The Gene

by Siddhartha Mukherjee

  The hierarchical organization of this genetic cascade illustrates a crucial principle about the link between genes and environments in general. The perennial debate rages on: nature or nurture, genes or environment? The battle has gone on for so long, and with such animosity, that both sides have capitulated. Identity, we are now told, is determined by nature and nurture, genes and environment, intrinsic and extrinsic inputs. But this too is nonsense—an armistice between fools. If genes that govern gender identity are hierarchically organized—starting with SRY on top and then fanning out into thousands of rivulets of information below—then whether nature predominates or nurture is not absolute, but depends quite acutely on the level of organization one chooses to examine.

  At the top of the cascade, nature works forcefully and unilaterally. Up top, gender is quite simple—just one master gene flicking on and off. If we learned to toggle that switch—by genetic means or with a drug—we could control the production of men or women, and they would emerge with male versus female identity (and even large parts of anatomy) quite intact. At the bottom of the network, in contrast, a purely genetic view fails to perform; it does not provide a particularly sophisticated understanding of gender or its identity. Here, in the estuarine plains of crisscrossing information, history, society, and culture collide and intersect with genetics, like tides. Some waves cancel each other, while others reinforce each other. No force is particularly strong—but their combined effect produces the unique and rippled landscape that we call an individual’s identity.

  * * *

  I. With such steep liabilities, it is a genuine wonder that the XY system of gender determination exists in the first place. Why did mammals evolve a mechanism of sex determination burdened with such obvious pitfalls? Why carry the sex-determination gene in, of all places, an unpaired, hostile chromosome, where it’s most likely to be assailed by mutations?

  To answer the question, we need to step back and ask a more fundamental question: Why was sexual reproduction invented? Why, as Darwin wondered, should new beings “be produced by the union of two sexual elements, instead of by a process of parthenogenesis”?

  Most evolutionary biologists agree that sex was created to enable rapid genetic reassortment. No quicker way exists, perhaps, to mix genes from two organisms than by mixing their eggs and sperm. And even the genesis of spermatozoa and egg cells causes genes to be shuffled through the gene recombination. The powerful reassortment of genes during sexual reproduction increases variation. Variation, in turn, increases an organism’s fitness and survival in the face of a constantly changing environment. The phrase sexual reproduction, then, is a perfect misnomer. The evolutionary purpose of sex is not “reproduction”: organisms can make superior facsimiles—re-productions—of themselves in the absence of sex. Sex was invented for quite the opposite reason: to enable recombination.

  But “sexual reproduction” and “sex determination” are not the same. Even if we recognize the many advantages of sexual reproduction, we might still ask why most mammals use the XY system for gender determination. Why, in short, the Y? We do not know. The XY system for gender determination was clearly invented in evolution several million years ago. In birds, reptiles, and some insects, the system is reversed: the female carries two different chromosomes, while the male carries two identical chromosomes. And in yet other animals, such as some reptiles and fish, gender is determined by the temperature of the egg, or the size of an organism relative to its competitors. These systems of gender determination are thought to predate the XY system of mammals. But why the XY system was fixed in mammals—and why it is still in use—remains a mystery. Having two sexes has some evident advantages: males and females can carry out specialized functions and occupy different roles in breeding. But having two sexes does not require a Y chromosome per se. Perhaps evolution stumbled on the Y chromosome as a quick and dirty solution for sex determination—confining the male-determinant gene in a separate chromosome and putting a powerful gene in it to control maleness is certainly a workable solution. But it is an imperfect solution in the long run: in the absence of a backup copy, male-determining genes are extremely vulnerable. As humans evolve, we might eventually lose the Y altogether and revert to a system in which females have two X chromosomes, and males have only one—a so-called XO system. The Y chromosome—the last identifiable genetic feature of masculinity—will become completely dispensable.

  The Last Mile

  Like sleeping dogs, unknown twins might be better left alone.

  —William Wright, Born That Way

  Whether sex identity is innate or acquired in the one-in-two-thousand babies born with ambiguous genitals does not typically incite national debates about inheritance, preference, perversity, and choice. Whether sexual identity—the choice and preference of sexual partners—is innate or acquired does, absolutely. For a while in the 1950s and 1960s, it seemed that that discussion had been settled for good. The dominant theory among psychiatrists was that sexual preference—i.e., “straightness” versus “gayness”—was acquired, not inborn. Homosexuality was characterized as a frustrated form of neurotic anxiety. “It is the consensus of many contemporary psychoanalytic workers that permanent homosexuals, like all perverts, are neurotics,” the psychiatrist Sándor Lorand wrote in 1956. “The homosexual’s real enemy,” wrote another psychiatrist in the late sixties, “is not so much his perversion but [his] ignorance of the possibility that he can be helped, plus his psychic masochism which leads him to shun treatment.”

  In 1962, Irving Bieber, a prominent New York psychiatrist known for his attempts to convert gay men to straightness, wrote the enormously influential Homosexuality: A Psychoanalytic Study of Male Homosexuals. Bieber proposed that male homosexuality was caused by the distorted dynamics of a family—by the fatal combination of a smothering mother who was often “close-binding and [sexually] intimate,” if not overtly seductive, to her son, and by a detached, distant, or “emotionally hostile” father. Boys responded to these forces by exhibiting neurotic, self-destructive, and crippling behaviors (“a homosexual is a person whose heterosexual function is crippled, like the legs of a polio victim,” Bieber famously said in 1973). Ultimately, in some such boys, a subconscious desire to identify with the mother and to emasculate the father became manifest as a choice to embrace a lifestyle that fell outside the norm. The sexual “polio victim” adopts a pathological style of being, Bieber argued, just as victims of polio might grasp a pathological style of walking. By the late 1980s, the notion that homosexuality represented the choice of a deviant lifestyle had sclerosed into dogma, leading Dan Quayle, then vice president, to sanguinely proclaim in 1992 that “homosexuality is more of a choice than a biological situation. . . . It is a wrong choice.”

  In July 1993, the discovery of the so-called gay gene would incite one of the most vigorous public discussions about genes, identity, and choice in the history of genetics. The discovery would illustrate the power of the gene to sway public opinion and almost fully invert the terms of the discussion. In People magazine (not, we might note, a particularly strident voice for radical social change), the columnist Carol Sarler wrote that October, “What do we say of the woman who will opt for an abortion rather than raising a gentle, caring boy who might—only might, mind you—grow up to love another gentle caring boy? We say that she is a warped, dysfunctional monster who—if forced to have the child—will make the child’s life hell. We say that no child should be forced to have her as a parent.”

  The phrase “gentle, caring boy”—chosen to illustrate a child’s inborn propensity rather than an adult’s perverted preferences—exemplified the inversion of the debate. Once genes had been implicated in the development of sexual preference, the gay child was instantly transformed to normal. His hateful enemies were the abnormal monsters.

  It was boredom, more than activism, that prompted the search for the gay gene. Dean Hamer, a researcher at the National Cancer Institute, was not looking for controversy. He was not
even looking for himself. Although openly gay, Hamer had never been particularly intrigued by the genetics of any form of identity, sexual or otherwise. He had spent much of his life comfortably ensconced in a “normally quiet US government laboratory . . . jumbled floor to ceiling with beakers and vials,” studying the regulation of a gene called metallothionine—or MT—that is used by cells to respond to poisonous heavy metals, such as copper and zinc.

  In the summer of 1991, Hamer flew to Oxford to present a scientific seminar on gene regulation. It was his standard research talk—well received, as usual—but when he opened the floor to discussion, he experienced the most desolate form of déjà vu: the questions seemed exactly the same as the queries raised by his talk a decade ago. When the next speaker, a competitor from another lab, presented data that affirmed and extended Hamer’s work, Hamer found himself becoming even more bored and depressed. “I realized that even if I stuck with this research for another ten years, the best thing I could hope for was to build a three-dimensional replica of our little [genetic] model. It didn’t seem like much of a lifetime goal.”

  In the lull between sessions, Hamer walked out in a daze, his mind churning. He stopped at Blackwell’s, the cavernous bookstore on High Street, and descended into its concentric rooms, browsing through books on biology. He bought two books. The first was Darwin’s Descent of Man, and Selection in Relation to Sex. Published in 1871, Darwin’s book had set off a storm of controversy by claiming human descent from an apelike ancestor (in Origin of Species, Darwin had coyly skirted the question of human descent, but in Descent of Man, he had taken the question head-on).

  Descent of Man is to biologists what War and Peace is to graduate students of literature: nearly every biologist claims to have read the book, or appears to know its essential thesis, but few have actually even opened its pages. Hamer had never read it either. To his surprise, Hamer found that Darwin had spent a substantial portion of the book discussing sex, the choice of sexual partners, and its influence on dominance behaviors and social organization. Darwin had clearly felt that heredity had a powerful effect on sexual behavior. Yet the genetic determinants of sexual behavior and preference—“the final cause of sexuality,” as Darwin described it—had remained mysterious to him.

  But the idea that sexual behavior, or any behavior, was linked to genes had fallen out of fashion. The second book, Richard Lewontin’s Not in Our Genes: Biology, Ideology, and Human Nature, proposed a different view. Published in 1984, Lewontin had launched an attack on the idea that much of human nature was biologically determined. Elements of human behavior that are considered genetically determined, Lewontin argued, are often nothing more than arbitrary, and often manipulative, constructions of culture and society to reinforce power structures. “There is no acceptable evidence that homosexuality has any genetic basis. . . . The story has been manufactured out of whole cloth,” Lewontin wrote. Darwin was broadly right about organismal evolution, he argued—but not about the evolution of human identity.

  Which of these two theories was correct? To Hamer, at least, sexual orientation seemed far too fundamental to be entirely constructed by cultural forces. “Why was Lewontin, a formidable geneticist, so determined not to believe that behavior could be inherited?” Hamer wondered. “He could not disprove the genetics of behavior in the lab and so he wrote a political polemic against it? Maybe there was room for real science here.” Hamer intended to give himself a crash course on the genetics of sexual behavior. He returned to his lab to start exploring—but there was little to be learned from the past. When Hamer searched a database of all scientific journals published since 1966 for articles concerning “homosexuality” and “genes,” he found 14. Searching for the metallothionine gene, in contrast, brought up 654.

  But Hamer did find a few tantalizing clues, even if they were half buried in the scientific literature. In the 1980s, a professor of psychology named J. Michael Bailey had tried to study the genetics of sexual orientation using a twin-study experiment. Bailey’s methodology was classical: if sexual orientation was partly inherited, then a higher proportion of identical twins should both be gay compared to fraternal twins. By placing strategic advertisements in gay magazines and newspapers, Bailey had recruited 110 male twin pairs in which at least one twin was gay. (If this seems difficult today, imagine running this experiment in 1978, when few men were publicly out of the closet, and gay sex in certain states was punishable as a crime.)

  When Bailey looked for concordance of gayness among twins, the results were striking. Among the fifty-six pairs of identical twins, both twins were gay in 52 percent.I Of the fifty-four pairs of nonidentical twins, 22 percent were both gay—lower than the fraction for identical twins, but still significantly higher than the estimate of 10 percent gay in the overall population. (Years later, Bailey would hear of striking cases such as this: In 1971, two Canadian twin brothers were separated within weeks of birth. One was adopted by a prosperous American family. The other was raised in Canada by his natural mother under vastly different circumstances. The brothers, who looked virtually identical, knew nothing of each other’s existence until they ran into each other, by accident, in a gay bar in Canada.)

  Male homosexuality was not just genes, Bailey found. Influences such as families, friends, schools, religious beliefs, and social structure clearly modified sexual behavior—so much so that one identical twin identified as gay and the other as straight as much as 48 percent of the time. Perhaps external or internal triggers were required to release distinct patterns of sexual behavior. Undoubtedly, the pervasive and repressive cultural beliefs that surrounded homosexuality were potent enough to sway the choice of a “straight” identity in one twin but not the other. But the twin studies provided incontrovertible evidence that genes influenced homosexuality more strongly than, say, genes influenced the propensity for type 1 diabetes (the concordance rate among twins is only 30 percent), and almost as strongly as genes influence height (a concordance of about 55 percent).

  Bailey had profoundly changed the conversation around sexual identity away from the 1960s rhetoric of “choice” and “personal preference” toward biology, genetics, and inheritance. If we did not think of variations in height or the development of dyslexia or type 1 diabetes as choices, then we could not think of sexual identity as a choice.

  But was it one gene, or many genes? And what was the gene? Where was it located? To identify the “gay gene,” Hamer needed a much larger study—preferably a study involving families in which sexual orientation could be tracked over multiple generations. To fund such a study, Hamer would need a new grant—but where on earth might a federal researcher studying metallothionine regulation find money to hunt for a gene that influences human sexuality?

  In early 1991, two developments enabled Hamer’s hunt. The first was the announcement of the Human Genome Project. Even though the precise sequence of the human genome would not be known for another decade, the mapping of pivotal genetic signposts along the human genome made it vastly easier to hunt for any gene. Hamer’s idea—of mapping genes related to homosexuality—would have been methodologically intractable in the 1980s. A decade later, with genetic markers strung like marquee lights along most chromosomes, it was at least conceptually within reach.

  The second was AIDS. The illness had decimated the gay community in the late 1980s—and goaded by activists and patients, often through civil disobedience and militant protests, the NIH had eventually committed hundreds of millions of dollars to AIDS-focused research. Hamer’s tactical genius was to piggyback the gay gene hunt on an AIDS-related study. He knew that Kaposi’s sarcoma, a previously rare, indolent tumor, had been found at a strikingly high frequency among gay men with AIDS. Perhaps, Hamer reasoned, the risk factors for the progression of Kaposi’s sarcoma were related to homosexuality—and if so, finding genes for one might lead to identifying genes for the other. The theory was spectacularly wrong: Kaposi’s sarcoma would later be found to be caused by a virus, transmitted se
xually and occur mainly in immunocompromised people, thus explaining its co-occurrence with AIDS. But it was tactically brilliant: in 1991, the NIH granted Hamer $75,000 for his new protocol, a study to find homosexuality-related genes.

  Protocol #92-C-0078 was launched in the fall of 1991. By 1992, Hamer had attracted 114 gay men to his study. Hamer planned to use the cohort to create elaborate family trees to determine if sexual orientation ran in families, to describe the pattern of its inheritance, and to map the gene. But mapping the gay gene, Hamer knew, would become vastly easier if he could find brother pairs where both were known to be gay. Twins share the same genes, but brothers share only some sections of their genomes. If Hamer could find brothers who were gay, he would find the subsections of the genome shared by them, and thereby isolate the gay gene. Beyond family trees, then, Hamer needed samples of genes from such brothers. His budget allowed him to fly such siblings to Washington and provide a $45 stipend for a weekend. The brothers, often estranged, got a reunion. Hamer got a tube of blood.

  By the late summer of 1992, Hamer had collected information about nearly one thousand family members and built family trees for each of the 114 gay men. In June, he sat down for the first glimpse of the data on his computer. Almost instantly, he felt the gratifying heave of validation: as with the Bailey study, the siblings in Hamer’s study had a higher concordance in sexual orientation—about 20 percent, nearly twice the population rate of about 10 percent. The study had produced real data—but the gratification soon turned cold. As Hamer pored through the numbers, he could find no other insight. Beyond the concordance between gay siblings, he found no obvious pattern or trend.

  Hamer was devastated. He tried organizing the numbers into groups and subgroups, but to no avail. He was about to throw the family trees, sketched on pieces of paper, back into their piles, when he stumbled on a pattern—an observation so subtle that only the human eye could have discerned it. By chance, while drawing the trees, he had placed the paternal relatives on the left, and maternal relatives on the right, for each family. Gay men were marked with red. And as he shuffled the papers, he instinctively discerned a trend: the red marks tended to cluster toward the right, while the unmarked men tended to cluster to the left. Gay men tended to have gay uncles—but only on the maternal side. The more Hamer hunted up and down the family trees for gay relatives—a “gay Roots project,” as he called it—the more the trend intensified. Maternal cousins had higher rates of concordance—but not paternal cousins. Maternal cousins through aunts tended to have higher concordance than any other cousins.