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Pac-Man meets genetics in new DNA editing that plays like the game

By Elizabeth Rayne

CRISPR, the gene-editing device that could someday make deadly diseases a thing of the past, has been the subject of endless fascination and controversy. Now take that and put it on steroids.

Those CRISPR breakthroughs you’ve heard about (including that scandalous one) were all made possible by the CRISPR-Cas9 system. Cas9 can remove small pieces of harmful DNA with unreal precision, but now an upgrade to the CRISPR-Cas3 system has created what could be a miracle or a monster. Cas3 targets DNA, chases it and chomps down an entire strand like Pac-Man eats Power Pellets. Because Cas3 can remove much longer stretches of DNA in pathogenic bacteria quickly and accurately, it could be how we finally figure out to genetically warp pathogens so they no longer make us sick.

“Cas3 is a really potent bacterial immune system that targets phages—it can chew up the whole phage genome,” UCSF microbiologist and professor Joseph Bondy-Denomy, who recently led a study published in Nature Methods, told SYFY WIRE. “Our focus was deleting large non-mobile regions. So we simply started targeting different regions and isolating survivors. We were surprised to see the bacteria survived this and could repair the big cut.”

CRISPR actually spawned in bacteria as a defense against their nemeses, viruses known as bacteriophages. Think of bacteriophages as those candy-colored ghosts who want nothing better than to take down Pac-Man. They especially act like Pinky, that pink phantom who is always trying to ambush him in chase mode. Cas3 and Cas9 are both enzymes in the bacterial immune system. When phages threaten bacteria, the bacteria fight back by messing with their genes. They steal some viral DNA and incorporate it into their own, which makes RNA that binds to its DNA mirror image in the phage. CRISPR enzymes will then obliterate the enemy.

Now imagine that a CRISPR enzyme can be manipulated to edit out genetic information in other things besides bacteriophages, including the bacteria that originally evolved this immune system. Having Pac-Man chew up the DNA that makes pathogenic bacteria cause illness could render it harmless.

Cas9 can snap up a small piece of DNA. Cas3 is part of a different bacterial immune system, and behaves more like the pixelated yellow guy with an endless appetite. Think of Pac-Man eating one Power Pellet at a time versus an entire row of them. It chomps on one strand of the DNA double helix and leaves the other strand exposed. When there is an entire strand of harmful DNA that needs to be deleted, what would take Cas9 a hundred bites to erase will take Cas3 just one. This genetic Pac-Man can chow down on as many as 100 bacterial genes. But how exactly does it “chew”?

“Cas3 has a helicase domain which hydrolyzes ATP and pushes it along DNA while it cuts,” Bondy-Denomy said.

Meaning, Cas3 is the type of enzyme that breaks down ATP—adenosine triphosphate, the main source of energy in all life-forms—through the process of hydrolysis. It reacts with water to break bonds that release high amounts of energy which fuel processes inside cells and makes it possible for those cells to transfer energy from one area to another so an organism can survive. Experimenting with this Pac-Man in a lab and modifying it will enable scientists to study parts of bacterial DNA that have defied understanding. Bacteria often have long strands DNA that originally came from outside sources, and this is where Cas3 comes in. Some of these DNA stretches have no use. Others could be dangerous.

The research team modified the CRISPR-Cas3 system of the pathogenic Pseudomonas aeruginosa and other species of bacteria, some of which were also pathogens. They were able to prove that it was possible for bacteria to function after DNA erasure.

In the future, it could potentially disarm over a thousand types of pathogenic bacteria that swarm in the gut. Not much is known about most of them except food poisoning culprit E.coli and a few others. There are certain genes in these types of bacteria that make you want to hold a paper bag over your face, but imagine if those could be deleted and you never had to worry about food poisoning again. Bondy-Denomy can see even further beyond that.

“One of the most promising future uses for Cas3 is deleting large regions of bacterial genomes to screen for new phenotypes, new molecules that get produced, and vaccine production,” he said.

Could this potentially be used on the COVID-19 virus? CRISPR systems did originally evolve to fight off viruses, so you never know.

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