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The Dream of the Human Genome

The Code of Codes: Scientific and Social Issues in the Human Genome Project

edited by Daniel J. Kevles, edited by Leroy Hood
Harvard University Press, 397 pp., $29.95

Mapping the Code: The Human Genome Project and the Choices of Modern Science

by Joel Davis
Wiley, 294 pp., $19.95

Genethics: The Ethics of Engineering Life

by David Suzuki, by Peter Knudtson
Harvard University Press, 372 pp., $12.95 (paper)

Mapping and Sequencing the Human Genome

Committee on Mapping and Sequencing the Human Genome
National Academy Press, 116 pp., $14.95 (paper)

Genome: The Story of the Most Astonishing Scientific Adventure of Our Time—The Attempt to Map All the Genes in the Human Body

by Jerry E. Bishop, by Michael Waldholz
Simon and Schuster, 352 pp., $10.95 (paper)

Exons, Introns, and Talking Genes: The Science Behind the Human Genome Project

by Christopher Wills
Basic Books, 368 pp., $23.00

DNA Technology in Forensic Science

Committee on DNA Technology in Forensic Science
National Academy Press, 200 pp., $24.95 (prepublication copy)

1.

FETISH…An inanimate object worshipped by savages on account of its supposed inherent magical powers, or as being animated by a spirit. (OED)

Scientists are public figures, and like other public figures with a sense of their own importance, they self-consciously compare themselves and their work to past monuments of culture and history. Modern biology, especially molecular biology, has undergone two such episodes of preening before the glass of history. The first, characteristic of a newly developing field that promises to solve important problems that have long resisted the methods of an older tradition, has used the metaphor of revolution. Tocqueville observed that when the bourgeois monarchy was overthrown on February 24, 1848, the Deputies compared themselves consciously to the “Girondins” and the “Montagnards” of the National Convention of 1793.

The men of the first Revolution were living in every mind, their deeds and words present to every memory. All that I saw that day bore the visible impress of those recollections; it seemed to me throughout as though they were engaged in acting the French Revolution rather than continuing it.

The romance of being a revolutionary had infected scientists long before Thomas Kuhn made Scientific Revolution the shibboleth of progressive knowledge. Many of the founders of molecular biology began as physicists, steeped in the lore of the quantum mechanical revolution of the 1920s. The Rousseau of molecular biology was Erwin Schrödinger, the inventor of the quantum wave equation, whose What is Life? was the ideological manifesto of the new biology. Molecular biology’s Robespierre was Max Delbruck, a student of Schrödinger, who created a political apparatus called the Phage Group, which carried out the experimental program. A history of the Phage Group written by its early participants and rich in the consciousness of a revolutionary tradition was produced twenty-five years ago.1

The molecular biological revolution has not had its Thermidor, but on the contrary it has ascended to the state of an unchallenged orthodoxy. The self-image of its practitioners and the source of their metaphors have changed accordingly, to reflect their perception of transcendent truth and unassailable power. Molecular biology is now a religion, and molecular biologists are its prophets. Scientists now speak of the “Central Dogma” of molecular biology, and Walter Gilbert’s contribution to the collection The Code of Codes is entitled “A Vision of the Grail.” In their preface, Daniel Kevles and Leroy Hood take the metaphor with straight faces and no quotation marks:

The search for the biological grail has been going on since the turn of the century, but it has now entered its culminating phase with the recent creation of the human genome project, the ultimate goal of which is the acquisition of all the details of our genome…. It will transform our capacities to predict what we may become….

Unquestionably, the connotations of power and fear associated with the holy grail accompany the genome project, its biological counterpart…. Undoubtedly, it will affect the way much of biology is pursued in the twenty-first century. Whatever the shape of that effect, the quest for the biological grail will, sooner or later, achieve its end, and we believe that it is not too early to begin thinking about how to control the power so as to diminish—better yet, abolish—the legitimate social and scientific fears.

It is a sure sign of their alienation from revealed religion that a scientific community with a high concentration of Eastern European Jews and atheists has chosen for its central metaphor the most mystery-laden object of medieval Christianity.

As there were legends of the Saint Graal of Perceval, Gawain, and Galahad, so there is a legend of the Grail of Gilbert. It seems that each cell of my body (and yours) contains in its nucleus two copies of a very long molecule called deoxyribonucleic acid (DNA). One of these copies came to me from my father and one from my mother, brought together in the union of sperm and egg. This very long molecule is differentiated along its length into segments of separate function called genes, and the set of all these genes is called, collectively, my genome.

What I am, the differences between me and other human beings, and the similarities among human beings that distinguish them from, say, chimpanzees, are determined by the exact chemical composition of the DNA making up my genes. In the words of a popular bard of the legend, genes “have created us body and mind.”2 So when we know exactly what the genes look like we will know what it is to be human, and we will also know why some of us read The New York Review while others cannot get beyond The New York Post. “Genetic variations in the genome, various combinations of different possible genes…create the infinite variety that we see among individual members of a species,” according to Joel Davis in Mapping the Code. Success or failure, health or disease, madness or sanity, our ability to take it or leave it alone—all are determined, or at the very least are strongly influenced, by our genes.

The substance of which the genes are made must have two properties. First, if the millions of cells of my body all contain copies of molecules that were originally present only once in the sperm and once in the egg with which my life began, and if, in turn, I have been able to pass copies to the millions of sperm cells that I have produced, then the DNA molecule must have the power of self-reproduction. Second, if the DNA of the genes is the efficient cause of my properties as a living being, of which I am the result, then DNA must have the power of self-action. That is, it must be an active molecule that imposes specific form on a previously undifferentiated fertilized egg, according to a scheme that is dictated by the internal structure of DNA itself.

Because this self-producing, self-acting molecule is the ground of our being, “precious DNA” must be guarded by a “magic shield” against the “hurricane of forces” that threaten it from the outside, according to Christopher Wills, by which he means the bombardment by the other chemically active molecules of the cell that may destroy the DNA. It is not idly that DNA is called the Grail. Like that mystic bowl, DNA is said to be regularly self-renewing, providing its possessors with sustenance “sans serjant et sans seneschal,” and shielded by its own Knights Templar from hostile forces.

How is it that a mere molecule can have both the power of self-reproduction and self-action, being the cause of itself and the cause of all the other things? DNA is composed of basic units, the nucleotides, of which there are four kinds, adenine, cystosine, guanine, and thymine (A, C, G, and T), and these are strung one after another in a long linear sequence which makes a DNA molecule. So one bit of DNA might have the sequence of units…CAAATTGC…and another the sequence…TATCGCTA,…and so on. A typical gene might consist of 10,000 basic units, and since there are four different possibilities for each position in the string, the number of different possible kinds of genes is a great deal larger than what is usually called “astronomically large.” (It would be represented as a 1 followed by 6,020 zeros.) The DNA string is like a code with four different letters whose arrangements in messages thousands of letters long are of infinite variety. Only a small fraction of the possible messages can specify the form and content of a functioning organism, but that is still an astronomically large number.

The DNA messages specify the organism by specifying the makeup of the proteins of which organisms are made. A particular DNA sequence makes a particular protein according to a set of decoding rules and manufacturing processes that are well understood. Part of the DNA code determines exactly which protein will be made. A protein is a long string of basic units called amino acids, of which there are twenty different kinds. The DNA code is read in groups of three consecutive nucleotides, and to each of the triplets AAA, AAC, GCT, TAT, etc., there corresponds one of the amino acids. Since there are sixty-four possible triplets and only twenty amino acids, more than one triplet matches the same amino acid (the code is “redundant”). Another part of the DNA determines when in development and where in the organism the manufacture of a given protein will be “turned on” or “turned off.” By turning genes on and off in the different parts of the developing organism at different times, the DNA “creates” the living being, “body and mind.”

But how does the DNA recreate itself? By its own dual and self-complementary structure (as the blood of Christ is said to be renewed in the Grail by the dove of the Holy Ghost). The string of nucleic acids in DNA that carries the message of protein production is accompanied by another string helically entwined with it and bound to it in a chemical embrace. This DNA Doppelgänger is matched nucleotide by nucleotide with the message strand in a complementary fashion. Each A in the message is matched by a T on the complementary strand, each C by a G, each A by a C, and each T by an A. (See the upper part of the illustration on the opposite page.)

Reproduction of DNA is, ironically, an uncoupling of the mated strands, followed by a building up of a new complementary strand on each of the parental strings. (See the lower part of the figure.) So the self-reproduction of DNA is explained by its dual, complementary structure, and its creative power by its linear differentiation.

The problem with this story is that although it is correct in its detailed molecular description, it is wrong in what it claims to explain. First, DNA is not self-reproducing, second, it makes nothing, and third, organisms are not determined by it.

DNA is a dead molecule, among the most nonreactive, chemically inert molecules in the living world. That is why it can be recovered in good enough shape to determine its sequence from mummies, from mastodons frozen tens of thousands of years ago, and even, under the right circumstances, from twenty-million-year-old fossil plants. The forensic use of DNA for linking alleged criminals with victims depends upon recovering undegraded molecules from scrapings of long-dried blood and skin. DNA has no power to reproduce itself. Rather it is produced out of elementary materials by a complex cellular machinery of proteins. While it is often said that DNA produces proteins, in fact proteins (enzymes) produce DNA. The newly manufactured DNA is certainly a copy of the old, and the dual structure of the DNA molecule provides a complementary template on which the copying process works. The process of copying a photograph includes the production of a complementary negative which is then printed, but we do not describe the Eastman Kodak factory as a place of self-reproduction.

No living molecule is self-reproducing. Only whole cells may contain all the necessary machinery for “self”-reproduction and even they, in the process of development, lose that capacity. Nor are entire organisms self-reproducing, as the skeptical reader will soon realize if he or she tries it. Yet even the sophisticated molecular biologist when describing the process of copying DNA lapses into the rhetoric of “self-reproduction.” So Christopher Wills, in the process of a mechanical description of DNA synthesis, tells us that “DNA cannot make copies of itself unassisted” (my emphasis) and further that “for DNA to duplicate [itself], the double helix must be unwound into two separate chains….” The reflexive verb formation creeps in unobserved.

Not only is DNA incapable of making copies of itself, aided or unaided, but it is incapable of “making” anything else. The linear sequence of nucleotides in DNA is used by the machinery of the cell to determine what sequence of amino acids is to be built into a protein, and to determine when and where the protein is to be made. But the proteins of the cell are made by other proteins, and without that protein-forming machinery nothing can be made. There is an appearance here of infinite regress (What makes the proteins that are necessary to make the protein?), but this appearance is an artifact of another error of vulgar biology, that it is only the genes that are passed from parent to off-spring. In fact, an egg, before fertilization, contains a complete apparatus of production deposited there in the course of its cellular development. We inherit not only genes made of DNA but an intricate structure of cellular machinery made up of proteins.

It is the evangelical enthusiasm of the modern Knights Templar and the innocence of the journalistic acolytes whom they have catechized that have so fetishized DNA. There are, too, ideological predispositions that make themselves felt. The more accurate description of the role of DNA is that it bears information that is read by the cell machinery in the productive process. Subtly, DNA as information bearer is transmogrified successively into DNA as blueprint, as plan, as master plan, as master molecule. It is the transfer onto biology of the belief in the superiority of mental labor over the merely physical, of the planner and designer over the unskilled operative on the assembly line.

The practical outcome of the belief that what we want to know about human beings is contained in the sequence of their DNA is the Human Genome Project in the United States and, in its international analogue, the Human Genome Organization (HUGO), called by one molecular biologist “the UN for the human genome.”

These projects are, in fact, administrative and financial organizations rather than research projects in the usual sense. They have been created over the last five years in response to an active lobbying effort, by scientists such as Walter Gilbert, James Watson, Charles Cantor, and Leroy Hood aimed at capturing very large amounts of public funds and directing the flow of those funds into an immense cooperative research program.

The ultimate purpose of this program is to write down the complete ordered sequence of A’s, T’s, C’s, and G’s that make up all the genes in the human genome, a string of letters that will be 3 billion elements long. The first laborious technique for cutting up DNA nucleotide by nucleotide and identifying each nucleotide in order as it is broken off was invented fifteen years ago by Allan Maxam and Walter Gilbert, but since then the process has become mechanized. DNA can now be squirted into one end of a mechanical process and out the other end will emerge a four-color computer printout announcing “AGGACTT….” In the course of the genome project yet more efficient mechanical schemes will be invented and complex computer programs will be developed to catalog, store, compare, order, retrieve, and otherwise organize and reorganize the immensely long string of letters that will emerge from the machine. The work will be a collective enterprise of very large laboratories, “Genome Centers,” that are to be specially funded for the purpose.

The project is to proceed in two stages. The first is so-called “physical mapping.” The entire DNA of an organism is not one long unbroken string, but is divided up into a small number of units, each of which is contained in one of a set of microscopic bodies in the cell, the chromosomes. Human DNA is broken up into twenty-three different chromosomes, while fruit flies’ DNA is contained in only four chromosomes. The mapping phase of the genome project will determine short stretches of DNA sequence spread out along each chromosome as positional landmarks, much as mile markers are placed along superhighways. These positional markers will be of great use in finding where in each chromosome particular genes may lie. In the second phase of the project, each laboratory will take a chromosome or a section of a chromosome and determine the complete ordered sequence of nucleotides in its DNA. It is after the second phase, when the genome project, sensu strictu, has ended, that the fun begins, for biological sense will have to be made, if possible, of the mind-numbing sequence of three billion A’s, T’s, C’s, and G’s. What will it tell us about health and disease, happiness and misery, the meaning of human existence?

The American project is run jointly by the National Institutes of Health and the Department of Energy in a political compromise over who should have control over the hundreds of millions of dollars of public money that will be required. The project produces a glossy-paper newsletter distributed free, headed by a coat of arms showing a human body wrapped Laocoön-like in the serpent coils of DNA and surrounded by the motto, “Engineering, Chemistry, Biology, Physics, Mathematics.” The Genome Project is the nexus of all sciences. My latest copy of the newsletter advertises the free loan of a twenty-three minute video on the project “intended for high school age and older,” featuring, among others, several of the contributors to The Code of Codes, and a calendar of fifty “Genome Events.”

None of the authors of the books under review seems to be in any doubt about the importance of the project to determine the complete DNA sequence of a human being. “The Most Astonishing Adventure of Our Time,” say Jerry E. Bishop and Michael Waldholz; “The Future of Medicine,” according to Wingerson; “today’s most important scientific undertaking,” dictating “The Choices of Modern Science,” Joel Davis declares in Mapping the Code.

Nor are these simply the enthusiasms of journalists. The molecular biologist Christopher Wills says that “the outstanding problems in human biology…will all be illuminated in a strong and steady light by the results of this undertaking”; the great panjandrum of DNA himself, James Dewey Watson, explains, in his essay in the collection edited by Kevles and Hood, that he doesn’t “want to miss out on learning how life works,” and Gilbert predicts that there will be “a change in our philosophical understanding of ourselves.” Surely, “learning how life works” and “a change in our philosophical understanding of ourselves” must be worth a lot of time and money. Indeed, there are said to be those who have exchanged something a good deal more precious for that knowledge.

2.

Unfortunately, it takes more than DNA to make a living organism. I once heard one of the world’s leaders in molecular biology say, in the opening address of a scientific congress, that if he had a large enough computer and the complete DNA sequence of an organism, he could compute the organism, by which he meant totally describe its anatomy, physiology, and behavior. But that is wrong. Even the organism does not compute itself from its DNA. A living organism at any moment in its life is the unique consequence of a developmental history that results from the interaction of and determination by internal and external forces. The external forces, what we usually think of as “environment,” are themselves partly a consequence of the activities of the organism itself as it produces and consumes the conditions of its own existence. Organisms do not find the world in which they develop. They make it. Reciprocally, the internal forces are not autonomous, but act in response to the external. Part of the internal chemical machinery of a cell is only manufactured when external conditions demand it. For example, the enzyme that breaks down the sugar, lactose, to provide energy for bacterial growth is only manufactured by bacterial cells when they detect the presence of lactose in their environment.

Nor is “internal” identical with “genetic.” Fruit flies have long hairs that serve as sensory organs, rather like a cat’s whiskers. The number and placement of those hairs differ between the two sides of a fly (as they do between the left and right sides of a cat’s muzzle), but not in any systematic way. Some flies have more hairs on the left, some more on the right. Moreover, the variation between sides of a fly is as great as the average variation from fly to fly. But the two sides of a fly have the same genes and have had the same environment during development. The variation between sides is a consequence of random cellular movements and chance molecular events within cells during development, so-called “developmental noise.” It is this same developmental noise that accounts for the fact that identical twins have different fingerprints and that the fingerprints on our left and right hands are different. A desk-top computer that was as sensitive to room temperature and as noisy in its internal circuitry as a developing organism could hardly be said to compute at all.

The scientists writing about the Genome Project explicitly reject an absolute genetic determinism, but they seem to be writing more to acknowledge theoretical possibilities than out of conviction. If we take seriously the proposition that the internal and external codetermine the organism, we cannot really believe that the sequence of the human genome is the grail that will reveal to us what it is to be human, that it will change our philosophical view of ourselves, that it will show how life works. It is only the social scientists and social critics, such as Kevles, who comes to the Genome Project from his important study of the continuity of eugenics with modern medical genetics; Nelkin, both in her book with Tancredi and in her chapter in Kevles and Hood; and, most strikingly, Evelyn Fox Keller in her contribution to The Code of Codes, for whom the problem of the development of the organism is central.

Nelkin, Tancredi, and Keller suggest that the importance of the Human Genome Project lies less in what it may, in fact, reveal about biology, and whether it may in the end lead to a successful therapeutic program for one or another illness, than in its validation and reinforcement of biological determinism as an explanation of all social and individual variation. The medical model that begins, for example, with a genetic explanation of the extensive and irreversible degeneration of the central nervous system characteristic of Huntington’s chorea, may end with an explanation of human intelligence, of how much people drink, how intolerable they find the social condition of their lives, whom they choose as sexual partners, and whether they get sick on the job. A medical model of all human variation makes a medical model of normality, including social normality, and dictates a therapeutic or preemptive attack on deviance.

There are many human conditions that are clearly pathological and that can be said to have a unitary genetic cause. As far as is known, cystic fibrosis and Huntington’s chorea occur in people carrying the relevant mutant gene irrespective of diet, occupation, social class, or education. Such disorders are rare: 1 in 2,300 births for cystic fibrosis, 1 in 3,000 for Duchenne’s muscular dystrophy, 1 in 10,000 for Huntington’s disease. A few other conditions occur in much higher frequency in some populations but are generally less severe in their effects and more sensitive to environmental conditions, as for example sickle cell anemia in West Africans and their descendants, who suffer severe effects only in conditions of physical stress. These disorders provide the model on which the program of medical genetics is built, and they provide the human interest drama on which books like Mapping our Genes and Genome are built. In reading them, I saw again those heroes of my youth, Edward G. Robinson curing syphilis in Dr. Ehrlich’s Magic Bullet, and Paul Muni saving children from rabies in The Story of Louis Pasteur.

It is said that a wonder-rabbi of Chelm once saw, in a vision, the destruction by fire of the study house in Lublin, fifty miles away. This remarkable event greatly enhanced his fame as a wonderworker. Several days later a traveler from Lublin, arriving in Chelm, was greeted with expressions of sorrow and concern, not unmixed with a certain pride, by the disciples of the wonder-rabbi. “What are you talking about?” asked the traveler. “I left Lublin three days ago and the study house was standing as it always has. What kind of a wonder-rabbi is that?” “Well, well,” one of the rabbi’s disciples answered, “burned or not burned, it’s only a detail. The wonder is he could see so far.” We live still in an age of wonder-rabbis, whose sacred trigram is not the ineffable YWH but the ever-repeated DNA. Like the rabbi of Chelm, however, the prophets of DNA and their disciples are short on details.

According to the vision, we will locate on the human chromosomes all the defective genes that plague us, and then from the sequence of the DNA we will deduce the causal story of the disease and generate a therapy. Indeed, a great many defective genes have already been roughly mapped onto chromosomes and, with the use of molecular techniques, a few have been very closely located and, for even fewer, some DNA sequence information has been obtained. But causal stories are lacking and therapies do not yet exist; nor is it clear, when actual cases are considered, how therapies will flow from a knowledge of DNA sequences.

The gene whose mutant form leads to cystic fibrosis has been located, isolated, and sequenced. The protein encoded by the gene has been deduced. Unfortunately, it looks like a lot of other proteins that are a part of cell structure, so it is hard to know what to do next. The mutation leading to Tay-Sachs disease is even better understood because the enzyme specified by the gene has a quite specific and simple function, but no one has suggested a therapy. On the other hand, the gene mutation causing Huntington’s disease has eluded exact location, and no biochemical or specific metabolic defect has been found for a disease that results in catastrophic degeneration of the central nervous system in every carrier of the defective gene.

A deep reason for the difficulty in devising causal information from DNA messages is that the same “words” have different meanings in different contexts and multiple functions in a given context, as in any complex language. No word in English has more powerful implications of action than “do.” “Do it now!” Yet in most of its contexts “do” as in “I do not know” is periphrastic, and has no meaning at all. While the periphrastic “do” has no meaning, it undoubtedly has a linguistic function as a place holder and spacing element in the arrangement of a sentence. Otherwise, it would not have swept into general English usage in the sixteenth century from its Midlands dialect origin, replacing everywhere the older “I know not.”

So elements in the genetic messages may have meaning, or they may be periphrastic. The code sequence GTAAGT is sometimes read by the cell as an instruction to insert the amino acids valine and serine in a protein, but sometimes it signals a place where the cell machinery is to cut up and edit the message; and sometimes it may be only a spacer, like the periphrastic “do,” that keeps other parts of the message an appropriate distance from each other. Unfortunately, we do not know how the cell decides among the possible interpretations. In working out the interpretive rules, it would certainly help to have very large numbers of different gene sequences, and I sometimes suspect that the claimed significance of the genome sequencing project for human health is an elaborate cover story for an interest in the hermeneutics of biological scripture.

Of course, it can be said, as Gilbert and Watson do in their essays, that an understanding of how the DNA code works is the path by which human health will be reached. If one had to depend on understanding, however, we would all be much sicker than we are. Once, when the eminent Kant scholar, Lewis Beck, was traveling in Italy with his wife, she contracted a maddening rash. The specialist they consulted said it would take him three weeks to find out what was wrong with her. After repeated insistence by the Becks that they had to leave Italy within two days, the physician threw up his hands and said, “Oh, very well, Madam. I will give up my scientific principles. I will cure you today.”

Certainly an understanding of human anatomy and physiology has led to a medical practice vastly more effective than it was in the eighteenth century. These advances, however, consist in greatly improved methods for examining the state of our insides, of remarkable advances in micro-plumbing, and of pragmatically determined ways of correcting chemical imbalances and of killing bacterial invaders. None of these depends on a deep knowledge of cellular processes or on any discoveries of molecular biology. Cancer is still treated by gross physical and chemical assaults on the offending tissue. Cardiovascular disease is treated by surgery whose anatomical bases go back to the nineteenth century, by diet, and by pragmatic drug treatment. Antibiotics were originally developed without the slightest notion of how they do their work. Diabetics continue to take insulin, as they have for sixty years, despite all the research on the cellular basis of pancreatic malfunction. Of course, intimate knowledge of the living cell and of basic molecular processes may be useful eventually, and we are promised over and over that results are just around the corner. But as Vivian Blaine so poignantly complained:

You promised me this
You promised me that.
You promised me everything under the sun.


I think of the time gone by
And could honestly die.

Not the least of the problems of turning sequence information into causal knowledge is the existence of large amounts of “polymorphism.” While the talk in most of the books under review is of sequencing the human genome, every human genome differs from every other. The DNA I got from my mother differs by about one tenth of one percent, or about 3,000,000 nucleotides, from the DNA I got from my father, and I differ by about that much from any other human being. The final catalog of “the” human DNA sequence will be a mosaic of some hypothetical average person corresponding to no one. This polymorphism has several serious consequences. First, all of us carry one copy, inherited from one parent, of mutations that would result in genetic diseases if we had inherited two copies. No one is free of these, so the catalog of the standard human genome after it is compiled will contain, unknown to its producers, some fatally misspelled sequences which code for defective proteins or no protein at all. The only way to know whether the standard sequence is, by bad luck, the code of a defective gene is to sequence the same part of the genome from many different individuals. Such polymorphism studies are not part of the Human Genome Project and attempts to obtain money from the project for such studies have been rebuffed.

Second, even genetically “simple” diseases can be very heterogeneous in their origin. Sequencing studies of the gene that codes for a critical protein in blood-clotting has shown that hemophiliacs differ from people whose blood clots normally by any one of 208 different DNA variations, all in the same gene. These differences occur in every part of the gene, including bits that are not supposed to affect the structure of the protein.

The problem of telling a coherent causal story, and of then designing a therapy based on knowledge of the DNA sequence in such a case, is that we do not know even in principle all of the functions of the different nucleotides in a gene, or how the specific context in which a nucleotide appears may affect the way in which the cell machinery interprets the DNA; nor do we have any but the most rudimentary understanding of how a whole functioning organism is put together from its protein bits and pieces. Third, because there is no single, standard, “normal” DNA sequence that we all share, observed sequence differences between sick and well people cannot, in themselves, reveal the genetic cause of a disorder. At the least, we would need the sequences of many sick and many well people to look for common differences between sick and well. But if many diseases are like hemophilia, common differences will not be found and we will remain mystified.

3.

The failure to turn knowledge into therapeutic power does not discourage the advocates of the Human Genome Project because their vision of therapy includes gene therapy. By techniques that are already available and need only technological development, it is possible to implant specific genes containing the correct gene sequence into individuals who carry a mutated sequence, and to induce the cell machinery of the recipient to use the implanted genes as its source of information. Indeed, the first case of human gene therapy for an immune disease—the treatment of a child who suffered from a rare disorder of the immune system—has already been announced and seems to have been a success. The supporters of the Genome Project agree that knowing the sequence of all human genes will make it possible to identify and isolate the DNA sequences for large numbers of human defects which could then be corrected by gene therapy. In this view, what is now an ad hoc attack on individual disorders can be turned into a routine therapeutic technique, treating every physical and psychic dislocation, since everything significant about human beings is specified by their genes.

However, gene implantation may affect not only the cells of our temporary bodies, our somatic cells, but the bodies of future generations through accidental changes in the germ cells of our reproductive organs. Even if it were our intention only to provide properly functioning genes to the immediate body of the sufferer, some of the implanted DNA might get into and transform future sperm and egg cells. Then future generations would also have undergone the therapy in absentia and any miscalculations of the effects of the implanted DNA would be wreaked on our descendants to the remotest time. So David Suzuki and Peter Knudtson make it one of their principles of “genethics” (they have self-consciously created ten of them) that

while genetic manipulation of human somatic cells may lie in the realm of personal choice, tinkering with human germ cells does not. Germ-cell therapy, without the consent of all members of society, ought to be explicitly forbidden.

Their argument against gene therapy is a purely prudential one, resting on the imprecision of the technique and the possibility that a “bad” gene today might turn out to be useful some day. This seems a slim base for one of the Ten Commandments of biology, for, after all, the techniques may get a lot better and mistakes can always be corrected by another round of gene therapy. The vision of power offered to us by gene therapists makes gene transfer seem rather less permanent than a silicone implant or a tummy tuck. The bit of ethics in Genethics is, like a Unitarian sermon, nothing that any decent person could quarrel with. Most of the “genethic principles” turn out to be, in fact, prudential advice about why we should not screw around with our genes or those of other species. While most of their arguments are sketchy, Suzuki and Knudtson are the only authors among those under review who take seriously the problems presented by genetic diversity among individuals, and who attempt to give the reader enough understanding of the principles of population genetics to think about these problems.

Most death, disease, and suffering in rich countries do not arise from muscular dystrophy and Huntington’s chorea, and, of course, the majority of the world’s population is suffering from one consequence or another of malnutrition and overwork. For Americans, it is heart disease, cancer, and stroke that are the major killers, accounting for 70 percent of deaths, and about 60 million people suffer from chronic cardiovascular disease. Psychiatric suffering is harder to estimate, but before the psychiatric hospitals were emptied in the 1960s, there were 750,000 psychiatric inpatients. It is now generally accepted that some fraction of cancers arise on a background of genetic predisposition. That is, there are a number of genes known, the so-called oncogenes, that have information about normal cell division. Mutations in these genes result (in an unknown way) in making cell division less stable and more likely to occur at a pathologically high rate. Although a number of such genes have been located, their total number and the proportion of all cancers influenced by them is unknown.

In no sense of simple causation are mutations in these genes the cause of cancer, although they may be one of many predisposing conditions. Although a mutation leading to extremely elevated cholesterol levels is known, the great mass of cardiovascular disease has utterly defied genetic analysis. Even diabetes, which has long been known to run in families, has never been tied to genes and there is no better evidence for a genetic predisposition to it in 1992 than there was in 1952 when serious genetic studies began. No week passes without the announcement in the press of a “possible” genetic cause of some human ill which upon investigation “may eventually lead to a cure.” No literate public is unassailed by the claims. The Morgunbladid of Reykjavik asks its readers rhetorically, “Med allt í genunum?” (“Is it all in the genes?”) in a Sunday supplement.

The rage for genes reminds us of Tulipomania and the South Sea Bubble in McKay’s Great Popular Delusions of the Madness of Crowds. Claims for the definitive location of a gene for schizophrenia and manic depressive syndrome using DNA markers have been followed repeatedly by retraction of the claims and contrary claims as a few more members of a family tree have been observed, or a different set of families examined. In one notorious case, a claimed gene for manic depression, for which there was strong statistical evidence, was nowhere to be found when two members of the same family group developed symptoms. The original claim and its retraction both were published in the international journal Nature, causing David Baltimore to cry out at a scientific meeting, “Setting myself up as an average reader of Nature, what am I to believe?” Nothing.

Some of the wonder-rabbis and their disciples see even beyond the major causes of death and disease. They have an image of social peace and order emerging from the DNA data bank at the National Institutes of Health. The editor of the most prestigious general American scientific journal, Science, an energetic publicist for large DNA sequencing projects, in special issues of his journal filled with full-page multicolored advertisements from biotechnology equipment manufacturers, has visions of genes for alcoholism, unemployment, domestic and social violence, and drug addiction. What we had previously imagined to be messy moral, political, and economic issues turn out, after all, to be simply a matter of an occasional nucleotide substitution. While the notion that the war on drugs will be won by genetic engineering belongs to Cloud Cuckoo Land, it is a manifestation of a serious ideology that is continuous with the eugenics of an earlier time.

Daniel Kevles has quite persuasively argued in his earlier book on eugenics3that classical eugenics became transformed from a social program of general population improvement into a family program of providing genetic knowledge to individuals facing reproductive decisions. But the ideology of biological determinism on which eugenics was based has persisted and, as is made clear in Kevles’s excellent short history of the Genome Project in The Code of Codes, eugenics in the social sense has been revivified. This has been in part a consequence of the mere existence of the Genome Project, with its accompanying public relations and the heavy public expenditure it will require. These alone validate its determinist Weltanschauung. The publishers declare the glory of DNA and the media showeth forth its handiwork. strong

4.

The nine books reviewed here are only a sample of what has been and what is to come. The cost of sequencing the human genome is estimated optimistically at 300 million dollars (10 cents a nucleotide for the 3 billion nucleotides of the entire genome), but if development costs are included it surely cannot be less than a half billion in current dollars. Moreover the genome project sensu strictu is only the beginning of wisdom. Yet more hundreds of millions must be spent on chasing down the elusive differences in DNA for each specific genetic disease, of which some 3,000 are now known, and some considerable fraction of that money will stick to entrepreneurial molecular geneticists. None of our authors has the bad taste to mention that many molecular geneticists of repute, including several of the essayists in The Code of Codes, are founders, directors, officers, and stockholders in commercial biotechnology firms, including the manufacturers of the supplies and equipment used in sequencing research. Not all authors have Norman Mailer’s openness when they write advertisements for themselves.

It has been clear since the first discoveries in molecular biology that “genetic engineering,” the creation to order of genetically altered organisms, has an immense possibility for producing private profit. If the genes that allow clover plants to manufacture their own fertilizer out of the nitrogen in the air could be transferred to maize or wheat, farmers would save great sums and the producers of the engineered seed would make a great deal of money. Genetically engineered bacteria grown in large fermenting vats can be made into living factories to produce rare and costly molecules for the treatment of viral diseases and cancer. A bacterium has already been produced that will eat raw petroleum, making oil spills biodegradable. As a consequence of these possibilities, molecular biologists have become entrepreneurs. Many have founded biotechnology firms funded by venture capitalists. Some have become very rich when a successful public offering of their stock has made them suddenly the holders of a lot of valuable paper. Others find themselves with large blocks of stock in international pharmaceutical companies who have bought out the biologist’s mom and pop enterprise and acquired their expertise in the bargain.

No prominent molecular biologist of my acquaintance is without a financial stake in the biotechnology business. As a result, serious conflicts of interest have emerged in universities and in government service. In some cases graduate students working under entrepreneurial professors are restricted in their scientific interchanges, in case they may give away potential trade secrets. Research biologists have attempted, sometimes with success, to get special dispensations of space and other resources from their universities in exchange for a piece of the action. Biotechnology joins basketball as an important source of educational cash.

Public policy too, reflects private interest. James Dewey Watson resigned in April as head of the NIH Human Genome Office as a result of pressure put on him by Bernardine Healey, Director of the NIH. The immediate form of this pressure was an investigation by Healey of the financial holdings of Watson or his immediate family in various biotechnology firms. But nobody in the molecular biological community believes in the seriousness of such an investigation, because everyone including Dr. Healey knows that there are no financially disinterested candidates for Watson’s job. What is really at issue is a disagreement about patenting the human genome. Patent law prohibits the patenting of anything that is “natural,” so, for example, if a rare plant were discovered in the Amazon whose leaves could cure cancer, no one could patent it. But, it is argued, isolated genes are not natural, even though the organism from which they are taken may be. If human DNA sequences are to be the basis of future therapy, then the exclusive ownership of such DNA sequences would be money in the bank.

Dr. Healey wants the NIH to patent the human genome to prevent private entrepreneurs, and especially foreign capital, from controlling what has been created with American public funding. Watson, whose family is reported to have a financial stake in the British pharmaceutical firm Glaxo, has characterized Healey’s plan as “sheer lunacy,” on the grounds that it will slow down the acquisition of sequence information.4
(Watson has denied any conflict of interest.) Sir Walter Bodmer, the director of the Imperial Cancer Research Fund, and a major figure in the European Genome organization, spoke the truth that we all know lies behind the hype of the Human Genome Project when he told the Wall Street Journal that “the issue [of ownership] is at the heart of everything we do.”

The study of DNA is an industry with high visibility, a claim on the public purse, the legitimacy of a science, and the appeal that it will alleviate individual and social suffering. So its basic ontological claim, of the dominance of the Master Molecule over the body physical and the body politic, becomes part of general consciousness. Evelyn Fox Keller’s chapter in The Code of Codes brilliantly traces the percolation of this consciousness through the strata of the state, the universities, and the media, producing an unquestioned consensus that the model of cystic fibrosis is a model of the world. Daniel Koshland, the editor of Science, when asked why the Human Genome Project funds should not be given instead to the homeless, answered, “What these people don’t realize is that the homeless are impaired…. Indeed, no group will benefit more from the application of human genetics.”5

Beyond the building of a determinist ideology, the concentration of knowledge about DNA has direct practical social and political consequences, what Dorothy Nelkin and Laurence Tancredi call “The Social Power of Biological Information.” Intellectuals in their self-flattering wish-fulfillment say that knowledge is power, but the truth is that knowledge further empowers only those who have or can acquire the power to use it. My possession of a Ph.D. in nuclear engineering and the complete plans of a nuclear power station will not reduce my electric bill by a penny. So with the information contained in DNA, there is no instance where knowledge of one’s genes does not further concentrate the existing relations of power between individuals and between the individual and institutions.

When a woman is told that the fetus she is carrying has a 50 percent chance of contracting cystic fibrosis, or for that matter that it will be a girl although her husband desperately wants a boy, she does not gain additional power just by having that knowledge, but is only forced by it to decide and to act within the confines of her relation to the state and her family. Will her husband agree to or demand an abortion, will the state pay for it, will her doctor perform it? The slogan “a woman’s right to choose” is a slogan about conflicting relations of power, as Ruth Schwartz Cowan makes clear in her essay “Genetic Technology and Reproductive Choice: An Ethics for Autonomy” in The Code of Codes.

Increasingly, knowledge about the genome is becoming an element in the relation between individuals and institutions, generally adding to the power of institutions over individuals. The relations of individuals to the providers of health care, to the schools, to the courts, to employers are all affected by knowledge, or the demand for knowledge, about the state of one’s DNA. In the essays by both Henry Greeley and Dorothy Nelkin in The Code of Codes, and in much greater detail and extension in Dangerous Diagnostics, the struggle over biological information is revealed. The demand by employers for diagnostic information about the DNA of prospective employees serves the firm in two ways. First, as providers of health insurance, either directly or through their payment of premiums to insurance companies, employers reduce their wage bill by hiring only workers with the best health prognoses. Second, if there are workplace hazards to which employees may be in different degrees sensitive, the employer may refuse to employ those whom it judges to be sensitive. Not only does such employment exclusion reduce the potential costs of health insurance, but it shifts the responsibility of providing a safe and healthy work-place from the employer to the worker. It becomes the worker’s responsibility to look for work that is not threatening. After all, the employer is helping the workers by providing a free test of susceptibilities and so allowing them to make more informed choices of the work they would like to do. Whether other work is available at all, or worse paid, or more dangerous in other ways, or only in a distant place, or extremely unpleasant and debilitating is simply part of the conditions of the labor market. So Koshland is right after all. Unemployment and homelessness do indeed reside in the genes.

Biological information has also become critical in the relation between individuals and the state, for DNA has the power to put a tongue in every wound. Criminal prosecutors have long hoped for a way to link accused persons to the scene of a crime when there are no fingerprints. By using DNA from a murder victim and comparing it with DNA from dried blood found on the person or property of the accused, or by comparing the accused’s DNA with DNA from skin scrapings under the fingernails of a rape victim, prosecutors attempt to link criminal and crime. Because of the polymorphism of DNA from individual to individual, a definitive identification is, in principle, possible. But, in practice, only a bit of DNA can be used for identification so there is some chance that the accused will match the DNA from the crime scene even though someone else is in fact guilty.

Moreover, the methods used are prone to error, and false matches (as well as false exclusions) can occur. For example, the FBI characterized the DNA of a sample of 225 FBI agents and then, on a retest of the same agents, found a large number of mismatches. Matching is almost always done at the request of the prosecutor, because tests are expensive and most defendants in assault cases are represented by a public defender or court-appointed lawyer. The companies who do the testing have a vested commercial interest in providing matches, and the FBI, which also does some testing, is an interested party.

Because different ethnic groups differ in the frequency of the various DNA patterns, there is also the problem of the appropriate reference group to whom the defendant is to be compared. The identity of that reference group depends in complex ways on the circumstances of the case. If a woman who is assaulted lives in Harlem near the borderline between black, Hispanic, and white neighborhoods at 110th Street, which of these populations or combination of them is appropriate for calculating the chance that a “random” person would match the DNA found at the scene of the crime? A paradigm case was tried last year in Franklin County, Vermont. DNA from blood stains found at the scene of a lethal assault matched the DNA of an accused man. The prosecution compared the pattern with population samples of various racial groups, and claimed that the chance that a random person other than the accused would have such a pattern was astronomically low.

Franklin County, however, has the highest concentration of Abenaki Indians and Indian/European admixture of any county in the state. The Abenaki and Abenaki/French Canadian population are a chronically poor and underemployed sector in rural Franklin County and across the border in the St. Jacques River region of Canada, where they have been since the Western Abenaki were resettled in the eighteenth century. The victim, like the accused, was half Abenaki, half French-Canadian and was assaulted where she lived, in a trailer park, about one third of whose residents are of Abenaki ancestry. It is a fair presumption that a large fraction of the victim’s circle of acquaintance came from the Indian population. No information exists on the frequency of DNA patterns among Abenaki and Iroquois, and on this basis the judge excluded the DNA evidence. But the state could easily argue that a trailer park is open to access from any passer-by and that the general population of Vermont is the appropriate base of comparison. Rather than objective science we are left with intuitive arguments about the patterns of people’s everyday lives.

The dream of the prosecutor, to be able to say, “Ladies and gentlemen of the jury, the chance that someone other than the defendant could be the criminal is 1 in 3,426,327” has very shaky support. When biologists have called attention to the weaknesses of the method in court or in scientific publications they have been the objects of considerable pressure. One author was called twice by an agent of the Justice Department, in what the scientist describes as intimidating attempts to have him withdraw a paper in press.6 Another was asked questions about his visa by an FBI agent attorney when he testified, a third was asked by a prosecuting attorney how he would like to spend the night in jail, and a fourth received a fax demand from a federal prosecutor requiring him to produce peer reviews of a journal article he had submitted to the American Journal of Human Genetics, fifteen minutes before a fax from the editor of the journal informed the author of the existence of the reviews and their contents. Only one of our authors, Christopher Wills, discusses the forensic use of DNA, and he has been a prosecution witness himself. He is dismissive of the problems and seems to share with prosecutors the view that the nature of the evidence is less important than the conviction of the guilty.

Both prosecutors and defense forces have produced expert witnesses of considerable prestige to support or question the use of DNA profiles as a forensic tool. If professors from Harvard disagree with professors from Yale (as in this case), what is a judge to do? Under one legal precedent, the so-called “Frye rule,”7such a disagreement is cause for barring the evidence which “must be sufficiently established to have gained general acceptance in the particular field in which it belongs.” But all jurisdictions do not follow Frye, and what is “general acceptance,” anyway? In response to mounting pressure from the courts and the Department of Justice, the National Research Council was asked to form a Committee on DNA Technology in Forensic Science, to produce a definitive report and recommendations. They have now done so, adding greatly to the general confusion.8

Two days before the public release of the report, The New York Times carried a front page article by one of its most experienced and sophisticated science reporters, announcing that the NRC Committee had recommended that DNA evidence be barred from the courts. This was greeted by a roar of protest from the committee, whose chairman, Victor McKusick of Johns Hopkins University, held a press conference the next morning to announce that the report, in fact, approved of the forensic use of DNA substantially as it was now practiced. The Times, acknowledging an “error,” backed off a bit, but not much, quoting various experts who agreed with the original interpretation. A quoting various experts who agreed with the original interpretation. A member of the committee was quoted as saying he had read the report “fifty times” but hadn’t really intended to make the criticisms as strong as they actually appeared in the text.

One seems to have hardly any other choice but to read the report for oneself. As might be expected the report says in effect, “none of the above,” but in substance it gives prosecutors a pretty tough row to hoe. Nowhere does the report give wholehearted support to DNA evidence as currently used. The closest it comes is to state:

The current laboratory procedure for detecting DNA variation…is fundamentally sound [emphasis added] …

It is now clear that DNA typing methods are a most powerful adjunct to forensic science for personal identification and have immense benefit to the public.

and further that

DNA typing is capable, in principle, of an extremely low inherent rate of false results [emphasis added].

Unfortunately for the courts looking for assurances, these statements are immediately preceded by the following:

The committee recognizes that standardization of practices in forensic laboratories in general is more problematic than in other laboratory settings; stated succinctly, forensic scientists have little or no control over the nature, condition, form, or amount of sample with which they must work.

Not exactly the ringing endorsement suggested by Professor McKusick’s press conference. On the other hand there are no statements calling for the outright barring of DNA evidence. There are, however, numerous recommendations which, taken seriously, will lead any moderately businesslike defense attorney to file an immediate appeal of any case lost on DNA evidence. On the issue of laboratory reliability the report says:

Each forensic-science laboratory engaged in DNA typing must have a formal, detailed quality-assurance and quality-control program to monitor work.

and

Quality-assurance programs in individual laboratories alone are insufficient to ensure high standards. External mechanisms are needed… .

Courts should require that laboratories providing DNA typing evidence have proper accreditation for each DNA typing method used.

The committee then discusses mechanisms of quality control and accreditation in greater detail. Since no laboratory currently meets those requirements and no accreditation agency now exists, it is hard to see how the committee’s report can be read as an endorsement of the current practice of presenting evidence. On the critical issue of population comparisons the committee actually uses legal language sufficient to bar any of the one-in-a-million claims that prosecutors have relied on to dazzle juries:

Because it is impossible or impractical to draw a large enough population to test directly calculated frequencies of any particular profile much below 1 in 1,000, there is not a sufficient body of empirical data on which to base a claim that such frequency calculations are reliable or valid.

Reliable” and “valid” are terms of art here and Judge Jack Weinstein, who was a member of the committee, certainly knew that. This sentence should be copied in large letters and hung framed on the wall of every public defender in the United States. On balance, The New York Times had it right the first time. Whether by ineptitude or design the NRC Committee has produced a document rather more resistant to spin than some may have hoped.

In order to understand the committee’s report, one must understand the committee and its sponsoring body. The National Academy of Sciences is a self-perpetuating honorary society of prestigious American scientists, founded during the Civil War by Lincoln to give expert advice on technical matters. During the Great War, Woodrow Wilson added the National Research Council as the operating arm of the Academy, which could not produce from its own ranks of eminent ancients enough technical competence to deal with the growing complexities of the government’s scientific problems. Any arm of the state can commission an NRC study and the present one was paid for by the FBI, the NIH Human Genome Center, the National Institute of Justice, the National Science Foundation, and two non-federal sources, the Sloan Foundation and the State Justice Institute.

Membership in study committees almost inevitably includes divergent prejudices and conflicts of interest. The Forensic DNA Committee included people who had testified on both sides of the issue in trials and at least two members had clear financial conflicts of interest. One was forced to resign near the end of the committee’s deliberations when the full extent of his conflicts was revealed. A preliminary version of the report, much less tolerant of DNA profile methods, was leaked to the FBI by two members of the committee, and the Bureau made strenuous representations to the committee to get them to soften the offending sections. Because science is supposed to find objective truths that are clear to those with expertise, NRC findings do not usually contain majority and minority reports, and, of course, in the present case a lack of unanimity would be the equivalent of a negative verdict. So we may expect reports to contain contradictory compromises among contending interests, and public pronouncements about a report may be in contradiction to its effective content. DNA Technology in Forensic Science in its formation and content is a gold-mine for the serious student of political science and scientific politics.

There is no aspect of our lives, it seems, that is not within the territory claimed by the power of DNA. In 1924, William Bailey published in The Washington Post an article about “Radithor,” a radioactive water of his own preparation, under the headline, “Science to Cure All the Living Dead. What a Famous Savant has to Say about the New Plan to Close Up the Insane Asylums, Wipe Out Illiteracy, and Make over the Morons by his Method of Gland Control.”9Nothing was more up-to-date in the 1920s than a combination of radioactivity and glands. Famous savants, it seems, still have access to the press in their efforts to sell us, at a considerable profit, the latest concoction.

  1. 1

    Phage and the Origins of Molecular Biology, edited by J. Cairn, G.S. Stent, and J.D. Watson (Cold Spring Harbor Laboratory of Quantitative Biology, 1966).

  2. 2

    Richard Dawkins in The Selfish Gene (Oxford University Press, 1976), p. 21.

  3. 3

    Daniel J. Kevles, In the Name of Eugenics: Genetics and the Uses of Human Heredity (University of California Press, 1986).

  4. 4

    See The New York Times, April 9, 1992, p. A26, the Wall Street Journal, April 17, 1992, p. 1, and Nature, April 9, 1992, p. 463.

  5. 5

    Remarks made at the First Human Genome Conference in October 1989. Quoted by Keller in “Nature, Nurture, and the Human Genome Project” in The Code of Codes.

  6. 6

    Pressure against the paper was also brought by scientists in the genome sequencing establishment on the editor of the journal in which it was to be published, including one of the contributors to The Code of Codes. As a result the editor delayed its publication, demanded changes in galley proof, and asked two defenders of the method to write a counterattack. One report of the scandal is given in Lesley Roberts’s “Fight Erupts over DNA Fingerprinting,” Science, December 20, 1991, pp. 1,721–1,723.

  7. 7

    Based on Frye v. United States 293 F. 2nd DC Circuit 1013, 104 (1923).

  8. 8

    DNA Technology in Forensic Science. Report of the Committee on DNA Technology in Forensic Science (National Academy Press, 1992). The reader should know that I am not a disinterested party either with respect to the report or to the body that sponsored it. I have twice testified in federal court on the weaknesses of DNA profiles, am the author of a position paper that was a basis for the original very critical version of the NRC report’s chapter on population considerations, and am the author, with Daniel Hartl, of a highly critical paper in Science that was the object of considerable controversy. I resigned from the National Academy of Sciences in 1971 in protest against the secret military research carried out by its operating arm, the National Research Council.

  9. 9

    See M. Allison, “The Radioactive Elixir,” Harvard Magazine, January–February 1992, pp. 73–75.

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