Dna: The Secret of Life

by Watson, James

  Civil libertarians will always object to the broad application of DNA fingerprinting in society as a whole. But it is hard to argue with the social utility of applying the technology to those who, for whatever reason, pass through the criminal justice system; for the chances are, sadly, that those who pass through once will pass through again. Criminological data indicate that those convicted of minor crimes are likely to commit more serious offenses; 28 percent of homicides and 12 percent of sexual assaults in Florida have been linked to individuals previously convicted of burglary. And such patterns of recidivism can be detected among white-collar criminals as well: of twenty-two who had been convicted for forgery in Virginia, ten were linked through DNA fingerprinting to murders or sexual assaults. It would seem prudent to make the corporate bosses of Enron, ImClone, and Adelphia Communications provide DNA samples.

  Efforts are under way to broaden DNA fingerprint databases. Recently, the British government has proposed allowing the police to keep DNA samples taken both from acquitted defendants and from those arrested but never charged. The same rule would permit the authorities to keep samples given voluntarily (when, for example, the police test everyone in a location, as they did in Narborough). These changes in collection rules will triple the number of entries in the police database within three years. In the United States, nineteen states now collect DNA samples from all felons, not just those involved in violent crime.

  I think everyone should give a DNA sample. It is not that I am insensitive to the concerns about individual privacy or to the potential for inappropriate use of genetic information; as I have said earlier, in my role as the first director of the Human Genome Project, I set aside a substantial chunk of our funding to examine such questions in relation to clinically applied genetic information. But criminal justice is a different matter. Here by my calculation the potential for the greater social good far outweighs the risks of abuse. And since we must all surrender something for the benefit of living in a free society, the sacrifice of this particular form of anonymity does not seem an unreasonable price to pay, provided our laws see to a strict and judicious control over access to databases. Frankly, the remote possibility that Big Brother will one day be perusing my genetic fingerprint for some nefarious end worries me less than the thought that tomorrow a dangerous criminal may go free – perhaps only to do further evil – or an innocent individual may languish in prison for want of a simple DNA test.

  But objections to DNA collection in general continue to be heard, and often from the most surprising and far-flung quarters. In both New York City and the Australian state of Tasmania, lawmakers have proposed that the entire police force be fingerprinted. The logic is simple: keep the police on file so their DNA can readily be excluded from any crime they might investigate. Remarkably, the measures were denounced by law enforcement bodies in both jurisdictions: those presumed to be the most law-upholding of citizens, those whose work only promises to be facilitated by the widespread availability of DNA fingerprinting, want no part of it where their own DNA is concerned. My suspicion is that there is something of the irrational at play here. As in the case of genetically modified foods, DNA has in the popular imagination a voodoo quality: there's something scary, mysterious about it. And a lack of understanding of genetic complexities leaves one susceptible to the worst anxieties and conspiracy theories. Once people understand the issues, I hope this hesitation in making the most of a new and powerful beneficial technology will vanish.

  Barry Scheck and Peter Neufeld put it well in the preface to their book Actual Innocence: "DNA testing is to justice what the telescope is for the stars; not a lesson in biochemistry, not a display of the wonders of magnifying glass, but a way to see things as they really are." What could be wrong with that?

  CHAPTER ELEVEN

  GENE HUNTING:

  THE GENETICS OF HUMAN DISEASE

  It was too early in the day for anyone, let alone an impeccably dressed middle-aged woman, to be drunk. But as she swayed unsteadily across the street, drunk is what she seemed, even to the cop on duty near the courthouse, who reprimanded her for creating a public spectacle. In fact, Leonore Wexler wasn't drunk at all. She was beginning to succumb to a ghastly fate that had already destroyed several close relatives before her eyes, a fate she had hoped would pass her by.

  Not long thereafter, in 1968, Wexler's ex-husband, Milton, was to celebrate his sixtieth birthday in Los Angeles with their two daughters, Alice, 26, and Nancy, 23. But celebration, as it turned out, was not the order of the day. Milton told his daughters that their mother, 53, was suffering from Huntington disease (HD), a devastating neurological disorder that causes a progressive deterioration in brain function such that those afflicted gradually lose all knowledge of themselves and their loved ones. They also lose control of their arms and legs; at first walking is affected, as in Leonore's case, but as the decline continues patients also experience involuntary, jerky movements. There was no cure and no treatment to delay the relentless slide toward death.

  Now Alice and Nancy could make sense of some disquieting facts about their mother's relatives as well as hints she herself had dropped that all was not right in the family. They knew that their uncles, Leonore's three brothers, had all died young; before his end, each had developed the same strange grimace, unsteady walk, and slurred speech. They knew that Leonore's father, their grandfather, Abraham Sabin, had also died young, though Leonore had carefully never mentioned he too had shown those symptoms. Huntington disease, it was becoming clear to them, ran in the family. It was Milton's grim task to answer their immediate question: What was the risk that Alice or Nancy might succumb? "Fifty-fifty," their father told them.

  The disease that would afflict Abraham Sabin and his descendants was first identified by George Huntington. Born into a medical family, Huntington grew up in East Hampton, Long Island, where as a young boy he accompanied his father on his rounds. After qualifying as a physician at Columbia University, Huntington returned to the family practice on Long Island for a few years before moving to Pomeroy, Ohio. In 1872, he presented a paper at the Meigs and Mason Academy of Medicine in nearby Middleport entitled "On Chorea." Derived from the Greek word for dance, "chorea" was the name physicians had since the seventeenth century given to illnesses that produced jerky movements in their victims. Late in life Huntington would recount how he had come to be fascinated by the mysterious malady:

  Over 50 years ago, in riding with my father on his rounds I saw my first case of "that disorder," which was the way the natives always referred to the dreaded disease. I recall it as vividly as though it had occurred but yesterday. It made a most enduring impression upon my boyish mind, an impression which was the very first impulse to my choosing chorea as my virgin contribution to medical lore. Driving with my father through a wooded road leading from East Hampton to Amagansett, we suddenly came upon two women both bowing, twisting, grimacing. I stared in wonderment, almost in fear. What could it mean? My father paused to speak with them and we passed on. Then my Gamaliel-like* instruction began; my medical instruction had its inception. From this point on my interest in the disease has never wholly ceased.

  *Gamaliel, a famous rabbi and teacher of St. Paul (Acts 22:3), believed in integrating book learning with everyday experience.

  Drawing on his own observations as well as the clinical notes of both his father and grandfather (the original manuscript has annotations penciled in by his father), the young physician's paper offered a masterful description of what became known as Huntington's chorea and is now called Huntington disease. The "chorea" movements, he explained, "gradually increase when muscles hitherto unaffected take on the spasmodic action, until every muscle in the body becomes affected." He noted the attendant mental deterioration: "As the disease progresses the mind becomes more or less impaired, in many amounting to insanity, while in others mind and body gradually fail until death relieves them of their suffering." And he recognized that the disorder was inherited: "When either or both the p
arents have shown manifestations of the disease, one or more of the offspring invariably suffer from the condition. It never skips a generation to again manifest itself in another. Once having yielded its claims, it never regains them."

  Huntington correctly identified the key features of this kind of genetic disorder. He recognized that it affected both males and females and understood that it passed from generation to generation. Each child of a parent with Huntington disease has a 50-50 chance of inheriting it. By the luck of the draw, in some families everyone is affected; in others, none are. If a person does not inherit the abnormal gene from a parent, he or she cannot pass on the gene to the next generation. Today we know Huntington disease is caused by a mutation and since the gene is not preferentially expressed in one sex over the other (i.e., is not sex-linked), we have inferred that the affected gene is on neither the X nor Y sex chromosome. Let's call the normal version of the gene H and the mutant version h. We have two copies of each non-sex chromosome (called "autosomes") and so two copies of the Huntington gene. Individuals with the two copies of the normal gene (HH) are, predictably, disease free. But individuals with two (hh) or even one copy of the mutated gene (Hh) are bound to develop the disease. We call this pattern "autosomal dominant inheritance." ("Dominant" means that only one copy of a mutated gene is sufficient to cause disease – the abnormal gene dominates its normal partner.)

  Since it is far likelier that a person will acquire one rather than two copies of the mutant form, most Huntington sufferers are Hh. Such individuals could pass on H or h to their children, yielding a 50 percent chance that a particular child would be affected, just as Milton Wexler told Alice and Nancy.

  Back in 1968, not much was known about Huntington disease beyond these facts: it is heritable, and it makes its irreversible progress by killing nerve cells in specific areas of the brain. Milton Wexler resolved that he would take on the terror striking his family: he established the Hereditary Disease Foundation (HDF) to raise money and press for more government funding for Huntington disease research. His daughter Nancy was drawn in as well. While completing a doctorate in psychology at the University of Michigan – her thesis fittingly concerned the psychology of being at risk – she found herself increasingly involved in the affairs of the foundation. In the 1970s, when it became apparent that real progress would depend upon a better understanding of the genetics of the disease, Nancy Wexler began to reinvent herself as a geneticist.

  On the shores of Lake Maracaibo, Venezuela, the burden of grinding poverty is compounded by a remarkably high incidence of Huntington disease. If Huntington were to divulge its genetic secrets anywhere, Lake Maracaibo seemed a likely place. In 1979, Wexler began to collect DNA samples and to record family histories with the goal of preparing a genealogy of all affected people. For the geneticist it was a great labor, but for Wexler, the daughter of a Huntington victim with the possibility of the disease in her own future, it was more than that. It involved seeing the familiar in such unfamiliar surroundings: people who lived in tin-roofed wooden huts on poles above the waters of the lake yet walked with that same drunken stagger that had overtaken her mother. Since her first trip to Lake Maracaibo in 1979, Wexler has returned annually to continue the work there. The people she works with have come to call her La Catira for her long blond hair. As Americo Negrette, her Venezuelan colleague and the scientist who first reported the occurrence of Huntington at Lake Maracaibo, describes it, she has made of them an extended family, greeting them each time "without theater, without simulation, without pose. With a tenderness that jumps from her eyes." (see Plate 53).

  But tenderness could only mitigate the devastation Huntington disease had visited upon so many. The goal of Wexler's expeditions was ultimately to find the gene responsible for the disease. But how could her Maracaibo genealogies help to identify the culprit? The key lay in advances in human genetics.

  If they were to home in on the Huntington gene, Wexler and others interested in genetic disease knew they would have to do for humans what Morgan and his students had started doing for fruit flies more than half a century earlier. As we have seen (in chapter 1), Morgan compared rates at which particular genetic markers – white (as opposed to red) eye color, say, and curly (as opposed to straight) wings – coincided in the offspring of crosses between parents showing various combinations of these traits; from these data he was able to determine how near each other on a chromosome were the genes governing those traits. But human genetics had lagged behind the fruit fly's for two major reasons. First was the impossibility – on moral and practical grounds – of doing the kind of experiments that were still the mainstay of genetic analysis: you can't simply breed two human beings you're interested in and then analyze the progeny two weeks later. Second, even if humans could be crossed at will, they were still lacking in genetic markers. Morgan was able to track a number of simple and obvious differences in appearance caused by specific mutations in individual genes. Humans unfortunately don't possess many easily analyzed traits that are inherited in this simple way; even the canonical example, eye color, turns out to be governed by several genes, not just one. Furthermore, with fruit flies, you can increase levels of genetic variation by subjecting individuals to X rays, or to other mutagenic agents: such options, happily, are not available in dealing with humans. Only with the advent of recombinant DNA did solutions to the two major obstacles present themselves.

  In the age of DNA sequencing, genetic markers need no longer be visible, like white eyes in a fruit fly; a variation in the sequence itself will suffice, and you can track such a DNA marker through a family tree – that is, through a number of genetic crosses – simply by analyzing DNA from several generations. The revolution had begun the year before Wexler started her genealogical research. And, as with so many advances in science, a measure of serendipity was involved.

  It had become an annual ritual: a small group of graduate students from the University of Utah would accompany their advisers to the Wasatch Mountain ski resort of Alta for an intensive workshop on their research (and, well, a little skiing on the side). Typically, a couple of big-shot scientists from other institutions would be invited, to cast a critical eye over the data presented by each nervous student. In 1978, the big shots included David Botstein from MIT and Ron Davis from Stanford.

  David Botstein, it's been noted, "tends to think and talk excessively fast, and often at the same time." Ron Davis is quiet and retiring. That April in Utah, despite their contrasting styles, Botstein and Davis shared an epiphany. As they listened to Mark Skolnick's graduate students discuss genetic disorders traced in the very large pedigrees of Mormon families, Botstein's and Davis's eyes suddenly met as both registered simultaneously the same insight. Though both were experts on yeast, they saw a way to locate human genes! What they saw was that cutting-edge recombinant DNA techniques would allow them to apply to humans the very sort of genetic analysis first used by Morgan to study the fruit fly. In fact, DNA markers had already been used to map genes in a number of other species, but Botstein and Davis would be the first to develop the technique's potential in humans.

  The technique, called "linkage analysis," determines the position of a gene in relation to the known positions of particular genetic landmarks. The principle is simple: it would be difficult for you, given no other information, to find Springfield on a map of the United States, but if I tell you that Springfield lies about halfway between New York and Boston – two landmarks labeled on the map – then your task is made very much easier. Linkage analysis aims to do this with genes: it establishes links between known genetic markers and unknown genes. It was a very successful method with the fruit fly, but, as we have seen, the dearth of known genetic markers in human beings prevented its application to human diseases – until Botstein and Davis recognized that advances in molecular biology had solved the problem.

  The DNA markers that caught their eye were restriction fragment length polymorphisms (RFLPs). They occur when a DNA sequence cut by a
particular restriction enzyme in one individual has changed in another so that it can no longer be cut by that enzyme. (Remember that restriction enzymes are sequence-specific: enzyme EcoRl cuts only when it encounters GAATTC. That sequence occurs at a given location in the genome, but through mutation some individuals may have a variant form of that segment – say, GAAGTC. The enzyme will be able to cut only unchanged sequences, not the altered version.) These are naturally occurring differences in DNA sequence; they occur most often in junk DNA, and so there is no functional effect. Still, literally millions of them are scattered through our genome.