When people talk about the gene-editing technology CRISPR, it’s usually accompanied by adjectives like “revolutionary” or “world-changing.” For this reason, it’s no surprise that a study out last month questioning just how game-changing the technology really is caused quite a stir.
It’s well-known that using CRISPR can sometimes also result in some unintended genomic changes, and scientists have long been working on ways to fine-tune it. But the researchers found that when they had used CRISPR to cure blindness in mice, it had resulted in not just a few but more than a thousand, unintended off-target effects.
“This finding warns that CRISPR technology must be further tailored, particularly before it is used for human gene therapy,” the researchers wrote. The technique has already been used in two human trials in China, and next year one is slated to kick off in the US.
Their finding kicked off a battle for CRISPR’s honor, with some researchers speaking out to question the study’s methods while others piped up to agree that CRISPR is not yet ready for people.
The first criticism came the day after the study was published, via a comment from a researcher on PubMed who argued “careless mistakes” and flaws in the methodology cast “serious doubts about the results or interpretation,” concluding that it was “hard to imagine CRISPR-cas9 causes so many [unintended] homozygous deletions in two independent mice.”
On social media, scientists raised red flags about basic mistakes, such as misidentifying genes, mislabeling genetic defects, and the small number of animals the researchers had included in their research.
“I think the Nature Methods paper was a false alarm on CRISPR induced mutations,” the geneticist Eric Topol told Gizmodo. “Ironically, the methods used were flawed. While we remain aware of such concerns —unintended genomic effects that might occur with editing—that report was off-base.”
“Based on the information available on the mouse study, the more plausible conclusion is that the genetic differences reflect a normal level of variation between individuals in a colony.
“We believe that the conclusions drawn from this study are unsubstantiated by the disclosed experiments as they were designed and carried out,” the scientists from Editas wrote. “Further, it is impossible to ascribe the observed differences in the subject mice to the effects of CRISPR per se. The genetic differences seen in this comparative analysis were likely present prior to editing with CRISPR.”
The study sent the stocks of those two companies—and a third, CRISPR Therapeutics—tumbling. Nearly two weeks later, those market prices had still not fully recovered. Some went so far as to call for a retraction.
“All of our methods are described in our peer reviewed Correspondence and sopplemental materials in Nature Methods and the raw data have all been publicly deposited, so that others may further learn from our data,” one of the authors, Alexander Bassuk, told Gizmodo via email.
Springer Nature, which owns Nature Methods, said that they have received “ a number of communications” regarding the paper and said that it had undergone peer review as all papers in the journal do.
“We are carefully considering all concerns that have been raised with us and are discussing them with the authors,” a spokesperson said.
On his blog, UC Davis professor Paul Knoepfler asked several scientists about the study and got mixed results. One cited the same flaws in methodology others have brought us. Another posited that it was a good reminder to hunt thoroughly for off-target effects.
“Overall, this study adds a bit to the knowledge base, but it has been over-interpreted in the media,” Knoepfler concluded. It was unlikely, he wrote, that so many unintended edits were occurring in most research, but it still suggested more studies to investigate the problem are necessary.
This brings us to the one thing that is definitely true: Despite all our recent progress, there is still a lot we don’t know about CRISPR. It does indeed allow us to make precise gene edits more easily than ever before, but this ability has limitations that could wind up being disastrous if used in humans, and disappointing when genetically engineering everything else. CRISPR is still a nascent technology, and whether one day it might really be used to cure diseases or create a unicorn, there are still a whole lot of things that need to happen first.
Update: This story has been updated to include comments from one of the study authors, Nature Methods and Eric Topol.