Why Genetic Engineering Is So Dangerous

By Barry Commoner

Human Genome Project
Background by Barry Commoner
(founder of the Center for the Biology of Natural Systems, Queens
College, CUNY)

The recent reports about the outcome of the Human Genome Project illuminate the contradictory aspects of molecular genetics and its application to biotechnology. When the federal effort to create the Human Genome Project was launched in 1990, the director, James  Watson, defined its purpose as 'The ultimate description of life...that determines if you have a life as a fly, a carrot, or a man.' This goal was justified by a singular idea that for decades has dominated biological and medical research. Enshrined by Francis Crick (with Watson, co-discoverer of the DNA double helix) as the 'Central Dogma,' it reduces inheritance, a property that only living things possess, to molecular dimensions:

Each of a living thing's DNA genes, which collectively comprise the genome, exclusively governs the formation of each of the individual proteins that, through their biochemical activity (for example as enzymes), give rise to the creature's inherited traits. The gene's DNA carries a 'code' that is represented by the linear sequence of its four types of components (nucleotides). Through a series of intervening steps, this code is expected to determine the distinctive linear order of the amino acids that are strung together to form a particular protein molecule. Finally, based on this distinctive amino acid sequence, the protein achieves a specific biochemical activity that gives rise to a given inherited trait.

In theory, then, by identifying and enumerating all of the human genes and characterizing the unique sequence of their constituent nucleotides, the genome project could use the encoded, one-to-one correspondence between gene and protein to define the molecular structure and therefore the function of each of the human proteins that determine our inherited traits.

In February, the chief outcome of the genome project was announced. It was 'unexpected.' After a massive and ingenious search, only about 30,000 human genes were found. Based on the expected one-to-one gene/protein correspondence, this is too few to account for the 100,000 or more known human proteins. Moreover, by this measure, people are only about as gene-rich as a mustard-like weed (which has 25,000 genes) and about twice as genetically endowed as a fruit fly or a primitive worm. If the human gene count is too low to match the protein count and cannot explain the vast inherited difference between a weed and a person, there must be much more to the 'ultimate description of life' than the genes can tell us. Thus, the main outcome of the genome project was to contradict the scientific premise on which it was undertaken and to overthrow, or at least critically damage, its guiding icon, the Central Dogma.

In retrospect, it is clear that this 'unexpected' result was anticipated by discoveries made nearly 20 years earlier. In 1982, well before the genome project was even planned, experiments had shown that protein enzymes can cut out bits of the DNA that comprises a single gene ('gene splicing'), which are then reassembled in different ways and prescribe not just one protein but a variety of them. For example, the several hundred different proteins that establish the tone-sensitivity of the array of cells in the cochlea of the inner ear are all derived, by splicing, from a single gene. Thus, such results contradict the assumption that a single particular gene exclusively governs the structure of a single particular protein - and hence the individual inherited trait that it generates.

This is but one of a series of experimental results that over the last 40 years have contradicted the basic precepts of the Central Dogma.  For example, in the 1960s researchers had already found that the DNA code is often so poorly copied that it cannot account for the much greater reliability of biological inheritance itself; here too, it was discovered, protein enzymes are at work, this time to repair the mis-coded DNA. Another discordant observation relates to the fact that in order to become biochemically active and actually generate the inherited trait, the newly made protein, a strung-out ribbon of a molecule, must be folded up into a precisely organized ball-like structure. Crick assumed that the strung-out protein simply 'folds itself up' in the right way. But in  the 1980s, it was discovered that, on their own, nascent proteins are  likely to become misfolded, and therefore remain biochemically inactive -  unless they come in contact with a special type of Achaperone protein  that somehow manages to properly fold them.

Thus, over time experimental evidence has accumulated to show that,contrary to the Central Dogma, a given gene is not in exclusive controlof an inherited trait. Rather, it exerts its effect on inheritance onlythrough the intervention of a system of protein-mediated processes, anarrangement that can give rise to a far more complex array of inherited traits than can the genes alone.

What has been learned in the last 20 years about the 'prion,' the infectious agent that causes the Mad Cow disease and related human brain degenerations is perhaps the most portentous example of theunacknowledged discrepancies in the Cental Dogma. According to that theory, biological replication, and therefore infectivity, cannot occur without nucleic acid. Yet, when scrapie, the earliest known degenerative diseases of the brain (in sheep), was analyzed biochemically, no nucleic acid could be found in the infectious material. In 1980, Stanley Prusiner at the University of California Medical School, San Francisco, began a detailed study of the infectious agents that cause scrapie and similar human diseases. His work confirmed that these agents are indeed nucleic acid-free proteins (which he named prions) and showed that they replicate in an entirely unprecedented way. Invading the brain, the prion encounters a normal brain protein, which it then refolds to match the prion's distinctive three-dimensional structure. The newly refolded protein itself becomes infectious, and, acting on another molecule of the normal protein, sets up a chain reaction that propagates the disease to its fatal end. This process, in which the prion's ability to replicate is directly transmitted to another protein, contradicts the Central Dogma, which includes Crick's dictum that the discovery of such a genetic transfer between proteins '...would shake the whole intellectual basis of molecular biology.'

All of the foregoing examples are the outcome of research on the molecular basis of inheritance, typically guided by the precepts of the Central Dogma. By any reasonable measure, their results contradict the theory's cardinal maxim: that DNA genes exclusively govern the molecular processes that give rise to inherited traits. But if nucleic acids are not solely responsible for inheritance, and if genes do not uniquely specify protein activity, then it is hazardous to rely on this flawed theory for assurance that the consequences of genetic engineering are - as the biotechnology industry claims - entirely predictable. Yet this conclusion is rarely even mentioned, let alone debated, in the scientific community. The press has been equally silent on this issue. For example, a computer search of articles in the major U.S. newspapers between 1980 and 2000 finds none on chaperones or the infidelity of the DNA code. That a gene, reassembled from fragments, can govern the production of a multiplicity of proteins became news only this February (after it was mentioned in the genome reports), some two decades after this critical discovery was actually made.

The Central Dogma's ideological grip on the research community has been so strong that in 1997, when Stanley Prusiner was awarded the Nobel Prize, several fellow scientists publicly denounced the decision because his claim that the prion, although infectious, is a nucleic acid-free protein contradicted the prevailing belief in the Central Dogma and was, therefore, too 'controversial' to warrant the award. This dogma-induced bias has seriously impeded not only scientific progress, but human health as well. In response to the vocal criticism of Prusiner's work, Ralf Peterson, the deputy chairman of the Nobel Assembly, has pointed out that, by casting doubt on Prusiner's work (which, incidently, explained the prion's unique resistance to the conventional sterilization procedures that were relied on, ineffectually, to control the disease), his critics delayed effective remedial action against the Mad Cow disease in Britain for so long that by then it was too late.

How do such discrepancies in its guiding theory affect the reliability and safety of genetically engineered agricultural crops? This technology is based on the precept that the specific biochemical properties of a protein that give rise to a plant's inherited traits are derived, via the genetic 'code,' exclusively from a particular DNA gene. It follows, then, that a gene artificially transferred from a wholly unrelated species - for example, from a bacterium, in which the gene produces an insecticidal protein - will produce the same outcome, and no more, in a corn or soybean plant.

Within a single species the overall outcome of the gene's influence on the protein - and hence on the inherited trait that it governs - is usually predictable. But this does not reflect the gene's exclusive control of the inherited trait, since, as we have seen, this outcome depends as well on an array of other protein-mediated processes such as: DNA code repair, gene splicing, and chaperone-mediated protein folding. Rather, the reliability of the natural genetic process results from the compatibility between the gene system and the equally necessary protein-mediated systems. This harmonious interaction between the genome and the protein-mediated systems is developed during their coexistence over very long evolutionary periods, in which the incompatible variants that may arise are rejected. In other words, within a single species the reliability of the successful outcome of the complex molecular process that gives rise to the inheritance of particular traits is guaranteed by many thousands of years of testing, in nature, that ensures the compatibility of its component parts.

In contrast, in a genetically engineered transgenic plant, an alien bacterial gene must properly interact with the plant's protein-mediated systems, such as DNA code repair and chaperones. But these plant systems have an evolutionary history very different from the bacterial gene's. As a result, in the transgenic plant the harmonious interdependence of the alien gene and the new host's protein-mediated systems is likely to be disrupted in unspecified, imprecise and wholly unpredictable ways. These are revealed by the numerous experimental failures that occur before a transgenic organism is actually produced and by genetic defects that occur even when the gene is successfully transferred.

Thus, a recent study has shown that in transgenic bacteria the new host's code-repair system fails to correct the faulty replication of the alien gene, a necessary repair process that does occur in the original host. This means that in the new transgenic host, random uncorrected errors in gene replication can persist, giving rise to unforeseeable genetic changes. Similarly, in a recent experiment, a jellyfish gene that governs the production of a green-glowing protein was successfully transferred to a monkey egg, and later detected in the tissues of the resulting offspring. But there, the green glowing protein itself was absent, signifying a failure in one or more of the processes that must translate the gene's code into an active protein. Moreover, since the protein was detected in the egg, this defect arose at some later time,  during fetal development. These are examples of how the disruptive effect of a 'successful' gene transfer between different species may be not only unpredictable but also long delayed in its appearance. The likelihood, in genetically engineered crops, of some instances of even exceedingly rare, disruptive effects of gene transfer is greatly amplified by the billions of individual transgenic plants that are already being grown in the United States.

The degree to which such disruptions do occur in genetically modified crops is not known at present, for the biotechnology industry is not required to provide even the most basic information about the actual composition of the transgenic plants to the regulatory agencies. For example, in the case of corn plants that carry a bacterial gene for a specific insecticidal protein, no tests are required to show that the plant actually produces a protein with the same amino acid sequence as the original bacterial protein. Yet, this information is the only way to confirm that the transferred gene is in fact yielding the theory-predicted product.

Moreover, there are no reported studies to investigate the long-term, multi-generational consequences of the gene transfer. This would require, for example, detailed analysis of the molecular structure and biochemical activity of the alien gene's protein product not only in laboratory test plants, but in the transgenic commercial crop as well. Since some unexpected effects may appear in only a fraction of the commercial crop plants, such analyses should be made in samples grown in different regions that are large enough to detect plant-to-plant variation in protein products. Given that some unexpected effects may develop very slowly, crop plants should be monitored in successive generations as well. None of these essential tests are being made.

In sum, billions of transgenic plants are now being grown with only the most rudimentary knowledge about the resulting changes in their composition. Without detailed, ongoing analyses of the transgenic crops, there is no way of knowing what hazardous consequences may arise. But, given the failure of the Central Dogma, there is no assurance that they will not. The genetically engineered crops now being grown represent a huge uncontrolled experiment; its outcome is inherently unpredictable. Our project is designed to help develop effective public understanding of the dangerous implications of this critical predicament.