Virus World

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:

 https://doi.org/10.1038/d41586-020-00053-0

A new genetic engineering technology could help eliminate malaria and stave off extinctions — if humanity decides to unleash it. One early summer evening in 2018, the biologist Anthony James drove from his office at the University of California, Irvine, to the headquarters of the Creative Artists Agency, a sleek glass-and-steel high-rise in Los Angeles. There, roughly 200 writers, directors and producers — many of them involved in the making of science-and-technology thrillers — were gathered for an event called Science Speed Dating, where James and other scientists would explain their work. The sessions were organized, James told me, “in hopes of getting the facts at least somewhat straight.” Attendees were assigned to different groups, so each scientist had just seven minutes to describe his or her work to one group before running to the next room and starting over. “There were a lot of stairs, so I would get really out of breath,” James recalled. “I would arrive panting.” He also felt a bit overwhelmed. There were executives in expensive suits, young men and women looking unaccountably dressy in ripped jeans and, according to James, a disconcerting number of people wearing hats. Few, if any, had a deep knowledge of genetics; one participant in particular kept referring to “the dark genome,” as though that were a thing. “I had to tell him, ‘Real geneticists don’t usually talk that way,’ ” James said.

James began his presentation with a brief overview of mosquito-borne diseases like malaria and Zika. Then he turned cautiously to talking about his own area of scientific expertise: an obscure but powerful invention known as a gene drive. James began by noting that two brown-eyed human parents can sometimes produce a blue-eyed child, though only if both parents carry a copy of the recessive gene. A gene drive, he explained, was a tool that in some species could turn such events into a near certainty. For one thing, it guaranteed that a particular gene would be inherited, even if only one parent had it. And it would automatically insert the chosen gene into both copies of the offspring’s DNA, effectively turning a recessive trait into a dominant one. That alone, James explained, “lets you change the odds, so you get blue eyes 99 percent of the time.”

What made the gene drive truly strange and remarkable, though, was that it didn’t stop with one set of offspring. Generation after generation, it would relentlessly copy and paste the gene it carried, until it was present in every descendant. “For most of the people in the room, you could tell it was the first they’d heard of this,” James recalled. “You could see their eyes getting big.” This mattered, James explained, because it allowed you to change not just a single creature but — potentially — an entire population, and quickly. A few months after the technique was discovered in 2014, James engineered two mosquitoes to carry a gene drive that was tied to a gene for red fluorescent color that would target the mosquitoes’ eyes. He then put each into a box with 30 ordinary purple-eyed mosquitoes. As the mosquitoes bred, they produced offspring: roughly 3,900 after two generations. (Mosquitoes lay a lot of eggs.) Under the normal rules of inheritance, there should have been an equal number of red-eyed and purple-eyed mosquitoes. Instead, when James opened the boxes to check on the offspring, all but 25 of the 3,900 mosquitoes had red eyes....