The Gene

by Siddhartha Mukherjee

  Had Mendel stopped his experiments here, he would already have made a major contribution to a theory of heredity. The existence of dominant and recessive alleles for a trait contradicted nineteenth-century theories of blending inheritance: the hybrids that Mendel had generated did not possess intermediate features. Only one allele had asserted itself in the hybrid, forcing the other variant trait to vanish.

  But where had the recessive trait disappeared? Had it been consumed or eliminated by the dominant allele? Mendel deepened his analysis with his second experiment. He bred short-tall hybrids with short-tall hybrids to produce third-generation progeny. Since tallness was dominant, all the parental plants in this experiment were tall to start; the recessive trait had disappeared. But when crossed with each other, Mendel found, they yielded an entirely unexpected result. In some of these third-generation crosses, shortness reappeared—perfectly intact—after having disappeared for a generation. The same pattern occurred with all seven of the other traits. White flowers vanished in the second generation, the hybrids, only to reemerge in some members of the third. A “hybrid” organism, Mendel realized, was actually a composite—with a visible, dominant allele and a latent, recessive allele (Mendel’s word to describe these variants was forms; the word allele would be coined by geneticists in the 1900s).

  By studying the mathematical relationships—the ratios—between the various kinds of progeny produced by each cross, Mendel could begin to construct a model to explain the inheritance of traits.I Every trait, in Mendel’s model, was determined by an independent, indivisible particle of information. The particles came in two variants, or two alleles: short versus tall (for height) or white versus violet (for flower color) and so forth. Every plant inherited one copy from each parent—one allele from father, via sperm, and one from mother, via the egg. When a hybrid was created, both traits existed intact—although only one asserted its existence.

  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.

  It is a word not typically used to describe science, or scientists. It shares roots, of course, with tending—a farmer’s or gardener’s activity—but also with tension, the stretching of a pea tendril to incline it toward sunlight or to train it on an arbor. Mendel was, first and foremost, a gardener. His genius was not fueled by deep knowledge of the conventions of biology (thankfully, he had failed that exam—twice). Rather, it was his instinctual knowledge of the garden, coupled with an incisive power of observation—the laborious cross-pollination of seedlings, the meticulous tabulation of the colors of cotyledons—that soon led him to findings that could not be explained by the traditional understanding of inheritance.

  Heredity, Mendel’s experiments implied, could only be explained by the passage of discrete pieces of information from parents to offspring. Sperm brought one copy of this information (an allele); the egg brought the other copy (a second allele); an organism thus inherited one allele from each parent. When that organism generated sperm or eggs, the alleles were split up again—one was passed to the sperm, and one to the egg, only to become combined in the next generation. One allele might “dominate” the other when both were present. When the dominant allele was present, the recessive allele seemed to disappear, but when a plant received two recessive alleles, the allele reiterated its character. Throughout, the information carried by an individual allele remained indivisible. The particles themselves remained intact.

  Doppler’s example returned to Mendel: there was music behind noise, laws behind seeming lawlessness, and only a profoundly artificial experiment—creating hybrids out of purebred strains carrying simple traits—could reveal these underlying patterns. Behind the epic variance of natural organisms—tall; short; wrinkled; smooth; green; yellow; brown—there were corpuscles of hereditary information, moving from one generation to the next. Each trait was unitary—distinct, separate, and indelible. Mendel did not give this unit of heredity a name, but he had discovered the most essential features of a gene.

  On February 8, 1865, seven years after Darwin and Wallace had read their papers at the Linnean Society in London, Mendel presented his paper, in two parts, at a much less august forum: he spoke to a group of farmers, botanists, and biologists at the Natural Science Society in Brno (the second part of the paper was read on March 8, a month later). Few records exist of this moment in history. The room was small, and about forty people attended. The paper, with dozens of tables and arcane symbols to denote traits and variants, was challenging even for statisticians. For biologists, it may have seemed like absolute mumbo jumbo. Botanists generally studied morphology, not numerology. The counting of variants in seeds and flowers across tens of thousands of hybrid specimens must have mystified Mendel’s contemporaries; the notion of mystical numerical “harmonies” lurking in nature had gone out of fashion with Pythagoras. Soon after Mendel was done, a professor of botany stood up to discuss Darwin’s Origin and the theory of evolution. No one in the audience perceived a link between the two subjects being discussed. Even if Mendel was aware of a potential connection between his “units of heredity” and evolution—his prior notes had certainly indicated that he had sought such a link—he made no explicit comments on the topic.

  Mendel’s paper was published in the annual Proceedings of the Brno Natural Science Society. A man of few words, Mendel was even more concise in his writing: he had distilled nearly a decade’s work into forty-four spectacularly dreary pages. Copies were sent to the Royal Society and the Linnean Society in England, and to the Smithsonian in Washington, among dozens of institutions. Mendel himself requested forty reprints, which he mailed, heavily annotated, to many scientists. It is likely that he sent one to Darwin, but there is no record of Darwin’s having actually read it.

  What followed, as one geneticist wrote, was “one of the strangest silences in the history of biology.” The paper was cited only four times between 1866 and 1900—virtually disappearing from scientific literature. Between 1890 and 1900, even as questions and concerns about human heredity and its manipulation became central to policy makers in America and Europe, Mendel’s name and his work were lost to the world. The study that founded modern biology was buried in the pages of an obscure journal of an obscure scientific society, read mostly by plant breeders in a declining Central European town.

  On New Year’s Eve in 1866, Mendel wrote to the Swiss plant physiologist Carl von Nägeli in Munich, enclosing a description of his experiments. Nägeli replied two months later—already signaling distance with his tardiness—sending a courteous but icy note. A botanist of some repute, Nägeli did not think much of Mendel or his work. Nägeli had an instinctual distrust of amateur scientists and scribbled a puzzlingly derogatory note next to the first letter: “only empirical . . . cannot be proved rational”—as if experimentally deduced laws were worse than those created de novo by human “reason.”

  Mendel pressed on, with further letters. Nägeli was the scientific colleague whose respect Mendel most sought—and his notes to him took an almost ardent, desperate turn. “I knew that the results I obtained were not easily compatible with our contemporary science,” Mendel wrote, and “an isolated experiment might be doubly dangerous.” Nägeli remained cautious and dismissive, often curt. The possibility that Mendel had deduced a fundamental natural rule—a dangerous law—by tabulating pea hybrids seemed absurd and far-fetched to Nägeli. If Mendel believed in the priesthood, then he should stick to it; Nägeli believed in th
e priesthood of science.

  Nägeli was studying another plant—the yellow-flowering hawkweed—and he urged Mendel to try to reproduce his findings on hawkweed as well. It was a catastrophically wrong choice. Mendel had chosen peas after deep consideration: the plants reproduced sexually, produced clearly identifiable variant traits, and could be cross-pollinated with some care. Hawkweeds—unknown to Mendel and Nägeli—could reproduce asexually (i.e., without pollen and eggs). They were virtually impossible to cross-pollinate and rarely generated hybrids. Predictably, the results were a mess. Mendel tried to make sense of the hawkweed hybrids (which were not hybrids at all), but he couldn’t decipher any of the patterns that he had observed in the peas. Between 1867 and 1871, he pushed himself even harder, growing thousands of hawkweeds in another patch of garden, emasculating the flowers with the same forceps, and dusting pollen with the same paintbrush. His letters to Nägeli grew increasingly despondent. Nägeli replied occasionally, but the letters were infrequent and patronizing. He could hardly be bothered with the progressively lunatic ramblings of a self-taught monk in Brno.

  In November 1873, Mendel wrote his last letter to Nägeli. He had been unable to complete the experiments, he reported remorsefully. He had been promoted to the position of abbot of the monastery in Brno, and his administrative responsibilities were now making it impossible for him to continue any plant studies. “I feel truly unhappy that I have to neglect my plants . . . so completely,” Mendel wrote. Science was pushed to the wayside. Taxes piled up at the monastery. New prelates had to be appointed. Bill by bill, and letter by letter, his scientific imagination was slowly choked by administrative work.

  Mendel wrote only one monumental paper on pea hybrids. His health declined in the 1880s, and he gradually restricted his work—all except his beloved gardening. 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.”

  * * *

  I. Several statisticians have examined Mendel’s original data and accused him of faking the data. Mendel’s ratios and numbers were not just accurate; they were too perfect. It was as if he had encountered no statistical or natural error in his experiments—an impossible situation. In retrospect, it is unlikely that Mendel actively faked his studies. More likely, he constructed a hypothesis from his earliest experiments, then used the later experiments to validate his hypothesis: he stopped counting and tabulating the peas once they had conformed to the expected values and ratios. This method, albeit unconventional, was not unusual for his time, but it also reflected Mendel’s scientific naïveté.

  “A Certain Mendel”

  The origin of species is a natural phenomenon.

  —Jean-Baptiste Lamarck

  The origin of species is an object of inquiry.

  —Charles Darwin

  The origin of species is an object of experimental investigation.

  —Hugo de Vries

  In the summer of 1878, a thirty-year-old Dutch botanist named Hugo de Vries traveled to England to see Darwin. It was more of a pilgrimage than a scientific visit. Darwin was vacationing at his sister’s estate in Dorking, but de Vries tracked him down and traveled out to meet him. Gaunt, intense, and excitable, with Rasputin’s piercing eyes and a beard that rivaled Darwin’s, de Vries already looked like a younger version of his idol. He also had Darwin’s persistence. The meeting must have been exhausting, for it lasted only two hours, and Darwin had to excuse himself to take a break. But de Vries left England transformed. With no more than a brief conversation, Darwin had inserted a sluice into de Vries’s darting mind, diverting it forever. Back in Amsterdam, de Vries abruptly terminated his prior work on the movement of tendrils in plants and threw himself into solving the mystery of heredity.

  By the late 1800s, the problem of heredity had acquired a near-mystical aura of glamour, like a Fermat’s Last Theorem for biologists. Like Fermat—the odd French mathematician who had tantalizingly scribbled that he’d found a “remarkable proof” of his theorem, but failed to write it down because the paper’s “margin was too small”—Darwin had desultorily announced that he had found a solution to heredity, but had never published it. “In another work I shall discuss, if time and health permit, the variability of organic beings in a state of nature,” Darwin had written in 1868.

  Darwin understood the stakes implicit in that claim. A theory of heredity was crucial to the theory of evolution: without any means to generate variation, and fix it across generations, he knew, there would be no mechanism for an organism to evolve new characteristics. But a decade had passed, and Darwin had never published the promised book on the genesis of “variability in organic beings.” Darwin died in 1882, just four years after de Vries’s visit. A generation of young biologists was now rifling through Darwin’s works to find clues to the theory that had gone missing.

  De Vries also pored through Darwin’s books, and he latched onto the theory of pangenesis—the idea that “particles of information” from the body were somehow collected and collated in sperm and eggs. But the notion of messages emanating from cells and assembling in sperm as a manual for building an organism seemed particularly far-fetched; it was as if the sperm were trying to write the Book of Man by collecting telegrams.

  And experimental proof against pangenes and gemmules was mounting. In 1883, with rather grim determination, the German embryologist August Weismann had performed an experiment that directly attacked Darwin’s gemmule theory of heredity. Weismann had surgically excised the tails of five generations of mice, then bred the mice to determine if the offspring would be born tailless. But the mice—with equal and obdurate consistency—had been born with tails perfectly intact, generation upon generation. If gemmules existed, then a mouse with a surgically excised tail should produce a mouse without a tail. In total, Weismann had serially removed the tails of 901 animals. And mice with absolutely normal tails—not even marginally shorter than the tail of the original mouse—had kept arising; it was impossible to wash “the hereditary taint” (or, at least, the “hereditary tail”) away. Grisly as it was, the experiment nonetheless announced that Darwin and Lamarck could not be right.

  Weismann had proposed a radical alternative: perhaps hereditary information was contained exclusively in sperm and egg cells, with no direct mechanism for an acquired characteristic to be transmitted into sperm or eggs. No matter how ardently the giraffe’s ancestor stretched its neck, it could not convey that information into its genetic material. Weismann called this hereditary material germplasm and argued that it was the only method by which an organism could generate another organism. Indeed, all of evolution could be perceived as the vertical transfer of germplasm from one generation to the next: an egg was the only way for a chicken to transfer information to another chicken.

  But what was the material nature of germplasm? de Vries wondered. Was it like paint: Could it be mixed and diluted? Or was the information in germplasm discrete and carried in packets—like an unbroken, unbreakable message? De Vries had not encountered Mendel’s paper yet. But like Mendel, he began to scour the countryside around Amsterdam to collect strange plant variants—not just peas, but a vast herbarium of plants with twisted stems and forked leaves, with speckled flowers, hairy anthers, and bat-shaped seeds: a menagerie of monsters. When he bred these variants with their normal counterparts, he found, like Mendel, that the variant traits did not blend away, but were maintained in a discrete and independent form from one generation to the next. Each plant seemed to possess a collection of features—flower color, leaf shape, seed texture—and each of these features seemed to be encoded by an independent, discrete piece of information that moved from one generation to the next.

  But de Vries still lacked Mendel’s crucial insight—that bolt of mathematical reasoning that had so clearly ill
uminated Mendel’s pea-hybrid experiments in 1865. From his own plant hybrids, de Vries could dimly tell that variant features, such as stem size, were encoded by indivisible particles of information. But how many particles were needed to encode one variant trait? One? One hundred? A thousand?

  In the 1880s, still unaware of Mendel’s work, de Vries edged toward a more quantitative description of his plant experiments. In a landmark paper written in 1897, entitled Hereditary Monstrosities, de Vries analyzed his data and inferred that each trait was governed by a single particle of information. Every hybrid inherited two such particles—one from the sperm and one from the egg. And these particles were passed along, intact, to the next generation through sperm and egg. Nothing was ever blended. No information was lost. He called these particles “pangenes.” It was a name that protested its own origin: even though he had systematically demolished Darwin’s theory of pangenesis, de Vries paid his mentor a final homage.

  While de Vries was still knee-deep in the study of plant hybrids in the spring of 1900, a friend sent him a copy of an old paper drudged up from the friend’s library. “I know that you are studying hybrids,” the friend wrote, “so perhaps the enclosed reprint of the year 1865 by a certain Mendel . . . is still of some interest to you.”

  It is hard not to imagine de Vries, in his study in Amsterdam on a gray March morning, slitting open that reprint and running his eyes through the first paragraph. Reading the paper, he must have felt that inescapable chill of déjà vu running through his spine: the “certain Mendel” had certainly preempted de Vries by more than three decades. In Mendel’s paper, de Vries discovered a solution to his question, a perfect corroboration of his experiments—and a challenge to his originality. It seemed that he too was being forced to relive the old saga of Darwin and Wallace: the scientific discovery that he had hoped to claim as his own had actually been made by someone else. 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.”