PROJECT ABSTRACT: Mammalian cell biology happens in 3 dimensions. Advances in high-throughput genomics and cellular profiling ‘omics methods have made massively-parallel cell biology experiments routine for many labs, but the vast majority of these studies in human cells have been limited to homogeneous 2-dimensional models. This drastically reduces the range of cell types and interactions that can be studied ex vivo. And, despite advances in the growth of organoids and microtissues for the study of human biology in 3D, next generation ‘omics approaches still require the dissociation of these structures and the destruction of their cells to extract biomolecules for study. Researchers need tools that can interrogate human biology at scale and in situ to generate rich phenotyping data from single cells while still preserving complex spatial relationships and interactions between cells in 3D. The lack of such tools is a major limitation in biomedical research. Here I propose a technology that combines the discovery potential of genome scale screening with the information content of high-dimensional single-cell profiling, with full integration of 3D spatial information to enable rich in situ phenotypic readout of complex cellular phenomena at scale.

PROJECT NARRATIVE: Mammalian cell biology happens in 3 dimensions, but our most powerful tools (whole genome screening, single cell analysis) cannot access complex 3D biology. This program will develop a new approach that combines powerful functional genomics tools with 3D cell culture and advanced computational analysis, enabling us to gain deep insight into complex disease biology at scales that were previously impossible.