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2022 Guthikonda Lectureship: Professor David Liu, Harvard University

2022 Guthikonda Lectureship: Professor David Liu, Harvard University
Wed March 16th 2022, 12:00 - 1:00pm

2022 Guthikonda Lectureship: Professor David Liu, Harvard University (Host: Matthew Kanan)

**This seminar is only available for virtual attendance.**

"Base Editing and Prime Editing: Precise Gene Correction Without Double-Strand DNA Breaks"

About the Seminar

In this lecture I describe the development and pre-clinical therapeutic application of two precision gene editing technologies that install or correct targeted mutations without requiring double-strand DNA breaks, thereby minimizing chromosomal translocations, p53 activation, chromothripsis, and uncontrolled mixtures of indels. We developed base editors, proteins that directly perform chemistry on individual DNA bases in living cells to install or correct mutations at targeted positions in genomic DNA. We also engineered CRISPR-free, all-protein base editors that enable the first purposeful changes in the sequence of mitochondrial DNA in living cells. By integrating base editors with ex vivo and in vivo delivery strategies, including our recent development of engineered virus-like particles (eVLPs) that deliver therapeutic proteins, we have rescued animal models of human genetic diseases including sickle-cell disease and progeria. I will also describe prime editors, engineered proteins that directly write new genetic information into a specified DNA site without requiring double-strand DNA breaks or donor DNA templates. Prime editing can mediate any base substitutions, small insertions, and/or small deletions in living cells in vitro and in vivo, and has been applied to directly correct pathogenic alleles that previously could not be reversed in therapeutically relevant cells. We recently illuminated the cellular determinants of prime editing outcomes, and used the resulting insights to develop next-generation prime editing systems with substantially higher editing efficiencies and product purities. The combination of prime editing and recombinases enable targeted gene-sized integration and inversion at loci of our choosing in human cells. Base editing and prime editing enable precise target gene correction, rather than target gene disruption, in a wide range of organisms with broad implications for the life sciences and therapeutics.

Key references:

Programmable Editing of a Target Base in Genomic DNA Without Double-Stranded DNA Cleavage. Komor, A. C.; Kim, Y. B.; Packer, M. S.; Zuris, J. A.; Liu, D. R. Nature 533, 420-424 (2016). PDF, SI

Programmable Base Editing of A*T to G*C in Genomic DNA Without DNA Cleavage. Gaudelli, N. M.; Komor, A. C.; Rees, H. A.; Packer, M. S.; Badran, A. H.; Bryson, D. I.; Liu, D. R. Nature 551, 464-471 (2017). PDFSI

Search-and-Replace Genome Editing Without Double-Strand Breaks or Donor DNA. Anzalone, A.V.; Randolph, P.B.; Davis, J.R.; Sousa, A.A.; Koblan, L.W.; Levy, J.M.; Chen, P.J.; Wilson, C.; Newby, G.A.; Raguram, A.; Liu, D.R. Nature 576, 149–157 (2019). PDF SI

A Bacterial Cytidine Deaminase Toxin Enables CRISPR-Free Mitochondrial Base Editing. Mok, B. Y; de Moraes, M. H; Zeng, J; Bosch, D. E; Kotrys, A. V; Raguram, A.; Hsu, F; Radley, M.C; Peterson, S. B; Mootha, V.K; Mougous, J.D; Liu, D. R. Nature. 583, 631-637 (2020). PDF, SI

In Vivo Adenine Base Editing Corrects Hutchinson-Gilford Progeria Syndrome. Koblan L. W.; Erdos, M. R.; Wilson, C.; Cabral, W. A.; Levy, J. M.; Xiong, Z.-M.; Taarez, U. L.; Davison, L.; Gete, Y. G.; Mao, X.; Newby, G. A.; Doherty, S. P.; Lin, C. Y.; Gordon, L. B.; Cao, K.; Collins, F. S.; Brown, J. D.; Liu, D. R. Nature 589, 608-614 (2021). PDF, SI  

Base Editing of Hematopoietic Stem Cells Rescues Sickle Cell Disease in Mice Newby, G. A.; Yen. J. S.; Woodard, K. J.; Mayuranathan, T.; Lazzarotto, C. R.; Li, Y.; Sheppand-Tillman, H.; Porter, S. N.; Yao, Y.; Mayberry, K.; Everette, K. A.; Jang, Y.; Podracky, C. J.; Thaman, E.; Lechauve, C.; Sharma, A; Henderson, J. M.; Richter, M. F.; Zhao, K. T.; Miller, S. M.; Wang, T.; Koblan, L. W.; McCaffrey, A. P.; Tisdale, J. F.; Kalfa, T. A.; Pruett-Miller, S. M.; Tsai, S. Q.; Weiss, M. J.; Liu, D. R. Nature 595, 295-302 (2021).  PDF SI

Enhanced Prime Editing Systems by Manipulating Cellular Determinants of Editing Outcomes. Chen. P. J.; Hussmann, J. A.; Yan, J.; Knipping, D.; Ravisankar, P.; Chen, P.-F.; Chen, C.; Nelson, J. W.; Newby G. A.; Sahin, M.; Osborn, M. J.; Weissman, J. S.; Adamson, B.; Liu, D. R. Cell. in press, available online (2021). PDF  SI

Engineered Virus-Like Particles for Efficient In Vivo Delivery of Therapeutic Proteins. Banskota, S.; Raguram, A.; Suh, S.; Du, S.W.; Davis, J.R.; Choi, E.H. Wang, X.; Nielsen, S.C.; Newby, G.A.; Randolph, P.B.; Osborn, M.J.; Musunuru, K.; Palczewski, K.; Liu, D. R. Cell.  in press, available online. (2021). PDF

About the Speaker

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 Harvard and MIT, 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 for his research in gene editing. 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.