A Geneticist's Opinion about Genetic Engineering in Agriculture
R. H. (Dick) Richardson, Ph.D., Professor of Integrative Biology, Univ. of Texas at Austin
NOTE: REVISIONS PENDING
Is genetic engineering a good idea? In my opinion this technology is the most powerful yet invented by humankind, and our enthusiasm overwhelms good judgment and respectful caution.
I am euphoric about the new insights I can teach in my genetics classes. Examples of different genetic interactions arrive with each new journal issue. Identifying similar genes in vastly different organisms and determining their effects has been beyond the capabilities of traditional genetic analysis. With our new technology, even the genetic differences between viruses, bacteria and higher forms can be compared in their DNAs. I am astounded at how extremely different organisms are surprisingly similar in their genetic organization, yet how they can accomplish similar functions differently. Remarkably, we can identify genes in ourselves that appear to once have been in viruses that infected our ancestors, but are now transmitted along with normal genes from parents to offspring . Using genetic engineering, we have extended our range of moving genes from closely related species to the entire span of the diversity of life.
The fruit fly (Drosophila melanogaster) has been the principle animal of genetic experimentation for a century. Its genetic system is as well understood as any higher organism. Only this year has the complete DNA sequence of its genome been published. But, we do not know how many proteins are coded by the approximately 13,600 genes! An antibody gene can produce more than 10 million different proteins, while other genes may produce only one protein. Different DNA architectures of protein synthesis are related to modes of development and cell specialization. The genetic blueprint of an organism does not explain how it lives - this blueprint no more describes a life than a dictionary can sing a song.
In a discussion of the Drosophila genome publication, Brenner emphatically states, But there is one important piece of information that is almost totally missing: the sequence information that specifies when and where and for how long a gene is turned on or off. This switching information ... cannot be deduced from the sequence.
Gene regulation is the process that primarily distinguishes species, and lies at the root of genetic diseases and abnormal development. Mules and hinneys are sterile, but a hybrid between species less related than a horse and a donkey would die in early development. A hybrid between a fish and a tomato is unthinkable. Moving genes among species is easy with molecular technology that avoids the behavioral and developmental necessities for making hybrids. When such partial hybrids are made with molecular techniques, identifying the effects at the various scales in processes of living organisms, populations, communities, ecosystems, biosphere is overwhelming since the normal biological filtering is bypassed. The detrimental effects may be delayed, waiting for biological or environmental signals to create a cascade of responses otherwise impossible.
Even in medicine, at an individual organism scale, the revolutionary benefits promised by proponents of gene therapy have not yet been realized. And we have not resolved serious ethical questions of right to die and right to live, informed consent, social and economic justice, and humane treatment of non-human animals increased enforcement and canceled research projects.
Use of genetic technology in medicine has been regulated by the Recombinant DNA Advisory Committee (RAC) for 25 years! Before implementation of any medical application using genetic technology, researchers must evaluate potential harm as well as benefit. Each experiment must be reviewed, and unexpected harmful results must be reported. In the past few months there have been serious repercussions when investigators neglected timely reporting of many experimental failures. The RAC is an imperfect restraint, but it is the best we have. It was formed in more cautious times.
For agriculture, which functions at larger scales of life, there is no equivalent of the RAC. However, Secretary of Agriculture Glickman convened on March 29, 2000, a new USDA Advisory Committee on Agricultural Biotechnology. This action came only after tens of millions of acres of genetically engineered crops had been planted globally within the decade after the first was created. The complexities were well known, presented by the FDA in the Federal Register, and summarily dismissed.
The potential for environmental and population effects from agricultural uses of genetic engineering is vastly greater than for medical uses that are assumed to be restricted to the individual treated (although that can change in the future). Agricultural genetically modified organisms (GMOs) are distributed globally and grown in gargantuan (1017 more or less) populations. This greatly increases the opportunity to disrupt habitats and food security of humans directly and indirectly throughout our food web, to genetically alter other species, and to disrupt natural genetic variation of wild relatives of our crops. These conditions create serious limitations for future crop improvement, potentially jeopardize essential ecosystem services and degrade our evolutionary and ecological resources for future study of living systems. Relative to the risks and long-term consequences of mistakes, a rational position suggests even greater caution for agricultural applications of genetic engineering than for medical applications.
Sound science is a misnomer being used by politicians and corporations to direct attention toward predictions within a scientific model that are considered favorable to their agenda and to discount those that are deemed unfavorable. Any results that suggest unfavorable predictions are attacked and disputed, often by attempting to discredit the integrity of the scientist. This substitutes rhetoric for investigation. Good science is conservative, methodical, searches for understanding, and is self-correcting by refuting predictions through testing. Instead of encouraging good science, the regulations and policies of sound science were designed to deflect attention away from the potential environmental effects of GMOs. FDA memos (1991-93 internal discussions of hazards and administrative flaws) note that no risk analysis was done, and that appropriate specialists were excluded from the review process.
In 1998 in Scotland, a peer reviewed research journal paper was published. It reported evidence of toxicity in test animals after feeding trials using genetically modified potatoes. The researcher was suspended, and his results were publicly attacked by corporate connected scientists.
A key feature of such attacks is their focus on the investigators with rhetoric about the interpretation. Scientifically, the focus needs to be on experiments and on the relevance of the data presented. If the models or the data are to be refuted, new experiments are necessary. The knee-jerk reaction of the research institutions, scientists, politicians and corporate public relations staff demonstrates motives and values that are the antithesis of good science. They are disrespectful of the need for discussion of the models and available data, and of the critical need for continuing investigation. The very nature of scientific dialog is being undermined by the shift away from public funding and by the lack of accountability to both the pubic and scientific community. It is being replaced by increasing corporate manipulation of both results and interpretation.
Scientists around the world, including supporters of GMO foods, have expressed strong concerns about long-term effects . These concerns should spur extensive research. Instead, our traditional public research and regulatory institutions - FDA, EPA and USDA - have given low priority to serious research regarding the environmental effects of genetically engineered crops.
These changes have been discussed in Science, published by the American Association for the Advancement of Science . The psychology of scientists conducting DNA research has changed since the beginning of the gene manipulation period in life sciences. Marcia Barinaga's report comparing the recent 25th anniversary meeting of molecular biologists, Symposium of Science, Ethics, and Society to the original Asilomar Conference is particularly poignant. Twenty-five years ago, leading scientists of the new discipline in biology that was to produce genetic engineering technology considered the implications to humankind and beyond. There was a sense of urgency. After much haggling, the group settled on a set of safety guidelines that involved working with disabled bacteria that could not survive outside the lab. They convinced Congress that they could govern themselves and the RAC serves in this capacity - for medicine. Even their concerns were understatements about the potential for different bacteria to share through recombination of their genomes. Now we know that even inactive bacteria can contribute their DNA to others! Furthermore, similar jumping genes (transposons) are widely found in nature, but typically lack an active enzyme to achieve transfer. However, in a recent laboratory test where an inactive salmon transposon system was activated it functioned in salmon, mouse and human tissue cells.
The recent meeting, involving several of the original members, was strikingly different. There was less urgency, safety was of little concern in spite of greater known danger, and the objectivity of the scientists was dramatically compromised. She continues, Those who gathered at Asilomar in 1975 represented a research community that was purely academic in its interests. As genetic engineering has gone commercial, academics have followed, and today most senior academic researchers have ties to biotechnology companies that would complicate any attempts at self-scrutiny. Good science judged by consensus and self correcting features of peer review are being compromised. In Great Britain, the Royal Society has gone even further to quell dissension about scientific matters, as evidenced by Parliament. News editors have been reminded that they should quote only certain scientists, whose names will be on a list supplied by the Society.
Leading scientists in many fields see monumental ethical and environmental problems posed by agricultural genetic engineering because of the self-replication capability of GMOs and ease of creating potentially dangerous organisms. They are beginning to emphatically express these concerns in the popular press in an effort to offset the corporate infomercials.
There is miniscule funding going toward research directed at finding side effects of GMOs due to the insertion of DNA, minimally containing the desired gene, a selected promoter (usually from a virus), markers (that will indicate whether the piece has inserted), flanking sequences for enzymatic insertion and attached segments of unknown function. Multiple effects (pleiotropy - each gene has multiple effects, and epistasis - all genes interact with others) occur in complex biological systems. The uniqueness of GMOs was pointed out, and disregarded in order to regulate them under the Food, Drug and Cosmetic Act, where generally regarded as safe (GRAS) criteria would omit requirements for testing. The FDA in the Federal Register explicitly recognized these illogical connections but accepted the conclusions. Why? Testing is expensive and takes time. With the rush to market engineered crops, the profit incentive in the globalized market marginalized a scientifically rational exploration of concurrent effects. The public and the ecosystem are placed at risk due to narrowly conceived and minimally tested releases of living materials. It takes only one serious mistake to create an irreversible disaster.
An example with a fortunate ending illustrates the counterpoint. In the Oregon valley between the Coast Ranges and the Cascade Range of mountains lies a fertile agricultural plain where most of the ryegrass seed for the US is grown. The straw is a nuisance because it decays slowly in the field. Rather than burning the straw, researchers thought this would be a good source for biofuel if a bacterium were engineered to form alcohol in a digester of straw and water. The alcohol could be collected and the residue then could be returned to the fields as compost. The organism was created. The investigators realized that before the first field trials the effects of the residue on the following crop should first be tested in the lab. Potted plants were inoculated. The alcohol-forming bacteria grew around the roots, formed alcohol as designed, and the plants died. What would have been the ecological and agronomic consequences if these organisms had been field tested? What would have happened when the soil with the organisms was transported to nearby fields by wind, water, wildlife and humans. Once released, engineered organisms that survive on their own cannot be recovered, unlike many environmental pollutants that at least stay in superfund sites until decontaminated. This was a fortunate laboratory test. The scientist recognized the potential hazard before the GMO was released into the ecosystem and reported the results.
Universally well-established principles of genetics and ecology give reasons to be very cautious with GMOs. Unpredictable effects of hybridization, when possible by normal crossing, is indisputable. Drastic yet unpredictable effects of mobile genetic elements (transposons) are well established. Genetic engineering employing synthetic transposons is undeniable. Development of insecticide, herbicide and antibiotic resistance is common knowledge. That biological systems are optimized, not maximized, is elementary biology. There were many examples of complexity in genetic mechanisms that were discovered by geneticists in the first 50 years of Mendelian genetics before Watson and Crick showed that DNA could code the genetic information. Now we understand molecular mechanisms for many of these interactions. These genetic processes have profound scientific and social implications, revealed by the same molecular tools that are used in genetic engineering. We have learned not only that all genes interact with many other genes, but that they also function with intimate coordination -achieved in different ways in different organisms. The FDA discounted this knowledge. However, we know that at molecular and developmental levels a single character actually results from the action of many genes, and every gene tested is expressed multiple times in specific cells to form many characters. From theoretical studies, we know that a gene that has desirable features can also cause extinction of a species. The FDA and EPA discounted this knowledge. We have learned that a gene often affects the function of its neighbors on a chromosome, and that similar clusters of genes are responsible for determining morphological features of appendages in such diverse animals as mammals, birds and insects. We know that inserting a foreign gene can disrupt the dynamics of these coordinated systems of genes, and that the technology of inserting genes has no control of where the insertion occurs, or how many insertions occur in a cell. The FDA discounted this knowledge. The malfunctions sometimes have surfaced as cancer or distortions of normal development. We do not even know to look for malfunctions that are more subtle, or that have long delays before manifestation. They would not be recognized in any of our test conditions. We can with certainty predict from what we do know that there are serious possibilities for unwanted effects. These issues were dismissed as irrelevant by the FDA. They have been ignored by the USDA and EPA. And they are ridiculed by the infomercials.
Barbara McClintock received the Nobel Prize for Physiology or Medicine in 1983 for identifying natural mutations that result from natural DNA insertions, which are structurally and functionally similar to engineered insertions. We know many examples where the controlling regions of a virus or bacterial gene have spontaneously replaced the controlling regions of a normal gene. These changes are a common mechanism of mutation. Several of these examples illustrate the conversion of a proto-oncogene, which controls normal cell cycles, into an oncogene, so named because it can produce cancer . These possibilities are improbable individually. But where many possibilities have astronomically large opportunities to occur, they become almost a certainty. (A one in a million chance of a detrimental occurrence is 10-6 but when the opportunities to occur are 1017, simplistically the chances of it occurring are 1-10-11 or 0.99999999999, give or take a few decimal places.) The FDA discounted this knowledge, and set the stage for the essentially numerous inevitable detrimental outcomes year after year ñ until we recognize how detrimental they are. Of course, recognizing them may take a few years since few people are looking for them and there is no system to track an undesirable outcome to it's source until it's seen in large numbers. (It took decades to identify asbestos as a carcinogen, for example, or pesticides that act as endocrine disrupters.) Nevertheless, I'm optimistic that many potential benefits to agriculture and medicine are hiding in the unknowns of our genetic and ecological systems. Systems is a key word. Scientific differences of opinion are rooted in perspectives of how living systems work since experiments are in greatly simplified conditions. Reaggregating the parts into the essential whole takes time and cross disciplinary understanding. The recent formation of the USDA's Advisory Committee on Agricultural Biotechnology is an opening to begin correcting our priorities. However, the committee is over representative of industry interests, in my opinion, and its charges are restricted to modest scope. For a rational use of the technology, we need to proceed with open minds, aggressive research, and reasonable caution, being ever alert for the unexpected. Full exercise of the Precautionary Principle is scientifically supported common sense, but its use is unlikely to prevail in the present situation unless there is a strong public demand.
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