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NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 11 NOVEMBER 2006 1329
5. Prescott, V.E. et al. J. Agric. Food Chem 53, 9023–9030 (2005).
6. de Folter, S. & Angenent, G.C. Trends Plant Sci. 11, 224–231 (2006).
7. Tetko, I.V. et al. PLoS Comput. Biol. 2, e21 (2006).8. Lessard, P.A., Kulaveerasingam, H., York, G.M., Strong,
A. & Sinskey, A.J. Metab. Eng. 4, 67–79 (2002).9. Brodersen, P. & Voinnet, O. Trends Genet. 22, 268–280
(2006).10. Bradford, K.J., Van Deynze, A., Gutterson, N., Parrott,
W. & Strauss, S.H. Nat. Biotechnol. 23, 439–444 (2005).
11. Schubert, D. Nat. Biotechnol. 23, 785–787 (2005).12. Lai, J., Li, Y., Messing, J. & Dooner, H.K. Proc. Natl.
Acad. Sci. USA 102, 9068–9073 (2005).13. Cecchini, E., Mulligan, B.J., Covey, S.N. & Milner, J.J.
Mutat. Res. 401, 199–206 (1998).14. Vizir, I.Y., Thorlby, G. & Mullian, B.J. in Gene Isolation,
Principles and Practice (eds. G.D. Foster & D. Twell) 215–245 (Wiley, London, 1996).
15. Cook, G.W.D. Genetically Modified Language. The Discourse of Arguments for GE Crops and Food (Routledge, London, 2005).
16. Bradford, K.J., Gutterson, N., Parrott, W., Van Deynze, A. & Strauss, S.H. Nat. Biotechnol. 23, 787–789 (2005).
17. Fernandez–Cornejo, J. & Caswell, M. Adoption of bioen-gineered crops (United States Department of Agriculture, Economic Research Service, Washington, 2006).
18. Kumar, S., Allen, G.C. & Thompson, W.F. Trends Plant Sci. 11, 159–161 (2006).
19. Varshney, R.K., Graner, A. & Sorrells, M.E. Trends Plant Sci. 10, 621–630 (2005).
To the editor:In their recent articles in July issue (Nat. Biotechnol. 24, 753, 2006) and EMBO Reports1, Schouten et al. propose a rationale for a new subcategory of genetically modified (GM) plants. This new category should, in their view, be regulated not according to the rules applied to transgenics, but instead, no differently from the products of conventional breeding. This is a well-intended and clever proposal; but in my opinion, too clever by half. And although the last thing any reasonable person should discourage is anything that would get Europe out of the regulatory/political quagmire of a corner into which it has painted itself, this is a dog that won’t hunt.
The crux of their argument is that “deliberate release and market introduction of cisgenic plants is as safe as the release and market introduction of traditionally bred plants.” They define a ‘cisgenic’ plant as “a crop plant…genetically modified with one or more genes…isolated from a crossable donor plant” and construe this to establish that the environmental and health consequences are no different from those associated with the products of traditional breeding. They conclude therefore that ‘cisgenic’ plants should be exempt from the regulations applied to transgenics. To indict them in their own words, “this is merely a semantic adaptation, rather than a means of controlling risk.”
No one familiar with the relevant facts and global experience with transgenic plants over
the past two decades would disagree with the conclusion that the plant products generated thus far using recombinant technology are generally very safe indeed and that risks, although in theory perhaps not totally absent (though conspicuously missing to date), are in fact quite low, if not altogether infinitesimal. All of the arguments marshaled by Schouten et al. about the relative risk associated with ‘cisgenic’ plants seem reasonable, though exceptions can be found or conjured to each. But the logical flaws and factual errors in their rationale are numerous, and fatal. Critically, none of their arguments succeeds in drawing a sustainable distinction between ‘cisgenic’ and transgenic plants based on any defensible, risk associated criterion. What is proposed, in fact, is a regime no less indefensibly rooted in manufacturing process than other regimes that have been justifiably blistered for the same intellectually bankrupt foundation.
It has been a long time, but I think I remember witnesses testifying before hearings of the US Congress’ House of Representatives Committee on Science, Space, and Technology, perhaps in 1983 or 1984 (chaired by Representative Al Gore), in which the proposition was explored as to whether or not the phylogenetic distance between DNA donor and recipient was necessarily an indicator of risk. It was not then, and it is not today. In fact, if there is any correlation between risk and phylogenetic distance, it may be inverse! But about the only rock solid universal truth on which one can rely in this arena is that the risk associated with a novel plant, whether it is genetically modified by in vitro recombinant DNA techniques, classical breeding or any other mechanism, is critically dependent on the encoded trait and the expression patterns of that trait (that is, the phenotype) in the recipient. Other details may be interesting, but are essentially irrelevant to the question of risk.
En route to their well-intended but ill-considered proposal, Schouten et al. misunderstand or mischaracterize a number of facts. Dismissing all regulatory regimes but Canada’s as process based, they fairly damn the European regime they hope to ameliorate, while incidentally slandering those in Australia, New Zealand and the United States (“When it gives trouble, they profane even the beautiful and the good.”—Goethe, in Faust). They also misleadingly imply the existence of “current international GMO [genetically modified organism] regulations.” They offer no citation here, but surely they cannot be referring to the ill-conceived but purely hortatory language of the Biosafety Protocol to the Convention on Biological
Diversity? There are excellent guidelines from the Organization for Economic Cooperation and Development (OECD; Geneva) and numerous national bodies, and any number of national regulatory regimes, but nothing that could fairly be described as “international GMO regulations” as invoked. But no matter—these are incidental errors; the take-home message here is clear.
Numerous authoritative bodies on both sides of the pond and around the world have concluded that the risks of transgenic plants are no different from the risks associated with the products of conventional breeding. This finding does indeed have implications for current regulatory regimes: they are all, even the best of them, disproportionate to the level of risk actually posed by the transgenic plants we have seen to date. Those regimes that are easily adapted need to be updated to take this juggernaut truth into account. Regimes that are not easily adapted should be junked and replaced with something (or nothing) that does less damage to reason, common sense and those billions who desperately need agricultural innovations around the world.
L. Val Giddings
Consultant, and Former Vice President for Food and Agriculture, Biotechnology Industry Organization, Washington, DC, USA.e-mail: [email protected]
1. Schouten, H.J., Krens, F.A. & Jacobsen, E. EMBO Rep. 7, 750–753 (2006).
To the editor:Cisgenesis (more commonly called intragenesis1) and transgenesis are two technically similar approaches to create genetic variability through gene-splicing technology. Cisgenic plants are defined as plants that have been genetically modified with one or more genes (including introns and flanking regions such as native promoter and terminator regions in a sense orientation) isolated from a crossable donor plant; that is, of the same or a closely related species2,3 or isolated from within the existing genome1. Transgenic plants can be described as plants that contain recombined DNA from unrelated organisms1. Thus, the sources of the genes used to genetically modify the plant are different.
This difference has been exploited in two articles by Schouten et al.2,3 to suggest that cisgenic plants pose fewer environmental risks, evoke less moral objection and should thus warrant mitigated requirements in the biosafety regulations for testing and use of genetically modified organisms (GMOs). Schouten et al. argue that “cisgenic plants are fundamentally different from transgenic
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1330 VOLUME 24 NUMBER 11 NOVEMBER 2006 NATURE BIOTECHNOLOGY
plants” because the gene and promoter introduced into cisgenic plants are already present in the species, or in crossable relatives, and therefore do not add an extra trait into the species. Consequently, neither the fitness nor the environmental risk posed by a cisgenic plant changes beyond what may occur through traditional breeding. As in both cisgenic breeding and in breeding through mutagenesis sometimes unwanted mutations and rearrangements occur, they conclude that “cisgenic plants are similar to and as safe as traditionally bred plants” and do not require the type of special regulatory oversight applied to transgenic plants. In addition, they suggest that the origin of the introduced gene is considered an important determinant for “acceptability of genetically modified plants by the public.”
Here, we challenge three of the central arguments made by Schouten et al. that downplay certain differences between cisgenesis and traditional breeding and exaggerate certain similarities between cisgenic and transgenic plants to place the former in a positive light: first, their contention that cisgenic plants are fundamentally different from transgenic plants; second, their assertion that cisgenesis is equivalent to traditional breeding; and third, their assumption that cisgenesis will gain wider ethical and societal acceptance than transgenesis. Finally, we propose an alternative approach for the risk assessment of ‘trait-enhanced’ plants.
To emphasize the ‘fundamental difference’ between cisgenesis and transgenesis, Schouten et al. build a one-sided image from the arguments often used by environmentalists against transgenesis; for example, “that novel traits [in transgenic plants] can affect the fitness in ways new to the species, potentially leading to increased invasiveness.” As in all rhetoric, this is merely half of the truth, stressing a single aspect of transgenesis, which is not necessarily limited to the domain of transgenic plants: in a cisgenic scenario, toxic potatoes or tomatoes can be engineered by inserting extra copies of species-specific alkaloid genes that raise the concentration of solanines (e.g., for pest resistance). In this case, one would certainly regard a consistent risk management regime still relevant for cisgenic plants.
It is also conceivable that a cisgenic plant could be equipped with a desirable trait from a wild relative that has not been present in a crop plant before; thus, a ‘novel’ trait would be added. Many of the desired ‘cisgenes’ will be resistance genes, which certainly will affect the invasiveness of a genetically modified
plant species. The argument of novelty and associated invasiveness applies to both cis- and transgenic plants and loses therefore its power as a categorical and trustful discriminator between safe cisgenic plants and risky transgenic plants. More specifically, the pitfall is hidden in the proposed extension of the definition of cisgenes: “from a crossable donor plant, i.e. of the same or a closely related species”2,3. Note the difference with the more precise term ‘intragenic plant’1. Juiciness, enhanced taste, color, pest resistance and improved storability or processing quality are novel traits compared with the traditional crop, but the moment that the traits originate from a “closely related species,” these potentially ‘risky’ novel genotypes are defined away as safe cisgenic plants without possessing an ‘extra trait’. Extra traits, novel genotype or just novelty are not well defined and tend to serve the needs of the one who hijacks them. Salesmen will market the novelties and the regulatory officer will play them down. To avoid these ambiguities, one should strive for a clear and restricted definition to describe the category of GMOs that bears fewer risks and warrants a lighter risk assessment. We regard this current demarcation definition between cisgenic and transgenic plants inadequately wide and ambiguous.
Apart from distinguishing cisgenesis from transgenesis, Schouten et al. also propose that, at the regulatory level, cisgenic plants should not be treated differently from traditionally bred plants because of their equivalence. They assert that plants derived from cisgenesis are similar to plants derived from mutagenesis and subsequent traditional breeding. The process of genetic modification itself can lead to (unwanted) mutations and rearrangements, similar to those observed in mutation breeding. The long history of plant breeding has shown, however, that there are no adverse effects of mutagenic breeding on the environment or on food. Schouten et al. therefore plead for the same regulatory process for cisgenic plants.
But there are two problems with this line of thinking. First, the authors are stretching the definition of traditional plant breeding beyond its limit; although plants produced via mutagenesis or traditional breeding are not subjected to GMO regulations, in the European Union regulations, mutagenesis is still defined as a type of genetic modification. Second, cisgenesis relies on the random introduction of large genomic fragments using the Agrobacterium tumefaciens T-DNA transfer system. This introduces the cisgene in novel positions in the genome, which it has never occupied before. Experiments with
resistance genes have shown that ‘cisgenic’ plants do not always express the resistance trait, whereas progeny of crosses with the original wild relative do4. Furthermore, it is likely that the insertion will be close to a genic region5, which may affect the behavior of a cisgenic plant in an unpredictable manner. One should be careful not to overstate the extent of genome reorganization in crop plants due to mutational breeding and downplay the effects of random insertion of a cisgene in the plant genome.
This brings us to the final point made by Schouten et al.: will cisgenic plants diminish moral concerns? At least one historical case indicates no. One of the first experiments with cis- and transgenesis in animals, known as the Beltsville’s pigs experiment, illustrated the irrelevance of the origin of the inserted genes, the relevance of the unexpected phenotype, the strong reaction of the public and the major setback of R&D investment in genetically modified animals. The pigs received extra copies of the gene coding for porcine somatotropin6 or human somatotropin7 to stimulate muscle growth in pigs. Genes from either source induced similar crippled animals whose bones could not bear the weight. The animals were suffering from all kinds of illnesses related to an infringed hormonal system. In their phenotype, these pigs showed a new ‘body building’ trait. As a result, in both the United States and Europe, genetic modification of animals was heavily criticized by the public.
Even so, Myskja8 has made the argument that the public should have fewer moral objections against cisgenic plants merely because inserting genes from the same genome reduces risks and because scientists will be better able to predict and control the effects of human intervention in cisgenesis than in transgenesis. Although part of society may have fewer moral problems with cisgenesis than with transgenesis8, another part will continue to perceive cisgenesis as unnatural, artificial manipulation and not in harmony with their world view9. Especially for the latter, who in Europe protected their rights to exert a freedom of choice in food products—a situation that has led to repeated clashes in the World Trade Organization (Geneva) between the United States (and others) and Europe—no perceptions will be changed by the introduction of ‘cisgenic’ plants.
Even if many citizens consider cisgenic plants different from transgenic plants, this is no guarantee of improved acceptance. Citizens’ trust in regulation of genetic engineering might also be an important
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NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 11 NOVEMBER 2006 1331
factor in the acceptance of the technology. Analysis of the results of the most recent Eurobarometer on biotech10 demonstrates that the lack of trust of citizens in regulation of genetic engineering and negative opinions about encouraging genetically modified foods are related. Lack of trust in regulation, which prevails in Greece and—to a lesser extent—in Germany, corresponds with relatively low levels of support for the application of genetic engineering in food. Relatively high levels of trust in regulation in countries like the Netherlands, Belgium and the Czech Republic correspond with relatively high levels of support. Therefore, it is questionable that relaxing regulatory oversight on cisgenic plants will enhance acceptance.
Governmental administrations tend to find a fair balance between safety for the citizens, economic growth and political expediency. Biosafety assessments are costly for all parties. Currently, competent authorities investigate options to classify types of genetic modifications based on risk levels. Low-risk level modifications might then be assessed with a light (and less costly) dossier. However, in our analysis, cisgenesis is not a suitable candidate for a low-risk category.
To sum up, Schouten et al.’s cisgenic proposal is flawed on several levels but is instructive in highlighting several aspects that might enable the definition of a subcategory of gene-spliced plants that could be both scientifically defensible and societally acceptable.
Such products—which, for the sake of argument, we will term ‘enhanced trait products’ (similar to cisgenic products, but defined on the basis of the phenotype)—would be acknowledged (unlike cisgenic products) to still fall within the various legal definitions of genetic modification. They would be defined as products created by the insertion of original gene fragments (containing introns and flanking regions, such as native promoter and terminator regions in a sense orientation, excluding other regulatory elements) that enhance traits that are already expressed in naturally crossable plants. A full description of the insertion site of the novel cisgene and the effect on the expression of nearby located genes in such products would also be provided.
The existing risk assessment process could then be supplemented with a flexible expert-based, gene-by-gene approach to allow legal shortcuts based on advancing knowledge of risks related to the ‘expression’ and ‘nature’ of the gene to acquire simultaneous approval for field experiments and market introduction.
And finally, to acknowledge freedom-of-choice for consumers and create new opportunities for new niche-markets, such products could be promoted under a new label (e.g., for ‘enhanced traits’).
Tjard de Cock Buning1, Edith T. Lammerts van Bueren2, Michel A. Haring3, Huib C. de Vriend4 & Paul C. Struik5
1ATHENA Institute of the Free University, Earth & Life Sciences, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands. 2Plant Sciences Group, Wageningen University, Droevendaalsesteeg 1,PO Box 386, 6700 AJ Wageningen, The Netherlands. 3Plant Physiology, University of Amsterdam, Kruislaan 318, 1098 SM Amsterdam, The Netherlands. 4LIS Consult, Laan van Hoornwijck 1, 2289 DG Rijswijk, The Netherlands. 5Plant Sciences Group, Crop and Weed Ecology, Wageningen University, PO Box 430, 6700 AK Wageningen, The Netherlands.e-mail: [email protected]
1. Nielsen, K.M. Nat. Biotechnol. 21, 227–228 (2003).2. Schouten, H.J., Krens, F.A. & Jacobsen, E. Nat.
Biotechnol. 24, 753 (2006).3. Schouten, H.J., Krens, F.A. & Jacobsen, E. EMBO Rep.
7, 1–4 (2006).4. Simons, G. et al. Plant Cell 10, 1055–1068 (1998).5 Alonso, J.M. et al. Science 301, 653–657 (2003).6. Ebert, K.M., Smith, T.E., Buonoma, F.C., Overstrom, E.W.
& Low, M.J. Animal Biotechnol. 1, 145–159 (1990)7. Pursel, V.G. et al. Vet. Immunol. Immunopathol. 17,
303 (1987).8. Myskja, B.K. J. Agric. Environ. Ethics 19, 225–238
(2006).9. Lammerts van Bueren, E.T., Struik, P.C., Tiemens-
Hulscher, M. & Jacobsen, E. Crop Sci. 43, 1922–1929 (2003).
10. http://www.ec.europa.eu/research/press/2006/pr1906en.cfm
Schouten and colleagues respond:Schubert and Williams contend that genetic engineering is a highly mutagenic and imprecise process, an argument that they have previously touted in a correspondence to this journal1 relating to an article by Strauss and colleagues2 published in the April 2005 issue. Readers who are interested in the scientific evidence rebutting their old arguments—with respect to (i) comparison of the ‘lack of precision’ of genetic engineering with ‘lack of precision’ in conventional breeding (including wide crosses), (ii) genetic changes that do occur naturally due to the inherent dynamic nature of the plant’s genome and (iii) the elaborate screening in the laboratory, greenhouse and field for abnormal, unstable or undesirable genetically modified (GM) genotypes during cultivar development—are referred to the responses provided by Strauss and colleagues3, as well as the literature cited in our articles4,5. Here, we respond only to the new arguments raised by Schubert and Williams.
Schubert and Williams state that expression of a cisgene may change when not all relevant regulatory elements are co-inserted with the coding sequence of that gene. Although we concur with this statement, variation in expression of a gene is a natural phenomenon because of, for example, mutations in the promoter region or allelic variation in regulating genes, such as transcription factors or post-transcriptional factors. In addition, in conventional breeding, expression of a specific gene may vary at the phenotypic level, depending on the genetic background, even if the promoter region of the gene is constant6. In our scheme, however, only cisgenic plants that have the desired gene expression and phenotype would be selected for further cultivar development.
Schubert and Williams state it would be difficult to characterize cisgenic plants at the genomic level and monitor them after release. However, this is not the case. As long as the insertion site differs from the native genomic site, an event-specific PCR reaction can be developed with one primer that anneals to the inserted sequence and another primer that anneals to flanking DNA. The flanking DNA can be sequenced by using commonly available genome walking kits.
In our definition of cisgenesis, we used the wording ‘crossable’ or ‘sexually compatible’, to link to the wording of the European Commission’s Directive 2001/18/EC; that is, “organisms which can exchange genetic material through traditional breeding methods” 7. We did not use the term ‘related plants’ as Schubert and Williams mistakenly state. ‘Related’ is too vague and subject to semantic or taxonomical discussions.
The closing argument of Schubert and Williams about direct benefit for the consumer is outside the scope of our texts and intentions. However, there is no reason that future cisgenic or other GM plants will not have clear benefits for the consumer as this is likely to lead to higher acceptance of such products8.
In his letter, Giddings also raises concerns with our scheme. He states there are “numerous and fatal…logical flaws and factual errors” in our rationale, but fails to provide either clear scientific arguments or citations to support his criticisms. Rather, he refers to testimonies of witnesses of a meeting of more than 20 years ago and to Goethe.
Giddings is mistaken in stating that “the crux” of our argument “is that deliberate release of cisgenic plants into the environment is as safe as the deliberate
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