SimpleBio 4

From the earliest days of the CRISPR-Cas9 era, scientists have known that the first step in how it edits genomes—snipping DNA—creates an unholy mess: Cellular repairmen frantically try to fix the cuts by throwing random chunks of DNA into the breach and deleting other random bits. Research published on Monday suggests that’s only the tip of a Titanic-sized iceberg: CRISPR-Cas9 can cause significantly greater genetic havoc than experts thought, the study concludes, perhaps enough to threaten the health of patients who would one day receive CRISPR-based therapy.

The results come hard on the heels of two studies that identified a related issue: Some CRISPR’d cells might be missing a key anti-cancer mechanism and therefore be able to initiate tumors.

The DNA damage found in the new study included deletions of thousands of DNA bases, including at spots far from the edit. Some of the deletions can silence genes that should be active and activate genes that should be silent, including cancer-causing genes.

Leading CRISPR companies scrambled to play down the latest threat to what they hope will be a multibillion-dollar business—and to their stock prices, but investors reacted with alarm. Within the first 20 minutes of when the study was released, the three publicly traded CRISPR companies lost more than $300 million in value.

The companies questioned whether the CRISPR-caused DNA damage reported in the new study applied to the kind of cells they’re planning to CRISPR. They emphasized that if genomic scrambling is at all common then it should also be seen in earlier forms of genome-editing such as zinc fingers and TALENs (but apparently isn’t). And they insisted they’re on the case.

“We’re not Pollyannaish about this,” said geneticist Tom Barnes, chief innovation officer at Intellia Therapeutics. For its mouse experiments, Intellia analyzes edited genomes for collateral damage both near the editing target and tens of thousands of DNA letters away, he said, but “we have not seen any [cancer-causing] transformation of these cells, even with all the edits we’ve introduced.”

In a statement, Editas Medicine spokeswoman Cristi Barnett said the possibility of genetic chaos from CRISPR is “an interesting topic” that the company “actively examine[s].” The reported DNA havoc, she said, is not “specifically problematic in our work to make CRISPR-based medicines.” CRISPR Therapeutics did not respond to requests for comment.

Academic scientists were less dismissive of the new study, in Nature Biotechnology. One leading CRISPR developer called it “well-done and credible,” “a cautionary note to the [genome-editing] community,” and consistent with other research showing that the DNA cuts that CRISPR makes, called double-stranded breaks, “can induce the types of genomic DNA rearrangements and deletions they report.” He asked not to be identified so as not to jeopardize business relationships with genome-editing companies.