A leading genome-editing researcher is urging extra caution as drug companies race to turn the landmark technology he helped create into human medicine.
In a paper published today in Nature Medicine, Feng Zhang of the Broad Institute of MIT and Harvard and colleague David Scott argue that researchers should analyze the DNA of patients before giving them experimental medicines that alter their genes with the breakthrough technology CRISPR. The suggestion, among others in the paper, stems from a deeper look at the wide array of subtle differences in human DNA.
Zhang is a key inventor of CRISPR-Cas9, which describes a two-part biological system that slips into the nucleus of cells and irreversibly alters DNA. One part is an enzyme, nature’s molecular scissors, which cuts DNA. The second part is a string of ribonucleic acid (RNA) that guides the enzyme to the proper spot. In five years since its invention, CRISPR-Cas9 has become a mainstay of biological research, and researchers including Zhang (pictured above) have moved quickly to improve upon its components. His work is at the center of a long-running patent battle to determine ownership of the technology.
Zhang and Scott’s recommendation taps into a long-running debate in the gene-editing field about off-target effects—the fear of misplaced cuts causing unintended harm. Most recently, the FDA took up a similar issue at a meeting to assess a type of cell therapy, known as CAR-T, for kids with leukemia. The FDA highlighted the risk that the cells, which have certain genes edited to make them better cancer fighters, may cause secondary cancers long after a patient’s leukemia has been cured. (FDA advisors unanimously endorsed the therapy’s approval nonetheless.)
Some researchers say there should be near certainty that gene altering techniques won’t go awry before testing in humans, caution that stems in part from gene therapy experiments in the U.S. and Europe nearly 20 years ago that killed an American teenager and triggered leukemia in several European boys.
While no medicine is risk-free, other researchers say the tools to gauge risk have improved.
Andy May, senior director of genome engineering at the Chan Zuckerberg Biohub in San Francisco, calls Zhang and Scott’s recommendation for patient prescreening “a good discussion point,” but “the danger is someone will pick up on this and say you can’t push forward [with a CRISPR drug] until everyone is sequenced.”
“It’s an extremely conservative path to take,” says May, who until recently was the chief scientific officer at Caribou Biosciences, a Berkeley, CA-based firm in charge of turning the discoveries of UC Berkeley’s Jennifer Doudna and her colleagues into commercial technology. (May was also a board member of Cambridge, MA-based Intellia Therapeutics (NASDAQ: [[ticker:NTLA]]), which has exclusive license to use Caribou’s technology in human therapeutics.)
Berkeley is leading the challenge to Zhang’s CRISPR patents and last week filed the first details in its appeal of a recent court decision in favor of Zhang and the Broad Institute.
Zhang sees prescreening as a form of companion diagnostic, which drug companies frequently use to identify the right patients for a study. A whole genome sequence—which costs about $1,000—could filter out patients unlikely to benefit from a treatment or at higher risk of unintended consequences, such as cancer. In the long run, it could also encourage developers to create more variations of a treatment “to make genome-editing based therapeutics as broadly available as possible,” said Zhang.
It’s well known that human genetic variation is a hurdle in the quest to treat genetic diseases either by knocking out disease-causing genes or replacing them with healthy versions. But Zhang and Scott use newly available genetic information to deepen that understanding. In one Broad Institute database with genetic information from more than 60,000 people, they find one genetic variation for every eight letters, or nucleotides, in the exome—that is, the sections of DNA that contain instructions to make proteins. (There are 6 billion nucleotides in each of our cells.) The wide menu of differences is, in effect, an open door to misplaced cuts that CRISPR’s enzymes might be prone to.
Zhang and others are working on many kinds of enzymes, from variations on the workhorse Cas9, to new ones entirely. He and Scott found that the deep pool of genetic variation makes some forms of the Cas enzyme more likely than others to go awry, depending on the three-nucleotide sequence they lock onto in the targeted DNA.
Zhang and Scott write that CRISPR drug developers should avoid trying to edit DNA strings that are likely to have “high variation.” In their paper, they examine 12 disease-causing genes. While more common diseases, such as those related to high cholesterol, will contain higher genetic variation because of the broader affected population, every gene, common or not, contains regions of high and low variation. Zhang and Scott say developers can build strategies around the gene regions they are targeting.
For example, going after a more common disease might require a wider variety of product candidates, akin to a plumber bringing an extra-large set of wrenches, with finer gradations between each wrench, to a job site with an unpredictable range of pipe sizes.
CRISPR companies say they are doing just that. “We have always made specificity a fundamental part of our program,” says Editas Medicine CEO Katrine Bosley. Zhang is a founder of Editas (NASDAQ: [[ticker:EDIT]]), which has exclusive license to the Broad’s
