CRISPR doesn’t always work. In 2012, the microbiologist Joseph Bondy-Denomy pitted phages against CRISPR-wielding bacteria. Some of the viruses were destroyed, but others unexpectedly survived and infected the bacteria. Bondy-Denomy showed that those phages succeeded by relying on proteins that could shut down CRISPR inside the bacteria, by sticking to the scissor-like enzymes and blunting them.
So, bacteria and phages are locked in an arms race. The bacteria use CRISPR to defang the phages, and the phages use anti-CRISPRs to subvert the bacterial defenses. The only problem is that the anti-CRISPRs shouldn’t work.
It’s all a matter of timing. Once the phages inject their genes into their bacterial victims, some of those genes serve as blueprints for manufacturing anti-CRISPR proteins. That takes time. By contrast, the bacteria have their CRISPR defenses ready-made. These ought to immediately start destroying the phages before they can construct their anti-CRISPR countermeasures. Based on that, “we didn’t think the anti-CRISPRs would work,” says Bondy-Denomy, who now works at the University of California at San Francisco. “It seemed like a race against time.”
His colleague Adair Borges showed that the slower phages can still win this race—as long as there are enough of them. The first one attacks the bacterium, and is destroyed by CRISPR before it can make enough anti-CRISPR countermeasures. Still, whatever anti-CRISPRs it does manage to make will linger in the bacterium, partly suppressing its immune defenses. The next phages to invade might also be destroyed, but each one weakens the CRISPR defense even further, until finally, the viruses overwhelm their victim.
A second group of scientists, led by Stineke van Houte from the University of Exeter, independently found the same thing. They, too, showed that anti-CRISPRs are imperfect, and that their success depends entirely on how many phages there are. As long as there are enough phages to successively attack the same bacterium, the later ones will eventually succeed even if the first ones fail.
Indeed, it’s only because the first ones fail that any succeed at all. The first phages are like kamikaze bombers, throwing themselves at enemy forces. They sacrifice themselves, but they give the next wave a chance of breaking through. “Those next phages benefit from what the first phage leaves behind,” says van Houte. “That’s how they cooperate.”
There are very few microbes that can successfully infect a host from a single cell or particle, says Britt Koskella from UC Berkeley, who studies phages. Infections are almost always a numbers game. Still, the phages are unusual in that “previously unsuccessful infections can increase the success of future ones,” she says. “This is the opposite of what happens in most other systems, where previous exposure to pathogens typically primes the immune system and decreases the likelihood of future infection.”