ASSOCIATE PARLIAMENTARY FOOD & HEALTH FORUM GM Crops and Food Security Wednesday 21 July 2010 House of Commons Is GM technology simply an extension of traditional breeding methods for the production of new varieties of crops and, if not, does it matter? Michael Antoniou King’s College London School of Medicine, Guy’s Hospital, London

Central Tenets of Genetic Modification in Agriculture The use of genetic modification (GM) in agriculture is a natural extension of traditional breeding methods but more precise and safer. Genes are isolated units of information that can function in a totally predictable manner even when moved between unrelated species using GM technology.

Substantial Equivalence and Generally Recognised as Safe Only GM gene and its product are seen as source of risk General biochemical analysis only Assessment of known toxins/allergens only GM and non-GM parental plant are “substantially equivalent” if they contain similar amounts of biochemical components within limits of natural variation No feeding trials required if they substantial equivalence is found (USA); only 90-day feeding test required in EU. FLAWS: Only looks at gross biochemical composition; only looks at known components. NOTE: BSE cow is “substantially equivalent” to a normal cow!

The New Genetics 1. Gene order/organisation in DNA is very precise. 3. Genes exist in groups or families. 4. Genes work in groups; no gene works in isolation. 5. Gene function is tightly regulated in a highly coordinated manner by both local and distant genetic elements and layers of epigenetic control. 6. Genes have co-evolved to function together as an integrated whole within a given organism. 7. Genes are now defined more by their context than by purely their information content. 2. In most cases, more than one RNA/protein is produced from a given gene. Many proteins perform more than one function. 8. Normal sexual reproduction or breeding can take place only between closely related organisms. Genes are inherited in their natural groupings that have been finely tuned to work harmoniously together by millions of years of evolution.

Genetic Modification : The Fundamentals  New technology: only ~28 years old.  Does not involve natural sexual reproduction methods: GMOs are laboratory “creations”; e.g. genes inserted into plant cells under laboratory culture using mechanical (“biolistics”) or bacterial infection methods.  Allows transfer of one or few genes between totally unrelated organisms: e.g. bacterial, viral or animal genes into plants.  Employs artificial combinations of genetic material: e.g. Cauliflower mosaic virus/petunia genetic switch control elements linked to a bacterial gene inserted into soya beans to confer herbicide resistance.  The GM transformation process is very inefficient. Only a very low percentage of plant cells take up the foreign gene cassette; antibiotic resistance genes have to be used to select for transformants.  Generation of GM plants involves the random insertion or splicing of a foreign gene into the host DNA/genome.  The GM transformation process as a whole is highly mutagenic, invariably to a lesser or greater degree always disrupting gene order and function.

GM in Plants  GM bears no resemblance to natural sexual reproduction and bypasses natural species barriers.  GM brings about novel combinations of genes that have not evolved to function together.  GM transformation process (transgene insertion plus tissue culture) is highly mutagenic.  GM to a lesser or greater degree, always disrupts host genetic order and function.

Consequences of GM Transformation  Combined effects of GM (mutation effects; novel combinations of gene products) can disrupt genetic and protein biochemical function leading to the generation of novel toxic effects, allergies and altered nutritional value.  Introduces new substances with potential toxic effects from: transgene product, altered farming practice.  GM in agriculture possesses an unpredictable component that can frequently be greater than the intended change.  CONCLUSION: from basic science and technological perspective, GM is NOT a natural extension of traditional breeding and is NOT technically neutral.

GM Transformation Can Interfere with Crop Performance and Reduce Yields Growth Problems  Certain varieties of GM cotton suffered cotton ball and root development problems  Certain varieties of GM cotton are more susceptible to nematode attack  GM soya has a lower tolerance to heat  GM soya has highly reduced uptake of manganese No Increase in Yield Potential  GM soya beans have given consistently lower yields for more than a decade; “yield drag”*.  Field trials show GM soya to have a 10% lower yield potential with 50% of the drop due to the genetic disruptive effect of the GM transformation process  Field trials of Bt insecticide producing maize hybrids showed that they took longer to reach maturity and produced up to 12% lower yields *Note: RR2 Soya development

GM Transformation Can Interfere with Crop Performance and Reduce Yields Report claims no yield advantage for Bt crops Nature Biotechnology, 27: , Failure to Yield: Evaluating the Performance of Genetically Modified Crops (April 14, Union of Concerned Scientists, USA), argues that the adoption of expensive, GE-based approaches to agriculture has been at the cost of cheaper alternatives that carry less environmental risk

Ideal GM Food Animal Feeding Studies GM foods designed for life long consumption, therefore and animal feeding study evaluating safety should be: Long-term; that is life long Multigenerational Employ at least three animal species including farm animals that will consume them Measure a broad range of physiological and biochemical parameters Only valid as GM vs non-GM parental (“isogenic”) comparison Note: OECD guidelines; 3 animals but ONLY for 90 days feeding!

Controlled Animal Feeding Studies Show Clear Signs of Toxicity linked with GM crops

Academic Based Studies

Potential Health Effects of GM Foods : Some Current Evidence for Unexpected Toxic and Allergenic Events Extensive laboratory animal feeding studies with commercialised GM food raise worrying health concerns Liver, pancreas and testes function was disturbed in mice fed GM soya (Malatesta et al., 2002, 2003, Vecchio et al., 2004) Mice fed GM soya over their entire life time (24 months) show more acute signs of ageing in their liver (Malatesta et al., 2008)  Old and young mice fed with GM insecticide producing maize showed a marked perturbation in immune system cell populations and in plasma cytokine profiles (Finamore et al., 2008)

Potential Health Effects of GM Foods : Some Current Evidence for Unexpected Toxic and Allergenic Events Extensive laboratory animal feeding studies with commercialised GM food raise worrying health concerns Rats fed GM insecticide producing maize over three generations: Higher incidence in necrotic areas in liver and kidneys; alterations in blood biochemistry (Kılıc and Akay, 2008)  Feeding of GM insecticide producing maize to mice over 4 generations: Build up of abnormal structural changes in various organs (liver, spleen, pancreas) Major changes in the pattern of gene function in the gut - disturbances in the chemistry of this organ system (e.g. in cholesterol production, protein production and breakdown) Significantly reduced fertility (Velimirov et al., 2008)

Industry Studies

MON863 GM maize causes haematological disturbances and organ weight loss in rats Only a 90-day feeding study comparing GM and non-GM equivalent diets showed significant changes in their blood cells, livers and kidneys, which might indicate disease. Review of Some of the Significant Differences: MeasureFunctionMight indicateComments Increased Basophil Counts Creates histamineAllergic reactionOther Bt corn studies suggest possible allergic reactions. Increased Lymphocytes and white blood cells Immune reactions to fight infections, etc. Infections, various toxins and diseases Researchers omitted tests to see if the spleen, which creates lymphocytes, was affected. Decreased Reticulocytes Becomes mature erythrocytes (red blood cells) Anemia5% variability is allowable. Astoundingly, Monsanto claimed a 52% decrease was “attributable to normal biological variability.” Decreased Kidney Weight To clear waste products Blood pressure problems Any inadequacy in kidney function is potentially life threatening. Increased Blood Sugar Essential energy source A 10% elevation cannot be written off as insignificant, given the diabetes epidemic. Rats fed insecticide-producing GM maize grew more slowly, suffered problems with liver and kidney function, and showed higher levels of certain fats in their blood

Signs of Toxicity from Commercialised GM Maize Varieties

Flaws and Counterclaims Use of irrelevant control comparators Use too few animals; not enough animal types Wrong statistical analytical methods Too short feeding trial time; only 90 day max at present required/conducted Statistically significant but not biologically significant Sex differential effects

Significance of Rodent GM Food Feeding Studies Surrogates for human toxicological investigations “Facts do not cease to exist because they are ignored” Aldous Huxley

Central Tenets of Genetic Modification in Agriculture The use of genetic modification (GM) in agriculture is a natural extension of traditional breeding methods but more precise and safer. Genes are isolated units of information that can function in a totally predictable manner even when moved between unrelated species using GM technology.

Sources of Possible Toxic Effects of GM Foods GM gene product: Enzymes responsible for herbicide tolerance Bt toxin: immunogenic, adjuvant Changes in farming practice: Broad spectrum herbicide residues Adverse mutagenic effects of GM transformation: Novel toxins, allergens and disturbed nutritional value

Consequences of GM Mutagenic Effects Zolla L et al., Journal of Proteome Research, 7: , Disturbance in GM MON 810 maize protein expression profile (“proteome”):  43 proteins up or down in level in GM vs controls which could be specifically  related to the transgene insertion  GM plants responded differentially to the same environment compared to  their non-GM isogenic controls, as a result of the genome rearrangement derived from gene insertion  Newly expressed protein: zein, a well-known allergenic protein  Major concern, a number of seed storage proteins exhibited truncated forms having molecular masses significantly lower than the native ones  This and animal feeding studies invalidates the approval of MON810 for commercial use.

Is there a place for Biotechnology in Agriculture?

Marker Assisted Selection - MAS Responsible, More Effective and Safe Use of Biotechnology in Agriculture The New Genetics tells us that preservation of species barriers, natural gene order and function is vital to maintain integrity and safety  Use of more holistic (“systems biology”) aspects of modern biotechnology: Marker Assisted Selection (MAS): a non-GM biotechnology Guide and accelerate the traditional breeding process Genetically complex properties possible (e.g. enhanced nutrition, taste and yield potential, pest and blight resistance, and tolerance to drought, heat, salinity and flooding).  Use of existing crop varieties and related wild relatives in traditional breeding programmes to develop varieties with enhanced characteristics useful in contemporary agriculture.

Marker Assisted Selection (MAS)

Novel upland rice variety bred using marker-assisted selection and client-oriented breeding released in Jharkhand, India Monday, May 4, 2009 By Katherine Steele rker_assisted_selection_and_client_oriented_br A novel upland rice variety, Birsa Vikas Dhan 111 (PY 84), has recently been released in the Indian state of Jharkhand. It was bred using marker-assisted backcrossing with selection for multiple quantitative trait loci (QTL) for improved root growth to improve its performance under drought conditions. It is an early maturing, drought tolerant and high yielding variety with good grain quality suitable for the direct seeded uplands and transplanted medium lands of Eastern India.

Genetics of high-rise rice Laurentius A. C. J. Voesenek and Julia Bailey-Serres Nature, 460: Hattori, Y. et al. Nature 460, (2009). SNORKEL1, SNORKEL2 genes THREE different gene regions on THREE different chromosomes Transferred to short, non-flood responsive rice by natural breeding assisted by MAS

The Use of GM in Agriculture - Summary  The New Genetics tells us that GM in crop production:  Has no basic scientific foundation  Conceptually and technically flawed; not technically neutral  Yesterday’s technology based on yesterday’s understanding of genes and genetics  GM possesses inherent unpredictability for health and the environment which is currently impossible to quantify.  The release of viable GMOs into the environment is not justified and possibly irresponsible as once released into the environment GMOs cannot be recalled. There already exist proven alternatives to meet future food needs in a sustainable manner, a role that GM in its current form is unable to fulfil: "Genetic-modification technologies just treat the symptoms rather than dealing with the causes", Hans Herren, president of the Millennium Institute, Arlington, Virginia (USA); co-chair of the International Assessment of Agricultural Knowledge, Science and Technology for Development (IAASTD). [Nature, 455: , 2008].

The Precautionary Principle "When an activity raises threats of harm to human health or the environment, precautionary measures should be taken, even if some cause and effect relationships are not fully established scientifically" ‘Wingspread Statement on Chemically-Induced Alterations to immune system.’ Environmental Health Perspectives, 104:4, August 1996.

Random insertion or splicing of the GM gene: Insertional Mutagenesis Foreign gene or “transgene” unit Random Insertion/Splicing Host genome Disruption of host gene functions at short/long distances and even on separate chromosomes GM gene insertion: Selects for active regions Direct gene disruption Not a “clean” process; deletions (loss) of host genes GM gene element mediated disturbances

The Mutational Consequences of Plant Transformation Jonathan R. Latham, Allison K.Wilson and Ricarda A. Steinbrecher Journal of Biomedicine and Biotechnology Volume 2006, Article ID 25376, Pages 1–7 Tissue culture phase and gene insertion process combine to cause “… genome-wide mutations can number from hundreds to many thousands per diploid genome. Despite the fact that confidence in the safety and dependability of crop species rests significantly on their genetic integrity, the frequency of transformation-induced mutations and their importance as potential biosafety hazards are poorly understood.”

Potential Health Effects of GM Foods : Some Current Evidence for Unexpected Toxic and Allergenic Events Laboratory animal feeding studies with GM food raise worrying health concerns Rats fed GM tomatoes developed stomach ulcerations GM peas caused allergic reactions in mice Rats fed GM oilseed rape developed enlarged livers, often a sign of toxicity GM potatoes fed to rats caused excessive growth of the lining of the gut similar to a pre-cancerous condition

The USA Experience No baseline data - where did we start from? No labelling; no exposure data - who eats what? GM food ingredients at present account for only a small part of the US diet (maize, less than 15%; soya bean products less than 5%) No human feeding trials No official epidemiological data If GM food was causing changes to common conditions (e.g. allergy, auto-immune disease, cancer) there is absolutely no way that we could know! Scientifically indefensible, uncontrolled experiment!!

Bt toxin Impact on Health - Generally unknown Artificial and totally novel; constructed from modified genes of a soil bacterium, a reservoir of more than 100 Bt insecticides Ex. 44% difference in GM Bt176 maize

Consequences of GM Mutagenic Effects Disturbed structure and nutritional composition

Effects of low doses of Roundup herbicide Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines. Gasnier C, Dumont C, Benachour N, Clair E, Chagnon MC, Séralini GE. Toxicology, 2009 Jun 17. [Epub ahead of print]. Glyphosate formulations induce apoptosis and necrosis in human umbilical, embryonic, and placental cells. Benachour N and Seralini, GE. Chem Res Toxicol, 22: , Time- and dose-dependent effects of roundup on human embryonic and placental cells. Benachour N, Sipahutar H, Moslemi S, Gasnier C, Travert C, Séralini GE. Arch Environ Contam Toxicol, 53: , 2007.

Control human embryonic 293 cellsSame cells treated only 24 h with 0.05% Roundup