The Gene

  In fact, such humans existed—although identifying them was a much more complicated task than anticipated. In 1955, Gerald Swyer, an English endocrinologist investigating female infertility, had discovered a rare syndrome that made humans biologically female but chromosomally male. “Women” born with “Swyer syndrome” were anatomically and physiologically female throughout childhood, but did not achieve female sexual maturity in early adulthood. When their cells were examined, geneticists discovered that these “women” had XY chromosomes in all their cells. Every cell was chromosomally male—yet the person built from these cells was anatomically, physiologically, and psychologically female. A “woman” with Swyer syndrome had been born with the male chromosomal pattern (i.e., XY chromosomes) in all of her cells, but had somehow failed to signal “maleness” to her body.

  The most likely scenario behind Swyer syndrome was that the master-regulatory gene that specifies maleness had been inactivated by a mutation, leading to femaleness. At MIT, a team led by the geneticist David Page had used such sex-reversed women to map the male-determinant gene to a relatively narrow region of the Y chromosome. The next step was the most laborious—the gene-by-gene sifting to find the correct candidate among the dozens of genes in that general location. Goodfellow was making slow, steady progress when he received devastating news. In the summer of 1989, he learned that Page had landed on the male-determinant gene. Page called the gene ZFY, for its presence in the Y chromosome.

  Initially, ZFY seemed like the perfect candidate: it was located in the right region of the Y chromosome, and its DNA sequence suggested that it could act as a master switch for dozens of other genes. But when Goodfellow looked carefully, the shoe wouldn’t fit: when ZFY was sequenced in women with Swyer syndrome, it was completely normal. There was no mutation that would explain the disruption of the male signal in these women.

  With ZFY disqualified, Goodfellow returned to his search. The gene for maleness had to be in the region identified by Page’s team: they must have come close, but just missed it. In 1989, rooting about close to the ZFY gene, Goodfellow found another promising candidate—a small, nondescript, tightly packed, intronless gene called SRY. Right at the onset, it seemed like the perfect candidate. The normal SRY protein was abundantly expressed in the testes, as one might expect for a sex-determination gene. Other animals, including marsupials, also carried variants of the gene on their Y chromosomes—and thus only males inherited the gene. The most striking proof that SRY was the correct gene came from the analysis of human cohorts: the gene was indisputably mutated in females with Swyer syndrome, and nonmutated in their unaffected siblings.

  But Goodfellow had one last experiment to clinch the case—the most dramatic of his proofs. If the SRY gene was the singular determinant of “maleness,” what if he forcibly activated the gene in female animals? Would females be forced to turn into males? When Goodfellow inserted an extra copy of the SRY gene into female mice, their offspring were born with XX chromosomes in every cell (i.e., genetically female), as expected. Yet the mice developed as anatomically male—including growing a penis and testicles, mounting females, and performing every behavior characteristic of male mice. By flicking a single genetic switch, Goodfellow had switched an organism’s sex—creating Swyer syndrome in reverse.

  Is all of sex just one gene, then? Almost. Women with Swyer syndrome have male chromosomes in every cell in the body—but with the maleness-determining gene inactivated by a mutation, the Y chromosome is literally emasculated (not in a pejorative but in a purely biological sense). The presence of the Y chromosome in the cells of women with Swyer syndrome does disrupt some aspects of the anatomical development of females. In particular, breasts do not form properly, and ovarian function is abnormal, resulting in low levels of estrogen. But these women feel absolutely no disjunction in their physiology. Most aspects of female anatomy are formed perfectly normally: the vulva and vagina are intact, and a urinary outlet is attached to them with textbook fidelity. Astonishingly, even the gender identity of women with Swyer syndrome is unambiguous: just one gene flicked off and they “become” women. Although estrogen is undoubtedly required to enable the development of secondary sexual characteristics and reinforce some anatomical aspects of femininity in adults, women with Swyer syndrome are typically never confused about gender or gender identity. As one woman wrote, “I definitely identify with female gender roles. I’ve always considered myself one hundred percent female. . . . I played on a boy’s soccer team for a while—I have a twin brother; we look nothing alike—but I was definitely a girl on a boy’s team. I didn’t fit in well: I suggested that we name our team ‘the butterflies.’ ”

  Women with Swyer syndrome are not “women trapped in men’s bodies.” They are women trapped in women’s bodies that are chromosomally male (except for just one gene). A mutation in that single gene, SRY, creates a (largely) female body—and, more crucially, a wholly female self. It is as artless, as plain, as binary, as leaning over the nightstand and turning a switch on or off.

  If genes determine sexual anatomy so unilaterally, then how do genes affect gender identity? On the morning of May 5, 2004, David Reimer, a thirty-eight-year-old man in Winnipeg, walked into the parking lot of a grocery store and killed himself with a sawed-off shotgun. Born in 1965 as Bruce Reimer—chromosomally, and genetically, male—David had been the victim of a ghoulish attempt at circumcision by an inept surgeon, resulting in a severely damaged penis in early infancy. Reconstructive surgery was impossible, and so Bruce’s parents had rushed him to see John Money, a psychiatrist at Johns Hopkins University, known internationally for his interest in gender and sexual behavior. Money evaluated the child and, as part of an experiment, asked Bruce’s parents to have their son castrated and raise him as a girl. Desperate to give their son a “normal” life, his parents capitulated. They changed his name to Brenda.

  Money’s experiment on David Reimer—for which he never asked or received permission from the university or hospital—was an attempt to test a theory widely fashionable in academic circles in the sixties. The notion that gender identity was not innate and was crafted through social performance and cultural mimicry (“you are who you act; nurture can overcome nature”) was in its full prime in that era—and Money was among its most ardent and most vocal proponents. Casting himself as the Henry Higgins of sexual transformation, Money advocated “sexual reassignment,” the reorientation of sexual identity through behavioral and hormonal therapy—a decades-long process invented by him that allowed his experimental subjects to emerge with their identities sanguinely switched. Based on Money’s advice, “Brenda” was dressed and treated as a girl. Her hair was grown long. She was given female dolls and a sewing machine. Her teachers and friends were never informed about the switch.

  Brenda had an identical twin—a boy named Brian—who was brought up as a male child. As part of the study, Brenda and Brian visited Money’s clinic in Baltimore at frequent intervals throughout their childhood. As preadolescence approached, Money prescribed estrogen supplements to feminize Brenda. The surgical construction of an artificial vagina was scheduled to complete her anatomical transformation into a woman. Money published a steady stream of highly cited papers touting the extraordinary success of the sexual reassignment. Brenda was adjusting to her new identity with perfect equanimity, he proposed. Her twin, Brian, was a “rough and tumble” boy, while Brenda was an “active little girl.” Brenda would ease into womanhood with scarcely any hurdles, Money declared. “Gender identity is sufficiently incompletely differentiated at birth to permit successful assignment of a genetic male as a girl.”

  In reality, nothing could have been further from the truth. At age four, Brenda took scissors and shredded the pink and white dresses she had been forced to wear. She lapsed into fits of fury when told to walk or talk like a girl. Pinioned to an identity that she found evidently false and discordant, she was anxious, depressed, confused, anguished, and often frankly enraged. In her school reports,
Brenda was described as “tomboyish” and “dominant,” with “abundant physical energy.” She refused to play with dolls or other girls, preferring her brother’s toys (the only time she played with her sewing machine was when she sneaked a screwdriver out of her father’s toolbox and took the machine meticulously apart, screw by screw). Perhaps most confoundingly to her young classmates, Brenda went to the girl’s bathroom dutifully—but then preferred to urinate with her legs spread wide, standing up.

  After fourteen years, Brenda brought this grotesque charade to an end. She refused the vaginal operation. She stopped the estrogen pills, underwent a bilateral mastectomy to excise her breast tissue, and began injecting testosterone to revert back to male. She—he—changed her name to David. He married a woman in 1990, but the relationship was tormented from the start. Bruce/Brenda/David—the boy who became a girl who became a man—continued to ricochet between devastating bouts of anxiety, anger, denial, and depression. He lost his job. The marriage failed. In 2004, shortly after a bitter altercation with his wife, David killed himself.

  David Reimer’s case was not unique. In the 1970s and 1980s, several other cases of sexual reassignment—the attempted conversion of chromosomally male children into females through psychological and social conditioning—were described, each troubled and troubling in its own right. In some cases, the gender dysphoria was not as acute as David’s—but the wo/men often suffered haunting pangs of anxiety, anger, dysphoria, and disorientation well into adulthood. In one particularly revealing case, a woman—called C—came to see a psychiatrist in Rochester, Minnesota. Dressed in a frilly, floral blouse and a rough cowhide jacket—“my leather-and-lace look,” as she described it—C had no problems with some aspects of her duality, yet had trouble reconciling her “sense of herself as fundamentally female.” Born and raised as a girl in the 1940s, C recalled being a tomboy in school. She had never thought of herself as physically male, but had always felt a kinship with men (“I feel like I have the brain of a man”). She married a man in her twenties and lived with him—until a chance ménage à trois involving a woman kindled her fantasies about women. Her husband married the other woman, and C left him and entered a series of lesbian relationships. She oscillated between periods of equanimity and depression. She joined a church and discovered a nurturing spiritual community—except for a pastor who railed against her homosexuality and recommended therapy to “convert” her.

  At forty-eight, goaded by guilt and fear, she finally sought psychiatric assistance. During the medical examination, her cells were sent for chromosomal analysis, and she was found to have XY chromosomes in her cells. Genetically speaking, C was male. She later discovered that s/he had been born with ambiguous, underdeveloped genitals, although chromosomally male. Her mother had consented to reconstructive surgery to transform her into a female. Sexual reassignment had begun when she was six months old, and she had been given hormones at puberty on the pretext of curing a “hormonal imbalance.” Throughout her childhood and adolescence, C did not have the faintest spasm of doubt about her gender.

  C’s case illustrates the importance of thinking carefully about the link between gender and genetics. Unlike David Reimer, C was not confused about the performance of gender roles: she wore female clothes in public, maintained a heterosexual marriage (for a while, at least), and acted within the range of cultural and social norms to pass as female for forty-eight years. Yet despite her guilt about her sexuality, crucial aspects of her identity—kinship, fantasy, desire, and erotic drive—remained fastened to maleness. C had been able to learn many of the essential features of her acquired gender through social performance and mimesis, but she couldn’t unlearn the psychosexual drives of her genetic self.

  In 2005, a team of researchers at Columbia University validated these case reports in a longitudinal study of “genetic males”—i.e., children born with XY chromosomes—who had been assigned to female gender at birth, typically because of the inadequate anatomical development of their genitals. Some of the cases were not as anguished as David Reimer’s or C’s—but an overwhelming number of males assigned to female gender roles reported experiencing moderate to severe gender dysphoria during childhood. Many had suffered anxiety, depression, and confusion. Many had voluntarily changed genders back to male upon adolescence and adulthood. Most notably, when “genetic males” born with ambiguous genitals were brought up as boys, not girls, not a single case of gender dysphoria or gender change in adulthood was reported.

  These case reports finally put to rest the assumption, still unshakably prevalent in some circles, that gender identity can be created or programmed entirely, or even substantially, by training, suggestion, behavioral enforcement, social performance, or cultural interventions. It is now clear that genes are vastly more influential than virtually any other force in shaping sex identity and gender identity—although in limited circumstances a few attributes of gender can be learned through cultural, social, and hormonal reprogramming. Since even hormones are ultimately “genetic”—i.e., the direct or indirect products of genes—then the capacity to reprogram gender using purely behavioral therapy and cultural reinforcement begins to tip into the realm of impossibility. Indeed, the growing consensus in medicine is that, aside from exceedingly rare exceptions, children should be assigned to their chromosomal (i.e., genetic) sex regardless of anatomical variations and differences—with the option of switching, if desired, later in life. As of this writing, none of these children have opted to switch from their gene-assigned sexes.

  How can we reconcile this idea—of a single genetic switch that dominates one of the most profound dichotomies in human identity—with the fact that human gender identity in the real world appears in a continuous spectrum? Virtually every culture has recognized that gender does not exist in discrete half-moons of black and white, but in a thousand shades of gray. Even Otto Weininger, the Austrian philosopher famous for his misogyny, conceded, “Is it really the case that all women and men are marked off sharply from each other . . . ? There are transitional forms between the metals and nonmetals; between chemical combinations and simple mixtures, between animals and plants, between phanerogams and cryptogams, and between mammals and birds. . . . The improbability may henceforth be taken for granted of finding in Nature a sharp cleavage between all that is masculine on the one side and all that is feminine on the other.”

  In genetic terms, though, there is no contradiction: master switches and hierarchical organizations of genes are perfectly compatible with continuous curves of behavior, identity, and physiology. The SRY gene indubitably controls sex determination in an on/off manner. Turn SRY on, and an animal becomes anatomically and physiologically male. Turn it off, and the animal becomes anatomically and physiologically female.

  But to enable more profound aspects of gender determination and gender identity, SRY must act on dozens of targets—turning them on and off, activating some genes and repressing others, like a relay race that moves a baton from hand to hand. These genes, in turn, integrate inputs from the self and the environment—from hormones, behaviors, exposures, social performance, cultural role-playing, and memory—to engender gender. What we call gender, then, is an elaborate genetic and developmental cascade, with SRY at the tip of the hierarchy, and modifiers, integrators, instigators, and interpreters below. This geno-developmental cascade specifies gender identity. To return to an earlier analogy, genes are single lines in a recipe that specifies gender. The SRY gene is the first line in the recipe: “Start with four cups of flour.” If you fail to start with the flour, you will certainly not bake anything close to a cake. But infinite variations fan out of that first line—from the crusty baguette of a French bakery to the eggy mooncakes of Chinatown.

  The existence of a transgender identity provides powerful evidence for this geno-developmental cascade. In an anatomical and physiological sense, sex identity is quite binary: just one gene governs sex identity, resulting in the striking anatomical and physiological dimorphism th
at we observe between males and females. But gender and gender identity are far from binary. Imagine a gene—call it TGY—that determines how the brain responds to SRY. One child might inherit a TGY gene variant that is highly resistant to the action of SRY on the brain, resulting in a body that is anatomically male, but a brain that does not read or interpret that male signal. Such a brain might recognize itself as psychologically female; it might consider itself neither male or female, or imagine itself belonging to a third gender altogether.

  These men (or women) have something akin to a Swyer syndrome of identity: their chromosomal and anatomical gender is male (or female), but their chromosomal/anatomical state does not generate a synonymous signal in their brains. In rats, notably, such a syndrome can be caused by changing a single gene in the brains of female embryos or exposing embryos to a drug that blocks the signaling of “femaleness” to the brain. Female mice engineered with this altered gene or treated with this drug have all the anatomical and physiological features of femaleness, but perform the activities associated with male mice, including mounting females: these animals might be anatomically female, but they are behaviorally male.