Date: Wednesday, April 30th, 2025
Time: 1-2pm
Room: Ragon Auditorium
CSB Ph.D. Candidate: Ivy Liu
Advisor: Alex Shalek (Chemistry, IMES/Broad/Ragon)
TDC Members: Forest White (chair), Ernest Fraenkel, Srivatsan Raghavan (external)
Title: Decoding Disease Drivers Through Single-Cell Omics and Scalable Phenotypic Screens
Abstract:
High-throughput phenotypic screens using biochemical perturbations and high-content readouts are constrained by limitations of scale. In this thesis, we establish a method of pooling exogenous perturbations followed by computational deconvolution to reduce required sample size, labor and cost. We demonstrate the increased efficiency of compressed experimental designs compared to conventional approaches through benchmarking with a bioactive small-molecule library and a high-content imaging readout. We then apply compressed screening in two biological discovery campaigns. In the first, we use early-passage pancreatic cancer organoids to map transcriptional responses to a library of recombinant tumor microenvironment protein ligands, uncovering reproducible phenotypic shifts induced by specific ligands distinct from canonical reference signatures and correlated with clinical outcome. In the second, we identify the pleotropic modulatory effects of a chemical compound library with known mechanisms of action on primary human peripheral blood mononuclear cell immune responses. In sum, our approach empowers phenotypic screens with information-rich readouts to advance drug discovery efforts and basic biological inquiry.