Declaration of Dr. Richard Lacey, M.D., Ph.D.

United States District Court for the District of Columbia
Alliance for Bio-Integrity, et al. Plaintiffs
v. Donna Shalala, et al. Defendants.
Civil Action No. 98-1300 (CKK)

I, Richard Lacey, state:

1. I reside at [ ] Leeds, UK.

2. I earned both a B.A. in biochemistry and an M.D. from the University of Cambridge and a Ph.D. in genetics from the University of Bristol. Since 1971, I have been a member of the Royal College of Pathologists, and since 1983, I have been Professor of Medical Microbiology at the University of Leeds. (I have been on Emeritus status since 1995.)

3. I am an expert in food safety issues, and my background makes me especially qualified to assess the potential risks of genetically engineered food products. I served four years on a U.K. government advisory panel on food as it relates to human and animal health, and I have written five books on food safety, including one published by Cambridge University Press in 1994 containing a detailed discussion of genetically engineered food. (This book has been translated into Japanese and Polish.) In addition, I have written over 200 articles published in standard scientific journals and attended and spoken at numerous scientific conferences both in the U.K. and abroad. (A list of my publications and honors is attached.)

4. In 1989, I anticipated that there could be serious health risks to the British cattle and human populations from the practice of feeding cattle rendered meat from sheep and other animals. I published my warnings in Food Microbiology, 1990. In this article, I explained the nature of the malady that could result. This was the first prediction of what eventually became the "mad cow" epidemic in the United Kingdom. Unfortunately, the governmental authorities were slow to respond to my warning. Had they properly assessed and acted upon the information I presented, much hardship would have been avoided, and the citizens would not have been subjected to as high a degree of risk. (Because of the long latency period between exposure to the infectious agent and development of symptoms, there is a potential for widespread incidence of infection within the British public over the next forty years.)

5. It is my considered judgment that employing the process of recombinant DNA technology (genetic engineering) in producing new plant varieties entails a set of risks to the health of the consumer that are not ordinarily presented by traditional breeding techniques. It is also my considered judgment that food products derived from such genetically engineered organisms are not generally recognized as safe on the basis of scientific procedures within the community of experts qualified to assess their safety. Paragraphs 6 through 10 explain why these new foods entail higher risks, and paragraphs 12 through 15 explain why none of them is generally recognized as safe.

6. Recombinant DNA technology is an inherently risky method for producing new foods. Its risks are in large part due to the complexity and interdependency of the parts of a living system, including its DNA. Wedging foreign genetic material in an essentially random manner into an organism's genome necessarily causes some degree of disruption, and the disruption could be multi-faceted. Further, whether singular or multi-faceted, the disruptive influence could well result in the presence of unexpected toxins or allergens or in the degradation of nutritional value. Further, because of the complexity and interactivity of living systems -- and because of the extent to which our understanding of them is still quite deficient -- it is impossible to predict what specific problems could result in the case of any particular genetically engineered organism. Prediction is even more difficult because even when dealing with one variety of a food-producing organism and one particular set of foreign genetic material, each insertion event is unique and can yield deeply different results.

7. The mechanics and risks of recombinant DNA technology are substantially different from those of natural methods of breeding. The latter are typically based on sexual reproduction between organisms of the same or closely related species. Normally, entire sets of genes are paired in an orderly manner that maintains a fixed sequence of genetic information. Every gene remains under the control of the organism's intricately balanced regulatory system. The substances produced by the genes are those that have been within the species for a long stretch of biological time. (In cases where mating is between closely related species, there is generally close correspondence between the substances produced by each.) In contrast, biotechnicians take cells that are the result of normal reproduction and randomly splice a chunk of foreign genetic material into their genome. This always disturbs the function of the region of native DNA into which the material wedges. Further, the foreign genes will usually not express within their new environment without a big artificial boost, which is supplied by fusing them to promoters from viruses or pathogenic bacteria. As a result, these genes operate essentially as independent agents outside the host organism's regulatory system, which can lead to many deleterious imbalances. Moreover, this unregulated activity produces substances that have never been in the host species before and are usually very different from any that have -- which could lead to problems even if production were at a low rather than a high level. There are several other major differences between genetic engineering and traditional breeding, all of which could, as can the above-mentioned ones, induce the presence of unpredicted toxins or allergens or the degradation of nutritional value.

8. Consequently, whereas we can generally predict that food produced through conventional breeding will be safe, we cannot make a similar prediction in the case of any genetically engineered food.

9. Therefore, the only way even to begin to assure ourselves about the safety of a genetically engineered food-yielding organism is through carefully designed long-term feeding studies employing the whole food; and it would be necessary to test each distinct insertion of genetic material, regardless of whether the same set of genetic material in the same type of organism has previously been tested.

10. Even if the most rigorous types of testing were performed on each genetically engineered food, it might not be possible to establish that any is safe to a reasonable degree of certainty, as is possible in the case of most ordinary chemical additives. However, we at least would be in a far better position than now to have greater confidence in these new foods.

11. I regularly attend professional conferences in my specialities and I keep abreast of the scientific literature. I also stay in communication with many life scientists and health professionals.

12. To the best of my judgment, neither genetically engineered foods as a general class nor any genetically engineered food in particular is generally recognized as safe among those experts qualified by training and experience to evaluate their safety.

13. I base this judgment on two factors. First, although many life scientists (including some molecular biologists) claim that genetically engineered foods pose no unreasonable risk, I know of many well-qualified life scientists who do not think that their safety has been established. For instance, a recent official statement of the British Medical Association seriously questions the assumption that genetically engineered foods are in general as safe as those produced by traditional methods. In my opinion, the number of scientists who are not convinced about the safety of genetically engineered foods is substantial enough to prevent the existence of a general recognition of safety. Second, there is insufficient evidence to support a belief that genetically engineered foods are safe. I am not aware of any study in the peer-reviewed scientific literature that establishes the safety of even one specific genetically engineered food let alone the safety of these foods as a general class. Few properly designed toxicological feeding studies have even been attempted, and I know of none that was satisfactorily completed. Those who claim that genetically engineered foods are as safe as naturally produced ones are clearly not basing their claims on scientific procedures that demonstrate safety to a reasonable degree of certainty. Rather,they are primarily basing their claims on a set of assumptions that, besides being empirically unsubstantiated, are in several respects at odds with the bulk of the evidence.

14. The main assumptions are: (a) that producing food through recombinant DNA technology in itself entails no greater risks than producing it through sexual reproduction between members of the same species and (b) that the same safeguards commonly employed by breeders using conventional techniques will suffice for genetically engineered foods. As I have explained in paragraphs 6 and 7, the first assumption is unsound and at odds with biological reality. Paragraphs 8, 9 and 10 explain the unsoundness of the second assumption.

15. As far as I can ascertain, the current policy of the U.S. Food and Drug Administration is primarily based on these two assumptions. Therefore, although it claims to be "science-based," this claim has no solid basis in fact. The only way to base the claims about the safety of genetically engineered food in science is to establish each one to be safe through standard scientific procedures, not through assumptions that reflect more wishful thinking than hard fact.

16. In accordance with 28 U.S.C. ß 1746, I declare under penalty of perjury that the foregoing is true and correct.

Executed on: May 28, 1998.

[signed]__________________
Dr. Richard Lacey

Taking Science Seriously in the GM Debate

By Dr. Mae-Wan Ho

If there is one thing that distinguishes the Third World from the industrialised countries, it is that they take science a lot more seriously than we do in the GM debate.

I was researcher and university lecturer of genetics throughout the mid-1970s to the early1980s when new discoveries on the fluid genome made headlines every week. Researchers back then were building a new paradigm, dispelling once and for all the notion that a gene is constant and independent of context. The thought that a gene could be patented as an invention probably never crossed their mind. And if it did, they would have dismissed it as a joke. Craig Venter of Celera may have only just discovered that genetic determinism cannot deliver the goods after he's sequenced the human genome. But many of us knew that genetic determinism had died with the revelations of the fluid genome, if not before [1]. And now, almost two decades later, science is in crisis in more ways than one.

The paradigm change that should have occurred, did not. On the contrary, the scientific establishment remained strongly wedded to genetic determinism, which has misguided genetic engineering, making even the most unethical applications appear compelling, such as 'therapeutic' human cloning, for one [2]. Bioethics became a contradiction in terms as rampant commercialisation of science took hold.

Since the 1980s, preoccupation with patenting and start-up companies has compromised the quality of molecular genetics research, stifling basic science and innovation, and failing to serve the public good. Worse still, many scientists are consciously or unconsciously ignoring scientific evidence of the hazards. I got involved in the genetic engineering debate in 1994, to try to inform our policymakers and the public, and to start debate and discussion from within the scientific community.

For the past seven years, I have had to follow developments in genetic engineering science much more carefully and extensively than many of the practitioners, only to find that all my fears concerning the problems and dangers of genetic engineering are being confirmed. I shall highlight some of these before going to discuss what needs to be done.

Genetic engineering superviruses

The top news in the Jan. 13 issue of the New Scientist [3] was on a deadly virus created accidentally by researchers in Canberra Australia, who were trying to genetic engineer a contraceptive vaccine for mice [4]. They spliced a gene for the protein interleukin-4 (IL-4) into a relatively harmless mousepox virus in the hope that IL-4 would boost the immune system. When they injected the recombinant virus into mice belonging to a strain genetically resistant to mouse-pox virus, all the mice died. IL-4 suppressed both natural killer cells and cytotoxic lymphocytes responses to viral infection. The recombinant virus also killed 50% of the genetically resistant mice that were immunized against mouse-pox virus.

That is not all. The IL-4 gene, spliced into the vaccinia virus, was found to delay clearance of the virus from experimental animals, and to undermine the animals' anti-viral defence [5,6]. Vaccinia and mouse-pox both belong to the family that contains the human smallpox virus, raising the spectre of biological warfare. But the far greater danger lies in the unintentional creation of deadly pathogens in the course of apparently innocent genetic engineering experiments. Some scientists are already creating viruses deliberately in their laboratories, just to show it could be done, or in the course of cloning existing viruses [7]. And dangerous recombinant viruses and bacteria may also be inadvertently created in making vaccines against AIDS, as Yugoslav virologist Veljkovic has been warning since 1990 [8].

The New Scientist editorial [9] accompanying the report remarked that five years ago, when biomedical researchers were asked if genetic engineering could create "a virus or bacteria more virulent than nature's worst", they replied it would be "difficult if not impossible".

Some of us have been warning of 'accidents' such as this for at least the past six years. The basic tools of genetic engineering are bacteria, viruses and other genetic parasites that cause diseases and spread drug and antibiotic resistance. All that fall into the hands of genetic engineers are exploited. Genes from dangerous agents, including antibiotic resistance genes, are profusely mixed and matched, or recombined. As every geneticist should know, recombination of genetic material is one of the main routes to creating new strains of bacteria and viruses, some of which may be pathogens. (The other route is mutation.) Moreover, the predominant orientation of genetic engineering in the past two decades has been to design artificial GM constructs and vectors that cross species barriers and invade genomes, both of which will enhance horizontal gene transfer and further increase the chance for recombination.

We published a detailed review on the possible links between genetic engineering and the recent resurgence of drug and antibiotic resistant infectious diseases in 1998 [10]. We were by no means the first. Those who pioneered genetic engineering declared a moratorium in Asilomar in the mid- 1970s precisely because they were concerned about this dire possibility. Unfortunately, overwhelming pressures for commercial exploitation cut the moratorium short. The scientists set up guidelines, based largely on assumptions that have all fallen by the wayside as the result of new scientific findings. The two most important findings are the persistence of nucleic acids in all environments including the gut of animals, and the ease with which nucleic acids can get into all cells, especially those of human beings, as shown in so-called gene therapy research [11].

Instead of tightening the guidelines, our regulators have relaxed them. Transgenic wastes are being recycled as food, feed, fertilizer and landfills under the current EC Directive on Contained Use [12], and I would not be surprised if this applies also in the US. There is a lesson to be learned from the 650 or more adverse reactions associated with gene therapy trials, including several deaths. The same kinds of constructs are made, whether it is to genetic engineer human beings or plants and animals, and the same crude first generation technology is used.

The instability of transgenic lines

The instability of transgenic lines has been well known since 1994, particularly in connection with gene silencing. This not only affects agronomic performance, but also safety. We have drawn attention to the structural instability of GM constructs in general, which may enhance horizontal gene transfer and recombination, especially because the cauliflower mosaic virus (CaMV) 35S promoter, present in practically all GM crops already commercialized or undergoing field trials, actually has a recombination hotspot. We raised our concerns in a series of scientific papers [13 -16].

In the course of debating with plant molecular geneticists in UK's top research institute, the John Innes Centre (JIC), we discovered that the CaMV 35S promoter is active, not only in all plants, bacteria, algae and yeast, but also in animal and human cells [17,18]. None of our critics was aware that the promoter is active in human cells, including a molecular geneticist on the UK Agriculture & Environmental Biotechnology Commission set up to oversee our farmscale field trials [19].

This year, researchers in JIC admitted in their annual report that GM crops are unstable and prone to recombination. But when we pointed this out [20], they issued a strong denial, and accused us of ignoring one of their papers where they claim to have demonstrated that transgenic rice lines are stable. I have since reviewed that paper in detail [21] and concluded, "A generous interpretation of the data presented would suggest that 7 out of 40 (18%) transgenic rice lines may be stable to the R3 generation." In other words, at least 82% of the lines are unstable. That paper is not at all exceptional in making claims in the abstract, and often in the title, which are not supported by the evidence presented [22]. No reply has come from the JIC since. My colleague, Prof. Joe Cummins has summarised more up-to-date literature showing that all GM crops may be unstable [23].

Roundup Ready soya has consistently performed less well than non GM soya over the years, and this year's seeds are experiencing problems in germination, according to a report from the University of Missouri [24].

Terminator crops at large

Last December, I was asked to act as expert witness in defence of citizens who have taken civil action against GM crops which they strongly believe to be a threat to health and biodiversity. Among the crops were GM oilseed rape varieties used to produce F1 hybrids belonging to AgrEvo UK (now Aventis). At the time, I was also preparing a joint submission, with two other scientists, to the consultation document, "Guidance on Best Practice in the Design of GM Crops" put out by the UK Government's Advisory Committee for Release to the Environment (ACRE). One of the main enabling technologies' for 'best practice' suggested in the document is precisely Agrevo's seed/pollen sterility system, for it prevents GM gene flow.

It soon dawned on us that the GM oilseed rape lines undergoing field trials in the UK are engineered with 'terminator technology' - so named by critics because it renders harvested seeds sterile - for no other reason than to enforce corporate patents on GM seeds. Not only that, according to AgrEvo's application, similar crops produced by the company Plant Genetic Systems (PGS), a subsidiary of AgrEvo, have been undergoing field-trials in Europe since the beginning of 1990.

In the US, similar male sterile lines engineered with the 'terminator-gene', barnase have been tested at least as early as 1992. There have been 115 field trials, the vast majority done without risk assessment, as the first environmental assessment came up with 'FONSI' - Finding of No Significant Impact. Crops modified for male sterility include rapeseed, corn, tobacco, cotton. Brassica oleracea, potato, poplar, chicory, petunia and lettuce. The USDA commercial release data include 4 crops with barnase: a corn and a canola by AgrEvo, a chicory by Bejo, and another corn by Plant Genetic Systems.

Separately, the other genetic component in terminator crops, site-specific recombinase, has also been engineered into corn and papaya, and there have been 14 field trials between 1994 and 1998, with no environmental impact assessment at all.

There are more than 150 US patents listing barnase or site-specific recombination or both, the oldest, on site-specific recombinase, going back to 1987.

The first terminator patents that came to public attention were those jointly owned by US Department of Agriculture and Delta and Pine Land Company, which Monsanto had intended to acquire. The novelty in those patents is the proposal to combine the terminator-gene system with the site-specific recombinase system, giving the company complete control over the hybrids as well as proprietary chemicals that control gene expression.

As a result of universal condemnation and rejection, Monsanto had announced it will not commercialise terminator crops, to everyone's relief. Research and development, however, have continued unabated. Everyone has assumed such crops only exist in theory, when they have been out there for more than 10 years.

It is no coincidence that simultaneous consultation went on in the United States on the USDA-Delta and Pine terminator patents. The USDA has since committed itself to commercial development of the technology, and, like the UK ACRE, also argued in its favour because it could prevent GM gene flow. But it cannot [24], because male sterile lines will be pollinated by non GM crops, and there is no way to prevent horizontal gene transfer.

On the contrary, the increased complication of the constructs may enhance horizontal gene transfer and recombination. The genes and gene products themselves are also known to be harmful. The terminator-gene barnase kills cells by breaking down RNA, an intermediate in the expression of all genes. The recombinase, in theory, breaks and rejoins DNA at specific sites, but is far from accurate and can scramble genomes. A male transgenic mouse engineered with only one copy of Cre recombinase was 100% sterile, because the recombinase enzyme managed to scramble the genomes of both daughter spermatids when they are still connected by a cytoplasmic bridge [25]. The mouse genome does not even have the lox sites recognized by the Cre recombinase.

Terminator insects give wings to genome invaders

The US Department of Agriculture has approved field release of GM pink bollworms this summer, made with a mobile genetic element, piggyBac, already known to jump many species. The element was first discovered in cell cultures of the cabbage looper, where it caused high mutations of the baculovirus infecting the cells, by jumping into the viral genome. In experiments in silkworms, researchers already found evidence that the inserts were unstable, and had a tendency to move again from one generation to the next [26].

"These artificial transposons are already aggressive genome invaders, and putting them into insects is to give them wings, as well as sharp mouthparts for efficient delivery to all plants and animals... The predictable result is rampant horizontal gene transfer and recombination across species barriers. The unpredictable unknown is what kinds of new deadly viruses might be generated, and how many new cases of insertion mutagenesis and carcinogenesis they may bring." [27].

"Food biotech is dead"

I have presented only a small fraction of the scientific findings indicating problems and dangers specific to genetic engineering, which both the practitioners and regulators are ignoring or dismissing. These and other concerns have persuaded more than 410 scientists from 55 countries around the world to sign an Open Letter to all Governments demanding a moratorium on environmental releases of GMOs because they are unsafe, and a ban on patenting life-forms and living processes because those patents are unethical. They also demand support for non-corporate, sustainable, organic agricultural methods that can truly bring food security and health for all.

Since we launched the Open Letter two years ago, the terms of the GM debate have shifted. It is no longer a moratorium that is needed. GMOs, as currently made, are unsafe and unsustainable, as well as immoral. We must abandon GM crops and all other attempts to genetic engineer plants, animals and human beings with a technology that is widely acknowledged to be unreliable, uncontrollable and unpredictable.

Even the corporations are coming around to the view that "Food biotech is dead" [28]. One by one, Aventis, Monsanto and Syngenta have announced they will concentrate on genomics and marker assisted conventional breeding. Though meanwhile, they are still forcing the world, especially the Third World to accept GM crops.

But the whole world is in revolt. The governments of Thailand and Sri Lanka, among others, have banned GM crops and GM imports. In Indonesia, armed guards had to be sent to protect Monsanto's shipment of cotton seeds, which have already been shown not to perform as well as the indigenous non GM variety [29]. In the Philippines, mass demonstrations are taking place against GMOs and the International Rice Research Institute (IRRI) by MASIPAG (Farmer Scientist Partnership for Development) and other ngos. They condemn IRRI for restructuring sound traditional practices over the past 40 years to make farmers dependent on chemical inputs produced by corporations, the same corporations that are now forcing GMOs on farmers with the help of IRRI [30]. People are demanding farmer's rights over the genetic resources in the collection and genebanks of IRRI and they renounce any form of IPR. Those sentiments are widely shared, not just all over the Third World, but in Europe and the United States.

The organic revolution

Europe is fed up with the intensive corporate agriculture that has brought BSE and the food and mouth epidemic now threatening to get out of control, and is going organic in earnest. The annual growth rate in organic agriculture in Europe from 1989 to 1999 averaged 25%, which, extrapolated forward, would lead to 10% of Western European agriculture being organic by 2005, and 30% by 2010 [31]. The same is happening in the rest of the world. As scientists, we must take all evidence seriously.

Organic and sustainable agricultural practices and technologies are succeeding, documented in study after study, despite the appalling lack of research funding compared to the hundreds millions that have gone into biotech. At least 3% of the arable land, some 28.9m hectares in Africa, Asia and Latin America are already farmed sustainably, with impressive gains in crop yield as well as social, economic and health benefits [32]. Organic farming is also working well in the United States and Europe, with yields matching and even surpassing agrochemical agriculture. Organic farms are good for wild-life, supporting many more species of plants, songbirds butterflies spiders, earthworms [33]. We need organic farming for the world to feed itself and for the planet to regenerate and thrive.

Sustainable agriculture is also important for alleviating, if not reversing global warming. A new report shows that sustainable agriculture can contribute significantly, not only to reducing consumption of fossil fuel, but increasing sequestration of carbon in the soil [34].

Sustainable agriculture is predicated on a holistic, ecological perspective anathema to reductionist mechanistic science. Mechanistic science has been thoroughly discredited in the course of the 20th century. Mechanical physics went first of all with relativity and quantum physics. Biology was the last to go with the new genetics.

The new genetics is radically ecological, organic and holistic. That is why genetic engineering, at least in its current form, can never succeed. It is based on misconceptions that organisms are machines, and on a denial of the complexity and flexibility of the organic whole.

The challenge for western scientists is to develop a holistic science to help revitalise all kinds of non corporate sustainable agriculture and holistic medicine that can truly bring food security and health to the world.

Visit ISIS website  http://www.i-sis.org.uk for complete list of references.

The Institute of Science in Society
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Tel: 44 -020-7242 9831

The Risks of GM Food

Prof. David Schubert
July 2002

As a cell biologist I am very much discouraged by the content of the ongoing debate about introducing genetically modified (GM) plants into the marketplace. While the voiced concerns usually center around irrational emotional arguments on the one hand, and the erroneous concept that genetic engineering is just like plant breeding on the other, I believe that the three issues which should be of most concern on the basis of established science receive little or no discussion.

These are:

ntists from 55 countries around the world to sign an Open Letter to all Governments demanding a moratorium on environment

2. the recent observations that the introduction of any gene, be it from a different or the same species, always significantly changes overall gene expression and therefore the phenotype of the recipient cell; and

3. the possibility that enzymatic pathways introduced to synthesize small molecules such as vitamins can interact with endogenous pathways to produce novel molecules.

The potential consequence of all of these perturbations could be the production of biomolecules that are either toxic or carcinogenic, and there is no a priori way of predicting the outcome.

I will give a few examples and then argue why GM food is not a safe alternative.

In addition to their primary sequence of amino acids, the structure and biological activity of proteins can be modified by the addition of molecules such as phosphate, sulfate, sugars or lipids. The nature of these secondary modifications is totally dependent upon the cell type in which they are expressed. For example, if a protein involved in the cause of Alzheimer's disease, the beta amyloid precursor protein, is expressed in liver cells it contains covalently-attached chondroitin sulfate carbohydrate, while the identical gene expressed in brain nerve cells contains a much simpler sugar. This is because each cell type expresses a unique repertoire of enzymes capable of modifying proteins after they are synthesized. Once modified, the biological activity of the molecule may be changed. In the case of the beta-amyloid precursor protein, the adhesive properties of the cells are changed, but there is, at our current state of knowledge, no way of knowing the biological effects of these modifications.

The second concern is the potential for inducing the synthesis of poisonous or toxic compounds following the introduction of a foreign gene. These observations are clearly at odds with the individuals who imply that everything is fine because they are simply introducing one gene. In fact, the introduction of a single gene invariably alters the gene expression pattern of the whole cell and each cell of the individual or plant responds differently. One recently published example is the transfection of a receptor gene into human cells. In this case, the gene was a closely related isoform of an endogenously expressed gene. The pattern of gene expression was monitored using gene chip technology, and the mRNA levels of 5% of the genes was significantly upregulated or downregulated. Similarly, the simple introduction of a bacterial enzyme used for growth selection of transfected cells changes the expression of 3% of the genes. While these types of unpredicted changes in gene expression are very real, they have not received much attention outside the community of the DNA chip users.

Furthermore, they are not unexpected. The maintenance of a specific cell phenotype is a very precise balancing act of gene regulation, and any perturbation is going to change the overall patterns of gene expression. The problem, like that of secondary modifications, is that there is currently no way to predict the resultant changes in protein synthesis.

Third, the introduction of genes for a new enzymatic pathway into plants could lead to the synthesis of totally novel or unexpected products via the interaction with endogenous pathways. Some of the products could be toxic. For example, retinoic acid (vitamin A) and derivatives of retinoic acid are used in many signaling events that control mammalian development. Since these compounds are soluble and work at ultralow concentrations, a GM plant making vitamin A may also produce retinoic acid derivatives which act as agonists or antagonists in these pathways, resulting in abnormal embryonic development.

Given the fact that genetically modified plants are going to make proteins in different amounts and perhaps totally new proteins than their parental species, what are the potential outcomes? A worst case scenario could be that an introduced bacterial toxin is modified to make it toxic to humans. Direct toxicity may be rapidly detected once the product enters the marketplace, but carcinogenic activity or toxicity caused by interaction with other foods would take decades to detect, if ever. The same outcomes would be predicted for the production of toxins or carcinogens via indirect changes in gene expression.

Finally, if the above problems are real, what can be done to address these concerns? The issue of secondary modification could be addressed by continual monitoring of the introduced gene product by mass spectroscopy. The problem is that some secondary modifications, like phosphorylation or sulfation can be lost during purification. However, the best, and to me the only reasonable solution, is to require all genetically engineered plant products for human consumption be tested for toxicity and carcinogenicity before they are marketed. These safety criteria are required for many chemicals and all drugs, and the magnitude of harm caused by a widely consumed toxic food would be much greater than that of any single drug.

Professor David Schubert
Cellular Neurobiology Lab
The Salk Institute for Biological Studies
P.O. Box 85800
San Diego, CA 92186-5800
USA
Phone: (001) (858) 453-4100

GM Crops May Face Genetic Meltdown

ISIS Report
June 12, 2001

All GM crops may be unstable, and worse, they may face total genetic meltdown due to escalating error catastrophes. Prof. Joe Cummins reviews recent research findings suggesting how this might occur.

'Error catastrophe' 'or extinction mutagenesis' is a theory about mutations and survival of populations. The idea is that mutation contributes to variability and variability drives the success of a population in the face of a changing environment. However, most mutations are deleterious. Error catastrophe occurs when high mutation rates give rise to so many deleterious mutations that they make the population go extinct. For example, foot and mouth disease virus treated with mutagens (base analogues fluorouracil and azacytidine) eventually become extinct [1]. Polio virus treated with the mutagenic drug ribavirin similarly went extinct [2]. Error catastrophe theory has led to a strategy of mutagenesis to control disease viruses.

Somaclonal variation a form of gene and chromosome instability that results from the tissue and embryo culture technique used in making GM plants [3]. Somaclonal variation occurs in tissue and embryo culture even without genetic modification, but genetic modification often makes it worse. Somaclonal variation is associated with replication of genetic elements called retrotransposons that replicate in the plant cell nucleus and are inserted into structural genes, causing mutation and chromosome rearrangement [4]. The genetic changes activated in GM may be numerous and subtle, and may produce gradual loss in productivity of GM varieties or unexpected toxic plant products. Transposons have been shown to have powerful impacts on genetic stability. For example, the P transposon of the fruit fly, Drosophila, when activated under appropriate conditions, causes 'hybrid dysgenesis', a slow destruction of the genome receiving the transposon due to chromosome and gene mutation [5]. Gressel [6] has suggested that hyperactive transposons could be introduced into weed populations in order to eradicate them.

There has not been adequate study of ongoing transposition in GM crops, all of which have been produced by embryo culture. Somaclonal variation has been patented in some crops as a means of producing genetic variability for selection, and it was assumed that the crops were genetically stable once established. But that assumption was not tested in most instances. Certainly, there has been inadequate study of the factors reactivating dormant transposons following plant embryo culture. The threat of extinction mutagenesis has never been discussed in governmental reviews that led to the deregulation of experimental GM crops, nor has there been effort to examine the factors leading to subtle yield-depression in GM crops. It may be only a question of time until GM crops dramatically decrease yield and become extinct. Finally, little or no thought seems to have been given to the havoc that could be wreaked upon the human genome by GM crop retrotransposon running amok within humans and farm animals.

The Promise of Plant Biotechnology -
The Threat of Genetically Modified Organisms

July 2000
Patrick Brown
Professor
College of Agriculture & Environmental Science
University of California
Davis, CA 95616

Crop cultivars developed using recombinant-DNA technologies (rDNA crops) have been rapidly adopted by agricultural producers in the United States; and until recently, foods derived from these crops have been tacitly accepted by US consumers. In contrast, many European consumers have shown a marked resistance to these technologies which, in turn, has resulted in the passage of trade restrictions and of laws that limit the import, growth or use of rDNA crops throughout much of Europe. The public uproar in Europe, and the protests surrounding the World Trade Organization meeting in Seattle, have now raised the awareness of many in the USA and given birth to a vocal and growing group of concerned consumers.

The intensity of the current debate has surprised many in the scientific community and has escalated into a highly polarized and increasingly antagonistic debate. Scientists, and the professional organizations that represent them, have been publicly supportive of this technology and often dismissive of public concerns. Most scientific comment suggests that 'education' is the key to gaining the needed acceptance, while almost no comment has recognized or addressed the fears of the public. Those who oppose rDNA technology interpret the apparent willingness of the US scientific community to embrace this new technology, while failing to adequately address the potential risks, as a betrayal of public trust.

Public uncertainty has resulted in the loss of markets, and will increasingly do so, for the current generation of rDNA crops and foods. Though this is clearly of substantial economic concern, by far the most significant consequence of public concern is the threat that this conflict poses for the entire field of plant biotechnology which holds far greater promise of human benefit than that offered by any existing rDNA crop. The loss of this technology through careless and premature implementation would be truly devastating to the goal of developing more abundant and nutritious foods in an environmentally sensitive fashion.

This issue requires immediate and thoughtful attention from plant scientists. We must recognize that our knowledge of the processes that regulate gene incorporation and expression are in their infancy and that our capacity to manipulate the plant genome is crude. Given this current lack of understanding it is certainly possible that the current regulatory safeguards are inadequate and may not be offering sufficient protection against inadvertent creation of health and ecological problems.

Since the public education and research system is based upon a foundation of public trust, it is essential that we recognize and admit the unknowns associated with molecular biology and act with caution and integrity.

The following text describes some of the uncertainties associated with rDNA technology and illustrates how the scientific community's defense of the current generation of rDNA crops represents a substantial threat to the future of this promising new technology.

GMOs because they are unsafe, and a ban on patenting life-forms and living processes because those patents are unethical.

In 1989 the National Research Council, following extensive scientific review, publicly concluded that crops derived from rDNA techniques do not differ substantially from those derived using traditional techniques. This conclusion forms the basis for current FDA policy that regulates the production and use of rDNA crops and foods. This conclusion is based upon the principle of "substantial equivalence" which states that the introduction of a gene of known and safe function into a crop of known characteristics is technologically neutral, hence the resulting crop can be presumed to be safe and is not subject to mandatory testing prior to release or use in foods. As this principle is central to the scientific and regulatory acceptance of this technology it deserves careful examination.

Is There Equivalence between rDNA and 'Traditional' Sexual Gene Transfer?

To adequately compare these technologies it is essential that each is well characterized and understood. The molecular processes that control gene incorporation and expression following a normal sexual crossing event, however, are only poorly understood and the extent of our ignorance is further revealed weekly as new processes involved in the regulation of gene expression in plants are determined. The inadequacy of our understanding is well illustrated by the host of genetic phenomena (such as co-suppression, intron-mediated enhancement, transcriptional regulation, protein-gene interactions etc) for which we have essentially no mechanistic understanding. Our knowledge of these processes is clearly in its infancy and few would claim that we understand more than a small percentage of the processes regulating sexual reproduction in plants.

Further, most of what is known of gene transfer using traditional and rDNA techniques illustrates the profound manner in which they differ. Traditional crossing involves the movement of clusters of functionally linked genes, primarily between homologous chromosomes, and including the relevant promoters, regulatory sequences and associated genes involved in the coordinated expression of the character of interest in the plant. The molecular regulation of this process and the biochemical and evolutionary significance of these controls is poorly understood.

In contrast to traditional techniques, current rDNA technologies (those used in all currently approved rDNA crops) involve the random insertion of genes in the absence of normal promoter sequences and associated regulatory genes. As there are very few examples of plant traits in which we have identified the associated regulatory genes, the introduction of a fully 'functional' gene using rDNA techniques is currently not possible. R-DNA techniques also involve the simultaneous insertion of viral promoters and selectable markers and facilitates the introduction of genes from incompatible species. These genetic transformations cannot occur using traditional approaches - which further illustrates the profound manner in which these processes differ.

Genetic material can be moved within and between species by the poorly understood processes of gene transposition. Though the occurrence of this phenomenon in traditionally bred plants is superficially equivalent to rDNA techniques (which involve the random insertion of "artificial transposons"), the mechanisms governing this process and the significance of transposition in traditional gene transfer are unknown. Given our profound lack of understanding of these processes it is impossible to compare sensibly the two processes. Indeed, it can be argued that gene transfer via rDNA techniques resembles the process of viral infection far more closely than it resembles traditional breeding.

In summary, it is clear that gene transfer using rDNA techniques is substantially different from the processes that govern gene transfer in traditional breeding. The extent to which these processes differ will become increasingly clear as as we gain a better understanding of the processes governing gene movement, expression and regulation.

The presumption of "Substantial Equivalence" - the basis for current regulatory principles - is profoundly flawed and scientifically insupportable.

Do rDNA Techniques offer Greater Precision?

One of the much-touted benefits of r-DNA techniques is the capablity to introduce only a discrete and well defined number of genes into the new cultivar whereas a traditional crossing event introduces thousands of genes. This ability to control the types and numbers of genes introduced speeds the introduction of a gene of interest by eliminating the need for extensive backcrossing to the elite parent. Many have suggested that this approach is fundamentally more "precise" than traditional breeding techniques and have argued that the technique is consequently "safer".

The ability to introduce a precisely defined compliment of genes using rDNA techniques, however, is not equivalent to the introduction of a precisely defined and biologically integrated character. Whereas the incorporation of a new character using traditional techniques occurs in a fully functional and appropriately regulated manner, rDNA gene introduction is more or less random, and does not involve introduction of the regulatory sequences normally associated with that gene. Traditional techniques, therefore, result in greater "biological precision" than random gene insertion using rDNA techniques.

The FDA policy statement further suggests that it is highly unlikely that rDNA techniques will result in the inadvertent production of allergens or toxic compounds and that once incorporated into the genome, the introduced gene functions like all other genes in the genome. These statements are offered in support of the premise that rDNA experiments are more predictable than traditional breeding approaches. This presumption is, however, clearly contradicted by a large volume of scientific literature and experimental experience that illustrates the propensity of rDNA techniques to produce unexpected and often lethal perturbations. Indeed metabolic and phenological perturbations are very frequently observed following transformation events and a high percentage of transformants show profound growth aberrations. Indeed the propensity of random gene introduction to cause metabolic disruption is well documented and actively used to probe gene function.

While extreme aberrations can be easily selected out, it is also highly likely that undetected biochemical perturbations remain following essentially all transformation events. Since it is not standard practice to screen transformants there is clearly a potential for biochemically abnormal trangenic plants to persist. This is further exacerbated through the use of tissue culture and embryo rescue etc. which can be used to "rescue" metabolically altered transgenic plants that might otherwise have been eliminated during early plant growth. Whether or not these same perturbations occur following traditional breeding is unknown. Lack of knowledge, however, is not proof of safety.

The metabolic perturbations caused by rDNA gene introduction may result in production of toxic compounds. Many plant species have the capacity to produce toxic compounds which under natural conditions serve to protect against animal and insect predation as well as contributing to disease resistance mechanisms. In certain species, such as those in the Solanum family, there are many well characterized and highly unpalatable or toxic compounds. It is very likely that the majority of the genes involved in the formation of these toxic and unpalatable compounds are still present (though not expressed) in modern tomato and potato. Given the random nature of rDNA gene insertion, and the use of a promiscuous viral promoter sequence, the potential clearly exists that tomato could be induced to produce a toxin as a result of a rDNA gene transfer. Whether this would occur with the same frequency following traditional sexual breeding is unknown. The presumption that it cannot occur is clearly invalid.

Clearly the assumption that a transformed crop is exactly the sum of the original crop and the introduced gene is not acceptable. rDNA techniques are profoundly different from traditional breeding methods and are well known to cause unexpected metabolic perturbations. The principle of substantial equivalence is not scientifically justifiable; hence we can make no a priori assumption of the safety of any rDNA manipulation.

Do rDNA Techniques Provide an Acceptable Level of Risk?

The preceeding discussion clearly demonstrates that the risks associated with rDNA technology cannot be determined given current understanding of gene expression. Nevertheless it has been argued that risk is a normal part of technological advancement and that acceptance of this risk is warranted in the instance of rDNA crops.

While it is true that we accept risks as a normal part of life, most of the risks we accept are defined by experience and are understood before they are taken. Some risks are also taken because the rewards are perceived to outweigh the risks. Traditional breeding has on the whole been an acceptable risk with 10,000 years of experience, and a trust in the motives of those producing the new cultivars.

Many, however, are not yet prepared to accept the risks of rDNA technologies. This is in part due to a lack of understanding of the risks, the minimal benefit of the current crop of GMOs, and a mistrust of the motives of those selling the technology. Given the current state of our knowledge of this technology and the nature of the GMOs currently available, this lack of public trust is entirely reasonable. Public acceptance will require convincing demonstration of safety and the development of crops with a more direct benefit to the consumers.

The concerns expressed by many are further validated by the current generation of GMOs that have been incorporated into the food system without adequate public consultation and scientific scrutiny. The current generation of GMO crops do not provide any tangible public benefit, have not contributed to reduced food costs, and have no confirmed ecological benefit. This is well illustrated by the two most prevalent types of GMOs in use in the US.

Insect-resistant crops containing the gene encoding the Bacillus thuringiensis toxin have been planted widely in the US. This transgenic technique promises to reduce the use of pesticides and reduce growers' costs. While reduction in pesticide use is an admirable goal there are significant grounds to question the appropriateness of the current generation of Bt-producing crops and to question the haste with which these crops were released for widespread use.

The current generation of Bt crops utilize a single Bt gene rather than the complex of Bt genes that are available. There is widespread agreement amongst scientists that this use of a single Bt gene will increase the speed with which pest resistance will develop. To help alleviate the development of insect resistance the USDA and Monsanto now advise growers to plant refuge areas to ensure non-resistant insects persist under the premise that this will reduce the rate of resistance development. While this is theoretically sound there is insufficient ecological data to determine optimal size of these refuges or to estimate how effective they will be.

The current generation of Bt crops also utilize antibiotic resistance as the selectable marker and rely upon viral promoters to ensure high degrees of expression. This clearly introduces a risk associated with a promoter designed to be free of regulatory controls, it excites those who see viral and antibiotic-resistance genes as threatening, and it ensures that the Bt protein is distributed uniformly throughout the plant. The uniform presence of the Bt protein enhances the likelihood of resistance development and ensures that the protein is present throughout plant development and is present in the pollen. The death of Monarch larvae was a direct consequence of the presence of active Bt toxin in the pollen. While some have questioned the scientific relevance of this study it did illustrate the inherent flaws in this cultivar.

Methods exist (or will soon exist) that make the use of viral promoters and antibiotic resistance markers unnecessary. There is no justification for the expression of Bt in the pollen, and the release of cultivars with a single Bt gene is certain to hasten resistance development. In the absence of data to support the refugia concept there is very little to prevent the development of widespread insect tolerance of Bt.

Clearly the release of the first generation of Bt-containing crops was premature and based upon flawed scientific principles. Regulatory and scientific support for this cultivar is clearly questionable.

The other dominant type of GMO in use today is the Roundup-Ready varieties of cotton, soyabean and corn. Not only do these cultivars contain many of the same questionable genes as those in Bt crops, but also they have the additional propensity to contribute to the development of herbicide-resistant weed species for which the consequences are poorly understood. Roundup-Ready crops are also of questionable ecological value and build a long-term dependence on the use of the herbicide Glyphosate. Not insignificantly, the overtly 'corporate' nature of these crops and the dependence they build on high cost and ecologically questionable technologies has resulted in widespread suspicion of the motives of those promoting these cultivars.

It is abundantly clear that the current generation of GMO's were developed using an untested and unsophisticated technology and were released prematurely to ensure early returns on corporate investment. Clearly this does not represent a sound jusification for the release and widespread use of these crops.

Perhaps one of the most profoundly flawed justifications of GMOs is illustrated in the often cited refrain "GMO foods have been widely available in the marketplace for the past 5 years and not one incident of harm to public health has been documented". Since every introduced gene is inserted into a different genetic location, and every gene differs in functions and interactions within the genome, and as every species can be expected to 'react' differently to the gene introduction process, it is clear that the safety of one GMO is in no way predictive of the safety of another. In many respects the claim of safety by association is no more valid than the claim that the safety of aspirin predicts the safety of all future drugs.

Conclusion

The real threat to the future of plant biotechnology is the irresponsible and premature releases of the first generation of GMOs that are full of unsound scientific assumptions, rife with careless science, and arrogantly dismissive of valid concerns. The current generation of GMOs provide little real benefit except corporate profit and marginally improved grower returns, while at the same time introducing a host of poorly studied human and ecological risks. Not surprisingly, many have questioned the value of these crops and the integrity of those who support their use.

Given these issues and the overall lack of knowledge of rDNA technology it can only be concluded that the current FDA regulations guiding the release and testing of GMOs is inadequate. It can further be concluded that the technology is inadequately developed to ensure its safety. In the absence of a sound scientific basis to predict the full consequences of rDNA crop development, we must either subject all new crops to a rigorous testing program that considers all potential health, social and environmental concerns or halt further release of rDNA crops until a firm scientific understanding of the biological principles is attained.

As scientists it is our responsibility to recognize that we do not yet have sufficient knowledge of the process to use it safely. We must work towards adressing all of the concerns explicit in the current generation of crops, and must support a rigorous testing program to ensure the safety of all GMO food stuffs in the interim. To date many in the scientific community have been unwilling to rationally consider the concerns surrounding the current GMOs and have wrongly considered that a defense of GMOs is a prerequisite to protect the science of plant biotechnology. Nothing could be further from the truth or more threatening to the future of this technology.

Declaration of Philip J. Regal, Ph.D.

United States District Court for the District of Columbia
Alliance for Bio-Integrity, et al. Plaintiffs
v. Donna Shalala, et al. Defendants.
Civil Action No. 98-1300 (CKK)

I, Philip J. Regal, state:

l. I am a biologist in the College of Biological Sciences and am Professor of Ecology, Behavior and Evolution at the University of Minnesota (St. Paul), where I have been on the faculty since 1970.

2. I have made several important contributions to the study of plant biology, particularly in the area of how genetics relates to adaptability and organization of organisms. I have nine publications on this particular topic among my contributions to the peer reviewed scientific literature. (A list of my publications and key presentations is attached.)

3. Since 1983, I have closely studied various safety issues concerning the use of recombinant DNA technology (RDNA technology; genetic engineering) to develop new plant varieties. My involvement has been both intensive and extensive. I have attended and sometimes organized scientific biosafety workshops for government agencies and scientific societies, presented at conferences, and published articles on agricultural genetic engineering in the scientific literature. I have consulted for and worked closely with government regulatory agencies, Congressional staff, scientific organizations, private corporations, and public interest groups.

4. It is my professional opinion that utilizing RDNA technology in production of food-producing organisms can be very powerful biologically and very different biologically from conventional forms of breeding. It entails a set of risks to human health that are not ordinarily associated with the latter. Such use of RDNA technology has the well-recognized potential to interfere with the normal activities of the engineered organism, for example so as to generate unexpected and unknown toxins, carcinogens, allergens and other anti-nutritive substances.

5. My own analyses, as well as a substantial body of published research, clearly establish that these types of unintended side effects are risks that cannot be lightly discounted. Moreover, although I have kept abreast of developments in biotechnology and have regularly read the relevant scientific literature, I am not aware of any reliable study published in the peer-reviewed scientific literature which demonstrates that these risks are categorically either (1) negligible or (2) no greater than in the case of conventionally produced organisms. Nor am I aware of even one such peer-reviewed, professionally published study which has detailed scientific criteria for testing and evaluation and gone on to demonstrate that even one particular genetically engineered food is reasonably certain to produce no harm when eaten by a human being.

6. Rather, it is my considered judgment that the evidence to date, in its entirety, indicates there are scientifically justified concerns about the safety of genetically engineered foods and that some of them could be quite dangerous. Further, in the absence of reliable toxicological tests, it is not possible to determine which of these new foods are dangerous and which are not.

7. It is also my observation that there is not general recognition of the safety of genetically engineered foods among those members of the scientific community qualified to make such a judgment. In fact, it has been my personal experience over numerous years that many of those experts who publicly subscribe to the position that these foods are as safe as their natural counterparts privately admit they have serious doubts. For instance, when I attended a conference on biotechnology in Annapolis, Maryland in 1988, at which many officials from federal regulatory agencies (including the FDA) were present, I was shocked to learn the extent of uncertainty. In informal discussions at meals and on walks, government scientist after scientist acknowledged there was no way to assure the safety of genetically engineered foods. Several expressed the idea that, in order to take this important step of progress, society was going to have to bear an unavoidable measure of risk.

8. Consequently, I am deeply troubled by the FDA's decision to permit the widespread marketing of untested genetically food products based on a stated presumption they are, in the general case, equivalent to, and thus are as safe as, their natural counterparts. As I have pointed out, there is no sound scientific basis for such a presumption and the weight of the evidence is against it. It is my considered opinion that such a presumption can only be made by systematically ignoring a large body of solid and relevant evidence.

9. To support its policy, the FDA appears to claim that if a gene from one species is forcibly and with only variable precision implanted into the DNA of a distant and dissimilar species, we can reliably assess the safety of the new organisms merely by analyzing the known characteristics of the two species and of the specific substance(s) that it was intended the foreign gene would produce. One prop of this argument is the notion that (1) if the substance produced by the foreign gene is substantially similar to a substance that is generally recognized as safe and (2) if the organisms of the target species are already generally recognized as safe to eat, then the genetically engineered organisms will also be safe -- assuming we observe no obvious change in key constituents or superficial qualities of taste or texture.

10. This notion is grossly at odds with biological reality. It is well known that science cannot reliably predict how a given substance will act within a genetic and cellular environment that is quite foreign to it. Not only could the chemical attributes or behavior of the foreign substance markedly change, but its very presence could alter important behaviors of the host cells. Moreover, the process of implanting the foreign gene that produces that substance could in itself disrupt cellular metabolism in numerous ways. Genetic vectors, markers, and regulatory bits of code are also commonly added along with the foreign gene, to further complicate uncertainties. To ignore the fact that the living systems involved have complex biochemical and developmental dynamics and that unusual high-technology genetic interventions have the real potential for unpredicted deleterious side effects is, at best, biologically naive.

11. However, while it might be no more than naive for a layperson to make such simplistic assumptions, it is otherwise in the case of a government regulatory agency that has been repeatedly informed of the facts. When such an agency persists in ignoring these facts, even though the safety of the food supply is at stake, its behavior is not merely scientifically unsound but morally irresponsible.

12. It is because I view the FDA's policy and practices regarding genetically engineered food to be irresponsible -- and because I regard the consequent risk posed for public health to be substantial -- that I have taken the step of joining the above-named lawsuit as a plaintiff. By standing as a plaintiff rather than merely participating as an expert witness, I hope to make clear to the public and the Court not only the extent to which I disagree with the agency's assumptions as a purely intellectual matter, but the degree to which I deplore its behavior on ethical grounds. Ultimately, I was compelled by my conscience to become a plaintiff, and I am proud to stand with so many other scientific experts who have similarly acted on the basis of ethical as well as strictly scientific principles.

Executed on: May 28, 1999

[Signed]________________
Philip Regal, Ph.D.

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