THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE
Dear friends and colleagues,
Re: New kinds of GM plants and pesticides not being assessed for safety
A paper published in the journal Environmental International highlights how regulators have not assessed the safety of GM plants that may produce new double-stranded RNA (dsRNA) molecules, as well as for products where the active ingredient is 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. Recent research has shown that dsRNAs can transfer from plants to humans and other animals through food. Potentially, they 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.
While some genetically modified organisms (GMOs) are intended to produce new regulatory-RNA molecules, these may also arise in other GMOs not intended to express them.
The authors looked at how the safety of these plants was determined. They reviewed their experience with three government safety regulators (for either food or the environment) in three different countries over the past ten years. They found that the safety of dsRNA molecules was usually not considered at all, and if it was considered in any way, the regulator simply assumed that any dsRNA molecules were safe, rather than requiring proof that they were safe.
As a result, the regulators did not assess whether the dsRNAs could cause adverse effects in people or in the environment by, for example, silencing or activating genes in people that come into contact with the plant when it is grown commercially. Contact could include eating the crop or processed products derived from it, inhaling dust from the crop when harvesting it, or inhaling flour from the crop when baking with it. And regulators made that decision regardless of whether the dsRNA was generated intentionally or unintentionally by the crop.
As a result of their analysis, the authors have developed and provided a safety testing procedure for all GM plants that may produce new dsRNA molecules, as well as for products where the active ingredient is dsRNA.
The paper is available for free download here: http://www.sciencedirect.com/science/journal/01604120
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Item 1
Heinemann, J. A., Agapito-Tenfen, S. Z. and Carman, J. A.
A comparative evaluation of the regulation of GM crops or products containing dsRNA and suggested improvements to risk assessments.
Environ Int in press.
Abstract
Changing the nature, kind and quantity of particular regulatory-RNA molecules through genetic engineering can create biosafety risks. While some genetically modified organisms (GMOs) are intended to produce new regulatory-RNA molecules, these may also arise in other GMOs not intended to express them. To characterise, assess and then mitigate the potential adverse effects arising from changes to RNA requires changing current approaches to food or environmental risk assessments of GMOs. We document risk assessment advice offered to government regulators in Australia, New Zealand and Brazil during official risk evaluations of GM plants for use as human food or for release into the environment (whether for field trials or commercial release), how the regulator considered those risks, and what that experience teaches us about the GMO risk assessment framework. We also suggest improvements to the process.
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Item 2
New kinds of genetically modified plants and pesticides not being assessed for safety
Press release
Centre for Integrated Research in Biosafety, University of Canterbury, New Zealand
European Network of Scientists for Social and Environmental Responsibility (ENSSER)
21 March
Contact: +64 3 354 2500, Fax: + 64 364 2590
Christchurch, NZ, 22.03.2013 – In a new peer-reviewed paper published by an international team from New Zealand, Brazil and Australia in the prestigious journal Environment International, the researchers Jack A. Heinemann, Sarah Z. Agapito-Tenfen and Judy A. Carman have found that government safety regulators are failing to consider important risks of new kinds of genetically modified (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. Recent research has shown that dsRNAs can transfer from plants to humans and other animals through food. Potentially, they 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.
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.
While RNA is a normal component of all cells, in dsRNA form it can have effects that depend on the species and tissues exposed to it. According to Adjunct Associate Professor Judy Carman of Flinders University and a co-author of the paper: "The dsRNA molecules in GM plants may work exactly as intended and have no other effects. On the other hand, they may have effects that were not predicted, both on their target organisms and other organisms such as people and wildlife. We won’t know until we do thorough assessments, and these assessments have not yet been done."
The authors collectively reviewed three food or environment safety regulators with jurisdiction in three countries, Australia, Brazil and New Zealand. The regulatory decisions were on three different kinds of GM plants that do or may produce new dsRNA molecules and were intended for use as food or animal feed. The authors recorded their advice to the regulators and the responses from the regulators.
"Each regulator found reasons not to ask the product developers to specifically test for effects from dsRNA, and thus relied on assumptions rather than testing to determine safety," said co-author Sarah Agapito-Tenfen, a doctoral student at the Universidade Federal de Santa Catarina in Brazil.
"To our surprise, we found that there are no internationally agreed protocols or even guidelines for how to conduct a thorough and proper risk assessment on products with new dsRNA molecules in them," said Prof. Jack Heinemann of Canterbury University in New Zealand, member of ENSSER and the study’s lead author. To fill this gap, the authors have developed the first formal assessment procedure for dsRNA-based products, whether they are living genetically modified organisms or agents that are sprayed onto plants.
Contacts for further comment
Jack Heinemann: jack.heinemann@canterbury.ac.nz; +64 3 364 2500
Sarah Agapito: sarahagro@gmail.com; +55 48 37215336
Judy Carman: judycarman@ozemail.com.au; +61 408 480 944
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, 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 in biochemistry and epidemiology.
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.
The Centre for Integrated Research in Biosafety (INBI, previously NZIGE) was founded in 2001 as a research centre at the University of Canterbury. The Centre is dedicated to public good science with a focus on research in biotechnology of relevance to those with limited or no access to science research funding.
The European Network of Scientists for Social and Environmental Responsibility (ENSSER) brings together independent scientific expertise to develop public-good knowledge for the critical assessment of existing and emerging technologies. The objective of ENSSER is the advancement of public-good science and research for the protection of the environment, biological diversity and human health against adverse impacts of new technologies and their products. ENSSER advocates benign and peaceful use of scientific discoveries and technological developments, while expanding diverse approaches to assess their utility and safety in society. More information available at: http://www.ensser.org.
Notes for editors:
Open access (free download) http://www.sciencedirect.com/science/journal/01604120
The new paper is available for free download here:
http://www.sciencedirect.com/science/journal/01604120
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Item 3
A briefing document for non-specialists describing the lack of regulation of a new class of products and GM crops based on dsRNA technology
by
Adjunct Associate Professor Judy Carman, Professor Jack Heinemann and Sarah Agapito-Tenfen
21 March 2013
This is a briefing about the contents of a new, peer-reviewed scientific paper: "A comparative evaluation of the regulation of GM crops or products containing dsRNA and suggested improvements to risk assessment" by Professor Jack Heinemann, Sarah Agapito-Tenfen and Adjunct Associate Professor Judy Carman.
To date, most [1] genetically modified (GM) plants have been made by inserting a new piece of DNA into a plant so that the GM version makes a new protein. Most of these new proteins are designed to either kill insects that try to eat the plant or to make the plant resistant to a herbicide. The process works like this: the DNA is changed so that when a section of the DNA is read and copied, a new piece of messenger RNA (mRNA) is made. The mRNA then goes to another part of the cell and is read to make the new protein.
However, there is a new type of GM plant now being made. These are not designed to make a new protein, but to just make a new RNA molecule. However, the RNA molecule made is different to the single-stranded mRNA described earlier, because it is either double-stranded (dsRNA) or it is designed to find another single-stranded RNA molecule and bind to it to create a dsRNA molecule. These dsRNA molecules have important roles in cells. For example, they can silence or activate genes. For this to happen, the order of the nucleotide units in the dsRNA molecule is crucial. A different sequence can result in the dsRNA having different effects, and silencing or activating a different gene, or multiple other genes.
A number of GM plants have now been made using this technology. For example, Australia’s CSIRO has developed GM wheat and barley varieties where genes have been silenced in order to change the type of starch made by the plant. Another example is biopesticide plants, which are designed to silence a gene in insects that eat the plant. That is, the insect eats the plant, the dsRNA in the plant survives digestion in the insect, travels into the tissues of the insect to silence a gene in the insect so that the insect dies as a result.
There is evidence that the gene silencing may be inherited by the offspring of some organisms that eat the dsRNA.
Furthermore, there is massive, ongoing investment occurring to develop products that directly transfer dsRNA into the living cells of plants, animals and microbes via their food or by being absorbed through their "skin". This allows dsRNA molecules to be sprayed onto fields of crops to kill insects or to be delivered to beehives as oral medicine for bees.
Last year, a high profile scientific paper was published that showed that dsRNA molecules produced in non-GM plants can be taken into the bodies of people who eat the plant. The dsRNA from the plant was found circulating in blood, indicating that it survives cooking and digestion. Research has also shown that:
*at least one dsRNA produced in plants (called mir168a) can change the expression of genes in mice; and
*dsRNA (mir168a) can change the expression of a gene in human cells growing in tissue culture. Therefore, there is a real risk that the dsRNA produced by these new GM crops could survive digestion in people and change how those people’s genes are expressed. These effects of dsRNA were predicted long ago by some scientists. The proof has now arrived.
So, are all dsRNA molecules safe?
A new paper has just been published in Environment International by Professor Jack Heinemann of New Zealand, Sarah Agapito-Tenfen of Brazil and Adjunct Associate Professor Judy Carman of Australia. These authors looked at how the safety of some plants, designed to produce new dsRNA, was determined. They reviewed their experience with three government safety regulators (for either food or the environment) in three different countries over the past ten years. They found that the safety of dsRNA molecules was usually not considered at all, and if it was considered in any way, the regulator simply assumed that any dsRNA molecules were safe, rather than requiring proof that they were safe.
The authors found that government regulators:
*dismissed any need for any assessment of the sequence of the nucleotides in the dsRNAs produced by GM plants;
*seemed to assume that dsRNAs produced by these plants are much the same as the more fragile single-stranded RNAs (eg mRNA), and therefore would not survive cooking and digestion; and
*claimed that these new dsRNA molecules are safe because humans and non-target animals would simply not be exposed to them.
However, the authors found many scientific studies showing that these assumptions were incorrect.
As a result, the regulators did not assess whether the dsRNAs could cause adverse effects in people or in the environment by, for example, silencing or activating genes in people that come into contact with the plant when it is grown commercially. Contact could include eating the crop or processed products derived from it, inhaling dust from the crop when harvesting it, or inhaling flour from the crop when baking with it. And regulators made that decision regardless of whether the dsRNA was generated intentionally or unintentionally by the crop. All three regulators decided that there were no risks to be considered, based on their own unproven and incorrect assumptions, rather than the scientific evidence.
As a result of their analysis, the authors developed and provided a safety testing procedure for all GM plants that may produce new dsRNA molecules, as well as for products where the active ingredient is dsRNA.
It is important to realise that our current understanding of dsRNA in GM plants is in its infancy and we are still trying to understand how dsRNA molecules may work and therefore how they may affect humans, animals and the environment. Even so, some GM plants using this technology have already been approved for human consumption, using the sorts of assumptions described earlier. Of these crops, several have been withdrawn from the market, while others are about to enter it.
Meanwhile, spraying dsRNAs directly onto crops can be expected to result in large exposures to dsRNA molecules in the environment. For example, we know that existing agricultural sprays can travel for several miles on the wind and can enter surface water and ground water due to run-off after rain. This will also happen with dsRNA molecules if they are sprayed onto crops. We also know that dsRNAs can persist for a long time in the environment.
GM plants and products based on dsRNA technology need a thorough, fit-for-purpose safety evaluation before we use them commercially. The authors provide a step-by-step procedure of how this could be done.
After all, we don’t want to learn that one or more of these crops or sprays is toxic after millions of people have been exposed to them for years.
Notes
1. There are some extremely minor exceptions to this, such as virus-resistant papaya, some nutritionally- altered soybeans, and some other plants that are not yet on the market.
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Item 4
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. 7111-421; 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