DAVID LIU: Gene corrector
A biologist developed gene-editing tools that are new to nature, and that could one day save lives.
When David Liu was an undergraduate student 25 years ago, he wrote a dissertation that his adviser remembers to this day. “It was absolutely word perfect,” says Nobel-prizewinning chemist E. J. Corey, now an emeritus professor at Harvard University in Cambridge, Massachusetts. It needed no editing.
Liu is nevertheless obsessed with editing. For more than a decade, he has been in the vanguard of researchers tinkering with powerful gene-editing technologies, most recently with the much-hailed method known as CRISPR. For all the excitement about the ability to edit the genome deftly, however, the technique is not yet perfect. CRISPR won’t reliably rewrite snippets of DNA in some cells, for example, and certain changes that scientists want to create in the genome pose problems.
In October, Liu’s team at the Broad Institute in Cambridge, Massachusetts, published the results of a daring attempt to tweak the CRISPR system. They used an enzyme created in the laboratory to chemically convert pairings of the DNA bases adenine (A) and thymine (T) into guanine (G) and cytosine (C). No such enzyme exists in nature — and there was no guarantee that Liu and his team could make it.
But Liu’s career has revolved around risk-taking. As a PhD student at the University of California, Berkeley, he developed a way to incorporate non-natural amino acids into proteins in living cells. “I remember well some respected senior graduate students advising me that it would be pretty crazy to take on that project,” Liu says.
While Liu was in his fourth year of graduate studies, Corey invited him back to Harvard to give a seminar. Members of the chemistry faculty there were so impressed that they offered him a job as soon as he got his PhD. His group moved to the Broad in February 2017.
Liu’s lab pioneered methods for developing new enzymes in the laboratory, and then added gene editing to its repertoire. In 2013, Liu joined a host of other luminaries in founding a company now called Editas Medicine, also in Cambridge, to develop treatments based on CRISPR technology.
Such clinical applications could be limited by the unpredictability of CRISPR–Cas9 gene editing, the most commonly used version of the tool. Although the Cas9 enzyme cuts DNA where directed, researchers must rely on the cells’ own DNA-repair systems to fix the break. This can create a variety of different edits to the genome.
Liu’s lab looked for ways to improve on that. In 2016, postdoc Alexis Komor and others on Liu’s team reported its first base editor, which relied on naturally occurring enzymes and could convert a C to a T or a G to an A. For the first time, researchers had a reliable, predictable way to make a single-letter change in the genome of a living cell.
The approach has since been deployed in a range of organisms, from wheat to zebrafish and mice. And in September, researchers in China reported that they had used Liu’s base editor to correct a single-letter mutation, or point mutation, for a blood disorder in human embryos. (The embryos were not allowed to develop further.)
Another postdoc in Liu’s lab, Nicole Gaudelli, was eager to build on that work and create an enzyme that could convert As and Ts into Gs and Cs. Gaudelli was proposing to break a cardinal rule in the Liu lab: no one takes on a project if the first step is to create a new enzyme. The risk of lost time and failure is too high. Liu nevertheless encouraged her, and months of work yielded a protein that could, in theory, reverse about 48% of known disease-causing point mutations in humans. In October, the team reported that the new protein does so more reliably than the classical CRISPR–Cas9 system. Such tools could help in the future development of gene-therapy approaches.
“This will cover a good number of disease mutations,” says Dana Carroll, a genome engineer at the University of Utah in Salt Lake City. “There will be significant impact.”
Posted in 12/2017