Memorial Sloan-Kettering Cancer Center has received a USD 1.78 million NIH UM1 renewal to continue building a large-scale catalog of human gene knockout phenotypes across genetically diverse stem cell lines — work that could sharpen understanding of how gene loss drives neurodevelopmental and metabolic disease.
The award, administered by the National Human Genome Research Institute (NHGRI), supports the center's participation in the NIH Molecular Phenotypes of Null Alleles in Cells (MorPhiC) consortium, which aims to systematically define the function of every human gene. Principal investigators Lorenz Studer and Danwei Huangfu lead the production center, which will curate approximately 100 human pluripotent stem cell (hPSC) lines — predominantly induced pluripotent stem cell lines drawn from ancestrally diverse donors — and apply CRISPR-Cas9 knockout approaches across this panel. Phenotyping will be conducted in three multicellular systems: a micropatterned gastruloid model, a neuro-glial tri-culture, and a 3D pancreatic islet-like organoid. The center will prioritize genes implicated in autism spectrum disorder and type 2 diabetes.
The scientific rationale centers on a recognized limitation in functional genomics: gene loss-of-function effects are highly context-dependent, varying with cell type and genetic background. By conducting knockouts in genetically diverse hPSC lines and phenotyping them in multicellular rather than single-cell systems, the program aims to generate data more reflective of human biological complexity than previous large-scale screens. Primary human islets will be included in select assays to test whether findings from stem cell models generalize to primary tissue.