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Saturday, May 18, 2024

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.

The discovery of this process—called RNA interference (RNAi)—earned two scientists the 2006 Nobel Prize in Physiology or Medicine. It also sparked a race to develop new tools based on it. Scientists soon realized that if you could introduce dsRNA into a pesky pathogen—a particularly irritating fungus, for example—you could instruct that pathogen’s cells to destroy its own mRNA and stop it from making crucial proteins. In essence, they could switch off genes within pathogens at will. “We’re just going in there and looking at the orchestra of genes and proteins out there and we’re silencing the violins. That’s all we’re doing,” says Michael Helmstetter, chair of RNAissance Ag, another startup vying to bring RNA crop sprays to the market.

A handful of RNA sprays are already in the works. RNAissance Ag is working on a spray that targets the diamondback moth, which has an insatiable appetite for cabbages and has already evolved some resistance to common pesticides. GreenLight Biosciences has an RNA spray targeting the Colorado potato beetle that’s currently being evaluated by the Environmental Protection Agency. The company is expecting a decision on that spray by the middle of 2022. It’s also working on a spray for Botrytis, as well as one that combats the Varroa mite, a widespread pest that infects honey bees. After initial laboratory trials, GreenLight is now field testing its Botrytis spray on grapes in California and strawberries in Italy. Singleton says they’re looking to find out how long the spray sticks to plants and how it compares to chemical fungicides.

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.

Taning warns that the public and politicians—particularly in Europe—have a track record of being squeamish when it comes to new crop technologies. In the mid-1990s, GMO tomatoes were marketed in the UK for the first time. Everything seemed to be going well for the first couple of years, until some dodgy scientific research about the safety of GMO foods sparked a media storm. No GMO foods have been on sale in the UK since then. Post-Brexit, the UK government has indicated that it wants to loosen its regulations on gene-edited food, but the whole debacle is a stark warning that people have strong feelings about how the food that they put in their mouths is grown.

And when it comes down to it, the impact of dsRNA may be relatively modest. Both Singleton and Helmstetter say their RNA sprays wouldn’t replace other pesticides altogether—they’d just be another tool in the arsenal against pests. And RNA sprays might be particularly handy at certain times of year. The EPA sets strict limits on the level of pesticides in foods, which prevents certain sprays from being used close to harvest time, but because RNA degrades quickly in the environment, that timing may not be an issue. “There will be a lot of focus on the closer-to-harvest applications. That is one of the real benefits of an RNA product,” says Singleton.

RNA crop sprays alone aren’t going to save farmers from Botrytis, but they might help cut down our reliance on other pesticides. “You bring it all together—everything that can help you control the pests. If you bring one single method, it will not work,” Taning says.

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