Earlier this week, the world of science awoke to news that suddenly cast uncomfortable doubt on many of the past five years’ major breakthroughs: A new paper had identified a possible barrier to using the revolutionary gene-editing tool CRISPR-Cas9 in humans. The news incited a temporary hysteria that sent the stocks of all three major CRISPR biotech firms tumbling in premarket trading, declining by as much as 11.9 per cent.
In recent years, CRISPR has become a buzzword credited with the power to correct any number of devastating diseases. Researchers have used it to cure mice of deadly genetic conditions like hemophilia B, Lou Gehrig’s disease, and Huntington’s disease. In the U.S., the first human CRISPR trials are slated to begin this year.
But, in a new study, the presence of the Cas9 proteins responsible for slicing DNA in the CRISPR system triggered an immune response in samples of human blood. That suggested many people might be immune to CRISPR-based treatments for disease, or at risk of experiencing dangerous side effects because of them – an implication that spells bad news for hopes that CRISPR will be a 21st-century cure-all. The paper, released as a pre-print Friday just before one of the year’s biggest biotech conferences, caused CRISPR Therapeutics, Editas, and Intellia stocks to start the day at a low on Monday. One influential finance blog said that the stocks might now be “worthless.”
But there’s no need to panic. This isn’t a death knell for the CRISPR – at least not yet.
“This isn’t a roadblock. I think it’s a bump,” Stanford’s Matthew Porteus, a senior author of the paper, told Gizmodo. “As far as how big a bump? It’s too early to tell.”
In the preprint posted to the site bioRxiv on Friday, researchers tested for immune reaction against two of the most common Cas9 proteins used in the CRISPR system. CRISPR-Cas9 is the most common CRISPR system, and the Cas9 proteins come from bacteria. The most common Cas9 proteins come from two bacteria called S. aureus and S. pyogenes, which humans commonly encounter. They took blood samples from 22 newborns and 12 adults, finding that 79 per cent of donors had antibodies against the S. aureus Cas9 and 65 per cent had antibodies against the S. pyogenes Cas9. Those are pretty high percentages.
The then also looked for immune cells called T cells, and found about half of the donors had T cells that specifically targeted the S. aureus Cas9, meaning that if immune cells detected the presence of that CRISPR protein it would try to destroy it. They did not find T cells targeting the S. pyogenes Cas9.
“People kept saying, ‘are you worried there will be an immune response?’ And we thought, ok let’s do a quick look,” said Porteus. “It’s there. Now the question is what do we do about it?”
Scientists not involved with the study echoed Porteus’s comments, suggesting that the results were unlikely to hold back the fast-advancing field of gene editing.
“This was a fully expected observation, since we are all constantly exposed to many microbes,” said Harvard geneticist George Church.
“This was a fascinating article that I think was in some ways anticipated,” UC Berkeley scientist David Schaffer told Gizmodo.
“I am not losing any sleep over it,” said Daniel Anderson of MIT.
Cas9 proteins are derived from bacteria that people commonly encounter, and so, experts said, it was not exactly surprising that our bodies have developed immune responses to them.
Church said that there are plenty of potential workarounds to the problem, such as simply using other Cas9 proteins, perhaps those derived from bacteria less commonly encountered by humans.
The reaction might also be avoided by editing cells outside of the body, as is common for diseases that affect the blood. For editing inside the body, new delivery mechanisms could potentially be developed the protect the CRISPR-Cas9 system from immune response and detection.
Anderson pointed out that it’s also still unclear how severe the immune response would be. In the worst case scenario, it could trigger a dangerous inflammatory attack in a patient. It also could just not work altogether. Or, it could have little effect on the efficacy of a treatment at all.
The Scripps Research Institute geneticist Eric Topol was not alone in feeling that the paper was actually a good thing for the industry – it’s better to know about potential technological hurdles sooner than later.
“This emphasises the need for screening for an immune response, checking for antibodies and T cell response, in the clinical trials that are getting off the ground now,” he said.
Porteus said his team decided to publish the paper as a pre-print – before it has gone through the traditional rigour of peer review – for exactly that reason. His own work is focused on finding a CRISPR cure for sickle cell disease. They plan to file a clinical trial application with the FDA by the end of 2018 and begin trials in 2019
“We wanted to put this out there, not to say it isn’t possible to use CRISPR to treat disease in humans, but to say let’s think about this as a field before we get too far down the line,” he said. “It sounds bad, but I think it’s actually a good thing.”