I will be in Rome on Feb 15-17 for an International Symposium on “The Role of Agricultural Biotechnologies in Sustainable Food Systems and Nutrition”. Apparently, the details are still being worked out.
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Oxford Real Farming Conference
I will be on a panel at the Oxford Real Farming Conference on Jan 6th. The other participants will be Helena Paul and Michel Pimbert. The session will be on “The Corruption of Agricultural Science”.
What Is Nature Biotechnology Good For?
Jonathan Latham and Allison Wilson
Quite likely it surprised many regular readers of Nature Biotechnology that for the September (2007) issue their journal had invented a new article format specifically in order to describe, and then extensively criticise, the work of a researcher that most of them had never heard of before (1). That surprise will only increase if they read the translation, featured on our website, of a Nov 1st article (The excommunication of a heretic) in the Swiss Newspaper WOZ. Readers who thought this new format was simply a curious, if rather aggressive, literary innovation, can now see that this was a story with a disturbing history. Even more interesting however than the ethical shenanigans behind the publication of the interview with Dr Ermakova, is a point not raised by the Swiss newspaper article.
In science, opinions may differ, but it is not usual to attempt to embarrass opponents with overt public criticism. The existence (or imminent prospect) of reproducible data that will settle the issue is usually sufficient to ensure that most disputes never reach the printed page. So why has this dispute followed a different course?
Roundup Ready™ Soybeans, all of which are derived from a single transgene insertion event (40-3-2), have been on the market for approximately twelve years. They have been grown on millions of hectares and passed regulatory safety assessments in many countries. If a researcher makes a seemingly anomalous finding that RR Soy harms rats then surely all that should be necessary is for their critics to reach for the multitude of studies already in existence for a handy refutation? For Roundup Ready soy however, such a body of incontestable data does not exist. It is this remarkable data gap that seems to be behind the Nature Biotechnology interview with Dr Ermakova and quite probably it is for this reason that her unpublished study so alarms the biotech industry.
In the case of Roundup Ready soy, there is a single broadly comparable (i.e. multi-generational) study that examines similar endpoints in rodents (in this case mice) fed Roundup Ready Soy and that also supports the contention that mice are unaffected by Roundup Ready soy (Brake and Evenson 2004). The problem however is that this is only a single small study and, although published in a peer reviewed journal, it suffers from as many flaws as does the study carried out by Dr Ermakova. For those interested, we can recommend applying the Nature Biotechnology criticisms of Dr Ermakovas’ study, to the Brake and Evenson study.
For example, Dr Ermakova is criticised in the interview for having bought her seeds from ADM Netherlands, even though she says she tested to confirm that they contained the Roundup Ready (40-3-2) transgene. Brake and Evenson in contrast report that they relied on an unnamed seed dealer taking them to a single field of Roundup Ready soy and a single non-transgenic field, where they obtained soybeans from unspecified cultivars. Brake and Evenson report no attempt to verify the dealers’ identification of the soybeans as transgenic or otherwise (Brake and Evenson 2004). It is therefore hard to understand why Brake and Evenson’s should be considered a superior method for obtaining samples.
There is one further published study, not mentioned by the Nature Biotechnology critics, that is comparable (in the sense of being multigenerational) to those of Ermakova and Brake and Evenson. It reports histological studies on the offspring of mice fed Roundup Ready soy (Malatesta et al., 2002a). These authors reported ultrastructural alterations to hepatocytes only in the offspring of pregnant mice fed Roundup Ready soy, but no other differences (Malatesta et al., 2002a). A further paper from the same laboratory reported biochemical (but not visible) alterations to pancreatic cells of mice fed Roundup Ready soy for up to 8 months after weaning (Malatesta et al., 2002b). These two papers arguably offer some support for Dr Ermakova’s work in that effects of Roundup Ready soy were observed, although the effects seen were not the same. For example, no effects on offspring body weight or mortality were noted.
Perhaps the most important general point about all these multigenerational studies is that none of them used near-isogenic soybeans grown side-by-side, which is a prerequisite for a properly controlled test of the question that we all want answered: whether the 40-3-2 transformation event can be responsible for altered toxicological or nutritional properties of soybeans.
The critics’ challenges to Dr Ermakova’s work are mostly reasonable (2). They rest on demonstrating flaws in her methodology and also on the assertion that her work is further contradicted by four mammalian feeding studies of Roundup Ready soy, even though, unlike Dr Ermakova’s, all of these are single generation studies (Zhu et al., 2004; Teshima et al., 2000; Cromwell et al., 2002; Hammond et al., 1996). As in their comparison with the Brake and Evenson work however, the criticisms create the impression that these papers do not themselves suffer from the flaws noted in Dr Ermakova’s work. This is not the case however and from a toxicological perspective, the limitations of all these studies (summarised in Tables A and B) are strikingly similar to those pointed out by Dr Ermakova’s critics.
Table A details for each study the preparation and selection of soybeans for consumption (e.g. whether Roundup Ready and control soybeans were grown under the same conditions, whether isogenic lines were used, whether the presence/absence of the transgene was ascertained, etc.) while Table B details key attributes of the feeding studies themselves (such as how many animals were used, what percent soy was included in the diet etc). Looking at Tables A and B it is plain to see that, as a result of their collective limitations (which include short study durations, small numbers of animals and lack of replication), while no adverse effects were reported (though see footnote 3), their individual and collective limitations are highly significant.
These inadequacies, which are fundamental to any discussion about whether Dr Ermakova’s data are in conflict with the published literature, appear to have been missed entirely by the Nature Biotechnology critics. It is not the only mistake they make however. They seem to have been unaware of the Malatesta papers, they cite Teshima et al. and Zhu et al. in stating that “Previous reports in the literature have shown no effects of Roundup Ready soy on birth weights or pup mortality” (p983) yet neither paper studied birth weights, pregnant rats or pregnant mice. In fact, Teshima et al. started their study on rats and mice that were both seven weeks old and Zhu et al. started theirs on 28 day old rats. None of these are trivial errors and they make the question-raised by Roland Fischer of WOZ-of why Nature Biotechnology failed to use truly expert referees, a highly pertinent one.
Ultimately, more important than any misrepresentation of the evidence by these four critics, is a question that is central for regulators who are asked to approve and consumers who are offered Roundup Ready soy: does the existence of these seven flawed studies tell us anything useful about the safety or otherwise of Roundup Ready cultivars? This question is also an interesting one purely from a scientific perspective because current scientific understandings (especially in regulatory science) are very frequently constructed from small numbers of highly imperfect studies. The answer would seem to depend on at least three parameters, all of which are mutually dependent. Firstly, the precise nature of those flaws, because some, such as failing to positively determine the presence of the transgene in the treatments, and equally its’ absence from the controls, ought to invalidate any experiment regardless of the subsequent quality of data collected (4). The second significant parameter is whether the flaws in each paper are the same or overlapping. Flaws in one paper, and usually these will be data gaps, can sometimes be made up for by the results of another. Lastly, an experiment may be perfectly useful, but nevertheless not support the conclusions which the authors draw. Failure to use isogenic lines and/or to grow them side-by-side means that, whatever the title of a paper may imply, any effect seen in the treatment group cannot be attributed specifically to presence of the Roundup Ready transgene. Using these criteria, any conclusions about the safety of Roundup Ready soy based on these data must be extremely limited and highly provisional, and consequently deeply unsatisfactory.
All of which raises an issue for Nature Biotechnology as a scientific journal. The safety or otherwise of Roundup Ready soybeans is a matter of great public health significance. New research suggesting that it might not be safe, especially when the prior research is inconclusive at best, should be a matter of significant concern. Yet Nature Biotechnology saw Dr Ermakovas’ work only as an industry threat and publicised her work seemingly only in order to dismiss it. There is no difference at all between what Nature Biotechnology has done to Irina Ermakova and what Fox news did to Marion Nestle when they hired Steven Milloy, then at the Cato Institute, to review her book Food Politics: How the Food Industry Influences Nutrition and Health. And if there is no difference in behaviour between Fox News and Nature Biotechnology, what is the value of Nature Biotechnology as a journal of science?
It seems to us that this interview is part of a pattern and that Nature Biotechnology has for some time been unclear where the line that traditionally separates trade magazines from science journals lies (5). Its’ owner, Nature Publishing Group no doubt finds that publishing a magazine that does double duty, as a science journal and as a trade journal, is a highly profitable combination, but equally it is never going to be one that encourages disinterested science (6). Consider what Nature Biotechnology could have done to address the question of transgenic soya biosafety: it could have invited Dr Ermakova to submit her work formally and, whether it was accepted or rejected; it could have written an editorial calling for appropriately controlled high quality independent research to fill the data gaps. It could have pointed out that, if anything the existing data provides hints that there is a need for such experiments. The fact that Nature Biotechnology did none of these should be of deep concern to all its readers.
Footnotes
1) Marshall, A. (2007) Nature Biotechnology 25: 981-98
2) Not all of their points are fair though. For example, Dr Ermakova is criticised for not double-blinding her experiments, yet none of the studies discussed in Nature Biotechnology or in this commentary were double-blinded.
3) Interestingly, though Zhu et al. make no mention of it, for all time points tested and for both sexes their results show an almost perfect correlation of decreasing white blood cell counts as Roundup Ready soy replaces conventional soy in the diet fed to their rats.
4) Although the fact that in some papers the developers of RR Soy were also the experimenters might be considered to mitigate this defect (Table A). Equally however, their collaborators might have tested for their own satisfaction.
5) Compare the treatment of non-target effects of Bt in the review by Romeis et al. (2006) in Nature Biotechnology 24: 63-71 with that of Lovei and Arpaia (2005) in Entomologia Experimentalis et Applicata 114: 1-14 or Hilbeck and Schmidt (2006) in Biopesticides International 2: 1-50.
6) It is also interesting to note that, unlike most journals, NPG journals have no association with any scientific societies and no independent editorial board.
References
Brake, D. G. and Evenson, D. (2004) Food Chem. Toxicol. 42 29-36.
Cromwell, G.L. et al (2002) J. Anim. Sci. 80: 708-715.
Hammond, B.G. et al (1996 J. Nutr. 126: 717-727.
Malatesta,M. et al (2002a) Cell Struct. Funct. 27: 173-180.
Malatesta, M. et al (2002b) J. Anat. 201: 409-446.
Teshima, R. et al (2000) J. Food Hyg. Soc. Japan 41: 188-193.
Zhu, Y. et al (2004) Arch. Anim. Nutr. 58: 295-310.
How the Science Media Failed the IAASTD
Jonathan Latham, PhD and Allison Wilson, PhD
You may not have heard of it, but a potential landmark document in the fields of development and agriculture (called by some the Intergovernmental Panel on Climate Change (IPCC) of agriculture) is currently in the late stages of reaching fruition.
Drafted by around 400 scientific and social science experts from around the world, it is called the International Assessment of Agricultural Science and Technology for Development (IAASTD). The IAASTD (www.agassessment.org/) is unusual in being a collaborative document evaluating solutions for agriculture, poverty and development that is actively inclusive. Thus, it is not only multi-disciplinary but also inclusive in terms of geography, institution and gender. As such, the IAASTD is potentially extraordinarily valuable as a uniquely representative and holistic document of the best current thinking in agriculture and development. In this it is a significant departure from most international agriculture reports that are typically dominated by one perspective, one government or one interest group (and which typically fails to help poverty for that reason).
In addition to the above, there is a further reason to value the IAASTD. It asserts repeatedly what it terms the multi-functionality of agriculture, by which it means that agriculture is not just a provider of food or fodder, but a provider also of social security, of ecosystem services, of landscape value, as well as other ‘outputs’.
Perhaps inevitably, given this broad and deep perspective, the current IAASTD draft adopts a more sophisticated analysis than is usual in international reports which have a habit of proposing solutions to poverty that resemble Escher’s impossible objects. Each report may be internally consistent but clashes with other goals. Thus agricultural objectives, for example, typically are incompatible with social objectives and environmental objectives for development. IAASTD, therefore, should be seen as a novel attempt to use an inclusive and multidisciplinary approach to circumvent these problems.
Therefore, instead of understanding agricultural development problems as principally functions of low yields and lack of productivity, the IAASTD considers wider issues such as food quality, sustainability, water use, land tenure, and energy use as crucially important components of any solution. Furthermore, it attempts to recognise the rights and needs of small farmers, women farmers and the hungry while also giving appropriate emphasis to the significance of power and its unequal distribution in the creation and maintenance of poverty. In line with this analysis the draft promotes special policy emphasis on small/poor farmers, the involvement of women in farming and non-chemical farming in order to promote food security.
If they are ever implemented, the lessons drawn by IAASTD (at least those in the current draft) would represent a remarkable break with current practices which typically emphasise farm consolidation and chemical-intensive agriculture (though these goals are often not described explicitly).
It is often lamented that our societies have an abundance of knowledge and a shortage of wisdom, but the current IAASTD draft comes as close to providing wise guidance for agriculture and development as we have yet seen. Its chief message is appropriately revolutionary: we have so far fed the world principally by depleting natural capital, and we must now look beyond business as usual if we really want to address poverty.
The GMO Angle
The IAASTD draft document is surprising for still another reason. Although supported by the World Bank, it does not offer much support for transgenic crops as the best hope, or even as a particularly useful tool, to alleviate the agricultural ills that beset developing countries, the hungry and the poor.
Most likely, inclusiveness and scarce support for GMOs by the IAASTD are in fact connected. It is probably no coincidence that a document arrived at transparently, using a tolerably democratic process (i.e. it was not written behind closed doors), and using a multidisciplinary approach, should conclude that GM crops have ‘lingering safety concerns’ and may even be harmful to rural development.
These conclusions in general, and the lack of support for GMOs in particular, are immensely unwelcome in some quarters. The publicity machines of Monsanto, Syngenta and others have not spent twenty years carefully positioning transgenics as the solution to every agricultural problem in order for them to be ignored by the largest and most diverse collection of agriculture and development policy experts ever assembled.
Last October, Monsanto and Syngenta resigned altogether from the IAASTD project. Though they gave no public reasons for their resignation, the industry body CropLife International told Nature magazine that an inability to make progress in arguing for GMOs was the fundamental reason (1).
A Tragedy for the Poor?
In a recent editorial, Nature magazine argued the interesting point that withdrawal of these companies was a tragic event. The companies, said Nature, were ‘deserting the poor’ (1). Leaving aside that Monsanto and Syngenta were a very small part of the IAASTD process, this statement is hard to support from a scientific point of view. Are Monsanto scientists more knowledgeable about poverty, development and the needs of developing country agriculture than university or government scientists? Probably not. Do Syngenta scientists have fore-knowledge of impending agricultural developments not available to the rest of us? They may have, but if so these are company secrets which have not so far been made available for discussion or disputation. Does Nature believe that academics and government scientists are unable to make the arguments for biotechnology? But if the scientific need for the companies’ presence was hardly overwhelming, it follows that neither is their loss a particularly significant one.
The inclusion of these company scientists was primarily a recognition, not of their expertise but of something else – most likely the power and influence of their employers, plus the company presence on the IAASTD steering committee and the companies’ financial support of the IAASTD. All of these are essentially political reasons for inclusion. Once included, it would be naive, however, not to have expected that their primary goal would be anything other than to ensure that the assessment erected no obstacles to the introduction of transgenics, and so it proved. It was predictable perhaps, but Monsanto and Syngenta were about as useful to the assessment as Exxon would have been at the IPCC.
The Real Motive for Withdrawal?
As the science media correctly asserted, the IAASTD is important (which begs the rather important question of why they have up to now ignored it). But if their accounts are to be believed, Syngenta and Monsanto’s withdrawal from the IAASTD can be fully explained by the frustration and difficulties of a handful of mid-level employees (2, 3). But is this really a plausible explanation? That multinational companies base strategic decisions on the ‘frustration’ or convenience of their employees? Far more likely surely, especially given that some negative publicity for the companies would (and did) accompany withdrawal, is that this explanation is not the real one. More plausible by far is the possibility that Monsanto and Syngenta’s withdrawal was carefully calculated.
History tells us that the most common reason participants abandon important but frustrating multi-party negotiations is when they believe they can better achieve their aims by abandoning, and therefore delegitimising, whatever agreement is eventually reached. And for maximum effect delegitimisation has to occur in public. If this was, in fact, their strategy, then Monsanto and Syngenta would have been very pleased indeed by what happened next.
Following their withdrawal, Nature Biotechnology devoted its full editorial page to questioning the credibility of the (post-corporate) assessment, reporting that IAASTD’s criticisms of GMOs were “unsubstantiated” and reflective of a “bias against top-down solutions” and further that the report was “skewed” and not “representative” (2). Nature’s editorial called the report “undoubtedly over-cautious and unbalanced” and agreed that the company defections were “a blow to the credibility” of the IAASTD (1). The largest article of all was a feature in Science (3). As with Nature Biotechnology, the core of the Science article focused on the “question of balance” and assertions that the outcome was negative because of “bias”. Science even reported the no doubt impartial molecular biologist Jonathan Gressel as saying “The whole thing was incredibly stacked”. Though giving more-or-less respectful attention and space to defenders of inclusiveness, Science gave no space at all, in four pages, to anyone prepared to argue the possibility that the IAASTD assessment of GMOs was fair and realistic. Perhaps what would have made Monsanto and Syngenta most pleased was the allegation by a person “who asked not to be named” that the “best scientists” were not on the IAASTD (3).
In placing the blame for the corporate boycott exclusively with the IAASTD, perhaps it never occurred to any of the journal editors that in so doing they were supporting a tiny handful of corporate biotechnologists against the aggregated views of 400 independent scientists?
Monsanto and Syngenta have so far won the media battle, but the real test of their strategy is still to come: will they attempt, and if they do, will they succeed, in derailing adoption (or modifying the text) of the final report? If they were to succeed that really would be a tragedy for the poor, because the IAASTD, at least in its draft form, is a potentially world-changing document. It offers a lot and it asks a lot: a chance to make a real improvement to livelihoods and sustainability in return for rethinking agriculture as usual. It is a shame that the science media would rather support (big) business as usual.
References
(1) Anonymous (2008) Deserting the hungry? Nature 451: 223-24.
(2) Anonymous (2008) Off the rails. Nature Biotechnology 26: 247.
(3) Stokstad, E. (2008) Dueling visions for a hungry world. Science 319: 1474-76.
Download the draft executive summary of the IAASTD (called the Synthesis report)
Long-term persistence of GM oilseed rape in the seedbank
Jonathan Latham, PhD and Allison Wilson, PhD
A key aspect of transgenic agriculture is control of gene flow. Gene flow is important for many reasons including: 1) protecting intellectual property from unwanted incursions into farmers’ fields (and vice-versa); 2) maintaining the genetic integrity of crop cultivars; 3) maintaining labelling and consumer choices; and 4) biosafety risk assessments which presume limited transgene dispersion and that transgenic traits can be removed from circulation.
Coexistence between genetically modified (GM) and non-GM plants is a field of rapid development and considerable controversy. Predicting GM volunteer emergence in subsequent non-GM crops is one important aspect of this. Theoretical models suggest recruitment from the seedbank over extended periods, but empirical evidence matching these predictions has been scarce.
In a paper published in Biology Letters, D’Hertefeldt, Jørgensen and Pettersson (2008) provide evidence of long-term GM seed persistence in conventional agriculture. Ten years after a trial of GM herbicide-tolerant oilseed rape, emergent seedlings were collected and tested for herbicide tolerance. In line with volunteer reduction recommendations established at the time of the original experimental trial, the field had been ploughed every year, harrowed, and planted with wheat, barley and sugar beet. Volunteers were controlled by herbicide application and visual inspection to ensure that no transgenic volunteers would flower. Seedlings that survived the glufosinate herbicide (15 out of 38 volunteers) tested positive for at least one GM insert and most probably originated from the original trial. The resulting density was equivalent to 0.01 volunteer GM plants per square metre. These results are important in relation to debating and regulating coexistence of GM and non-GM crops.
Reference
D’Hertefeldt T, Jørgensen RB, and Pettersson LB (2008) Long-term persistence of GM oilseed rape in the seedbank. Biology Letters DOI: 10.1098/rsbl.2008.0123
Is a Major GMO Safety Test Ineffective?
Jonathan Latham, PhD and Allison Wilson, PhD
Commercially, insect-resistant transgenic (GMO) plants are made by inserting a gene coding for one of a family of toxins produced by the soil bacterium Bacillus thuringiensis. These Bt toxins are regarded by most regulators to be safer for the environment than externally applied synthetic pesticides and this is because, as plant-expressed proteins, they are considered specifically targeted to organisms that consume the crop (Glaser and Matten, 2003). As a result of this understanding Bt toxins expressed by transgenics are managed as a ‘public good’ by the US Environmental Protection Agency (US-EPA 1998).
However, Bt toxins are often expressed at high levels within plant tissues (typically for insertion event MON810 this means around 10ug/g fresh weight of Cry1Ab) and they persist in the soil, either within plant cells or as native protein (Baumgarte and Tebbe 2005; Griffiths et al., 2006). Therefore, contained within a field of Bt maize there can be many kilograms of a Bt protein at any one time. As a consequence, there is potential for significant exposure of non-target organisms, both in and around fields growing transgenic Bt crops.
Environmental risk assessments of transgenic crops have until now focused exclusively on consequences for non-aquatic organisms (NRC 2000). A recent study however, showed that debris and pollen of plants transgenic for Bt-toxins can enter nearby agricultural streams in large quantities (Rosi-Marshall et al., 2007). This same paper also reported that two caddisfly species, which are ecologically important stream organisms, are sensitive to Cry1Ab-containing leaves and pollen (Rosi-Marshall et al., 2007). As Bt researcher Angelika Hilbeck (ETH-Zurich) told the BSR News Service: “We have entirely overlooked aquatic ecosystem effects of transgenic toxins”.
Now, a further aspect of freshwater toxicology has been addressed by a study published in the journal Archives of Environmental Contamination and Toxicology. This study reports that Daphnia magna, a freshwater crustacean arthropod commonly used in toxicological investigations, can also be negatively affected by Bt transgenic plant debris containing the Bt toxin Cry1Ab (Bøhn et al. 2008). In this study, D. magna populations were fed either kernels of ground transgenic maize (containing event MON810) or non-modified isogenic maize kernels. The plant material for these experiments was grown in adjacent fields.
The Results
Bøhn et al. found that mortality, growth and fertility of D. magna were all negatively affected by the MON810-containing line compared to the control maize. Interestingly, however, the animals fed transgenic maize showed early maturation, indicating a likely toxic response to a component of the transgenic maize, rather than a response to malnutrition.
The authors suggest that their results reinforce the possibility that Cry1Ab transgenics may have significant implications for aquatic ecosystems. However, the mechanism by which the transgenic maize affects D. magna is not resolved by this data. One possibility is that the assumption that Cry1Ab is lepidopteran-specific may be inaccurate or, alternatively, Cry1Ab may be modified within the cellular environment of plants. In either case, transgenic Cry1Ab, and perhaps other cultivars containing different Bt toxins, may be toxic to non-target organisms to an unexpected degree. Cry proteins may thus be having effects on soil arthropods (for which there are no published studies on Bt toxin effects). Angelika Hilbeck however is cautious: “It is difficult to make cross-comparisons from water to land ecosystems, since they are such different environments”.
Since MON810 was the only Cry1Ab event studied by Bøhn et al., there remains an alternative mechanistic possibility, however, which is that the effects on D. magna are a result of some unanticipated consequence of transgene insertion or expression. Such unanticipated effects are not merely theoretical: Rosi-Marshall et al. normalised their results for C:N ratios because Cry1Ab containing Bt maize varieties have more lignin than non-Bt varieties (Saxena and Stotzky 2001). This normalisation was done to prevent any confounding influences of nutritional quality from affecting their results (Rosi-Marshall et al., 2007).
A recent paper detailing the first proteomic analysis of a MON810-containing cultivar may be relevant to this discussion. The authors found at least 43 significant protein expression differences between the MON810 line and a near-isogenic control (Zolla et al., 2008). Given this perhaps surprising degree of difference between a transgenic cultivar and a non-transgenic isoline, it becomes plausible to imagine that one of these differences might be responsible for the effects observed on D. magna.
A substantial equivalence connection?
Irrespective of whether Cry1Ab (or some other MON810 constituent) turns out to be the specific cause of increased D. magna mortality, Bøhn et al.’s result (and also the caddisfly result) constitute a challenge also to the regulatory doctrine of substantial equivalence. According to this principle, MON810 has been declared ‘substantially equivalent’ and it should be safe for all organisms (other than known targets of Cry1Ab), whether they are D. magna or H. sapiens. Instead, MON810 is apparently substantially equivalent but not safe.
These new results may stimulate discussion of the concept of substantial equivalence and its relationship to GMO safety. One possible interpretation of this data is that it disproves absolutely the existence of any fundamental relationship between substantial equivalence and safety. Instead, it supports the longstanding view that substantial equivalence never was a true scientific concept. Rather, it is a regulatory ‘principle’ associated with no biological relationship nor any theoretical validity (Millstone et al., 1999).
Other interpretations are also possible however: that substantial equivalence is still useful, even if the relationship with safety is not absolute. In this view recent results weaken the relationship but do not disprove it, rather like examples of differences between human and rat toxicology weaken, but do not wholly invalidate, the predictive power of that relationship. Either interpretation however accepts that it may no longer be appropriate to say that a transgenic crop is substantially equivalent and therefore safe.
Thomas Bøhn, however, takes a very different tack: his answer to this conundrum is that MON810 was originally determined incorrectly by US (and also EU) regulators as substantially equivalent. This answer, however, illustrates another apparent problem of substantial equivalence: that there is no agreed, universal or a priori set of criteria of what, in terms of crop composition, constitutes a finding of a substantial difference (Millstone et al., 1999).
Other things being equal, substantial equivalence, it seems, will either have to be reconsidered, or it will acquire the probably unique distinction of violating twice, Karl Popper’s falsifiability criteria of a scientific theory.
Put another way, is substantial equivalence so elastic, either in its specific determination for a particular crop, or in its application as a general measure of safety, that it is not in practice falsifiable?
References
Baumgarte, S. and Tebbe, C.C. (2005) Field studies on the environmental fate of the Cry1Ab Bt-toxin produced by transgenic maize (MON810) and its effect on bacterial communities in the maize rhizosphere. Mol. Ecology 14: 2539–2551.
Bøhn T., Primicerio R., Hessen D.O., Traavik T. (2008) Reduced Fitness of Daphnia magna Fed a Bt-Transgenic Maize Variety. Arch. Environ. Contam. Toxicol. DOI 10.1007/s00244-008-9150-5.
Glaser, J.A. and Matten, S.R. (2003) Sustainability of insect resistance management strategies for transgenic Bt corn. Biotechnology Advances 22: 45-69.
Griffiths, B.S.; Caul, S.; Thompson, J.; Birch, A.N.E.; Scrimgeour, C.; Cortet, J.; Foggo, A.; Hackett, C.; Krogh, P. (2006) Soil Microbial and Faunal Community Responses to Bt Maize and Insecticide in Two Soils J. Environmental Quality 35: 734-741.
Millstone, E. Brunner, E. and Mayer, S. (1999) Beyond ‘substantial equivalence’. Nature 401: 525-26.
NRC (2000) Genetically Modified Pest-Protected Plants: Science and Regulation Natl. Acad. Press Washington, DC, USA.
Rosi-Marshall, E.J.; J. L. Tank; T. V. Royer; M. R. Whiles; M. Evans-White; C. Chambers; N. A. Griffiths; J. Pokelsek and M. L. Stephen (2007) Toxins in transgenic crop byproducts may affect headwater stream ecosystems. Proc Natl Acad Sci USA 104: 16204–16208.
Saxena, D. and Stotzky, G. (2001) Bt corn has a higher lignin content than non-Bt corn. Am. J. Bot. 88: 1704-1706.
US-EPA (1998) The environmental protection agency’s white paper on Bt plant-pesticide resistance management. Washington: http://www.epa.gov/biopesticides.
Zolla, L. Rinalducci, S. Antonioli, P. and Righetti, P. G. (2008) Proteomics as a Complementary Tool for Identifying Unintended Side Effects Occurring in Transgenic Maize Seeds As a Result of Genetic Modifications. J. Proteome Res., 7: 1850–1861, 10.1021/pr0705082
Bee Learning Behaviour Affected by GMO Toxin
Jonathan Latham and Allison Wilson
Concerns over bees, especially the European honey bee (Apis mellifera) have rarely been higher. Although there are few hard data there is a general consensus that both solitary and social bee populations are declining and that recently the still-mysterious colony collapse disorder (CCD) has dramatically worsened this situation. No definitive cause for CCD has yet been established but there is widespread agreement that CCD is caused by more than one factor (Calderone, 2008 ; Oldroyd, 2007).
One of the speculated contributors to this decline is transgenic crops and specifically those containing Bt proteins since these are insect-active toxins to which bees are exposed through various routes. In particular, bee larvae are exposed since they consume large quantities of pollen which bees sometimes source from maize plants (Sabugosa-Madeira et al., 2007). Up to now however there has been no specific evidence that any Bt toxin has negative effects on bees, but equally such studies have been rare. Particularly lacking are studies on sub-lethal effects of Bt toxins on bees.
In the view of many, there is clear evidence from laboratory settings that Bt toxins can affect non-target organisms. Usually, but not always, affected organisms are closely related to intended targets (reviewed in Lovei and Arpaia 2005 and Hilbeck and Schmidt 2006). Typically, exposure is through the consumption of plant parts such as pollen or plant debris or through Bt ingested by their predatory food choices. Nevertheless, due to significant data gaps, the real-world consequences of Bt transgenics remain unclear.
Thus the lepidopteran-active Cry1Ab is, not unexpectedly, toxic to some butterflies (e.g. Losey et al., 1999 and Lang and Vojtech 2006) while more distantly-related organisms affected by Cry1Ab are ladybird larvae, caddisflies and Daphnia Magna (Rosi-Marshall et al., 2007; Bøhn et al., 2008; Schmidt et al 2008). Other variants of Bt, such as Cry3Bb, are considered coleopteran-active but have been the subject of less research. Nevertheless, these may also affect non-target coleopterans such as ladybird larvae as well as more distantly related organisms such as lacewings (Hilbeck and Schmidt 2006; Schmidt et al., 2008).
A recent paper adds to the non-target story by demonstrating that honey bees fed on the active form of purified Cry1Ab protein can be affected in the learning responses necessary to associate nectar sources with odourants (Ramirez-Romero et al., 2008). This learning response is important in bee foraging behaviour and it has attracted the attention of CCD researchers since it is known to be inhibited by the insecticide imidacloprid (e.g. Decourtye et al., 2004). In this latest study bees consuming artificial nectar containing 5000ppb of Cry1Ab continued to respond positively to a learned odour even in the absence of a food reward, while normal bee behaviour is to become discouraged and seek more abundant food sources.
Left unstudied by the authors, however, was the likely mode of action of this behavioural effect. This is of considerable interest since the principal means of Bt lethality, which is thought to be a receptor-mediated effect on gut integrity, fails to explain the observed behavioural modification. The new finding is therefore particularly interesting since it lends weight to a previous suggestion that Bt toxins may have other, non-lethal effects which become apparent only when the normal (i.e. lethal) effect is absent (Hilbeck and Schmidt 2006; Schmidt et al., 2008). If there were to be multiple modes of Bt action then many more non-target organisms would likely be at risk from Bt transgenics.
The authors propose that bees are unlikely to be exposed to the quantity of Cry1Ab that led to the defects in behaviour they observed. However, this conclusion seems premature since Bt concentrations in plants are highly variable (Lorch and Then 2007). It is also probable that in real situations bees may be exposed earlier in their development and over longer periods. Bt Researcher Angelika Hilbeck believes that experiments simulating real-world bee experiences are still lacking. “What really needs to be looked at are combinations of both the Bt toxin AND imidacloprid and not Bt toxin OR imidacloprid, and in a form that simulates the exposure routes in the field”.
Roundup Ready 2 Yield as much as Conventional Soybeans?
Jonathan Latham, PhD and Allison Wilson, PhD
Gore Vidal once wrote that “I told you so,” is the most satisfying sentence in the English language. If so, then the imminent launch of Monsanto’s Roundup Ready 2 Yield soybean line is going to provide a lot of satisfaction, though not to supporters of Monsanto. The role of the new glyphosate-resistant line (insertion event MON88978) in the following story is to provide a single, but highly significant, new data point.
The new Roundup Ready 2 Yield line will supercede Monsanto’s original Roundup Ready transgenic soybean (event 40-3-2) and yet it confers the exact same trait and contains the exact same gene as Roundup Ready. So why would Monsanto feel the need, probably at substantial cost, to replace the original Roundup Ready?
A big clue, along with the advertising, is the name. Monsanto claims that Roundup Ready 2 Yield produces a 7-11% superior yield than the original Roundup Ready. This ought to be rather surprising since herbicide resistance is not a yield trait. But the answer is in fact simple: the introduction of Roundup Ready 2 Yield is an admission that the original Roundup Ready had a major yield drag, one of several unanticipated consequences of this insertion event.
What we argued
Many groups and individuals have argued that transgenic plants may be prone to unanticipated consequences, either due to pleiotropy or to effects of transgene insertion (Schubert 2002). Our review papers on the molecular characteristics of transgene insertion sites and the associated genetic consequences of plant transformation techniques provided the first, and still only, review of the mutagenic nature of plant transformation and the consequences for the biosafety of transgenic plants (Wilson et al. 2006; Latham et al. 2006).
Our analysis reached two principal conclusions. The first was that transgene insertions, especially those resulting from particle bombardment, are frequently complex and frequently disruptive, often of multiple coding regions. Secondly, current plant transformation techniques are typically associated with very large numbers of mutations, some of which will inevitably be closely linked to the transgene and therefore hard to separate genetically. Based on these observations we speculated that unanticipated phenotypic consequences were likely to be associated with transgenic plants, and furthermore, that these would sometimes be deleterious or otherwise harmful (see Nature Biotechnology correspondence Bradford et al. 2005; Wilson et al. 2006; Latham et al. 2006).
At the time, a frequent response from regulators, and others, was that, nevertheless, transgene insertion sites and/or linked mutations, were unlikely to result in phenotypic consequences of any significance. This point has been argued in print by Bradford et al. (2005), Altpeter et al. (2005) and Schouten and Jacobsen (2007).
The unanticipated traits of Roundup Ready soybean (event 40-3-2)
Launched in 1996, Roundup Ready soybeans, which express an enol pyruvate shikimate-3-phosphate synthase (EPSPS) gene from the microbe Agrobacterium tumefaciens (and contain no other transgenes), have been an undoubted commercial success. However, they have been controversial, both because of complaints from farmers and because of revelations of unanticipated physiological consequences. These have included stem splitting and probably lignin overproduction (Coghlan, 1999; Gertz and Vencill 1999), small seed size and a yield drag (Elmore et al. 2001; Nelson et al. 2002; Benbrook 1999; Gordon 2007), and last but certainly not least, a significant manganese (Mn) deficiency (Gordon 2007).
Two powerful arguments together suggest that of these unanticipated traits, the manganese deficiency and the yield drag, are caused specifically by the 40-3-2 insertion event, which is contained in all current commercial Roundup Ready soybeans. First, even though the 40-3-2 insertion event has been backcrossed into hundreds of soybean cultivars, Monsanto has consistently failed to separate the unanticipated traits from the transgene, suggesting that they are extremely closely linked to, or inseparable from, the actual site of insertion. This fact alone still allows, however, the possibility that the action of the EPSPS protein might be responsible for the unanticipated traits. The introduction of Roundup Ready 2 Yield, however, suggests that this is not the case. Although Roundup Ready 2 Yield contains different transgene promoter and termination sequences from Roundup Ready, the transgene product, the bacterial EPSPS protein, is identical in sequence (USDA petition 06-178-01p). Nevertheless, according to the same petition, Roundup Ready 2 Yield yields 7-11% over Roundup Ready, which just happens to approximate to the yield penalty that researchers have suggested Roundup Ready confers.
The learning curve
In principle, much could be learned from this story. The first, and perhaps the most significant, is to lay to rest the notion that unintended traits in transgenic plants are invariably unimportant and rare. Not only is 95% of the soybean crop of the United States currently yielding 7-11% less than it should, Roundup Ready soybeans can contain less than 40% of the Mn contained in isogenic lines (Gordon, 2007). Neither of these traits can reasonably be called insignificant.
Secondly, the original petition for Roundup Ready soybeans inadequately analysed the transgenic line prior to commercial approval. As was subsequently shown, the 40-3-2 insertion site of Roundup Ready had a complex and scrambled insertion site and a non-functional transcription termination sequence, which allowed aberrant transcripts to transcribe beyond the transgene and into scrambled DNA (Hernandez et al. 2003; Rang et al. 2005; Wilson et al. 2006). Additionally, the compositional and phenotypic analyses, which were supposed to demonstrate the identity of Roundup Ready to conventional soybeans, omitted important data points. Thus, the petition failed entirely to detect a deficiency in a major nutrient (Mn) as well as the assorted agronomic defects of Roundup Ready soybeans. Attention to any one of these data gaps might have alerted regulators to the problems.
Now available for public inspection is the Monsanto petition for Roundup Ready 2 Yield (USDA petition 06-178-01p). Monsanto, it appears, has learned from some of the mistakes of Roundup Ready. They have replaced the nos terminator, they have also avoided callus culture and instead used meristem culture, which should be much less mutagenic, and also transformed this time with Agrobacterium tumefaciens rather than particle bombardment.
For regulators, however, the learning curve is conspicuous by its absence. Regulators in the USA, the EU and China, as well as elsewhere have already approved Roundup Ready 2 Yield, even though the petition is again flawed. The petition again fails to present a DNA sequence for the insertion site or to analyse DNA flanking the insertion site; it fails to search for aberrant mRNA transcripts; and perhaps most remarkably, its compositional analysis fails to measure even a single mineral nutrient.
Of particular interest to us, the petition also demonstrates that the new Roundup Ready 2 Yield soybean has its own unanticipated plant trait: Roundup Ready 2 Yield plants are consistently 5% shorter than isogenic lines. Evidently, the regulators who have approved Roundup Ready 2 Yield (including the famously ‘stringent’ EU) have agreed with Monsanto’s conclusion that there is “no biological meaning” to this difference (USDA petition 06-178-01p). To us, however, this difference has, in fact, two biological meanings. On a practical level, as any farmer could have pointed out, crop stature is an important agronomic trait: as well as being typically an important weed suppression character; plant stature is important in mechanical harvesting; and also for disease susceptibility, where ground contact and foliage positioning affect in-crop humidity. Secondly, many commercial transgenic crops have unanticipated traits compared to their isogenic lines (e.g. Colyer et al. 2000; Escher et al. 2000; Brodie 2003; Poerschmann et al. 2005; Herrero et al. 2007). Unlike these, however, Roundup Ready 2 Yield used the best available plant transformation methods, yet still has at least one unanticipated trait.
Although Roundup Ready 2 Yield is now approved in many countries, the unsatisfactory nature of the petition means that obvious and important questions regarding its unanticipated traits are still unresolved. Is the reduced stature phenotype an indicator of other defects? Are there other independent unanticipated traits present in Roundup Ready 2 Yield soybeans? These are not unreasonable questions, yet it is difficult not to conclude that regulators are currently uninterested in them.
Perhaps the increasing evidence for unanticipated traits in commercial cultivars will change that and the precision myth of transgenic crops will fade into oblivion. In the meantime, Monsanto has a tricky decision to make, whether to charge farmers more for their ‘yield trait’.
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US Crop Yield Increases Owe Little to Biotechnology
Jonathan Latham, PhD and Allison Wilson, PhD
The latest advertising campaign from Monsanto claims that already its “advanced seeds… significantly increase crop yields…”, while since the mid-1990s the biotechnology industry has consistently proposed that higher yielding genetically engineered crops will be necessary to feed the world.
According to Failure to Yield, a new report by the Union of Concerned Scientists, that promise has proven to be a mirage. Despite 20 years of research and 13 years of commercialization, genetic engineering has failed so far to significantly increase U.S. crop yields.
“Failure to Yield” reviews two dozen academic studies of corn and soybeans, the two primary genetically engineered food and feed crops grown in the United States. Based on those studies, UCS concludes that genetically engineering herbicide-tolerant soybeans and herbicide-tolerant corn have not increased yields, while insect-resistant corn has improved yields only marginally. The increase in yields for both crops over the last 13 years, the report found, was largely due to traditional breeding or improvements in agricultural practices.
The UCS report therefore debunks the current yield claim, but it also concludes that genetic engineering is unlikely to play a significant role in increasing food production in the foreseeable future.
In addition to evaluating genetic engineering’s record, “Failure to Yield” considers the technology’s potential role in increasing food production over the next few decades. The report does not discount the possibility of genetic engineering eventually contributing to increase crop yields. It does, however, suggest that it makes little sense to support genetic engineering at the expense of technologies that have already proven to substantially increase yields, especially in many developing countries. In addition, recent studies have shown that organic and similar farming methods that minimize the use of pesticides and synthetic fertilizers can more than double crop yields at little cost to poor farmers in such developing regions as Sub-Saharan Africa.
The report recommends that the U.S. Department of Agriculture, state agricultural agencies, and universities increase research and development for proven approaches to boost crop yields. Those approaches should include modern conventional plant breeding methods, sustainable and organic farming, and other sophisticated farming practices that do not require farmers to pay significant upfront costs. The report also recommends that U.S. food aid organizations make these more promising and affordable alternatives available to farmers in developing countries.
Charles Benbrook of the The Organic Center says that a low contribution of GMOs to yield is perhaps anyway to be expected. Firstly, yield is a complex trait which probably will prove difficult to manipulate directly, but also that “although increases in yield are usually credited to plant breeders, actually many factors contribute to yield, such as soil quality and water management improvements and it is to these we should be looking for future agricultural improvements”.
Welsh Farmer’s Defiance of GMO ‘Ban’ Not So Defiant After All
Jonathan Latham and Allison Wilson
An investigation by Welsh trading standards officers into the claims of a farmer to have contravened Welsh GMO-Free status has concluded there was no evidence that he grew GMO maize.
Jonathon Harrington created global headlines in January of this year when he claimed to have grown GMO maize on his farm in Powys, Wales, as a protest against the Welsh Assembly’s opposition to GM crops. His story was widely reported after he claimed to have grown two varieties of maize and used them to make silage, some of which he supplied to neighbours.
However, information obtained under freedom of information legislation by the campaigning group GM Free Cymru shows that Powys County Council investigated these claims under trading standards regulations. These require labeling and traceability records to be maintained as well as registration as a seed trader. According to the information obtained by GM Free Cymru, however, Harrington is not registered and kept no written records.
According to the County Council report Harrington “….had received a quantity of 50 seeds of two varieties of GM maize which he had used to grow crops on his holding for his own interest as a biologist, and that the crops were destroyed on his holding following harvesting. It is impossible to prove or disprove these claims. Samples of seed supplied to the Trading Standards Service by Harrington were analysed by a Public Analyst and found not to be GM modified seed.”
In a letter to GM Free Cymru, Mr Lee Evans of Powys CC said: “I can confirm that during the course of the investigation, (we found) no evidence that GM crops were grown, cultivated, circulated to any farms in the Powys area or fed to any stock in the county.”
Harrington is a member of Cropgen, a lobby group funded by the biotechnology industry.