The Gene

by Siddhartha Mukherjee

  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.”

  In the spring of 1951, Maurice Wilkins gave a scientific talk at the Zoological Station in Naples—at the laboratory where Boveri and Morgan had once worked on urchins. The weather was just beginning to warm up, although the sea might still send a blast of chill through the corridors of the city. In the audience that morning—“shirttails flying, knees in the air, socks down around his ankles . . . cocking his head like a rooster”—was a biologist Wilkins had never heard of, an excitable, voluble young man named James Watson. Wilkins’s talk on the structure of DNA was dry and academic. One of his last slides, presented with little enthusiasm, was an early X-ray diffraction picture of DNA. The photograph flickered onto the screen at the end of a long talk, and Wilkins showed little, if any, excitement about the fuzzy image. The pattern was still a muddle—Wilkins was still hampered by the quality of his sample and the dryness of his chamber—but Watson was instantly gripped by it. The general conclusion was unmistakable: in principle, DNA could be crystallized into a form amenable to X-ray diffraction. “Before Maurice’s talk, I had worried about the possibility that the gene might be fantastically irregular,” Watson would later write. The image, however, quickly convinced Watson otherwise: “Suddenly, I was excited about chemistry.” He tried to talk to Wilkins about the image, but “Maurice was English, and [didn’t] talk to strangers.” Watson slunk away.

  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.”

  Impetuously, Watson returned to Copenhagen and asked to be transferred to Max Perutz’s lab at Cambridge (Perutz, the Austrian biophysicist, had fled Nazi Germany and moved to England during the exodus of the 1930s). Perutz was working on molecular structures, and it was the closest that Watson could get to Wilkins’s image, whose haunting, prophetic shadows he could not get out of his brain. Watson had decided that he was going to solve the structure of DNA—“the Rosetta stone for unraveling the true secret of life.” He would later say, “As a geneticist, it was the only problem worth solving.” He was all of twenty-three years old.

  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.III “A youthful arrogance, a ruthlessness, and an impatience with sloppy thinking came naturally to both of us,” Crick would later write.

  Crick was thirty-five—a full twelve years older than Watson, and still without a PhD (in part because he had worked for the Admiralty during the war years). He was not conventionally “academic,” and he certainly was not “stifled.” A former physics student with an expansive personality and a booming voice that often sent his coworkers running for cover and a bottle of aspirin, he too had read Schrödinger’s What Is Life?—that “small book that had started a revolution”—and become transfixed by biology.

  Englishmen hate many things, but no one is despised more than the man who sits by you on the morning train and solves your crossword puzzle. Crick’s intelligence was as free ranging and as audacious as his voice; he thought nothing of invading the problems of others and suggesting solutions. To make things worse, he was usually right. In the late 1940s, switching from physics to graduate work in biology, he had taught himself much of the mathematical theory of crystallography—that swirl of nested equations that made it possible to transmute silhouettes into three-dimensional structures. Like most of his colleagues in Perutz’s lab, Crick focused his initial studies on the structures of proteins. But unlike many others, he had been intrigued by DNA from the start. Like Watson, and like Wilkins and Franklin, he was also instinctively drawn to the structure of a molecule capable of carrying hereditary information.

  The two of them—Watson and Crick—talked so volubly, like children let loose in a playroom, that they were assigned a room to themselves, a yellow brick chamber with wooden rafters where they were left to their own devices and dreams, their “mad pursuit[s].” They were complementary strands, interlocked by irreverence, zaniness, and fiery brilliance. They despised authority but craved its affirmation. They found the scientific establishment ridiculous and plodding, yet they knew how to insinuate themselves into it. They imagined themselves quintessential outsiders, yet felt most comfortable sitting in the inner quadrangles of Cambridge colleges. They were self-appointed jesters in a court of fools.

  The one scientist they did revere, if begrudgingly, was Linus Pauling—the larger-than-life Caltech chemist who had recently announced that he had solved an important conundrum in the structure of proteins. Proteins are made of chains of amino acids. The chains fold in three-dimensional space to form substructures, which then fold into larger structures (imagine a chain that first coils into a spring and then a spring that further jumbles into a spherical or globular shape). Working with crystals, Pauling had found that proteins frequently folded into an archetypal substructure—a single helix coiled like a spring. Pauling had revealed his model at a meeting at Caltech with the dramatic flair of a sorcerer pulling a molecular bunny out of a hat: the model had been hidden behind a curtain until the end of the talk, and then—presto!—it had been revealed to a stunned, applauding audience. Rumor had it that Pauling had now turned his attention from proteins to the structure of DNA. Five thousand miles away, in Cambridge, Watson and Crick could almost feel Pauling breathing down their necks.

  Pauling’s seminal paper on the protein helix was published in April 1951. Festooned with equations and numbers, it was intimidating to read, even for experts. But to Crick, who knew the mathematical formulas as intimately as anyone, Pauling had hidden his essential method behind the smoke-and-mirrors algebra. Crick told Watson that Pauling’s model was, in fact, the “product of common sense, not the result of complicated mathematical reasoning.” The real magic was imagination. “Equations occasionally crept into his argument, but in most cases words would have sufficed. . . . The alpha-helix had not been found by staring at X-ray pictures; the essential trick, instead, was to ask which atoms like to sit next to each other. In place of pencil and paper, the main working tools were a set of molecular models superficially resembling the toys of preschool children.”

  Here, Watson and Crick took their most intuitive scientific leap. What if the solution to the structure of DNA could be achieved by the same “tricks” that Pauling had pulled? X-ray pictures would help, of course—but trying to determine structures of biological molecules using experimental methods, Crick argued, was absurdly laborious—“like trying to determine the structure of a piano by listening to the sound it made while being dropped down a flight of stairs.” But what if the structure of DNA was so simple—so elegant—that it could be deduced by “common sense,” by model building? What if a stick-and-stone assemblage could solve DNA?

  Fifty miles away, at King�
�s College in London, Franklin had little interest in building models with toys. With her laserlike focus on experimental studies, she had been taking photograph after photograph of DNA—each with increasing clarity. The pictures would provide the answer, she reasoned; there was no need for guesswork. The experimental data would generate the models, not the other way around. Of the two forms of DNA—the “dry” crystalline form and a “wet” form—the wet form seemed to have a less convoluted structure. But when Wilkins proposed that they collaborate to solve the wet structure, she would have none of it. A collaboration, it seemed to her, was a thinly disguised capitulation. Randall was soon forced to intervene to formally separate them, like bickering children. Wilkins was to continue with the wet form, while Franklin was to concentrate on the dry form.

  The separation hobbled both of them. Wilkins’s DNA preparations were of poor quality and wouldn’t generate good photographs. Franklin had pictures, but she found them difficult to interpret. (“How dare you interpret my data for me?” she once snapped at him.) Although they worked no more than a few hundred feet apart, the two of them might as well have inhabited two warring continents.

  On November 21, 1951, Franklin gave a talk at King’s. Watson was invited to the talk by Wilkins. The gray afternoon was fouled by the soupy London fog. The room was an old, damp lecture hall buried in the innards of the college; it resembled a dreary accountant’s chamber in a Dickens novel. About fifteen people attended. Watson sat in the audience—“skinny and awkward . . . pop-eyed, and wrote down nothing.”

  Franklin spoke “in a quick nervous style [with] . . . not a trace of warmth or frivolity in her words,” Watson would later write. “Momentarily I wondered how she would look if she took off her glasses and did something novel with her hair.” There was something purposefully severe and offhanded in Franklin’s manner of speaking; she delivered her lecture as if reading the Soviet evening news. Had anyone paid real attention to her subject—and not the styling of her hair—he might have noticed that she was circling a monumental conceptual advance, albeit with deliberate caginess. “Big helix with several chains,”IV she had written in her notes, “phosphates on the outside.” She had begun to glimpse the skeleton of an exquisite structure. But she gave only some cursory measurements, pointedly declined to specify any details about the structure, and then brought a witheringly dull academic seminar to its close.

  The next morning, Watson excitedly brought news of Franklin’s talk to Crick. They were boarding a train for Oxford to meet Dorothy Hodgkin, the grande dame of crystallography. Rosalind Franklin had said little in her talk except to provide a few preliminary measurements. But when Crick quizzed Watson about the precise numbers, Watson could provide only vague answers. He had not even bothered to scribble numbers on the back of a napkin. He had attended one of the most important seminars in his scientific life—and failed to take notes.

  Still, Crick got enough of a sense of Franklin’s preliminary thoughts to hurry back to Cambridge and begin building a model. They started the next morning, with lunch at the nearby Eagle Pub and some gooseberry pie. “Superficially, the X-ray data was compatible with two, three or four strands,” they realized. The question was, how to put the strands together and make a model of an enigmatic molecule?

  A single strand of DNA consists of a backbone of sugars and phosphates, and four bases—A, T, G, and C—attached to the backbone, like teeth jutting out from a zipper strand. To solve the structure of DNA, Watson and Crick had to first figure out how many zippers were in each DNA molecule, what part was at the center, and which part at the periphery. It looked like a relatively simple problem—but it was fiendishly difficult to build a simple model. “Even though only about fifteen atoms were involved, they kept falling out of the awkward pincers set up to hold them.”

  By teatime, still tinkering with an awkward model set, Watson and Crick had come up with a seemingly satisfactory answer: three chains, twisted around each other, in a helical formation, with the sugar phosphate backbone compressed in the center. A triple helix. Phosphates on the inside. “A few of the atomic contacts were still too close for comfort,” they admitted—but perhaps these would be fixed by additional fiddling. It wasn’t a particularly elegant structure—but maybe that was asking too much. The next step, they realized, was to “check it with Rosy’s quantitative measurements.” And then, on a whim—in a misstep that they would later come to regret—they called Wilkins and Franklin to come and have a look.

  Wilkins, Franklin, and her student, Ray Gosling, took the train down from King’s the next morning to inspect the Watson and Crick model. The journey to Cambridge was loaded with expectations. Franklin was lost in her thoughts.

  When the model was unveiled at last, it was an epic letdown. Wilkins found the model “disappointing”—but held his tongue. Franklin was not as diplomatic. One look at the model was enough to convince her that it was nonsense. It was worse than wrong; it was unbeautiful—an ugly, bulging, falling-apart catastrophe, a skyscraper after an earthquake. As Gosling recalled, “Rosalind let rip in her best pedagogical style: ‘you’re wrong for the following reasons’ . . . which she proceeded to enumerate as she demolished their proposal.” She may as well have kicked the model with her feet.

  Crick had tried to stabilize the “wobbly unstable chains” by putting the phosphate backbone in the center. But phosphates are negatively charged. If they faced inside the chain, they would repel each other, forcing the molecule to fly apart in a nanosecond. To solve the problem of repulsion, Crick had inserted a positively charged magnesium ion at the center of the helix—like a last-minute dab of molecular glue to hold the structure together. But Franklin’s measurements suggested that magnesium could not be at the center. Worse, the structure modeled by Watson and Crick was so tightly packed that it could not accommodate any significant number of water molecules. In their rush to build a model, they had even forgotten Franklin’s first discovery: the remarkable “wetness” of DNA.

  The viewing had turned into an inquisition. As Franklin picked the model apart, molecule by molecule, it was as if she were extracting bones from their bodies. Crick looked progressively deflated. “His mood,” Watson recalled, “was no longer that of a confident master lecturing hapless colonial children.” By now, Franklin was frankly exasperated at the “adolescent blather.” The boys and their toys had turned out to be a monumental waste of her time. She caught the 3:40 train home.

  In Pasadena, meanwhile, Linus Pauling was also trying to solve the structure of DNA. Pauling’s “assault on DNA,” Watson knew, would be nothing short of formidable. He would come at it with a bang, deploying his deep understanding of chemistry, mathematics, and crystallography—but more important, his instinctual grasp of model building. Watson and Crick feared that they would wake up one morning, open the pages of an august scientific journal, and find the solved structure of DNA staring back at them. Pauling’s name—not theirs—would be attached to the article.

  In the first weeks of January 1953, that nightmare seemed to come true: Pauling and Robert Corey wrote a paper proposing a structure of DNA and sent a preliminary copy to Cambridge. It was a bombshell casually lobbed across the Atlantic. For a moment, it seemed to Watson that “all was lost.” He rifled through paper like a madman until he had found the crucial figure. But as he stared at the proposed structure, Watson knew instantly “that something was not right.” By coincidence, Pauling and Corey had also suggested a triple helix, with the bases A, C, G, and T pointed outside. The phosphate backbone twisted inside, like the central shaft of a spiral staircase, with its treads facing out. But Pauling’s proposal did not have any magnesium to “glue” the phosphates together. Instead, he proposed that the structure would be held together by much weaker bonds. This magician’s sleight of hand did not go unnoticed. Watson knew immediately that the structure would not work: it was energetically unstable. One colleague of Pauling’s would later write, “If that were the structure of DNA, it would explode.” Pau
ling had not produced a bang; he had created a molecular Big Bang.

  “The blooper,” as Watson described it, “was too unbelievable to keep secret for more than a few minutes.” He dashed over to a chemist friend in the neighboring lab to show him Pauling’s structure. The chemist concurred, “The giant [Pauling] had forgotten elementary college chemistry.” Watson told Crick, and both took off for the Eagle, their favorite pub, where they celebrated Pauling’s failure with shots of schadenfreude-infused whiskey.

  Late in January 1953, James Watson went to London to visit Wilkins. He stopped to see Franklin in her office. She was working at her bench, with dozens of photographs strewn around her, and a book full of notes and equations on her desk. They spoke stiffly, arguing about Pauling’s paper. At one point, exasperated by Watson, Franklin moved quickly across the lab. Fearing “that in her hot anger, she might strike [him],” Watson retreated through the front door.

  Wilkins, at least, was more welcoming. As the two commiserated about Franklin’s radioactive temper, Wilkins opened up to Watson to a degree he never before had. What happened next is a twisted braid of mixed signals, distrust, miscommunication, and conjecture. Wilkins told Watson that Rosalind Franklin had taken a series of new photographs of the fully wet form of DNA over the summer—pictures so staggeringly crisp that the essential skeleton of the structure virtually jumped out of them.