Force of Nature- The Life of Linus Pauling

by Thomas Hager

  Langmuir championed Wrinch's ideas in print and in private, cowriting papers with her, bringing her together with Harker—a special privilege to get support from one of Pauling's own students—and convincing Mirsky that denaturation might proceed in steps more closely matching those predicted by the cyclol theory. With Langmuir's help, the cyclol theory was rising from the dead.

  Pauling was both confused and aggravated by the attention lavished on what he believed was a mistaken theory. This was not only a distraction from the real problems of protein research; it was an attack on Pauling's hydrogen-bonding ideas, a diminution of his reputation as a leading protein researcher, a challenge to his view of nature. He decided it was time to end it.

  In the early spring of 1939 he enlisted Niemann's help in preparing a paper that would examine and demolish, one by one, every major argument in favor of the cyclol structure. They worked on it for weeks; their final product, "The Structure of Proteins," was published in the Journal of the American Chemical Society (JACS) that July. It was a tour de force, the most strongly worded attack on an opposing theory that Pauling had ever written. Chemistry was the main weapon they used, especially data on bond energies that Pauling thought clearly showed that the proposed cyclol structure was much less stable, therefore much less probable, than polypeptide chains. From energy considerations alone, Pauling and Niemann wrote, "we draw the rigorous conclusion that the cyclol structure cannot be of primary importance for proteins; if it occurs at all (which is unlikely because of its great energetic disadvantage relative to polypeptide chains) not more than about three percent of the amino acid residues could possess this configuration" (emphasis theirs). After highlighting what they considered Wrinch and Langmuir's other major inconsistencies and mistaken interpretations, Pauling and Niemann briefly put forward their own idea of protein structure. It had not changed much in the three years since Mirsky and Pauling's denaturation paper: Proteins were long, peptide-bonded chains held in specific shapes by a mixture of hydrogen and sulfur-sulfur bonds and "similar interatomic interactions." What those final specific shapes were, no one could yet tell. The only thing that seemed certain was that they were not cyclol cages.

  "The Structure of Proteins" was devastating and immediate in its effect. "I must say that I derived enormous enjoyment from reading 'The De-Bunking of Wrinch' by Pauling and Niemann!" Alex Todd wrote after he got his copy. "It really was high time that somebody put the case against the cyclol theory in definite terms, and I think that all chemists here at least will welcome it. As far as I can see, the case is unanswerable and I shall be intrigued to see what response, if any, it will evoke from Wrinch."

  - - -

  Ironically, a few weeks before Pauling and Niemann sent in their paper, Wrinch had decided to give up protein work. In the spring of 1939, hurt by the hostility of Bernal and the Cambridge group, she fled England for America, telling Weaver when she arrived that the conclusions she had drawn from the insulin data were premature and she was dropping any further studies. Pauling and Niemann's paper could not have appeared at a worse time. She was looking for a faculty position for herself and a home for her daughter; in order to raise her stock as a job prospect, she had to answer the attack. She stormed into the Harvard offices of Arthur Lamb, the editor of JACS, and demanded space for a rebuttal. Lamb explained that he would publish any correction of fact or relevant new research findings but that the journal was not a place to rehash old arguments. Her twenty-one-page riposte arrived a few weeks later, refuting Pauling and Niemann point by point, ending with the conclusion that "opponents of the cyclol hypothesis have felt compelled to fall back upon arguments which are specious (due to errors in logic), and upon experiments which are irrelevant... or incompetent to decide the issue." Lamb, following standard procedure, sent her manuscript to Pauling and Niemann with a cover note requesting their comments to attach to Wrinch's paper when it went out for peer review.

  They in turn answered Wrinch's rebuttal paragraph by paragraph in what was becoming an escalating war of words: ". . . there is no reason why this ghost should be permitted to continue to parade across the literature of protein chemistry"; "no reason for republishing this disputed fancy"; "all we have here are further hopes and no facts." Lamb then sent the entire smoking package to two referees, whose responses so differed that everything had to be sent to two more referees. Everyone who read the papers was struck by the acidity of the debate; each suggested a different solution. Lamb and one referee thought there should be simultaneous publication of both Wrinch's work and Pauling and Niemann's response to it after both parties had reviewed the final drafts; another referee advised quickly publishing Wrinch's paper alone and then closing the issue; another compared the battle to the opening salvos of a world war and advised slowing down the process "to give each a chance for cooling down and taking second thoughts."

  Then Wrinch found that Pauling and Niemann had erred in calculating the energies of formation of proteins; correcting the figures reduced the energy discrepancy between the chain and cyclol structures by about one-third. When she pointed it out in a letter to Pauling, he replied that it was too small a change to alter their conclusions and therefore that "it has not seemed to us worthwhile to correct this error in print."

  Wrinch then stung Pauling from another angle. She had gotten a temporary appointment at Johns Hopkins, where David Harker worked, and the two of them began talking. Harker had had his own run-ins with Pauling as his student and listened sympathetically as Wrinch told him how Pauling had attacked her and was, to her mind, preventing her rebuttal from being published. Harker in turn told her about what he considered to be Pauling's fast-and-loose use of resonance to explain anything and everything about the chemical bond. They ended up publishing a short letter together in the Journal of Chemical Physics in the spring of 1940 in which they proposed an approach to chemical bonding that eliminated the need to invoke resonance. Although the letter mentioned Pauling only in footnotes, it was clearly a challenge to his basic approach.

  "I have just noticed again the letter by you and Dorothy Wrinch . . . and have decided that its publication shows that you are in need of some advice," Pauling wrote Harker, his words those of a father betrayed. "The general tone of the letter indicates that it represents a criticism of the work done here. Even if there were grounds for this criticism, your personal indebtedness to this Institute should have kept you from being a party to it." After some specific criticisms, Pauling ended, "Although the casual reader might be misled by your letter into thinking it represented some small contribution to knowledge, I shall not trouble to set him straight by publishing a reply. ... I think that you could be about better business and in better company." He then wrote the editor of the journal suggesting that it might have been wise to submit the Harker-Wrinch letter to him before publication.

  Pauling was throwing his weight around, and Harker resented it. "I have heard rumors from time to time concerning your allegedly unfair attitude toward Dr. Wrinch and her right to discuss her theories in print," he wrote back. "I have invariably thought—and said—that such an attitude on your part was impossible. ... I should be most unhappy to be forced to believe otherwise."

  - - -

  An abbreviated form of Wrinch's rebuttal finally appeared in the JACS nineteen months after Pauling and Niemann's original paper. But by then both the cyclol theory and Wrinch's career were essentially dead. Warren Weaver informed her that there would be no more Rockefeller money, telling her that five years was more than enough time to convince her colleagues about cyclols. She had trouble getting money anywhere and had trouble getting further criticisms of Pauling into print. By the end of 1940 she wrote a friend, "I get absolutely in despair, for I see the whole set-up as a power syndicate just like Hitler's and only the strong and powerful can survive. . . . This new Pauling business gets me down. He is a most dangerous fellow. . . . Even decent people hesitate to stand up to LP. He is bright and quick and merciless in repartee when he likes and
I think people are just afraid of him. It takes poor [Dorothy] to point out where he is wrong: truly none of them would."

  Wrinch would spend the rest of her life in scientific obscurity, still tough and outspoken, committed to the cyclol theory, and telling anyone who would listen about her beautiful protein fabrics and how Pauling and his cronies had silenced her. The Wrinch affair made anyone look bad. It ruined her career and chained her interesting and wide-ranging intellect to a single lost cause. It deepened a rift between Pauling and Harker that was years healing. It fed rumors that Pauling was a bully who would run over those who disagreed with him. The semi-public scientific fistfight was also disturbing to the one man no one wanted to alienate: Warren Weaver. The Rockefeller director expressed his annoyance quietly but pointedly to Pauling in a letter at the end of 1939: "It is my own feeling that the very lively and somewhat contentious interest in theoretical approaches to protein problems has, perhaps up to about the present time, served a purpose which is on the whole useful; and that the time has now definitely arrived when it is of far greater importance to get a wider and more dependable body of facts. There is nothing which ever speaks so convincingly as the quiet presentation of facts."

  Wrinch would later blame her problems on sexism, telling friends, "Ah, it's the Y chromosome. If I had the Y chromosome, people wouldn't talk to me like this in public journals." There is little doubt that gender discrimination played a role in the way she was treated. Sexism was endemic in the sciences at the time and was institutionalized at all-male Caltech.

  But it was not an important influence on Pauling. Ava Helen made sure that Pauling was about as "liberated" as a man of the era could be; he respected the work of the few other women in his field, such as Dorothy Crowfoot Hodgkin. He was as enthusiastic in attacking Langmuir as he was in going after Wrinch. Langmuir, however, with his renown secure, did not suffer. Wrinch did.

  Pauling merely put into print, more completely and strongly than anyone else, what almost every knowledgeable protein researcher who came in contact with Wrinch already thought. Not even a Y chromosome would have made the cyclol theory right.

  But the Wrinch incident did illuminate less appealing sides of Pauling's character. The evidence was scanty on both sides of the debate—as Wrinch often pointed out, it was impossible to say conclusively that cyclols did not exist. During the 1950s, in fact, another researcher found a cyclol-like structure in some ergot alkaloids—a discovery that Wrinch tried unsuccessfully to leverage into grants for a review of all other protein structures. Cyclols were not impossible. At the time of the debate, however, Pauling, taking the role of a scientific papa silencing a noisy child, spoke with an authority that ended the argument.

  It was a demonstration of his new power. Within a few years of assuming the chairmanship of the Caltech Division of Chemistry and Chemical Engineering, Pauling had become an established player in chemistry's power structure. He, like Noyes before him, sat on editorial boards, nominated people for office, selected award winners, provided advice, and spoke widely. He was invited, consulted, honored, and deferred to. He drank it in. But the prestige and acclaim brought out negative factors in his personality that became more evident as his power grew: a tendency toward self-righteousness, a desire to control situations and frame debates, and a willingness to silence those with aberrant ideas.

  The Serologist

  Pauling emerged from his debate with Wrinch more convinced than ever that proteins were long chains of amino acids pinned by weak bonds into specific shapes. That belief now led him into an entirely new and unexpected field of research.

  In the spring of 1936, after delivering a talk on hemoglobin at the Rockefeller Institute for Medical Research, Pauling was given a note asking if he could he find time before he left New York to spend an hour or two discussing some research of mutual interest? It was signed by Karl Landsteiner.

  Pauling knew the name. Landsteiner was a highly respected Austrian medical researcher who had won the Nobel Prize five years earlier for discovering the ABO blood groups, leading for the first time to safe blood transfusions and saving thousands of lives. Landsteiner had come, late in life, to America to continue his studies of blood, particularly the agents in the plasma serum that made up the immune system. Pauling was intrigued by the invitation to talk and by the man himself. When he arrived at Landsteiner's laboratory the next day, he was greeted by a scientist who looked like an aristocrat: Tall, mustachioed, erect, and distinguished looking, Landsteiner had retained the short-cropped gray hair and air of gentility and confidence that had been part of his persona since his early years in Vienna. In softly accented English, he invited his visitor to sit down. Then he began telling Pauling a mystery story.

  It had to do with antibodies, Landsteiner explained, an unusual class of protein molecules that helped the body fight infection. Pauling's talk on hemoglobin had given Landsteiner the idea that perhaps Pauling might be able to help explain some observations Landsteiner had been making. For instance, antibodies were made by the body with thousands, perhaps hundreds of thousands, of different specificities, each one capable of recognizing and locking on to a different target molecule, or antigen. An antibody to Pneumococcus bacteria, for instance, would recognize and attach only to antigens specific to that organism and ignore antigens specific to Streptococcus, and vice versa. Landsteiner's own experiments using a range of man-made chemicals as antigens had shown that this specificity could be impressively precise: In some cases, antigens that differed by only a few atoms would react differently with a given antibody.

  This sort of specificity was not unknown, of course; enzymes, for instance, also were highly specific for their target molecules, called substrates. But each enzyme had only one substrate. Specific antibodies could be made to thousands upon thousands of targets, including artificial chemicals. There were a number of puzzling things, Landsteiner said. One was how antibodies achieved that specificity in chemical terms. How could protein molecules like antibodies tell the difference between one antigen and another? What were the forces that held an antibody molecule to an antigen? How was the body capable of making such a range of antibodies with such high precision? How could the body know how to fashion proteins directed against synthetic targets that it had never been exposed to before?

  Pauling hadn't the slightest idea how to respond to these questions—beyond his immediate assumption that the answers must have to do with how the molecules were built. But he liked Landsteiner, whom he found an engaging, far-ranging thinker ("a great man," he would soon be telling others), and he was fascinated by his work. Landsteiner was turning the study of antibodies into a tool that might be used to understand how proteins were built. The new field Landsteiner was helping to create, immunochemistry, might be another powerful tool for Pauling’s laboratory. At the end of their visit, Pauling told Landsteiner he would think about his questions and they would talk again.

  But he needed a quick education first. He immediately bought a copy of Landsteiner's most recent book on immunology and read it on the train back to Pasadena. He was intrigued from the opening page, where Landsteiner had written, "The morphological characteristics of plant and animal species form the chief subject of the descriptive natural sciences and are the criteria for their classification. But not until recently has it been recognized that in living organisms, as in the realm of crystals, chemical differences parallel the variation in structure." Pauling had found a kindred spirit, a man who could in two sentences tie together biology, chemistry, and crystallography. He became fascinated in what Landsteiner had been learning about the body, about how the immune system allowed each individual animal to recognize the chemical differences between self and nonself.

  As the countryside blurred outside the train window, Pauling immersed himself in the book. Landsteiner, who had studied chemistry with the great Emil Fischer, had helped make the study of the immune system into a chemical science, perfecting systems for producing and measuring the activity of antib
odies to known organic compounds. This was a tool that could work two ways: First, antibodies could function as fine probes for chemical structure capable of telling the difference between closely related organic molecules, including proteins; and, second, selected antigens could function as probes for investigating the structure of antibodies. Because no one knew how antibodies were made or how they attached to their targets, the field was full of gray areas, contradictory findings, and confusing experimental results. Most immunologists came to the field from biology or medicine and appeared to ignore or misunderstand chemistry. Immunology, in other words, was a field ripe for colonization.

  - - -

  By the time he got back to Pasadena, Pauling was ready to devote part of his time to immunology. He and Mirsky were just putting the finishing touches on their theory of protein denaturation, and Pauling began relating what he was learning about antibodies to his idea of proteins as long-chain molecules held in place by hydrogen bonds. He took it almost for granted that antibodies, like all molecules, worked the way they did because of their structure. Suppose they were built to complement the shape of a specific antigen, to form around it like a glove around a hand? This idea of complementary shapes was an old one, first put forward by Paul Ehrlich at the end of the nineteenth century—he talked about it in terms of locks and keys—and updated by others since then, but Pauling began to think of it in a new way, in terms of denaturation. What if a newly made antibody molecule was like a denatured protein, its hydrogen bonds broken, the chain opened out in a line. If it then made contact with an antigen, the two molecules would be attracted by weak, nonspecific forces—the van der Waals attraction and electrostatic attraction between oppositely charged areas on the antigen and antibody chain. Energy considerations would then tend to maximize contact between antibody and antigen; free energy would be minimized when the antibody's electrically charged atoms came close to oppositely charged areas on the antigen's surface and the greatest number of van der Waals interactions were made. The closer the fit between antigen and antibody, the more of these nonspecific weak links that snapped into place, the more stable the paired system. The antibody would naturally form itself to the antigen's shape, like soft clay pressed around a coin. Soon after returning to Caltech, Pauling roughed out a manuscript about antibody formation.