Professor of Chemistry and Chemical Biology
David R. Liu is Professor of Chemistry and Chemical Biology at Harvard University, a Howard Hughes Medical Institute Investigator, a Core Institute Member and Vice-Chair of the Faculty of the Broad Institute of Harvard and MIT, and an Associate Faculty Member of the Wyss Institute for Biologically Inspired Engineering. Liu graduated first in his class at Harvard in 1994 with a bachelor’s degree in chemistry. He performed synthetic organic and bioorganic chemistry research on sterol biosynthesis under Professor E. J. Corey’s guidance throughout his undergraduate years. During his Ph.D. research in the group of Professor Peter Schultz at U. C. Berkeley, Liu initiated the first general effort to expand the genetic code in living cells. He earned his Ph.D. in 1999 and became Assistant Professor of Chemistry and Chemical Biology at Harvard University in the same year. He was promoted to Associate Professor in 2003 and to Full Professor in 2005. Liu became a Howard Hughes Medical Institute Investigator in 2005 and joined the JASONs, academic advisors to the U.S. government on science and technology, in 2009.
"Protein Evolution and Engineering to Enable Biotechnology, Genome Editing, and Novel Therapeutics"
In this lecture I will describe two efforts in our laboratory that integrate chemistry, evolution, and macromolecular engineering to address significant problems in biotechnology, genome editing, and therapeutics science.
To overcome the time- and labor-intensive nature of protein evolution in the laboratory, we developed phage-assisted continuous evolution (PACE), a method that enables proteins to evolve continuously in the laboratory. PACE accelerates protein evolution ~100-fold compared to stepwise protein-evolution methods. Our group has used PACE to rapidly evolve a wide variety of proteins, including those with the potential to serve as novel therapeutic agents and several that have been recalcitrant to traditional laboratory evolution approaches. We have also used PACE to study the reproducibility and path dependence of evolution over thousands of generations in a practical time frame. Most recently, we used PACE to address a major problem threatening worldwide agricultural productivity: the rise of insects resistant to a widely used protein insecticide.
The advent of genome editing agents including CRISPR-Cas9 have fueled a revolution in the life sciences that has the potential to provide the first cures for many genetic diseases. These genome editing agents begin by making a double-stranded break in genomic DNA at a targeted site, resulting most frequently in the stochastic insertion or deletion of nucleotides leading to gene disruption. The substantial majority of known human genetic variants associated with disease, however, are point mutations that cannot be corrected by gene disruption. We recently developed “base editing”, a new approach to genome editing that enables the programmable conversion of one base in a genome into another base with much higher efficiency than other genome editing methods, and without requiring DNA backbone cleavage or donor DNA templates. Base editing has the potential to advance the scope and effectiveness of genome editing for point mutations, which represent the largest class of disease-driving mutations but are difficult to correct cleanly and efficiently using standard genome editing methods.