The Gene

by Siddhartha Mukherjee

  The theory was so seductive—so artfully vivid—that even the invention of the microscope was unable to deal the expected fatal blow to the homunculus. In 1694, Nicolaas Hartsoeker, the Dutch physicist and microscopist, conjured a picture of such a minibeing, its enlarged head twisted in fetal position and curled into the head of a sperm. In 1699, another Dutch microscopist claimed to have found homuncular creatures floating abundantly in human sperm. As with any anthropomorphic fantasy—finding human faces on the moon, say—the theory was only magnified by the lenses of imagination: pictures of homunculi proliferated in the seventeenth century, with the sperm’s tail reconceived into a filament of human hair, or its cellular head visualized as a tiny human skull. By the end of the seventeenth century, preformation was considered the most logical and consistent explanation for human and animal heredity. Men came from small men, as large trees came from small cuttings. “In nature there is no generation,” the Dutch scientist Jan Swammerdam wrote in 1669, “but only propagation.”

  But not everyone could be convinced that miniature humans were infinitely encased inside humans. The principal challenge to preformation was the idea that something had to happen during embryogenesis that led to the formation of entirely new parts in the embryo. Humans did not come pre-shrunk and premade, awaiting only expansion. They had to be generated from scratch, using specific instructions locked inside the sperm and egg. Limbs, torsos, brains, eyes, faces—even temperaments or propensities that were inherited—had to be created anew each time an embryo unfurled into a human fetus. Genesis happened . . . well—by genesis.

  By what impetus, or instruction, was the embryo, and the final organism, generated from sperm and egg? In 1768, the Berlin embryologist Caspar Wolff tried to finesse an answer by concocting a guiding principle—vis essentialis corporis, as he called it—that progressively shepherded the maturation of a fertilized egg into a human form. Like Aristotle, Wolff imagined that the embryo contained some sort of encrypted information—code—that was not merely a miniature version of a human, but instructions to make a human from scratch. But aside from inventing a Latinate name for a vague principle, Wolff could provide no further specifics. The instructions, he argued obliquely, were blended together in the fertilized egg. The vis essentialis then came along, like an invisible hand, and molded the formation of this mass into a human form.

  While biologists, philosophers, Christian scholars, and embryologists fought their way through vicious debates between preformation and the “invisible hand” throughout much of the eighteenth century, a casual observer may have been forgiven for feeling rather unimpressed by it all. This was, after all, stale news. “The opposing views of today were in existence centuries ago,” a nineteenth-century biologist complained, rightfully. Indeed, preformation was largely a restatement of Pythagoras’s theory—that sperm carried all the information to make a new human. And the “invisible hand” was, in turn, merely a gilded variant of Aristotle’s idea—that heredity was carried in the form of messages to create materials (it was the “hand” that carried the instructions to mold an embryo).

  In time, both the theories would be spectacularly vindicated, and spectacularly demolished. Both Aristotle and Pythagoras were partially right and partially wrong. But in the early 1800s, it seemed as if the entire field of heredity and embryogenesis had reached a conceptual impasse. The world’s greatest biological thinkers, having pored over the problem of heredity, had scarcely advanced the field beyond the cryptic musings of two men who had lived on two Greek islands two thousand years earlier.

  “The Mystery of Mysteries”

  . . . They mean to tell us all was rolling blind

  Till accidentally it hit on mind

  In an albino monkey in a jungle,

  And even then it had to grope and bungle,

  Till Darwin came to earth upon a year . . .

  —Robert Frost, “Accidentally on Purpose”

  In the winter of 1831, when Mendel was still a schoolboy in Silesia, a young clergyman, Charles Darwin, boarded a ten-gun brig-sloop, the HMS Beagle, at Plymouth Sound, on the southwestern shore of England. Darwin was then twenty-two years old, the son and grandson of prominent physicians. He had the square, handsome face of his father, the porcelain complexion of his mother, and the dense overhang of eyebrows that ran in the Darwin family over generations. He had tried, unsuccessfully, to study medicine at Edinburgh—but, horrified by the “screams of a strapped-down child amid the blood and sawdust of the . . . operating theater,” had fled medicine to study theology at Christ’s College in Cambridge. But Darwin’s interest ranged far beyond theology. Holed up in a room above a tobacconist’s shop on Sidney Street, he had occupied himself by collecting beetles, studying botany and geology, learning geometry and physics, and arguing hotly about God, divine intervention, and the creation of animals. More than theology or philosophy, Darwin was drawn to natural history—the study of the natural world using systematic scientific principles. He apprenticed with another clergyman, John Henslow, the botanist and geologist who had created and curated the Cambridge Botanic Garden, the vast outdoor museum of natural history where Darwin first learned to collect, identify, and classify plant and animal specimens.

  Two books particularly ignited Darwin’s imagination during his student years. The first, Natural Theology, published in 1802 by William Paley, the former vicar of Dalston, made an argument that would resonate deeply with Darwin. Suppose, Paley wrote, a man walking across a heath happens upon a watch lying on the ground. He picks up the instrument and opens it to find an exquisite system of cogs and wheels turning inside, resulting in a mechanical device that is capable of telling time. Would it not be logical to assume that such a device could only have been manufactured by a watchmaker? The same logic had to apply to the natural world, Paley reasoned. The exquisite construction of organisms and human organs—“the pivot upon which the head turns, the ligament within the socket of the hip joint”—could point to only one fact: that all organisms were created by a supremely proficient designer, a divine watchmaker: God.

  The second book, A Preliminary Discourse on the Study of Natural Philosophy, published in 1830 by the astronomer Sir John Herschel, suggested a radically different view. At first glance, the natural world seems incredibly complex, Herschel acknowledged. But science can reduce seemingly complex phenomena into causes and effects: motion is the result of a force impinging on an object; heat involves the transference of energy; sound is produced by the vibration of air. Herschel had little doubt that chemical, and, ultimately, biological phenomena, would also be attributed to such cause-and-effect mechanisms.

  Herschel was particularly interested in the creation of biological organisms—and his methodical mind broke the problem down to its two basic components. The first was the problem of the creation of life from nonlife—genesis ex nihilo. Here, he could not bring himself to challenge the doctrine of the divine creation. “To ascend to the origin of things, and speculate on creation, is not the business of the natural philosopher,” he wrote. Organs and organisms might behave according to the laws of physics and chemistry—but the genesis of life itself could never be understood through these laws. It was as if God had given Adam a nice little laboratory in Eden, but then forbidden him from peering over the walls of the garden.

  But the second problem, Herschel thought, was more tractable: Once life had been created, what process generated the observed diversity of the natural world? How, for instance, did a new species of animal arise from another species? Anthropologists, studying language, had demonstrated that new languages arose from old languages through the transformation of words. Sanskrit and Latin words could be traced back to mutations and variations in an ancient Indo-European language, and English and Flemish had arisen from a common root. Geologists had proposed that the current shape of the earth—its rocks, chasms, and mountains—had been created by the transmutation of previous elements. “Battered relics of past ages,” Herschel wrote, “contain . . . in
delible records capable of intelligible interpretation.” It was an illuminating insight: a scientist could understand the present and the future by examining the “battered relics” of the past. Herschel did not have the correct mechanism for the origin of species, but he posed the correct question. He called this the “mystery of mysteries.”

  Natural history, the subject that gripped Darwin at Cambridge, was not particularly poised to solve Herschel’s “mystery of mysteries.” To the fiercely inquisitive Greeks, the study of living beings had been intimately linked to the question of the origin of the natural world. But medieval Christians were quick to realize that this line of inquiry could only lead to unsavory theories. “Nature” was God’s creation—and to be safely consistent with Christian doctrine, natural historians had to tell the story of nature in terms of Genesis.

  A descriptive view of nature—i.e., the identification, naming, and classification of plants and animals—was perfectly acceptable: in describing nature’s wonders, you were, in effect, celebrating the immense diversity of living beings created by an omnipotent God. But a mechanistic view of nature threatened to cast doubt on the very basis of the doctrine of creation: to ask why and when animals were created—by what mechanism or force—was to challenge the myth of divine creation and edge dangerously close to heresy. Perhaps unsurprisingly, by the late eighteenth century, the discipline of natural history was dominated by so-called parson-naturalists—vicars, parsons, abbots, deacons, and monks who cultivated their gardens and collected plant and animal specimens to service the wonders of divine Creation, but generally veered away from questioning its fundamental assumptions. The church provided a safe haven for these scientists—but it also effectively neutered their curiosity. The injunctions against the wrong kinds of investigation were so sharp that the parson-naturalists did not even question the myths of creation; it was the perfect separation of church and mental state. The result was a peculiar distortion of the field. Even as taxonomy—the classification of plant and animal species—flourished, inquiries into the origin of living beings were relegated to the forbidden sidelines. Natural history devolved into the study of nature without history.

  It was this static view of nature that Darwin found troubling. A natural historian should be able to describe the state of the natural world in terms of causes and effects, Darwin reasoned—just as a physicist might describe the motion of a ball in the air. The essence of Darwin’s disruptive genius was his ability to think about nature not as fact—but as process, as progression, as history. It was a quality that he shared with Mendel. Both clergymen, both gardeners, both obsessive observers of the natural world, Darwin and Mendel made their crucial leaps by asking variants of the same question: How does “nature” come into being? Mendel’s question was microscopic: How does a single organism transmit information to its offspring over a single generation? Darwin’s question was macroscopic: How do organisms transmute information about their features over a thousand generations? In time, both visions would converge, giving rise to the most important synthesis in modern biology, and the most powerful understanding of human heredity.

  In August 1831, two months after his graduation from Cambridge, Darwin received a letter from his mentor, John Henslow. An exploratory “survey” of South America had been commissioned, and the expedition required the service of a “gentleman scientist” who could assist in collecting specimens. Although more gentleman than scientist (having never published a major scientific paper), Darwin thought himself a natural fit. He was to travel on the Beagle—not as a “finished Naturalist,” but as a scientist-in-training “amply qualified for collecting, observing and noting any thing worthy to be noted in Natural History.”

  The Beagle lifted anchor on December 27, 1831, with seventy-three sailors on board, clearing a gale and tacking southward toward Tenerife. By early January, Darwin was heading toward Cape Verde. The ship was smaller than he had expected, and the wind more treacherous. The sea churned constantly beneath him. He was lonely, nauseated, and dehydrated, surviving on a diet of dry raisins and bread. That month, he began writing notes in his journal. Slung on a hammock bed above the salt-starched survey maps, he pored over the few books that he had brought with him on the voyage—Milton’s Paradise Lost (which seemed all too apposite to his condition), and Charles Lyell’s Principles of Geology, published between 1830 and 1833.

  Lyell’s work in particular left an impression on him. Lyell had argued (radically, for his time) that complex geological formations, such as boulders and mountains, had been created over vast stretches of time, not by the hand of God but by slow natural processes such as erosion, sedimentation, and deposition. Rather than a colossal biblical Flood, Lyell argued, there had been millions of floods; God had shaped the earth not through singular cataclysms but through a million paper cuts. For Darwin, Lyell’s central idea—of the slow heave of natural forces shaping and reshaping the earth, sculpting nature—would prove to be a potent intellectual spur. In February 1832, still “squeamish and uncomfortable,” Darwin crossed over to the southern hemisphere. The winds changed direction, and the currents altered their flow, and a new world floated out to meet him.

  Darwin, as his mentors had predicted, proved to be an excellent collector and observer of specimens. As the Beagle hopscotched its way down the eastern coast of South America, passing through Montevideo, Bahía Blanca, and Port Desire, he rifled through the bays, rain forests, and cliffs, hauling aboard a vast assortment of skeletons, plants, pelts, rocks, and shells—“cargoes of apparent rubbish,” the captain complained. The land yielded not just a cargo of living specimens, but ancient fossils as well; laying them out on long lines along the deck, it was as if Darwin had created his own museum of comparative anatomy. In September 1832, exploring the gray cliffs and low-lying clay bays near Punta Alta, he discovered an astonishing natural cemetery, with fossilized bones of enormous extinct mammals splayed out before him. He pried out the jaw of one fossil from the rock, like a mad dentist, then returned the next week to extract a huge skull from the quartz. The skull belonged to a megatherium, a mammoth version of a sloth.

  That month, Darwin found more bones strewn among the pebbles and rocks. In November, he paid eighteen pence to a Uruguayan farmer for a piece of a colossal skull of yet another extinct mammal—the rhino-like Toxodon, with giant squirrel teeth—that had once roamed the plains. “I have been wonderfully lucky,” he wrote. “Some of the mammals were gigantic, and many of them are quite new.” He collected fragments from a pig-size guinea pig, armor plates from a tanklike armadillo, more elephantine bones from elephantine sloths, and crated and shipped them to England.

  The Beagle rounded the sharp jaw-bend of Tierra del Fuego and climbed the western coast of South America. In 1835, the ship left Lima, on the coast of Peru, and headed toward a lonely spray of charred volcanic islands west of Ecuador—the Galápagos. The archipelago was “black, dismal-looking heaps . . . of broken lava, forming a shore fit for pandemonium,” the captain wrote. It was a Garden of Eden of a hellish sort: isolated, untouched, parched, and rocky—turds of congealed lava overrun by “hideous iguanas,” tortoises, and birds. The ship wandered from island to island—there were about eighteen in all—and Darwin ventured ashore, scrambling through the pumice, collecting birds, plants, and lizards. The crew survived on a steady diet of tortoise meat, with every island yielding a seemingly unique variety of tortoise. Over five weeks, Darwin collected carcasses of finches, mockingbirds, blackbirds, grosbeaks, wrens, albatrosses, iguanas, and an array of sea and land plants. The captain grimaced and shook his head.

  On October 20, Darwin returned to sea, headed toward Tahiti. Back in his room aboard the Beagle, he began to systematically analyze the corpses of the birds that he had collected. The mockingbirds, in particular, surprised him. There were two or three varieties, but each subtype was markedly distinct, and each was endemic to one particular island. Offhandedly, he scribbled one of the most important scientific sentences that he would ever w
rite: “Each variety is constant in its own Island.” Was the same pattern true of other animals—of the tortoises, say? Did each island have a unique tortoise type? He tried, belatedly, to establish the same pattern for the turtles—but it was too late. He and the crew had eaten the evidence for lunch.

  When Darwin returned to England after five years at sea, he was already a minor celebrity among natural historians. His vast fossil loot from South America was being unpacked, preserved, cataloged, and organized; whole museums could be built around it. The taxidermist and bird painter John Gould had taken over the classification of the birds. Lyell himself displayed Darwin’s specimens during his presidential address to the Geological Society. Richard Owen, the paleontologist who hovered over England’s natural historians like a patrician falcon, descended from the Royal College of Surgeons, to verify and catalog Darwin’s fossil skeletons.

  But while Owen, Gould, and Lyell named and classified the South American treasures, Darwin turned his mind to other problems. He was not a splitter, but a lumper, a seeker of deeper anatomy. Taxonomy and nomenclature were, for him, merely means to an end. His instinctive genius lay in unearthing patterns—systems of organization—that lay behind the specimens; not in Kingdoms and Orders, but in kingdoms of order that ran through the biological world. The same question that would frustrate Mendel in his teaching examination in Vienna—why on earth were living things organized in this manner?—became Darwin’s preoccupation in 1836.