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ISIS Report 16/11/06

GM Crops and Microbes for Health or Public Health Hazards?

Food crops genetically modified to overproduce single nutrients could be public health hazards as overdose of many single nutritional factors are known to be toxic

Genetically modifying natural gut bacteria could turn them into pathogens pre-adapted to invade the human gut

Prof. Joe Cummins and Dr. Mae-Wan Ho

A fully referenced version of this paper is posted on ISIS members’ website. Details here

Metabolic engineering

The first genetically modified crop, Calgene's Flavr Savr tomato for prolonged shelf life, was approved for commercial release in 1992. It was a complete flop. Since then, however, the area planted to GM crops has been increasing, and according to industry sources, reached 90 million ha in 2005 [1]. Two traits, herbicide-tolerance and insect-resistance, currently account for nearly all GM crops; but that will soon change.

New GM crops with other traits are poised to enter the market, in the guise of nutritional benefits and health foods. In 2004, Monsanto received approval for commercial release of high lysine corn modified with a bacterial gene to produce enhanced production of the amino acid lysine [2] ( Why Not Transgenic High Lysine Maize ). In the same year, Monsanto released ‘Vistive' soybeans with reduced linolenic acid, a trait selected using traditional breeding but bred into a glyphosate resistant soybean [3] ( Beware Monsanto's "Vistive Soybeans" ) , and hence should not have been considered a crop modified only for food quality. In 2005, Syngenta applied for commercial release of a corn modified to produce a heat stable amylase enzyme as an aid in food and feed processing [4].

There are many more crop modifications for ‘food quality' in the pipelines. In addition, much activity is also devoted to creating GM microbes to enhance nutrition and health. But are they safe? And what criteria are used in their food safety assessment?

The Codex Alimentarius, UN's food safety regulator, has issued a Consultation that ended 1 October 2006, and that is a sure sign of serious commercialisation.

A number of timely reviews have appeared, one of the most comprehensive coming from the International Life Sciences Institute of Washington DC, whose Trustees include academics as well as representatives of Monsanto, Syngenta, Novartis, Unilever and other corporations [5]. “Metabolic engineering” is highlighted, which involves up or down regulating metabolic pathways, or introducing entirely new pathways to enhance production of key nutrients in foods [6]. Genes for biosynthetic enzymes or regulatory genes are introduced, as well as anti-sense genes to block competing pathways to increase production of desired secondary metabolites [7]. Engineering soybeans has focused on altering functional properties of soy protein to improve processing and on improving the flavour of soy products [8].

Plant genomics is also put forward as an alternative to genetic modification. Using marker assisted selection in conventional breeding to improve flavour, health and nutritional value would obviate the need for genetic modification of the crops [9], and ultimately prove much more acceptable to consumers worldwide.

Nevertheless, a lot of work involving genetic modification is in progress, targeting every aspect of nutrition and health. We present an overview of what biotech companies are intending to put into our diet; based on a much longer report produced previously [10] ( GM Crops for Health? ).

GM crops for health and nutrition

A large class of GM crops under development is aimed at improving the nutritional and health promoting quality of food plants. It includes those that improve storage proteins, increase cancer-fighting antioxidant compounds, enchance the levels of specific vitamins, minerals, and essential fatty acids. In addition, plants are modified with natural and synthetic peptides as antimicrobials and with enzymes that improve food processing.

Storage protein

Cassava root, a staple food for over 500 million people in the tropics, has been targeted with a completely synthetic and novel storage protein to enhance its protein content. Potato tuber has been genetically modified with the seed albumin gene from Amaranthus hypochondriacus ( Prince-of-Wales feather), again, to increase its protein content. An attempt to transfer a methionine-rich maize delta-zein storage protein into soybean to overcome its deficiency in sulphur amino-acids failed to increase the methionine content of seed flour. In rice, the level of storage protein could be increased only in low storage protein mutant strains that had “room” in the seed .

Cancer fighting and health promoting nutrients

As evidence has accumulated that organic produce are richer in cancer fighting antioxidants [11] ( Organic Strawberries Stop Cancer Cells, this issue), genetic engineers have been busy trying to enhance these compounds, especially flavonoids by genetic modification, and t omato was the first target. Red wine is rich in the flavonoid stilbene, thought to be responsible its health benefit in preventing heart disease. Tomatoes have been transformed with the grape stilbene synthase gene; with a petunia flower gene that makes stilbene as well as similar genes from grape, alfalfa and the flower Gerbera , resulting in the production of high levels of health related flavonoids. Phenolic precursors of health related flavonoids, lignans and phenols were enhanced in tomato by down regulating a competing metabolic pathway, using RNAi to inhibit the gene for cinnanomyl-CoA reductase, though RNAi has turned out to be highly fatal to mice in recent ‘gene therapy' experiments [12] ( Gene Therapy Nightmare for Mice ) . Tomatoes were also modified with the genes for enzymes that enhanced production of phytosterols, which lower cholesterol and may prevent cancer.

Apple too, has been modified to enhance stilbene synthesis with a gene for stilbene synthase from grape.

Seed phytosterol levels were enhanced in tobacco using a shortened gene of a rubber tree enzyme 3-hydroxy-3-methyl-CoA reductase (the gene was shortened to remove a cell membrane binding domain to increase activity in seeds). Phytosterol was increased more than 3 fold to 3.5 percent of the seed oil. Such constructs are likely to be transferred to food oil crops such as canola, soybean or maize.

Metabolic engineering of proanthocyanidines (anthocyanidines are a class of flavonoid antioxidants) using genes for anthocyanidine reductase and for the Myb protein transcription factor from Arabidopsis provided a way to enhance the (epi)-flavan-3-ol antioxidants. Myb protein was first identified as a virus oncogene (cancer-associated gene).


A 2004 review identified a crisis in the availability of certain micronutrients globally. Children (primarily the poor) may be dying from deficiencies of iron, zinc and vitamin A, in particular.

“Golden rice” was promoted as the answer to vitamin A deficiency (and hence how GM crops can help the poor). The entire beta-carotene biosynthesis pathway was engineered into rice endosperm in a single transformation step. The genes originated from the daffodil and from bacteria. One daffodil gene was subsequently replaced with the maize gene to enhance synthesis in rice. ISIS critically reviewed golden rice in 2000 [13] ( The 'Golden Rice' ) . Among the observations was that the rice produced too little beta-carotene to relieve the existing dietary deficiency. Since then, golden rice strains have been improved, but still fall short of relieving dietary deficiency. On the other hand, increasing the level of beta-carotene may cause vitamin A overdose to those diets provide adequate amounts of the vitamin. In fact, both vitamin A deficiency and supplementation may cause birth defects . This is where labelling is absolutely necessary if golden rice is to be sold in the market, to alert sensitive people of its potential adverse impacts.

Plants are natural sources of vitamin E, a class of compounds called tocochromanols comprising four tocopherols and four tocotrienols. Corn seed oil, soybean seed oil and wheat germ oil are all rich in tocopherols. Arabidopsis has been the main source of genes to enhance production of vitamin E by over-expression in Arabidopsis , canola and soybean. V itamin E supplementation has been promoted for preventing heart disease and cancer and in treating cancer. However, vitamin E supplementation caused significantly elevated ovarian cancer in one study, while another major study found that high dosage supplementation increased all-cause mortality and should be avoided.

Plants have been subject to metabolic engineering to over produce vitamin C, but the increases have been very modest.

Folate levels have been enhanced in Arabidopsis using a bacterial gene, but with yet no success when transferred to crop plants

B vitamins include riboflavin (B2) and pantothenate (B5). Their metabolic pathways in crop plants are known, but there has been no success as yet to engineer over- production of the vitamins in food crops.

The metabolic pathways of vitamin synthesis in food crops are well understood. This knowledge can be exploited for marker assisted breeding to enhance vitamin production much more profitably than genetic modification.


There has been extensive genetic manipulation to improve the mineral nutrition of plants for both macronutrients such as calcium and nitrogen, and micronutrients such as selenium.

A 3-fold enhancement of calcium in potato tubers was achieved using an Arabidopsis calcium exchanger and transporter gene.

Inorganic nitrogen fertilizer is linked to a variety of problems including the pollution of drinking water, harming infants and causing eutrification of water and depletion of oxygen for aquatic animals. Improving utilization of nitrates by crops should deliver human health benefits in terms of cleaner drinking water, but those benefits could be offset by the harm from increased levels of nitrates in crops. So far, th ere has been little progress in developing transgenic crops that take up and utilize nitrogen more efficiently.

Iron deficiency in food crops plagues much of the globe, particularly Asia. About 40 percent of the world's women suffer some degree of iron deficiency. Pre-menopausal women are most severely affected by iron deficiency, while men tend to retain iron. Rice has been targeted for increased iron, though increasing iron in rice risks increasing the level of arsenic as well [14] ( Rice in Asia: Too Little Iron, Too Much Arsenic ) . Food crops enhanced with elevated iron content must be labelled in the marketplace because iron overload is a significant problem in males, and may lead to haemochromatosis, a disorder of excessive absorption and storage of iron that could damage the liver and other organs, resulting in liver cancer or colorectal cancer. One percent of the population may carry a mutation (hereditary haemochromatosis) that makes them sensitive to iron overload at relatively modest iron intake levels; and there is an association between increasing iron stores and risk of cancer .

Selenium is essential for humans, but has a toxic side that makes it poisonous at relatively low levels. A mouse gene for the enzyme selenocysteine lyase was introduced into the Brassica juncea (canola) chloroplast genome to limit accumulation of selenocysteine to mitigate selenium toxicity. The transgenic canola had a reduced content of selenium in its proteins. Like iron and other minerals, selenium is an essential nutrient, but becomes toxic at high levels.

Fatty Acids

Long chain polyunsaturated acids are vital for human health, and fish and marine oils are the main sources, but efforts are being made to modify oil crop plants to produce the essential fish fats. So far, successful gene transfer from microalgae has been accomplished in Arabidopsis in the laboratory.

Monsanto is modifying canola seeds to accumulate stearidonic acid, another long chain polyunsaturated omega-3 fatty acid that has 18 carbons and 4 double bonds. USDA and the University of Nebraska created transgenic soybean that produces stearidonic acid.

Sunflower seed oil has been modified with multiple copies of a desaturase gene from castor bean to reduce stearic acid, which spoils the quality of sunflower seed oil.

There is good evidence that n-3 and n-6 polyunsaturated fatty acids are therapeutic at moderate levels in the diet but may be detrimental at high levels by causing oxidation stress and forming lipid peroxides that are toxic. Daily intake of the polyunsaturated fatty acids above 10 percent of energy intake is not recommended. Furthermore, high intake of marine fat rich in n-3 polyunsaturated fatty acids may prolong gestation, resulting in high birth weight, and exposes the foetus to methylmercury in fish.

Amino Acids

Certain amino acids are essential in the human diet because mammals cannot synthesize them. Maize is normally deficient in the essential amino acid lysine. As mentioned earlier, high lysine transgenic maize was approved for commercial release in 2004, while high lysine maze varieties are already available through conventional breeding.

A sunflower seed albumin, rich in the essential sulphur amino acids methionine and cysteine, was used to modify lupine, a significant feed crop in many countries. Methionine and cysteine were also enhanced in alfalfa by over-expressing an Arabidopsis cystathionine gamma-synthase gene (the first enzyme in the metabolic pathway for methionine).

Maize has a high methionine-rich storage protein usually under-represented in the seeds. A cis -acting regulator was replaced to give greater stability to its messenger RNA, resulting in increased levels of methionine in transgenic seeds .

Potato was modified with a bacterial ( E. coli ) serine acetyl-transferas e gene and an Arabidopsis transit sequence to direct the transgenic protein to the chloroplast, resulting in elevated levels of cysteine and glutathione. Metabolic engineering was also used to enhance production of sulphur-containing compounds in potato.

Manipulating single genes to overproduce any single mineral, vitamin, or other essential nutrient is fraught with difficulties as these essential nutrients are often toxic at inappropriately high levels. It highlights the importance of getting a balance of essential nutrient content in our food. This can only be achieved by phasing out external inputs of chemical fertilisers in favour of organic fertilisers coupled with integrated farming that provides a complete diet consisting of fresh vegetables, meat and fish [11, 15] ( Organic Strawberries Stop Cancer Cells ; ; Dream Farm 2 - Story So Far ).

Peptides both natural and synthetic

Glutathione (GSH) is an antioxidant consisting of three amino acids that protects cells from free radicals and participates in metabolic reaction. GSH is the most abundant low molecular weight thiol (compounds with -SH group) in plants. It accumulates to high concentrations particularly in response to stress. A bacterial enzyme catalyzing glutathione synthesis and lacking feed back inhibition was used to enhance glutathione production in plants, but increasing glutathione levels in tobacco unexpectedly resulted in continuous oxidative stress in the plants.

Anti-microbial peptides provide the first line of defence against invading bacteria, fungi and viruses in both plants and animals and are part of the host's innate immunity, acting mainly at the cell membrane. They are 15 to 40 amino acids in length, most of them hydrophobic (water-hating) and cationic (positively charged), and are beginning to find applications in medicine and in crop protection.

A synthetic peptide D4E1 based on the cecropin B peptide toxin (obtained from the moth, Cecropia ), was found to have broad-spectrum anti-microbial action, and was active against fungi belonging to the orders Ascomycete, Basidiomycete, Deuteromycete and Oomycetes, as well as bacterial pathogens Psuedomonas and Xanthomonas . It also proved effective in treating Chlamydia infection in humans. Synthetic peptides of 11 amino acids proved effective against bacterial plant pathogens, with minimal cytotoxicity and protease degradation, offering improved crop protection as an external pesticide or incorporated into transgenic crops.

Researchers in Japan have created transgenic rice with the anti-microbial peptide defensin from Brassica . The transgenic rice plants were resistant to rice blast disease caused by the fungus Magnaporthe grisea . The researchers then systematically altered the genetic code for defensin to produce synthetic peptides that were far more toxic to the fungus than the natural peptides. Rice with the synthetic genes and peptides are being field-tested prior to commercial release in Japan.

A potato virus X expression system was used to produce a killer peptide with a strong activity against human pathog ens. The killer peptide was tested against both bacterial and fungal plant pathogens and proved very effective. The killer toxin was fused to the virus X coat protein in a system that allowed its rapid production . The virus production system is capable of spreading the toxin to non-transgenic potato, for better or for worse.

There have been criticism and objections to open field-testing of crops modified with the synthetic peptides. The evolution of resistance to anti-microbial peptides will severely compromise both the natural defence of the human immune system against disease and the possibilities of effective therapies emerging in the wake of the disaster of widespread antibiotic resistance [16] ( No to Releases of Transgenic Plants with Antimicrobial Peptides ) .

Enzymes for improved food processing

Glutenin is a major storage protein in barley. Barley is malted to make beer. During malting, glutenin is digested by a beta-glucanase enzyme. The heat stability of the enzyme can be problematic during industrial scale malting. A heat stable hybrid enzyme was made from genes of two bacillus bacteria species, with codon adjustments in the DNA sequence to enhance protein synthesis in barley.

GM Microbes in Food

GM probiotics

Probiotics - natural symbionts of the human and animal gut including Lactobacillus species, Bifidobacterium species and the yeast Saccharomyces boulardii - have been used as food supplement, providing health benefits such as protection against gastroenteric pathogens, neutralisation of food mutagens produced in the colon, shifting the immune system to alleviate allergy and lowering serum cholesterol [17] ( Health-promoting Germs ) .

Probiotic lactic acid bacteria have been extensively modified to serve the food industry and other purposes, such as gene therapy. Modifications included modulation of the proteolytic system to enhance cheese ripening, increasing the production of the Kreb's cycle enzyme alpha keto-glutarate, using antisense RNA to silence lytic Lactoccocus phage, introducing a folate gene cluster, re-routing pyruvate to L-alanine, and over-expressing the riboflavin biosynthesis pathway. Further genetic modifications of lactic acid bacteria involved inactivation of glucose fermentation and introduction of lactose fermentation, introduction of alpha-galactosidase, of phytase, of alpha amylase and cellulose. Lactic acid bacteria have also been genetically modified with bacteriocin toxin to prevent dental carries, for increased activity of beta-galactosidase, for lacticin (a bacteriocin) production, for increased nicin production, and increased proteolytic and acidifying activity. Probiotic bacteria have been enhanced for glutathione production, and for oxidative stress tolerance. Lysostaphin, a glycylglycine endopeptidase that specifically cleaves the pentaglycine cross-bridges found in the staphylococcal peptidoglycan was inserted into lactic acid bacteria for use in destroying the pathogen.

GM probiotic bacteria have not received much public scrutiny mainly because the regulation of such microbes is separate from the regulation of GM crops. There is a strong likelihood that GM probiotic bacteria may be introduced to the market before serious safety concerns are addressed.

Using GM probiotic bacteria requires special caution. These natural symbionts of the gastrointestinal tract have adapted to their human and animal hosts over millions if not billions of years of evolution. Genetically modifying them could easily turn them into pathogens pre-adapted to invade the human and animal gut. Furthermore, the gastroinstestinal tract is an ideal environment for horizontal gene transfer and recombination, the major route to creating pathogens. For these reasons, we have proposed that any genetic modification of probiotic bacteria should be banned [18,19] ( Ban GM Probiotics ; GM Probiotic Bacteria in Gene Therapy ).

Other GM bacteria

Fowls grew 10 percent faster when fed transgenic yeast Pichia pastoris modified with a pig growth hormone gene . Growth hormone food microbes may be attractive for chicken farmers, but their use may carry the microbes over into the human population; and not everyone would want to grow like pigs.

Microbial bio-control agents have been developed and the impact of such agents on foods requires careful consideration. A modified Trichoderma atroviride with a glucose oxidase gene from Aspergilus niger rapidly overgrew and lysed the plant pathogens Rhizoctonia solani and Pythium ultimum . The transgenic bio-control agent both defeated the pathogens and induced systemic resistance in treated plants, but they should be studied extensively for their impact on food safety and quality.

The modification of food microbes requires comprehensive public scrutiny especially as numerous modified strains are awaiting release into the commercial markets.

Yield or nutrition – a false dichotomy

The pressure to use genetics to boost crop yield, first with the green revolution, and then with genetic modification, may have resulted in a crisis in nutrition. Too many of the crops have become depleted in mineral nutrients, vitamins and essential building blocks [20], particularly as soils become depleted and exhausted. Healthy soils are needed for the production of healthy crops [21] ( Organic Farms Make Healthy Plants Make Healthy People ).

But maximising yield does not necessarily sacrifice nutrition if the land is properly managed for maximum internal organic input. This can be achieved by turning otherwise polluting livestock and crops wastes into food and energy resources [15], thereby mitigating climate change and solving the global energy crisis while providing food security for all.

Genetic modification fails to address climate change and the depletion of energy, water, soil nutrients, and other agricultural resources that already threaten food security, and is a diversion of time and resources that the world can ill afford.

Hazards of GM plant and microbial ‘health' foods

Foods enhanced in single nutrients do not constitute health foods and must be labelled

We question the enormous amount of effort and resources being devoted to improving the nutritional quality of food through genetic modification to enhance production of single essential nutrients. Nutrition depends on a balance of macro and micronutrients, cofactors and vitamins, which is best achieved by adopting organic agricultural practices and a complete diet containing fresh fruits and vegetables, meat and fish. Overdose of any single nutritional factor is likely to be harmful; and hence genetically modified ‘health-enhancing' food crops may well turn out to be serious public health hazards.

Codex's own consultation document [22] states: “Working Group members recognized that safe upper intake levels should be determined for nutrients and related substances to prevent excessive intake by vulnerable populations. It was also recognized that there is a need to determine the safety of nutrients and related substances when upper limits have not been determined and to also consider the history of safe use of the nutrient when appropriate. However, it was also recognized that the issue was generic in nature.”

It is already clear that many of the nutrients being genetically manipulated have upper limits of toxicity, particularly iron and selenium among minerals, vitamin A and possible vitamin E.

It would be misleading and indeed dangerous to market foods enhanced in single nutritional factors as ‘health' foods. And it is imperative to label such products clearly in order to avoid toxic overdose.

The safety of synthetic genes and transgenes in general

Codex has not addressed the safety of synthetic genes that are being used, some of which produce proteins that are completely new to our food chain. Extreme examples are the synthetic storage protein genes to enhance protein or amino acid content, and synthetic peptides for controlling pathogens. By definition, the products of synthetic genes are not “substantially equivalent” as they have no natural counterparts [23] ( GM Food Animals Coming , this issue).

Apart from the completely synthetic genes, many genes are synthetic approximations of natural genes or hybrid genes made of synthetic approximations of two or more genes. These too, constitute novel proteins in our food chain. All transgenic proteins should be comprehensively tested for toxicity and immunogenicity, bearing in mind that gene transfer even between closely related species involves changes in glycosylation patterns that may transform a normally harmless protein into a potent immunogen, as was recently demonstrated in the case of bean to pea gene transfer [24] ( Transgenic Pea that Made Mice Ill ) .

Some transgenes code for proteins with potent biological activities; these include growth hormones and antimicrobial peptides, which are likely to have untoward effects on human physiology and the immune system.

The safety of metabolic engineering

The Codex consultation document states that [22], “foods derived from rDNA plants that have undergone modification to intentionally alter nutritional quality or functionality should be subjected to additional nutritional assessment - beyond that conducted when modifications are for other purposes - to assess the consequences of the changes and whether the nutrient intakes are likely to be altered by the introduction of such foods into the food supply.”

Many of the genetic modifications involve massive alterations, such as the replacement of one or more metabolic pathways. Such changes increase the probability of creating unintended toxic by-products, and call for comprehensive comparisons of metabolic- transcriptional- and protein-profiles between GM varieties and the non-GM controls, as well as extensive safety trials.

RNA interference already shown to cause massive fatalities in mice

RNAi – short sequences of RNA that interfere with gene function - is being used increasingly to up or down regulate genes and pathways. The need for adequately testing such constructs is clear; the massive deaths of mice subjected to RNAi ‘gene therapy' [12] should serve as a warning. RNA interference is currently not included as genetic modification, and requires special attention.

Safety tests should not be done on children in developing nations

The Codex consultation document [22] states: “…additional safety and nutritional considerations for the assessment of foods derived from rDNA plants modified for nutritional or health benefits include such aspects as bioavailability and physiological function of the intended modification. Particular focus will be given to staple crops of interest to populations in developing countries.”

Safety and nutritional testing of all of the modifications described in the accompanying literature is clearly essential for all the areas of the world. But we emphasize that the initial testing of the modified crops should not be done on children of developing countries under the guise of providing medical care, as has been the case with GM rice producing proteins found in milk [25] ( FDA in Third World Drug Trial Scandals ), and those undertaking such unethical tests should be prosecuted.

GM probiotics should be banned

The genetic modification of probiotic bacteria should be banned until and unless extensive studies and safety tests have been carried out. These bacteria have co-evolved with their animal and human hosts for millions and billions of years, with an intricate network of relationships that is only just beginning to be understood, and if thrown out of balance, could result in serious disease. Genetically modifying these bacteria runs the risk of creating pathogens that are pre-adapted to invade the gastrointestinal tracts of their hosts, where horizontal gene transfer and recombination are rife.

The concept of “substantial equivalence” has no place in scientific risk assessment

Finally, the concept “substantial equivalence” has no validity in risk assessment of GM food and food products, least of all in the area of metabolic engineering (see GM Food Animals Coming , this issue [23] and should be rejected by Codex Alimentarius.

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