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2013 articles

New paper on dsRNA type GMOs - Q&A with the authors

on .

NOTE: In a new peer-reviewed paper published in the journal Environment International, the researchers Jack A. Heinemann, Sarah Z. Agapito-Tenfen and Judy A. Carman found that government safety regulators are failing to consider important risks of new kinds of GM plants and some emerging co-technologies.

These plants are designed to make a form of genetic information called double-stranded RNA (dsRNA). While most existing GM plants are designed to make new proteins, these new GM plants make dsRNA in order to alter the way genes are expressed. This is most commonly called RNAi for RNA interference, or post-transcriptional gene silencing. Recent research has shown that dsRNAs can transfer from plants to humans and other animals through food. 
- Zhang, L., et al. (2012). "Exogenous plant MIR168a specifically targets mammalian LDLRAP1: Evidence of cross-kingdom regulation by microRNA." Cell research 22(1): 107-126.
  http://www.ncbi.nlm.nih.gov/pubmed/21931358

Potentially, dsRNAs could also be transferred into people by inhaling dust from the plant (e.g., breathing in flour from GM wheat while baking with it), or by absorption through the skin - with unpredictable effects. The same technology is being developed for spraying directly onto plants as a type of pesticide spray. Another proposed use is to feed dsRNAs to insects such as bees to try to control bee viruses.

The paper's authors kindly agreed to answer some questions from GMWatch (below).

The paper "A comparative evaluation of the regulation of GM crops or products containing dsRNA and suggested improvements to risk assessments" by J.A. Heinemann, S.Z. Agapito-Tenfen and J.A. Carman is published by Environment International. The paper is open access (free download), thanks to sponsorship of the open access fee by the Safe Food Institute of Australia:
 http://www.sciencedirect.com/science/journal/01604120/55
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Interview with the authors of the dsRNA paper
by GMWatch
22 March 2013

GMW: Why should we care about this paper? 

Authors: The paper chronicles the systematic neglect by leading food and environmental safety regulators of important safety issues with GM crops, and emerging products containing molecules called double-stranded RNA (dsRNA). The record of neglect and the analysis of the failings have been verified through the judgment of rigorous blind peer-review.

The paper also establishes that all GM crops should be evaluated for the presence of unintended dsRNA molecules. That is, even crops not purposefully constructed to express these molecules need to be evaluated for them, because they are a common by-product of the engineering process. To date, GM crops have not been evaluated in this way.

Finally, the paper shows that the prevailing systems for evaluating the potential for adverse effects from dsRNA would fail. And for the first time, a robust process for testing GMOs or other products that may contain dsRNAs is suggested.

GMW: Won't industry and regulators say that the risks have been considered and GM crops have a clear track record of safety?

Authors: We show in the paper that the regulators have a priori denied the need to assess either the direct or important potential secondary effects of the dsRNA molecules. Instead they have resorted to flawed and outdated assumption-based reasoning on the biochemistry of dsRNA. Thus, there is no public record of regulators ever having required or reviewed studies that provide evidence for no: (a) off-target effects of intended novel dsRNA molecules in the GMO; (b) effects of unintended novel dsRNA molecules in the GMO; and (c) production of unintended secondary dsRNA molecules in the GMO or in those exposed to the GMO (e.g., through ingestion, inhalation or absorption) – including non-target insects, wildlife and people. Consequently, there has never been an acute or chronic toxicity study done, for any commercial GMO, that has had the ability to detect any effect that could arise specifically from the primary or secondary dsRNA molecules that could be generated by the GMO
.

There is no validated safety testing procedure for dsRNAs either for human food or the environment. And there are no international guidance documents that regulators can turn to for advice.

GMW: But surely, RNA is, and always has been, a part of the foods we eat.

Authors: In this and a previous paper (Heinemann and others 2011), we have shown that there is no basis for extrapolating the safety of novel dsRNA molecules from the history of safe use of dsRNA molecules in the cells of plants, animals, fungi and microorganisms that we eat. This is the key distinction: the adverse effects that might arise from dsRNA are determined by the actual sequence of nucleotides in the molecule (sequence-determined risks) and not the chemical nature of RNA. While there are also sequence-independent risks that should not be ignored, there is a difference between the sequence of novel dsRNA molecules in GM crops and those in nature, and that is why arguments about all dsRNAs being safe are dangerously flawed.

An example that provides proof is corn engineered to resist the corn rootworm pest. Corn rootworm has always eaten maize roots and maize roots contain RNA (including forms of dsRNA). However, when Monsanto introduces a novel dsRNA of a specific sequence into the cells of the plant, the corn rootworm eating that RNA dies (Baum and others 2007; Gordon and Waterhouse 2007).

GMW: We're told though that it is very difficult to deliver dsRNAs to mammals, including people. That's what is stopping their use in medicine.

Authors: While this is true, it is irrelevant. Although researchers have not managed to find a pill or injectable form of dsRNA that works on people by design, it is now known that plant dsRNA molecules can be efficiently taken up through food to circulate through blood and alter gene expression in organs. Not all dsRNA molecules seem to be equally efficiently taken up, which indicates that there are processes involved that we still do not understand. Current thinking is that the way plants chemically modify dsRNA, and the presence of receptors for some dsRNAs on animal cells, determines the fate of dsRNA when it is taken up through food. It is also known that dsRNAs can be delivered to humans by breathing it into their noses.

GMW: But doesn't your paper overstate the risks? There are already safe GM products on the market using dsRNA.

Authors: The paper has a table of all the dsRNA food approvals that we know of (from our countries). It can be seen that most have either not been commercialized or have been withdrawn (e.g., Flavr Savr tomato, the G series of oleic acid soybeans, new leaf potato), and the remainder are in early commercial stages (e.g., Brazil's pinto bean, Monsanto's high oleic acid soybeans). The exceptions are boutique crops such as the Hawaiian papaya, which may not always make the dsRNA molecule the plant has been designed to make. Thus, we have almost no real experience upon which to base a track record of safety.

Importantly, the range of companies, the kinds of traits, and the means of delivery are due to change rapidly. Thus, so will the sequence-determined risks because all the new novel dsRNA molecules will have unique sequences. For example: Australia's CSIRO (a government body that does commercially-oriented research) holds significant patents on food-borne delivery of dsRNAs intended to harm target insects, and is developing wheat with altered nutritional characteristics using dsRNA. A consortium of Alnylam Pharmaceuticals, Isis Pharmaceuticals, Monsanto, Genzyme and Sanofi (Aventis) is capturing THE patent space on chemical delivery systems for topical (i.e., absorption through skin or cell membranes) RNA applications. Monsanto (and probably other agrichemical companies) intends to develop pesticide sprays based on dsRNA (called its Biodirect line). These sprays are designed to transverse cell surfaces, so that they are absorbed by the organism and then transported through the tissues of that organism. The range of exposures, the scale of exposure, and the nature of the risk are without precedent.

Monsanto has purchased Beeologics, a company developing dsRNA molecules that are eaten by bees and mites through their preferred foods. The dsRNA molecules intended for mites are biocidal, the dsRNAs intended for bees are medicinal. Monsanto has also purchased the Rosetta Green company's "activity", which includes its work using dsRNA to manipulate a range of crops and traits.

GMW: You've proposed a risk assessment scheme for dsRNA products. Won't industry say it's too impractical, too expensive, and an unnecessary barrier to bringing food to poor and starving people?

Authors: The proposed safety scheme, illustrated in Figure 3 of the paper, is based on the proper application of cutting edge science. However, the capacity for this science is well within the expertise of both the industry and the academic community and is not particularly expensive. For example, the bioinformatics techniques suggested require a personal computer, access to the internet and trained personnel (of a kind that are common now in molecular biology). 

Meanwhile, the transcriptomic work is well within the industry's ability as illustrated by papers they publish, and an extension of the molecular work already done. The costs of this kind of work are in the same range as the costs needed to identify the intended dsRNAs for commercial development and are a minor part of the marketing, intellectual property rights registration, research and development program for the product.

Moreover, the products are not intended to feed poor people. The pesticide 'technology package' that is being delivered is designed for large industrial monoculture farms, which produce mainly animal feed and biofuel. For example, high oleic acid soybeans are promoted to food safety regulators as a 'safer' alternative to conventional soybean oil when in fact they are being developed to appeal to biofuel manufacturers (Graef and others 2009). Companies do not intend to sell these products in countries that do not recognise their intellectual property claims and for which they cannot extract a price premium, in other words, they are not intended for direct sale to the poor and starving.

GMW: Thinking back to the GM lobby's response to Prof Seralini's 2012 paper on GM maize and Roundup, won't they say that you are just anti-GM activists? And that the journal is obscure?

Authors: Environment International is an Elsevier journal ranked in the top 4% of environmental sciences journals by impact factor; A* by Excellence in Research for Australia, its highest standing; and A1 in the Brazilian/Capes ranking, also the highest standing.

All three authors are academics in good standing at recognised world-class public universities. They have extensive and credible publication records in the peer-reviewed literature and are biosafety experts of standing.

Dr. Jack A. Heinemann is professor of Molecular Biology and Genetics in the School of Biological Sciences, and Director of the Centre for Integrated Research in Biosafety, at the University of Canterbury, New Zealand.

Sarah Z. Agapito-Tenfen has a masters degree in Plant Genetic Resources from the Universidade Federal de Santa Catarina in Brazil and is currently a PhD student there.

Dr. Judy Carman is an adjunct associate professor in Health and the Environment, School of the Environment, at Flinders University in South Australia and is also Director of the Institute of Health and Environmental Research. She has qualifications and experience in biochemistry and epidemiology.

Paper is open access (free download) from  http://www.sciencedirect.com/science/journal/01604120

References to the Q&A

Baum, J.A.; Bogaert, T.; Clinton, W.; Heck, G.R.; Feldmann, P.; Ilagan, O., et al. Control of coleopteran insect pests through RNA interference. Nat Biotechnol. 25:1322-1326; 2007

Gordon, K.H.J.; Waterhouse, P.M. RNAi for insect-proof plants. Nat Biotechnol. 25:1231-1232; 2007

Graef, G.; LaVallee, B.J.; Tenopir, P.; Tat, M.; Schweiger, B.; Kinney, A.J., et al. A high-oleic-acid and low-palmitic-acid soybean: agronomic performance and evaluation as a feedstock for biodiesel. Pl Biotechnol J. 7:411-421; 2009

Heinemann, J.A.; Kurenbach, B.; Quist, D. Molecular profiling — a tool for addressing emerging gaps in the comparative risk assessment of GMOs. Env Int. 37:1285-1293; 2011