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The Next Big Thing for RNA? Fixing Moldy Food

The Next Big Thing for RNA? Fixing Moldy Food

Of all the fungi out there, Botrytis cinerea is the one that keeps farmers up at night. The scuzzy fungus has a voracious appetite. It’ll happily munch through hundreds of plant species—although soft fruits like grapes are its favorite—covering everything it feasts on with a velvety layer of mold. If you’ve ever left a tub of strawberries in the refrigerator a little too long and returned to find them looking a sort of gray-green, there’s a good chance that one of the ever-present spores of Botrytis floating through the air decided to make its forever home in your dessert.

A spoiled dessert is a pain, sure, but for the food industry Botrytis poses a major problem. That single species of fungus is responsible for at least $10 billion in damage to crops each year. Some estimates put the figure as high as $100 billion. It’s so troublesome that a survey of plant pathologists ranked it as the second most important plant fungal pathogen, in what can only be described as their industry’s equivalent of TIME magazine’s “Most Influential People” list. (The top spot went to Magnaporthe oryzae: a fungus that devastates rice fields all over the world.)

“It’s the big one,” says Mark Singleton, head of plant and animal health at GreenLight Biosciences, a Massachusetts-based biotech startup working on a new generation of sprays to defend against Botrytis and other pests that bedevil farmers. The downsides of existing fungicides and pesticides are well-known: Residue from the sprays can build up in the environment and damage non-target organisms, while their overuse can lead to pests and weeds evolving resistance. Singleton is working on a way around these problems. And his starting point is RNA: a molecule similar to DNA that is one of the fundamental building blocks of life.

This new generation of pesticides is based on a cellular trick that dates back more than a billion years, at least as far as the last common ancestor of animals, plants, fungi, and protists. At some point—we’re not exactly sure when—cells evolved the ability to chop up and destroy genetic material from invading pathogens, like viruses. When a cell detects the presence of double-stranded RNA (dsRNA)—a stretch of genetic code that viruses use to duplicate themselves—it hacks this dsRNA up into tiny pieces. These chunks of dsRNA are like teeny-tiny wanted posters. Molecules in the cell pick them up and use them to hunt down any matching stretches of messenger RNA (mRNA)—the molecules cells use to turn genetic instructions into proteins. If the molecular bad guys get chopped up before they can start being made into proteins, the cell will have headed off a successful invasion.

RNA crop sprays could have some major advantages over the current toolbox of chemical-based pesticides. Microbes break down RNA in the soil within a couple of days, which lessens the problem of environmental buildup. And because RNA sprays would target genes specific to individual species, there is—at least theoretically—a much lower chance that other organisms would get caught in the crossfire. Even two very similar species have enough genetic differences that it’s possible to make RNA sprays that target one bug while leaving the other one alone, says Clauvis N. T. Taning, a postdoctoral researcher who studies RNAi pesticides at Ghent University in Belgium.

Developing RNA crop sprays could also open up shortcuts to new pesticides—a process that typically takes at least a decade and hundreds of millions of dollars. It’s very difficult to transform an existing pesticide into something new, says Taning. “You can tweak here and there, but if you want a new product that will have a new patent you cannot just change one thing on the surface and expect it to be new.”

With RNA sprays, this whole dynamic is flipped on its head. Each new spray will target a different gene—or combination of genes—in the pest that its creators want to get rid of. One spray might interfere with genes that control fungal cell division, while another might target genes that help the fungi produce toxins. RNAissance Ag is working on a spray that messes with diamondback moths’ immune systems, leaving them vulnerable to bacteria that the bugs usually have no problem fighting off. Since it is relatively easy to produce new dsRNA that targets a particular gene, it means scientists can go back to the lab and reformulate a spray if pests start evolving resistance to particular modes of action. Of course, the new spray would still have to be tested and go through approval, but the way the dsRNA is packaged and delivered wouldn’t change: Only the genetic information itself would be tweaked.

There is one big unknown that could send hopes for RNA crop sprays careening off course. RNA crop sprays should work, as long as pests actually absorb the molecules. But what if pests started to become resistant to dsRNA itself? “This is a big, big, big area of concern,” says Mark Belmonte, a professor of plant biology at the University of Manitoba in Canada. “We are currently seeing, at least within a lab environment, that when you make a double-stranded RNA that targets an insect pest, you are at least able to artificially induce resistance within the insect against dsRNA technology.”

How did scientists figure this out? By playing Squid Game with beetles. Researchers led by Swati Mishra at the University of Tennessee exposed multiple generations of Colorado potato beetles to high levels of a dsRNA pesticide. After each exposure, the scientists picked out the survivors and let them breed with each other, creating a new generation of beetles with more resistance against dsRNA. The ninth generation of beetles to go through this process had 11,000-fold higher resistance to dsRNA than beetles from the starting population. When exposed to high levels of dsRNA, 95 percent of adult beetles in the resistant population died, while every single adult in the original population died. If a similar thing happens when dsRNA sprays are used for real, this could be extremely bad news.

Singleton agrees that resistance is always a concern. “It’s unavoidable. But we will do everything we can to make sure that growers use the products the way we believe minimizes that risk.” He says that growers might be directed to use dsRNA only at certain times of the year, and that since RNA breaks down so quickly in the environment it’s less likely that pests will be exposed enough to develop resistance. Helmstetter also adds that his RNA sprays will likely be mixed with existing pesticides—attacking pests from several angles rather than taking a single one-spray-to-kill-them-all approach. “It’s [reducing] the number of ag chemicals that are used, but not full replacement of them,” he says.

This content was originally published here.