Point mutations represent the substantial majority of known human genetic variants associated with disease but are difficult to correct cleanly and efficiently using standard genome editing methods. In this lecture I will describe the development, application, and expansion of base editing, a novel approach to genome editing that catalyzes the direct conversion of a target base pair to another base pair in living cells without requiring DNA backbone cleavage or donor DNA templates. Base editing has been successfully performed in a wide range of organisms including bacteria, fungi, plants, fish, mammals, and even human embryos. Through a combination of protein engineering and protein evolution, we recently developed two classes of base editors (BE4 and ABE) that together enable all four transition mutations (C to T, T to C, A to G, and G to A) to be efficiently and cleanly installed at positions in genomic DNA specified by the researcher. We characterize key molecular features of both classes of base editors, including their efficiency, product purity, DNA specificity, off-target activity, and potential to correct pathogenic point mutations, as well as introduce disease-suppressing mutations.

<b>Award Address</b> (Ronald Breslow Award for Achievement in Biomimetic Chemistry sponsored by the Ronald Breslow Award Endowment). Base editing: Chemistry on a target nucleotide in the genome of living cells

255th National Meeting (2018)

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Award Address (Ronald Breslow Award for Achievement in Biomimetic Chemistry sponsored by the Ronald Breslow Award Endowment). Base editing: Chemistry on a target nucleotide in the genome of living cells