Gene-Silencing Pesticides

Chemical & Engineering News - 17-Feb-2014

Regulators prepare for next wave of pesticides based on RNA interference

(edited)

When farmers began seeing increased damage from the western corn rootworm a few years ago, they knew that the beetle was developing resistance to a widely used toxin produced by the bacterium Bacillus thuringiensis (Bt). The approach of GE corn to produce Bt toxin was losing its effectiveness against the insect.

 

Monsanto raced to find an alternative weapon to combat the devastating pest. The company is now close to seeking regulatory approval for a strain of corn engineered to produce double-stranded RNA (dsRNA). When a rootworm larva eats the roots of the corn, it ingests dsRNA, which silences an essential gene in the pest, thereby killing it.

 

The approach relies on a biological process called RNA interference (RNAi), which is used by cells to suppress gene expression. The process is triggered by dsRNA, which cells break into pieces that interfere with the transcription of messenger RNA and the translation of that mRNA into protein.

But some scientists are raising concerns about the potential risks of the technology to nontarget organisms, including humans.

 

The EPA held a meeting last month to get advice from experts on whether its current framework is adequate for assessing the risks of the new technology. These experts and others say that regulators must better understand the toxicity issues unique to RNAi-based pesticides, as well as the persistence of dsRNA in the environment.

 

EPA has some experience examining the risks associated with RNAi-based pesticides, but most of the products were reviewed before scientists had a good understanding of the RNAi process, says Chris Wozniak, a biologist with EPA's Biopesticides & Pollution Prevention Division. The first RNAi-based pesticides were approved by EPA in 1997 for targeting infectious plant viruses, but the mechanism behind RNAi was not widely understood until 1998 (Nature, DOI: 10.1038/35888).

EPA acknowledges there is insufficient data in the published literature on the stability and activity of dsRNA in soil and aquatic systems to determine how long a dsRNA molecule will last in the environment. Its lifetime could depend on the size of the molecule, whether it is in a clay soil or a loamy soil, and whether it binds to organic matter or other soil particles, Wozniak says.

 

Thus far, all of the RNAi-based pesticides reviewed by EPA have used a similar strategy: They require incorporation of the pesticide into the plant genome to be effective. But companies are also working on RNAi-based products that are intended to be directly sprayed on plants, insects, or other pests, or applied in granular form. Such products could be mixed with surfactants, stabilizers, and other pesticide active ingredients.

 

Monsanto is currently developing an RNAi-based spray designed to make weeds less resistant to its herbicide Roundup. Syngenta acquired the Belgian biotech company Devgen in late 2012 to work on RNAi-based pesticide sprays.

 

The EPA does not have any experience with hazard and risk assessments for dsRNA products that are applied directly to the environment, says Russell Jones, a senior biologist in EPA's Biopesticides & Pollution Prevention Division.

Some of the hazards that are unique to dsRNA active ingredients include off-target gene silencing, silencing of the target gene in unintended organisms, immune system stimulation, and the saturation and disruption of the RNAi machinery in nontarget organisms, Jones notes. These hazards were first pointed out by USDA's entomologists Jonathan G. Lundgren and Jian J. Duan in a BioScience paper last year (DOI: 10.1525/bio.2013.63.8.8).

 

The USDA scientists also highlighted areas where information is lacking, including the persistence of dsRNA in the environment. Without such information, it is difficult to assess exposure.

Much of the concern related to human health effects of dsRNA was raised after a study led by Chen-Yu Zhang of Nanjing University, in China, that reports the presence of exogenous plant micro dsRNA in human blood plasma after the consumption of rice (Cell Res. 2012, DOI: 10.1038/cr.2011.158). The paper stoked concerns about the safety of RNA-based technology in food.

Beekeepers are urging EPA to thoroughly evaluate RNAi designed to protect crops to look for unintended effects on nontarget organisms such as bees.