SUMMARY OF THE CAMPAIGN POSITION ON GM CROPS AND FOOD

A Challenge to Gene Theory, a Tougher Look at Biotech

AN INTERVIEW WITH DR. CHARLES BENBROOK ON GENETIC ENGINEERING

Super Organics - Forget Frankenfruit - the new-and-improved flavor of gene science is Earth-friendly and all-natural. Welcome to the golden age of smart breeding - Richard Manning

Unravelling the DNA Myth - Barry Commoner

The DNA Era - Richard C. Lewontin, Gene Watch vol 16, no. 4, July 2003

Unravelling the DNA Myth - Barry Commoner
(Barry Commoner has a long and rich history in environmental science and social activism. After gaining his PhD in biology from Harvard University in the US, he spent 34 years at Washington University in St Louis, Missouri, There he explored viral function and led cellular research with implications for cancer diagnosis. In the 1950s, Commoner was heavily involved in the debates on nuclear weapons, and in the 1960s, he became involved in other environmental issues including pollution and energy sources. In 1980, Commoner set up and headed the Center for the Biology of Natural Systems at Queens College, New York. He now directs the Critical Genetics Project there (www.criticalgenetics.org), which aims to look at new ways of understanding the roles of the living cell’s molecular constituents, such as DNA, RNA and protein, in the biology of inheritance. Barry Commoner is the author of nine books and has served on numerous advisory and editorial boards. He can be reached by email at commoner@criticalgenetics.org .)
There is a crucial problem in molecular genetics and in its applications to agriculture, medicine and the production of pharmaceutical drugs. This science is based on a 50-year old theory that says DNA alone governs inheritance. Molecular genetics is now confronted with a growing disjunction between this widely accepted premise and an array of discordant experimental results that contradict it. But this disparity remains largely unacknowledged and experiments with transgenic plants and animals (many of which are not even recognised to be experiments) continue on a massive scale.
Biology once was regarded as a languid, largely descriptive discipline, a passive science that was content, for much of its history, merely to observe the natural world rather than change it. No longer. Today biology, armed with the power of genetics, has replaced physics as the Science of the Century, and it stands poised to assume godlike powers of creation, calling forth artificial forms of life. The initial steps toward this new Genesis have been widely touted in the press. It wasn’t so long ago that Scottish scientists stunned the world with Dolly, [1] the fatherless sheep cloned directly from her mother’s cells; these techniques have now been applied, unsuccessfully, to human cells. ANDi, a photogenic rhesus monkey, recently was born carrying the gene of a luminescent jellyfish. [2] Pigs now carry a gene for bovine growth hormone and show significant improvement in weight gain, feed efficiency, and reduced fat. Most soybean plants grown in the US have been genetically engineered to survive the application of powerful herbicides.
Our leading scientists and scientific entrepreneurs (two labels that are increasingly interchangeable) assure us that these feats of technological prowess, though marvellous and complex, are nonetheless safe and reliable. We are told that everything is under control. Conveniently ignored, forgotten, or in some instances simply suppressed, are the caveats, the fine print, the flaws and spontaneous abortions. Most clones exhibit developmental failure before or soon after birth, and even apparently normal clones often suffer from kidney or brain malformations. [3] And it, perversely, has failed to glow like a jellyfish. Genetically modified pigs have a high incidence of gastric ulcers, arthritis, enlarged hearts, dermatitis, and renal disease. Despite the biotechnology industry’s assurances that genetically engineered soybeans have been altered only by the presence of the alien gene, the plant’s own genetic system has been unwittingly altered as well, with potentially dangerous consequence. [4] The list of malfunctions gets little notice; biotechnology companies are not in the habit of publicising studies that question the efficacy of their miraculous products or suggest the presence of a serpent in the biotech garden.
The mistakes might be dismissed as the necessary errors that characterise scientific progress. But behind them lurks a more profound failure. The wonders of genetic science are all founded on the discovery of the DNA double helix – by Francis Crick and James Watson in 1953 – and they proceed from the premise that this molecular structure is the exclusive agent of inheritance in all living things: in the kingdom of molecular genetics, the DNA gene is absolute monarch. Known to molecular biologists as the "Central Dogma," the premise assumes that an organism’s genome – its total complement of genes – should fully account for its characteristic assemblage of inherited traits. [5] Since Crick first proposed it forty-four years ago, the Central Dogma has come to dominate biomedical research. Simple, elegant, and easily summarised, it seeks to reduce inheritance to molecular dimensions. The molecular agent of inheritance is DNA, deoxyribonucleic acid, a very long, linear molecule tightly coiled within each cell’s nucleus (see diagram opposite). DNA is made up of four different kinds of nucleotides, strung together in each gene in a particular linear order or sequence. Segments of DNA comprise the genes that, through a series of molecular processes, give rise to each of our inherited traits.
But the premise of the Central Dogma, unhappily, is false. Tested between 1990 and 2001 in one of the largest and most highly publicised scientific undertakings of our time, the Human Genome Project, the theory collapsed under the weight of fact. There are far too few human genes to account for the complexity of our inherited traits or for the vast inherited differences between plants, say, and people. By any reasonable measure, the finding (published in February 2001) signalled the downfall of the Central Dogma. It also destroyed the scientific foundation of genetic engineering and the validity of the biotechnology industry’s widely advertised claim that its methods of genetically modifying food crops are "specific, precise, and predictable" [6] and therefore safe. In short, the most dramatic achievement to date of the $3 billion Human Genome Project is the refutation of its own scientific rationale.
In 1990, James Watson described the Human Genome Project as "the ultimate description of life". It will yield, he claimed, the information "that determines if you have life as a fly, a carrot, or a man." How could the minute dissection of human DNA into a sequence of 3 billion nucleotides support such a claim? Crick’s crisply stated Central Dogma attempts to answer that question. It hypothesises a clear-cut chain of molecular processes that leads from a single DNA gene to the appearance of a particular inherited trait. Crick’s second hypothesis neatly links the gene to the protein. This "sequence hypothesis" states that the gene’s genetic information is transmitted, altered in form but not in content, though RNA intermediaries, to the distinctive amino acid sequence of a particular protein. It follows that in each living thing there should be a one-to-one correspondence between the total number of genes and the total number of proteins. The entire array of human genes must therefore represent the whole of a person’s inheritance. Finally, because DNA is made of the same four nucleotides in every living thing, the genetic code is universal, which means that a gene should be capable of producing its particular protein wherever it happens to find itself, even in a different species.
Crick’s theory is based on an extravagant proposition: that genes have unique, absolute, and universal control over the totality of inheritance in all forms of life. According to Crick, genetic information originates in the DNA nucleotide sequence and terminates, unchanged, in the protein amino acid sequence. The pronouncement is crucial because it endows the gene with undiluted control over the identity of the protein and the inherited trait that the protein creates. To stress the importance of this genetic taboo, Crick bet the future of the entire enterprise on it, asserting that "the discovery of just one type of present-day cell" in which genetic information passed from protein to nucleic acid or from protein to protein "would shake the whole intellectual basis of molecular biology." [7] Crick was aware of the brashness of his bet, for it was known even then that in living cells proteins come into promiscuous molecular contact with numerous other proteins and with molecules of DNA and RNA. He insisted that these interactions are genetically chaste.
In February 2002, Crick’s gamble suffered a spectacular loss. In the journals Nature and Science and at joint press conferences and television appearances, the two genome research teams reported their results. The major result was "unexpected." [8] Instead of the 100,000 or more genes predicted by the estimated number of human proteins, the gene count was only about 30,000. By this measure, people are only about as gene-rich as a mustard-like weed (which has 26,000 genes) and about twice as genetically endowed as a fruit fly or a primitive worm. [9] The surprising results contradicted the scientific premise on which the genome project was undertaken and dethroned its guiding theory, the Central Dogma. After all, if the human gene count is too low to match the number of proteins and the numerous inherited traits that they engender, and if it cannot explain the vast inherited difference between a weed and a person, there must be much more to Watson’s "ultimate description of life" than the genes alone can tell us.
Scientists and journalists somehow failed to notice what had happened. The project’s scientific reports offered little to explain the shortfall in the gene count. One of the possible explanations for why the gene count was "so discordant with our predictions" was described in Science as follows: "nearly 40% of human genes are alternatively spliced." [10] Properly understood, this modest, if esoteric, account fulfills Crick’s dire prophecy: it "shakes the whole intellectual basis of molecular biology" and undermines the scientific validity of its application to genetic engineering. Alternative splicing is a startling departure from the orderly design of the Central Dogma, in which a single gene encodes the amino acid sequence of a single protein. In alternative splicing, the gene’s original nucleotide sequence is split into fragments that are then recombined in different ways to encode a multiplicity of proteins, each of them different in their amino acid sequence from each other and from the sequence that the original gene, if left intact, would encode. Alternative splicing can have an extraordinary impact on the gene/protein ratio. The current record for the number of different proteins produced from a single gene by alternative splicing is held by the fruit fly, in which one gene generates up to 38,016 variant protein molecules. [11]
Alternative splicing thus has a devastating impact on Crick’s theory: it breaks open the hypothesised isolation of the molecular system that transfers genetic information from a single gene to a single protein. It also contradicts the theory that proteins cannot transmit genetic information to nucleic acid (in this case, messenger RNA). [12] The discovery of alternative splicing also nullifies the exclusiveness of the gene’s hold on the molecular process of inheritance. The gene’s effect on inheritance thus cannot be predicted simply from its nucleotide sequence – the determination of which is one of the main purposes of the Human Genome Project.
By 1989, when the Human Genome Project was still being debated among molecular biologists, its champions were surely aware that more than 200 scientific papers on alternative splicing of human genes had already been published. [13] The shortfall in the human gene count could – and indeed should – have been predicted. It is difficult to avoid the conclusion – troublesome as it is – that the project’s planners knew in advance that the mismatch between the numbers of genes and proteins in the human genome was to be expected, and that the $3 billion project could not be justified by the extravagant claims that the genome would tell us who we are. [14]
Alternative splicing is not the only discovery over the last forty years that has contradicted basic precepts of the Central Dogma. Other research has tended to erode the centrality of the DNA double helix itself, the theory’s ubiquitous icon. In their original description of the discovery of DNA, Watson and Crick commented that the helix’s structure "immediately suggests a possible copying mechanism for the genetic material." Such self-duplication is the crucial feature of life, and in ascribing it to DNA, Watson and Crick concluded, a bit prematurely, that they had discovered life’s magic molecular key. [15]
Biological replication does include the precise duplication of DNA, but this is accomplished by the living cell, not by the DNA molecule alone. In the development of a person from a single fertilised egg, the genome is replicated many billions of times, its precise sequence of three billion nucleotides retained with extraordinary fidelity. [16] The rate of error – that is, the insertion into the newly made DNA sequence of a nucleotide out of its proper order – is about one in 10 billion nucleotides. But on its own, DNA is incapable of such faithful replication. In a test-tube experiment, a DNA strand, provided with a mixture of its four constituent nucleotides, will line them up with about one in a hundred of them out of its proper place. On the other hand, when the appropriate protein enzymes are added to the test tube, the fidelity with which nucleotides are incorporated in the newly made DNA strand is greatly improved, reducing the error rate to one in 10 million. These remaining errors are finally reduced to one in 10 billion by a set of "repair" enzymes (also proteins) that detect and remove mismatched nucleotides from the newly synthesised DNA. [17]
Thus, in the living cell the gene’s nucleotide code can be replicated faithfully only because an array of specialised proteins intervenes to prevent most of the errors – which DNA by itself is prone to make – and to repair the few remaining ones. In this sense, genetic information arises not from DNA alone but through its essential collaboration with protein enzymes – a contradiction of the Central Dogma’s precept that inheritance is uniquely governed by the self-replication of the DNA double helix.
Another important divergent observation that in order to generate the inherited trait, the newly made protein, a strung-out ribbon of a molecule, must be folded up into a precisely organised ball-like structure. The biochemical events that give rise to genetic traits – for example, enzyme action that synthesises a particular eye-colour pigment – take place at specific locations on the outer surface of the three-dimensional protein, which is created by the particular way in which the molecule is folded into that structure. To preserve the simplicity of the Central Dogma, Crick was required to assume, without any supporting evidence, that the nascent protein – a linear molecule – always folded itself up in the right way once its amino acid sequence had been determined. In the 1980s, however, it was discovered that some nascent proteins are on their own likely to become misfolded – and therefore remain biochemically inactive – unless a special type of "chaperone" protein properly folds them. [18]
By the mid 1980s, long before the $3 billion Human Genome Project was funded, and long before genetically modified (GM) crops began to appear in our fields, a series of protein-based processes had already intruded on the DNA gene’s exclusive genetic franchise. An array of protein enzymes must repair the all-too-frequent mistakes in gene replication and in the transmission of the genetic code to proteins as well. Certain proteins, assembled in spliceosomes, can reshuffle the RNA transcripts, creating hundreds and even thousands of different proteins from a single gene. A family of chaperones, proteins that facilitate the proper folding – and therefore the biochemical activity – of newly made proteins, form an essential part of the gene-to- protein process. By any reasonable measure, these results contradict the Central Dogma’s cardinal maxim: that a DNA gene exclusively governs the molecular processes that give rise to a particular inherited trait. The DNA gene clearly exerts an important influence on inheritance, but it is not unique in that respect and acts only in collaboration with a multitude of protein-based processes that prevent and repair incorrect sequences, transform the nascent protein into its folded, active form, and provide crucial added genetic information well beyond that originating in the gene itself.
The credibility of the Human Genome Project is not the only casualty of the scientific community’s stubborn resistance to experimental results that contradict the Central Dogma. Nor is it the most significant casualty. The fact that one gene can give rise to multiple proteins also destroys the theoretical foundation of a multi-billion dollar industry, the genetic engineering of food crops. In genetic engineering it is assumed, without adequate experimental proof, that a bacterial gene for an insecticidal protein, for example, transferred to a maize plant, will produce precisely that protein and nothing else. Yet in that alien genetic environment, alternative splicing of the bacterial gene might give rise to multiple variants of the intended protein – or even to proteins bearing little structural relationship to the original one, with unpredictable effects on ecosystems and human health.
The delay in dethroning the all-powerful gene led in the 1990s to a massive invasion of genetic engineering into American agriculture, though its scientific justification had already been compromised a decade or more earlier. Nevertheless, ignoring the profound fact that in nature the normal exchange of genetic material occurs exclusively within a single species, biotech-industry executives have repeatedly boasted that, in comparison, moving a gene from one species to another is not only normal but also more specific, precise, and predictable.
That the industry is guided by the Central Dogma was made explicit by Ralph Hardy, president of the US’ National Agricultural Biotechnology Council and formerly director of life sciences at DuPont, a major producer of GM seeds. In 1999, in Senate testimony, he succinctly described the industry’s guiding theory this way: "DNA (top management molecules) directs RNA formation (middle management molecules) directs protein formation (worker molecules)." [19] The outcome of transferring a bacterial gene into a maize plant is expected to be as predictable as the result of a corporate takeover: what the workers do will be determined precisely by what the new top management tells them to do. This version of the Central Dogma is the scientific foundation upon which each year billions of transgenic plants of soybeans, maize, and cotton are grown with the expectation that the particular alien gene in each of them will be faithfully replicated in each of the billions of cell divisions that occur as each plant develops; that in each of the resultant cells the alien gene will encode only a protein with precisely the amino acid sequence that it encodes in its original organism; and that throughout this biological saga, despite the alien presence, the plant’s natural complement of DNA will itself be properly replicated with no abnormal changes in composition.
In an ordinary unmodified plant the reliability of this natural genetic process results from the compatibility between its gene system and its equally necessary protein-mediated systems. The harmonious relation between the two systems develops during their cohabitation, in the same species, over very long evolutionary periods, in which natural selection eliminates incompatible variants. 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. In a genetically engineered transgenic plant, however, the alien transplanted bacterial gene must properly interact with the plant’s protein-mediated systems. Higher plants, such as maize, soybeans, and cotton, are known to possess proteins that repair DNA miscoding; [20] proteins that alternatively splice messenger RNA and thereby produce a multiplicity of different proteins from a single gene; [21] and proteins that chaperone the proper folding of other, nascent proteins. [22] But the plant systems’ evolutionary history is 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 inherently unpredictable ways. In practice, these disruptions are revealed by the numerous experimental failures that occur before a transgenic organism is actually produced and by unexpected genetic changes that occur even when the gene has been successfully transferred. [23]
Most alarming is the recent evidence that in a widely grown genetically modified food crop - soybeans containing an alien gene for herbicide resistance – the transgenic host plant’s genome has itself been unwittingly altered. Monsanto admitted in 2000 that its soybeans contained some extra fragments of the transferred gene, but nevertheless concluded that "no new proteins were expected or observed to be produced." [24] A year later, Belgian researchers discovered that a segment of the plant’s own DNA had been scrambled. The abnormal DNA was large enough to produce a new protein, a potentially harmful protein. [25]
One way that such mystery DNA might arise is suggested by a recent study showing that in some plants carrying a bacterial gene, the plant’s enzymes that correct DNA replication errors rearrange the alien gene’s nucleotide sequence. [26] The consequences of such changes cannot be foreseen. The likelihood in GM crops of even exceedingly rare, disruptive effects of gene transfer is greatly amplified by the billions of individual transgenic plants already being grown annually in the US. The degree to which such disruptions do occur in GM crops is not known at present, because 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. No tests, for example, are required to show that the plant actually produces a protein with the same amino acid sequence as the original bacterial protein. Moreover, there are no required studies based on detailed analysis of the molecular structure and biochemical activity of the alien gene and its protein product in the transgenic commercial crop. 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 performed, and 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 if hazardous consequences might arise. Given the failure of the Central Dogma, there is no assurance that they will not. The GM crops now being grown represent a massive uncontrolled experiment whose outcome is inherently unpredictable. The results could be catastrophic.
Crick’s Central Dogma has played a powerful role in creating both the Human Genome Project and the unregulated spread of GM food crops. Yet as evidence that contradicts this governing theory has accumulated, it has had no effect on the decisions that brought both of these monumental undertakings into being. It is true that most of the experimental results generated by the theory confirmed the concept that genetic information, in the form of DNA nucleotide sequences, is transmitted from DNA via RNA to protein. But other observations have contradicted the one-to-one correspondence of gene to protein and have broken the DNA gene’s exclusive franchise on the molecular explanation of heredity. In the ordinary course of science, such new facts would be woven into the theory, adding to its complexity, redefining its meaning, or, as necessary, challenging its basic premise. Scientific theories are meant to be falsifiable; this is precisely what makes them scientific theories. The Central Dogma has been immune to this process. Divergent evidence is duly reported and, often enough, generates intense research, but its clash with the governing theory is almost never noted.
Because of their commitment to an obsolete theory, most molecular biologists operate under the assumption that DNA is the secret of life, whereas the careful observation of the hierarchy of living processes strongly suggests that it is the other way around: DNA did not create life; life created DNA. [27] When life was first formed on the earth, proteins must have appeared before DNA because, unlike DNA, proteins have the catalytic ability to generate the chemical energy needed to assemble small ambient molecules into larger ones such as DNA. DNA is a mechanism created by the cell to store information produced by the cell. Early life survived because it grew, building up its characteristic array of complex molecules. It must have been a sloppy kind of growth; what was newly made did not exactly replicate what was already there. But once produced by the primitive cell, DNA could become a stable place to store structural information about the cell’s chaotic chemistry, something like the minutes taken by a secretary at a noisy committee meeting. There can be no doubt that the emergence of DNA was a crucial stage in the development of life, but we must avoid the mistake of reducing life to a master molecule in order to satisfy our emotional need for unambiguous simplicity. The experimental data, shorn of dogmatic theories, points to the irreducibility of the living cell, the inherent complexity of which suggests that any artificially altered genetic system, given the magnitude of our ignorance, must sooner or later give rise to unintended, potentially disastrous, consequences. We must be willing to recognise how little we truly understand about the secrets of the cell, the fundamental unit of life.
Why, then, has the Central Dogma continued to stand? To some degree the theory has been protected from criticism by a device more common to religion than science: dissent, or merely the discovery of a discordant fact, is a punishable offence, a heresy that might easily lead to professional ostracism. Much of this bias can be attributed to institutional inertia, a failure of rigor, but there are other, more insidious, reasons why molecular geneticists might be satisfied with the status quo; the Central Dogma has given them such a satisfying, seductively simplistic explanation of heredity that it seemed sacrilegious to entertain doubts. The Central Dogma was simply too good not to be true.
As a result, funding for molecular genetics has rapidly increased over the last twenty years; new academic institutions, many of them "genomic" variants of more mundane professions, such as public health, have proliferated. At Harvard and other universities, the biology curriculum has become centred on the genome. But beyond the traditional scientific economy of prestige and the generous funding that follows it as night follows day, money has distorted the scientific process as a once purely academic pursuit has been commercialised to an astonishing degree by the researchers themselves. Biology has become a glittering target for venture capital; each new discovery brings new patents, new partnerships, new corporate affiliations. But as the growing opposition to transgenic crops clearly shows, there is persistent public concern not only with the safety of GM foods but also with the inherent dangers in arbitrarily overriding patterns of inheritance that are embedded in the natural world through long evolutionary experience. Too often those concerns have been derided by industry scientists as the "irrational" fears of an uneducated public. The irony, of course, is that the biotechnology industry is based on science that is forty years old and conveniently devoid of more recent results, which show that there are strong reasons to fear the potential consequences of transferring a DNA gene between species. What the public fears is not the experimental science but the fundamentally irrational decision to let it out of the laboratory into the real world before we truly understand it.

[1] I Wilmut et al, "Viable offspring derived from fetal and adult mammalian cells". Nature 385(6619):810-3, 1997.
[2] Chan et al, "Transgenic monkeys produced by retroviral gene transfer into mature oocytes". Science, 291:309-312, 2001.
[3] R Jaenisch and I Wilmut, "Don’t clone humans". Science 291:2552, 2001.
[4] P Windels et al, "Charact-erisation of the Roundup Ready soybean insert". Eur. Food Res. Technol. 213:107-112, 2001.
[5] FHC Crick, "On Protein Synthesis". In: Symposium of the Society for Experimental Biology XII, p153. New York: Academic Press, 1958.
[6] P Gorner and R Kotulak, "Life by Design". Chicago Tribune, April 8, 1990
[7] FHC Crick, The Central Dogma of Molecular Biology, Nature 227:561-563 (see p 563), 1970.
[8] International Human Genome Sequencing Consortium. "Initial sequencing and analysis of the human genome". Nature 409(6822): 860-921, 2001.
[9] C Venter et al, "The Sequence of the Human Genome". Sci-ence 291:1304-1351, 2001.
[10] ibid, p 1345.
[11] D Schmucker et al, "Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity". Cell, 101(6):671-84, 2000.
[12] CA Collins and C Guthrie, "Allelespecific genetic inter-actions ....." Genes Dev, 13(15):1970-82, 1999.
[13] Results of PubMed search for articles cont-aining "alternative splicing" AND "human".
[14] C Venter et al, "The Sequence of the Human Genome". Science 291:1304-1351, 2001.
[15] JD Watson and FHC Crick, "Molecular structure of nucleic acids: A structure for DNA". Nature 171:737-738, 1953.
[16] M Radman and R Wagner, "The High Fidelity of DNA Replication". Scientific Amer-ican, August:40-46, 1988.
[17] B Commoner, "Failure of the WatsonCrick theory as a chemical explanation of inheritance". Nature 220:334-340, 1968.
[18] RJ Ellis and SM Hemmingsen, "Molecular chaperones", Trends Bioch Sci. 14(8):339-42, 1989.
[19] RWF Hardy, In "Agricultural Research and Development", Hearing before Senate Comm-ittee on Agriculture, Nutrition and Forestry. Oct 6, 1999.
[20] N Tuteja et al, "Molecular mechanisms of damage and repair: progress in plants". Crit Rev Biochem Mol Biol. 36(4):337-97, 2001.
[21] P Comelli et al, Alternative splicing of two leading exons partitions promoter activity....". Plant Mol Biol. 41(5):615-25, 1999.
[22] AA Lund et al, "Heat-stress response of mito-chondria", Plant Physiol. 116(3):1097-110, 1998.
[23] VG Pursel et al, "Inte-gration, expression and germ-line transmission of growth-related genes in pigs". Reprod Fertil Suppl. 41:7787, 1990.
[24] Monsanto Product Safety Center. Confidential Report (MSL-16712). Updated Molecular Characterisation & Safety Assessment of Roundup Ready Soybean Event 403-2. Monsanto Company. St Louis, Missouri.
[25] P Windels et al, "Chara-cterisation of the Roundup Ready soybean insert", Eur Food Res Technol. 213:107-112, 2001.
[26] A Kohli et al, "Transgene organisation in rice ....." Proc Natl Acad Sci USA 95(12):7203-8, 1998.
[27] B Commoner, "Relationship between biological information and the origin of life". In: K Matsuno et al, eds. Molecular Evolution and Protobiology, p 283, Plenum Press. New York. 1984.
Reference for this article: Unravelling the DNA myth, Seedling, July 2003, GRAIN
Copyright notice: Copyright © 2002 by Harper’s Magazine. All rights reserved. Reproduced (and shortened) from the February issue by special permission.
Website link: http://www.grain.org/seedling/seed-03-07-2-en.cfm
Seedling is the quarterly magazine of GRAIN.

The DNA Era - Richard C. Lewontin, Gene Watch vol 16, no. 4, July 2003
(Richard C. Lewontin is an evolutionary geneticist, philosopher of science, and social critic. An early pioneer in the development of molecular population genetics, his works include Biology as Ideology, The Triple Helix: Gene, Organism, and Environment, and Not in Our Genes, co-authored with Steven Rose and Leon Kamin. He is Alexander Agassiz Research Professor at Harvard University, and regularly writes for the New York Review of Books.)
No one who reads the newspapers or scientific journals can have missed the fact that this is the 50th anniversary of the publication of the correct three-dimensional structure of DNA. That structure, a double helix of two chains of nucleotides, has become a popular icon and the very phrase, double helix has been spoken and written so often as to become part of ordinary discourse.
The fact that genes were composed of DNA had already been established nine years before the publication of Watson and Cricks paper on its structure, and the chemical, as opposed to the spatial, configuration of DNA was also well known before 1953. Yet, despite the obvious importance of DNA in understanding the molecular details of both heredity and development, it was not until after the publication of the proposed double helical structure that DNA started increasingly to occupy the interest of biologists and finally became the focus of the study of genetics and development. The last fifty years have seen the reorganization of most of biology around DNA as the central molecule of heredity, development, cell function and evolution. Nor is this reorganization only a reorientation of experiment. It informs the entire structure of explanation of living processes and has become the center of the general narrative of life and its evolution. An entire ideology has been created in which DNA is the Secret of Life, the Master Molecule, the Holy Grail of biology, a narrative in which we are lumbering robots created, body and mind by our DNA. This ideology has implications, not only for our understanding of biology, but for our attempts to manipulate and control biological processes in the interests of human health and welfare, and for the situation of the rest of the living world.
The first step in building the claim for the dominance of DNA over all living processes has been the assignment of two special properties to DNA, properties that are asserted over and over again, not only in popular expositions but in textbooks. On the one hand, it is said that DNA is self-replicating; on the other, that DNA makes proteins, the molecular building blocks of cells. But both of these assertions are false and what is sodisturbing is that every biologist knows they are false.
First, DNA is not self replicating. It is manufactured out of small molecular bits and pieces by an elaborate cell machinery made up of proteins. If DNA is put in the presence of all the pieces that will be assembled into new DNA, but without the protein machinery, nothing happens. What actually happens is that the already present DNA is copied by the cellular machinery so that new DNA strands are replicas of the old ones. The process is analogous to the production of copies of a document by an office copying machine, a process that would never be described as self-replication. In fact, many errors are made in the DNA copying process; there is protein proofreading machinery devoted to comparing the newly manufactured strands to the old ones and correcting the errors. An office copier that made such mistakes would soon be discarded.
Second, DNA does not make anything, certainly not proteins. New proteins are made by a protein synthesis machinery that is itself made up of proteins. The role of the DNA is to provide a specification of the serial order of amino acids that are to be strung together by the synthetic machinery. But this string of amino acids is not yet a protein. To become a protein with physiological and structural functions, it must be folded into a three dimensional configuration that is partly a function of the amino acid sequence, but is also determined by the cellular environment and by special processing proteins that, among other things, may cut out parts of the amino acid chain and splice what remains back together again.
The other function of DNA is to provide a set of on-off switches that are responsive to cellular conditions so that different cells at different times will produce different proteins. When the conditions of the cell set a switch associated with a particular gene to the on position, then the protein manufacturing machinery of the cell will read that gene. Otherwise the cell will ignore it.
In this mechanical description of the relation of DNA to the rest of the cellular machinery there is no master molecule, no secret of life. The DNA is an archive of information about amino acid sequences to which the synthetic machinery of the cell needs to refer when a new protein molecule is to be produced. When and where in the organism that information is read depends on the physiological state of the cells. An organism cannot develop without its DNA, but it cannot develop without its already existing protein machinery (unless it is a parasite like a virus that has no synthetic power of its own but gets a free ride on its hosts protein machinery).
The unjustified claim for special autonomous powers of DNA is the prelude to the next step in building a picture of a DNA-dominated world. This picture is simply the molecular version of a biological determinism that has dominated explanations of the properties of organisms, and especially of humans, since the nineteenth century. Differences in temperament, talents, social status, wealth, and power were all said to reside in the blood. The physical manifestations of these claimed hereditary differences could be seen by criminal and racial anthropologists in the shapes of noses and heads and the color of skins. With the rise of Mendelian genetics, genes were substituted for blood in the explanations, but they remained, for the fifty years of genetics, merely formal entities with no concrete description beyond the fact that they were some bit of a chromosome. The discovery that DNA is the material of the gene, and the subsequent determination of the correspondence between nucleotide sequences of genes and amino acid sequences of proteins, then provided a concrete molecular basis for a total scheme of explanation of the organism. The fact that organisms are built primarily of proteins and that DNA carries the archive of information for the amino acid sequence of the proteins gave an immense weight to the conclusion that the organism as a whole is coded in its DNA. A manifestation of this view is the claim made, at a symposium in commemoration of the 100th anniversary of the death of Darwin, by a founder of the molecular biology of the gene: that if he were given the DNA sequence of an organism and a large enough computer, he could compute the organism. One is reminded of Archimedes claim that, given a long enough lever and a place to stand, he could move the earth. But while Archimedes may have at least been right in principle, the molecular biologist was not. An organism cannot be computed from its DNA because the organism does not compute itself from its own DNA.
It is a basic principle of biology, known to all biologists but ignored by most of them as inconvenient, that the development of an organism is the unique consequence of its genes and the temporal sequence of environments in which it developed. The current fascination of developmental genetics is with the way in which information from different genes enters into the formation of the major features of an organism. How does the front end of the animal become differentiated from the back end? Why does the egg of a horse develop into an animal with four legs while the egg of a bird produces an organism with two legs and two wings, and the egg of a butterfly results in an animal with six legs and two sets of wings? This concentration on the major differences and similarities between different species has resulted in a genetically determinist view of development that ignores the actual variation among individuals. There is an immense experimental literature in plants and animals showing that individuals of the same genetic constitution differ widely from each other in physical characteristics if they develop in different environments. Moreover, the relative ranking in some physical trait of individuals of different genotypes changes from environment to environment. Thus, a genetic type that is the fastest growing at one temperature may be the slowest at another. But even genes and environment together do not determine the organism. All symmetrical organisms show a fluctuating asymmetry between their two sides and the variation between left and right sides is often as great as the difference between individuals. For example, the fingerprint pattern on the left and right hands of a human individual are not identical; on some fingers, they may be extremely dissimilar. This variation is the manifestation of random growth differences that arise from small differences in the local tissue and cell conditions in different parts of the body, and from the fact that there is random variation in the number of copies of particular molecules in different cells. A consequence is that two individuals with identical genes and identical environments will not develop identically. If we want to understand human variation, we need to ask far more subtle and complex questions than is the rule in DNA-dominated biology.
The other side of the movement of DNA to the center of attention in biology has been the development of tools for the automated reading of DNA sequences, for the laboratory replication and alteration of DNA sequences and for the insertion of pieces of DNA into an organisms genome. Taken together, these techniques provide the power to manipulate an organisms DNA to order. The three obvious implications of this power are in the detection and possible treatment of diseases, the use of organisms as productive machines for the manufacture of specific biological molecules, and the breeding of agricultural species with novel properties.
The Human Genome Project has been largely justified by the promise that it will now be possible to locate genes that cause human disease by comparing the DNA sequences of affected and unaffected individuals. Once the nucleotide difference has been established, that difference can be used as a diagnostic criterion, as a predictor of a future onset of the disease, and as a basis for a cure by gene replacement therapy. It is undoubtedly true that some fraction of human ill health is a consequence of deleterious mutations. However, while family studies can strongly suggest that a disease is being inherited as a single Mendelian gene difference, the determination that it is a consequence of mutation of a particular gene is not a trivial problem. A blind search for a genetic difference that is common to all affected individuals is impractical given that, on the average, any two humans differ from each other at 3 million nucleotide sites. On the other hand, if the biochemistry of the disease is sufficiently well understood, it may be that a few candidate genes can be singled out for investigation. Alternatively, studies of the pattern of inheritance may show that the disorder is inherited coordinately with an associated gene of known location in the genome, greatly narrowing down the search for the DNA variation implicated in the disease.
As in all other species, for any given gene, human mutations with deleterious effects almost always occur in low frequency. Hence specific genetic diseases are rare. Even in the aggregate, genes do not account for most of human ill health. Given the cost and expenditure of energy that would be required to locate, diagnose and genetically repair any single disease, there is no realistic prospect of such genetic fixes as a general approach for this class of diseases. There are exceptions, such as sickle cell anemia and conditions associated with other abnormal hemoglobins, in which a non-negligible fraction of a population may be affected, so that these might be considered as candidates for gene therapy. But for most disease that represents a substantial fraction of ill health and for which some evidence of genetic influence has been found, the relation between disease and DNA is much more complex and ambiguous. Claims for the discovery of genes for schizophrenia and bipolar syndrome have repeatedly been made and retracted. It is generally accepted that cancer is a consequence of mutations in a variety of genes related to the control of cell division, but even in the strongest individual case, the breast cancer-inducing BRCA1 mutations, only about 5% of such cancers are linked to these specific mutations.
Up to the present we do not have a single case of a successful cure for a disease by means of gene therapy. All successful interventions, whether in genetically simple disorders like phenylketonuria or in complex cases like diabetes, have been at the level of biochemistry and were in place well before anything was known about DNA. Of course, a successful gene therapy for some disease may be produced in the future, but the claim that the manipulation of DNA is the path to general health is unfounded. In fact, on a world scale, most ill-health and premature death is caused by a combination of infectious disease and undernourishment factors which genetic manipulation will never solve.
The second implication, the possibility of using genetically transformed organisms as factories for the commercial production of biologically useful molecules, has been realized in practice. The most famous case, the mass production of human insulin by bacteria, is particularly instructive. Insulin for diabetics was originally extracted from cow and pig pancreases. This molecule, however, differed in a couple of amino acids from human insulin. Recently, the DNA coding sequence for human insulin has been inserted into bacteria, which are then grown in large fermenters; a protein with the amino acid sequence of human insulin is extracted from the liquid culture medium. But amino acid sequence does not determine the shape of a protein. The first proteins harvested through this process, though they possessed the correct amino acid sequence, were physiologically inactive. The bacterial cell had folded the protein incorrectly.
A physiologically active molecule was finally produced by unfolding the bacterially produced protein and refolding it under conditions that are a trade secret known only to the manufacturer, Eli Lilly. This success, however, has a severely negative consequence. For some diabetics this human insulin produces the symptoms of insulin shock, including loss of consciousness. Whether this effect is caused by a manufacturing impurity, or because the insulin is not folded in the same way as in the human pancreas, or because the molecule is simply too physiologically active to be taken in large discrete doses rather than internal, continuously released amounts calibrated by a normal metabolism, is unknown.
The problem is that Eli Lilly, which holds the patent on the extraction of insulin from animal pancreases, no longer produces pig or cow insulin. Hypersensitive diabetics for whom Eli Lillys standard treatment is dangerous no longer have an easily obtainable alternative supply. The most widely known and contentious application of DNA technology to production is in agriculture. The introduction of DNA sequences derived from widely divergent species into agricultural varieties has resulted in a struggle of immense proportions in both North America and Europe. The proximate purpose of the creation of varieties with DNA introduced from other kinds of organisms is to produce agricultural crops with novel features that cannot be obtained by the usual methods of selection because the relevant genes are not present in the agricultural species. The benefits to farmers, consumers and commercial seed producers vary considerably from case to case, although in every case the ultimate goal of the commercial breeder is increased profit and the protection of their property rights. There are four cases to be distinguished. First there is the introduction of pest and disease resistance, as in the introduction of the BT protein from Bacillus thuringiensis into maize. This is intended to reduce the labor, chemicals and machinery needed by the farmer for pest control. Some of the cost reduction is lost in the higher price of the commercial seed, but saving labor is important to farmers. Second, there is creation of varieties that are resistant to herbicides used to control weeds. The best-known examples are the Roundup Ready varieties produced by Monsanto, designed to coerce farmers into purchasing Monsantos general herbicide (Roundup) as well as their seed. The supposed advantage to the farmer is a reduction in machinery and labor involved in tillage, but again the cost saving is reduced by the increased price of seed. The third case is the pure protection of property rights of the seed producers with no benefit to farmers or consumers. The most infamous example is the attempted introduction of Terminator technology by the Delta Pine and Land Company, which was later purchased by Monsanto. Terminator seed varieties will germinate and produce sterile crops, thus forcing farmers to purchase commercial seed anew every year. (It should be noted that this technology, of no advantage to farmers or consumers, was produced in cooperation with the U.S. Department of Agriculture). The fourth case is the introduction into mass produced field crops of DNA coding for particular compounds normally only produced by specialty species. This technology has the potential to destroy much of the economy of Third World countries that are dependent on the export of agriculturally produced commodities. An example is the transfer into rape seed, a widely grown crop in North America, of the DNA coding for palmitic acid oils that are used in industrial processes. Normally these oils are extracted from oil palm seed grown in Southeast Asia.
While much of the opposition to transgenic agriculture has been based on the unnaturalness of the process, this objection misses the point. No agricultural variety is natural,but is the product of centuries of gradual, cumulative genetic modification from its wild ancestors to produce varieties that are utterly different from the ancestral forms. Moreover, crosses between different species have been a standard method of plant breeding for more than a century. The real issue is that DNA technology provides a powerful tool for the control of agricultural production by monopolistic producers of the inputs into agriculture with no ultimate advantage either to farmers or consumers and with the possibility of destroying entire national agricultural economies. All of the elements that characterize the era of DNA have in common an underlying simplistic view of living organisms. By concentrating in practice and in theory on the properties and functions of a single molecule, biologists, both in their professional work and in their public statements, reduce the extraordinary complexity of life processes to the structure and metabolism of DNA. This emphasis ignores the intricate and multiple ways in which organisms are built and function. The intricacy is a consequence of the structural and metabolic functions of proteins and the interactions of those proteins with each other, with other molecules, and with the environment in the course of development.
Moreover, for human life, no account at all is taken of the role of social and economic processes in determining health and life activities and molding the processes of industrial and agricultural production. We cannot understand our size, shape and internal functioning except by a detailed understanding of the extremely complex web of interactions among the various molecules which form the body in concert with influences exerted by our environments. We cannot understand the origin and development of our mental states except by an understanding of the map of nervous connections and how that map is influenced by experience. We cannot understand why agricultural technology develops in particular directions if we do not understand the social, political and economic interactions that drive technological innovation. The bottom line is that life in all its manifestations is complex and messy and cannot be understood or influenced by concentrating attention on a particular molecule of rather restricted function.
Gene Watch is published by the Council for Responsible Genetics - http://www.gene-watch.org
Council for Responsible Genetics, 5 Upland Rd. Suite 3, Cambridge, MA 02140, Tel: 617) 868-0870