Discovery and characterization of programmable biological systems

Abstract The natural world is filled with fascinating proteins and the arms race between bacteria and viruses is a particularly rich reservoir for their discovery. Research in this area over the past decades has uncovered restriction enzymes for genetic mapping, T7 phage polymerase used in the production of mRNA vaccines, and Cas9 for genome editing, and motivates continued exploration into this genetic conflict for useful molecular machines. Bacteria have many defense strategies against foreign elements, including CRISPR-Cas systems, which typically provide immunity through RNA-guided nuclease activity, however, my work has uncovered new RNA-guided functions including CRISPR-associated transposases that perform RNA-targeted DNA insertion, and CRISPR- associated proteases that cleave protein substrates upon target RNA detection. These systems reveal exciting new biology and how diverse enzymes can acquire, or be acquired by, RNA-guided proteins and I believe only scratch the surface of programmable functions that exist in nature. Practically, the characterization of new RNA-guided functions will enable new capabilities in biology to alter and control cells based on genetic information. The discovery of Cas9 and programmable nucleases opened the door for genome editing technology and I envision that additional programmable modalities could similarly transform biology and provide much needed molecular tools to interrogate the function and regulation of the human genome. Advances in DNA and RNA sequencing have provided insight into gene function, mutations that cause disease, and unique cell populations based on gene expression signatures, however, we lack the ability to alter and control cells based on their genomic and transcriptomic state. My goal is to discover and characterize proteins that are regulated via nucleic acid recognition and to harness these discoveries to engineer and control human cells.