by Thomas Hager
Then he put it aside. There was the paper with Mirsky to finish first. Then Noyes died, and Pauling's troubles with Millikan began. Pauling did not forget about immunology entirely—he began reading journals in the field, becoming increasingly irritated by the welter of conflicting research results—but he did not spend much time on it.
- - -
Landsteiner got him back into the game. When Pauling was at Cornell on his Baker lectureship in November 1937, he was pleasantly surprised to see Landsteiner again. The old man had made a special point of coming to Ithaca to see Pauling. Immunology was not the only thing on his agenda—Landsteiner was also sounding Pauling on the possibility of an appointment at Caltech—but once they began talking about antibodies, they could not stop. Landsteiner's brief visit turned into "the best course of instruction in a complicated field that anyone ever received," Pauling remembered, an intensive four-day mini-seminar in immunology devoted primarily to answering Pauling's questions. Pauling came out of it with a head cleared of many of the contradictory research results that he had been reading for the past year. He also enthusiastically recommended to Millikan that Landsteiner, whom he called "the father of immunology," be invited to Caltech to work.
That never happened (Millikan grumbled something about the cost of supporting every old Nobelist who wanted to retire to sunny Southern California) and Pauling's attention was diverted again. He still thought and talked about antibodies through 1938 and 1939—in fact, his enthusiasm led members of the biology department to start experimenting with creating antibodies to fruit-fly genes and gene products—but there was the Crellin Laboratory to get started, the new house to build, the Dorothy Wrinch controversy to settle, and The Nature of the Chemical Bond to write. He was also hesitant about starting serious work in this completely new field because he had no one on staff who knew how to run immunological experiments.
In July 1939, Landsteiner nudged him again, this time with a note in Science that related Pauling and Mirsky's theory of protein structure to the formation of antibodies. To explain the specificity of antibodies, he wrote, "One idea to be considered among others is the possibility of different ways of folding the same polypeptide chain."
This was exactly what Pauling had been thinking, and he now set about polishing his ideas for publication before someone else beat him to it. There were already a number of papers out in which immunologists had theorized that antigens acted as templates against which antibodies were formed, but they generally proposed that the system worked by somehow ordering the sequence of amino acids in a growing protein chain, an approach Pauling thought unnecessarily complex. His idea of taking a one-sequence-fits-all protein and twisting it into a specific shape was simpler.
It also explained the controversial idea some researchers had that antibodies were two-armed or "bivalent," able to attach to two antigens at the same time, clumping them together. A common test for antibodies was to mix them with an antigen and see if they formed a fuzzy precipitate, an indication that antigen and antibody were combining. Pauling knew that chemical precipitates formed in some cases when molecules linked end to end, and he visualized the same thing happening with antibodies. Antibodies with two combining sites for antigens were the simplest way to form antigen-antibody-antigen-antibody precipitates.
The picture that began forming in Pauling's mind was this: A "denatured," fresh antibody chain would start to emerge from an antibody-producing cell. The free end would come into contact with an antigen and would attach to it. The middle part of the chain would fold into layers like a stack of pancakes, back and forth, building a roughly spherical shape needed to fit the data that showed antibodies were globular proteins. Hydrogen bonds would hold the stack together. The newly secreted back end of the chain would then be able to attach itself to another antigen, creating a "bivalent" antibody structure. This was an elegantly simple way of explaining how a myriad of antibodies could be formed from a single protein pattern, how precipitates formed, how antibodies could be raised against synthetic chemicals, and, of course, how a system of nonspecific weak forces could combine through complementary shaping to explain how antibodies attached to antigens.
In January 1940, a young assistant professor of immunology from the University of Chicago, Dan Campbell, arrived at Caltech on a fellowship, and Pauling set him to work on some confirming experiments while he drafted a final version of his antibody theory for publication. There were problems to work out. His theory was powerful not only because it was simple but because it led to specific, testable predictions. In Pauling's scheme, for instance, the two ends of an antibody molecule could form around identical reactive sites on an antigen, at two different reactive sites on the same antigen, or into two completely different antigens. But this sort of dual-action antibody, a single molecule specific for two different antigens, had never been detected. Landsteiner's own evidence weighed strongly against such configurations, and after Campbell arrived, Pauling and Landsteiner mailed sera and antigens back and forth through the spring in an unsuccessful attempt to resolve the question.
The correspondence showed Pauling that he and his immunological mentor did not think about problems in the same way. "I found that Landsteiner and I had a much different approach to science," Pauling remembered. "Landsteiner would ask, 'What do these experimental observations force us to believe about the nature of the world?' and I would ask, 'What is the most simple, general, and intellectually satisfying picture of the world that encompasses these observations and is not incompatible with them?'" Pauling held off publication until this point could be settled. When it proved intractable, he decided to move on, banking on the possibility that new experiments would show he was right.
A second prediction had far greater implications. If Pauling's theory was right, it should be possible to create artificial antibodies in the laboratory by carefully denaturing ordinary globulins and then renaturing them in the presence of antigens. Using easily available animal or human serum globulin as the starting material, it would then be possible to cheaply, purely, and safely produce antibodies in bulk against almost any dangerous pathogen. A physician with a patient dying of pneumonia could reach into the refrigerator, pull out a vial of antibodies directed against the specific bacterium involved, and effect a cure. Pauling imagined magic bullets made to order on an industrial scale. Artificial antibodies could revolutionize medicine. Someone would make a fortune. He started Campbell to work on this question as well.
While he waited for results in the spring of 1940, Pauling, still too unsure of his theory to publish, began distributing draft manuscripts and offering his ideas at scientific meetings. Everyone seemed to think his work was very interesting, although without confirming experiments no one was convinced. Even Landsteiner was only cautiously enthusiastic about Pauling's model of antibody formation.
Campbell's work was not helping. While his experiments buttressed Pauling's belief that antibodies were bivalent, the critical experiments—testing for dual-action antibodies and creating artificial ones—were inconclusive. Pauling became impatient with the slow pace of experimental work and decided he had waited long enough. Inconclusive experiments did not prove his theory, but neither did they disprove it. His was a theoretical paper, after all, meant to be a guide to productive experiments, not the final word. In June 1940, Pauling sent his paper on antibody formation to the JACS.
At first the paper appeared to be a rousing success. Written with Pauling's characteristic clarity and confidence, the paper answered the questions Pauling posed at the beginning: "What is the simplest structure which can be suggested . . . for a molecule with the properties observed for antibodies, and what is the simplest reasonable process of formation for such a molecule?" Pauling convincingly argued that a bivalent antibody molecule, with each end complementary to an area on the surface of an antigen, was both sufficient and necessary to explain the precipitation reaction. He outlined his idea of how the folding of a protein chain could result in a shape that g
ave an antibody its specificity. He explained how the "glue" that held antibody to antigen could be formed from a number of relatively small forces acting together: electrostatic attraction between negatively and positively charged areas, hydrogen bonds, van der Waals forces. It was fascinating to many readers that antibodies, these most precisely built proteins, achieved their specificity through an accumulation of nature's weakest and least specific bonds.
Pauling was pleasantly surprised to see his idea quickly supplant the older template schemes and become a leading theory—to many observers the leading theory— of antibody formation. He was delighted to find himself deluged with hundreds of requests for reprints, more than he had received for any other paper.
Again he had entered a new field, bringing the power of structural chemistry to bear, and leaping to a valuable new theory. Again, his work was seen as a triumph.
- - -
Just before Pauling sent in the antibody paper for publication, he ran into physicist-turned-biologist Max Delbruck while walking across campus. Pauling liked the young German immigrant, another of the Rockefeller-funded boundary-crossers interested in the mysteries of the New Biology; he found Delbruck's approach to biological problems through the study of the simplest possible life form, viruses, "sensible." Knowing of Pauling's recent interest in antibodies, Delbruck told him that he might like to look at some papers Pascual Jordan had written during the past few years in which the German researcher promoted the idea that molecules identical with one another might, because of quantum-mechanical resonance, tend to stick together. This, he said, might help explain the ability of molecules such as genes, viruses—even, according to Jordan, antibodies—to replicate exact copies of themselves. Pauling was interested, and he and Delbruck strolled to the library to review Jordan's papers. After five minutes' study, Delbruck remembered, Pauling announced that Jordan's ideas were "baloney." A few days later, Pauling told Delbruck, "I have written a little note to Science about this; would you like to join me in publishing this?" Delbruck had not done any real work on the paper, but he agreed with it and did not want to appear impolite. He signed on.
Pauling's "little note" was to prove prophetic. "The Nature of the Intermolecular Forces Operative in Biological Processes" by Pauling and Delbruck appeared in the discussion section of Science in the summer of 1940. After demolishing, in typically straightforward language, the notion of resonance as a basis for Jordan's ideas about attraction between identical molecules—"We have reached the conclusion that the theory cannot be applied in the ways indicated by him, and that his explanations of biological phenomena on this basis can not be accepted"—Pauling stated his own case: "We . . . feel that complementariness should be given primary consideration in the discussion of the specific attraction between molecules and the enzymatic synthesis of molecules." Complementary shapes, die-and-coin relationships, were how specificity was achieved in biology. Pauling made a special point of stressing the importance of the concept for cases where molecules make copies of themselves, where "complementariness and identity might coincide."
Apart from discouraging Jordan, the note sank into the literature with hardly a ripple. It was only years later that it was resurrected and hailed by historians of science as one of the founding documents of a new science, "a manifesto of molecular biology." DNA would turn out to be a molecule in which complementariness and identity coincided.
- - -
After a few months of relaying to Weaver his growing excitement over immunology—especially the chance of making artificial antibodies— Pauling made an informal funding request at the beginning of 1941: twenty thousand dollars per year to start a full-blown research program in immunochemistry, enough to bring to Caltech three research assistants, three graduate assistants, a visiting professor, a roomful of research animals, and a laboratory outfitted with the best equipment. This was as much money as Pauling's entire structural chemistry budget, and during a visit to Caltech in February, Weaver let him know that he was being "distinctly over-adventurous." Pauling cut his request nearly in half. Weaver, after checking with leaders in the field—Landsteiner and others told him that the creation of artificial antibodies would be of "revolutionary" importance—convinced the Rockefeller Foundation to award Pauling eleven thousand dollars per year for three years for his immunological work. The money enabled Pauling to hire Dan Campbell permanently, provided support for a promising young postdoctoral student, David Pressman, and bought enough equipment, rabbits, and syringes to perform the experiments he wanted.
The only minor note of warning among Weaver's contacts came from the acerbic British biochemist Norman Pirie, who hoped, Weaver noted, "that Pauling will not pile hypothesis upon hypothesis, and will not insist on speaking of this hypothesis on every conceivable occasion, but will now quietly await experimental evidence." In other words, Pirie said, he hoped that Pauling would not "Wrinch it."
CHAPTER 11
The Hawk
The Orderly Organism of the World
The first letter from Albert Schoenflies reached Pauling in December 1938. Even through the German in which it was written, Pauling could detect a tone of controlled panic. Schoenflies was a Jew. His father had been a well-known German scientist, a pioneer of x-ray crystallography, a friend of Laue's. Schoenflies himself had practiced law, serving ten years as a German judge before Hitler's laws stripped him of his position. This was madness, he thought, but like many in Germany, he also thought it would pass. He treated his time off as an enforced holiday, spending more time with his three young children, taking a few courses in chemistry. Then he was told Jews could no longer attend classes. On a freezing November night in 1938 came the murders and beatings, the broken glass and bloodied heads of Kristallnacht. Schoenflies woke up. Along with thousands of others, he made a desperate attempt to leave the country. Laue told him to write to scientists in America, including Pauling, in the hope that one could get him a student visa.
Schoenflies's was one of a growing number of increasingly desperate inquiries from German academics that Pauling received in the late 1930s; his replies were unfailingly sympathetic and courteous, although there was not much that he could do to cut through the red tape of immigration restrictions. He took a special interest in the Schoenflies situation because Laue wrote him personally and asked for his help. Pauling contacted some committees that had been set up to handle German refugees but found that they acted very slowly. When Pauling tried to contact Schoenflies, he got no reply. It was four months before Pauling heard from him again, this time from a refugee camp in Holland. He was penniless, Schoenflies wrote; he was unable to withdraw any of his savings from his German bank account and had drawn an impossibly high quota number for getting into the United States. "At present I am living here without any means whatever and I am very sorrowful. ... As my children aged 6, 8, and 10 years cannot go to any school here and as I have no opportunity to work or to find any occupation whatsoever. ... I beg you with the request whether you can see your way clear to be of any help to me in my difficult and not enviable position." Pauling wrote back immediately with assurances that he would do everything he could to help; he wrote letters to international education boards and to committees to aid refugees. It was relatively easy to get seasoned German scientists into the United States, but ex-judges were another thing. Pauling offered to find money to support the family in Pasadena and tried to devise a way to get at least the Schoenflies children out. But he could not make the immigration bureaucracy move fast enough. When he wrote Schoenflies in the spring of 1939 to tell him that he would keep trying, his letter was returned stamped "Address Unknown."
Horror stories like this were told by scores of Jewish scientists who began reaching the United States in the mid-1930s. Hitler was destroying the great German universities, using the excuse of racial purity to expel and imprison Jewish professors and those sympathetic to the Jews. In the process, he cast down much of German science. Following Einstein's example, scores of Jewish research
ers fled, many taking up residence in America. Many non-Jews in German science, including Sommerfeld, tried their best to help and, in the early days, spoke out against the Nazis. Others, like Heisenberg, were silent. Still others led the purges. It was nightmarish; it undermined everything Pauling believed about the rationality of science.
By 1939, Pauling believed Hitler had to be stopped. "The feeling in America is uniformly that of sympathy for England in her inability to stand for Hitlerism any longer," Pauling wrote a British friend in September. "And I hope that the democracies will line up together strong enough to put an end to the situation soon." After France fell in the spring of 1940, Pauling's concern increased. He became convinced that without direct U.S. involvement Britain, too, would fall, giving Hitler the world's largest war fleet and dominion over the seas.
- - -
The question became what to do. Scientists were traditionally apolitical, sticking to provable facts and letting statesmen handle world affairs. Steering clear of politics was an unspoken rule of science, accepted implicitly because it was a proper and natural division of expertise: Most scientists felt that they should remain as impartial and objective in any public role as they were in their research, that they should stick to what they knew, the objective pursuit of knowledge, and leave the confusing and unverifiable concerns of politics to politicians. This was not to say that scientists did not hold political views; they simply kept them private. This had been true of Pauling, too, who, despite his move toward the left wing of the American political spectrum under Ava Helen's influence in the early 1930s, had not publicly spoken or published a word about politics.
