David R. Liu
· Thomas Dudley Cabot Professor of the Natural Sciences Howard Hughes Medical Institute InvestigatorHarvard University · Chemistry
Active 1992–2024
About
David R. Liu is the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, 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, and a Howard Hughes Medical Institute investigator. His 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 and prime 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. Liu's laboratory pioneered technologies such as base editing, prime editing, PACE, and DNA-templated synthesis, which are used worldwide and have facilitated the study and treatment of genetic diseases. His work has led to at least 15 clinical trials targeting diseases including leukemias, hypercholesterolemia, alpha-1 antitrypsin deficiency, sickle-cell disease, beta-thalassemia, and chronic granulomatous disease, with reported first clinical benefits such as life-saving treatments and symptom-free patients. Liu graduated first in his class at Harvard College in 1994, earned his Ph.D. from U.C. Berkeley in 1999 where he initiated efforts to expand the genetic code in living cells, and has held faculty positions at Harvard since 1999. He has published over 275 papers, holds more than 110 U.S. patents, and has received numerous awards and honors, including election to the US National Academy of Sciences, the US National Academy of Medicine, and the American Association for the Advancement of Science. He is also recognized as a leading global thinker and influential figure in biopharma, founding several biotechnology companies.
Research topics
- Biology
- Genetics
- Computational biology
- Computer Science
- Biochemistry
- Artificial Intelligence
- Political Science
- Cell biology
- Mathematics
- Agronomy
- Engineering ethics
- Microbiology
- Biotechnology
- Chemistry
- Molecular biology
- Data science
- Medicine
- Neuroscience
- Engineering
- Combinatorics
- Law
Selected publications
Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins
Cell · 2022 · 615 citations
Senior authorCorresponding- Biology
- Computational biology
- Cell biology
Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.
The NIH Somatic Cell Genome Editing program
Nature · 2021 · 130 citations
- Computer Science
- Computer Science
- Computational biology
The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.
Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity
Science · 2021 · 75 citations
Senior authorCorresponding- Chemistry
- Biology
- Microbiology
Although bespoke, sequence-specific proteases have the potential to advance biotechnology and medicine, generation of proteases with tailor-made cleavage specificities remains a major challenge. We developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light-chain proteases. We evolved BoNT/X protease into separate variants that preferentially cleave vesicle-associated membrane protein 4 (VAMP4) and Ykt6, evolved BoNT/F protease to selectively cleave the non-native substrate VAMP7, and evolved BoNT/E protease to cleave phosphatase and tensin homolog (PTEN) but not any natural BoNT protease substrate in neurons. The evolved proteases display large changes in specificity (218- to >11,000,000-fold) and can retain their ability to form holotoxins that self-deliver into primary neurons. These findings establish a versatile platform for reprogramming proteases to selectively cleave new targets of therapeutic interest.
Enhanced prime editing systems by manipulating cellular determinants of editing outcomes
Cell · 2021 · 784 citations
Senior authorCorresponding- Computer Science
- Biology
- Computational biology
While prime editing enables precise sequence changes in DNA, cellular determinants of prime editing remain poorly understood. Using pooled CRISPRi screens, we discovered that DNA mismatch repair (MMR) impedes prime editing and promotes undesired indel byproducts. We developed PE4 and PE5 prime editing systems in which transient expression of an engineered MMR-inhibiting protein enhances the efficiency of substitution, small insertion, and small deletion prime edits by an average 7.7-fold and 2.0-fold compared to PE2 and PE3 systems, respectively, while improving edit/indel ratios by 3.4-fold in MMR-proficient cell types. Strategic installation of silent mutations near the intended edit can enhance prime editing outcomes by evading MMR. Prime editor protein optimization resulted in a PEmax architecture that enhances editing efficacy by 2.8-fold on average in HeLa cells. These findings enrich our understanding of prime editing and establish prime editing systems that show substantial improvement across 191 edits in seven mammalian cell types.
Determinants of Base Editing Outcomes from Target Library Analysis and Machine Learning
Cell · 2020 · 291 citations
Senior authorCorresponding- Computer Science
- Biology
- Computational biology
Prime genome editing in rice and wheat
Nature Biotechnology · 2020 · 852 citations
- Biology
- Biotechnology
- Computational biology
Nature Biotechnology · 2020 · 1013 citations
Senior authorCorresponding- Computational biology
- Biology
- Genetics
Continuous evolution of SpCas9 variants compatible with non-G PAMs
Nature Biotechnology · 2020 · 355 citations
Senior authorCorresponding- Biology
- Computational biology
- Genetics
Nature Biomedical Engineering · 2020 · 164 citations
- Biology
- Genetics
- Molecular biology
Reactions to the National Academies/Royal Society Report on <i>Heritable Human Genome Editing</i>
The CRISPR Journal · 2020 · 26 citations
- Political Science
- Computer Science
- Political Science
was published. The report offers a translational pathway for the limited approval of germline editing under limited circumstances and assuming various criteria have been met. In this perspective, some three dozen experts from the fields of genome editing, medicine, bioethics, law, and related fields offer their candid reactions to the National Academies/Royal Society report, highlighting areas of support, omissions, disagreements, and priorities moving forward.
Recent grants
NIH · $1.3M · 2015
NIH · $5.0M · 2019–2027
NIH · $1.8M · 2020
NIH · $1.6M · 2018–2023
NIH · $2.5M · 2012
Frequent coauthors
- 366 shared
Gregory A. Newby
Howard Hughes Medical Institute
- 66 shared
Aditya Raguram
Whitehead Institute for Biomedical Research
- 58 shared
Jonathan M. Levy
- 58 shared
Holly A. Rees
Beam Therapeutics (United States)
- 57 shared
Kevin T. Zhao
- 54 shared
Jessie R. Davis
University College Dublin
- 53 shared
Luke W. Koblan
Whitehead Institute for Biomedical Research
- 49 shared
J. Keith Joung
Center for Cancer Research
Labs
Education
- 1990
B.S., Chemistry
Harvard University
- 1995
Ph.D., Chemistry
Harvard University
Awards & honors
- 2025 Breakthrough Prize Laureate in the Life Sciences
- 2022 King Faisal Prize Laureate in Medicine
- 2024 Jacob and Louise Gabbay Award
- Joseph R. Levenson Memorial Teaching Prize
- Roslyn Abramson Award
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