BOSTON — In science journalism, there’s a well-worn technique reporters reach for when they’re interviewing a researcher and the technical material starts whizzing over their heads. “OK, explain it again, and this time, as if you were talking to your mother.” The conjured image of a parent tends to do just the trick; prompting an illuminating alchemy of clarity infused with excitement. “Look, ma, how cool is this?!”
That’s essentially what biochemist David Liu did when first describing CRISPR to his own mother, now nearly a decade ago. But he didn’t expect her response would be both profound and incisive: “I explained to her it’s like a pair of scissors that cuts DNA, except, crucially it can be programmed,” he said Tuesday during the 2022 STAT Summit in Boston. “And she said, ‘Well, how do you fix DNA by cutting it?’”
In fact, most of the time, you can’t. There are only a few kinds of diseases where breaking a glitchy gene, by cutting it in two, improves or eliminates the problem. For gene editing to realize its therapeutic potential, scientists would need methods for precisely correcting a mutated DNA sequence to a healthy one. From his lab at the Broad Institute of MIT and Harvard, Liu has spent the last 10 years arguably doing more than anyone else to advance tools to make this a reality.
In 2016, Liu and his junior colleagues invented CRISPR “base editing,” which seamlessly transforms a single DNA letter. That one-to-one base pair swap, the simplest of all edits, may be all that’s required to repair mutations that cause thousands of inherited diseases. Three years later, his team gave the world “prime editing,” which can delete long lengths of disease-causing DNA or insert DNA to repair dangerous mutations, all without triggering the chaotic (and possibly harmful) genome responses introduced by other forms of CRISPR.
It was for these accomplishments, as well as other crucial contributions to expanding the genome editing toolkit that Liu was named the recipient of STAT’s 2022 Biomedical Innovation Award on Tuesday.
“We anticipate that in most cells when you make a gene edit, you are making a permanent change to that cell, so we have to take seriously the responsibility to minimize the amount of unwanted changes that we introduce into the genome as a result of treating patients with gene editing therapies,” said Liu. But he’s also a realist when it comes to balancing the risks of off-target effects with the benefits of gene correction.
“It’s important to realize that there will probably never be a perfectly specific gene-editing agent, just as there has never been a perfectly specific drug that we’ve ever put into a human that only does exactly what we want and engages no other molecules, no other sites in the genome in this case,” he said. “That’s more a function of physics, ultimately.”
To push these various technologies toward treating inherited human diseases, Liu has co-founded multiple companies, including Editas Medicine, Beam Therapeutics, and Prime Medicine. Earlier this week, Beam announced that it had enrolled its first patient in a trial for its leading sickle cell treatment, which works by activating a dormant fetal hemoglobin gene.
This workaround is also being tested by other CRISPR 1.0 companies like Intellia Therapeutics, CRISPR Therapeutics, and Graphite Bio. In June, CRISPR Therapeutics reported that its version of the therapy, developed jointly by Vertex Pharmaceuticals, has eliminated symptoms for all 31 of the sickle cell patients participating in an early-stage trial.
Beam is also developing a more direct approach for treating sickle cell, which involves directly correcting the adult hemoglobin gene, as well as therapies for other genetic disorders including alpha-1 antitrypsin deficiency and glycogen storage disease.
When asked at the Summit about how different patient communities might advocate for access and equity as CRISPR moves from basic research into clinical trials, Liu said that it’s the responsibility of everyone involved in the enterprise — scientists, doctors, regulators, companies — to engage with the question of how to ensure these game-changing medicines can reach the broadest possible range of patients.
“There’s no simple answer for how to do that,” he said. But he urged streamlining the regulatory process so that companies developing gene-editing drugs for a specific indication don’t have to start over at step one, if all they’ve done is change the guide RNA of an FDA-approved drug so that it sends the DNA-altering machinery to a different site in the disease-causing gene. “That will go a long way toward maximizing access because it will maximize the number of different patient cohorts with different mutations that can benefit from gene editing therapeutics,” he said.
Those days are still off in the future. There are currently no FDA-approved gene-editing medicines. But with 54 trials now underway, Liu argued that CRISPR and its newer cousins have already done a lot to democratize gene editing.
“CRISPR has and gene editing in general has really revolutionized the life sciences,” Liu said. “I realize it’s an overused phrase, but virtually every lab who works in the molecular life sciences with genetics uses CRISPR as a tool.”