Unraveling the DNA Myth

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 activist Science of the Century, and it stands poised to assume godlike powers of creation, calling forth artificial forms of life rather than undiscovered elements and subatomic particles. 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 Dolly¹, the fatherless sheep cloned directly from her mother's cells; these techniques have now been applied, unsuccessfully, to human cells. ANDi², a photogenic rhesus monkey, recently was born carrying the gene of a luminescent jellyfish. Pigs now carry a gene for bovine growth hormone and show significant improvement in weight gain, feed efficiency, and reduced fat.³ Most soybean plants grown in the United States have been genetically engineered to survive the application of powerful herbicides. Corn plants now contain a bacterial gene that produces an insecticidal protein rendering them poisonous to earworms.⁴

Our leading scientists and scientific entrepreneurs (two labels that are increasingly interchangeable) assure us that these feats of technological prowess, though marvelous 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.⁵ ANDi, perversely, has failed to glow like a jellyfish. Genetically modified pigs have a high incidence of gastric ulcers, arthritis, cardiomegaly (enlarged heart), 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, as a matter of fact the plant's own genetic system has been unwittingly altered as well, with potentially dangerous consequences.⁶ The list of malfunctions gets little notice; biotechnology companies are not in the habit of publicizing 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 characterize 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 DNA genes---should fully account for its characteristic assemblage of inherited traits.⁷ The premise, unhappily, is false. Tested between 1990 and 2001 in one of the largest and most highly publicized 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 last February) signaled 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"⁸ 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.

Since Crick first proposed it forty-four years ago, the central dogma has come to dominate biomedical research. Simple, elegant, and easily summarized, it seeks to reduce inheritance, a property that only living things possess, to molecular dimensions: The molecular agent of inheritance is DNA, deoxyribonucleic acid, a very long, linear molecule tightly coiled within each cell's nucleus. 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.

Guided by Crick's theory, the Human Genome Project was intended to identify and enumerate all of the genes in the human body by working out the sequence of the three billion nucleotides in human DNA. 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." Walter Gilbert, one of the project's earliest proponents, famously observed that the 3 billion nucleotides found in human DNA would easily fit on a compact disc, to which one could point and say, "Here is a human being; it's me!"⁹ President Bill Clinton described the human genome as "the language in which God created life."¹⁰ How could the minute dissection of human DNA into a sequence of 3 billion nucleotides support such hyperbolic claims? Crick's crisply stated theory attempts to answer that question. It hypothesizes a clear-cut chain of molecular processes that leads from a single DNA gene to the appearance of a particular inherited trait. The explanatory power of the theory is based on an extravagant proposition: that the DNA genes have unique, absolute, and universal control over the totality of inheritance in all forms of life.

In order to control inheritance, Crick reasoned, genes would need to govern the synthesis of protein, since proteins form the cell's internal structures and, as enzymes, catalyze the chemical events that produce specific inherited traits. The ability of DNA to govern the synthesis of protein is facilitated by their similar structures-both are linear molecules composed of specific sequences of subunits. A particular gene is distinguished from another by the precise linear order (sequence) in which the four different nucleotides appear in its DNA. In the same way, a particular protein is distinguished from another by the specific sequence of the twenty different kinds of amino acids of which it is made. The four kinds of nucleotides can be arranged in numerous possible sequences, and the choice of any one of them in the makeup of a particular gene represents its "genetic information" in the same sense that, in poker, the order of a hand of cards informs the player whether to bet high on a straight or drop out with a meaningless set of random numbers.

Crick's "sequence hypothesis" neatly links the gene to the protein: the sequence of the nucleotides in a gene "is a simple code for the amino acid sequence of a particular protein."¹¹ This is shorthand for a series of well-documented molecular processes that transcribe the gene's DNA nucleotide sequence into a complementary sequence of ribonucleic acid (RNA) nucleotides that, in turn, delivers the gene's code to the site of protein formation, where it determines the sequential order in which the different amino acids are linked to form the 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-that is, the genome must therefore represent the whole of a person's inheritance, which distinguishes a person from a fly, or Walter Gilbert from anyone else. 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 includes a second doctrine, which he originally called the "central dogma" (though this term is now generally used to identify his theory as a whole). The hypothesis is typical Crick: simple, precise, and magisterial. "Once (sequential) information has passed into protein it cannot get out again."¹² This means that genetic information originates in the DNA nucleotide sequence and terminates, unchanged, in the protein amino acid sequence. The pronouncement is crucial' to the explanatory power of the theory 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."¹³

Crick was aware of the brashness of his bet, for it was known that in living cells proteins come into promiscuous molecular contact with numerous other proteins and with molecules of DNA and RNA. His insistence that these interactions are genetically chaste was designed to protect the DNA's genetic message-the gene's nucleotide sequence-from molecular intruders that might change the sequence or add new ones as it was transferred, step by step, from gene to protein and thus destroy the theory's elegant simplicity.

Last February, 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."¹⁴ 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-hardly an adequate basis for distinguishing among "life as a fly, a carrot, or a man." In fact, an inattentive reader of genomic CDs might easily mistake Walter Gilbert for a mouse, 99 percent of whose genes have human counterparts.¹⁵

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 the "ultimate description of life" than the genes, on their own, can tell us.

Scientists and journalists somehow failed to notice what had happened. The discovery that the human genome is not much different from the roundworm's led Dr. Eric Lander, one of the leaders of the project, to declare that humanity should learn "a lesson in humility."17 In the New York Times, Nicholas Wade merely observed that the project's surprising results will have an "impact on human pride" and that "human self-esteem may be in for further blows" from future genome analyses, which had already found that the genes of mice and men are very similar.¹⁶

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 is "so discordant with our predictions" was described, in full, last February in Science as follows: "nearly 4096 of human genes are alternatively spliced."¹⁸ 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 the distinctive nucleotide sequence of a single gene encodes the amino acid sequence of a single protein. According to Crick's sequence hypothesis, the gene's nucleotide sequence (i.e., its "genetic information") is transmitted, altered in form but not in content, through RNA intermediaries, to the distinctive amino acid sequence of a particular protein. In alternative splicing, however, 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.

The molecular events that accomplish this genetic reshuffling are focused on a particular stage in the overall DNA-RNA-protein progression. It occurs when the DNA gene's nucleotide sequence is transferred to the next genetic carrier-messenger RNA. A specialized group of fifty to sixty proteins, together with five small molecules of RNA-known as a "spliceosome"-assembles at sites along the length of the messenger RNA, where it cuts apart various segments of the messenger RNA. Certain of these fragments are spliced together into a number of alternative combinations, which then have nucleotide sequences that differ from the gene's original one. These numerous, redesigned messenger RNAs govern the production of an equal number of proteins that differ in their amino acid sequence and hence in the inherited traits that they engender. For example, when the word TIME is rearranged to read MITE, EMIT, and ITEM, three alternative units of information are created from an original one. Although the original word (the unspliced messenger RNA nucleotide sequence) is essential to the process, so is the agent that performs the rearrangement (the spliceosome).¹⁹

Alternative splicing can have an extraordinary impact on the gene/protein ratio. We now know that a single gene originally believed to encode a single protein that occurs in cells of the inner ear of chicks (and of humans) gives rise to 576 variant proteins, differing in their amino acid sequences.²⁰ 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.²¹

Alternative splicing thus has a devastating impact on Crick's theory: it breaks open the hypothesized isolation of the molecular system that transfers genetic information from a single gene to a single protein. By rearranging the single gene's nucleotide sequence into a multiplicity of new messenger RNA sequences, each of them different from the unspliced original, alternative splicing can be said to generate new genetic information. Certain of the spliceosome's proteins and RNA components have an affinity for particular sites and, binding to them, form an active catalyst that cuts the messenger RNA and then rejoins the resulting fragments. The spliceosome proteins thus contribute to the added genetic information that alternative splicing creates. But this conclusion conflicts with Crick's second hypothesis-that proteins cannot transmit genetic information to nucleic acid (in this case, messenger RNA)--and shatters the elegant logic of Crick's interlocking duo of genetic hypotheses.²²

The discovery of alternative splicing also bluntly contradicts the precept that motivated the genome project. It nullifies the exclusiveness of the gene's hold on the molecular process of inheritance and disproves the notion that by counting genes one can specify the array of proteins that define the scope of human 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. Perhaps this is why the crucial role of alternative splicing seems to have been ignored in the planning of the project and has been obscured by the cunning manner in which its chief result has been reported. Although the genome reports do not mention it, alternative splicing was discovered well before the genome project was even planned-in 1978 in virus replication²³, and in 1981 in human cells.²⁴ 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.²⁵ Thus, the shortfall in the human gene count could-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-or perhaps God speaking through it would tell us who we are.²⁶

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.²⁷

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 fertilized egg, the egg cell and the multitude of succeeding cells divide in two. Each such division is preceded by a doubling of the cell's DNA; two new DNA strands are produced by attaching the necessary nucleotides (freely available in the cell), in the proper order, to each of the two DNA strands entwined in the double helix. As the single fertilized egg cell grows into an adult, the genome is replicated many billions of times, its precise sequence of three billion nucleotides retained with extraordinary fidelity.²⁸ 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 rube, 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 synthesized DNA.²⁹

Thus, in the living cell the gene's nucleotide code can be replicated faithfully only because an array of specialized proteins intervenes to prevent most of the errors-which DNA by itself is prone to make-and to repair the few remaining ones. Moreover, it has been known since the 1960s that the enzymes that synthesize DNA influence its nucleotide sequence. 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 is the following: 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. The biochemical events that give rise to genetic traits-for example, enzyme action that synthesizes a particular eye-color 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 they come in contact with a special type of "chaperone" protein that property folds them.

The importance of these chaperones has been underlined in recent years by research on degenerative brain diseases that are caused by "prions," research that has produced some of the most disturbing evidence that the central dogma is dangerously misconceived.30 Crick's theory holds that biological replication, which is essential to an organism's ability to infect another organism, cannot occur without nucleic acid. Yet when scrapie, the earliest known such disease, was analyzed biochemically, no nucleic acid-neither DNA nor RNA-could be found in the infectious material that transmitted the disease. In the 1980s, Stanley Prusiner confirmed that the infectious agents that cause scrapie, mad cow disease, and similar very rare but invariably fatal human diseases are indeed nucleic-acid-free proteins (he named them prions), which 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 shape. 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.³¹

The prion's unusual behavior raises important questions about the connection between a protein's amino acid sequence and its biochemically active, folded-up structure. Crick assumed that the protein's active structure is automatically determined by its amino acid sequence (which is, after all, the sign of its genetic specificity), so that two proteins with the same sequence ought to be identical in their activity. The prion violates this rule. In a scrapie-infected sheep, the prion and the brain protein that it refolds have the same amino acid sequence, but one is a normal cellular component and the other is a fatal infectious agent. This suggests 'that the protein's folded-up configuration is, to some degree, independent of its amino acid sequence and therefore determined, in part, by something other than the DNA gene that governed the synthesis of that sequence. And since the prion protein's three-dimensional shape is endowed with transmissible genetic information, it violates another fundamental Crick precept as well-the forbidden passage of genetic information from one protein to another.* Thus, what is known about the prion is a somber warning that processes far removed from the conceptual constraints of the central dogma are at work in molecular genetics and can lead to fatal disease.**

** In 1997, when Prusiner was awarded the Nobel Prize, several scientists publicly denounced the decision because that the prion, through infectious, is a nucleic-acid-free protein contradicted the central dogma and was too controversial to warrant the award. This bias impeded not only scientific progress but human health as well. Although Prusiner's results explained why the prion's structure resists them, conventional sterilization procedures were nevertheless relied on to fight mad cow disease in Britain, with fatal results.

By the mid 1980s, therefore, long before the $3 billion Human Genome Project was funded, and long before genetically modified 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 net outcome is that no single DNA gene is the sole source of a given protein's genetic information and therefore of the inherited trait.

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 multibillion-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 corn 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. In only the last five years such transgenic crops have taken over 68 percent of the U.S. soybean acreage, 26 percent of the corn acreage, and more than 69 percent of the cotton acreage.³²

That the industry is guided by the central dogma was made explicit by Ralph W.F. Hardy, president of the National Agricultural Biotechnology Council and formerly director of life sciences at DuPont, a major producer of genetically engineered 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)."³³ The outcome of transferring a bacterial gene into a corn 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 Reaganesque version of the central dogma is the scientific foundation upon which each year billions of transgenic plants of soybeans, corn, 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 corn, soybeans, and cotton, are known to possess proteins that repair DNA miscoding;³⁴ proteins that alternatively splice messenger RNA and thereby produce a multiplicity of different proteins from a single gene;³⁵ and proteins that chaperone the proper folding of other, nascent proteins.³⁶ 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.³⁷

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. The Monsanto Company 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."³⁸ 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.³⁹

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.⁴⁰ The consequences of such changes cannot be foreseen. The likelihood in genetically engineered 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 United States.

The degree to which such disruptions do occur in genetically modified 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. Yet this information is the only way to confirm that the transferred gene does in fact yield the theory-predicted product. 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 genetically engineered 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 genetically engineered 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.⁴¹ 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 recognize 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 die 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 offense, 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 centered 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 commercialized 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 genetically engineered 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.

How about something from the American Spectator?

The genome isn't a code and we can't read it

By Tom Bethell

The principal actors had appeared in the White House last June -- Francis Collins of the National Human Genome Research Institute, and J. Craig Venter of Celera Genomics. Now they were back with a supporting cast and a more detailed analysis, in the Capital Hilton Hotel, with the TV lights glinting off the ballroom chandeliers, 250 journalists packed into the hot room, and James Watson of DNA fame on hand to take a bow. There would be one more blaze of publicity about the project to decipher the human genome. The new findings were about to be published in long articles, with a comical abundance of co-authors, in the journals Nature and Science.

New Mexico's Sen. Pete Domenici, an early and eager supporter of the project on Capitol Hill, received a vigorous round of applause. He was sitting next to Watson, and in his remarks Domenici said that Watson had just whispered to him, "You must say that this project was congressionally driven." The senator added, "And that's true…. This project, in terms of the U.S. government, was truly started in the Congress." One of the new buildings going up on the "campus" of the National Institutes of Health will surely be named after Domenici.

One news item was prominently reported. The number of human genes is now believed to be about 30,000, one-third or even one-fourth the number recently estimated. At first this was played as the familiar object lesson in humility for us self-satisfied anthropoids. We thought we were at the center of the universe. Silly old us! Now, our supposedly overweening pride receives another setback. For we have "only twice as many genes as a fruit fly, or a lowly nematode worm," said the ever-so-humble Eric Lander, head of genome research at the NIH-funded Whitehead Institute in Cambridge, Mass. "What a comedown!" The journalists roared on cue. That would be the sound-bite for National Public Radio, you knew, and the Washington Post would publish it the next day.

There was, however, a more disturbing implication. It took a few days to sink in. There followed a kind of appalled silence, and then the alarm bells began to ring, if only faintly. "The way these genes work must therefore be far more complicated than the mechanism long taught," whispered the Washington Post. The alarms will grow louder. For if what Craig Venter said is true -- and it was accepted by James Watson when I spoke to him immediately after the press conference -- the genetics textbooks will have to be rewritten and the therapeutic breakthroughs promised by the map of the genome may not come for decades, if ever. No one at the press conference disputed Venter's claims. That included the editors of Science and Nature, who made brief remarks.

Craig Venter's opening statement contained the bombshell. Since last June, he said:

"[O]ur understanding of the human genome has changed in the most fundamental ways. The small number of genes -- some 30,000 -- supports the notion that we are not hard wired. We now know the notion that one gene leads to one protein, and perhaps one disease, is false.

"One gene leads to many different protein products that can change dramatically once they are produced. We know that some of the regions that are not genes may be some of the keys to the complexity that we see in ourselves. We now know that the environment acting on our biological steps may be as important in making us what we are as our genetic code."

The old dogma of genetics, prevailing in the textbooks to this day, was that one gene made one protein. George Beadle and Edward Tatum won the Nobel Prize in 1958 for their formulation of this doctrine. Usually it is put, "one gene, one enzyme," but an enzyme is a special kind of protein, and today it is most often expressed as "one gene, one protein." Now, in front of some of the country's most eminent molecular biologists, Venter was telling us that there may be ten times as many proteins as genes. "Perhaps 300,000 proteins," he said at one point.

The genome consists of a string of four nucleotide bases, symbolized by the letters A, C, G, and T, and the string is over 3 billion letters long. Over 98 percent of the genome appears to be inactive, consisting of "non-coding regions," and some dismiss it as "junk DNA." (Not Collins or Venter, however, who say we just don't know what it does.) The intermittent "coding" segments along the way are called genes, and they give instructions for the manufacture of the body's proteins. In people with heritable diseases, some of those proteins are defective. So what the science of genomics would do was find the defective genes along the genome string by comparing the nucleotide sequence of sick people with the genomes of well people. If the defect could then be corrected, the protein made by that gene would be restored to its healthy state. That is the underlying theory of gene therapy.

Seemingly intractable problems have arisen, however, and they have been well known to the gene hunters for several years. There are indeed diseases that are caused by a simple defect in the genome -- just as in a rare case a single typographical error will radically alter the meaning of a text. (But most "typos" are immediately apparent as such and cause no defect in the reader's understanding.) The genetic character of these diseases -- sickle cell anemia, cystic fibrosis, and Huntington's Disease are among the best known -- was initially established not by searching the genome but by tracing them in family histories. This showed their predictably inheritable character. When both parents carry a copy of the "typo," there is a good chance that their child will have the disease.

With many of these diseases the defective gene has indeed been discovered. The problem is that a cure is still no closer. "We've had our gene since 1989," Dr. Robert Beall, president of the Cystic Fibrosis Foundation told the Wall Street Journal last June. Yet no gene therapy for the 30,000 cystic fibrosis sufferers has yet emerged. In other words, while we have waited for the "breakthrough" in mapping the human genome, so that we may cure diseases, this "breakthrough" already occurred for cystic fibrosis a dozen years ago, to no effect. In the case of sickle cell anemia, the genetic defect has been known for over 30 years, yet the disease can only be treated by non-genetic therapy. It is the same with all the other heritable diseases. Because the genetic defect is in the germ-line, the "typo" occurs in every one of the one hundred trillion cells in the body. The problem for genetic engineering is how to get the "corrected" gene into enough cells to make a difference. It's an unsolved problem.

True genetic diseases are rare, appearing in only one or two percent of all births. Therefore, it is said, they "do not fit the business model." Nonetheless, millions of dollars were spent by medical research institutions to locate these genetic defects on the genome. Still, nothing has come of these findings, beyond the patenting of screening tests, which can be used to warn couples that any of their children might have a one-in-four chance of being born with a disease.

But the field of biotechnology can expect little or no payoff from diseases that affect anywhere from a handful to a few thousand people worldwide. As a result, some years back the focus of gene therapy quietly shifted toward far more common and potentially highly profitable diseases; in particular cancer, heart disease, AIDS, and Alzheimer's. Dr. Collins told us that his own lab at NIH is engaged in a "huge and very complicated" search for genes for adult-onset diabetes, the latest cause celebre for gene hunters.

All along, however, the idea that these very widespread conditions are caused by the sort of clear, isolated genetic "misspellings" that seem to explain sickle cell or cystic fibrosis was entirely speculative. In the case of cancer, nothing definite has been found after a 20-year search. Cancer researchers will tell you otherwise and mean it, but it is not at all reassuring to learn that they claim to have found over one hundred "oncogenes" that "predispose" us to, or are "associated with" cancer; and that about 30 defective "tumor suppressor" genes have also been located. That is far too many to be useful, and therapeutic benefits have been elusive. Some of these genes have already been patented, which means that companies can, once again, charge a monopoly price to "screen for" the presence of these oncogenes. But their causal role has never been established and probably never will be. There has been a concerted effort to blur the difference between those rare diseases that are plainly and predictably heritable, and the common ones that are not.

Contrary to what the headlines say, the genome has not yet been decoded. It might never be, as the genome now does not appear to be a code at all in the conventional sense. It turns out that genes are not simple "strings," each one encoding for one message, but are combinations of separated segments along the genome. Between them lie intervening segments which can be cut out by the cell, as it translates DNA into proteins, and the relevant or coding parts (called exons, as opposed to the intervening parts, which are called introns) can be put together in numerous different ways. Gene therepy send different messages and make a variety of proteins as the occasion demands.

Imagine that an intelligence service were to discover some unintelligible messages being sent by a spy. At first the intelligence agents naturally assume they are looking at a code. They assume the task of decoding will be straightforward. But on closer analysis it turns out that the message means one thing if the signal has been received and acted upon, another thing if it has been received and not acted upon, another thing if the receiving apparatus is not switched on, and so on. Rather than just a code the message is a bit like a set of rules for a rather complex interactive game. There are feedback loops, and circuits within circuits, and a lot of things happening inside the cell but outside the genome, in the unfashionable realm of cytogenetics. NIH-funded geneticists don't even want to think about that, because they thought that by sticking to the four nucleotide bases, they had the problem neatly "digitized." Computers would hum away unaided, 24 hours a day, and unravel the mysteries for them while they slept.

We should have known that it would not be so simple. Successful biological systems resist simple analysis for the very same reason that they are successful. Every time we gain greater knowledge of any such system we discover that it is far more complicated, redundant, self-healing, adaptable, and resistant to "single points of failure" than it first appeared. If the functioning of the genome were as simple -- and therefore easily manipulated -- as the advocates of the genome project have been implying, it would be impossibly fragile. Significant genetic defects would be far more common, assuming any organism based on such an easily cracked and therefore easily corrupted code could survive in the first place.

In the case of genetics, the illusion of simplicity arises in large part from the genius of Mendel's insight in constructing the original genetic metaphor. Studying peas in a monastery garden, Gregor Mendel sorted them by their outward traits (size, shape, and color), and, observing that these traits appeared in the regular ratio of three to one, he ingeniously posited internal "factors" which occurred in "dominant" and "recessive" form. These were the genes. No one actually observed them, for no one then had the microscopes or the machinery to do so. But the theory was that when the parental contributions to reproduction are combined, one set of genes from each parent, the factors or genes do not "blend" but live on internally, one "dominating" the other in the expression of the trait that each gene controls. One gene, one trait. That was how a gene was defined. Hence, it was said, we have genes "for" this trait or for that; genes for skin color, for example. Where blending is obviously real, as in the case of skin color (a black mother and a white father have a child of intermediate color), geneticists could just say that there were several genes "for" that trait, and one or more from each parent was expressed in the child. No one has yet located the "skin color" genes on the DNA, incidentally.

Mendel made no claims about the structure of genes or how they might accomplish their task. The Mendelian gene was a hypothetical construct, possibly standing for an infinitely more complex set of processes.

Along came Thomas Hunt Morgan at Columbia University. The chromosomes had been discovered and in 1902 Walter Sutton noticed that they came in pairs -- a convenient fit with the dominant-recessive understanding of the gene. Morgan set out to "map" the chromosomes, which is where the genes would have to be located. He didn't get very far with that but he won the Nobel for his valiant effort. The word Drosophila began to appear in the newspapers. Hermann J. Muller zapped a lot of fruit flies with x-rays and heritable body changes were observed -- more Nobels for that. Enter Watson and Crick. Their discovery of the double helical structure of DNA worked nicely too, because it showed how a complex message could be replicated. "Genes," henceforth, would be thought of as nucleotide sequences along the string of DNA, which in turn was packed inside the chromosomes.

This reformulated gene was not an entirely satisfactory fit with the old Mendelian gene. But labels are powerful. In the decades since, genetics has largely consisted of an awkward attempt to combine under one name the Mendelian gene of the late 19th century and the DNA of the 20th century.

What DNA actually did was carry the instructions for making proteins, as we have seen. And proteins were not the same thing as the visible and outward bodily traits, such as chins and noses and skin color, that the Mendelian genes were said to make. Still, it was close enough for government work, and university work; it sustained the bandwagon of forward progress, and the truth was that no one really had much more than a hazy knowledge of these things anyway. And there was this -- chins and noses and skin pigments were made of protein, so the different versions of the gene could be cobbled together, rather like a pantomime horse. Actually we had Mendel and Morgan and Watson and Crick all galumphing around onstage together under this gene umbrella, and it held together pretty well throughout the 20th century.

So the idea of one gene, one protein was a carry-over from the earlier one gene, one trait formulation. And in their work with bread molds in the 1940s, Beadle and Tatum had seemed to confirm the idea that a gene is something that performs a single task. Now, it begins to look as though the gene is going to have to be rethought completely. It is a task that has long been postponed. The pantomime horse has begun to look ridiculous. Not only has our understanding of the gene become massively more complicated, the analysis of protein structure, which now moves to the fore, is truly a daunting prospect for biology. Proteins have 20 building blocks, not four, and are arrayed in three dimensions, not along one, like genes.

Both Celera Genomics and the government-funded consortium have an interest in sustaining the old "breakthrough" refrain; Venter to attract investors, Collins to keep Congress happy. According to a spokesman at NIH's National Human Genome Research Institute in Bethesda, federal appropriations for the human genome project have totaled $1.5 billion to date. As government projects always do, it started small, with $10.7 million appropriated for the Department of Energy and $17.2 million for NIH, in 1988. "Frankly, it was a gamble that we would be able to expand the [research-dollar] pie," said Maynard Olson, head of the publicly funded genome center at the University of Washington in Seattle. But expand it they did. The amount appropriated in fiscal year 2000 was $271 million, and the estimate for this year is $291 million. In the process, a whole new institute at NIH was created. "A lot of people don't mention those numbers," said the NIH spokesman. In contrast, at the time of the White House announcement last June, Celera said that it had spent a total of $200 million on the project. The government is now on a genome-spending path that will consume more dollars every year than Celera has spent overall.

And yet it was from Celera that the new understanding came, not from those with government funds. The contrived truce between the participants concealed this: It was Celera that was willing to advance the new insight even though it may end up undermining the company's original premise and business plan. (And it was the Whitehead Institute's Lander who had tried to stop Science from publishing Celera's article.) With the real world of investors to consider, Celera can less easily survive in the cushioned, sometimes make-believe world that government science has fashioned for itself. If there was bad news, Celera needed it sooner rather than later. Thus armed, perhaps Venter can adjust the business model.

Nonetheless, Celera's message is not likely to comfort investors. Gene therapy holds out less promise as a result of this new understanding. At the press conference, a journalist asked Francis Collins if the smaller number of genes would make medical advances easier or more difficult. "I would say easier," he said. Every gene search is like trying to find a needle in a haystack. "Guess what? The haystack just got three times smaller." But when another journalist asked a similar question about the genes interacting combinatorially, Collins retreated from the haystack metaphor. The straw interacts with itself, and the needle has other objects bumping into it, he allowed. Craig Venter said more simply that when you consider there is maybe a "tenfold expansion" in the number of proteins compared to the number of genes, it "does indicate increased complexity."

Celera will no doubt continue to sell its genome information to the big research institutions, to the pharmaceuticals, and to other biotechs -- for a while at least. And the biotechs with patents will continue to charge high prices to screen for "predisposing" genes; or for the rare but real disease-causing defects.

To some biotechs the new announcement came as something of an embarrassment. As Andrew Pollack pointed out in the New York Times: "Incyte Genomics advertises access to 120,000 human genes, including 60,000 not available from any other source. Human Genome Sciences says it has identified 100,000 human genes, and Double Twist 65,000 to 105,000. Affymetrix sells DNA-analysis chips containing 60,000 genes." Some of these genes have already been patented, but "if genes are not the whole story," Pollack added, "it also means those patents could be worth less." Or worthless. Venter told the London Observer that the head of a biotech company had phoned him in some distress because he had already done a deal with SmithKline Beecham to sell them the details of 100,000 genes. "Where am I going to get the rest?" the man asked. How long before someone starts comparing genes to tulips?

Last June, under the headline "50,000 Genes and we Know Them All (Almost)," David Baltimore, the president of Caltech and the winner of the 1975 Nobel Prize for medicine, wrote that "humans have no more genetic secrets; our genes are a book open to all to read." But in the issue of Nature announcing the new analysis of the human genome he wrote more soberly:

"We wait with bated breath to see the chimpanzee genome. But knowing now how few genes humans have, I wonder if we will learn much about the origins of speech, the elaboration of the frontal lobes and the opposable thumb, the advent of upright posture, or the sources of abstract reasoning ability, from a simple genomic comparison of human and chimp. It seems likely that these features and abilities have mainly come from subtle changes…that are not now easily visible to our computers, and will require much more experimental study to tease out. Another half century of work by armies of biologists may be needed before this key step of evolution is fully elucidated."

The old dream of reducing biology to physics, or of believing that something simple -- four nucleotides on a string -- could explain the vast complexity of the human (or any other) body, has received a serious blow. A lot of the companies involved in this search for meaning in the genome were inordinately impressed with the idea that, with just four "building blocks," an abundance of computing power was all it would take. Strings of code with tens of millions of bases could be searched and analyzed in hours. Now, we may be looking at the beginning of the end for genomics. The word "proteomics" is already beginning to appear in science-journal headlines.

Writing in the New York Times, Stephen Jay Gould says that we may be now liberated from the "simplistic and harmful idea" that each aspect of our being, "either physical or behavioral, may be ascribed to the action of a particular gene ‘for' the trait in question." The collapse of the doctrine of one gene, one protein, he added, "and one direction of causal flow from basic codes to elaborate totality, marks the failure of reductionism for the complex system that we call biology…. Organisms must be explained as organisms, not as a summation of genes." I think he is right.

Francis Crick was invited to attend the event. He wasn't feeling up to it -- he is 84 -- so he sent along a videotaped message instead. It was played that afternoon at the packed, 500-seat Masur Auditorium at NIH. "We foresaw very little of what happened in molecular biology," Crick said. But the impact of the latest development on medicine "will be enormous," and we can only hope that "it will bring us on balance more good than evil." Watson then stood up before the NIH employees and with his customary tactlessness noted that Crick was "in perfect health, as you could see." He just doesn't like to travel. "He is one of the 20 percent who has had a heart bypass and whose brain isn't affected," Watson added.

After the press conference, I spoke to Watson briefly. A crowd was clustered around him, some of the journalists getting him to sign the issue of Nature in their press packets. A black woman asked him how long before we would see medical results from the genome. He said something about our children, then corrected himself: "Our grandchildren will have better lives because of what we are doing," he said. "You're worried about breast cancer," he said to the woman. "I'm worried about senility." He is 73. Forty-eight years have passed since his publication of the double helix with Crick. I asked him if the two concepts of the gene could continue to coexist. He said he didn't think they differed all that much. He analogized the shift in understanding to Einstein's modification of Newtonian physics. "We have relativity but it doesn't affect the way artillery works," he said. Newton was still largely right. When I asked Venter the same question, he gave me to understand that this would take too long to discuss, but that the question was pointing us "in the right direction."

I asked Watson if one gene can give rise to ten proteins. "Some genes can give rise to 50 different proteins," he said. No problem! He was unruffled, content, still in control at mission central. The new knowledge about genes and proteins would be smoothly integrated into the received wisdom of molecular biology, apparently. The higher councils were taking it all in stride. There was no cause for alarm. But those who would like to put the news to medical use are furrowing their brows.

Tom Bethell is a senior editor of The American Spectator.

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