Neville Sanjana

Forward genetic screens using CRISPR–associated nucleases like Cas9 are a powerful tool to pinpoint genes involved in disease. Recently, we have applied genome-wide loss-of-function screens to identify the host genes required for SARS-CoV-2 infection. Using top-ranked genes, we identified multiple small-molecule inhibitors that reduce COVID-19 infection. For genes where no inhibitor exists, we paired CRISPR perturbations of these genes with single-cell sequencing (Enhanced CRISPR-compatible Cellular Indexing of Transcriptomes and Epitopes, ECCITE-seq) to identify shared biological mechanisms and re-purposed an existing FDA-approved cholesterol medication to decrease SARS-CoV-2 infection of human lung cells by >100-fold.

Despite these advances, high-throughput screens of noncoding RNAs have been more challenging since small mutations are unlikely to abrogate function. For this reason, we recently developed a RNA-targeting, Cas13-based platform for massively-parallel forward transcriptomic screens in human cells. We compared several Cas13 orthologs and, using ~25,000 Cas13 guide RNAs, determined the optimal parameters for target RNA knockdown with Cas13. By targeting protein-coding transcripts, we find that gene essentiality from Cas13-based screens compares well with known essential genes from prior screens using Cas9 and RNA interference. In addition to RNA-targeting screens, we also explored the impact on transcript knockdown of RNA base modifications in Cas13 guide RNAs. With optimized chemical modifications of the guide RNA and Cas13 ribonucleoproteins, we demonstrate targeting of the conserved leader sequence of SARS-CoV-2 viral subgenomic RNAs and improved knockdown of endogenous human transcripts in primary T cells.

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 has developed high-throughput genome engineering tools to understand the impact of genetic changes on cancer evolution, viral pathogenesis, drug resistance and the nervous system.

Dr. Sanjana is a recipient of the Presidential Early Career Award for Engineers and Scientists, AAAS Wachtel Prize for Cancer Research, the NIH’s New Innovator Award, the Cancer Research Institute Technology Impact Award, the DARPA Young Faculty Award, the Kimmel Scholar Award, the MRA Young Investigator Award, and also is the Leichtung Family Investigator of the Brain and Behavior Foundation. 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.

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