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Genetic pesticide: Monsanto, startups seek alternatives to manage bugs and weedsqrcode

Jun. 27, 2016

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Jun. 27, 2016
If not treated, the invasive varroa mite will almost certainly show up in a honeybee hive, latching on to the pollinators, feeding off their internal fluids and threatening to weaken the colony to the point of collapse.
Western bees never evolved defenses to the Asian parasite, brought to North America about 30 years ago. Many of the existing treatments are mite-targeting pesticides that can damage the bees or their honey.
It’s a problem Monsanto scientists think they can help solve by tailoring a treatment with far more specificity than synthetic chemicals, one that uses the language of DNA to target genes unique to only the varroa mite. And the agriculture giant thinks it can do it by simply feeding the bees a sugar solution full of RNA, the molecule that transcribes DNA’s instructions.
Monsanto has already signed up 2,500 colonies around the country for trials of its bee health product, which started this year.
“In all my years in the industry, I’ve never heard of this big of a trial in beekeeping,” said Jerry Hayes, who heads Monsanto’s bee health operations.
The tests could prove significant, not only for honeybees crucial for pollinating the food supply, but for a technology platform that has potential applications far beyond beekeeping. Monsanto believes it will be the first of its products to market that utilize the new genetic technology, probably around 2020.
It isn’t alone. Startups with operations in the St. Louis region are looking at their own products using the technology, and other large agribusiness companies are racing to commercialize it.
The mechanism, known as RNA interference or RNAi, has stoked excitement among researchers and industry since its discovery won two scientists a 2006 Nobel Prize.
“This is a learning platform for RNA interference,” Hayes said. “So we can figure out how to use it on other bad bugs.”
Shooting the messenger

RNA is the messenger molecule that copies instructions from genes within a cell’s DNA to protein-making mechanisms in cells. Scientists discovered that if they introduced RNA into the cell that matched existing RNA messages but was made to look like some viruses, the cell’s defenses would fight it off like a virus.
In the process, the cell would destroy the RNA messages it was making naturally that matched the virus-mimicking RNA, essentially “silencing” a particular genetic trait.
RNA messages can carry the instructions for virtually every function of life, including making the proteins that some insects and mites need to live. If the cells stop making them, those pests die.
Creve Coeur-based Monsanto and other big seed and chemical companies have been criticized for their use of pesticides, particularly neonicotinoids, which many studies link to bee health problems and impacts to other beneficial insects. But the new approach, Monsanto says, would be valuable because it avoids any nontarget effects by acting only on genes unique to the pest, weed, virus or bacteria it wants to kill.
And, the company and scientists say, RNA molecules biodegrade in the environment, unlike some synthetic chemicals.
Beyond eliminating harmful organisms, there’s the prospect of adjusting genes to make food taste better or require less water.
“The overall potential of the platform is enormous,” said John McLean, a Monsanto scientist in charge of the BioDirect division, which is working to develop the bee product and several others using RNA interference.

Mosquitos and oranges

It’s big enough that several startups in the area are also aggressively pursuing commercialization of the technology.
One of them, Apse Inc., is working on methods to manufacture RNA molecules more cheaply for use in agriculture. Its CEO is a former Monsanto scientist, and Apse’s website tells investors that a potential exit could be acquisition by “a major agriculture company.”
Forrest Innovations, an Israeli company that established its U.S. headquarters in BRDG Park across Olive Boulevard from Monsanto last year, is on the forefront of using RNA interference in agriculture and pest control. The company’s founder, Nitzan Paldi, was also the co-founder of Beeologics, which Monsanto acquired in 2011 to help move its RNAi efforts forward.
Now, Forrest is working on using RNAi to breed sterile male mosquitos to compete with healthy ones and reduce the populations of the disease-carrying pests in countries like Brazil where concerns about Zika virus are mounting. Traditional sterilization techniques using radiation or chemicals are less effective or weaken the mosquitos, making them less able to compete with fertile males, said Roy Borochov, who heads Forrest’s U.S. lab.
Forrest Innovations is also working to develop an RNA treatment that protects fruit growers from a bacterial infection known as citrus greening. The molecule silences a reaction the fruit has to the bacteria while leaving its defense mechanisms in place, Borochov said.
The citrus treatment is only a year or two away from regulatory approval, Borochov said. The mosquito treatment could be on the market even sooner.
“I believe we will be one of the first, if not the first, companies out in the market with RNAi,” he said.

Spray-on genes

Finding the correct RNA molecule to trigger the desired effect isn’t the main stumbling block, Monsanto’s McLean said. It’s delivering it.
“It’s not always easy to get the key to the right cell, or to the right part of the plant or the right part of the insect,” he said. “The delivery challenges are really the biggest challenges for this technology.”
Monsanto is looking at applications that incorporate a gene that makes the RNA molecules within a plant — essentially genetically modified corn plants that emit RNA lethal to rootworms.
But the company is also pursuing an application route that could bypass much of the concern with genetically modified plants. It’s found that spraying plants with RNA molecules can in some instances deliver the molecules to the right spot to target weeds, or to get it ingested by bad insects.
Forrest Innovations, too, is looking at using a spray to target citrus bacteria. Often the application processes are the most important intellectual property, Borochov said.
“The delivery process is not an easy one,” he said. “Taking an external molecule and putting it inside the plant is not easy.”
An RNA spray is under development at Monsanto to target Colorado potato beetles. Another would target the genes in weeds that have developed resistance to glyphosate, allowing the key ingredient in its widely used Roundup herbicide to again break through the weed’s resistance. Viral control sprays are another new possibility.
“That provides the prospect of having an effect without having to use a (GMO),” said James Carrington, president of the Donald Danforth Plant Science Center. “It would be much faster to develop those types of products than it would be to develop GMO-type plants. And there’s the prospect that there would be greater acceptance at the consumer level as well.”
Jeffrey Scott, an entomology professor at Cornell University, has studied the use of spray-on RNA interference in controlling the Colorado potato beetle. One of the main stumbling blocks thought to stand in the way of an RNAi spray is that RNA molecules break down quickly in the environment. But Scott’s research found that it can last up to four weeks on leaves.
Outside of a greenhouse, conditions may be more challenging. And the cost of manufacturing enough RNA to hit a price point farmers are willing to spring at is another question.
“It’s effective,” Scott said. “It’s just a question of the economics of what you can apply to get the control.”
Monsanto’s McLean sounded an optimistic tone on the economics. Only a few years ago, many in the industry saw RNA manufacturing as a cost-prohibitive process more suited for the laboratory than large-scale application.
“We’re already producing now for our field trials at cost and volumes that weren’t even heard of a decade or five years ago,” he said.

Getting it right

The economics of RNA manufacturing is one of the reasons Monsanto finds itself closer to commercializing its bee product than RNAi that targets glyphosate resistance or the potato beetle. One of the reasons it bought Beeologics in 2011 was because the startup had also come up with a cheaper way to make RNA.
Hayes, Monsanto’s bee health expert, worked with Beeologics early on, before Monsanto scooped up its RNA interference know-how. A couple years later, he joined Monsanto from Florida’s agriculture department after being convinced the company would bring its resources to bear on helping to find at least part of the answer to improving bee health.
Hayes said the RNA interference technology isn’t working as well as he initially thought. But he’s hopeful it will be perfected.
“If it works half as well and you can eliminate one of those chemical treatments, you’re still ahead,” he said.
Neal Bergman, who owns Delta Bee Co., a large commercial beekeeping operation in Kennett, said concerns about Monsanto’s use of neonicotinoids wouldn’t dissuade him from using a new product for varroa.
“If they come up with a good treatment for mites, I have no problem with that,” Bergman said.
He’s always looking for a new treatment to control the ubiquitous pests in his hives.
“I think it’s right up there at the top,” he said of varroa’s negative impact on bees. “It’s one, two or three. It’s right at the top of important issues.”
But other groups are less certain of RNA interference’s safety. In 2013, the National Honey Bee Advisory Board sent comments to an Environmental Protection Agency panel looking into the safety of RNAi technology that asked the agency to hold off on registering such pesticides until they’re better understood.
“Since the whole genome sequences of most plants, animals and viruses are currently unknown, how can (RNA) sequences be designed to have minimal off-target impacts?” the group asked in one of a series of questions about the technology’s risks.
Doug Gurian-Sherman, a former EPA regulator and now the director of sustainable agriculture at the Center for Food Safety, said companies will have to be careful to make the RNA specific enough that it doesn’t interact with other organisms.
“There’s a lot of unknowns and the regulatory agencies have not caught up,” he said. “Ten years from now we may have data that shows us these things are everything we thought they would be in terms of efficacy and specificity, but we really are not at that stage.”
But Scott, the Cornell professor, argued the environmental benefits of more specific pesticides would outweigh the risks, and existing genetic knowledge can help scientists design RNA molecules that don’t act on beneficial insects. He doesn’t see “any logical connection” to human health risks.
“You’ll never have all the genomes of all the insects and be able to design something that specific,” Scott said. “But it’s pretty close. Rational choices can dictate compounds that are at least orders of magnitude more specific” than conventional pesticides.
The EPA panel, for its part, agreed that there was little risk to humans or mammals. But it did say that more data was needed on how long RNA remained in the environment before degrading and potential ecological impacts.
And like conventional pesticides, targeted insects and weeds could well develop resistance to the RNA molecules. A new treatment could target a new gene, but Scott said there’s the possibility defense mechanisms could evolve blocking the uptake of any outside RNA molecules.
“It depends a little bit on what evolution deals out as a mechanism for resistance,” he said.
Gurian-Sherman at the Center for Food Safety warned that such products would put producers on “another treadmill” that forces them to continue buying new treatments as resistance develops. And if Monsanto’s treatment for Roundup resistance in weeds succeeds, that’s just a recipe for more herbicide use.
“The problem is this kind of piecemeal approach and the companies attacking problems where they can sell products,” he said.
It remains to be seen how big a technology RNAi becomes for agriculture, Monsanto’s McLean said. But the company has invested millions in the platform, listing it alongside planting and weather services utilizing big data as one of its primary research focuses.
Few within the company, McLean said, realized how big genetically modified crops would become when the first Roundup resistant plants were being developed in the 1990s.
“I think we’re in the same place today, 20 years later, with another big technology platform,” he said.

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