by Thomas Hager
For the junior posts, Weaver suggested Carl Niemann, a young protein chemist who had quickly made a name for himself at the Rockefeller Institute for Medical Research; Pauling liked him very much and was happy to hire him. Then Pauling strongly suggested hiring a pair of brothers, R. R. and R.J. Williams, whose research interests included the B vitamins. When Weaver communicated his reaction as "not entirely enthusiastic," however, Pauling backed off. Instead, he hired one of the Williamses' young coworkers, Edwin Buchman, as the second junior man.
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A year into his chairmanship, Pauling was proving to be both a surprisingly adept leader and a person very different from A. A. Noyes. Noyes had worked quietly, cooperatively, behind the scenes, setting larger schemes into motion, changing the method of scientific education, and helping to build the institutions that would bring the United States to scientific prominence. He was the one and only King. Pauling, more adventurous, insightful, and inventive, more aggressive and involved with his own image and the success of his own research, would put a different stamp on the way chemistry was done at Caltech.
He would never be called the King. Closer to the mark was a comment Alfred Mirsky passed on from the Rockefeller Institute for Medical Research in 1938. "Oh, by the way, I was talking with Gasser [the institute's new president] about you the other day. He referred to you as a 'wizard,'" Mirsky wrote. "I hope you don't find being one a burden."
CHAPTER 10
The Fabric and the Chain
The Woman Einstein
Pauling was not the only scientist taking a theoretical approach to the molecular structure of proteins. An unusual and controversial British thinker named Dorothy Wrinch was also hard at work on the problem. In fact, she thought she had solved it.
Born in 1894 to a British engineer in Argentina, Wrinch started studying mathematics in Britain, then turned to philosophy, becoming a disciple of Bertrand Russell and a minor figure in his socialist-Bohemian circle. After marrying a physicist, she became the first woman to receive a D.Sc. degree from Oxford, where she taught mathematics and published widely. She was unconventional and ahead of her time: forceful, cigarette-smoking, acid-tongued, committed to an independent career (she published under her maiden name), and interested in everything. (Among many accomplishments, she wrote a sociological tract about the problems of parenthood in two-career families.) From her time with Russell, she came to believe that all scientific progress grew directly from mathematics and logic, a belief she applied first to physics and then to biology.
But significant discoveries eluded her. By the early 1930s—nearly forty years old, separated from her husband and caring for a small daughter—Wrinch had become an intellectual Gypsy, talking herself into apprentice positions in biological laboratories throughout Europe in order to learn about genetics, embryology, and the new field of protein chemistry. She fell in with the Biotheoretical Gathering, a small, informal group of British avant-garde scientists, including the protein crystallographers John Bernal and Dorothy Crowfoot, who believed that mixing old disciplines in new ways might result in the next great leap in understanding biology. Warren Weaver, always on the lookout for new talent to fund, had his eye on that group as well, learned of Wrinch and read her papers applying mathematics to the study of the contraction of chromosomes. He gave her a generous five-year grant in 1935.
She quickly came up with results. In 1936, Wrinch proposed an entirely new and intriguing structure for proteins. She theorized that amino acids, instead of linking only end to end, might be able to connect with each other in more complex ways, forming, instead of chains, protein fabrics. She recognized that the types of bonds she was proposing had not been shown to exist in nature, but argued that so little was known about proteins at the time that the possibility of undiscovered bonding patterns was not out of the question.
She was a mathematician, not a chemist, and her fabric patterns fit some of the experimental data beautifully. Her favorite fabric was a honeycomb of hexagonal rings of amino acids that could be folded around and stitched to form closed cage structures—one of which, according to her topological calculations, would contain a total of 288 amino acids—a number that some researchers thought represented a basic unit in many proteins. This "cyclol" structure, as she called it, was one of the first detailed schemes put forward for explaining the formation of globular, as opposed to fibrous, proteins, and it generated a good deal of talk.
At first the reaction was positive. A steady stream of papers began to appear in which Wrinch detailed how her cyclol cage could explain everything from proteins' ability to create films on liquid surfaces (the cage, she argued, would open up into a flat, floating sheet) to the stimulation of antibodies in animals (amino-acid side chains, she said, would stick out from the cyclol cages, providing reactive spots). Protein experts gave her papers a serious reading. Bill Astbury was sympathetic to her model at first because one of the folded chains he had proposed for keratin came close to doubling back on itself to make hexagonal patterns like those Wrinch proposed.
Protein research was a rich, promising field, and Wrinch threw herself into it, teaching herself the basics of x-ray crystallography, knocking on doors at the protein labs in Cambridge, suggesting experiments, engaging everyone she met in enthusiastic discussions of her work. She soon knew enough to devise useful ideas about the mathematical interpretation of x-ray diagrams. Her enthusiasm, love of argument, and growing obsession with her own theory kept her hammering away at anyone and everyone she thought should be convinced about cyclols. She started presenting her ideas at scientific conferences. Newspapers, always on the lookout for a fresh angle on science stories, began publicizing this remarkable female who, it appeared, was on her way to solving the structure of proteins. One called her a "Woman Einstein."
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The attention paid to Wrinch and her cyclols in the period 1936-38 set off a reaction among those most involved in the field of molecular structure. Globular protein workers like Bernal began noting weaknesses in Wrinch's arguments due to her lack of background in chemistry and biology. Wrinch's was certainly an interesting hypothesis, but it was only one among many, with good arguments to be made against it. The four-way amino-acid linkage required by her model had never been seen by organic chemists; while it was impossible to rule it out, no new evidence appeared to support its existence. Wrinch's retort, "Proteins are so different from other substances that it is surprising that there is a reluctance to accept for them a structure for which no analogue in organic chemistry can be found," didn't sit well with researchers who had a proven method of linkage with the peptide bond. Wrinch's personal style did not help, either; she was, some thought, rather too pushy for a scientist and certainly too pushy for a woman. There was an anti-feminine bias at play. She got people thinking, but she also got on their nerves. The small world of protein researchers began to fracture into pro-Wrinch and anti-Wrinch groups.
High on the list of people Wrinch wanted to convince of her theories was Linus Pauling. As early as the summer of 1936 she wrote him, "I would awfully like the chance of a conversation with you about proteins." His response was cordial; they traded research papers, and Wrinch wrote again, "I am . . . still extremely anxious to sit at your feet." In the spring of 1937, Pauling wrote, "She is a very clever person, and I am sympathetic to the type of speculative consideration which she is carrying on now. Without doubt there is a great deal of truth in her general picture." He doubted, however, that the hexagonal rings of amino acids she proposed were stable enough to replace the polypeptide chain as a preferred model, and he was growing increasingly disenchanted with the whole mathematical approach used to come up with cyclols; fifteen years before, he had seen a number of speculations about crystal structure put forward on the basis of pleasing symmetry and mathematical self-consistency rather than experimental results, and he had helped prove some of them wrong. Nature, he thought, did not work according to strict mathematical theories, or if it did, they were theo
ries complex enough to allow a great deal of leeway and a degree of strangeness. Pauling began to believe that Wrinch was relying too heavily on the creation of "nicely symmetrical structures" rather than ones that arose naturally from the dictates of chemistry. There was no chemical reason he could see to force proteins into a cyclol cage.
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By 1938, Warren Weaver, too, was having doubts about Wrinch. He had surveyed a number of scientists about her and found no consensus— some believed her a genius; others found her ideas preposterous. Weaver himself began to think that she was "a queer fish," valuable in spurring discussion but inclined to spend too much time trying to win converts to her theory and too little time proving it. He wanted the cyclol issue resolved and asked Pauling to help him do it as "one of the few persons who will not be in the slightest awed by [Wrinch's] facility in mathematics." Weaver arranged a meeting between Pauling and Wrinch in January 1938, while Pauling was at Cornell.
By the time they sat down with each other, however, Pauling had already made up his mind about Wrinch. Soon after arriving on the Cornell campus in Ithaca, New York, Pauling saw in the New York Times a photo of Wrinch "fondly holding her elaborate model of a globular protein" under the headline "Architecture of the Protein Molecule." He could tell from the grainy photo that the cyclol cage was too delicate, its interior too empty to match the known high density of globular proteins. Two months before the planned meeting, Pauling, Mirsky, Max Bergmann, and Weaver talked about Wrinch at the Rockefeller Institute for Medical Research. According to Weaver's diary, Pauling not only confirmed that he thought her work was too speculative, too strongly based on a desire for symmetry; he also felt that considering the early stage of her work, she had been getting too much publicity. Bergmann added that she did not give enough emphasis to the peptide bond; the point was made that the cage structure she proposed, linked with strong covalent bonds all around, could not be broken open easily enough to explain the first stage of denaturation—the reversible step that Pauling thought involved hydrogen bonding. It was decided at the end of the discussion that Pauling would "make a serious effort to learn more accurately just what definite results [Wrinch] has," during their January meeting.
Wrinch arrived in frozen Ithaca eager to talk. But their discussions, two hours a day for two days, simply confirmed what Pauling already believed. He grilled her about the details of her structures and found out that she knew a great deal about mathematics and very little about the hard facts of chemistry.
The private report he made to Weaver afterward was devastating. Pauling said that Wrinch was approaching the problem as a mathematician, "interested in the rigorous deduction of consequences from postulates rather than in the actual structure of proteins"; that "she did not seem to consider experimental evidence against her ideas very interesting"; and that "Dr. Wrinch is facile in the use of the terminology of chemists and biologists, but her arguments are sometimes unreliable and her information superficial."
More important, he attacked the whole idea of a structure devised to include 288 amino acids. There were no known chemical forces that would act to limit a protein molecule to that number, he wrote; the observation of many proteins and protein subunits roughly that size might be due to some sort of evolutionary pressure but was not the result of chemical necessity. With that prop kicked away and her knowledge of protein chemistry proved weak, Pauling concluded that Wrinch's papers were "dishonest." It was unfortunate, he wrote, that protein researchers "do not know that her feelings about science are completely different from theirs, and so they are deluded into taking her work seriously."
The only positive thing he found to say was that his talks with Wrinch had given him new energy to revisit the protein problem: "Since talking with Dr. Wrinch it has seemed to me that I should prepare a paper on my ideas. I have been averse to doing this because of their speculative nature; they are, however, superior to Dr. Wrinch's in my opinion." Weaver encouraged him to give his imagination free rein.
As far as the Rockefeller Foundation was concerned, Pauling's report finished Dorothy Wrinch. She was taken aback during their conversations by the closeness of Pauling’s questioning and the severity of his criticisms. She returned to England disheartened. There she encountered more attacks from Bernal and his friends. The scientific world was tilting away from her. As Weaver's representative in England, W. E. Tisdale wrote soon after reading Pauling's comments, "She certainly has been a catalyst, although I'm not sure how long a catalyst should continue to exist after the reactions have been catalyzed."
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After his return to Caltech from Cornell, Pauling made a forceful, four-pronged attack on protein structures. Now in command of a richly equipped suite of new laboratories in the Crellin building staffed by an ever-growing team of students and postdoctoral fellows, he started a program to take more x-ray photos of native proteins in hopes that something worthwhile might be discovered beyond what Astbury and Bernal had already found. He also began using Zechmeister's chromatographic techniques to separate and purify the bits and pieces that resulted from breaking proteins apart, hoping to solve the structure of a fragment as a step toward the whole protein, perhaps making it possible to reconstruct the order in which amino acids were strung in the chain.
But most of his effort still focused on the structure of the protein building blocks, amino acids. And here Corey's success with glycine and diketopiperazine was surprising because of its very lack of surprise. Amino acids, it appeared, were built very much as Pauling had thought. Bond angles and distances were in line with his predictions. The diketopiperazine structure gave strong evidence that the peptide bond had the double-bond character Pauling theorized it should have, enough to keep the atoms from rotating around each other, holding the atoms on either side of the peptide bond rigid and flat. It proved what Pauling had assumed in his 1937 attack on the structure of keratin. So why had that attempt failed? He put Corey and Hughes and their students to work on more amino acids and small peptides, making ever-more accurate maps. Perhaps the answer was somewhere in the fine details.
Pauling's 1936 paper on protein denaturation, cowritten with Mirsky, had not after two years made much of an impression. Despite the paper's persuasive chemical arguments and firm foundation in experimental observations, it did not persuade most protein researchers that a force as little known, nonspecific, and weak as hydrogen bonds could account for the ways in which proteins were held in precise shapes. Acceptance of the hydrogen-bonding idea proved disappointingly slow. But Pauling was still convinced it was correct, and he began talking with the new colleague he had hired, the protein researcher Carl Neimann, about ways to prove it.
In the middle of this new attack on proteins a bombshell fell: Dorothy Wrinch had found proof of her cyclol structure. Instead of slinking out of the field after her talk with Pauling, Wrinch had redoubled her efforts. And she found a powerful new ally: the Nobel Prize-winning physical chemist (and codeveloper of the shared-electron-bond idea) Irving Langmuir, whose interest in molecular films led him to an interest in the cyclol hypothesis.
"Extraordinary to relate the miracle that has happened," she wrote the Rockefeller Foundation in the fall of 1938. Dorothy Crowfoot had taken new x-ray photos of the small globular protein insulin. Although Crowfoot concluded that "the patterns as calculated do not appear to have any direct relation either to the cyclol or to the various chain structures," Wrinch and Langmuir, analyzing the data with the aid of a new mathematical approach, found evidence of cyclols. Their announcement, backed with Langmuir's Nobel laureate credibility, created shock waves among protein researchers. Langmuir confidently told Weaver that everyone should now be convinced of the cyclol hypothesis. Niels Bohr's group in Copenhagen began modeling cyclol cages. Wrinch began publishing a spate of new papers.
Pauling did not believe it. He thought that the new vector method of analysis Wrinch and Langmuir had used—codeveloped by one of Pauling's former students, David Harker—was too limited
to provide real proof. Even when Harker wrote him that he believed Wrinch and Langmuir's analysis was correct, Pauling was unmoved.
He was not alone. In Britain, Bernal and others, including Willie Bragg, stepped up their attacks on Wrinch. In January 1939 a series of short notes appeared in Nature, with Bragg writing that the vector analysis method was inadequate to give more than "vague and provisional" results with molecules as complex as proteins and Bernal calling Wrinch's ideas about insulin "demonstrably incorrect." When Wrinch responded, Bernal let loose again, writing that "no case whatever has been made out for the acceptance of the cyclol model on x-ray grounds; indeed so far as it goes, the x-ray evidence is definitely against the model." Wrinch felt betrayed; privately, she called Bernal, her old compatriot from the Biotheoretical Gathering, "jealous, brutal and treacherous."
