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LOGAN — Ryan Jackson and Thomson Hallmark just accomplished a feat that every scientist strives for.
Jackson, a Utah State University assistant professor in the department of chemistry and biochemistry, and Hallmark, a fellow USU biochemist, on Wednesday became published authors in the prestigious academic journal "Nature," the world's leading multidisciplinary science journal.
They joined other collaborators in publishing not one, but two papers in the renowned peer-reviewed journal.
"I've never done illicit drugs, but when we make these discoveries, it feels like you're on drugs. It's super high, you know, just super exciting," Jackson said.
Jackson and his colleague's findings describe the structure and function of a newly discovered CRISPR immune system called Cas12a2 that — unlike better-known CRISPR systems (like Cas9) that deactivate foreign genes to protect cells — shuts down infected cells to stop infection in its tracks.
"Instead of it protecting the bacteria, when Cas12a2 recognizes a virus RNA instead of a virus DNA, that recognition activates Cas12a2 to start cutting all of the nucleic acid inside the cell," Jackson said.
Essentially, this action severely impairs the cell, sometimes killing it.
"It's poor for that particular cell, but it protects the whole colony of bacteria so that virus doesn't spread through it," Jackson said. "This, on the surface, looks like it's programmable. What it means is that we have a tool to programmably kill cells," Jackson said, noting that it isn't yet to that point, but the potential is there.
The research was undertaken by Jackson and Hallmark, their colleagues from Germany's Helmholtz Institute for RNA-based Infection Research, U.S.-based biotechnology company Benson Hill and the University of Texas at Austin and is supported by the U.S. Department of Health and Human Services National Institutes of Health.
"You don't really make these kind of discoveries alone. You need a team of people who are working hard at it so I feel really fortunate to have had so many good people to work with there, too," Jackson said.
CRISPR is an acronym for the far more complicated-sounding "Clustered Regularly Interspaced Short Palindromic Repeats," which has captured national attention due to its gene-editing potential.
"(The) study of CRISPR DNA sequences and CRISPR-associated (Cas) proteins, which are actually bacterial immune systems, is still a young field, although it's receiving widespread attention for its gene-editing applications and the Nobel Prize awarded in 2020 to Jennifer Doudna and Emmanuelle Charpentier," a release from USU states.
Jackson said that when a typical CRISPR system binds to its target — whether it's DNA or RNA — it makes a cut in the target and then it's done.
"It's done its job to protect the cell because it's cut the virus DNA or the virus RNA," Jackson said.
The system that Jackson and his colleagues discovered, however, is different in the sense that CRISPR-Cas12a2 binds a different target than the typical Cas9 and that binding has a very different effect.
"When Cas12a2 binds RNA it changes its shape in a way that allows it to bind, bend, and cut DNA. This DNA-cutting activity shuts down the cell," Jackson said. "Thus, when Cas12a2 recognizes virus RNA, it shuts down the cell before the virus can replicate, effectively stopping the spread of infection through a bacterial colony."
Using a technology called cryo-electron microscopy, Jackson and his team demonstrated this unique aspect of CRISPR-Cas12a2, including its RNA-triggered degradation of single-stranded RNA, single-stranded DNA and double-stranded DNA, resulting in a naturally occurring defensive strategy called abortive infection.
"Abortive infection is a natural phage resistance strategy used by bacteria and archaea to limit the spread of viruses and other pathogens," Hallmark, a third-year doctoral student, said in a release. "For example, abortive infection prevents viral components that have infected a cell from replicating."
Jackson and Hallmark are two of many researchers working globally to decipher the basic structure of these systems and what makes them tick.
"This has been a challenging project," Jackson said. "We started working on it in 2017. There have been times where we wanted to give up on it because it just didn't make sense at times, but I had a lot of really talented students and other folks that just kept pushing."
"We're super glad we didn't give up on it," Jackson said.
Part of this excitement stems from what this discovery has unlocked as far as future potential for the CRISPR field.
"If Cas12a2 could be harnessed to identify, target and destroy cells at the genetic level, the potential therapeutic applications are significant," Jackson said in a release. "We're just scratching the surface, but we believe Cas12a2 could lead to improved and additional CRISPR technologies that will greatly benefit society."
For Jackson and his team, despite their lofty accomplishments, the work is far from finished.
"I feel like we have decades of work ahead of us just to follow up on all the cool, loose ends we have right now," Jackson said. "Today, we don't have new continents to explore or other things to discover in that way, but here in the molecular biosciences it's the new frontier and it's a place where you can make really cool discoveries."
People looking to dive deeper into Jackson and his team's report findings can do so by reading "Cas12a2 Elicits Abortive Infection via RNA-triggered Destruction of dsDNA" and "RNA Targeting Unleashes Indiscriminate Nuclease Activity of CRISPR-Cas12a2" in the Jan. 4, 2023, issue of Nature.
