Paper presented at Workshop on GM & Bio-weapons, ICCP Conference, Convention on Biology Diversity, The Hague, April 22-26, 2002.
Dr. Mae-Wan Ho
The basic tools and materials for making bio-weapons are the same as those used in 'legitimate' GM (genetic modification) applications. The possibilities for more lethal bio-weapons have increased in the post-genomics era. There is little or no effective defence against bio-weapons, and GM may be worse. While bio-weapons are made under strictly contained conditions, many dangerous experiments are being done without adequate safety precautions, and hazardous GM products released into the environment as if they were safe. Scientists need to take responsibility for the biosafety of their own research, to take all scientific evidence into account, to desist from research for aggressive military purposes or research that does more harm than good.
An article in Nature Genetics [1] warns that, compared with chemical and nuclear weapons, "biological weapons pose by far the greatest threat, because they can be as lethal as nuclear weapons and are easier to obtain."
The 1975 Biological and Toxin Weapons Convention (BTWC) Article 1 states, "Each State Party to this Convention undertakes never in any circumstances to develop, produce, stockpile or other wise acquire or retain:
1. Microbial or other biological agents, or toxins whatever their origin or method of production of types or in quantities that have no justification for prophylactic, protective or other peaceful purposes.
The italicised section has become known as the 'General Purpose Criterion', and applies to the intent of any activity. This prohibition is now accepted by more than 144 state parties who have signed up to the Convention, but it lacks provision to monitor and verify compliance. That is particularly serious in the era of genetic engineering and genomics, when new and dangerous pathogens can easily be created in small research laboratories. Monitoring is difficult because genetic engineering is used for "legitimate" purposes such as vaccine production or research on how bacteria and viruses cause diseases.
Towards the end of the Cold War, the USSR began using genetic engineering techniques to create bio-weapons. Microbiologists suggest it might be possible to enhance antibiotic resistance of pathogens and their virulence, make them harder to detect, diagnose and treat. What else will genomics bring?
In 1997, the US Dept. of Defence published a document entitled, Proliferation: Threat and Response, which identified a number of trends. These include the increasing use of genetic engineered vectors and growing understanding of both infectious disease mechanisms and the immune defence system.
A study on Biological Threats Enabled by Molecular Biology, carried out by a JASON Group of scientists in the late 1990s, considered, among other things, stealth viruses that could be introduced covertly into the genomes of a given population, and then triggered later by a signal. Also considered are 'designer diseases' that produce cell death.
More recently, a group of scientists considering "New Scientific and Technological Developments of Relevance to the Biological and Toxin Weapons Convention" at a NATO Advanced Studies workshop pointed to bio-warfare agents in agriculture. These include the Fusarium used against drug plantations in Colombia and elsewhere, that the Sunshine Project has drawn attention to (<hammond@sunshine-Project.org>).
In the post-genomics era, there could be misuse of large scale databases containing information on specific populations. Specific genetic variants of receptors for regulatory and signaling molecules could be targeted, for example. There is also increasing potential for manipulating the immune system, already being done in the course of seemingly innocent research on viruses (see later). Another suggestion is to use inhibitory RNA molecules to switch off key genes in an organism, again, a procedure employed in legitimate research in trying to understand gene regulation and the development of the simple worm, C. elegans.
The human genome sequence is well on its way to completion, and many controversial studies on human diversity are planned. Britain is setting up a human DNA database, 'BioBank' [2], similar to ones in Iceland, Tonga and Sweden. And DNA collections of indigenous peoples have been accumulating in university laboratories under the disreputable Human Genome Diversity Project.
In agriculture, the rice genome sequence drafts have just been announced, which will serve as a 'rosetta stone' to eventually unravel the genomes of all the other major cereals.
At the same time, complete sequence of more than 70 major bacterial, fungal and parasitic pathogens of human, animals and plants will be delivered in the next year or two. Hundreds of viral sequences are already available, and information on antibiotic and drug resistance, virulence, and toxins will increase the possibilities of creating new more deadly recombinants to attack humans and crops.
Several companies including Maxygen in Redwood City, California, are carrying out 'directed molecular evolution' by breaking up genes and allowing them to recombine at random to create new genes, accelerating the rates of recombination whereby new pathogens could arise. The authors claim these methods could also speed up the creation of effective vaccines and help in developing new antibiotics.
As the function of half of all genes in pathogens and the human and rice genomes are still unknown, genomics research will expand the possibilities for bio-weaponry. One application thought unlikely to succeed is the targeting specific ethnic groups, as analysis of the human genome sequence to-date has failed to reveal any genetic variants that can be used to absolutely define racial groups. Most of the human genetic diversity is found within populations. But it will be wrong to rule out this possibility
The threat of biological warfare is real, and genetic engineering and genomics have the potential to greatly increase its scope.
Contrary to what is generally believed, there is little or no effective defence against biological weapons. Events following the anthrax attacks have shown up huge inadequacies in coping with bio-warfare [3]. The United States and British governments are both stockpiling vaccines for smallpox. But evidence indicates that vaccines are no protection, and may be worse than useless, especially in populations containing substantial numbers of people with compromised immune systems, such as those suffering from immune deficiency disease. A theoretical study in Nature highlights the dangers of many partially effective vaccines, which may lead to increased virulence of the pathogens as more people are vaccinated [4].
The biomedical community is called upon to "play its proper part in the generation of a true web of deterrence" [1]. But those in the biomedical community in a position to generate a web of deterrence are too busy doing genetic engineering and genomics research, and worse, unwittingly becoming part of a larger problem for biosafety and biosecurity.
The basic materials and tools for genetic engineering are the same disease-causing agents employed in developing bio-weapons - deadly viruses and bacteria - plus enzymes and genetic material isolated from them.
The inherent dangers of genetic engineering hit home when researchers in Australia inadvertently transformed the relatively harmless mouse-pox virus into a lethal pathogen that killed all its victims [5]. They also showed one of the ways this could be done: by incorporating a gene that undermines the immune system.
Many 'legitimate' uses of GM have been raising serious safety concerns.
There have been numerous breaches of safety regulations in university laboratories researching dangerous pathogens in Britain, such as dengue fever virus, AIDS virus, TB bacteria, and lethal encephalitis virus [6].
Many dangerous research projects are being carried out in genetic engineering laboratories around the world. The lethal mousepox created was just the tip of a large iceberg. Genetic engineers are creating new viruses in the laboratory in the process of cloning them, or just to show it could be done. A more deadly mutant Ebola virus was created. Hybrids of the human and monkey AIDS viruses, called SHIVs, that can infect both species are being generated in large numbers, one of these - so lethal that it kills monkeys in weeks - is being routinely used as a 'challenge virus' to test AIDS vaccines in all US NIH-funded research.
The AIDS vaccines merit special consideration. Most are based on the HIV glycoprotein gp120, that a number of virologists have warned, not only undermines the immune system of individuals but is also likely to create deadly viruses and bacteria that can spread through entire populations [7]. These vaccines are being used effectively as slow bio-weapons in mass clinical trials around the world [8], as Dr. Veljkovic and I have warned in a letter to Dr. Gro Bruntland, Director General of the WHO.
The reason is that the envelope glycoprotein, gp120 of HIV-1 is similar to the region of human immunoglobulins that binds antigen, a crucial feature of the immune response. Thus, any AIDS vaccine containing the gp120 could interfere with the immune system and make people more vulnerable to the virus. And in the long term, it could accelerate disease progression in HIV patients that do not yet have symptoms.
Recombinant viruses expressing gp120 could also be a source of potential new pathogens. The gp120 gene contains genetic elements that stimulate recombination or are 'recombination hotspots'. These elements are similar to certain 'Chi' (pronouned 'kye') sequences found in bacteria and viruses such as Haemophilus influenzae, Mycobacterium tuberculosis, hepatitis B virus and herpes simplex virus that often co-infect with the HIV, and are also similar to immunoglobulin recombination elements in the human host. Recombination of HIV with bacteria and viruses mediated by Chi sequences would generate new pathogens, and such recombinations have been found. Within the human host, recombination with human genes would promote chromosomal rearrangements and formation of aberrant immunoglobulins, leading to inadequate immune responses. Furthermore, HIV-1 sequences integrated into the genome have the potential to initiate a wide variety of diverse genetic effects caused by all mobile genetic elements, especially mutations of genes due to random insertion, some of which might trigger cancer.
Recently, several gp120 vaccines have been withdrawn, the latest being a combination of canarypox virus engineered to carry HIV-1 proteins with a booster of the HIV protein gp120. The US NIH abandoned it before a phase III clinical trial, because it was found to be ineffective. But its dangers are still not sufficiently widely acknowledged.
A company in Texas, ProdiGene, is now putting gp120 into GM maize as a 'cheap, edible oral vaccine' against HIV [9]. This will surely lead to widespread contamination of our food crops with disastrous consequences, as Vejkovic and I have written in a correspondence to the journal [10]. Not only is this extremely hazardous for human beings. It will affect all organisms in the food chain and multiply the opportunities for this gene to recombine with bacteria and viruses in the environment, of which 99% cannot be cultured and are hence completely unknown.
And gp120 is not all that is going into our food crops. Our food crops are being tainted with antibodies, vaccines, and other pharmaceuticals, some of which are known to be harmful to human beings. How they will affect living things is anybody's guess. There have been field trials of 'pharm' crops in North America but it is difficult to determine the full extent of the trials because they are not regulated in the way that genetically modified food crops are.
A tobacco genetically modified with the gene for the human cytokine, interleukin-10, is being field tested near London, Ontario [11]. Interleukin-10 is known to be a powerful immune-suppressive, it is similar to the Interleukin-4 incorporated into the mousepox virus that turned the virus into a killer. In other words, a virus with interleukin-10 could also be deadly, as it disarms our immune system during an infection.
The hazards of gene therapy research are beginning to unfold since the death of teenager Gelsinger from a clinical trial two years ago. The common gene therapy vector that killed him from toxic shock is now found to cause cancer in mice [12] and to scramble genomes, just as introducing foreign genes into transgenic plants scramble genomes [13].
Despite copious evidence that DNA can readily find its way into human cells and insert into the cells' genomes, the hazards of 'naked' and 'free' nucleic acids including gene therapy vectors, DNA/RNA vaccines, are still not acknowledged by the regulatory authorities [14].
In a recent report, scientists in the Russian Academy of Sciences in Siberia suggest that DNA uptake is routine [15]. Under normal circumstances, circulating DNA from dead cells may be taken in by living cells in order to replace mutated genes with good copies of the same genes. However, this process may also lead to the substitution of 'bad' genes for 'good'. So, what happens when our bodies are flooded with transgenes in food and nucleic acid vaccines for example?
It is clear that the agricultural and biomedical applications cannot be neatly separated, and neither can the hazards involved. The same kinds of tools are used, the same materials and constructs. The cauliflower mosaic virus (CaMV) promoter, widely assumed to be specific to plants, is active in species across the entire living world, including human beings, as we discovered in literature dating back to 1989 [16].
Increasingly, genetic materials from animal and plant pathogens are recombined, and evidence is growing that 'plant' viruses can cross into animals and vice versa, and plant bacteria can infect human cells.
Two years ago, the most common gene transfer vector used in plants, Agrobacterium, was found to transfer genes into the human genome [17]. The soil bacterium Bacillus thuringiensis, from which endotoxin (Bt) genes are extracted and widely incorporated into GM crops as bio-pesticide, was found to be a very close relative of the anthrax bacterium [18]. These bacteria routinely exchange genes with each other and with another responsible for food poisoning.
In a recent experiment, researchers in Univ. of Oregon, Centers for Infectious Diseases US and Leiden University, Netherlands, investigated if the proteinase gene of the beet yellow virus (BYV) could be exchanged with those from other viruses from animals and fungi [19]. They found indeed that the gene could be replaced to varying extents with the proteinase from the equine arteritis virus (EAV), foot-and-mouth disease virus (FMDV) and the fungal virus CHVI. The EAV gene was especially good, and supported vigorous replication of the recombinant BYV in plant protoplasts (cells stripped of the cell wall). They didn't investigate whether the recombinant virus is active in animal cells. They see their work "as a step toward the ultimate goal of making designer viruses producing useful proteins or even desired phenotypes of infection." (italics mine)
As we have stated [6], "GM experiments are in some respects worse than biological weapons. For every biological warfare agent, it is possible to know its biological origin, its mode of action, where it is produced and where it is released, providing the BWC Protocol can be agreed. But in the case of accidental creation of deadly pathogens in GM experiments, or contamination with GM microorganisms, none of these parameters is known, and in most cases cannot even be predicted. In the event of disease outbreaks, diagnosis will be delayed, and more people will get ill and die."
The greatest danger, by far, is when scientists fail to take responsibility for the biosafety of their own research. They need to take all scientific evidence into account, to desist from research for aggressive military purposes or research that does more harm than good [20].
Article first published 30/4/02
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