Biology Seminar: Turning Genetic Mysteries into Clinical Answers

Join us for "Turning Genetic Mysteries into Clinical Answers" presented by Zachary Walsh '18, MD PhD, Columbia University Vagelos College of Physicians and Surgeons.

Genetic variants, single-letter changes in DNA, can dramatically alter how our immune cells function, which matters both for treating cancer and for understanding inherited immune disorders. The fundamental problem is that sequencing has uncovered thousands of these variants, but for most, we don't know whether they cause disease or are harmless, leaving patients in diagnostic limbo. To solve this, we built a system using CRISPR base editors to create and test hundreds of thousands of variants at once, directly in human T cells, so we could measure what each one does. This let us find "gain-of-function" variants that supercharge T cells, and we used them to make more effective cancer immunotherapies like CAR-T cells; it also enabled us to figure out which variants cause rare immune disorders, which led to an actual patient being diagnosed and treated in 2025. Together, this shows how studying natural genetic variation can both explain disease and help us engineer better therapies - an approach that could reach far beyond immunology.