The Gene

by Siddhartha Mukherjee

  A pair of twins had an identical manner of rubbing their noses, and—even though they had never met—had each invented a new word to describe the odd habit: squidging. Two sisters in Bouchard’s study shared the same pattern of anxiety and despair. As teenagers, they confessed, they had been haunted by the same nightmare: of feeling suffocated in the middle of the night because their throats were being stuffed with various—but typically metallic—things: “door-knobs, needles and fishhooks.”

  Several features were quite different in the reared-apart twins. Daphne and Barbara looked similar, but Barbara was twenty pounds heavier (although, notably, despite the twenty pounds, their heart rates and blood pressures were the same). The German twin, of the Catholic/Jewish set, had been a staunch German nationalist as a young man, while his twin brother had spent his summers at a kibbutz. Yet, both shared a fervor, a rigidity of belief, even if the beliefs themselves were almost diametrically opposed. The picture that emerged from the Minnesota study was not that reared-apart twins were identical, but that they shared a powerful tendency toward similar or convergent behaviors. What was common to them was not identity, but its first derivative.

  In the early 1990s, Richard Ebstein, a geneticist in Israel, read Thomas Bouchard’s paper on the separated-at-birth twins. Ebstein was intrigued: the Bouchard study had shifted our understanding of personality and temperament—away from culture and environment and toward genes. But like Hamer, Ebstein wanted to identify the actual genes that determined variant forms of behavior. Genes had been linked to temperaments before: the extraordinary, otherworldly sweetness of children with Down syndrome had long been noted by psychologists, and other genetic syndromes had been linked with outbursts of violence and aggression. But Ebstein was not interested in the outer bounds of pathology; he was interested in normal variants of temperament. Extreme genetic changes could evidently cause extreme variants of temperament. But were there “normal” gene variants that influenced normal subtypes of personality?

  To find such genes, Ebstein knew, he would have to begin with rigorous definitions of the subtypes of personality that he wished to link to genes. In the late 1980s, psychologists studying variations in human temperament had proposed that a questionnaire, containing just one hundred true/false questions, could effectively split personalities along four archetypal dimensions: novelty seeking (impulsive versus cautious), reward dependent (warm versus detached), risk avoidant (anxious versus calm), and persistent (loyal versus fickle). Twin studies suggested that each of these personality types had a strong genetic component: identical twins had reported more than 50 percent concordance in their scores on these questionnaires.

  Ebstein was particularly intrigued by one of the subtypes. Novelty seekers—or “neophiles”—were characterized as “impulsive, exploratory, fickle, excitable and extravagant” (think Jay Gatsby, Emma Bovary, Sherlock Holmes). In contrast, “neophobes” were “reflective, rigid, loyal, stoic, slow-tempered and frugal” (think Nick Carraway, the always-suffering Charles Bovary, the always-bested Dr. Watson). The most extreme novelty seekers—the greatest among the Gatsbys—seemed virtually addicted to stimulation and excitement. Scores aside, even their test-taking behavior was temperamental. They left questions unanswered. They paced the room, trying to look for ways to get out. They were frequently, hopelessly, maddeningly bored.

  Ebstein began to collect a cohort of extreme neophiles using surveys, advertisements, and questionnaires (do you “often try things just for fun and thrills, even if most people think it’s a waste of time”? Or “how often do things based on how [you] feel at the moment, without thinking about how they have been done in the past”?). Over three years, Ebstein gathered a group of 124 such men and women. He then used molecular and genetic techniques to determine the genotypes within his cohort with a limited panel of genes. The most extreme novelty seekers, he discovered, had a disproportionate representation of one genetic determinant: a variant of a dopamine-receptor gene called D4DR. (This kind of analysis is broadly termed an association study, since it identifies genes via their association with a particular phenotype—extreme impulsivity in this case.)

  Dopamine, a neurotransmitter—a molecule that transmits chemical signals between neurons in the brain—is especially involved in the recognition of “reward” to the brain. It is one of the most potent neurochemical signals that we know: a rat, given a lever to electrically stimulate the dopamine-responsive reward center in the brain, will stimulate itself to death because it neglects to eat and drink.

  D4DR acts as the “docking station” for dopamine, from which the signal is relayed to a dopamine-responsive neuron. Biochemically, the variant associated with novelty seeking, “D4DR-7 repeat,” dulls the response to dopamine, perhaps thereby heightening the requirement for external stimulation to reach the same level of reward. It is like a half-stuck switch, or a velvet-stuffed receiver: it needs a stronger push, or a louder voice, to be turned on. Novelty seekers try to amplify the signal by stimulating their brains with higher and higher forms of risk. They are like habituated drug users, or like the rats in the dopamine-reward experiment—except the “drug” is a brain chemical that signals excitement itself.

  Ebstein’s original study has been corroborated by several other groups. Interestingly, as one might suspect from the Minnesota twin studies, D4DR does not “cause” a personality or temperament. Instead, it causes a propensity toward a temperament that seeks stimulation or excitement—the first derivative of impulsivity. The precise nature of stimulation varies from one context to the next. It can produce the most sublime qualities in humans—exploratory drive, passion, and creative urgency—but it can also spiral toward impulsivity, addiction, violence, and depression. The D4DR-7 repeat variant has been associated with bursts of focused creativity, and also with attention deficit disorder—a seeming paradox until you understand that both can be driven by the same impulse. The most provocative human studies have cataloged the geographic distribution of the D4DR variant. Nomadic and migratory populations have higher frequencies of the variant gene. And the farther one moves from the original site of human dispersal from Africa, the more frequently the variant seems to appear as well. Perhaps the subtle drive caused by the D4DR variant drove the “out-of-Africa” migration, by throwing our ancestors out to sea. Many attributes of our restless, anxious modernity, perhaps, are products of a restless, anxious gene.

  Yet studies on the D4DR variant have been difficult to replicate across different populations and in differing contexts. Some of this, undoubtedly, is because novelty-seeking behaviors depend on age. Perhaps predictably, by age fifty or so, much of the exploratory impulse and its variance has been extinguished. Geographic and racial variations also affect the influence of D4DR on temperament. But the most likely reason for the lack of reproducibility is that the effect of the D4DR variant is relatively weak. One researcher estimates that the effect of D4DR explains only about 5 percent of the variance in novelty-seeking behavior among individuals. D4DR is likely only one of many genes—as many as ten—that determine this particular aspect of personality.

  Gender. Sexual preference. Temperament. Personality. Impulsivity. Anxiety. Choice. One by one, the most mystical realms of human experience have become progressively encircled by genes. Aspects of behavior relegated largely or even exclusively to cultures, choices, and environments, or to the unique constructions of self and identity, have turned out to be surprisingly influenced by genes.

  But the real surprise, perhaps, is that we should be surprised at all. If we accept that variations in genes can influence diffuse aspects of human pathology, then we can hardly be astonished that variations in genes can also influence equally diffuse aspects of normalcy. There is a fundamental symmetry to the idea that the mechanism by which genes cause disease is precisely analogous to the mechanism by which genes cause normal behavior and development. “How nice it would be if we could only get through into Looking-glass House!” says Alice. Human genetics has traveled t
hrough its looking-glass house—and the rules on one side have turned out to be exactly the same as the rules on the other.

  How can we describe the influence of genes on normal human form and function? The language should have a familiar ring to it; it is the very language that was once used to describe the link between genes and illness. The variations that you inherit from your parents, mixed and matched, specify variations in cellular and developmental processes that ultimately result in variations in physiological states. If these variations affect master-regulatory genes at the tip of a hierarchy, the effect can be binary and strong (male versus female; short statured versus normal). More commonly, the variant/mutant genes lie in lower rungs of cascades of information and can only cause alterations in propensities. Often, dozens of genes are required to create these propensities or predispositions.

  These propensities intersect with diverse environmental cues and chance to effect diverse outcomes—including variations in form, function, behavior, personality, temperament, identity, and fate. Mostly, they do so only in a probabilistic sense—i.e., only by altering weights and balances, by shifting likelihoods, by making certain outcomes more or less probable.

  Yet these shifts in likelihoods are sufficient to make us observably different. A change in the molecular structure of a receptor that signals “reward” to neurons in the brain might result in nothing more than a change in the length of time that one molecule engages with its receptor. The signal that emanates from that variant receptor might persist in a neuron for just one-half of a second longer. Yet that change is enough to tip one human being toward impulsivity, and his counterpart toward caution, or one man toward mania and another toward depression. Complex perceptions, choices, and feelings might result from such changes in physical and mental states. The length of a chemical interaction is thus transformed into, say, the longing for an emotional interaction. A man with a propensity toward schizophrenia interprets a fruit vendor’s conversation as a plot to kill him. His brother, with a genetic propensity for bipolar disease, perceives that same conversation as a grandiose fable about his future: even the fruit seller recognizes his incipient fame. One man’s misery becomes another man’s magic.

  This much is easy. But how can we explain an individual organism’s form, temperament, and choices? How do we go, say, from genetic propensities in the abstract to a concrete and particular personhood? We might describe this as the “last mile” problem of genetics. Genes can describe the form or fate of a complex organism in likelihoods and probabilities—but they cannot accurately describe the form or fate itself. A particular combination of genes (a genotype) might predispose you to a particular configuration of a nose or personality—but the precise shape or length of the nose that you acquire remains unknowable. A predisposition cannot be confused with the disposition itself: one is a statistical probability; the other, a concrete reality. It is as if genetics can nearly beat its way to the door of human form, identity, or behavior—but it cannot traverse the final mile.

  Perhaps we can reframe the last-mile problem of genes by contrasting two very different lines of investigation. Since the 1980s, human genetics has spent much of its time concerned with how identical twins separated at birth demonstrate all sorts of similarities. If separated-at-birth twins share a tendency toward impulsivity, depression, cancer, or schizophrenia, then we know that the genome must contain information that encodes predispositions for these characteristics.

  But it requires quite the opposite line of thought to understand how a predisposition is transformed into a disposition. To answer that, we need to ask the converse question: Why do identical twins raised in identical homes and families end up with different lives and become such different beings? Why do identical genomes become manifest in such dissimilar personhoods, with nonidentical temperaments, personalities, fates, and choices?

  For nearly three decades since the eighties, psychologists and geneticists have tried to catalog and measure subtle differences that might explain the divergent developmental fates of identical twins brought up in the same circumstances. But all attempts at finding concrete, measurable, and systematic differences have invariably fallen short: twins share families, live in the same homes, typically attend the same school, have virtually identical nutrition, often read the same books, are immersed in the same culture, and share similar circles of friends—and yet are unmistakably different.

  What causes the difference? Forty-three studies, performed over two decades, have revealed a powerful and consistent answer: “unsystematic, idiosyncratic, serendipitous events.” Illnesses. Accidents. Traumas. Triggers. A missed train; a lost key; a suspended thought. Fluctuations in molecules that cause fluctuations in genes, resulting in slight alterations in forms.III Rounding a bend in Venice and falling into a canal. Falling in love. Randomness. Chance.

  Is that an infuriating answer? After decades of musing, have we reached the conclusion that fate is, well . . . fate? That being happens through . . . be-ing? I find that formulation illuminatingly beautiful. Prospero, raging against the deformed monster Caliban in The Tempest, describes him as “a devil, a born devil, on whose nature, nurture can never stick.” The most monstrous of Caliban’s flaws is that his intrinsic nature cannot be rewritten by any external information: his nature will not allow nurture to stick. Caliban is a genetic automaton, a windup ghoul—and this makes him vastly more tragic and more pathetic than anything human.

  It is a testament to the unsettling beauty of the genome that it can make the real world “stick.” Our genes do not keep spitting out stereotypical responses to idiosyncratic environments: if they did, we too would devolve into windup automatons. Hindu philosophers have long described the experience of “being” as a web—jaal. Genes form the threads of the web; the detritus that sticks is what transforms every individual web into a being. There is an exquisite precision in that mad scheme. Genes must carry out programmed responses to environments—otherwise, there would be no conserved form. But they must also leave exactly enough room for the vagaries of chance to stick. We call this intersection “fate.” We call our responses to it “choice.” An upright organism with opposable thumbs is thus built from a script, but built to go off script. We call one such unique variant of one such organism a “self.”

  * * *

  I. A shared intrauterine environment, or exposures during gestation, might explain some of this concordance, but the fact that nonidentical twins share these environments, yet have a lower concordance compared to identical twins, argues against such theories. The genetic argument is also strengthened by the fact that gay siblings also have a higher rate of concordance than the general population (although lower than identical twins). Future studies might reveal a combination of environmental and genetic factors in the determination of sexual preference, but genes will likely remain important factors.

  II. Earlier versions of the paper appeared in 1984 and 1987.

  III. Perhaps the most provocative recent study on chance, identity, and genetics comes from the laboratory of Alexander van Oudenaarden, a worm biologist at MIT. Van Oudenaarden used the worm as a model to ask one of the most difficult questions about chance and genes: Why do two animals that have the same genome and inhabit the same environment—perfect twins—have different fates? Van Oudenaarden examined a mutation of a gene, skn-1, that is “incompletely penetrant”—i.e., one worm with the mutation manifests a phenotype (cells are formed in the gut), while its twin worm, with the same mutation, does not manifest the phenotype (the cells are not formed). What determines the difference between the two twin worms? Not genes, since both worms share the same skn-1 gene mutation, and not environments, since both are reared and housed in exactly the same conditions. How, then, might the same genotype cause an incompletely penetrant phenotype? Van Oudenaarden found that the expression level of a single regulatory gene, called end-1, is the crucial determinant. The expression of end-1—i.e., the number of molecules of RNA made during a particular phase of worm d
evelopment—varies between worms, most likely due to random or stochastic effects—i.e., chance. If the expression exceeds a threshold, the worm manifests the phenotype; if it is below the level, the worm manifests a different phenotype. Fate reflects random fluctuations in a single molecule in a worm’s body. For further details, see Arjun Raj et al., “Variability in gene expression underlies incomplete penetrance,” Nature 463, no. 7283 (2010): 913–18.

  The Hunger Winter

  Identical twins have exactly the same genetic code as each other. They share the same womb, and usually they are brought up in very similar environments. When we consider this, it doesn’t seem surprising that if one of the twins develops schizophrenia, the chance that his or her twin will also develop the illness is very high. In fact, we have to start wondering why it isn’t higher. Why isn’t the figure 100 percent?

  —Nessa Carey, The Epigenetics Revolution

  Genes have had a glorious run in the 20th century. . . . They have carried us to the edge of a new era in biology, one that holds out the promise of even more astonishing advances. But these very advances will necessitate the introduction of other concepts, other terms and other ways of thinking about biological organization, thereby loosening the grip that genes have had on the imagination of the life sciences.

  —Evelyn Fox Keller, An Anthropology of Biomedicine

  A question implicit in the last chapter must be answered: If the “self” is created through the chance interactions among events and genes, then how are these interactions actually recorded? One twin falls on ice, fractures a knee, and develops a callus, while the other does not. One sister marries a rising executive in Delhi, while the other moves to a crumbling household in Calcutta. Through what mechanism are these “acts of fate” registered within a cell or a body?