The Gene

by Siddhartha Mukherjee

  The challenge of genetics, as it moved from simple organisms to the human organism, was to confront new ways to think about the nature of heredity, information flow, function, and fate. How do genes intersect with environments to cause normalcy versus disease? For that matter, what is normalcy versus disease? How do the variations in genes cause variations in human form and function? How do multiple genes influence a single outcome? How can there be so much uniformity among humans, yet such diversity? How can the variants in genes sustain a common physiology, yet also produce unique pathologies?

  The Birth of a Clinic

  I start with the premise that all human disease is genetic.

  —Paul Berg

  In 1962, a few months after the DNA “triplet code” had been deciphered by Nirenberg and his colleagues in Bethesda, the New York Times published an article about the explosive future of human genetics. Now that the code had been “cracked,” the Times projected, human genes would become malleable to intervention. “It is safe to say that some of the biological ‘bombs’ that are likely to explode before long as a result of [breaking the genetic code] will rival even the atomic variety in their meaning for man. Some of them might be: determining the basis of thought . . . developing remedies for afflictions that today are incurable, such as cancer and many of the tragic inherited disorders.”

  Skeptics might, however, have been forgiven for their lack of enthusiasm; the biological “bomb” of human genetics had, thus far, burst forth with a rather underwhelming whimper. The astonishing growth spurt of molecular genetics between 1943 and 1962—from Avery’s experiment to the solution of the structure of DNA, and the mechanisms of gene regulation and repair—had produced a progressively detailed mechanistic vision of the gene. Yet the gene had barely touched the human world. On one hand, the Nazi eugenicists had so definitively scorched the earth of human genetics that the discipline had been leached of scientific legitimacy and rigor. On the other, simpler model systems—bacteria, flies, worms—had proved to be vastly more tractable to experimental studies than humans. When Thomas Morgan traveled to Stockholm to collect the Nobel Prize for his contributions to genetics in 1934, he was pointedly dismissive about the medical relevance of his work. “The most important contribution to medicine that genetics has made is, in my opinion, intellectual,” Morgan wrote. The word intellectual was not meant as a compliment, but as an insult. Genetics, Morgan noted, was unlikely to have even a marginal impact on human health in the near future. The notion that a doctor “may then want to call in his genetic friends for consultation,” as Morgan put it, seemed like a silly, far-fetched fantasy.

  Yet the entry, or rather reentry, of genetics into the human world was the product of medical necessity. In 1947, Victor McKusick, a young internist at Johns Hopkins University in Baltimore, saw a teenage patient with spots on his lips and tongue and multiple internal polyps. McKusick was intrigued by the symptoms. Other members of the family were also affected by similar symptoms, and familial cases with similar features had been published in the literature. McKusick described the case in the New England Journal of Medicine, arguing that the cluster of seemingly diffuse symptoms—tongue spots, polyps, bowel obstruction, and cancer—were all the product of a mutation in a single gene.

  McKusick’s case—later classified as Peutz-Jeghers syndrome, after the first clinicians who described it—launched his lifelong interest in the study of the links between genetics and human diseases. He began by studying human diseases in which the influence of genes was the simplest and strongest—where one gene was known to cause one disease. The best-established examples of such illnesses in humans, though few, were unforgettable: hemophilia among the English royals and sickle-cell anemia in African and Caribbean families. By digging through old papers from the medical libraries at Hopkins, McKusick discovered that a London doctor working in the early 1900s had reported the first example of a human disease apparently caused by a single genetic mutation.

  In 1899, Archibald Garrod, an English pathologist, had described a bizarre illness that ran in families and became manifest within days of childbirth. Garrod had first observed it in a child at the Sick Hospital in London. Several hours after the boy had been born, his diaper linens had turned black with a peculiar stain of urine. By meticulously tracking down all such afflicted patients and their relatives, Garrod discovered that the disease ran in families and persisted through adulthood. In adults, sweat darkened spontaneously, sending rivulets of deep brown stains under the arms of shirts. Earwax, even, turned red as it touched the air, as if it had rusted on contact.

  Garrod guessed that some inherited factor had been altered in these patients. The boy with the dark urine, Garrod reasoned, must have been born with an alteration in a unit of inheritance that had changed some metabolic function in cells, resulting in a difference in the composition of urine. “The phenomena of obesity and the various tints of hair, skin and eyes” can all be explained by variations in units of inheritance causing “chemical diversities” in human bodies, Garrod wrote. The prescience was remarkable. Even as the concept of the “gene” was being rediscovered by Bateson in England (and nearly a decade before the word gene had been coined), Garrod had conceptually visualized a human gene and explained human variation as “chemical diversities” encoded by units of inheritance. Genes make us human, Garrod had reasoned. And mutations make us different.

  Inspired by Garrod’s work, McKusick launched a systematic effort to create a catalog of genetic diseases in humans—an “encyclopedia of phenotypes, genetic traits and disorders.” An exotic cosmos opened up before him; the range of human diseases governed by individual genes was vaster and stranger than he had expected. In Marfan syndrome, originally described by a French pediatrician in the 1890s, a gene controlling the structural integrity of the skeleton and blood vessels was mutated. Patients grew unusually tall, with elongated arms and fingers, and had a propensity to die of sudden ruptures of the aorta or the heart’s valves (for decades, some medical historians have asserted that Abraham Lincoln had an undiagnosed variant of the syndrome). Other families were afflicted by osteogenesis imperfecta, a disease caused by a mutation in a gene for collagen, a protein that forms and strengthens bone. Children with this disease were born with brittle bones that, like dry plaster, could crumble at the slightest provocation; they might fracture their legs spontaneously or awake one morning with dozens of broken ribs (often mistaken for child abuse, the cases were brought to medical attention after police investigations). In 1957, McKusick founded the Moore Clinic at Johns Hopkins. Named after Joseph Earle Moore, the Baltimore physician who had spent his life working on chronic illnesses, the clinic would focus on hereditary disorders.

  McKusick turned into a walking repository of knowledge of genetic syndromes. There were patients, unable to process chloride, who were afflicted by intractable diarrhea and malnourishment. There were men prone to heart attacks at twenty; families with schizophrenia, depression, or aggression; children born with webbed necks or extra fingers or the permanent odor of fish. By the mid-1980s, McKusick and his students had cataloged 2,239 genes linked with diseases in humans, and 3,700 diseases linked to single genetic mutations. By the twelfth edition of his book, published in 1998, McKusick had discovered an astounding 12,000 gene variants linked to traits and disorders, some mild and some life threatening.

  Emboldened by their taxonomy of single-gene—“monogenic”—diseases, McKusick and his students ventured into diseases caused by the convergent influence of multiple genes—“polygenic” syndromes. Polygenic diseases, they found, came in two forms. Some were caused by the presence of whole extra chromosomes. In Down syndrome, first described in the 1860s, children are born with an extra copy of chromosome twenty-one, which has three-hundred-odd genes strung on it.I Multiple organs are affected by the extra copy of the chromosome. Men and women with the syndrome are born with flattened nasal bridges, wide faces, small chins, and altered folds in the eyes. They have cognitive deficits, acceler
ated heart disease, hearing loss, infertility, and an increased risk for blood cancers; many children die in infancy or childhood, and only a few survive to late adulthood. Most notably, perhaps, children with Down syndrome have an extraordinary sweetness of temperament, as if in inheriting an extra chromosome they had acquired a concomitant loss of cruelty and malice (if there is any doubt that genotypes can influence temperament or personality, then a single encounter with a Down child can lay that idea to rest).

  The final category of genetic diseases that McKusick characterized was the most complex—polygenic illnesses caused by multiple genes scattered diffusely throughout the genome. Unlike the first two categories, populated by rare and strange syndromes, these were familiar, pervasive, highly prevalent chronic illnesses—diabetes, coronary artery disease, hypertension, schizophrenia, depression, infertility, obesity.

  These illnesses lay on the opposite end of the One Gene–One Disease paradigm; they were Many Genes–Many Diseases. Hypertension, for instance, came in thousands of varieties and was under the influence of hundreds of genes, each exerting a minor additive effect on blood pressure and vascular integrity. Unlike Marfan or Down syndrome, where a single potent mutation or a chromosomal aberration was necessary and sufficient to cause the disease, the effect of any individual gene in polygenic syndromes was dulled. The dependence on environmental variables—diet, age, smoking, nutrition, prenatal exposures—was stronger. The phenotypes were variable and continuous, and the patterns of inheritance complex. The genetic component of the disease only acted as one trigger in a many-triggered gun—necessary, but not sufficient to cause the illness.

  Four important ideas emerged from McKusick’s taxonomy of genetic diseases. First, McKusick realized that mutations in a single gene can cause diverse manifestations of disease in diverse organs. In Marfan syndrome, for instance, a mutation in a fiberlike structural protein affects all connective tissues—tendons, cartilage, bones, and ligaments. Marfan patients have recognizably abnormal joints and spines. Less recognizable, perhaps, are the cardiovascular manifestations of Marfan disease: the same structural protein that supports tendons and cartilage also supports the large arteries and valves of the heart. Mutations in that gene thus lead to the catastrophic heart failures and aortic ruptures. Patients with Marfan syndrome often die in their youth because their blood vessels have been ruptured by the flow of blood.

  Second, the precise converse, surprisingly, was also true: multiple genes could influence a single aspect of physiology. Blood pressure, for instance, is regulated through a variety of genetic circuits, and abnormalities in one or many of these circuits all result in the same disease—hypertension. It is perfectly accurate to say “hypertension is a genetic disease,” but to also add, “There is no gene for hypertension.” Many genes tug and push the pressure of blood in the body, like a tangle of strings controlling a puppet’s arms. If you change the length of any of these individual strings, you change the configuration of the puppet.

  McKusick’s third insight concerned the “penetrance” and “expressivity” of genes in human diseases. Fruit fly geneticists and worm biologists had discovered that certain genes only become actualized into phenotypes depending upon environmental triggers or random chance. A gene that causes facets to appear in the fruit fly eye, for instance, is temperature dependent. Another gene variant changes the morphology of a worm’s intestine—but only does so in about 20 percent of worms. “Incomplete penetrance” meant that even if a mutation was present in the genome, its capacity to penetrate into a physical or morphological feature was not always complete.

  McKusick found several examples of incomplete penetrance in human diseases. For some disorders, such as Tay-Sachs disease, penetrance was largely complete: the inheritance of the gene mutation virtually guaranteed the development of the disease. But for other human diseases, the actual effect of a gene on the disorder was more complex. In breast cancer, as we shall later learn, inheritance of the mutant BRCA1 gene increases the risk of breast cancer dramatically—but not all women with the mutation will develop breast cancer, and different mutations in that gene have different levels of penetrance. Hemophilia, the bleeding disorder, is clearly the result of a genetic abnormality, but the extent to which a patient with hemophilia experiences bleeding episodes varies widely. Some have monthly life-threatening bleeds, while others rarely bleed at all.

  The fourth insight is so pivotal to this story that I have separated it from the others. Like the fly geneticist Theodosius Dobzhansky, McKusick understood that mutations are just variations. The statement sounds like a bland truism, but it conveys an essential and profound truth. A mutation, McKusick realized, is a statistical entity, not a pathological or moral one. A mutation doesn’t imply disease, nor does it specify a gain or loss of function. In a formal sense, a mutation is defined only by its deviation from the norm (the opposite of “mutant” is not “normal” but “wild type”—i.e., the type or variant found more commonly in the wild). A mutation is thus a statistical, rather than normative, concept. A tall man parachuted into a nation of dwarfs is a mutant, as is a blond child born in a country of brunettes—and both are “mutants” in precisely the same sense that a boy with Marfan syndrome is a mutant among non-Marfan, i.e., “normal,” children.

  By itself, then, a mutant, or a mutation, can provide no real information about a disease or disorder. The definition of disease rests, rather, on the specific disabilities caused by an incongruity between an individual’s genetic endowment and his or her current environment—between a mutation, the circumstances of a person’s existence, and his or her goals for survival or success. It is not mutation that ultimately causes disease, but mismatch.

  The mismatch can be severe and debilitating—and in such cases, the disease becomes identical to the disability. A child with the fiercest variant of autism who spends his days rocking monotonously in a corner, or scratching his skin into ulcers, possesses an unfortunate genetic endowment that is mismatched to nearly any environment or any goals. But another child with a different—and rarer—variant of autism may be functional in most situations, and possibly hyperfunctional in some (a chess game, say, or a memory contest). His illness is situational; it lies more evidently in the incongruity of his specific genotype and his specific circumstances. Even the nature of the “mismatch” is mutable: since the environment is constantly subject to change, the definition of disease has to change with it. In the land of the blind, the sighted man is king. But flood that land with a toxic, blinding light—and the kingdom reverts to the blind.

  McKusick’s belief in this paradigm—the focus on disability rather than abnormalcy—was actualized in the treatment of patients in his clinic. Patients with dwarfism, for instance, were treated by an interdisciplinary team of genetic counselors, neurologists, orthopedic surgeons, nurses, and psychiatrists trained to focus on specific disabilities of persons with short stature. Surgical interventions were reserved to correct specific deformities as they arose. The goal was not to restore “normalcy”—but vitality, joy, and function.

  McKusick had rediscovered the founding principles of modern genetics in the realm of human pathology. In humans, as in wild flies, genetic variations abounded. Here too genetic variants, environments, and gene-environment interactions ultimately collaborated to cause phenotypes—except in this case, the “phenotype” in question was disease. Here too some genes had partial penetrance and widely variable expressivity. One gene could cause many diseases, and one disease could be caused by many genes. And here too “fitness” could not be judged in absolutes. Rather, the lack of fitness—illness, in colloquial terms—was defined by the relative mismatch between an organism and environment.

  “The imperfect is our paradise,” Wallace Stevens wrote. If the entry of genetics into the human world carried one immediate lesson, it was this: the imperfect was not just our paradise; it was also, inextricably, our mortal world. The degree of human genetic variation—and the depth of its influence on h
uman pathology—was unexpected and surprising. The world was vast and various. Genetic diversity was our natural state—not just in isolated pockets in faraway places, but everywhere around us. Seemingly homogeneous populations were, in fact, strikingly heterogeneous. We had seen the mutants—and they were us.

  Nowhere, perhaps, was the increased visibility of “mutants” more evident than in that reliable barometer of American anxieties and fantasies—comic strips. In the early 1960s, human mutants burst ferociously into the world of comic characters. In November 1961, Marvel Comics introduced the Fantastic Four, a series about four astronauts who, trapped inside a rocket ship—like Hermann Muller’s fruit flies in bottles—are exposed to a shower of radiation and acquire mutations that bestow supernatural powers on them. The success of the Fantastic Four prompted the even more successful Spider-Man, the saga of young science whiz Peter Parker, who is bitten by a spider that has swallowed “a fantastic amount of radioactivity.” The spider’s mutant genes are transmitted to Parker’s body presumably by horizontal transfer—a human version of Avery’s transformation experiment—thus endowing Parker with the “agility and proportionate strength of an arachnid.”