Note: Slight spoilers for Spider-Man: Brand New Day.
A plot device in the new Spider-Man movie is real-world science. A trick used to turn off fictional superpowers in the movie is based on actual genetic therapies for rare diseases.
In Spider-Man: Brand New Day, Peter Parker (played by Tom Holland) has disturbing symptoms as the DNA he got from a spider bite manifests itself in new ways. He’d like to get rid of some of his powers while keeping others. He visits Bruce Banner (a scientist played by Mark Ruffalo) to discuss a device Banner has created to keep his own alter-ego, the Hulk, from emerging. It’s a superpower inhibitor.
In one scene, Parker asks Banner how the inhibitor turns off the genes that cause Banner to Hulk out. “You’re using target-specific short interfering RNA, right?”
That’s not just movie technobabble. Short interfering RNAs, or siRNAs, are real molecules. At least seven are approved by the U.S. Food and Drug Administration for treating a variety of genetic diseases. Others are in clinical trials.
Here’s how they work. RNA is a key component in the assembly line for making proteins. First, cells make RNA copies of the instructions of the DNA in genes. Those copies are known as messenger RNAs, or mRNA (most known for its role in COVID-19 vaccines). The copies feed into cellular machinery that reads the mRNA instructions and builds proteins accordingly.
How not to Hulk out
Small interfering RNAs, including naturally occurring microRNAs and their synthetic counterparts, work between the copying and protein-building steps to set levels of protein production. As the name implies, these interfering RNAs are tiny; just 21 or 22 RNA building blocks, or bases, long. By contrast, mRNAs may stretch for hundreds to thousands of bases.
Interfering RNAs share short runs of bases with specific mRNAs. When the little RNAs match up with the target mRNA, the longer partner is scheduled for destruction. This happens in a naturally occurring bit of cellular machinery called RISC. There, mRNAs that have interfering RNAs attached are chopped up. That prevents proteins from being made from those mRNAs, essentially silencing the corresponding genes.
Shutting down foreign DNA — such as inserted arachnid DNA — or mutated genes is the sort of thing siRNAs do well, says Anastasia Khvorova, a chemical biologist at the University of Massachusetts Chan Medical School’s RNA Therapeutics Institute in Worcester. “Absolutely, that is theoretically what is feasible.”
Presuming that Spider-Man’s powers come from a single gene, then an siRNA targeting that gene could be a good inhibitor, she says. But it’s rarely the case that a single gene would be responsible for such different traits as making webs, superstrength, heightened senses and Spidey’s other abilities. So Parker would probably need to make a cocktail of different siRNAs to tackle all the new spider traits.
Plus, says Khvorova, genes don’t work in isolation. Shutting one down may have unintended consequences for others. Banner warns as much in the movie, saying “it would be enormously dangerous and complex” to try to shut down some parts of Hulk but keep others.
siRNAs used as therapies work like natural interfering RNAs but are synthesized to have their own superpowers, Khvorova says. “They’re fully chemically modified.” The modifications make them stable in the body and send them to the correct organ. So far, all the FDA-approved siRNAs work in the liver. Khvorova and colleagues are developing others that can be dispatched to muscles, nerves, the placenta or to other organs.
Usually, siRNAs don’t completely shut off a gene, but they can knock it down enough that negligible levels of protein get built, says Judy Lieberman, an immunologist at Boston Children’s Hospital and Harvard Medical School. Lieberman has also been an advisor to Alnylam, the company that first solved the problem of delivering siRNAs to specific cells. The trickle of protein might help Spider-Man control the level of his superpowers, she says. He would want enough protein made to make him super, but not enough to cause problems. Unfortunately, no one has been able to tune siRNAs so precisely.
Spider-Man would also need the inhibitor to work everywhere in his body. That’s not something siRNAs are usually designed to do, says Gane Ka-Shu Wong, a physicist-turned-biomedical scientist at the University of Alberta in Edmonton, Canada.
There’s another issue with siRNAs that could be a problem for the web-slinger. “They tend to last,” Wong says. Current siRNA therapies may last for six months or longer with a single dose.
Parker would need to make his inhibitor biodegradable, Wong says. “It’s got to last long enough to get to where it needs to go and shut off whatever it needs to shut off. But it also needs to degrade so that the moment you stop injecting this drug,” the powers return.
Even then, taking the inhibitor off wouldn’t instantly return a superhero’s powers. At a minimum, it could take a few hours to make mRNA copies and get new proteins. But it would probably take longer to return to full power.
“He could reverse it,” Lieberman says, “but it might take a few days.”
Read the full article here
