The Gene: An Intimate History

by Siddhartha Mukherjee

Three profoundly destabilizing scientific ideas ricochet through the twentieth century, trisecting it into three unequal parts: the atom, the byte, the gene. Each is foreshadowed by an earlier century, but dazzles into full prominence in the twentieth. Each begins its life as a rather abstract scientific concept, but grows to invade multiple human discourses—thereby transforming culture, society, politics, and language. But the most crucial parallel between the three ideas, by far, is conceptual: each represents the irreducible unit—the building block, the basic organizational unit—of a larger whole: the atom, of matter; the byte (or “bit”), of digitized information; the gene, of heredity and biological information.1

Straining to see the world through triangle-shaped lenses, Pythagoreans argued that in heredity too a triangular harmony was at work. The mother and the father were two independent sides and the child was the third—the biological hypotenuse to the parents’ two lines. And just as a triangle’s third side could arithmetically be derived from the two other sides using a strict mathematical formula, so was a child derived from the parents’ individual contributions: nature from father and nurture from mother.

Between 1857 and 1864, Mendel shelled bushel upon bushel of peas, compulsively tabulating the results for each hybrid cross (“yellow seeds, green cotyledons, white flowers”). The results remained strikingly consistent. The small patch of land in the monastery garden produced an overwhelming volume of data to analyze—twenty-eight thousand plants, forty thousand flowers, and nearly four hundred thousand seeds. “It requires indeed some courage to undertake a labor of such far-reaching extent,” Mendel would write later. But courage is the wrong word here. More than courage, something else is evident in that work—a quality that one can only describe as tenderness.

On January 6, 1884, Mendel died of kidney failure in Brno, his feet swollen with fluids. The local newspaper wrote an obituary, but made no mention of his experimental studies. Perhaps more fitting was a short note from one of the younger monks in the monastery: “Gentle, free-handed, and kindly . . . Flowers he loved.”

In a fit of panic, de Vries rushed his paper on plant hybrids to print in March 1900, pointedly neglecting any mention of Mendel’s prior work. Perhaps the world had forgotten “a certain Mendel” and his work on pea hybrids in Brno. “Modesty is a virtue,” he would later write, “yet one gets further without it.”

“In research, as in all business of exploration, the stirring time comes when a fresh region is unlocked by the discovery of a new key.”

But where Maudsley proposed caution, others urged speed. H. G. Wells, the novelist, was no stranger to eugenics. In his book The Time Machine, published in 1895, Wells had imagined a future race of humans that, having selected innocence and virtue as desirable traits, had inbred to the point of effeteness—degenerating into an etiolated, childlike race devoid of any curiosity or passion. Wells agreed with Galton’s impulses to manipulate heredity as a means to create a “fitter society.” But selective inbreeding via marriage, Wells argued, might paradoxically produce weaker and duller generations. The only solution was to consider the macabre alternative—the selective elimination of the weak. “It is in the sterilization of failure, and not in the selection of successes for breeding, that the possibility of an improvement of the human stock lies.”

It was a charged time; the entire nation was frothing with anguish about its history and inheritance. The Roaring Twenties stood at the tail end of a historic surge of immigration to the United States. Between 1890 and 1924, nearly 10 million immigrants—Jewish, Italian, Irish, and Polish workers—streamed into New York, San Francisco, and Chicago, packing the streets and tenements and inundating the markets with foreign tongues, rituals, and foods (by 1927, new immigrants comprised more than 40 percent of the populations of New York and Chicago). And as much as class anxiety had driven the eugenic efforts of England in the 1890s, “race anxiety” drove the eugenic efforts of Americans in the 1920s.1

Six decades and two years, no more than a passing glance of time, separate Mendel’s initial experiments on peas and the court-mandated sterilization of Carrie Buck.

Sturtevant’s rudimentary genetic map would foreshadow the vast and elaborate efforts to map genes along the human genome in the 1990s. By using linkage to establish the relative positions of genes on chromosomes, Sturtevant would also lay the groundwork for the future cloning of genes tied to complex familial diseases, such as breast cancer, schizophrenia, and Alzheimer’s disease. In about twelve hours, in an undergraduate dorm room in New York, he had poured the foundation for the Human Genome Project.

Between 1905 and 1925, the Fly Room at Columbia was the epicenter of genetics, a catalytic chamber for the new science. Ideas ricocheted off ideas, like atoms splitting atoms. The chain reaction of discoveries—linkage, crossing over, the linearity of genetic maps, the distance between genes—burst forth with such ferocity that it seemed, at times, that genetics was not born but zippered into existence. Over the next decades, a spray of Nobel Prizes would be showered on the occupants of the room: Morgan, his students, his student’s students, and even their students would all win the prize for their discoveries.

In 1909, a young mathematician named Ronald Fisher entered Caius College in Cambridge. Born with a hereditary condition that caused a progressive loss of vision, Fisher had become nearly blind by his early teens. He had learned mathematics largely without paper or pen and thus acquired the ability to visualize problems in his mind’s eye before writing equations on paper. Fisher excelled at math as a secondary school student, but his poor eyesight became a liability at Cambridge. Humiliated by his tutors, who were disappointed in his abilities to read and write mathematics, he switched to medicine, but failed his exams (like Darwin, like Mendel, and like Galton—the failure to achieve conventional milestones of success seems to be a running theme in this story). In 1914, as war broke out in Europe, he began working as a statistical analyst in the City of London.

How could “particles of information”—pixels of heredity—give rise to the observed smoothness of the living world?

There is no such thing as perfection, only the relentless, thirsty matching of an organism to its environment. That is the engine that drives evolution.

But Griffith, an unassuming, painfully shy scientist—“this tiny man who . . . barely spoke above a whisper”—could hardly be expected to broadcast the broader relevance or appeal of his results. “Englishmen do everything on principle,” George Bernard Shaw once noted—and the principle that Griffith lived by was utter modesty.

Writing in an abjectly apologetic tone, Griffith seemed genuinely sorry that he had shaken genetics by its roots. His study discussed transformation as a curiosity of microbial biology, but never explicitly mentioned the discovery of a potential chemical basis of heredity. The most important conclusion of the most important biochemical paper of the decade was buried, like a polite cough, under a mound of dense text.

As Muller thought about the future of eugenics and the possibility of altering human genomes, he wondered whether Galton and his collaborators had made a fundamental conceptual error. Like Galton and Pearson, Muller sympathized with the desire to use genetics to alleviate suffering. But unlike Galton, Muller began to realize that positive eugenics was achievable only in a society that had already achieved radical equality. Eugenics could not be the prelude to equality. Instead, equality had to be the precondition for eugenics. Without equality, eugenics would inevitably falter on the false premise that social ills, such as vagrancy, pauperism, deviance, alcoholism, and feeblemindedness were genetic ills—while, in fact, they merely reflected inequality. Women such as Carrie Buck weren’t genetic imbeciles; they were poor, illiterate, unhealthy, and powerless—victims of their social lot, not of the genetic lottery. The Galtonians had been convinced that eugenics would ultimately generate radical equality—transforming the weak into the powerful. Muller turned that reasoning on its head. Without equality, he argued, eugenics would degenerate into yet another mechanism by which the powerful could control the weak.

The suicide attempt was unsuccessful, but it was symptomatic of his malaise. Muller was sick of America—its dirty science, ugly politics, and selfish society. He wanted to escape to a place where he could meld science and socialism more easily. Radical genetic interventions could only be imagined in radically egalitarian societies. In Berlin, he knew, an ambitious liberal democracy with socialist leanings was shedding the husk of its past and guiding the birth of a new republic in the thirties. It was the “newest city” of the world, Twain had written—a place where scientists, writers, philosophers, and intellectuals were gathering in cafés and salons to forge a free and futuristic society. If the full potential of the modern science of genetics was to be unleashed, Muller thought, it would be in Berlin.

The vast sterilization and containment programs required the creation of an equally vast administrative apparatus. By 1934, nearly five thousand adults were being sterilized every month, and two hundred Hereditary Health Courts (or Genetic Courts) had to work full-time to adjudicate appeals against sterilization. Across the Atlantic, American eugenicists applauded the effort, often lamenting their own inability to achieve such effective measures. Lothrop Stoddard, another protégé of Charles Daven port’s, visited one such court in the late thirties and wrote admiringly of its surgical efficacy. On trial during Stoddard’s visit was a manic-depressive woman, a girl with deaf-muteness, a mentally retarded girl, and an “ape-like man” who had married a Jewess and was apparently also a homosexual—a complete trifecta of crimes. From Stoddard’s notes, it remains unclear how the hereditary nature of any of these symptoms was established. Nonetheless, all the subjects were swiftly approved for sterilization.

By the late 1930s, though, the glacial equanimity of the German public response to the sterilization program made the Nazis bolder. Opportunity presented itself in 1939. In the summer of that year, Richard and Lina Kretschmar petitioned Hitler to allow them to euthanize their child, Gerhard. Eleven months old, Gerhard had been born blind and with deformed limbs. The parents—ardent Nazis—hoped to service their nation by eliminating their child from the nation’s genetic heritage. Sensing his chance, Hitler approved the killing of Gerhard Kretschmar and then moved quickly to expand the program to other children.

The killing began with “defective” children under three years of age, but by September 1939 had smoothly expanded to adolescents. Juvenile delinquents were slipped onto the list next. Jewish children were disproportionately targeted—forcibly examined by state doctors, labeled “genetically sick,” and exterminated, often on the most minor pretexts.

Hannah Arendt, the influential cultural critic who documented the perverse excesses of Nazism, would later write about the “banality of evil” that permeated German culture during the Nazi era. But equally pervasive, it seemed, was the credulity of evil. That “Jewishness” or “Gypsyness” was carried on chromosomes, transmitted through heredity, and thereby subject to genetic cleansing required a rather extraordinary contortion of belief—but the suspension of skepticism was the defining credo of the culture.

But it is impossible to separate this apprenticeship in savagery from its fully mature incarnation; it was in this kindergarten of eugenic barbarism that the Nazis learned the alphabets of their trade. The word genocide shares its root with gene—and for good reason: the Nazis used the vocabulary of genes and genetics to launch, justify, and sustain their agenda. The language of genetic discrimination was easily parlayed into the language of racial extermination. The dehumanization of the mentally ill and physically disabled (“they cannot think or act like us”) was a warm-up act to the dehumanization of Jews (“they do not think or act like us”). Never before in history, and never with such insidiousness, had genes been so effortlessly conflated with identity, identity with defectiveness, and defectiveness with extermination.

Although Nazi doctrine was unsurpassed in its virulence, both Nazism and Lysenkoism shared a common thread: in both cases, a theory of heredity was used to construct a notion of human identity that, in turn, was contorted to serve a political agenda.

The two theories of heredity may have been spectacularly opposite—the Nazis were as obsessed with the fixity of identity as the Soviets were with its complete pliability—but the language of genes and inheritance was central to statehood and progress: it is as difficult to imagine Nazism without a belief in the indelibility of inheritance as it is to conceive of a Soviet state without a belief in its perfect erasure. Unsurprisingly, in both cases, science was deliberately distorted to support state-sponsored mechanisms of “cleansing.” By appropriating the language of genes and inheritance, entire systems of power and statehood were justified and reinforced. By the mid-twentieth century, the gene—or the denial of its existence—had already emerged as a potent political and cultural tool. It had become one of the most dangerous ideas in history.

Indeed, whatever early advances in twin studies were achieved in Germany, Mengele’s experiments putrefied twin research so effectively, pickling the entire field in such hatred, that it would take decades for the world to take it seriously.

Germany had dominated science in the early twentieth century: it had been the crucible of atomic physics, quantum mechanics, nuclear chemistry, physiology, and biochemistry. Of the one hundred Nobel Prizes awarded in physics, chemistry, and medicine between 1901 and 1932, thirty-three were awarded to German scientists (the British received eighteen; the Americans only six). When Hermann Muller arrived in Berlin in 1932, the city was home to the world’s preeminent scientific minds. Einstein was writing equations on the chalkboards of the Kaiser Wilhelm Institute of Physics. Otto Hahn, the chemist, was breaking apart atoms to understand their constituent subatomic particles. Hans Krebs, the biochemist, was breaking open cells to identify their constituent chemical components.

This, perhaps, was the final contribution of Nazism to genetics: it placed the ultimate stamp of shame on eugenics. The horrors of Nazi eugenics inspired a cautionary tale, prompting a global reexamination of the ambitions that had spurred the effort. Around the world, eugenic programs came to a shamefaced halt. The Eugenics Record Office in America had lost much of its funding in 1939 and shrank drastically after 1945. Many of its most ardent supporters, having developed a convenient collective amnesia about their roles in encouraging the German eugenicists, renounced the movement altogether.

Proteins enabled chemical reactions, speeding and controlling the pace of biochemical processes, thereby acting as the switchboards of the biological world.

A dark-haired, dark-eyed daughter of a prominent English banker, with a gaze that bored through her listeners like X-rays, Franklin was a rare specimen in the lab—an independent female scientist in a world dominated by men.

She had little desire to work as anyone’s assistant—let alone for Maurice Wilkins, whose mild manner she disliked, whose values, she opined, were hopelessly “middle-class,” and whose project—deciphering DNA—was on a direct collision course with hers. It was, as one friend of Franklin’ s would later put it, “hate at first sight.”

What she was trying to drown, really, was noise. The chink of beer mugs in pubs infested by men; the casual bonhomie of men discussing science in their male-only common room at King’s. Franklin found most of her male colleagues “positively repulsive.” It was not just sexism—but the innuendo of sexism that was exhausting: the energy spent parsing perceived slights or deciphering unintended puns. She would rather work on other codes—of nature, of crystals, of invisible structures. Unusually for his time, Randall was not averse to hiring women scientists; there were several women working with Franklin at King’s. And female trailblazers had come before her: severe, passionate Marie Curie, with her chapped palms and char-black dresses, who had distilled radium out of a cauldron of black sludge and won not one Nobel Prize but two; and matronly, ethereal Dorothy Hodgkin at Oxford, who had won her own Nobel for solving the crystal structure of penicillin (an “affable looking housewife,” as one newspaper described her). Yet Franklin fit neither model: she was neither affable housewife nor cauldron-stirrer in a boiled wool robe, neither Madonna nor witch.

Franklin adjusted the humidity of the chamber using an ingenious apparatus that bubbled hydrogen through salt water. As she increased the wetness of DNA in the chamber, the fibers seemed to relax permanently. She had tamed them at last. Within weeks, she was taking pictures of DNA of a quality and clarity that had never before been seen. J. D. Bernal, the crystallographer, would later call them the “most beautiful X ray photographs of any substance ever taken.”

Watson knew “nothing about the X-ray diffraction technique,” but he had an unfailing intuition about the importance of certain biological problems. Trained as an ornithologist at the University of Chicago, he had assiduously “avoid[ed] taking any chemistry or physics courses which looked of even medium difficulty.” But a kind of homing instinct had led him to DNA. He too had read Schrödinger’s What Is Life? and been captivated. He had been working on the chemistry of nucleic acids in Copenhagen—“a complete flop,” as he would later describe it—but Wilkins’s photograph entranced him. “The fact that I was unable to interpret it did not bother me. It was certainly better to imagine myself becoming famous than maturing into a stifled academic who had never risked a thought.”

Watson had moved to Cambridge for the love of a photograph. The very first day that he landed in Cambridge, he fell in love again—with a man named Francis Crick, another student in Perutz’s lab. It was not an erotic love, but a love of shared madness, of conversations that were electric and boundless, of ambitions that ran beyond realities.3 “A youthful arrogance, a ruthlessness, and an impatience with sloppy thinking came naturally to both of us,” Crick would later write.

It was a Rube Goldberg disease. A change in the sequence of a gene caused the change in the sequence of a protein; that warped its shape; that shrank a cell; that clogged a vein; that jammed the flow; that racked the body (that genes built). Gene, protein, function, and fate were strung in a chain: one chemical alteration in one base pair in DNA was sufficient to “encode” a radical change in human fate.

Once again, the pairing of bases is used to build the gene back. The yin fixes the yang, the image restores the original: with DNA, as with Dorian Gray, the prototype is constantly reinvigorated by its portrait. Proteins chaperone and coordinate the entire process—guiding the damaged strand to the intact gene, copying and correcting the lost information, and stitching the breaks together—ultimately resulting in the transfer of information from the undamaged strand to the damaged strand.

“Monet is but an eye,” Cézanne once said of his friend, “but, God, what an eye.” DNA, by that same logic, is but a chemical—but, God, what a chemical.

Brenner became a connoisseur of tiny organisms, a god of small things.

The answer is that the “boat” is not made of planks but of the relationship between planks. If you hammer a hundred strips of wood atop each other, you get a wall; if you nail them side to side, you get a deck; only a particular configuration of planks, held together in particular relationship, in a particular order, makes a boat.

A memory: It is 1978 or ’79, and I am about eight or nine. My father has returned from a business trip. His bags are still in the car, and a glass of ice water is sweating on a tray on the dining room table. It is one of those blistering afternoons in Delhi when the ceiling fans seem to slosh heat around the room, making it feel even warmer. Two of our neighbors are waiting for him in the living room. The air seems tense with anxiety, although I cannot discern why.

Viruses have a simple structure: they are often no more than a set of genes wrapped inside a coat—a “piece of bad news wrapped in a protein coat,” as Peter Medawar, the immunolo-gist, had described them. When a virus enters a cell, it sheds its coat, and begins to use the cell as a factory to copy its genes, and manufacture new coats, resulting in millions of new viruses budding out of the cell. Viruses have thus distilled their life cycle to its bare essentials. They live to infect and reproduce; they infect and reproduce to live.

To produce such genetic chimeras, Berg recalled, “none of the individual procedures, manipulations, and re-agents used to construct this recombinant DNA was novel; the novelty lay in the specific way they were used in combination.” The truly radical advance was the cutting and pasting of ideas—the reassortment and annealing of insights and techniques that already existed in the realm of genetics for nearly a decade.

The birth of a new world was announced with no more noise than the mechanical tick-tick-tick of a bacterial incubator rocking through the night.

Ironically, the very features that enable a cell to read DNA are the features that make it incomprehensible to humans—to chemists, in particular. DNA, as Schrödinger had predicted, was a chemical built to defy chemists, a molecule of exquisite contradictions—monotonous and yet infinitely varied, repetitive to the extreme and yet idiosyncratic to the extreme.

Historically, scientists had rarely sought to become self-regulators. As Alan Waterman, the head of the National Science Foundation, wrote in 1962, “Science, in its pure form, is not interested in where discoveries may lead. . . . Its disciples are interested only in discovering the truth.”

“The most important lesson of Asilomar,” Berg said, “was to demonstrate that scientists were capable of self-governance.” Those accustomed to the “unfettered pursuit of research” would have to learn to fetter themselves.

As Berg put it, “The public’s trust was undeniably increased by the fact that more than ten percent of the participants were from the news media. They were free to describe, comment on, and criticize the discussions and conclusions. . . . The deliberations, bickering, bitter accusations, wavering views, and the arrival at a consensus were widely chronicled by the reporters that attended.”

There is an illuminated moment in the development of a child when she grasps the recursiveness of language: just as thoughts can be used to generate words, she realizes, words can be used to generate thoughts. Recombinant DNA had made the language of genetics recursive. Biologists had spent decades trying to interrogate the nature of the gene—but now it was the gene that could be used to interrogate biology. We had graduated, in short, from thinking about genes, to thinking in genes.

But the hormone was notoriously difficult to work with: insoluble, heat-labile, temperamental, unstable, mysterious—insular.