The Gene

by Siddhartha Mukherjee

  II. If the origin of this group was in southwestern Africa, as some recent studies suggest, then these humans traveled largely east and north.

  III. More recent estimates have pinned the correlation between identical twins to 0.6–0.7. When the 1950s data was reexamined in subsequent decades by several psychologists, including Leon Kamin, the methodologies used were found to be suspect, and the initial estimates called into question.

  IV. There can hardly be a more cogent genetic argument for equality. It is impossible to ascertain any human’s genetic potential without first equalizing environments.

  The First Derivative of Identity

  For several decades, anthropology has participated in the general deconstruction of “identity” as a stable object of scholarly inquiry. The notion that individuals craft their identity through social performances, and hence that their identity is not a fixed essence, fundamentally drives current research into gender and sexuality. The notion that collective identity emerges out of political struggle and compromise underlies contemporary studies of race, ethnicity and nationalism.

  —Paul Brodwin, “Genetics, Identity, and the Anthropology of Essentialism”

  Methinks you are my glass, and not my brother.

  —William Shakespeare, The Comedy of Errors, act 5, scene 1

  On October 6, 1942, five years before my father’s family left Barisal, my mother was born twice in Delhi. Bulu, her identical twin, came before her, placid and beautiful. My mother, Tulu, emerged several minutes later, squirming and crying murderously. The midwife must, fortunately, have known enough about infants to recognize that the most beautiful are often the most damned: the quiet twin, on the edge of listlessness, was quite severely undernourished and had to be swaddled in blankets and revived. The first few days of my aunt’s life were the most tenuous. She could not suckle at the breast, the story runs (perhaps apocryphally), and there were no infant bottles to be found in Delhi in the forties, so she was fed through a cotton wick dipped in milk, and then from the caul of a cowrie shell shaped like a spoon. A nurse was hired to tend to her. When the breast milk began to run dry at seven months, my mother was quickly weaned to let her sister have its last remnants. Right from the onset, then, my mother and her twin were living experiments in genetics—emphatically identical in nature and emphatically divergent in nurture.

  My mother—the “younger” of the two by minutes—was boisterous. She had a slippery, mercurial temper. She was carefree and fearless, fast to learn and willing to make mistakes. Bulu was physically timid. Her mind was more agile, her tongue sharper, her wit more lancing. Tulu was gregarious. She made friends easily. She was impervious to insults. Bulu was reserved and restrained, quieter and more brittle. Tulu liked theater and dancing. Bulu was a poet, a writer, a dreamer.

  Yet the contrasts only highlighted the similarities between the twins. Tulu and Bulu looked strikingly similar: they had the same freckled skin, almond-shaped face, and high cheekbones, unusual among Bengalis, and the slight downward tilt of the outer edge of the eye, the trick that Italian painters used to make Madonnas seem to exude a mysterious empathy. They shared the inner language that twins often share. They had jokes that only the other twin understood.

  Over the years, their lives drifted apart. Tulu married my father in 1965 (he had moved to Delhi three years earlier). It was an arranged marriage, but also a risky one. My father was a penniless immigrant in a new city, saddled with a domineering mother and a half-mad brother who lived at home. To my mother’s overly genteel West Bengali relatives, my father’s family was the very embodiment of East Bengali hickness: when his brothers sat down to lunch, they would pile their rice in mounds and punch volcanic holes in it for gravy, as if marking the insatiable, perpetual hunger of their village days in the form of craters on their plates. Bulu’s marriage seemed a vastly safer prospect by comparison. In 1966, she was engaged to a young lawyer, the eldest son of a well-established clan in Calcutta. In 1967, Bulu married him and moved to his family’s sprawling, decrepit mansion in South Calcutta, with a garden already choked by weeds.

  By the time I was born, in 1970, the sisters’ fortunes had started to move in unexpected directions. In the late 1960s, Calcutta began its steady descent into hell. Its economy was fraying, its tenuous infrastructure heaving under the weight of waves of immigration. Internecine political movements broke out frequently, shuttering the streets and businesses for weeks. As the city convulsed between cycles of violence and apathy, Bulu’s new family hemorrhaged its savings to keep itself afloat. Her husband kept up the pretense of a job, leaving home every morning with the requisite briefcase and tiffin box—but who needed a lawyer in a city without laws? Eventually, the family sold the mildewing house, with its grand veranda and inner courtyard, and moved into a modest two-room flat—just a few miles from the house that had sheltered my grandmother on her first night in Calcutta.

  My father’s fate, in contrast, mirrored that of his adoptive city. Delhi, the capital, was India’s overnourished child. Bolstered by the nation’s aspirations to build a mega-metropolis, fattened by subsidies and grants, its roads widened and its economy expanded. My father rose through the ranks of a Japanese multinational firm, clambering swiftly from lower-to upper-middle class. Our neighborhood, once girded by forests of thornbushes overrun with wild dogs and goats, was soon transformed into one of the most affluent pockets of real estate in the city. We vacationed in Europe. We learned to eat with chopsticks and swam in hotel pools in the summer. When the monsoons hit Calcutta, the mounds of garbage on the streets clogged the drains and turned the city into a vast infested swamp. One such stagnant pond, festering with mosquitoes, was deposited yearly outside Bulu’s house. She called it her own “swimming pool.”

  There is something in that comment—a lightness—that was symptomatic. You might imagine that the sharp vicissitudes of fortune had reshaped Tulu and Bulu in drastically different ways. On the contrary: over the years, their physical resemblance had dwindled to the point of vanishing, but something ineffable about them—an approach, a temperament—remained remarkably similar and even amplified in its convergence. Despite the growing economic rift between the two sisters, they shared an optimism about the world, a curiosity, a sense of humor, an equanimity that borders on nobility but comes with no pride. When we traveled abroad, my mother would bring home a collection of souvenirs for Bulu—a wooden toy from Belgium, fruit-flavored chewing gum from America that smelled of no earthly fruit, or a glass trinket from Switzerland. My aunt would read travel guides of the countries that we had visited. “I’ve been there too,” she would say, arranging the souvenirs in a glass case, with no trace of bitterness in her voice.

  There is no word, or phrase, in the English language for that moment in a son’s consciousness when he begins to understand his mother—not just superficially, but with the immersive clarity with which he understands himself. My experience of this moment, somewhere in the depths of my childhood, was perfectly dual: as I understood my mother, I also learned to understand her twin. I knew, with luminous certainty, when she would laugh, what made her feel slighted, what would animate her, or where her sympathies or affinities might lie. To see the world through the eyes of my mother was to also see it through the eyes of her twin, except, perhaps, with lenses tinted in slightly different colors.

  What had converged between my mother and her sister, I began to realize, was not personality but its tendency—its first derivative, to borrow a mathematical term. In calculus, the first derivative of a point is not its position in space, but its propensity to change its position; not where an object is, but how it moves in space and time. This shared quality, unfathomable to some, and yet self-evident to a four-year-old, was the lasting link between my mother and her twin. Tulu and Bulu were no longer recognizably identical—but they shared the first derivative of identity.

  Anyone who doubts that genes can specify identity might well have arrived from another planet and failed to notice that t
he humans come in two fundamental variants: male and female. Cultural critics, queer theorists, fashion photographers, and Lady Gaga have reminded us—accurately—that these categories are not as fundamental as they might seem, and that unsettling ambiguities frequently lurk in their borderlands. But it is hard to dispute three essential facts: that males and females are anatomically and physiologically different; that these anatomical and physiological differences are specified by genes; and that these differences, interposed against cultural and social constructions of the self, have a potent influence on specifying our identities as individuals.

  That genes have anything to do with the determination of sex, gender, and gender identity is a relatively new idea in our history. The distinction between the three words is relevant to this discussion. By sex, I mean the anatomic and physiological aspects of male versus female bodies. By gender, I am referring to a more complex idea: the psychic, social, and cultural roles that an individual assumes. By gender identity, I mean an individual’s sense of self (as female versus male, as neither, or as something in between).

  For millennia, the basis of the anatomical dissimilarities between men and women—the “anatomical dimorphism” of sex—was poorly understood. In AD 200, Galen, the most influential anatomist in the ancient world, performed elaborate dissections to try to prove that male and female reproductive organs were analogs of each other, with the male organs turned inside out and the female’s turned outside in. The ovaries, Galen argued, were just internalized testicles retained inside the female body because females lacked some “vital heat” that could extrude the organs. “Turn outward the woman’s [organs] and double the man’s, and you will find the same,” he wrote. Galen’s students and followers stretched this analogy, quite literally, to its absurd point, reasoning that the uterus was the scrotum ballooning inward, and that the fallopian tubes were the seminal vesicles blown up and expanded. The theory was memorialized in a medieval verse, an anatomical mnemonic for medical students:

  Though they of different sexes be

  Yet on the whole, they’re the same as we

  For those that have the strictest searchers been

  Find women are just men turned outside in.

  But what force was responsible for turning men “inside out,” or women “outside in,” like socks? Centuries before Galen, the Greek philosopher Anaxagoras, writing around 400 BC, claimed that gender, like New York real estate, was determined entirely by location. Like Pythagoras, Anaxagoras believed that the essence of heredity was carried by male sperm, while the female only “shaped” male semen in the womb to produce the fetus. The inheritance of gender also followed this pattern. Semen produced in the left testicle gave rise to male children, while semen produced in the right testicle gave rise to females. The specification of gender continued in the womb, extending the left-right spatial code sparked off during ejaculation. A male fetus was deposited, with exquisite specificity, in the right horn of the uterus. A female, conversely, was nurtured in the left horn.

  It is easy to laugh Anaxagoras’s theory off as anachronistic and bizarre. Its peculiar insistence on left and right placement—as if gender were determined by some sort of cutlery arrangement—clearly belongs to another era. But the theory was revolutionary for its time, for it made two crucial advances. First, it recognized that the determination of gender was essentially random—and so a random cause (the left or right origin of sperm) would need to be invoked to explain it. And second, it reasoned that once established, the original random act had to be amplified and consolidated to fully engender gender. The developmental plan of the fetus was crucial. Right-sided sperm found its way to the right side of the uterus, where it was further specified into a male fetus. Left-sided sperm was segregated to the left side to make a female child. Gender determination was a chain reaction, set off by a single step but then amplified by the location of the fetus into the full-fledged dimorphism between men and women.

  And there, for the most part, sex determination sat, for centuries. Theories abounded, but conceptually they were variants of Anaxagoras’s idea—that sex was determined by an essentially random act, consolidated and amplified by the environment of the egg or fetus. “Sex is not inherited,” one geneticist wrote in 1900. Even Thomas Morgan, perhaps the most prominent proponent of the role of genes in development, proposed that sex could not be determined through genes. In 1903, Morgan wrote that sex was likely determined by multiple environmental inputs rather than a single genetic one: “The egg, as far as sex is concerned, appears to be in a sort of balanced state, and the conditions to which it is exposed . . . may determine which sex it will produce. It may be a futile attempt to try to discover any one influence that has a deciding influence for all kinds of eggs.”

  In the winter of 1903, the very year that Morgan had published his casual dismissal of a genetic theory of sex determination, Nettie Stevens, a graduate student, performed a study that would transform the field. Stevens was born to a carpenter in Vermont in 1861. She took courses to become a schoolteacher, but by the early 1890s, had saved enough money from her tutoring jobs to attend Stanford University in California. She chose to attend graduate school in biology in 1900—an unusual choice for a woman in her time—and, even more unusually, chose to perform fieldwork at the zoological station in faraway Naples, where Theodor Boveri had collected his urchin eggs. She learned Italian so that she could speak the lingo of the local fishermen who brought her eggs from the shores. From Boveri, she learned to stain eggs to identify chromosomes—the strange blue-stained filaments that resided in cells.

  Boveri had demonstrated that cells with altered chromosomes could not develop normally—and so hereditary instructions for development had to be carried within chromosomes. But could the genetic determinant for sex also be carried by chromosomes? In 1903, Stevens chose a simple organism—the common mealworm—to investigate the correlation between an individual worm’s chromosomal makeup and its sex. When Stevens used Boveri’s chromosome-staining method on male and female worms, the answer leaped out of the microscope: a variation in just one chromosome correlated perfectly with the worm’s sex. Mealworms have twenty chromosomes in all—ten pairs (most animals have paired chromosomes; humans have twenty-three pairs). Cells from female worms inevitably possessed ten matched pairs. Cells from male worms, in contrast, had two unpaired chromosomes—a small, nublike band and a larger chromosome. Stevens suggested that the presence of the small chromosome was sufficient to determine sex. She termed it the sex chromosome.

  To Stevens, this suggested a simple theory of sex determination. When sperm was created in the male gonad, it was made in two forms—one bearing the nublike male chromosome, and another bearing the normal-size female chromosome—in roughly equal ratios. When sperm bearing the male chromosome—i.e., “male sperm”—fertilized the egg, the embryo was born male. When “female sperm” fertilized an egg, the result was a female embryo.

  Stevens’s work was corroborated by that of her close collaborator, the cell biologist Edmund Wilson, who simplified Stevens’s terminology, calling the male chromosome Y, and the female X. In chromosomal terms, male cells were XY, and females were XX. The egg contains a single X chromosome, Wilson reasoned. When a sperm carrying a Y chromosome fertilizes an egg, it results in an XY combination, and maleness is determined. When a sperm carrying an X chromosome meets a female egg, the result is XX, which determines femaleness. Sex was not determined by right or left testicles, but by a similarly random process—by the nature of the genetic payload of the first sperm to reach and fertilize an egg.

  The XY system discovered by Stevens and Wilson had an important corollary: if the Y chromosome carried all the information to determine maleness, then that chromosome had to carry genes to make an embryo male. At first, geneticists expected to find dozens of male-determining genes on the Y chromosome: sex, after all, involves the exacting coordination of multiple anatomical, physiological, and psychological features, and it was hard to imagine that a
single gene could be capable of performing such diverse functions all by itself. Yet, careful students of genetics knew that the Y chromosome was an inhospitable place for genes. Unlike any other chromosome, the Y is “unpaired”—i.e., it has no sister chromosome and no duplicate copy, leaving every gene on the chromosome to fend for itself. A mutation in any other chromosome can be repaired by copying the intact gene from the other chromosome. But a Y chromosome gene cannot be fixed, repaired, or recopied; it has no backup or guide. When the Y chromosome is assailed by mutations, it lacks a mechanism to recover information. The Y is thus pockmarked with the potshots and scars of history. It is the most vulnerable spot in the human genome.

  As a consequence of this constant genetic bombardment, the human Y chromosome began to jettison information millions of years ago. Genes that were truly valuable for survival were likely shuffled to other parts of the genome where they could be stored securely; genes with limited value were made obsolete, retired, or replaced. As information was lost, the Y chromosome itself shrank—whittled down piece by piece by the mirthless cycle of mutation and gene loss. That the Y chromosome is the smallest of all chromosomes is not a coincidence: it is a victim of planned obsolescence, destined to a male-only convalescence home where it can vanish, puffing its last cigar, into oblivion.

  In genetic terms, this suggests a peculiar paradox. Sex, one of the most complex of human traits, is unlikely to be encoded by multiple genes. Rather, a single gene, buried rather precariously in the Y chromosome, must be the master regulator of maleness.I Male readers of that last paragraph should take notice: we barely made it.

  In the early 1980s, a young geneticist in London named Peter Goodfellow began to hunt for the sex-determining gene on the Y chromosome. A die-hard soccer enthusiast—scruffy, bone-thin, taut, with an unmistakable East Anglian drawl and a “punk meets new romantic” dress sense—Goodfellow intended to use the gene-mapping methods pioneered by Botstein and Davis to narrow the search to a small region of the Y chromosome. But how could a “normal” gene be mapped without the existence of a variant phenotype, or an associated disease? Cystic fibrosis and Huntington’s disease genes had been mapped to their chromosomal locations by tracking the link between the disease-causing gene and signposts along the genome. In both cases, affected siblings carrying the gene also carried the signpost, while unaffected siblings did not. But where might Goodfellow find a human family with a variant gender—a third sex—that was genetically transmitted, and carried by some siblings but not others?