.

I conducted graduate studies at Harvard University with Dr. Douglas Melton as the first human embryonic stem cell lines were being derived. In those early days, research was focused on applying insights from developmental biology to yield material for cellular replacement therapy. This was a unique period, when the ethics of stem cell research was widely debated, private funding was required, and threats of violence necessitated posting armed guards outside the laboratory. The discovery of reprograming by Dr. Kazutoshi Takahashi and Dr. Shinya Yamanaka transformed stem cell research and made it possible to generate a patient’s own cells to model their disease in the laboratory dish.

I pivoted fields, seeking to apply stem cells to study brain diseases, conducting post-doctoral training with Dr. Fred Gage at the Salk Institute for Biological Studies. Together with others in the laboratory, we reported phenotypes in patient-derived neurons generated from human induced pluripotent stem cells (hiPSCs) from individuals with schizophrenia, autism spectrum disorder, and bipolar disorder. This unequivocally demonstrated that disease-relevant processes could be recapitulated in the laboratory dish, paralleling changes in brain development, and consistent with observations in post-mortem studies and animal models.

Two key contemporaneous advances--the first genome-wide association studies for brain disorders and the discovery CRISPR genome editing--foretold the era of functional genomics just as I established my independent laboratory at the Icahn School of Medicine at Mount Sinai, and so my research evolved again. Our early studies focused on case-control designs and then progressed to examining top hits identified by genetic studies. Although the disease risk conferred by common variants is small, when we experimentally manipulated a single nucleotide polymorphism in human neurons, we observed robust effects. Today, we simultaneously test thousands of disease-associated variants in human brain cells, towards understanding their aggregate effects.

Highly penetrant rare mutations underlie only a tiny fraction of cases, but they can explain fundamental disease mechanisms. For example, we unexpectedly demonstrated that patient-derived NRXN1+/- neurons showed wide-scale dysregulation of NRXN1α splicing, reflecting the impact of loss of NRXN1 dose coupled, in a subset of cases, with aberrant activity by mutant isoforms. By demonstrating that distinct therapeutic approaches might sometimes be required for patients sharing mutations in the same gene, we added nuance to future considerations of precision medicine. Most recently, across a larger number of such risk genes, we identified points of convergence that varied between cell types, but were greatest in mature glutamatergic neurons, where they broadly targeted synaptic and epigenetic biology, and unexpectedly, mitochondrial function.

Each person’s distinct genetics and environments predispose them to some phenotypes and confer resilience to others. For example, trauma exposure is necessary but not sufficient to result in post-traumatic stress disorder (PTSD). Neurons derived from combat-exposed veterans with PTSD, relative to those from combat-exposed controls, exhibited hyper-responsive glucocorticoid-elicited transcriptional signatures that were enriched for genes associated with psychiatric disorder risk. In follow-up analyses, we resolved trauma-dependent regulatory loci in the post-mortem human brain that overlapped with glucocorticoid-responsive elements in hiPSC-derived neurons, indicating that genetic variation mediates differences in stress response between individuals.

We seek to discern the regulation of phenotype and uncover those modifiers that lessen the impact of genetic risk. Our goal is to decipher the frameworks that buffer risk, towards conferring resilience and promoting healthy development for all.