Unravelling the DNA myth

Barry Commoner

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] ANDi, 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.

Reference for this article: GRAIN, 2003, Unravelling the DNA myth, Seedling, July 2003, GRAIN

Website link: www.grain.org/seedling/seed-03-07-2-en.cfm

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