Proteins are the workhorses of life. These molecular machines perform the vast majority of the processes that run our cells, in turn allowing our tissues and organs to work, and ultimately allowing us to be alive as organisms. Despite our scientific advancements, we do not fully understand how any given alteration to protein sequence impacts its function. This makes it difficult to predict the impacts of sequence variation on cellular processes, and hinders the utility of sequencing patients in the clinic. Without this mastery, every protein sequence must be experimentally tested in human cells to accurately ascribe their effects.
Unfortunately, experiments testing sequences individually are laborious, costly, and time-consuming. High throughput, single-cell approaches are needed to characterize the glut of protein variants observed in humans, and better understand the fundamental rules that dictate how genotype controls phenotype. My lab develops the biotechnologies necessary to advance our understanding of the impacts of protein alterations on protein function, cellular behavior, and disease in people.
We have previously applied these approaches to characterizing the impacts of coding variants on genes involved in development, cancer, and drug metabolism. Prompted by the pandemic, we characterized how variation in ACE2, the cell-surface receptor for SARS-CoV-2 and related sarbecoviruses, dictate the likelihoods of infection. We are also developing reporter systems capable of elucidating the impacts of protein sequence variations on intracellular signaling pathways. Our goal is to develop the biotechnologies and assays capable of simultaneously testing thousands of protein variants involved in diverse cellular processes, using these methodologies to gain quantitative insight into protein and cell biology, and distributing these tools to other researchers to enable scientific discoveries across disparate fields.