David Liu
David R. Liu is the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare, vice-chair of the faculty at the Broad Institute of MIT and Harvard, the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, and a Howard Hughes Medical Institute (HHMI) investigator. Liu’s research integrates chemistry and evolution to illuminate biology and enable next-generation therapeutics. His major research interests include the engineering, evolution, and in vivo delivery of genome editing proteins such as base editors to study and treat genetic diseases; the evolution of proteins with novel therapeutic potential using phage-assisted continuous evolution (PACE); and the discovery of bioactive synthetic small molecules and synthetic polymers using DNA-templated organic synthesis and DNA-encoded libraries. Base editing—the first general method to perform precision gene editing without double-stranded breaks, and a Science 2017 Breakthrough of the Year finalist—as well as prime editing, PACE, and DNA-templated synthesis are four examples of technologies pioneered in his laboratory. These technologies are used by thousands of laboratories around the world and have enabled the study and potential treatment of many genetic diseases.
Liu graduated first in his class at Harvard College in 1994. During his doctoral research at UC Berkeley, Liu initiated the first general effort to expand the genetic code in living cells. He earned his PhD 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 science advisors to the U.S. government, in 2009. In 2016 he became a Core Institute Member and Vice-Chair of the Faculty at the Broad Institute of MIT and Harvard, and Director of the Chemical Biology and Therapeutics Science Program.
Liu has been elected to the U.S. National Academy of Sciences, the U.S. National Academy of Medicine, and the American Association for the Advancement of Science. He is the 2022 King Faisal Prize Laureate in Medicine. He has earned several University-wide distinctions for teaching at Harvard, including the Joseph R. Levenson Memorial Teaching Prize, the Roslyn Abramson Award, and a Harvard College Professorship. Liu has published more than 220 papers and is the inventor on more than 85 issued U.S. patents. His research accomplishments have earned distinctions including the Ronald Breslow Award for Biomimetic Chemistry, the American Chemical Society David Perlman Award, ACS Chemical Biology Award, the American Chemical Society Pure Chemistry Award, the Arthur Cope Young Scholar Award, the NIH Marshall Nirenberg Lecturer, and awards from the Sloan Foundation, Beckman Foundation, NSF CAREER Program, and Searle Scholars Program. In 2016 and 2020 he was named one of the Top 20 Translational Researchers in the world by Nature Biotechnology, and was named one of Nature’s 10 researchers in world and to the Foreign Policy Leading Global Thinkers in 2017. He is the founder or co-founder of several biotechnology and therapeutics companies, including Beam Therapeutics, Prime Medicine, Editas Medicine, Pairwise Plants, Exo Therapeutics, Chroma Medicine, and Resonance Medicine.
The Broad Institute of MIT and Harvard
75 Ames Street
Cambridge, MA 02142
Tel: 617-714-8088
Email: drliu@chemistry.harvard.edu
Website:
https://liugroup.us/
Lab Size: Greater than 20
Summary
The Liu group conducts research in three major areas:
DNA-TEMPLATED SMALL MOLECULES The discovery, synthesis, delivery and testing of small bioactive molecules remains an active focus of chemists in both academic and industrial settings. The discovery of these bioactive molecules provide important insights into basic cellular function and are critical to identifying cellular targets implicated in human diseases. The Liu group developed and applied DNA-templated synthesis (DTS) to program chemical reactions of organic small molecules and sequence-defined synthetic polymers. By combining DTS and Darwinian selections, the Liu group has discovered several families of bioactive synthetic small molecules, such as inhibitors of kinases implicated in cancer, and inhibitors of insulin-degrading enzyme (IDE), which has been associated with diabetes. The Liu group has also applied the principles of DNA-programmed reactivity and DNA encoding to develop a new approach to reaction discovery, resulting in the discovery of several new chemical reactions.
PROTEIN EVOLUTION Biological evolution has efficiently solved many challenging molecular problems. By harnessing the power of biological evolution, researchers have started to address problems of their own choosing, rather than of nature’s choosing. The Liu group has developed a method that enables proteins to evolve continuously in the laboratory known as phage-assisted continuous evolution (PACE), increasing the speed of laboratory evolution by more than 100-fold over other methods. We applied PACE to evolve more than a dozen diverse classes of proteins including proteases, genome editing proteins, polymerases, antibodies, biosynthetic enzymes, and insecticidal proteins. PACE is now used both in academic and industry settings to evolve proteins with dramatically altered activities and specificities, and to reveal new basic scientific insights into the nature of biological evolution.
GENOME EDITING The life sciences are experiencing a revolution driven by the development of modern genome editing agents. These agents include RNA-guided programmable nucleases from CRISPR systems, which generate precise breaks in DNA or RNA at specified positions. In cells, this activity can lead to changes in DNA sequence or RNA transcript abundance. Base editing is a newer genome editing approach that uses components from CRISPR systems together with other enzymes to directly install point mutations without making double-stranded DNA breaks (DSBs). Base editors comprise a catalytically disabled nuclease fused to a nucleobase deaminase enzyme and, in some cases, a DNA glycosylase inhibitor. Base editors directly convert one base or base pair into another, enabling the efficient installation of point mutations in non-dividing cells without generating excess undesired editing byproducts.
The two classes of base editors (adenine base editors or ABEs and cytosine base editors or CBEs) developed by the Liu group can correct all four transition mutations, which collectively account for more than 60% of human pathogenic point mutations. These base editors have been distributed by Addgene to thousands of researchers around the world. Their use in a variety of species including prokaryotes, fungi, plants, insects, and mammals to install or correct point mutations, including those that drive genetic disease, has resulted in more than 100 publications. In addition to enabling precise point mutation with fewer byproducts using base editing, our group has also advanced our ability to address other major challenges facing genome editing, including improving the DNA specificity of editing agents, improving their targeting scope, and enabling their delivery in vivo to tissues of therapeutic relevance. We have integrated and applied these advances to treat animal models of human genetic diseases.
Publications
For an up-to-date publications list, please visit: https://liugroup.us/publications/
“A System for the Continuous Directed Evolution of Biomolecules” Esvelt, K. M.; Carlson, J. C.; Liu, D. R. Nature 472, 499–503 (2011).
“Highly Specific, Bisubstrate-Competitive Src Inhibitors From DNA-Templated Macrocycles” Georghiou, G.; Kleiner, R. E.; Pulkoski-Gross, M.; Liu, D. R.; Seeliger, M. A. Nature Chemical Biology 8, 366-374 (2012).
“Comprehensive Off-Target DNA Cleavage Profiling Reveals RNA-Programmed Cas9 Nuclease Specificity” Pattanayak, V.; Lin, S.; Guilinger, J.P.; Ma, E.; Doudna, J. A.; Liu, D. R. Nature Biotechnology in press (2013).
“Enzyme-Free Translation of DNA into Sequence-Defined Synthetic Polymers Structurally Unrelated to Nucleic Acids” Niu, J.; Hili, R.; Liu, D. R. Nature Chemistry 5, 282-292 (2013).
“Engineering, Identifying, and Applying Supercharged Proteins for Macromolecule Delivery into Mammalian Cells” Thompson, D. B.; Cronican, J. J.; Liu, D. R. Methods in Enzymology 503, 293-319 (2012).