The Gene

by Siddhartha Mukherjee

  To understand the significance of Morgan’s discovery, we need to return to Mendel. In Mendel’s experiments, every gene had behaved like an independent entity—a free agent. Flower color, for instance, had no link with seed texture or stem height. Each characteristic was inherited independently, and all combinations of traits were possible. The result of each cross was thus a perfect genetic roulette: if you crossed a tall plant with purple flowers with a short plant with white flowers, you would eventually produce all sorts of mixes—tall plants with white flowers and short plants with purple flowers and so forth.

  But Morgan’s fruit fly genes did not always behave independently. Between 1905 and 1908, Morgan and his students crossed thousands of fruit fly mutants with each other to create tens of thousands of flies. The result of each cross was meticulously recorded: white-eyed, sable-colored, bristled, short-winged. When Morgan examined these crosses, tabulated across dozens of notebooks, he found a surprising pattern: some genes acted as if they were “linked” to each other. The gene responsible for creating white eyes (called white eyed), for instance, was inescapably linked to maleness: no matter how Morgan crossed his flies, only males were born with white eyes. Similarly, the gene for sable color was linked with the gene that specified the shape of a wing.

  For Morgan, this genetic linkage could only mean one thing: genes had to be physically linked to each other. In flies, the gene for sable color was never (or rarely) inherited independently from the gene for miniature wings because they were both carried on the same chromosome. If two beads are on the same string, then they are always tied together, no matter how one attempts to mix and match strings. For two genes on the same chromosome, the same principle applied: there was no simple way to separate the forked-bristle gene from the coat-color gene. The inseparability of features had a material basis: the chromosome was a “string” along which certain genes were permanently strung.

  Morgan had discovered an important modification to Mendel’s laws. Genes did not travel separately; instead, they moved in packs. Packets of information were themselves packaged—into chromosomes, and ultimately in cells. But the discovery had a more important consequence: conceptually, Morgan had not just linked genes; he had linked two disciplines—cell biology and genetics. The gene was not a “purely theoretical unit.” It was a material thing that lived in a particular location, and a particular form, within a cell. “Now that we locate them [genes] on chromosomes,” Morgan reasoned, “are we justified in regarding them as material units; as chemical bodies of a higher order than molecules?”

  The establishment of linkage between genes prompted a second, and third, discovery. Let us return to linkage: Morgan’s experiments had established that genes that were physically linked to each other on the same chromosome were inherited together. If the gene that produces blue eyes (call it B) is linked to a gene that produces blond hair (Bl), then children with blond hair will inevitably tend to inherit blue eyes (the example is hypothetical, but the principle that it illustrates is true).

  But there was an exception to linkage: occasionally, very occasionally, a gene could unlink itself from its partner genes and swap places from the paternal chromosome to the maternal chromosome, resulting in a fleetingly rare blue-eyed, dark-haired child, or, conversely, a dark-eyed, blond-haired child. Morgan called this phenomenon “crossing over.” In time, as we shall see, the crossing over of genes would launch a revolution in biology, establishing the principle that genetic information could be mixed, matched, and swapped—not just between sister chromosomes, but between organisms and across species.

  The final discovery prompted by Morgan’s work was also the result of a methodical study of “crossing over.” Some genes were so tightly linked that they never crossed over. These genes, Morgan’s students hypothesized, were physically closest to each other on the chromosome. Other genes, although linked, were more prone to splitting apart. These genes had to be positioned farther apart on the chromosome. Genes that had no linkage whatsoever had to be present on entirely different chromosomes. The tightness of genetic linkage, in short, was a surrogate for the physical proximity of genes on chromosomes: by measuring how often two features—blond-hairedness and blue-eyedness—were linked or unlinked, you could measure the distance between their genes on the chromosome.

  On a winter evening in 1911, Sturtevant, then a twenty-year-old undergraduate student in Morgan’s lab, brought the available experimental data on the linkage of Drosophila (fruit fly) genes to his room and—neglecting his mathematics homework—spent the night constructing the first map of genes in flies. If A was tightly linked to B, and very loosely linked to C, Sturtevant reasoned, then the three genes must be positioned on the chromosome in that order and with proportional distance from each other:

  A . B . . . . . . . . . . C .

  If an allele that created notched wings (N) tended to be co-inherited with an allele that made short bristles (SB), then the two genes, N and SB, must be on the same chromosome, while the unlinked gene for eye color must be on a different chromosome. By the end of the evening, Sturtevant had sketched the first linear genetic map of half a dozen genes along a Drosophila chromosome.

  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.

  But beyond linkage and gene maps, even Morgan had a difficult time imagining or describing genes in a material form: What chemical could possibly carry information in “threads” and “maps”? It is a testament to the ability of scientists to accept abstractions as truths that fifty years after the publication of Mendel’s paper—from 1865 to 1915—biologists knew genes only through the properties they produced: genes specified traits; genes could become mutated and thereby specify alternative traits; and genes tended to be chemically or physically linked to each other. Dimly, as if through a veil, geneticists were beginning to visualize patterns and themes: threads, strings, maps, crossings, broken and unbroken lines, chromosomes that carried information in a coded and compressed form. But no one had seen a gene in action or knew its material essence. The central quest of the study of heredity seemed like an object perceived only through its shadows, tantalizingly invisible to science.

  If urchins, mealworms, and fruit flies seemed far removed from the world of humans—if the concrete relevance of Morgan’s or Mendel’s findings was ever in doubt—then the events of the violent spring of 1917 proved otherwise. In March that year, as Morgan was writing his papers on genetic linkage in his Fly Room in New York, a volley of brutal popular uprisings ricocheted through Russia, ultimately decapitating the czarist monarchy and culminating in the creation of the Bolshevik government.

  At face value, the Russian Revolution had little to do with genes. The Great War had whipped a starving, weary population into a murderous frenzy of discontent. The czar was considered weak and ineffectual. The army was mutinous; the factory workers galled; inflation ran amok. By March 1917, Czar Nicholas II had been forced to abdicate the throne. But genes—and linkage—were certainly potent forces in this history. The czarin
a of Russia, Alexandra, was the granddaughter of Queen Victoria of England—and she carried the marks of that heritage: not just the carved obelisk of the nose, or the fragile enamel-like sheen of her skin, but also a gene that caused hemophilia B, a lethal bleeding disorder that had crisscrossed through Victoria’s descendants.

  Hemophilia is caused by a single mutation that disables a protein in the clotting of blood. In the absence of this protein, blood refuses to clot—and even a small nick or wound can accelerate into a lethal bleeding crisis. The name of the illness—from Greek haimo (“blood”) and philia (“to like, or love”)—is actually a wry comment on its tragedy: hemophiliacs like to bleed all too easily.

  Hemophilia—like white eyes in fruit flies—is a sex-linked genetic illness. Females can be carriers and transmit the gene, but only males are afflicted by the disease. The mutation in the hemophilia gene, which affects the clotting of blood, had likely arisen spontaneously in Queen Victoria at birth. Her eighth child, Leopold, had inherited the gene and died of a brain hemorrhage at age thirty. The gene had also been passed from Victoria to her second daughter, Alice—and then from Alice to her daughter, Alexandra, the czarina of Russia.

  In the summer of 1904, Alexandra—still an unsuspecting carrier of the gene—gave birth to Alexei, the czarevitch of Russia. Little is known about the medical history of his childhood, but his attendants must have noticed something amiss: that the young prince bruised all too easily, or that his nosebleeds were often unstoppable. While the precise nature of his ailment was kept secret, Alexei continued to be a pale, sickly boy. He bled frequently and spontaneously. A playful fall, or a nick in his skin—even a bumpy horse ride—could precipitate disaster.

  As Alexei grew older, and the hemorrhages more life threatening, Alexandra began to rely on a Russian monk of legendary unctuousness, Grigory Rasputin, who promised to heal the czar-to-be. While Rasputin claimed that he kept Alexei alive using various herbs, salves, and strategically offered prayers, most Russians considered him an opportunistic fraud (he was rumored to be having an affair with the czarina). His continuous presence in the royal family and his growing influence on Alexandra were considered evidence of a crumbling monarchy gone utterly batty.

  The economic, political, and social forces that unloosed themselves on the streets of Petrograd and launched the Russian Revolution were vastly more complex than Alexei’s hemophilia or Rasputin’s machinations. History cannot devolve into medical biography—but nor can it stand outside it. The Russian Revolution may not have been about genes, but it was very much about heredity. The disjunction between the prince’s all-too-human genetic inheritance and his all-too-exalted political inheritance must have seemed particularly evident to the critics of the monarchy. The metaphorical potency of Alexei’s illness was also undeniable—symptomatic of an empire gone sick, dependent on bandages and prayers, hemorrhaging at its core. The French had tired of a greedy queen who ate cake. The Russians were fed up with a sickly prince swallowing strange herbs to combat a mysterious illness.

  Rasputin was poisoned, shot, slashed, bludgeoned, and drowned to death by his rivals on December 30, 1916. Even by the grim standards of Russian assassinations, the violence of this murder was a testimony to the visceral hatred that he had inspired in his enemies. In the early summer of 1918, the royal family was moved to Yekaterinburg and placed under house arrest. On the evening of July 17, 1918, a month shy of Alexei’s fourteenth birthday, a firing squad instigated by the Bolsheviks burst into the czar’s house and assassinated the whole family. Alexei was shot twice in the head. The bodies of the children were supposedly scattered and buried nearby, but Alexei’s body was not found.

  In 2007, an archaeologist exhumed two partially burned skeletons from a bonfire site near the house where Alexei had been murdered. One of the skeletons belonged to a thirteen-year-old boy. Genetic testing of the bones confirmed that the body was Alexei’s. Had the full genetic sequence of the skeleton been analyzed, the investigators might have found the culprit gene for hemophilia B—the mutation that had crossed one continent and four generations and insinuated itself into a defining political moment of the twentieth century.

  * * *

  I. Some of the work was also performed at Woods Hole, where Morgan would move his lab every summer.

  Truths and Reconciliations

  All changed, changed utterly:

  A terrible beauty is born.

  —William Butler Yeats, Easter, 1916

  The gene was born “outside” biology. By this, I mean the following: if you consider the major questions raging through the biological sciences in the late nineteenth century, heredity does not rank particularly high on that list. Scientists studying living organisms were far more preoccupied with other matters: embryology, cell biology, the origin of species, and evolution. How do cells function? How does an organism arise from an embryo? How do species originate? What generates the diversity of the natural world?

  Yet, attempts to answer these questions had all become mired at precisely the same juncture. The missing link, in all cases, was information. Every cell, and every organism, needs information to carry out its physiological function—but where does that information come from? An embryo needs a message to become an adult organism—but what carries this message? Or how, for that matter, does one member of a species “know” that it is a member of that species and not another?

  The ingenious property of the gene was that it offered a potential solution to all these problems in a single sweep. Information for a cell to carry out a metabolic function? It came from a cell’s genes, of course. The message encrypted in an embryo? Again, it was all encoded in genes. When an organism reproduces, it transmits the instructions to build embryos, make cells function, enable metabolism, perform ritual mating dances, give wedding speeches, and produce future organisms of the same species—all in one grand, unified gesture. Heredity cannot be a peripheral question in biology; it must rank among its central questions. When we think of heredity in a colloquial sense, we think about the inheritance of unique or particular features across generations: a peculiar shape of a father’s nose or the susceptibility to an unusual illness that runs through a family. But the real conundrum that heredity solves is much more general: What is the nature of instruction that allows an organism to build a nose—any nose—in the first place?

  The delayed recognition of the gene as the answer to the central problem of biology had a strange consequence: genetics had to be reconciled with other major fields of biology as an afterthought. If the gene was the central currency of biological information, then major characteristics of the living world—not just heredity—should be explicable in terms of genes. First, genes had to explain the phenomenon of variation: How could discrete units of heredity explain that human eyes, say, do not have six discrete forms but seemingly 6 billion continuous variants? Second, genes had to explain evolution: How could the inheritance of such units explain that organisms have acquired vastly different forms and features over time? And third, genes had to explain development: How could individual units of instruction prescribe the code to create a mature organism out of an embryo?

  We might describe these three reconciliations as attempts to explain nature’s past, present, and future through the lens of the gene. Evolution describes nature’s past: How did living things arise? Variation describes its present: Why do they look like this now? And embryogenesis attempts to capture the future: How does a single cell create a living thing that will eventually acquire its particular form?

  In two transformative decades between 1920 and 1940, the first two of these questions—i.e., variation and evolution—would be solved by unique alliances between geneticists, anatomists, cell biologists, statisticians, and mathematicians. The third question—embryological development—would require a much more concerted effort to solve. Ironically, even though embryology had launched the discipline of modern genetics, the reconciliation between genes and genesis would be a vastly more engaging
scientific problem.

  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.

  By day, Fisher examined statistical information for insurance companies. By night, with the world almost fully extinguished to his vision, he turned to theoretical aspects of biology. The scientific problem that engrossed Fisher also involved reconciling biology’s “mind” with its “eye.” By 1910, the greatest minds in biology had accepted that discrete particles of information carried on chromosomes were the carriers of hereditary information. But everything visible about the biological world suggested near-perfect continuity: nineteenth-century biometricians such as Quetelet and Galton had demonstrated that human traits, such as height, weight, and even intelligence, were distributed in smooth, continuous, bell-shaped curves. Even the development of an organism—the most obviously inherited chain of information—seemed to progress through smooth, continuous stages, and not in discrete bursts. A caterpillar does not become a butterfly in stuttering steps. If you plot the beak sizes of finches, the points fit on a continuous curve. How could “particles of information”—pixels of heredity—give rise to the observed smoothness of the living world?