David R. Liu

David Liu

Richard Merkin Professor and Director of the Merkin Institute of Transformative Technologies in Healthcare
Richard Merkin Professor and Director of the Merkin Institute of Transformative Technologies in Healthcare
Harvard University, Broad Institute
Cambridge, MA


Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells

Point mutations represent most known human genetic variants associated with disease but are difficult to correct cleanly and efficiently using standard nuclease-based genome editing methods. In this lecture I will describe the development, application, and evolution of base editing, a new approach to genome editing that directly converts a target base pair to another base pair in living cells without requiring double-stranded DNA breaks or donor DNA templates.

Through a combination of protein engineering and protein evolution, we recently developed two classes of base editors, CBE 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 installed or corrected at target positions in genomic DNA. The four transition mutations collectively account for most known human pathogenic point mutations. Base editing has been widely used by many laboratories around the world in a wide range of organisms including bacteria, fungi, plants, fish, mammals, and even human embryos.

We have recently expanded the scope of base editing by enhancing its efficiency, product purity, targeting scope, and DNA specificity. By optimizing base editor expression, we developed "max" versions of cytosine and adenine base editors with greatly increase editing efficiency in mammalian cells. We also show that base editing can function in vivo in post-mitotic somatic cells that do not support homology-directed repair. To improve the targeting scope of base editing, we used our phage-assisted continuous evolution, PACE, system to rapidly evolve Cas9 and base editor variants with broadened PAM compatibility, higher DNA specificity, and enhanced editing capabilities.

Finally, we integrated several of these developments to address cell and animal models of human genetic disease. Base editing can be used to correct pathogenic point mutations, introduce disease-suppressing mutations, and create new models of genetic diseases.


Professor David R. Liu


Broad Institute of Harvard and MIT, Harvard University, and HHMI


1. 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, 2016 533, 420-424
2. 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, 2017, 551, 464-471
3 .Increasing the Genome-Targeting Scope and Precision of Base Editing with Engineered Cas9-Cytidine Deaminase Fusions, Kim, Y. B.; Komor, A. C.; Levy, J. M.; Packer, M. S.; Liu, D. R. Nat. Biotechnol., 2017, 35, 371-376
4. Improving the DNA Specificity and Applicability of Base Editing Through Protein Engineering and Protein Delivery In Vitro and In Vivo Rees, H. A.; Komor, A. C.; Yeh, W.-H.; Edge, A. S. B.; Liu, D. R. Nat. Comm., 2017, 8, 15790.
5. In Vivo Base Editing of Post-Mitotic Sensory Cells Yeh, W.H.; Chiang, H.; Rees, H. A.; Edge, A. S.; Liu, D. R. Nat. Commun., 2018 9, 2184.
6. Evolved Cas9 Variants with Broad PAM Compatibility and High DNA Specificity Hu, J. H.; Miller, S. M.; Geurts, M. H.; Tang, W.; Chen, L.; Sun, N.; Zeina, C.; Gao, X.; Rees. H. A.; Lin, Z.; Liu, D. R. Nature, 2018, 556, 57-63
7. Improving Cytidine and Adenine Base Editors by Expression Optimization and Ancestral Reconstruction Koblan, L. W.; Doman, J. L.; Wilson, C.; Levy, J. M.; Tay, T.; Newby, G. A.; Maianti, J. P.; Raguram, A.; Liu, D. R. Nat. Biotechnol., 2018, 36, 843-846
8. Base Editing: Precision Chemistry on the Genome and Transcriptome of Living Cells Rees, H. A. and Liu, D. R. Nat. Rev. Genet., 2018, 19, 770-788.

Lecture Images

David Liu presenting at APS2019 David Liu presenting at APS2019 David Liu presenting at APS2019