The Gene

by Siddhartha Mukherjee

  On May 2, 1952, a Friday evening, she had exposed a DNA fiber to X-rays overnight. The picture was technically perfect—although the camera had cocked a little off center. “V.Good. Wet Photo,” she had written in her red notebook. At half past six the next evening—she worked on Saturday nights, of course, while the rest of the staff went to the pub—she set up the camera again. On Tuesday afternoon, she exposed the photograph. It was even crisper than the previous one. It was the most perfect image that she had ever seen. She had labeled it “Photograph 51.”

  Wilkins walked over to the next room, pulled the crucial photograph out of a drawer, and showed it to Watson. Franklin was still in her office, smoldering with irritation. She had no knowledge that Wilkins had just revealed the most precious piece of her data to Watson.V (“Perhaps I should have asked Rosalind’s permission and I didn’t,” a contrite Wilkins would later write. “Things were very difficult. . . . If there had been anything like a normal situation here, I’d have asked her permission naturally, though if there had been anything like a normal situation, the whole question of permission wouldn’t have come up. . . . I had this photograph, and there was a helix right on the picture, you couldn’t miss it.”)

  Watson was immediately transfixed. “The instant I saw the picture my mouth fell open and my pulse started to race. The pattern was unbelievably simpler than those obtained previously. . . . The black cross could arise only from a helical structure. . . . After only a few minutes’ calculations, the number of chains in the molecule could be fixed.”

  In the icy compartment of the train that sliced across the fens back to Cambridge that evening, Watson sketched what he remembered of the picture on the edge of a newspaper. He had come back the first time from London without notes. He wasn’t going to repeat the same error. By the time he had returned to Cambridge and jumped over the back gate of the college, he was convinced that DNA had to be made of two intertwined, helical chains: “important biological objects come in pairs.”

  The next morning, Watson and Crick raced down to the lab and started model building in earnest. Geneticists count; biochemists clean. Watson and Crick played. They worked methodically, diligently, and carefully—but left enough room for their key strength: lightness. If they were to win this race, it would be through whimsy and intuition; they would laugh their way to DNA. At first, they tried to salvage the essence of their first model, placing the phosphate backbone in the middle, and the bases projecting out to the sides. The model wobbled uneasily, with molecules jammed too close together for comfort. After coffee, Watson capitulated: perhaps the backbone was on the outside, and the bases—A, T, G, and C—faced in, apposed against each other. But solving one problem just created a bigger problem. With the bases facing outside, there had been no trouble fitting them: they had simply circled around the central backbone, like a spiral rosette. But with the bases turned inside, they had to be jammed and tucked against each other. The zipper’s teeth had to intercalate. For A, T, G, and C to sit in the interior of the DNA double helix, they had to have some interaction, some relationship. But what did one base—A, say—have to do with another base?

  One lone chemist had suggested, insistently, that the bases of DNA must have something to do with each other. In 1950, the Austrian-born biochemist Erwin Chargaff, working at Columbia University in New York, had found a peculiar pattern. Whenever Chargaff digested DNA and analyzed the base composition, he always found that the A and the T were present in nearly identical proportion, as were the G and the C. Something, mysteriously, had paired A to T and G to C, as if these chemicals were congenitally linked. But although Watson and Crick knew this rule, they had no idea how it might apply to the final structure of DNA.

  A second problem arose with fitting the bases inside the helix: the precise measurement of the outer backbone became crucial. It was a packing problem, obviously constrained by the dimensions of the space. Once again, unbeknownst to Franklin, her data came to the rescue. In the winter of 1952, a visiting committee had been appointed to review the work being performed at King’s College. Wilkins and Franklin had prepared a report on their most recent work on DNA and included many of their preliminary measurements. Max Perutz had been a member of the committee; he had obtained a copy of the report and handed it to Watson and Crick. The report was not explicitly marked “Confidential,” but nor was it evident anywhere that it was to be made freely available to others, to Franklin’s competitors, in particular.

  Perutz’s intentions, and his feigned naïveté about scientific competition, have remained mysterious (he would later write defensively, “I was inexperienced and casual in administrative matters and, since the report was not ‘Confidential,’ I saw no reason for withholding it.”). The deed, nonetheless, was done: Franklin’s report found its way to Watson’s and Crick’s hands. And with the sugar-phosphate backbone placed on the outside, and the general parameters of the measurements ascertained, the model builders could begin the most exacting phase of model building. At first, Watson tried to jam the two helices together, with the A on one strand matched with an A on the other—like bases paired with like. But the helix bulged and thinned inelegantly, like the Michelin Man in a wet suit. Watson tried to massage the model into shape, but it wouldn’t fit. By the next morning, it had to be abandoned.

  Sometime on the morning of February 28, 1953, Watson, still playing with cardboard cutouts in the shape of the bases, began to wonder if the interior of the helix contained mutually opposing bases that were unlike each other. What if A was paired with the T, and C with the G? “Suddenly I became aware that an adenine thymine pair (A→T) was identical in shape to a guanine cytosine pair (G→C) . . . no fudging was required to make the two types of base pairs identical in shape.”

  He realized that the base pairs could now easily be stacked atop each other, facing inward into the center of the helix. And the importance of Chargaff’s rules became obvious in retrospect—A and T, and G and C, had to be present in identical amounts because they were always complementary: they were the two mutually opposing teeth in the zipper. The most important biological objects had to come in pairs. Watson could hardly wait for Crick to walk into the office. “Upon his arrival, Francis did not get halfway through the door before I let loose that the answer to everything was in our hands.”

  One look at the opposing bases convinced Crick. The precise details of the model still needed to be worked out—the A:T and G:C pairs still needed to be placed inside the skeleton of the helix—but the nature of the breakthrough was clear. The solution was so beautiful that it could not possibly be wrong. As Watson recalled, Crick “winged into the Eagle to tell everyone within the hearing distance that we had found the secret of life.”

  Like Pythagoras’s triangle, like the cave paintings at Lascaux, like the Pyramids in Giza, like the image of a fragile blue planet seen from outer space, the double helix of DNA is an iconic image, etched permanently into human history and memory. I rarely reproduce biological diagrams in text—the mind’s eye is usually richer in detail. But sometimes one must break rules for exceptions:

  A schematic of the double-helical structure of DNA, showing a single helix (left) and its paired double helix (right). Note the complementarity of bases: A is paired with T, and G with C. The winding “backbone” of DNA is made of a chain of sugars and phosphates.

  The helix contains two intertwined strands of DNA. It is “right-handed”—twisting upward as if driven by a right-handed screw. Across the molecule, it measures twenty-three angstroms—one-thousandth of one-thousandth of a millimeter. One million helices stacked side by side would fit in this letter: o. The biologist John Sulston wrote, “We see it as a rather stubby double helix, for they seldom show its other striking feature: it is immensely long and thin. In every cell in your body, you have two meters of the stuff; if we were to draw a scaled-up picture of it with the DNA as thick as sewing thread, that cell’s worth would be about 200 kilometers long.”

  Each strand of DNA, re
call, is a long sequence of “bases”—A, T, G, and C. The bases are linked together by the sugar-phosphate backbone. The backbone twists on the outside, forming a spiral. The bases face in, like treads in a circular staircase. The opposite strand contains the opposing bases: A matched with T and G matched with C. Thus, both strands contain the same information—except in a complementary sense: each is a “reflection,” or echo, of the other (the more appropriate analogy is a yin-and-yang structure). Molecular forces between the A:T and G:C pairs lock the two strands together, as in a zipper. A double helix of DNA can thus be envisioned as a code written with four alphabets—ATGCCCTACGGGCCCATCG . . .—forever entwined with its mirror-image code.

  “To see,” the poet Paul Valéry once wrote, “is to forget the name of the things that one sees.” To see DNA is to forget its name or its chemical formula. Like the simplest of human tools—hammer, scythe, bellows, ladder, scissors—the function of the molecule can be entirely comprehended from its structure. To “see” DNA is to immediately perceive its function as a repository of information. The most important molecule in biology needs no name to be understood.

  Watson and Crick built their complete model in the first week of March 1953. Watson ran down to the metal shop in the basement of the Cavendish labs to expedite the fabrication of the modeling parts. The hammering, soldering, and polishing took hours, while Crick paced impatiently upstairs. With the shiny metallic parts in hand, they began to build the model, adding part to part, as if building a house of cards. Every piece had to fit—and it had to match the known molecular measurements. Each time Crick frowned as he added another component, Watson’s stomach took a turn—but in the end, the whole thing fit together, like a perfectly solved puzzle. The next day, they came back with a plumb line and a ruler to measure every distance between every component. Every measurement—every angle and width, all the spaces separating the molecules—was nearly perfect.

  Maurice Wilkins came to take a look at the model the next morning. He needed but “a minute’s look . . . to like it.” “The model was standing high on a lab table,” Wilkins later recalled. “[It] had a life of its own—rather like looking at a baby that had just been born. . . . The model seemed to speak for itself, saying—‘I don’t care what you think—I know I am right.’ ” He returned to London and confirmed that his most recent crystallographic data, as well as Franklin’s, clearly supported a double helix. “I think you’re a couple of old rogues, but you may well have something,” Wilkins wrote from London on March 18, 1953. “I like the idea.”

  Franklin saw the model later that fortnight, and she too was quickly convinced. At first, Watson feared that her “sharp, stubborn mind, caught in her self-made . . . trap” would resist the model. But Franklin needed no further convincing. Her steel-trap mind knew a beautiful solution when it saw one. “The positioning of the backbone on the outside [and] the uniqueness of the A-T and G-C pairs was a fact that she saw no reason to argue about.” The structure, as Watson described it, “was too pretty not to be true.”

  On April 25, 1953, Watson and Crick published their paper—“Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid”—in Nature magazine. Accompanying the article was another, by Gosling and Franklin, providing strong crystallographic evidence for the double-helical structure. A third article, from Wilkins, corroborated the evidence further with experimental data from DNA crystals.

  In keeping with the grand tradition of counterposing the most significant discoveries in biology with supreme understatement—recall Mendel, Avery, and Griffith—Watson and Crick added a final line to their paper: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” The most important function of DNA—its capacity to transmit copies of information from cell to cell, and organism to organism—was buried in the structure. Message; movement; information; form; Darwin; Mendel; Morgan: all was writ into that precarious assemblage of molecules.

  In 1962, Watson, Crick, and Wilkins won the Nobel Prize for their discovery. Franklin was not included in the prize. She had died in 1958, at the age of thirty-seven, from diffusely metastatic ovarian cancer—an illness ultimately linked to mutations in genes.

  In London, where the river Thames arches away from the city near Belgravia, one might begin a walk at Vincent Square, the trapezoid-shaped park that abuts the office of the Royal Horticultural Society. It was here, in 1900, that William Bateson brought news of Mendel’s paper to the scientific world, thereby launching the era of modern genetics. From the square, a brisk stroll northwest, past the southern edge of Buckingham Palace, brings us to the elegant town houses of Rutland Gate, where, in the 1900s, Francis Galton conjured up the theory of eugenics, hoping to manipulate genetic technologies to achieve human perfection.

  About three miles due east, across the river, sits the former site of the Pathological Laboratories of the Ministry of Health, where, in the early 1920s, Frederick Griffith discovered the transformation reaction—the transfer of genetic material from one organism to another, the experiment that led to the identification of DNA as the “gene molecule.” Cross the river to the north, and you arrive at the King’s College labs, where Rosalind Franklin and Maurice Wilkins began their work on DNA crystals in the early 1950s. Veer southwest again, and the journey brings you to the Science Museum on Exhibition Road to encounter the “gene molecule” in person. The original Watson and Crick model of DNA, with its hammered metal plates and rickety rods twisting precariously around a steel laboratory stand, is housed behind a glass case. The model looks like a latticework corkscrew invented by a madman, or an impossibly fragile spiral staircase that might connect the human past to its future. Crick’s handwritten scribbles—A, C, T, and G—still adorn the plates.

  The revelation of the structure of DNA by Watson, Crick, Wilkins, and Franklin brought one journey of genes to its close, even as it threw open new directions of inquiry and discovery. “Once it had been known that DNA had a highly regular structure,” Watson wrote in 1954, “the enigma of how the vast amount of genetic information needed to specify all the characteristics of a living organism could be stored in such a regular structure had to be solved.” Old questions were replaced by new ones. What features of the double helix enabled it to bear the code of life? How did that code become transcribed and translated into actual form and function of an organism? Why, for that matter, were there two helices, and not one, or three or four? Why were the two strands complementary to each other—A matched with T, and G matched with C—like a molecular yin and yang? Why was this structure, of all structures, chosen as the central repository of all biological information? “It isn’t that [DNA] looks so beautiful,” Crick later remarked. “It is the idea of what it does.”

  Images crystallize ideas—and the image of a double-helical molecule that carried the instructions to build, run, repair, and reproduce humans crystallized the optimism and wonder of the 1950s. Encoded in that molecule were the loci of human perfectibility and vulnerability: once we learned to manipulate this chemical, we would rewrite our nature. Diseases would be cured, fates changed, futures reconfigured.

  The Watson and Crick model of DNA marked the end of one conception of the gene—as a mysterious carrier of messages across generations—to another: as a chemical, or a molecule, capable of encoding, storing, and transferring information between organisms. If the keyword of early-twentieth-century genetics was message, then the keyword of late-twentieth-century genetics might be code. That genes carried messages had been abundantly clear for half a century. The question was, could humans decipher their code?

  * * *

  I. Experiments carried out by Alfred Hershey and Martha Chase in 1952 and 1953 also confirmed that DNA was the carrier of genetic information.

  II. Hemoglobin has multiple variants, including some that are specific to the fetus. This discussion applies to the most common, and best-studied, variant, which ex
ists abundantly in blood.

  III. In 1951, long before James Watson would become a household name around the world, the novelist Doris Lessing took a three-hour walk with the young Watson, whom she knew through a friend of a friend. During the entire walk, across the heaths and fens near Cambridge, Lessing did all the talking; Watson said not one word. At the end of the walk, “exhausted, wanting only to escape,” Lessing at last heard the sound of human speech from her companion: “The trouble is, you see, that there is only one other person in the world that I can talk to.”

  IV. In her initial studies on DNA, Franklin was not convinced that the X-ray patterns suggested a helix, most likely because she was working on the dry form of DNA. Indeed, at one point Franklin and her student had sent around a cheeky note announcing the “death of the helix.” However, as her X-ray images improved, she gradually began to envision the helix with the phosphates on the outside, as indicated by her notes. Watson once told a journalist that Franklin’s fault lay in her dispassionate approach to her own data: “She did not live DNA.”

  V. But was it her photograph? Wilkins later maintained that the photograph had been given to him by Gosling, Franklin’s student—and therefore it was his to do with what he desired. Franklin was leaving King’s College to take up a new job at Birkbeck College, and Wilkins thought that she was abandoning the DNA project.

  “That Damned, Elusive Pimpernel”

  In the protein molecule, Nature has devised an instrument in which an underlying simplicity is used to express great subtlety and versatility; it is impossible to see molecular biology in proper perspective until this peculiar combination of virtues has been clearly grasped.

  —Francis Crick

  The word code, I wrote before, comes from caudex—the pith of the tree that was used to scratch out early manuscripts. There is something evocative in the idea that the material used to write code gave rise to the word itself: form became function. With DNA too, Watson and Crick realized, the form of the molecule had to be intrinsically linked to function. The genetic code had to be written into the material of DNA—just as intimately as scratches are etched into pith.