In the past few years, scientists have learned how to manipulate an organism’s DNA to try to cure genetic disorders.
But there’s another type of genetic material that scientists are focusing on — RNA — which played a critical role in the COVID vaccines.
Today, scientists across Massachusetts are conducting RNA research on marine animals they hope will lead to better therapeutics for humans.
Squid as a model organism
On a recent sunny morning, scientist Josh Rosenthal was waiting on a dock in Woods Hole, on the southwest corner of Cape Cod.
Rosenthal, who works at the Marine Biological Laboratory, was checking in with the crew of the Gemma, a 50-foot research vessel that was about to go out for the day.
The crew catches marine animals that scientists study to help understand basic biology; they’re known as "model organisms."
On this day, they’re looking out for cephalopods, a marine category that includes squid and octopus, which are then held in tanks in a nearby building.
Rosenthal reached into one of the tanks and pulled out a translucent substance.
“You see those little jelly-like fingers down there? Those are each filled with 50 to 100 (squid) eggs," he said.
Rosenthal’s lab is focused on an even smaller stage; he studies cephalopods to understand the role of genetics in behavior, disease and physical sensations.
“Squid and octopus are by far the most behaviorally sophisticated invertebrates out there,” Rosenthal said.
He said their large, complex nervous systems rival many mammals, which is in part related to their RNA.
RNA is the molecule that carries instructions from DNA — the body’s genetic blueprint — into the cells to make proteins.
For a long time, scientists thought that transfer of information was always fairly direct, that the DNA was converted into an identical version of itself in RNA.
“But we know now that that's not always true, and that actually the information itself can be edited,” Rosenthal said.
And he said cephalopods do something interesting — they edit their own RNA at unusually high rates. That means they actually change the genetic message en route to the protein. So while the DNA may instruct the organism to make a certain protein in a certain way, the RNA can change those instructions on the fly, and tell the cells to do it differently.
“It seems to be going on in all organisms, but just thousands of times more frequently in squid, octopus and cuttlefish,” Rosenthal said.
The therapeutic advantages of RNA
RNA is hot right now in biochemistry.
We all heard about it with the COVID vaccines. Instead of injecting a protein into a person’s arm, the vaccine essentially injects instructions — via RNA — for the body to make its own protein, in this case, one from the COVID virus. The body then creates antibodies to fight it.
And while gene editing of DNA is permanent, RNA editing is temporary. The changes appear for a while and then go away. That offers an advantage to many animals.
“Because the environment that an organism is in — both the social environment and the physical environment — changes,” Rosenthal said. “So you might not want your change permanent. It might be only beneficial for a period when the environment is different.”
For humans, this process could have great therapeutic significance. Scientists could learn how to edit a message that comes from a mutated gene — one that causes disease or dysfunction — and fix it.
Craig Martin is a chemistry professor at UMass Amherst who, along with colleague Sarah Perry, works on developing RNA strands for research.
Martin said DNA editing, using a method called CRISPR, can also be effective, but “with permanent fixes you have to be sure you get it exactly right.”
That’s because the DNA can’t be changed back.
“If we develop an RNA therapeutic and then later on somebody comes along with something better, we can just replace that therapeutic with the better thing that comes along.”
Josh Rosenthal was so optimistic about the RNA technique that, in 2019, he pitched it to a group of venture capitalists in Cambridge and started a biotech company, Korro. The company’s scientists are now using RNA editing to work on a genetic disease of the liver and lung.
Meanwhile, Rosenthal has his eyes on another use for RNA, addressing one of the country’s biggest health conundrums: pain relief.
“If you're working with an organism like squid that can edit genetic information way better than any other organism, then it makes sense that that might be useful for a therapeutic application like deadening pain,” he said.
At the moment, Rosenthal said, the most effective short-term treatment for severe pain is opiates. But since they’re highly addictive, he’s hoping RNA editing can offer an alternative.
Rosenthal’s lab is focusing on a part of the nervous system called the nociceptive system. It recoils, through stimulated nerve fibers, when you experience something extreme, like the heat of a flame, or the pain of arthritic inflammation.
Researchers hope to mimic how squid and octopus use RNA editing in nerve channels that interpret pain and use that knowledge to manipulate human cells.
“So we want to try to re-engineer a protein in these nociceptor neurons to be less likely to generate pain signals,” he said.
Rosenthal has teamed up with pain researchers at Yale, the University of Texas Dallas and Tel Aviv University. They’ve been funded by a five-year, $6 million federal grant earmarked for addressing the addiction crisis.
“I'm interested in pain because it involves not correcting a genetic mistake or mutation,” he said, “but really rationally going in and saying, ‘We want to change a specific protein the way it operates a little bit.’”
And that could provide non-addictive pain relief for days or weeks.
Should those results be promising, Rosenthal hasn’t ruled out starting another biotech company to help bring RNA-driven pain relief to market.
