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Base editing: chemistry on a target nucleotide in the genome of living cells

Wednesday, September 5, 2018 - 3:00pm to 4:00pm

Speaker

David R. Liu, Ph.D.
Professor of Chemistry and Chemical Biology at Harvard University
Richard Merkin Professor
Director of the Merkin Institute of Transformative Technologies in Healthcare
Core Institute Member and Vice-Chair of the Faculty
Howard Hughes Medical Institute Investigator
Broad Institute of Harvard and MIT

Dr. 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 (named one of four 2017 Breakthrough of the Year finalists by Science), PACE, and DNA-templated synthesis are three examples of technologies pioneered in Dr. Liu’s laboratory.

Summary

Point mutations represent the majority of known human genetic variants associated with disease but are difficult to correct cleanly and efficiently using standard genome-editing methods. For his lecture, Dr. Liu will describe the development, application, and evolution of base editing, a novel approach to genome editing that directly converts a target base pair to another base pair in living cells without requiring DNA backbone cleavage or donor DNA templates. Through a combination of protein engineering and protein evolution, his lab recently developed two classes of base editors (BE4 and ABE) that together enable all four types of transition mutations (C to T, T to C, A to G, and G to A) to be efficiently and cleanly insta lled at target positions in genomic DNA. The four transition mutations collectively account for most known human pathogenic point mutations. Base editing has been successfully performed by laboratories around the world in a wide range of organisms including bacteria, fungi, plants, fish, frogs, insects, mammals, and even human embryos. Dr. Liu’s laboratory has recently expanded the scope of base editing by enhancing its efficiency, product purity, targeting scope, and DNA specificity. By optimizing base-editor expression, his lab developed “max” versions of cytosine and adenine base editors, which greatly increase editing efficiency in mammalian cells. His laboratory also showed that base editing can function in vivo in postmitotic somatic cells that do not support homology-directed repair. Finally, his lab has used its phage-assisted continuous evolution (PACE) system to rapidly evolve Cas9 and base-editor variants with both broade


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