Research

Our Goals

Neurological and Psychiatric disorders pose a major socioeconomic burden. Our goal is to determine how genetic mutations underlie the pathobiology of nervous system disorders. We take advantage of cutting-edge genomic technologies to study the human brain at unprecedented resolution. We specifically seek to:

  1. Identify molecular programs regulating cell type distinctions in the human nervous system, and to identify changes in disease.
  2. Uncover the regulatory networks that control stem cell differentiation that could be utilized to increase the precision and safety of stem cell-based therapies.
  3. Develop new experimentally tractable models of human disease that enable interrogation of disease mechanisms and discovery of new therapeutic opportunities.

Representative Projects and Contributions to Science

Developing Tools for Human Neuroscience

We have a long-standing interest in deciphering how cells of the human brain function in health and disease. Harnessing technologies that allow us to manipulate cells in the human brain have the potential to become next-generation treatments for brain disorders.

Key publications:

  • Andrews, J. P., et al. (2024). Multimodal evaluation of network activity and optogenetic interventions in human hippocampal slices. Nature Neuroscience. doi.org/10.1038/s41593-024-01782-5
  • Lee AT, Chang EF, Paredes MF, Nowakowski TJ. Large-scale neurophysiology and single-cell profiling in human neuroscience. Nature. 2024. PMID: 38898291
  • Zhu D, et al. Optimal trade-off control in machine learning-based library design, with application to AAV for gene therapy. Sci Adv. 2024. PMID: 38266077

Epigenetic Mechanisms of Brain Development

Epigenetics is the study of how gene expression is regulated. We seek to uncover the molecular mechanisms of gene expression regulation through functional genomics to better understand how epigenetic factors contribute to brain development and susceptibility to neurodevelopmental disorders.

Key publications:

  • Ziffra et al. (2021) Single-cell epigenomics reveals mechanisms of human cortical development. Nature. PMID: 34616060
  • Deng C, et al. (2024) Massively parallel characterization of regulatory elements in the developing human cortex. Science. PMID: 38781390

Development of the Thalamus

By applying unbiased genomic technologies, spatial transcriptomics, and in vitro modeling, we seek to uncover the rules by which progenitors of the thalamus give rise to thalamic nuclei and axonal projections to the cerebral cortex.

Key publications:

  • Shin D, et al. (2024) Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders. Cell Stem Cell. PMID: 38382530
  • Kim CN et al. (2023) Spatiotemporal molecular dynamics of the developing human thalamus. Science. doi: 10.1126/science.adf9941

Developmental Lineage Relationships in the Brain

We apply massively parallel molecular barcoding strategies to uncover what cell types are generated at different stages of development, from which progenitor types, and in what order.

Key publications:

  • Keefe MG*, Steyert MR*, Nowakowski TJ. Lineage-resolved atlas of the developing human cortex. Nature. 2025. PMID: 41193842
  • Allen DE, et al. 2022. Fate mapping of neural stem cell niches reveals distinct origins of human cortical astrocytes. Science. DOI: 10.1126/science.abm5224
  • Delgado RN, et al. 2022. Individual human cortical progenitors can produce excitatory and inhibitory neurons. Nature. PMID: 34912114

Neuroimmune Interactions in Developing Brain and Disease

Although immune cells are not abundant in the brain, they play important roles in protecting the developing brain from viral infections.

Key publications:

  • Popova G, et al. (2023). Rubella virus tropism and single cell responses in human primary tissue and microglia-containing organoids. eLife. PMID: 37470786
  • Winkler EA, et al. (2022) Single cell atlas of the normal and malformed human brain vasculature. Science. doi: 10.1126/science.abi7377.
  • Popova G, et al. (2021) Human microglia states are conserved across experimental models. Cell Stem Cell. PMID: 34536354

Collaborative Research

We are excited to actively participate in the following consortia:

In the News

Funding Sources

We are grateful for the generous support of our sponsors:
• Simons Foundation Autism Research Initiative (SFARI)
• National Institutes of Health (NIH)
• Chan Zuckerberg Biohub
• California Institute for Regenerative Medicine (CIRM)