Neville Sanjana

Neville Sanjana, PhD, is a Core Faculty Member at the New York Genome Center and Assistant Professor in the Departments of Biology and of Neuroscience and Physiology at New York University. As a bioengineer, Dr. Sanjana creates new tools to understand the impact of genetic changes on the nervous system and cancer evolution. His lab has harnessed high-throughput gene editing to pinpoint which regions of the genome, including both protein-coding genes and noncoding regulatory elements, are involved in diverse diseases.

Dr. Sanjana is a recipient of the NIH’s New Innovator Award and Pathway to Independence Award, the AAAS Wachtel Prize for Cancer Research, the DARPA Young Faculty Award, the Sidney Kimmel Scholar Award, the Melanoma Research Alliance Young Investigator Award, and the Allen Institute for Brain Science Next Generation Leader Award. Previously, he was a Simons Postdoctoral Fellow at the Broad Institute of Harvard and MIT. Dr. Sanjana holds a PhD in Brain and Cognitive Sciences from MIT, a BS in Symbolic Systems and a BA in English from Stanford University.

New Frontiers for Pooled Screens: Finding Regulatory Elements in the Noncoding Genome and Capturing Multi-Cell Interactions

Forward genetic screens using CRISPR (clustered regularly interspaced short palindromic repeats)–associated nucleases are a powerful tool to pinpoint genes involved in disease. Initial screens capitalized on genome-scale libraries to perturb nearly all protein-coding genes in the human genome to examine therapeutic resistance and gene essentiality in cancer cell lines. Recently, our lab has further developed the CRISPR screening toolbox in several new directions, such as in vivo screens to understand drivers of lung metastasis and in vitro saturation mutagenesis of noncoding regions to identify functional elements that drive chemotherapeutic resistance in melanoma. But certain disease-relevant phenotypes are difficult to probe in vitro in cell lines or in vivo in the complex multicellular environment.

To bridge the gap between the reductionism of in vitro screens and the full in vivo environment, we have recently developed two-cell type (2CT) whole-genome CRISPR screens to dissect the complex interactions between tumor cells and primary immune cells in cancer immunotherapy. Using primary human cytotoxic T cells, we identify loss-of-function mutations genome-wide that drive resistance to immunotherapy with T cells engineered with a transgenic, antigen-matched T cell receptor. We validate several novel immunotherapy resistance mechanisms across different melanomas, different cancers, and different antigens in human and mouse models. We also find that the enriched genes in our CRISPR screen correspond with mutated genes in a meta-analysis of cancer immunotherapy non-responders, suggesting that forward genetic screens could help predict which tumors would respond to therapy in advance of treatment.

In addition to genome-scale screens for protein-coding genes, we have recently adapted pooled CRISPR screens into noncoding regions of the genome, where it can be challenging to identify functional elements. We find that mutations at specific noncoding elements lead to changes in transcription factor occupancy and in the local epigenetic landscape and that these changes are coincident with modulation of nearby gene expression. Taken together, these new frontiers expand the potential of CRISPR screens for fundamental genomic discovery, gene regulation, and therapeutic development to overcome cancer resistance.