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In a typical move, the U.S. Environmental Protection Agency (EPA) proposes to greenlight a type of genetic engineering to solve a problem created by the industrial paradigm for pest control, i.e. vast acreages of monoculture treated with millions of tons of toxic pesticides leading to rapid resistance among crop pests.
In this case, EPA wants to approve using a nucleic acid — double-stranded RNA (dsRNA) called “interfering RNA,” or RNAi — to silence a gene crucial to the survival of the Colorado potato beetle (CPB), the scourge of potato farmers around the world. But EPA has skipped over important steps in its decision-making process and rushed to judgment.
Like chemical pesticides, genetically based pesticides are regulated under the Federal Insecticide, Fungicide, and Rodenticide Act. In 2020, Massachusetts-based GreenLight Biosciences applied for registration of its RNAi active ingredient, Ledprona, and its end-use product, Calantha. The company executive heading the effort is an alumnus of Monsanto and several other major chemical companies.
Last May EPA granted GreenLight an Experimental Use Permit (EUP) authorizing field studies in states that produce tons of potatoes. A mere five months later, the EPA announced its decision to approve the registration based almost entirely on incomplete EUP data and giving the public very little time to comment.
Formally titled “Colorado Potato Beetle (CPB)-specific recombinant double-stranded interfering Oligonucleotide GS2 Leptinotarsa decemlineata,” Ledprona disrupts an RNA process inside cells to block the expression of a particular CPB gene. This prevents the gene from specifying an important protein.
When a CPB ingests Ledprona on a potato leaf, the RNAi nucleotide spreads into the cells of the beetle’s gut. The cells die, which shortly kills the beetle.
Unfortunately, dsRNA molecules may wander from their intended targets. Inside a cell, the long dsRNA strand gets clipped into small pieces called siRNAs (“small interfering RNAs”), whose configuration may also align with many other sections of a genome and affect nontarget genes, with entirely different effects.
One experiment with interfering RNA found complete matches in 17% of off-target sequences. Neither EPA nor GreenLight has addressed this risk.
According to EPA’s Environmental Risk Assessment, GreenLight intends Calantha to be applied in ground spray, aerial spray (via airplane) and in irrigation water — in other words, very broadly, and in a manner that will inevitably entail some spray drift.
The Center for Food Safety (CFS) prepared a blistering comment to EPA noting the agency’s extreme disregard for both known biological processes and the unknowns of losing a novel piece of cellular machinery into the wild.
According to the CFS, the EUP field trials granted to GreenLight remain incomplete and will not expire until April 30, 2025, yet EPA admits that its approval of Ledprona and Calantha relies solely on data GreenLight submitted with its application for the EUP — whose data requirements are considerably lower than those for new use approvals.
Federal Insecticide, Fungicide, and Rodenticide Act requires, for example, data on toxicity to fish, birds, and plants. GreenLight has not provided that data so far.
EPA assumes that only organisms that resemble the CPB might be susceptible to Ledprona’s interference with their cellular machinery, yet dismisses even that possibility.
The agency’s Environmental Risk Assessment states that:
“There is a reasonable expectation of no discernible effects to occur to any non-coleopteran nontarget organisms exposed to Ledprona … EPA analysis also examined the 19 federally listed threatened and endangered (‘listed’) coleopteran species and determined that no exposure is expected for 15 of the 19 federally listed threatened and endangered (‘listed’) coleopteran species from a section 3 registration of Calantha containing Ledprona.”
(The CPB belongs to the order Coleoptera, along with 400,000 other beetle species known to science. Many coleopterans provide beneficial services.)
Additionally, the EPA says, “Physiological barriers are present within vertebrate species that prevent the dsRNA such as Ledprona from reaching and penetrating the gut in vertebrate species.” Given the unpredictable alignments of the small interfering RNAs in a genome, this too is an iffy assumption.
The CFS comment notes that, although EPA has not provided any information to the public about Ledprona’s nucleotide length, that data is an important factor in assessing the product’s potential toxicity. EPA has designated the dsRNA in Ledprona as “non-coding,” which it takes to mean that it would not function in a human body, but, in fact, nobody knows whether or how many such “long, non-coding RNAs” function in many species.
What is known, according to CFS, is that human innate immune systems respond to such sequences, which often come from viruses or from the body’s own damaged cells, with inflammation.
We can expect more pesticide products to be based on genetic processes such as RNAi’s regulation of gene expression as farmers and chemical companies get more desperate with each passing report of pests’ ability to evade pesticides.
It is unsurprising that the CPB is an early target because it is notorious for its rapid development of resistance. Currently, it is resistant to more than 50 pesticides.
In the long run, CPB will win. It is already ahead. In 2021, a research team, three of whom are employed by Monsanto, found that CPB “can develop high levels of resistance against insecticidal dsRNA” when the dsRNA is applied to leaves. The study also found that the dsRNA affected more than one gene.
Various analyses of CPB’s response to a range of doses led the scientists to conclude that, after a few generations, resistance to dsRNA reached 11,100 times that of the founding generation of beetles. The researchers attributed CPB’s virtuosic ability to resist pesticides partly to the beetle’s highly flexible and transposable genetic elements.
This indicates that creating precise and effective products using genetics is fraught with risks. A plain hydrocarbon molecule is understood vastly better than the interplay of the trillions of genes in the world.
Pesticide resistance was first noted in 1914, but the industry still fails to recognize that it cannot bet against the house. To cope with the inevitable triumph of natural selection, pesticide manufacturers are promoting the use of dsRNA products in combination with traditional pesticides, with the idea that their mechanisms of action will alternate and prevent pests from adapting.
Combining pesticides with RNA interference can be framed as part of “integrated pest management,” although as a 2018 review in Science noted, the notion that “such combinations will slow [the development of] resistance is theoretically controversial and lacks empirical support.”
Beyond Pesticides chronicled in 2019 the promotion of interfering dsRNA technologies by pesticide companies despite the recognition that their effects on nontarget organisms cannot be predicted.
“With the allowance of gene-manipulating RNAi pesticides, EPA is repeating a pattern of allowing uncertainty that has historically resulted in serious unexpected and uncontrolled hazards, despite the availability of organic practices and products that are currently available,” said Beyond Pesticides’ executive director, Jay Feldman.
“The agency has failed to fully evaluate the fate of genetic material and its degradation products on nontarget species and the likely potential for indiscriminate poisoning. We are calling for a moratorium on RNAi pesticides until these questions can be fully answered.”
An expert at another federal agency once observed that it is not a good idea to rely on “a conclusion drawn from a consensus” rather than from empirical evidence when making important decisions.
In this case, EPA has done exactly that, mistaking suppositions for facts. EPA’s decision rests on a foundation of uncertain assumptions, many of which are implicit in EPA’s evaluation rather than explicitly enumerated, and whose reliability EPA did not examine.
Originally published by Beyond Pesticides.