Two Feng Zhang lab alumni find a new CRISPR enzyme that could take a Big Gulp out of RNA — and a raft of devastating diseases
MIT buddy biologists Omar Abudayyeh and Jon Gootenberg were sitting in the Quebec Convention Center at the annual CRISPR conference in 2019 when, buried in a presentation on bacterial evolution, they heard a nugget that made them chase down the presenters the moment they walked off stage.
Abudayyeh and Gootenberg had worked together since they were graduate students at CRISPR pioneer Feng Zhang’s lab, where they discovered a new gene editing enzyme called Cas13. Unlike most previous Cas enzymes, Cas13 cut RNA instead of DNA. So the pair thought it might provide a potent tool for treating diseases, such as Huntington’s disease or muscular dystrophy, caused by mistyped RNA.
Cas13, though, works by a strange and ferocious mechanism; once it latches onto a precise shred, it goes ham and shreds genetic material left and right. In humans, the results would be disastrous.
“It actually starts cutting all the RNAs in the cell and actually destroying the cell, which is not really great” for making therapies, Abudayyeh told Endpoints News.
So the pair pivoted and launched a company, Sherlock, to turn Cas13 into easy-to-use diagnostics for RNA-based viruses, eventually including Covid-19. But they kept looking for something that might offer a path to patients, scanning published literature and databases for anything that might cut RNA.
On that day in Quebec, Eugene Koonin and Kira Makarova, researchers known for pioneering work on CRISPR evolution, suggested that the protein they were looking for might be out there, in one of the last places one would suspect.
Two years, a pandemic, a bit of protein engineering and terabytes of evolutionary biology later, the four on Monday unveiled a new CRISPR protein: Cas7-11, so named because it combines the otherwise separate proteins Cas7 and Cas11. In a Nature paper, they showed the new enzyme could accurately edit RNA in mammalian cells without damaging the cell.
“They have a lot of work ahead of them but this is really promising,” Ranjan Batra, R&D chief of the RNA editing biotech Locanabio, told Endpoints. “These things have the potential to be transformational.”
RNA editing could be used to target diseases ranging from infectious disease to neurodegeneration, and Abudayyeh and Gootenberg have plans for all that. But Cas7-11 is also notably for other, nerdier — albeit no less important — reasons.
CRISPR is generally referred to as a single system, but it’s actually many different ones. Different species of bacteria evolved them over eons as powerful tools to memorize and defend against deadly viruses. Biologists studying these systems today categorize them as either class 1 or class 2.
Class 2 systems can edit with just a single protein. Cas9, Cas13, CasX, CasΦ and all the other well-known Cas systems now used across biotech and academia belong in this bucket. When biologists like Gootenberg and Abudayyeh try to find new CRISPR protein, they search bacterial genes for those that bear the unique genetic signatures of CRISPR type 1 system.
By contrast, unless you’re a CRISPR researcher or a certain type of bacteriologist, you’ve probably never heard of any of the class 1 proteins. These require multiple different parts to come together to cut DNA or RNA. And that makes them virtually useless for therapeutics.
Cas7-11, though, is different. It’s a single editing protein, but, genetically, it clearly evolved from class 1 systems. And that means there are likely other medically valuable CRISPR proteins sitting in bacteria that researchers have overlooked for years.
“We’re showing that now, there’s a whole new stage that you can look for” CRISPR proteins, Abudayyeh said. “There’s probably a lot of valuable stuff out there.”
Harvard biochemist David Liu said the discovery was part of a decade-long trend, where researchers tapped bacteria to find proteins with better and better attributes. Cas 7-11 was found in bacteria isolated from Tokyo Bay 22 years ago.
“It’s tempting to speculate that staple CRISPR DNA- and RNA-targeting proteins such as Cas13, Cas12, or Cas9 might be superseded, or at least frequently replaced, by the best of these newly discovered CRISPR” proteins, Liu said in an email.
Gootenberg and Abudayyeh envision applying Cas7-11 in several different areas. It could be used as an antiviral, snipping out an RNA-based virus like coronavirus or HIV without touching human RNA. You could use it to target and shred tumors. It could be used to delete extraneous RNA in diseases like Huntington’s, where neurons churn out a single sequence of RNA on repeat until it destroys neurons. There are also applications in regenerating injured tissues.
The pair, however, has a ways to go before Cas 7-11 will be ready for patients. Batra, the Locanobio scientist, noted they only showed Cas 7-11 was safer than the original Cas13. And they only showed it was superior in a couple of cell lines, as opposed to in people.
Locanabio is using engineered and newly discovered forms of Cas13 to overcome its initial drawbacks. They are now using them to develop therapies for diseases marked by RNA repeats, including Huntington’s, certain muscular dystrophies, and ALS.
Batra also noted that, unlike Locanabio’s Cas13 enzymes, Cas7-11 is currently too big to fit inside the viruses researchers generally use to deliver CRISPR to patients. That could eventually build a smaller version, he said, but they haven’t yet.
“At this point,” he said, “I’m not sure what potential advantages I see.”
Still, at minimum, the discovery has opened another tool — and another batch of intellectual property — for a new company to go after RNA editing.
The research pair licensed Cas7-11 to a company in stealth mode. According to their conflict of interest statements on the paper, that’s either Moment Biosciences or Tome Biosciences, both based in Massachusetts.
Despite the current drawbacks, they have big hopes for the protein. Its curious name derives both because it combines the protein Cas7 and Cas11, and because of its resonance with the famous convenience chain.
“I have the email from Eugene [Koonin],” Gootenberg said. “He’s like oh yeah, Cas7-11, it’s so great. Maybe it’ll one day be as ubiquitous as 7/11.”