As newgenics rose in prominence nationally and internationally, its founders tried valiantly to dissociate the new movement from its ugly past—in particular, from the Hitlerian overtones of Nazi eugenics. German eugenics had fallen into the abyss of Nazi horrors, neo-eugenicists argued, because of two cardinal errors—its scientific illiteracy and its political illegitimacy. Junk science had been used to prop up a junk state, and the junk state had fostered junk science. Neo-eugenics would sidestep these pitfalls by sticking to two lodestone values—scientific rigor and choice.
Scientific rigor would ensure that the perversities of Nazi eugenics would not contaminate neo-eugenics. Genotypes would be evaluated objectively, without interference or mandates from the state, using strict scientific criteria. And choice would be conserved at every step, guaranteeing that eugenic selections—such as prenatal testing and abortion—would occur only with full freedom.
Yet to its critics, newgenics was riddled with some of the same fundamental flaws that had cursed eugenics. The most resonant criticism of neo-eugenics emerged, unsurprisingly, from the very discipline that had breathed life into it—human genetics. As McKusick and his colleagues were discovering with increasing lucidity, the interactions between human genes and illnesses were vastly more complicated than newgenics might have anticipated. Down syndrome and dwarfism offered instructive case studies. For Down syndrome, where the chromosomal abnormality was distinct and easily identifiable, and where the link between the genetic lesion and the medical symptoms was highly predictable, prenatal testing and abortion might seem justifiable. But even with Down syndrome, as with dwarfism, the variation between individual patients carrying the same mutation was striking. Most men and women with Down syndrome experienced deep physical, developmental, and cognitive disabilities. But some, undeniably, were highly functional—leading near-independent lives requiring minimal interventions. Even a whole extra chromosome—as significant a genetic lesion as was conceivable in human cells—could not be a singular determinant of disability; it lived in the context of other genes and was modified by environmental inputs and by the genome at large. Genetic illness and genetic wellness were not discrete neighboring countries; rather, wellness and illness were continuous kingdoms, bounded by thin, often transparent, borders.
The situation became even more complex with polygenic illnesses—schizophrenia or autism, say. Although schizophrenia was well-known to have a strong genetic component, early studies suggested that multiple genes on multiple chromosomes were intimately involved. How might negative selection exterminate all these independent determinants? And what if some of the gene variants that caused mental disorders in some genetic or environmental contexts were the very variants that produced enhanced ability in other contexts? Ironically, William Shockley—the most prominent donor to Graham’s genius bank—was himself afflicted by a syndrome of paranoia, aggression, and social withdrawal that several biographers have suggested was a form of high-functioning autism. What if—poring through Graham’s bank in some future era—the selected “genius specimens” were found to possess the very genes that, in alternative situations, might be identified as disease enabling (or vice versa: What if “disease-causing” gene variants were also genius enabling?)?
McKusick, for one, was convinced that “overdeterminism” in genetics, and its indiscriminate application to human selection, would result in the creation of what he called the “genetic-commercial” complex. “Near the end of his terms of office, President Eisenhower warned against the dangers of the military-industrial complex,” McKusick said. “It is appropriate to warn of a potential hazard of the genetic-commercial complex. The increasing availability of tests for presumed genetic quality or poor quality could lead the commercial sector and the Madison Avenue publicist to bring subtle or not so subtle pressure on couples to make value judgments in the choice of their gametes for reproduction.”
In 1976, McKusick’s concerns still seemed largely theoretical. Although the list of human diseases influenced by genes had grown exponentially, most of the actual genes were yet to be identified. Gene-cloning and gene-sequencing technologies, both invented in the late 1970s, made it conceivable that such genes could be successfully identified in humans, leading to predictive diagnostic tests. But the human genome has 3 billion base pairs—while a typical disease-linked gene mutation might result in the alteration of just one base pair in the genome. Cloning and sequencing all genes in the genome to find that mutation was inconceivable. To find a disease-linked gene, the gene would need to be somehow mapped, or localized, to a smaller part of the genome. But that, precisely, was the missing piece of technology: although genes that caused diseases seemed abundant, there was no easy way to find them in the vast expanse of the human genome. As one geneticist described it, human genetics was stuck in the ultimate “needle in a haystack problem.”
A chance meeting in 1978 would offer a solution to the “needle in a haystack” problem of human genetics, enabling geneticists to map and clone human disease-linked genes. The meeting, and the discovery that followed it, would mark one of the turning points in the study of the human genome.
A Village of Dancers, an Atlas of Moles
Glory be to God for dappled things.
—Gerard Manley Hopkins, “Pied Beauty”
We suddenly came upon two women, mother and daughter, both tall, thin, almost cadaverous, both bowing, twisting, grimacing.
—George Huntington
In 1978, two geneticists, David Botstein, from MIT, and Ron Davis, from Stanford, traveled to Salt Lake City to serve on a graduate review committee for the University of Utah. The meeting was held at Alta, high on the Wasatch Mountains, a few miles from the city. Botstein and Davis sat through the presentations taking notes—but one talk struck a particular chord with both of them. A graduate student, Kerry Kravitz, and his adviser, Mark Skolnick, were painstakingly mapping the inheritance of a gene that causes hemochromatosis, a hereditary illness. Known by physicians since antiquity, hemochromatosis is caused by a mutation in a gene that regulates iron absorption from the intestines. Patients with hemochromatosis absorb enormous amounts of iron, resulting in a body that is slowly choked by iron deposits. The liver asphyxiates on iron; the pancreas stops working. The skin turns bronze and then ashen gray. Organ by organ, the body transforms into mineral, like the Tin Man in The Wizard of Oz, ultimately leading to tissue degeneration, organ failure, and death.
The problem that Kravitz and Skolnick had decided to solve concerned a fundamental conceptual gap in genetics. By the mid-1970s, thousands of genetic diseases had been identified—hemochromatosis, hemophilia, and sickle-cell anemia among them. Yet, discovering the genetic nature of an illness is not the same as identifying the actual gene that causes that illness. The pattern of inheritance of hemochromatosis, for instance, clearly suggests that a single gene governs the disease, and that the mutation is recessive—i.e., two defective copies of the gene (one from each parent) are necessary to cause the illness. But the pattern of inheritance tells us nothing about what the hemochromatosis gene is or what it does.
Kravitz and Skolnick proposed an ingenious solution to identify the hemochromatosis gene. The first step to finding a gene is to “map” it to a particular chromosomal location: once a gene has been physically located on a particular stretch of a chromosome, standard cloning techniques can be used to isolate the gene, sequence it, and test its function. To map the hemochromatosis gene, Kravitz and Skolnick reasoned, they would use the one property that all genes possess: they are linked to each other on chromosomes.
Consider the following thought experiment. Say the hemochromatosis gene sits on chromosome seven, and the gene that governs hair texture—straight versus kinked or curly or wavy—is its immediate neighbor on the same chromosome. Now assume that somewhere in distant evolutionary history, the defective hemochromatosis gene arose in a man with curly hair. Every time this ancestral gene is passed from parent to child, the curly-haired gene travels
with it: both are bound on the same chromosome, and since chromosomes rarely splinter, the two gene variants inevitably associate with each other. The association may not be obvious in a single generation, but over multiple generations, a statistical pattern begins to emerge: curly-haired children in this family tend to have hemochromatosis.
Kravitz and Skolnick had used this logic to their advantage. By studying Mormons in Utah with cascading, many-branched family trees, they had discovered that the hemochromatosis gene was genetically linked to an immune-response gene that exists in hundreds of variants. Prior work had mapped the immune-response gene to chromosome six—and so the hemochromatosis gene had to be located on that chromosome.
Careful readers might object that the example above was loaded: the gene for hemochromatosis happened to be conveniently linked to an easily identifiable, highly variant trait on the same chromosome. But surely such traits were fleetingly rare. That Skolnick’s gene of interest happened to be sitting, cheek by jowl, with a gene that encoded an immune-response protein that existed in many easily detectable variants was surely a lucky aberration. To achieve this kind of mapping for any other gene, wouldn’t the human genome have to be littered with strings of variable, easily identifiable markers—lamplit signposts planted conveniently along every mile of chromosome?
But Botstein knew that such signposts might exist. Over centuries of evolution, the human genome has diverged enough to create thousands of minute variations in DNA sequence. These variants are called polymorphisms—“many forms”—and they are exactly like alleles or variants, except they need not be in genes themselves; they might exist in the long stretches of DNA between genes, or in introns.
These variants can be imagined as molecular versions of eye or skin color, existing in thousands of varied forms in the human population. One family might carry an ACAAGTCC at a particular location on a chromosome, while another might have AGAAGTCC at that same location—a one-base-pair difference.I Unlike hair color or the immune response, these variants are invisible to the human eye. The variations need not enable a change in phenotype, or even alter a function of a gene. They cannot be distinguished using standard biological or physical traits—but they can be discerned using subtle molecular techniques. A DNA-cutting enzyme that recognizes ACAAG, but not AGAAG, for instance, might discriminate one sequence variant and not the other.
When Botstein and Davis had first discovered DNA polymorphisms in yeast and bacterial genomes in the 1970s, they had not known what to make of them. At the same time, they had also identified a few such polymorphisms scattered across human genomes—but the extent and location of such variations in humans was still unknown. The poet Louis MacNeice once wrote about feeling “the drunkenness of things being various.” The thought of tiny molecular variations peppered randomly through the genome—like freckles across a body—might have provoked a certain pleasure in a drunken human geneticist, but it was hard to imagine how this information might be useful. Perhaps the phenomenon was perfectly beautiful and perfectly useless—a map of freckles.
But as Botstein listened to Kravitz that morning in Utah, he was struck by a compelling idea: if such variant genetic signposts existed in the human genome, then by linking a genetic trait to one such variant, any gene could be mapped to an approximate chromosomal location. A map of genetic freckles was not useless at all; it could be deployed to chart the basic anatomy of genes. The polymorphisms would act like an internal GPS system for the genome; a gene’s location could be pinpointed by its association, or linkage, to one such variant. By lunchtime, Botstein was nearly frantic with excitement. Skolnick had spent more than a decade hunting down the immune-response marker to map the hemochromatosis gene. “We can give you markers . . . markers spread all over the genome,” he told Skolnick.
The real key to human gene mapping, Botstein had realized, was not finding the gene, but finding the humans. If a large-enough family bearing a genetic trait—any trait—could be found, and if that trait could be correlated with any of the variant markers spread across the genome, then gene mapping would become a trivial task. If all the members of a family affected by cystic fibrosis inevitably “co-inherited” some variant DNA marker, call it Variant-X, located on the tip of chromosome seven, then the cystic fibrosis gene had to sit in proximity to this location.
Botstein, Davis, and Skolnick published their idea about gene mapping in the American Journal of Human Genetics in 1980. “We describe a new basis for the construction of a genetic . . . map of the human genome,” Botstein wrote. It was an odd study, tucked into the middle pages of a relatively obscure journal and festooned with statistical data and mathematical equations, reminiscent of Mendel’s classic paper.
It would take some time for the full implication of the idea to sink in. The crucial insights of genetics, I said before, are always transitions—from statistical traits to inheritable units, from genes to DNA. Botstein had also made a crucial conceptual transition—between human genes as inherited biological characteristics, and their physical maps on chromosomes.
Nancy Wexler, a psychologist, heard about Botstein’s gene-mapping proposal in the fall of 1979. She had a poignant reason to pay attention. In the summer of 1967, when Wexler was twenty-two, her mother, Leonore Wexler, was stopped by a policeman for driving erratically through the streets of Los Angeles. She was not drunk. Leonore had suffered inexplicable bouts of depression—sudden mood swings, bizarre behavioral changes—and had attempted suicide once, but had never been considered physically ill. Two of Leonore’s brothers, Paul and Seymour, once members of a swing band in New York, had been diagnosed with a rare genetic syndrome called Huntington’s disease, in the 1950s. Another brother, Jessie, a salesman who liked to perform magic tricks, had found his fingers dancing uncontrollably during his performances. He too was diagnosed with the same illness. Their father, Alfred Sabin, had died of Huntington’s disease in 1926—but Leonore had assumed that she had been spared. By the time she saw a neurologist that winter in 1967, spasmodic twitches and dancing movements had begun to appear. She was also diagnosed with the disease.
Named after the Long Island doctor who first described the condition in the 1870s, Huntington’s disease was once called Huntington’s chorea—chorea from the Greek word for “dance.” The “dance,” of course, is the opposite of dance, a joyless and pathological caricature, the ominous manifestation of dysregulated brain function. Typically, patients who inherit the dominant Huntington’s gene—only one copy is sufficient to precipitate the disease—are neurologically intact for the first three or four decades of their life. They might experience occasional mood swings or subtle signs of social withdrawal. Then minor, barely discernible twitches appear. Objects become hard to grasp. Wineglasses and watches slip between fingers, and movements dissolve into jerks and spasms. Finally, the involuntary “dance” begins, as if set to devil’s music. The hands and legs move of their own accord, tracing writhing, arclike gestures separated by staccato, rhythmic jolts—“like watching a giant puppet show . . . jerked by an unseen puppeteer.” The late stage of the disease is marked by deep cognitive decline and near-complete loss of motor function. Patients die of malnourishment, dementia, and infections—yet “dancing” to the last.
Part of the macabre denouement of Huntington’s is the late onset of the illness. Those carrying the gene only discover their fate in their thirties or forties—i.e., after they have had their own children. The disease thus persists in human populations by writhing its way past evolution’s grasp: the gene is passed on to the next generation before it can be eliminated through natural selection. Since every patient with Huntington’s disease has one normal copy and one mutant copy of the gene, every child born to him or her has a fifty-fifty chance of being affected. For these children, life devolves into a grim roulette—a “waiting game for the onset of symptoms,” as a geneticist described it. One patient wrote about the strange terror of this limbo: “I don’t know the point where the grey zone ends and a much da
rker fate awaits. . . . So I play the terrible waiting game, wondering about the onset and the impact.”
Milton Wexler, Nancy’s father, a psychiatrist in Los Angeles, broke the news of their mother’s diagnosis to his two daughters in 1968. Nancy and Alice were still asymptomatic, but they each carried a 50 percent chance of being affected, with no genetic test for the disease. “Each one of you has a one-in-two chance of getting the disease,” Milton Wexler told his daughters. “And if you get it, your kids have a one-in-two chance of getting it.”
“We were all hanging on to each other and sobbing,” Nancy Wexler recalled. “The passivity of just waiting for this to come and kill me was unbearable.”
That year, Milton Wexler launched a nonprofit institute, called the Hereditary Disease Foundation, dedicated to funding research on Huntington’s chorea and other rare inherited diseases. Finding the Huntington’s gene, Wexler reasoned, would be the first step toward diagnosis, future treatments, and cures. It would give his daughters a chance to predict and plan for their future illness.
Leonore Wexler, meanwhile, gradually descended into the chasm of her disease. Her speech began to slur uncontrollably. “New shoes would wear out the moment you put them on her feet,” her daughter recalled. “In one nursing home, she sat in a chair in the narrow space between her bed and the wall. No matter where the chair was put, the force of her continual movements edged it against the wall, until her head began bashing into the plaster. . . . We tried to keep her weight up; for some unknown reason, people with Huntington’s disease do better when they are heavy, although their constant motion makes them thin. . . . Once she polished off a pound of Turkish delight in half an hour with a grin of mischievous delight. But she never gained weight. I gained weight. I ate to keep her company; I ate to keep from crying.”
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