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For Monsanto, Variability in RNAi among Target Pests is Par for the Course

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Although a recent paper demonstrated variability of RNAi effects in different Western corn rootworm populations, researchers at Monsanto have long been aware of this issue and continue to monitor for it as the company prepares to launch a corn variety that uses the gene-silencing technology to kill the pest.

Earlier this year, a team from the University of Illinois published data in Pesticide Biochemistry and Physiology showing that the phenotypic impact of silencing two genes in colonies of corn rootworms taken from fields in three different locations was not consistent.

The scientists concluded that different responses to RNAi may occur without differences at the sequence level of a targeted transcript, and propose that variability in corn rootworm populations' "physiology, trophic interactions, or functionally related genes/transcripts may be capable of influencing the effectiveness of RNAi in the field."

One of the co-authors of the study, Barry Pittendrigh, cautioned in an email to Gene Silencing News about interpreting the findings beyond the context of the study. Yet they could suggest that transgenic plants that express dsRNAs to combat corn rootworms might not be as effective in some insect populations as others.

Notably, Monsanto is nearing the commercial launch of its Smart Stax Pro corn variety, which expresses dsRNAs against a gene called Snf7 and two widely used Bt proteins, which are derived from the bacterium Bacillus thuringiensis, to kill Western corn rootworms.

But according to William Moar, technical lead of corn insect resistance management at Monsanto, the results of the Pesticide Biochemistry and Physiology paper were not a surprise.

Moar pointed to a 1993 paper by Monsanto researchers that showed variable susceptibility to Bt traits in different populations of tobacco budworms and corn earworms. On the other hand, Monsanto scientists have also found very little variability in Bt susceptibility among populations of European corn borers, Moar said.

"That's why you need to test this — different insects can have a lot of variability," he added. And when it comes to Smart Stax Pro's RNAi component, "we have already done field work looking at [variability in] natural populations and we will be continuing to do that" prior to commercialization.

In fact, companies like Monsanto routinely study insect variability as part of their efforts to meet insect resistance management (IRM) rules established in conjunction with regulatory agencies, Moar noted.

"For every product that we have as a [genetically modified] crop, we have to do monitoring to measure for changes in baseline susceptibility to look for the potential for resistance development," he said. "Unless you know what the variation is in your baseline susceptibility, there is know way to have a benchmark to know when you see a difference, what it actually means."

But for Snf7, differences in variability are not expected to be an issue.

As one of the authors of the Pesticide Biochemistry and Physiology noted to Gene Silencing News, his team focused on two genes that are not as critical to corn rootworms as, for instance, the one targeted by Smart Stax Pro. In a number of publications, Monsanto has shown that the corn rootworm ortholog of Snf7 is an essential part of the insects' cellular machinery, and that its inhibition is lethal.

At the same time, the dsRNA doses the team tested and the level of insect control they achieved was "actually very minimal," Moar said, noting that current IRM guidelines consider doses of a pest-control agent that achieve 95 to 99 percent control as low to moderate.

"So we have to look at targets that give us extremely high mortality," he said. "The targets that these authors went after are not targets we would ever consider because they are not going to give us the toxicity we'd like."

Adding to this is the fact that Smart Stax Pro includes two Bt proteins that remain highly effective with control levels of at least 95 percent — similar to the level of control achieved with the Snf7 dsRNA component — despite the emergence of resistant corn rootworms.

"We know there is no cross resistance between the two Bt [proteins] and have shown there is no cross resistance between the dsRNA and Bt [proteins]," Moar said. "So you'd expect that when you have insects that are in a position to [develop resistance] against one particular mode of action, they would be susceptible to the other two and would never be able to perpetuate themselves."

Meanwhile, the natural mortality of corn rootworms is around 90 percent or greater in most populations. "Most of the insects that are laid by rootworms die anyway … [and] we go to at least 95 percent on top of that," he said.

In the end, Monsanto conducts a wide range of field tests in multiple locations and under multiple environmental conditions for all its products before they reach the market, Moar said.

"The bottom line is that we have to prove to growers that a product meets their standards," he added. "What that means is you need to have a very high level of kill … [and] the higher level of control you get, the less variation you're going to see."

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