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Advocacy Group Urges Caution over Agricultural RNAi

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As the Environmental Protection Agency develops a framework for assessing the risks posed by RNAi as pest-control strategy in plants, one consumer advocacy group has expressed concern over agricultural use of the technology and asked the agency to temporarily hold off on approving any such products.

However, the organization's comments come amid a wave of letters to the agency from scientists in both academia and industry pointing to a large and growing body of evidence on the safety and specificity of RNAi in plants.

With ag-bio giant Monsanto finalizing a regulatory application for a new strain of corn that expresses a widely used protein along with a dsRNA to combat corn rootworms, the EPA has been grappling with how best to evaluate the potential hazards of such products as none have yet been commercialized.

As reported by Gene Silencing News, late last month the agency held a meeting to discuss its efforts and to solicit the input of outside researchers, specifically on issues such as the possible effects of RNAi-expressing plants on humans and other non-target organisms.

Meanwhile, the EPA is soliciting comments from the public on the matter and, in response, the non-profit organization Food & Water Watch has raised red flags about the technology.

In a letter made public last week, Food & Water Watch Executive Director Wenonah Hauter warned that RNAi "has not been evaluated thoroughly enough for the EPA to allow pesticide-incorporated plants with this technology or genetically engineered crops intended for the food market."

Among Food & Water Watch's main concerns are a lack of field data on how RNAi-expressing or -modified crops, with the group noting that real-world outcomes may be different that those in the laboratory setting.

Additionally, the group worries about the genetic similarity of different organisms impacting the specificity of RNAi pesticides, and the potential for gene silencing to occur in different species.

"Many studies have shown that RNAi can actually suppress unintended genes that are similar to the target gene," Hauter wrote. "These unintended effects may also be heritable through reproduction, which could have serious ramifications for plant and animal populations."

Hauter also cites research indicating that plant-derived microRNAs could be detected in the tissues of mammals and insects, including a 2012 report in Cell Research claiming to show that miR-168a obtained through the consumption of rice decreased the clearance of low-density lipoprotein in humans.

Notably, the findings in this paper have been refuted by a number of groups, which found no uptake of dietary miRNAs in tightly controlled experiments in humans, mice, non-human primates, and honeybees.

Referring to the role of the RNAi machinery in heterochromatin formation, Hauter further raised concern about the possibility that RNAi-altered plants "could lead to defective chromosome function or make the cell vulnerable to viral infection."

Such a situation, she added, "could lead to 'genome instability and cancer late in life' in humans," referencing a 2003 review of RNAi, although the quote is in reference to situations where RNAi machinery is oversaturated or defective.

Overall, Food & Water Watch urged the EPA to "carefully weigh the risks associated with RNAi and to design a new risk assessment framework that can adequately capture the unintended consequences of the introduction of dsRNA molecules into agriculture and the environment."

As it does so, the agency should also enact a moratorium on "any new RNAi-based product approvals until a full evaluation by the EPA and [US Department of Agriculture] is completed," Hauter concluded.

Difference of Opinion

Food & Water Watch's cautionary comments to the EPA sharply contrast with many of the other statements provided to the agency — primarily by those with scientific backgrounds — as it figures out the best way to review RNAi products in agriculture.

For instance, University of Massachusetts Medical School researcher Craig Mello, who along with Stanford University's Andrew Fire won the 2006 Noble Prize for discovering RNAi, stated that "there is no basis for concern that dsRNA targeted at a pest species could cause inadvertent sequence-specific toxicity to humans who consume that RNA."

Mello noted that "humans unavoidably ingest natural dsRNA every day (with every meal) as a significant component of their diet," and that this is rapidly metabolized in the gut. Furthermore, he points out that oral delivery of dsRNA in mammals is "inefficient" and requires protection from nuclease degradation.

James Carrington, president of the Donald Danforth Plant Science Center with extensive expertise in RNA-mediated gene regulation, added in his own comment to the EPA that "there is no confirmed evidence in the scientific literature, to my knowledge, that associates consumption of plant-derived RNA molecules of any kind with any hazards in humans, other mammals, or domesticated animals."

He also noted that hundreds of organizations including his own are testing RNAi- and small RNA-based pest and disease control strategies, with "promising data" available in the literature.

And Robert Sears, president of the non-profit organization Eastern Missouri Beekeepers Association, told the EPA that RNAi "offers the potential for leveraging naturally occurring processes to fight bee viruses and parasites, without affecting other beneficial species or creating resistance, a severe problem associated with some of the pesticides beekeepers are using now."

Offering insights from the field of RNAi therapeutics, Quark Pharmaceuticals' Vice President of Development James Thompson wrote to the EPA that "RNAi is a process that occurs naturally in almost all metazoans and as such, ingested RNA is unlikely to pose any safety hazards based on a long history of safe consumption.

"In addition, the human body’s biochemical barriers to absorption and cellular uptake, along with rapid degradation of nucleic acids after ingestion, make oral delivery of siRNAs and dsRNAs very difficult, thus limiting exposure to ingested RNA at levels that could impact gene expression," he added.

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