Force of Nature- The Life of Linus Pauling

by Thomas Hager

  But it made all the difference to Crick and Watson. Franklin's criticisms had already pointed them toward putting the phosphates on the outside of the molecule; now they had the clue of a one-to-one relationship between the bases on the inside. They began thinking about helixes in which the purines and pyrimidines lined up somehow down the core of the molecule.

  When Pauling's much anticipated DNA manuscript arrived via Peter in early February 1953, both researchers were surprised to see something that looked like their own abortive three-chain effort, only more tightly put together. A few minutes' reading showed that there was no room at the core for the positive ions needed to hold together the negatively charged phosphates. Crick and Watson were dumbfounded. Pauling's structure depended on hydrogen bonds between the phosphate groups, but how could there be a hydrogen there when the phosphates in DNA lost their hydrogens at normal pH? "Without the hydrogen atoms, the chains would immediately fly apart," Watson said. They had already been through this with their own model, but they checked it again, and there it was in black and white in a respected text: The phosphates had to be ionized. The book they were looking at was Pauling's General Chemistry.

  There was an immense feeling of relief. "If a student had made a similar mistake, he would be thought unfit to benefit from Caltech's chemistry faculty," Watson later said. He and Crick immediately went off to confirm their criticism with Cambridge's chemists. Before the day was out, Pauling's mistake was the talk of the college: Linus's chemistry was wrong.

  Just as importantly for Watson, when he told Wilkins of Pauling's mistake and his idea that DNA was helical, he was given a reward: his first look at the more recent x-ray patterns Franklin had gotten from the molecule. She had found that DNA existed in two forms, a condensed dry form and an extended wet form the structure assumed when it drank up all that water. Astbury's photos, the ones Pauling had used, had been of a mixture of the two forms. Franklin's recent shots, much clearer and of only the extended form, immediately confirmed to Watson that the molecule was a helix and gave him several vital parameters for its solution.

  With obvious satisfaction, Crick, still smarting a bit from the coiled coil affair, wrote Pauling, to thank him for providing an advance copy of his nucleic acid paper. "We were very struck by the ingenuity of the structure," he wrote. "The only doubt I have is that I do not see what holds it together."

  Pauling's apparent misstep pleased Bragg so much that he agreed to let Crick and Watson go back full-time to DNA. There was a window of opportunity here, and he wanted the Cavendish to take advantage before Pauling had time to regroup.

  Pauling, however, had already moved on to a new project, a theory of ferromagnetism that he worked on through the spring. He also began making plans for a major international protein conference in Caltech the next fall and was drawn back to DNA only when Peter wrote him in mid-February about the English hooting at his structure. Corey had by now finally finished checking Pauling's atomic coordinates, some of which appeared again to be unacceptably tight. "I am checking over the nucleic acid structure again, trying to refine the parameters a bit," Pauling wrote Peter back. "I heard a rumor that Jim Watson and Crick had formulated this structure already sometime back, but had not done anything about it. Probably the rumor is exaggerated." In late February he finally tried Schomaker's suggestion of twisting the phosphate groups forty-five degrees and found that it eased some of the strain.

  Something was still wrong. When Pauling gave a seminar on his DNA structure at Caltech, the reception was cool; afterward, Delbruck told Schomaker that he thought Pauling's model was not convincing. He mentioned a letter he had gotten from Watson saying that Pauling's structure contained "some very bad mistakes" and in which Watson had added, "I have a very pretty model, which is so pretty that I am surprised that no-one ever thought of it before." Pauling wanted to know more. He quickly wrote Watson, inviting him to his fall protein conference, mentioning that he had heard from Delbruck about his DNA work, and encouraging him to keep working on the problem. "Professor Corey and I do not feel that our structure has been proven to be right," he wrote, "although we incline to think that it is." In early March he drove with Ava Helen to the University of California at Riverside to examine a collection of organic phosphates there, finding candidates for structural analysis that would be similar to the phosphate groups in DNA, looking for models to tell him how much he could deform his tetrahedra. Crick's barb about what held the molecule together led him to gather chemical precedents for the existence of adjoining negative charges in the same molecule, and he began to reason to himself that perhaps the DNA core environment was a special one that allowed the phosphates to exist as he had proposed. It was still, to Pauling, a matter of phosphate chemistry. Meanwhile, Todd had sent him the requested samples of nucleotides, and Pauling started their x-ray analysis.

  He was finally laying the groundwork for a reasonable structure. But it was too late.

  - - -

  Given the go-ahead to return to DNA, thanks to Pauling's paper, Crick and Watson each began feverishly devising models, focusing more on two-stranded models now that Chargaff had gotten them thinking of bases somehow pairing with each other. The "very pretty model" of which Watson had written Delbruck was one attempt, but it was wrong, as Jerry Donohue pointed out.

  Donohue's input turned out to be critical. A magna cum laude graduate of Dartmouth who had worked and studied with Pauling at Caltech since the early 1940s, Donohue knew structural chemistry inside and out. Hydrogen bonding had been a specialty of his, and he saw that Crick and Watson, chemical novices that they were, had been playing with the wrong structures for guanine and thymine. He set them right, switching the hydrogen atoms essential for cross-bonding into their correct positions, destroying their earlier model and pushing them toward the correct solution.

  With Donohue's corrections, Crick and Watson could now see hydrogen bonds forming naturally between specific pairs of purines and pyrimidines: adenine to thymine and guanine to cytosine. That was the last piece of the puzzle, and the result was dazzling. Matching a large with a small base not only smoothed the structure's outline but provided a simple explanation for Chargaff's findings. The resulting structure, a sort of ladder with base pairs as the steps and the sugar-phosphate backbone as the runners, formed easily into a helix that matched the x-ray data.

  More than beautiful, the structure had meaning. Each strand was a complementary image of the other; if separated, each could act as a mold for forming a new double helix identical with the original. This immediately provided ideas about replication that Pauling's model, with its bases facing out and unrelated to each other, could not.

  On March 12, Watson sent Delbruck a letter, illustrated with rough sketches, discussing their new model. He warned his mentor not to tell Pauling about it until they were more certain of their results, but Delbruck, never one to keep secrets, immediately showed the letter around. Pauling's mind raced as he read it. He saw immediately that the Cavendish structure was not only chemically reasonable but biologically intriguing. "The simplicity of the structural complementariness of the two pyrimidines and their corresponding purines was a surprise to me—a pleasant one, of course, because of the great illumination it threw on the problem of the mechanism of heredity," he said. In it he could see echoes of many of the things he had been thinking and writing about complementarity since his 1940 paper with Delbruck.

  The same day that Alex Rich first heard about the Watson-Crick structure, he awoke in the middle of the night, got out of bed, went into his office, and began building a rough version of the Watson-Crick double helix out of the pieces of molecular models he had there. All he knew was that they had paired the DNA bases across the center of the molecule, but knowing that was enough. He quickly paired the correct bases, saw that it worked beautifully, and went back to bed shaking his head.

  Pauling, while not yet ready to concede the race, was impressed. A few days after seeing Watson's letter, he wrote a colleague, "Yo
u must, of course, recognize that our proposed structure is nothing more than a proposed structure. There is a chance that it is right, but it will probably be two or three years before we can be reasonably sure. ..." A few days later, he received an advance copy of the Watson and Crick manuscript, which started by attacking his DNA model and ended by thanking Jerry Donohue for his help. Pauling looked it over and wrote his son, "I think that it is fine that there are now two proposed structures for nucleic acid, and I am looking forward to finding out what the decision will be as to which is incorrect. Without doubt the King's College data will eliminate one or the other."

  He still had not seen any of Franklin's or Wilkins's recent x-ray photos and withheld final judgment until he did. His chance would come soon: He was planning to go to Brussels in April for a Solvay Conference on proteins and intended to stop off in England on the way to see the Watson-Crick model and the photos from Wilkins's and Franklin's laboratories. When he applied for a passport, his old nemesis Ruth Shipley again recommended denial, this time based on her belief that Pauling's Industrial Employment Review Board (IERB) testimony proved that he was refusing to be considered for top-secret clearance. After Pauling explained that he had been cleared for top-secret material in the past and would be willing to be again, but only if it was required for his work—and after he once more swore in her presence that he was not a Communist—his passport was approved.

  In early April, a few days after Crick and Watson submitted their paper for publication, Pauling arrived in Cambridge. After spending the night with Peter, he walked into Crick's office and for the first time saw the three-dimensional model they had wired together out of diecut metal plates. Crick chattered nervously about the features of the double helix while Pauling scrutinized it. He then examined Franklin's photo of the extended form of the molecule. Watson and Crick waited. Then, "gracefully," Watson remembered, "he gave the opinion that we had the answer."

  It was a joyful moment for the two young men and a deflating one for Pauling. He was amazed that this unlikely team, an adolescent postdoc and an elderly graduate student, had come up with so elegant a solution to so important a structure. If they were right, his own model was a monstrous mistake, built inside out with the wrong number of chains. But he recognized now that the Cavendish team was almost certainly right.

  There was only one thing left for him to do: Show the world how to handle defeat with style.

  Pauling left Crick's office and met Bragg for lunch, during which Sir Lawrence vainly tried to restrain his ebullience. After so many years of coming in second, his team had finally beaten Pauling! Later, Pauling joined the Cricks at a pleasant dinner at their house at Portugal Place. Through it all he remained charming and funny and remarkably accepting of the new DNA structure, a true gentleman, both wise enough to recognize defeat and great enough to accept it with good humor. A day or two later both Bragg and Pauling went to the Solvay meeting—an occasional select gathering of the world's top researchers funded by a Belgian industrialist—where Bragg provided the first public announcement of the double helix. Pauling was generous in his support. "Although it is only two months since Professor Corey and I published our proposed structure for nucleic acid, I think that we must admit that it is probably wrong," he told the group. "Although some refinement might be made, I feel that it is very likely that the Watson-Crick structure is essentially correct."

  - - -

  Inside, however, Pauling was burning. Despite his generous crediting of Watson and Crick's work in England, he still thought there was an outside chance that some variation of his own idea would still prove correct. Soon after returning home in mid-April he put Alex Rich to work taking new x-ray photos of DNA and returned to fine-tuning the atomic positions in his model.

  It was hopeless. It quickly became clear that he had taken a pratfall on the world scientific stage. After the Watson-Crick paper was published, they were showered immediately with worldwide acclaim, while Pauling's model was shoved aside and forgotten. He had been wrong before—about artificial antibodies especially and a few relatively unimportant, small molecular structures—but never wrong as publicly and on such an important topic as this. It was all the more humiliating for the world's leading structural chemist to be beaten by a pair of beginners.

  What had gone wrong?

  Everyone seemed to have an opinion. Peter thought the problem was Pauling's strictly chemical approach to DNA, with his fascination with phosphate packing taking precedence over thoughts about biological function. "To my father, nucleic acids were just interesting chemicals, just as sodium chloride is an interesting chemical," he wrote. This was not strictly true, however. Thanks to Morgan's influence at Caltech, Pauling had been interested in genes ever since the early 1930s. He talked of "a chemical attack on the structure of chromosomes" in 1937 and had made the replication of the gene a central image in his late-1940s talks on complementarity. He had a strong idea about how genes duplicated themselves: They started as a complex of two complementary structures, each of which served as the mold for creating the other, together re-creating the complex. He simply got carried away by his pretty structure and figured that the biological facts would fall into place later.

  Chargaff concluded that the problem was obvious: Pauling "failed to take account of my results." Wilkins thought Pauling "just didn't try. He can't really have spent five minutes on the problem himself." Verner Schomaker theorized that Pauling did not put enough people onto the problem to gather sufficient hard data, and Alex Rich added that the Caltech coworkers who reviewed Pauling's model were partly to blame for being insufficiently critical. "In a way," he said, "the people around him let him down."

  Pauling had his own thoughts about how he had been led astray. At first, he blamed the x-ray photos he had used. Pauling wrote Delbruck a week or so after he visited the Cavendish, saying that poor crystallographic data had put him off track. "The x-ray photographs that we had, which had been made by Dr. Rich, and which are essentially identical with those obtained some years ago by Astbury and Bell, are really the superposition of two patterns. . . . Corey and I had tried to find the structure that accounted for one of the principal features of one pattern, and simultaneously for one of the principal features of the second pattern."

  Later, he put more emphasis on misreading DNA's density, the error that led to the idea of a three-chain structure. "The reason that I got off on this three-strand binge is that I did not know how much water of hydration there was in those preparations," he said. "More than a third of the material in the preparation was water and only two thirds was nucleic acid. So the calculation that I made ignoring the water gave three strands. And if you correct for the water—I just hadn't realized there was so much hydration—then it turns out to be two strands."

  He also blamed his lack of knowledge of the DNA subunits. "If we had also done some work on some purines or pyrimidines, I might well have had the background information that would have pushed me in the right direction. But we didn't do any purine or pyrimidine work."

  Each excuse contained a measure of truth. But each was a symptom of a problem, not the problem itself.

  There were two reasons Pauling failed with DNA: hurry and hubris. He rushed because DNA was the biggest prize around and if he did not crack it, someone else—probably someone in England—soon would. Although he later denied he was competing with the British researchers for the DNA structure—"I did not feel that I was in a race with Watson and Crick," he said. "They felt that they were in a race with me"—the fact was that he was in a race, perhaps not with the unknown Watson and Crick but certainly with Wilkins and Franklin and, above all, with his oldest rival, Sir William Lawrence Bragg. Pauling wanted to publish his DNA structure quickly in order to beat Bragg's group, and Wilkins, too, and he took a chance doing it without having done his homework.

  Pauling had no precise structures for the nucleotide subunits. The x-ray photos he used, those that Astbury had done years before, were muddy and vague,
and Pauling never attempted to make x-ray photos of his own prior to publication. He started with one idea, the phosphate core model, and never deviated from it. No three-dimensional models were ever built. Pauling did not even have Corey check his figures a final time before sending in the paper. He wanted the credit for solving DNA, and to get it he had to publish first.

  More importantly, he rushed because he thought he could get away with it. His success with the alpha helix had given him faith that he could jump ahead successfully. All of the basic assumptions that he had made in the late 1930s had been right; fifteen years of further research had only proved it. He was right about hydrogen bonding and the planar peptide bond and the nonintegral repeat. As long as he stuck with what he knew about chemistry, he was always right.

  The alpha helix had graced him with success and cursed him with overweening pride. After its solution, he believed he no longer needed to do the homework required by others. It was clear that he was the best person in the world at solving the structure of giant molecules— any molecules, for that matter. He knew that he had put together the correct basic structure of the alpha helix two years before he published it, two long years during which Bragg might have come up with the answer and beaten him to it. Pauling had hesitated then because of his doubts about the 5.1-angstrom x-ray reflection, an experimental observation that turned out to be irrelevant. The lesson was clear: In certain cases he had to trust himself, not the experimental results. He had to trust his intuition, his nose for a good structure. He knew that his triple-stranded DNA structure was very tight and that it begged the question of how the negatively charged phosphates could keep from repelling each other, but he believed that those matters would work themselves out, as the missing reflection in his alpha helix had worked itself out as a matter of coiled coils. The phosphate packing in the center of his model was too pretty, too clever not to be right.