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How anti-CRISPR proteins and other molecules could bolster biosecurity and improve medical treatments. It started out as “sort of a stupid thing to do”, recalls Joe Bondy-Denomy, a microbiologist at the University of California, San Francisco. As a graduate student in the early 2010s, he tried to infect bacteria with viruses that, on paper, shouldn’t have stood a chance. He knew that these viruses, or phages, were susceptible to CRISPR–Cas, the bacterial defence system that scientists have harnessed as a powerful tool for gene editing. And in most cases, he was right: the CRISPR machinery chopped the incoming phages into bits. But in a few instances, against the odds, the intruders survived. Bondy-Denomy thought he had messed up. “Then a light bulb went off,” he says. Maybe something inside the bacterial genome was disarming its defences. And maybe that self-sabotaging bit of DNA was coming from previous viral invaders.
A quick comparison of DNA sequences proved Bondy-Denomy’s intuition correct. Phage genes nestled inside the bacterial genome were completely shutting down the CRISPR–Cas system, making the bacteria vulnerable1. “Joe got the result that changed everything,” says Alan Davidson, a phage biologist at the University of Toronto in Canada, who was Bondy-Denomy’s PhD adviser at the time. “He found something amazing that we never expected.” Bondy-Denomy — together with Davidson, microbiologist Karen Maxwell and fellow graduate student April Pawluk — had stumbled onto tools now known as anti-CRISPRs. These proteins serve as the rocks to CRISPR’s molecular scissors. And soon, they were popping up everywhere: more than 50 anti-CRISPR proteins have now been characterized, each with its own means of blocking the cut-and-paste action of CRISPR systems.
The expansive roster opens up many questions about the archaic arms race between bacteria and the phages that prey on them. But it also provides scientists with a toolkit for keeping gene editing in check. Some are using these proteins as switches to more finely control the activity of CRISPR systems in gene-editing applications for biotechnology or medicine. Others are testing whether they, or other CRISPR-stopping molecules, could serve as biosecurity counter-measures of last resort, capable of reining in some genome-edited bioweapon or out-of-control gene drive. “For any reason you can think of to turn off CRISPR systems, anti-CRISPRs come into play,” says Kevin Forsberg, a microbial genomicist at the Fred Hutchinson Cancer Research Center in Seattle, Washington....
Published January 15, 2020 in Nature:
