by Thomas Hager
While Oswald Avery's work had been presented tentatively and made little impact, the "Waring blender experiment," as it became known, after a piece of decidedly nontechnical machinery that was used in the experiment, clearly showed that DNA was the genetic material. What worked with viruses might well work with higher organisms as well, and as word of the Hershey-Chase experiment spread, phage researchers, geneticists, and biochemists interested in replication began to switch their focus from protein to DNA. Pauling, too, quickly realized that he had been on the wrong track. It was not that proteins were unimportant; they were still critical in the functioning of the body. But it was clear now that the genetic master molecule, the one that directed the making of proteins, was DNA.
It was an unnerving realization, but Pauling took it in stride. He was confident that he could solve DNA. He had already started thinking about it, and it looked fairly simple. The only problem would be if someone beat him to it, but he could not take the possibility very seriously. Wilkins and Franklin were at work on it—Corey, in fact, had visited Franklin's laboratory while over for the Royal Society meeting in May and had seen some excellent x-ray photos she was getting of DNA—but there was no indication that either of them knew enough chemistry to be a serious threat. If Bragg were involved, that would be a different matter, but the only indication from the Cavendish that anyone was looking at DNA came from one of Delbruck’s protégés, there on a postdoctoral fellowship, twenty-two-year-old James Watson, who had written Delbruck something about looking for a DNA model a few months earlier. Delbruck had read Watson's letter to Pauling. It did not sound very serious. Although Delbruck thought Watson was promising, he had not been good enough to get admitted to Caltech when he applied for graduate work. The gentlemen at the Cavendish had, in any case, not yet beaten Pauling in any race.
At the Royaumont meeting, Pauling talked with a group about solving DNA the way he had solved the alpha helix: using precise x-ray work to confirm the structure of its building blocks, as Corey and his coworkers had done with amino acids. Nail down the precise form of the bases and their relationship to the sugars and phosphates, he said; then make a model of the most chemically probable long-chain structure that they would form.
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James Watson was among the group gathered around Pauling at Royaumont, and he listened closely. He already knew that Pauling's approach was the way to solve DNA, and he had already tried to do it.
Watson was at Royaumont ostensibly because he was part of "the phage group," an informal array of researchers gathered around Delbruck at Caltech and Salvador Luria at Indiana University, researchers who believed that bacterial viruses were as close as you could get to "naked genes," stripped-down versions of living organisms capable of nothing but replication. The simpler the system, the easier it was to study, and the phage group was convinced that viruses represented the next great genetics tool, following Morgan's fruit flies and Beadle's molds.
And Watson realized earlier than most that DNA was the key to learning about genes. After getting his Ph.D. under Luria, Watson had left on a European fellowship to study microbial metabolism and nucleic acid biochemistry, but he had quickly tired of it and began bouncing around looking for inspiration. He found it in Naples, at a meeting in the spring of 1951 where Wilkins displayed some of his x-ray photos of DNA. Although he did not know much about x-ray crystallography, Watson realized that Wilkins's work showed that DNA had a regular, repeating structure. It could form fibers that gave x-ray patterns, which meant that its structure was solvable—but Watson would need to learn x-ray crystallography to solve the structure. He tried to talk his way into Wilkins's lab but knew nothing about what they were doing and was turned down; with Delbruck’s help he ended up instead, in the fall of 1951, learning how to diffract x-rays from proteins with Kendrew at the Cavendish.
It was thought wise to give someone with such changeable interests as Watson as much guidance as possible, so he was assigned to share an office with a graduate student of Perutz's who knew crystallography inside and out. His name was Francis Crick.
The two men hit it off immediately. They made quite a pair: Crick, in his mid-thirties, old for a graduate student—his scientific progress delayed by wartime work—but self-confident and outgoing, talkative to a fault, with fashionably long sideburns and a love of three-piece suits; Watson, young, thin, and shy, with his American tennis shoes and crew cut. Erwin Chargaff painted an unkind contemporary picture of them: "One 35 years old, with the looks of a fading racing tout ... an incessant falsetto, with occasional nuggets gleaming in the turbid stream of prattle. The other, quite undeveloped ... a grin, more sly than sheepish ... a gawky young figure." Crick and Watson, he said, looked like "a variety act."
But they impressed each other. Crick soon understood why Watson "was regarded, in most circles, as too bright to be really sound." Watson wrote Delbruck a few weeks after meeting Crick that he was "no doubt the brightest person I have ever worked with and the nearest approach to Pauling I've ever seen." This was high praise, given both men's high regard for the wizard of Pasadena. Watson had first been exposed to Pauling's charisma in the summer of 1949, when he worked with Delbruck at Caltech for a few months and got to know some of the young men in Pauling's lab. Watson saw Pauling only from afar, but it was enough to make an impression. "There was no one like Linus in all the world," Watson later wrote. "Even if he were to say nonsense, his mesmerized students would never know because of his unquenchable self-confidence." Pauling had presence and style, he did great science, had an intriguing family, and loved to drive foreign sports cars very fast. To the nineteen-year-old Watson, Pauling was someone to emulate.
Crick started out not as a Pauling fan but as a competitor. He had been present during the discussions between Bragg, Perutz, and Kendrew that led to the misbegotten 1950 paper on protein structures, had failed, as they all did, to note the importance of the planar peptide bond, and had shared in the humiliation that resulted when Pauling beat them to the alpha helix. He learned three indelible lessons from that experience: The first was that Pauling's approach, with its guess at a reasonable solution based on firm chemical principles and its reliance on model building, was the fastest way to solve giant biomolecules. The second was that no single piece of experimental evidence should serve to dissuade one from a theory—witness Pauling's decision to ignore the anomalous 5.1-angstrom reflection. The third was that helixes were the form to look for.
By the time Watson arrived, Crick was ripe for a project that would free him from endless attempts at the mathematical interpretation of hemoglobin diffraction patterns. Within a few days, Watson provided him with what he was looking for, a relatively simple and potentially more important target: DNA. They quickly agreed on a method of attack: Rather than devising complex mathematical schemes to directly and unambiguously interpret x-ray results, they would use chemical common sense to build a model structure. As Watson put it, they would "imitate Linus Pauling and beat him at his own game."
The story of Crick and Watson's first attempt to solve the structure of DNA in the fall of 1951 has been told many times, most entertainingly in Watson's book The Double Helix. Suffice it to say that it was brief and unsuccessful. Using Pauling's approach, within a few weeks they came up with a model of three helixes wound around each other, phosphates at the core. It seemed to fit the density data, the x-ray data was compatible with anything from two to four strands per molecule, and it solved a theoretical problem. If DNA was the genetic material then it had to say something specific to the body; it had to have a language that could be translated somehow into the making of proteins. It was already known that the sugars and phosphates were simple repeating units, unvarying along the DNA strands. The bases were the variables. The bases varied, but the x-ray pattern indicated a repeating crystalline structure; ergo, the core—the part of the structure giving rise to the repeating patterns—must contain the repeating subunits, the sugars or phosphates, with the bases sticking out w
here they would not get in the way. DNA was, in other words, like the alpha helix. Watson and Crick were thinking very much like Pauling.
The problem was explaining how one could pack phosphates into the middle when at normal pH they would be generally expected to carry a negative charge. All those negative charges at the core would repel each other, blowing the structure apart. The triple helix they had devised was so pretty, though, and fit so much of the data that Crick and Wilson figured there had to be a place for positive ions at the core to cancel out the negative charges. They grabbed a copy of The Nature of the Chemical Bond, searched for inorganic ions that would fit their needs, and found that magnesium or calcium might fit. There was no good evidence for the presence of these positive ions, but there was no good evidence against them, either. They were trying to think like Pauling, after all, and Pauling would certainly have assumed that the structure came first and the minor details fell into place later.
The two young men, euphoric about cracking this problem so quickly, invited Wilkins and Franklin to come to the Cavendish to see their triumph. Franklin tore it apart. The problem was not only the assumption that their molecule was helical—Franklin was not convinced that the x-ray data proved that it was—but their idea that positive ions cemented the center together. Magnesium or any other ions, she pointed out, would undoubtedly be surrounded by water molecules in a cell nucleus and their effects neutered. They could not hold the phosphates together. And water was important. Crick and Watson, she pointed out, had gotten some data wrong. According to Franklin, DNA was a thirsty molecule, drinking up ten times more water than their model allowed. The molecule's ability to soak up water indicated to Franklin that the phosphates were on the outside of the molecule, where they would be encased in a shell of water. The wrong water content also meant that Crick and Watson's density calculations were off.
She was, as it turned out, right. The two men tried to convince Wilkins and Franklin to collaborate with them on another attempt but were turned down. When news of the fiasco reached Bragg, he quickly sent Crick back to proteins and Watson to something more in keeping with his background, a crystallographic study of tobacco mosaic virus.
But the pair, Watson in particular, did not stop thinking about nucleic acids. Pauling remembered Watson as "something of a monomaniac" where DNA was concerned, and rather than give up on the problem, he and Crick took it underground, talking it over quietly in their office or over drinks at a local pub. They might have gotten one model wrong, but they were certain their approach was right. Perhaps all they needed was a little more chemistry. For Christmas 1951, Crick gave Watson a copy of The Nature of the Chemical Bond. "Somewhere in Pauling's masterpiece," Watson remembered, "I hoped the real secret would lie."
Coiled Coils
Pauling, after his meetings in France, arrived in England eager to make up for the time lost because of his passport problems. Through August 1952 he toured the English protein centers, talking with his critics and answering their questions. New evidence had been found that the alpha helix was an important component of a number of natural proteins, including globular proteins, and the pleated sheet structures were also being confirmed. Pauling considered the alpha-helix case proved and was on to new ideas now about how his structure could bend around corners and fold back on itself to make the densely packed spheroid shapes of globular proteins. He found the English, too, more ready to accept his alpha helix as evidence of it turned up in their own investigations. "In this way I made up, I think, for the failure to attend the Royal Society meeting in May—at any rate, so far as I myself am concerned, in that the doubts that some of these people had about the correctness of our protein structures were strongly expressed to me," he wrote Arne Tiselius. Doubts strongly expressed could be strongly answered, and Pauling set about convincing the British on some points, modifying his own thinking on others.
While visiting the Cavendish, Pauling was introduced to a number of the younger researchers and was especially interested in meeting Crick. Crick had been spending most of his time since being directed away from DNA on a problem Bragg had set his team working on after reading Pauling's protein papers, that of finding a mathematical formula for predicting how helixes would diffract x-rays. In the spring of 1952, Crick and two coworkers published a paper that provided the necessary mathematical treatment. It was Crick's first significant scientific success and proved immensely useful. He had proudly sent Pauling an advance copy. He then started thinking about how his formula might help explain the 5.1-angstrom reflection that was missing from Pauling's alpha helix.
Crick was interested in coming to Caltech on a postdoctoral fellowship and found himself discussing the possibility with Pauling while sharing a car ride around Cambridge. For once the voluble Crick found himself tongue-tied. He was filled with an admixture of awe— here he was, a mere graduate student, in the presence of the man he felt was the world's leading scientist—and wariness. DNA was not a subject of conversation; after all, Crick was not supposed to be working on it. But he had devised a new theory to explain why Pauling's alpha helix did not provide the 5.1-angstrom reflection observed in most natural substances. He knew that Pauling was thinking about that, too, and he did not want to give too much away, but at the same time he wanted very much to impress his visitor. He did not have to worry; Pauling already had his eye on Crick, and invited him to spend a year at Caltech working with him. Thus warmed, Crick felt confident enough to ask, "Have you thought about the possibility that alpha helixes are coiled around one another?" Pauling, who had been considering a number of schemes for the higher-level protein organization, including some in which individual helixes wound around each other, remembers answering, "Yes, I have," before letting the matter drop. He felt that he was almost ready to publish his ideas and had no intention of sharing them with a Cavendish student, no matter how promising.
According to Crick, however, Pauling gave no indication that he had been working on the problem at all.
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Proteins were still in the forefront of Pauling's mind. During his month in England, Pauling thought so little about DNA that he did not even make an effort to visit King's College to see Wilkins and Franklin's increasingly valuable x-ray photographs. The reason was twofold, he later remembered: He was preoccupied with proteins, and he still assumed that Wilkins did not want to share his data.
It was a historic mistake. Franklin had new pictures now, crisp, focused patterns from DNA in its pure, extended, wet form, clearly showing both twofold symmetry—thus ruling out three-stranded structures—and the cross-like reflections of a helix. If Pauling had seen these—and there was no reason to think she would not have shown him; she had, after all, shown Corey her work during his May visit— if he had talked to Franklin, who was not shy about presenting her strong ideas about water content and its effect on the form of the molecule, if he had heard the ideas that had capsized the Crick-Watson model, he would undoubtedly have changed the nature of his later approach. At the very least, a visit with Franklin would have impressed upon him that Astbury's earlier photos, the ones he was using, showed a mixture of two forms of the molecule.
Historians have speculated that the denial of Pauling's passport for the May Royal Society meeting was critical in preventing him from discovering the structure of DNA, that if he had attended that meeting he would have seen Franklin's work and had a better shot at following the right path. The idea nicely illustrates the scientific view that bureaucrats should not interfere in open communication between researchers. But the real problem was not the passport policy. Instead, three unrelated factors combined to set Pauling wrong. The first was his focus on proteins to the exclusion of almost everything else. The second was inadequate data. The x-ray photos he was using were taken of a mixture of two forms of DNA and were almost worthless. The third was pride. He simply did not feel that he needed to pursue DNA full tilt. After talking to Perutz and Bragg, he was likely aware that Crick and Watson had made a stab at the
structure and failed; he knew for certain that Wilkins was after it. But he did not consider them to be real competition. How could they be? Events had proven that he was the only person in the world capable of solving large biological molecules.
"I always thought that sooner or later I would find the structure of DNA," Pauling said. "It was just a matter of time."
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After missing his chance to see Franklin's data, Pauling returned to Caltech in September and threw himself into finishing his work on higher-level helical structure. "The field of protein structure is in a very exciting stage now," he wrote. "I have a hard time to keep from spending all of my time on this problem, with the neglect of other things." He worked out a way that his alpha helix could itself be twisted, like a piece of yarn wound around a finger, into the sort of coiled coil Crick had mentioned, and how this form could provide the missing x-ray reflection that the alpha helix alone did not. Then he went further, proposing ways in which these coiled coils could wind about each other to form cables of various numbers of strands. He published his new ideas in October.
Crick, however, knew Pauling's ideas already via Pauling's son Peter, who arrived at Cambridge in the fall of 1952 to work as a graduate student in Kendrew's laboratory. Peter, twenty-one, breezy, fun loving, more interested in the structure of Nina, Perutz's Danish au pair girl, than in the structure of myoglobin—"slightly wild," according to Crick—immediately fell in with Crick and Watson and their new office mate, Jerry Donohue, another Caltech expatriate who arrived that fall on a Guggenheim after working for years with Pauling.