This year’s Breakthrough Prize in Life Sciences has been awarded to David Liu, a biochemist at Harvard University, for the development of base editing and prime editing, two novel genome editing technologies. The Breakthrough Prize in Life Sciences honors researchers whose work has improved scientific understanding of living systems and contributed towards extending human life.
David Liu, the inventor of base editing and prime editing, has been awarded the 2025 Breakthrough Prize in Life Sciences.
Casey Atkins
While researchers have long appreciated the enormous potential of genome editing to treat disease, applications of these technologies in humans have historically been limited by safety concerns. Even the much-publicized CRISPR-Cas9 system has limitations: These molecular scissors create double-stranded DNA breaks, which the cell must stitch back together with error-prone repair processes, leading to unwanted deletions and genomic rearrangements.1 Base editing and prime editing are transformative genomic technologies because they enable scientists to alter the genome without creating double-stranded DNA breaks, improving precision and safety.
Base editors allow researchers to change a single base at a precise location in the genome, for example, converting a cytosine to a thymine or vice versa.2,3 While this may sound like a small change, it has enormous potential for treating genetic diseases: Researchers have so far identified approximately 30,000 single-nucleotide polymorphisms that are associated with disease in humans.4 Prime editing, developed in 2019, enables researchers to change somewhat longer stretches of DNA.5 Prime editors contain RNA that directs them to a certain location in the genome, plus an RNA template of the desired genetic sequence, and a reverse transcriptase enzyme, which can “write” the new DNA sequence into the genome according to the RNA instructions.
The technologies developed by Liu’s research team have progressed from human cells to human patients in a remarkably short period of time. The group first published their work on base editing in Nature in April 2016, and by May 2022, the first clinical trial was underway.2 “It's been amazing,” said Liu. “The rule of thumb that I was taught is that if you come up with a new piece of science that could lead to a new therapeutic, it will probably take 15 or maybe even 20 years from the time you publish the first paper to the time it actually ends up benefiting a patient…So, it's been incredible that, in some cases, the students working on the original technology were still in the lab when the technology was first given to a patient.”
The first patient to be treated with base-edited cell therapy was a 13-year-old girl with relapsed T cell leukemia; within one month of treatment, she had achieved remission and remains healthy to this day.6 “It’s an amazing experience, an amazing opportunity, something I'm really grateful for—that patients and doctors are willing to try these new technologies,” Liu said.
These technologies could revolutionize the way that rare genetic diseases, which are often overlooked, are treated. Globally, said Liu, hundreds of millions of people are living with some type of genetic disease. If these disorders were grouped as a single disease, he said, “People would say that this is a global health crisis, something we all have to prioritize. But because they are subdivided into 10,000 different rare disease communities, I think it flies under the radar.”
Back to the Future: The Early Days of Targeted DNA Manipulation
Liu’s interest in combining chemistry and DNA in novel ways stretches back to his early days as a graduate student, when he experimented with using base pairing to coordinate chemical reactions between small molecules tethered to DNA. When he became an assistant professor at Harvard University in 1999, one of his team’s first projects was, he recalled, “the futuristically-nicknamed Unifactor 2000.” The goal was to develop a universal transcription factor by fusing a transcription activator to a strand of RNA; the RNA sequence could then be “programmed” to target specific regions of the genome. There, it would form a triplex with the two strands of DNA and turn on the desired gene.
“It turned out to work okay in a test tube, but not in cells,” Liu said. “Because the triplex formation itself doesn't really work under cellular conditions. It was a somewhat painful lesson.”
Undaunted, he continued on in other directions, making several notable advancements in the directed evolution of proteins, using principles of variation and selection to produce biomolecules with particular functions.7,8 Then in 2012, the CRISPR bombshell dropped and Liu began to consider how he might incorporate this new technique into his laboratory’s ecosystem of biochemical experiments.9
“Intellectually, the stage was set for the idea of programmably addressing DNA, but now revisiting it with new tools, new chemistries, and ideally with [laboratory] evolved proteins to do things that nature never evolved,” said Liu.
A New Wave of Genome Editing
In 2013, Alexis Komor was nearing completion of her PhD in chemistry at the California Institute of Technology and planning out her postdoctoral research. During graduate school, she had focused on nucleic acid chemistry and DNA repair. “But I knew I wanted to get some new training for my postdoc work,” said Komor, who currently studies precision genome editing and single nucleotide variants in the human genome at the University of California, San Diego. “I wanted to get training in molecular biology and protein engineering and directed evolution.” Liu was well-known for his directed evolution work, so she applied to join the lab.
They began brainstorming projects even before she had physically arrived in Cambridge, discussing how she might combine her nucleic acid expertise with the powerful new CRISPR-Cas9 tools. “David was very hands-on,” said Komor. “He was like, ‘Send me your ideas!’ And then we would email back and forth…He made sure that I didn't show up with some terrible, half-baked idea that hadn't been thoroughly vetted before.”
Komor said that her chemistry background helped her think about these tools from a different perspective than others in the field. “Biologists had been doing genome editing for so long using double stranded breaks, and I was just very naïve. I [wondered], ‘What if we just try something completely different and basically combine two different nucleic acid interacting proteins together?’”
Liu’s interactive mentoring style helped her work through problems and consider things in new ways. During their regularly scheduled one-on-one meetings, Komor said, “He would ask really probing questions, and it would just get you thinking really deeply about your project. And that helped a lot with building ownership of the project, too…It made me work harder, being so attached to this project and really wanting to see it succeed.”
To create the first base editors, Komor, Liu and the rest of the team fused a CRISPR-Cas9 system with an enzyme called cytidine deaminase. They used a guide RNA to direct the editing machinery to the appropriate region of the genome, where the Cas9 unwound the DNA so that the deaminase could convert a cytosine to a uridine. Since uridine is generally only found in RNA, the cell then naturally converted the uridine to a thymine.
“For the first time, we could make C to T changes in DNA sequences of our choosing,” said Liu.
“Every day there were little bits happening, and then there was one point where we had gotten it to work in human cells and I thought, ‘Oh, wow, this actually has a chance of being a really important story,’” said Komor. “I was just excited to be a part of it. And I was excited that this crazy idea had actually worked!”
Of course, not all point mutations involve a C where there should be a T. “And so, we developed this second base editor, the adenine base editor,” said Liu. “Statistically, this is the most important base editor, because it corrects the most common kind of single base mutation in humans, which is to convert a C to a T. [This base editor] reverses that change.”
This project, tackled by postdoctoral researcher Nicole Gaudelli, now a life sciences entrepreneur-in-residence at Google Ventures, came with its own set of challenges. For the original base editor, researchers had been able to borrow molecular tools, like cytidine deaminase, from nature. “In this case,” said Liu, “The main limitation was that there is no enzyme that performs the needed chemistry…So we had to evolve our own enzyme.”
By November 2017, they had a base editor that could convert a T to a C with about 50 percent efficiency in human cells with very low rates of unwanted genetic insertions or deletions at the editing site.3
Base editing was quickly put to use by Liu’s team as well as other researchers around the world. Liu co-founded Pairwise Plants, which applies base editing to agricultural crop improvements, and Beam Therapeutics, which is developing treatments for genetic diseases including sickle cell disease, beta thalassemia, and glycogen storage disease.
Other companies and research groups are also using base editing technologies in clinical trials. In addition to the girl treated with base-edited T cells for leukemia, preliminary results from Phase 1 trials have shown promise in base editing therapies for familial hypercholesterolemia and alpha-1 antitrypsin deficiency.10
Prime Time: Going Beyond Point Mutations
While base editing made its way into plants and humans, Liu and another postdoctoral researcher, Andrew Anzalone, tackled a new challenge: editing multiple bases at once. While many genetic diseases are associated point mutations, others, like Tay-Sachs disease, are caused by insertions or deletions of multiple base pairs. To address these kinds of mutations, Anzalone and Liu developed a technique that they named prime editing.
“Instead of performing chemistry on the individual DNA base, [prime editing] does a search and replace of the whole segment of DNA,” said Liu. “And that gives it enormous flexibility. You can correct insertions, deletions, or any kind of base-to-base substitution.”
Prime editors target a specific region of the genome and use a reverse transcriptase enzyme to rewrite a section of DNA according to a set of RNA instructions that they carry with them. The original version was capable of rewriting DNA sequences that were dozens of base pairs long. In 2019, the same year that the prime editing technique was first published in Nature, Anzalone and Liu co-founded Prime Medicine, a biotechnology company developing therapies to treat various genetic diseases, including those that affect the immune system, liver, and lungs.5
In April 2024, the FDA approved the first clinical trial of a prime editing therapy, which was designed to treat chronic granulomatous disease, a genetic immune deficiency that leads to recurrent life-threatening infections.11
Liu, however, is not content to rest on his laurels. “Now that we have these man-made, engineered molecular machines that literally rearrange the atoms in DNA to change one sequence to another sequence at a site of your choosing…we would like to develop ways to deliver those machines into as many different tissue types [as possible] in a clinically relevant way.”
Liu’s team is exploring different ways to deliver base editors and prime editors to tissues such as the heart, liver, and brain using a variety of strategies, including viral vectors and engineered virus-like particles.12,13 In mouse models, they have successfully treated devastating central nervous system disorders such as prion disease and spinal muscular atrophy.14,15
Since the initial publication of prime editing, Liu has also been working on ways to improve and expand the applications of this technique. While some diseases are caused by the same mutation in the same location in every individual, Liu said that most genetic diseases are not so consistent—Stargardt disease and cystic fibrosis, for example, can be caused by hundreds or even thousands of different mutations within a particular gene. “There's lots of ways you can break a gene or a protein,” Liu noted.
To address this problem, Liu wanted to develop mutation-agnostic therapies: Instead of creating a separate editor for each individual mutation, he wanted to replace the entire broken gene. This would mean that patients with any one of hundreds of mutations could all be treated to a single therapy.
This required replacing longer stretches of DNA than the original prime editors could handle, so Liu’s team developed an upgraded version called prime-editing-assisted site-specific integrase gene editing (PASSIGE).16 Using this strategy, prime editors insert a “landing site” for a laboratory-evolved recombinase, which can carry (and insert) DNA sequences longer than 10 kilobases, enabling total replacement of the faulty gene during in vitro experiments.
“There are increasingly broad ways of treating genetic disease that don't necessarily rely on just fixing one mutation at a time,” said Liu.
Even as Liu is being honored for his transformative contributions to the field, he emphasized that he has not made these discoveries alone. “I think it's really important to recognize the students who led all this work,” he said. “I value my students so highly because I'm just in awe of how hard they work and how talented they are and how much they teach me every day.”
- Kosicki M, et al. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol. 2018;36(8):765-771.
- Komor AC, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420-424.
- Gaudelli NM, et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464-471.
- Turcotte MA, Perreault JP. Pathogenic SNPs affect both RNA and DNA G-quadruplexes’ responses to ligands. ACS Chem Biol. 2024;19(5):1045-1050.
- Anzalone AV, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019;576(7785):149-157.
- Chiesa R, et al. Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia. N Engl J Med. 2023;389(10):899-910.
- Buskirk AR, et al. Directed evolution of ligand dependence: Small-molecule-activated protein splicing. Proc Natl Acad Sci U S A. 2004;101(29):10505-10510.
- Esvelt KM, et al. A system for the continuous directed evolution of biomolecules. Nature. 2011;472(7344):499-503.
- Jinek M, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816-821.
- Hooper AJ, et al. VERVE-101, a CRISPR base-editing therapy designed to permanently inactivate hepatic PCSK9 and reduce LDL-cholesterol. Expert Opin Investig Drugs. 2024;33(8):753-756.
- FDA clears prime editors for testing in humans. Nat Biotechnol. 2024;42(5):691.
- Davis JR, et al. Efficient prime editing in mouse brain, liver and heart with dual AAVs. Nat Biotechnol. 2024;42(2):253-264.
- Banskota S, et al. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell. 2022;185(2):250-265.e16.
- An M, et al. In vivo base editing extends lifespan of a humanized mouse model of prion disease. Nat Med. 2025.
- Arbab M, et al. Base editing rescue of spinal muscular atrophy in cells and in mice. Science. 2023;380(6642):eadg6518.
- Pandey S, et al. Efficient site-specific integration of large genes in mammalian cells via continuously evolved recombinases and prime editing. Nat Biomed Eng. 2025;9(1):22-39.
