“Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.” – Sydney Brenner
We are developing the next-generation of single-cell genomics technologies for high-resolution lineage tracing of the human brain. The brain contains hundreds of cell types that develop from diverse progenitors, giving rise to all levels of structure—from large-scale regions to functional circuits. However, although there are a large number of known mature cell types in the brain, there are only a small number of known progenitor cell types, suggesting that more remain to be discovered. The lineage relationships among the brain’s progenitors and cell types are also poorly understood, and much of our understanding of brain development is based on animal models. The lack of a complete catalogue of human brain cell types, lineages, and progenitors is a fundamental gap in neuroscience and is due to a major technological limitation— the absence of a method for systematically tracing lineages of cells in human tissues. We are creating multi-omics single-cell technologies for lineage tracing of human tissues with the goal of producing a complete catalogue of the progenitors and cell lineages that form the human brain.
Brain tumors are responsible for an immense burden of disease and are remarkably diverse, with more than 100 different defined types, yet their cellular origins— i.e. the brain cell type with the first genetic “hits” that initiates each tumor— are unknown. Animal models and in vitro studies have shown that the cell of origin has major impact on subsequent brain tumor phenotype and behavior. Therefore, identifying the cellular origins of specific brain tumors would help understand their phenotypic diversity, facilitate earlier detection, and may lead to new lineage-targeted therapies. We will apply our single-cell lineage tracing technologies to reconstruct phenotypically-annotated lineage trees of individual brain tumors and identify their earliest lineages and cell of origin.
The genome is never copied perfectly during cell division, and even in the absence of cell division, every cell in the body accumulates mutations over time. These mosaic mutations can cause cancer and may be a cause of aging, but the factors that affect their rates and patterns are poorly understood. Our lab is developing new approaches for studying mosaic mutations in healthy tissues and the endogenous and exogenous processes that give rise to them.
We direct an Undiagnosed Diseases Program at NYU Hassenfeld Children’s Hospital whose mission is to implement the latest genomics technologies to find diagnoses for children with rare genetic diseases. In every pediatric population there are children with medical conditions that are likely genetic, but who remain undiagnosed despite extensive evaluation and testing. These “medical mysteries” often lead to lengthy diagnostic odysseys for patients and their families. A genetic diagnosis can be critical for families and therapeutic decision-making, as well as for enabling research into the root cause of the disease, but there remains a gap between the genomics technologies available in the lab versus the clinic. We apply technologies that are ahead of what is available in the clinic to children with undiagnosed diseases to find definitive diagnoses and to continuously advance clinical genomics.