Sensible Regulations For GE Food Crops

By David Schubert
Nature Biotechnology (23, 785 - 787)
July 2005

In a recent article Bradford and colleagues argued that the methods used to produce food crops should not be the focus of regulatory oversight, only the phenotypic traits of the resultant plants as defined in terms of standard agricultural practice[1]. They propose that any risk and safety assessments of crops produced by genetic engineering (GE) should be based only upon the nature of the introduced genes. They also claim that transgenic crops face a "daunting" array of regulatory requirements.

However, safety testing requirements in the United States are largely voluntary and in my view inadequate. These regulations have been reviewed elsewhere[2] and will not be discussed further. Safety concerns related to the GE process itself as well as its unintended consequences are set aside by Bradford et al as irrelevant, for they claim that the products of genetic events that occur naturally and with standard plant breeding techniques are fundamentally the same as those that occur with GE. Are these arguments a valid reflection of what is known about the precision and consequences of the GE process as compared with naturally occurring genomic variation?

The basic assumption underlying the concept of a one-to-one relationship between the transgene and the resultant phenotype is that the GE process is relatively precise. However, none of the current transgene insertion techniques permit control over the location of the insertion site or the number and orientation of the genes inserted. Indeed, over one-third of all Agrobacterium-mediated insertion events disrupt functional DNA[3,4]. These and related transformation and cell culture-induced changes in chromosomal structure have been recently documented in great detail[5]. For example, translocations of up to 40 Kb[6], scrambling of transgene and genomic DNA[7], large scale deletions of over a dozen genes[8] and frequent random insertions of plasmid DNA[9] can all be caused by the procedures used to make GE plants. In fact, the most commonly used transformation procedure is sometimes itself used as a mutagen[10], and can activate dormant retrotransposons that are highly mutagenic[11]. Moreover, mutations linked to the transgene insertion site cannot be removed by additional breeding as long as there is selection for the transgene itself. Collectively these data indicate that the GE process itself is highly mutagenic.

Some modern breeding technologies introduce new traits into plants via chemical or radiation mutagenesis or by wide cross hybridizations that overcome natural species barriers. Mutagenesis was used in the United States during the middle part of the last century, but food crops made by this technique now constitute less than a few percent of US production, with sunflowers being the major representative[12]. However, plants produced by wide crosses, such as those between quackgrass and bread wheat to yield a widely planted grain that has all of the chromosomes of wheat and an extra half genome of the quackgrass, while unique, are fundamentally different from those produced by either mutagenesis or GE. In wide crosses and other forms of ploidy manipulation there are clearly changes in gene dosage, and proteins unique to only one parent can be produced in the hybrid, but there is no a priori reason to assume that mutations are going to occur simply because there is a change in chromosome or gene number. While the extent and suddenness of all of these modern breeding technologies are unlike anything known to occur during the course of evolution or with traditional breeding, only GE and mutagenesis introduce large numbers of mutations. Any new cultivars derived by the latter two methods should be subjected to similar regulatory requirements.

Bradford et al. correctly state that plants normally contain the same Agrobacterium and viral DNA sequences that are used to create GE transfection constructs, but fail to point out that with GE these pieces of DNA are part of a cassette of genes for drug resistance along with strong constitutive viral promoters that are used to express foreign proteins at high levels in all parts of the plant, hardly a natural event. They incorrectly imply that changes in ploidy, gene copy number, recombination, and high genomic densities of transposable elements in normal plants continually lead to mutations and changes in gene expression similar to those caused by GE.

Ploidy is notoriously unstable in plants, but changes involve moving around large blocks of intact genes while maintaining their regulated expression pattern. It should also be remembered that recombination is not the same as random mutagenesis, for there has been tremendous selective pressure for alleles to express functionally similar proteins. The statement that "retrotransposons continuously insert themselves between genes" is incorrect, for these high copy number elements are transpositionally inactive in normal modern food plants[13], have evolved and rearranged in the distant past[14], but can be activated by tissue culture or by mutagenesis[11]. In fact their discovery by Barbara McClintock was facilitated by the use of mutagenized corn[13].

While Bradford et al. propose that regulatory efforts should be focused upon the expression of the transgene, I believe that the major hazards of the highly mutagenic plant transformation techniques are the potentials for a decrease in nutritional content or an increase in dangerous metabolites. While it is widely recognized that the breeding of some crops can produce varieties with harmful characteristics, millennia of experience have identified these crops, and breeders test new cultivars for known harmful compounds, such as alkaloids in potatoes[15,16]. In contrast, unintended consequences arising from the random and extensive mutagenesis caused by GE techniques opens far wider possibilities of producing novel, toxic, or mutagenic compounds in all sorts of crops. Unlike animals, plants accumulate thousands of nonessential small molecules that provide adaptive benefits under conditions of environmental or predator-based stress[17]. Estimates are that they can make between 90,000 and 200,000 phytochemicals with up to 5000 in one species[18]. These compounds are frequently made by enzymes with low substrate specificity[19] in which mutations can readily alter substrate preference[20,21]

There are many examples of unpredictable alterations in small molecule metabolism in GE organisms. In yeast genetically engineered to increase glucose metabolism, the GE event caused the unintended accumulation of a highly toxic and mutagenic 2-oxoaldehyde called methylglyoxal[22]. In a study of just 88 metabolites in four lines of potatoes transformed for altered sucrose metabolism, Roessner et al. found that the amounts of the majority of these metabolites were significantly altered relative to controls[18]. In addition, nine of the metabolites in GE potatoes were not detected in conventional potatoes. Given the enormous pool of plant metabolites, the observation that 10% of those assayed are new in one set of transfections strongly suggests that undesirable or harmful metabolites may be produced and accumulate[23]. Contrary to the suggestions of Bradford et al., Kuiper and his colleagues strongly recommend that each transformation event should be assayed for these types of unintended events by metabolic profiling[24].

A well documented horticultural example of unintended effects is the alteration in the shikimic acid pathway in Bt corn hybrids derived from Monsanto's MON810 and Syngenta's Bt11 plants as well as glyphosate-tolerant soybeans. Stem tissue of both groups of plants has elevated levels of lignin, an abundant non-digestible woody component that makes the plants less nutritious for animal feed[25,26]. Components of this same biochemical pathway also produce both flavonoids and isoflavonoids that have a high nutritional value, and rotenone, a plant-produced insecticide that may cause Parkinson's disease[27]. Isoflavonoids are abundant in legumes like soy beans, and rotenone is synthesized directly from isoflavones in many legume species[28]. Because of the promiscuity of many plant enzymes and the large and varied substrate pools of phytochemical intermediates, it is impossible to predict the products of enzymes or regulatory genes mutated during the GE event[23]. While I are not aware of any testing of GE soybeans for rotenone, it has been shown that glyphosate-tolerant soybeans sprayed with glyphosate have a reduced flavonoid content[29].

The safety testing of GE crops need not be as extensive as that done with drugs, food additives or cosmetics. Many suggestions have been put forward (see, for example 30,2,5,24) including those by the World Health Organization[31]. I believe that the most important safety tests include metabolic profiling to detect unexpected changes in small molecule metabolism[24] and the Ames test to detect mutagens[32]. Molecular analysis of the gene insertion sites and transformation-induced mutations[5] should also be performed along with both multigenerational feeding trials in rodents to assay for teratogenic effects and developmental problems, and allergenicity testing performed according to a single rigorous protocol[31] The animal studies are of particular importance for crops engineered to produce precursors to highly biologically active compounds such as Vitamin A and retinoic acid, molecules that can act as teratogens at high doses[33].

In summary, Bradford et al. state that there is a low risk from the consumption of GE plants "where no novel biochemical or enzymatic functions are imparted". The question is, of course, how can one know if a novel and potentially harmful molecule has been created unless the testing has been done? How can one predict the risk in the absence of an assay? Because of the high mutagenicity of the transformation procedures used in GE, the assumptions made by Bradford et al. and also the FDA [34] about the precision and specificity of plant GE are incorrect. Nonetheless, it appears that the positions of Bradford et al. and the biotech industry, as well as the current regulatory framework for the labeling and safety testing of GE food crops, is to maintain the status quo and hope for the best.

The problem is that there are no mandatory safety testing requirements for unintended effects[2] and that it may take many years before any symptoms of a GE-caused disease appear. In the absence of strong epidemiology or clinical trials, any health problem associated with an illness caused by a GE food is going to be very difficult, if not impossible, to detect unless it is a disease that is unique or normally very rare. Therefore, while GE may be able to enhance world health and food crop production , its full potential is likely to remain unfulfilled until rigorous pre-release safety testing can provide some assurance to consumers that the products of this new technology are safe to eat.

A complete list of references is available on request.

Seeds of Ignorance

By Lin Gu
South China Morning Post
July 14, 2005

Tian Zihai of Zhongzhou village in Hubei province was among the first farmers to grow genetically modified (GM) rice, although China has not approved its commercial release. He bought two kilograms of GM rice seed in 2000 from a sales manager of the provincial seed company who said the new seed would create cost savings on pesticide and labour.

Mr Tian had no idea that the seed was genetically engineered to produce inbuilt pesticide, and that state law forbids its sale. All he knew was that the seed did prove effective in resisting pests, so he bought more the next year. Now the Tians grow about 0.7-hectare of GM rice a year, selling some and saving the rest for their own consumption.

Mr Tian dismissed any note of caution about a rice mutation that even pests dare not eat. "Look, I have eaten it for four years with no problem at all," he said, smiling reassuringly. Encouraged by Mr Tian's "success", the local seed station started to introduce the "magic seed" in 2003.

Also encouraged was Zhang Qifa, China's leading biotechnology scientist, who conducted the mainland's largest field trials on GM rice. When interviewed by Newsweek in December last year, Professor Zhang mentioned that farmers near the GM test areas in Hubei had grown and eaten such rice without any side effects. The scientist was quoted as saying: "A local company got some of the GM rice seed and began selling it to local farmers."

The claim triggered six undercover investigations in Hubei by the environmental group Greenpeace. Until April, when Greenpeace exposed the illegal growing and trading of GM rice in the province, few locals were aware that they had violated the law.

A two-day trip in Wuhan and Xianning made by this journalist in May, a month after Greenpeace announced its findings, found four out of the seven retailers investigated had sold anti-pest rice seed. Most investigations identified Professor Zhang - who works at the Chinese Academy of Sciences, and the Huazhong (Central China) Agricultural University - as the source of the illegal grain.

Greenpeace collected rice samples from the Hubei market and sent them to the GeneScan laboratory in Germany for transgenetic DNA testing, which proved they had GM traits identical to those long researched by Professor Zhang's team.

But the Ministry of Agriculture (MOA) refused to accept the test results, on the grounds that the standards might differ from China's. The ministry said it would rely on the findings of an investigation conducted by the local government.

In response to Greenpeace's appeal for urgent action to stop the spread of GM rice, Fang Xiangdong, vice-director of the MOA's bio-safety office, said: "We have to exercise extreme caution to find concrete evidence, so that serious legal action can be taken." That extreme caution is understandable, given Professor Zhang's prominent status. Among his multiple titles he also serves as vice-chairman of the China Association of Science and Technology, the mainland's highest government -controlled civil scientific organisation.

While awaiting reports from Hubei, the MOA issued a circular on April 27, requiring a nationwide investigation into the status of GM crops in field trials. To date, there are still no reports from Hubei and no sign that the MOA is going to make any more public announcements.

In fact, the local authorities did take action long before Greenpeace's investigation. One industry insider said that as early as last autumn, Hubei authorities had already conducted investigations into violations of bio-safety regulations and "punished some wrongdoers according to law", although they would not give details.

A newsletter, printed one month ahead of Greenpeace's April announcement, by a local agricultural technology centre in Jiangxia district on the outskirts of the provincial capital Wuhan, said that anti-pest rice seed is "a type of crop forbidden to grow by the country, because it may not be good for human health, and farmers must not buy and grow it".

Zhang Liangxing, manager of the centre, said the local government tried to halt the harvesting and sale of GM rice last year, but the ban was difficult to implement because farmers were so much in favour of the seeds.

The manager said Professor Zhang initiated the field trials of GM rice and that when the seed appeared on the market, it was at higher-than-average prices. "Even if Professor Zhang himself didn't sneak the seed into the market , people around him could have done," the manager said, adding that "as someone working for a state-owned agricultural centre, I would never sell a GM seed before its safety has been proven".

"China has a very strict legal system to regulate its seed market and GM crops, and we are regularly monitoring what's happening in the fields," said the MOA's Mr Fang.

Some, however, find that less than satisfactory. "The Hubei scandal shows that the government failed to control GM rice at the research stage, so how will it regulate large-scale commercialisation?" said Sze Pang Cheung, campaigner for Greenpeace China.

Yang Xiongnian, deputy director of the MOA's science, technology and education department, said: "We cannot guarantee the problem will disappear, given that China has more than 90,000 seed retailers and some profit-driven individuals may want to test the law."

Still, the man at the centre of the storm remains silent, despite repeated media inquiries. Five years ago, Professor Zhang began the process of applying for safety certification for his GM rice seed - a prerequisite for commercial release. He has conducted all the required procedures, such as field trials, environmental release trials, and pre-production trials - large-scale farmer field trials across Hubei's five counties. When final approval for commercialisation will come remains anyone's guess.

Last year, Professor Zhang and 15 other scholars, including the leading biotechnologists in the country, filed a report to the State Council, urging early approval of a commercialisation permit and complaining that "over-strict" bio-safety regulations had slowed the industrialisation of GM technology and contradicted "the strong need for new technology among Chinese farmers".

On June 22, the MOA's bio-safety committee held its biannual meeting where experts were invited to give their views on the safety issues involved in growing GM crops. However, to the chagrin of GM proponents, commercialisation has remained merely a topic for discussion.

China has ploughed millions of yuan into biotechnology, with GM crops at the cutting edge of the research. Professor Zhang's national plant gene centre alone received 15 million yuan from the Ministry of Science and Technology in 2002, in addition to the 56 million yuan he received for research into GM rice.

China's largest investment in biotechnology, however, "puts pressure on scientists to deliver something", said James Keeley, a British researcher studying China's biotechnology policy. "It is a problem when you have this high-level investment, because at some point policymakers are going to ask, 'what are the benefits of spending this money on biotech research if we are not going to use it?'"

One official, speaking on condition of anonymity, said: "Much of China's rice research funding goes to Professor Zhang." Professor Zhang has signed a contract with the Ministry of Science and Technology, which has set a timetable for the industrialisation of GM crops. It is possible that Hubei is being touted as a "we did it first" model to press for official recognition, as was the case with GM cotton in China.

That could well be the case, according to one Beijing-based scientist. "In some countries, popularisation happened before there were standardised regulations. It's such a nice technology, and farmers just can't wait."

That was also the case for one of China's neighbours, according to Mr Keeley. Indian authorities had long refused to commercialise anti-pest GM cotton, but scientists deliberately gave the cotton seeds to farmers and it was soon widely grown across one province. Due to their popularity among farmers, crops from the seeds quickly spread out of control. "Because it looks embarrassing, given that you can't enforce regulations, or you're persuaded that since farmers want it, you should just let them have it," Mr Keeley said.

Indeed, farmers like Mr Tian are always open to new technology, although he has no idea whether it's legal or not. But a seed retailer in Jiangxia sounds a cautious note: "Our country has not clearly stated whether GM rice can do us any harm or not. Even if we're OK, how about our children, and theirs?"

http://www.truthabouttrade.org/article.asp?id=4129

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