by Thomas Hager
Noyes now turned to Pauling. Around the time Pauling was applying his resonance ideas to benzene, Noyes asked him if he wouldn't think about changing his title to professor of organic chemistry. The benefit to Noyes was clear: He would have a proven talent to put in his new building, someone with enough pull to form the nucleus of a new department. But Pauling quickly said no. He enjoyed thinking about biology—Noyes had encouraged his faculty to attend the seminars given in the biology department, and Pauling, becoming friendly with the younger men in geneticist Thomas Hunt Morgan's group, had even given a talk of his own there based on a German genetics paper that he had been asked to translate—but his major interests still revolved around inorganic crystal structure and the chemical bond. He believed that his quantum-chemical, structural approach was the basis of all of chemistry, both organic and inorganic. When he was promoted to full professor, Pauling had made sure that his official title was changed from professor of physical chemistry to the more general professor of chemistry. Changing it now to organic chemistry would be a step back. He had no desire to be pigeonholed.
What Pauling called himself was less important than what he did, and Noyes was convinced that Pauling's work on the chemical bond was the most important advance being made in all of chemistry, organic included. Only Pauling had promise enough to energize an entire research program. One way or another, Pauling's group would be the centerpiece of the new building. It would help, though, if his research were oriented a little more toward biological problems.
Pauling was bright enough to see which way the wind was blowing. In February 1932 Pauling approached the foundations, making duplicate applications to the Rockefeller Foundation and the Carnegie Institute, asking for fifteen thousand dollars per year over five years to support "a unified series of investigations on the structure of inorganic and organic substances, involving both theoretical and experimental work." Much of what he requested involved x-ray crystallography and electron-diffraction studies, but he also outlined his growing interest—based on his success with benzene—in organic molecules. "I desire to solve the wave equation for simple organic crystals and molecules," he wrote, as part of a semi-empirical effort to "develop a set of atomic radii and of structural principles enabling one to predict with confidence the atomic arrangement, including interatomic distances, of the normal electronic state of any molecule, and its stability relative to other molecules. This knowledge may be of great importance to biochemistry, resulting in the determination of the structure of proteins, haemoglobin, and other complicated organic substances."
Weaver
Pauling's proposal—especially the remark about proteins—caught the attention of Warren Weaver, the man hired just two months earlier by the Rockefeller Foundation to dispense its grants in the natural sciences.
Weaver was a second-rate scientist with a first-rate knack for knowing the right people. One of them was Max Mason, his electrodynamics professor while an undergraduate at the University of Wisconsin, who later became president of the Rockefeller Foundation. Another was Robert Millikan, who was sufficiently impressed by Weaver when he taught him physics at the University of Chicago to offer him a teaching job when Millikan first went to Caltech. Weaver enjoyed teaching. He spent three happy years as a junior professor in Pasadena before Mason enticed him back to teach at Wisconsin in 1920; when Weaver left, Millikan refused to accept his resignation, saying that he should always consider himself a Caltech faculty member.
But Weaver was not good at laboratory work. "I lacked that strange and wonderful creative spark that makes a good researcher," Weaver said. "I never seemed to get a first-class original idea." So, like many scientists who faltered at the bench, he shifted to teaching and administration. He got along well with a variety of people and soon worked his way up through the ranks to become head of the Wisconsin mathematics division.
He was settling down to what looked like a long career at Wisconsin when, in early 1932, Mason called him again, this time to the New York offices of the Rockefeller Foundation. Wickliffe Rose was gone now, and so was his program of lump-sum grants, Mason explained; the Depression had changed things, and the Rockefeller trustees were now less willing to dole out huge sums without a clear idea of how they would be used. The trend was going to be toward granting smaller sums for specific research programs guided by individual researchers. The trustees wanted results. That meant, of course, tighter oversight on the part of foundation officers and a keen ability to pick winners from among the many scientists who would be jockeying for grants. Mason trusted Weaver's judgment. That's why, he explained to Weaver, he wanted him to take over the natural sciences division.
Weaver was speechless. It was a dizzying prospect. At age thirty-eight, this genial, owlish-looking laboratory failure and academic middle manager was being asked to take the reins of the single most important scientific funding agency in the world. He would have the power to open new areas of research, make or break careers, dispense millions of dollars, change the course of scientific history.
He eagerly accepted.
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Weaver's personal stock of original ideas may have been low, but he had a good eye for the ideas of others. He was especially enthusiastic about a new form of biology. Although he had no background in the field himself, he was convinced that there was a scientific revolution brewing there, the birth of a new approach to the field that would contribute mightily to the betterment of man. Like Noyes, Weaver believed that the revolution would be catalyzed when the methods of the more "successful" natural sciences—mathematics, physics, and chemistry—were applied to biology. He called this "the friendly invasion of the biological sciences by the physical sciences."
When talking about his ideas in the early 1930s, he did not even use the word "biology," calling it first "vital processes," then, in 1936, inventing a label that stuck: molecular biology. This was going to change the way we think about the living world, he told the Rockefeller trustees. Whereas the old biology focused on whole organisms, molecular biology would concentrate on the unknown world inside isolated cells, the charting of metabolic pathways and the structure of individual proteins. Qualitative observations would be supported by quantitative measurements. A focus on common natural laws arising from chemistry and physics would allow biology to progress from the field into the laboratory, where a new breed of scientist, armed with fantastically powerful equipment like x-ray crystallography devices, ultracentrifuges, and ever-more powerful microscopes, would discover the ultimate stuff of life.
Weaver was not alone in his enthusiasm. H. G. Wells and Julian Huxley's best-seller The Science of Life, a popular overview of the field in the late 1920s, was typical of the exuberance current among a small group of British and American researchers who believed in the same vision. Soon, they wrote, "biological science . . . equipped with a mass of proved and applicable knowledge beyond anything we can now imagine," would make possible "the ultimate collective control of human destinies." Scientists would "operate directly on the germ-plasm," making possible "the practical eugenic work of the future," when man would improve every species, including his own, in the same way he had improved stocks of wheat and corn.
Weaver took the idea further, telling the Rockefeller trustees that a new, laboratory-based approach to biology and psychology could help "rationalize human behavior" by laying bare the molecular mechanisms leading to violence, unhappiness, irrationality, and sexual problems. From here on, he said, Rockefeller funds should be concentrated on solving the mysteries of the human body and mind, using the most powerful new scientific techniques possible. The trustees, conservative men for the most part, were enticed by the idea of discovering the ultimate sources of social unrest. They gave Weaver carte blanche to pursue his plan, which he packaged under the heading "The Science of Man." From that point on, the Rockefeller Foundation stopped awarding grants for mathematics, physics, and chemistry that did not relate directly to the life sciences.
Success for hi
s new program, Weaver knew, would depend on finding chemists and physicists able to translate their skills to a new setting. Pauling, with his proven abilities in chemistry and newly stated interest in biochemical questions, was a natural. One of the first things Weaver did as director of the Rockefeller Foundation's natural sciences division was to give Pauling twenty thousand dollars for two years— enough money to pay the salaries of five postdoctoral fellows and one full-time assistant, with some left over to buy the meters, tubes, crystals, film, transformers, and other specialized equipment he needed for his work. It far more than made up for Pauling's Depression-trimmed research moneys. And it marked the beginning of a long and mutually beneficial association between the two men.
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For Caltech, the Rockefeller Foundation's more focused funding scheme was both good and bad. The new agenda meant the end of any chance for funds for astronomy and geology and most of the research in mathematics, physics, and chemistry. Anything unrelated to biology and psychology, Weaver told them, would not get a penny. Not even Millikan could convince the foundation to fund his cosmic ray research. But Thomas Hunt Morgan's genetic research would be richly funded by the Rockefeller Foundation, and so, increasingly, would Pauling's work.
Weaver visited Caltech soon after joining the Rockefeller Foundation and came away impressed. Noyes gave him a grand tour of the Gates Laboratory and told Weaver of his long-term plans for the development of organic chemistry—which he was now wisely calling bioorganic chemistry—and about his bank of talent, especially Pauling. That night in his diary Weaver wrote, "Noyes hopes that W[arren] W[eaver] will not think it is the normal California enthusiasm when he says that, were all the rest of the Chemistry Department wiped away except for Pauling, it would still be one of the most important departments of chemistry in the world."
Once he met Pauling, Weaver believed Noyes might be right. Compared to the other Caltech chemistry laboratories, with one or two graduate students quietly carrying out the professor's assignments, Pauling's rooms in the astrophysics building crackled with energy. The labs were crowded with nine postdoctoral fellows and five graduate students jostling for space and engaging in animated discussion among themselves. There was a bit of G. N. Lewis's Berkeley here in the free and open exchange of thoughts, the raw ideas quickly sketched on blackboards, the arguments and laughter. It reminded Weaver of a European-style center of theoretical chemistry—an institute within an institute, with Pauling in charge. After visiting Caltech, Weaver wrote that Pauling "has a speculative mind of the first order, great analytical ability, and the genius to keep in close and inspiring touch with experimental work. . . . [He] has been offered lucrative professorships at Harvard, MIT, Michigan, etc. and is nearly universally rated as the leading theoretical chemist of the world."
The only drawback was that Pauling was not thinking about The Science of Man—at least not yet. Weaver proselytized for his molecular biology approach during his visit, stressing that the Rockefeller Foundation was far more interested in the structure of biological molecules than in sulfide materials. During a long talk in Pauling's office, he tried to encourage Pauling to apply his structural chemistry ideas to unraveling the mysteries of the body.
But the message did not seem to sink in. When Weaver made his second visit to Caltech some months later, in October 1933, the first two years of Pauling's original grant were almost up. Of the two dozen papers Pauling put his name on in 1932 and 1933, only the benzene article and two or three others on the structures of small carbon-based molecules were even about organic chemistry, much less molecular biology. Everything else came from Pauling's inorganic crystal work and general quantum theoretical interests. Pauling knew that Weaver was looking for something else, and he greeted his patron with a six-page report explaining how he had spent his Rockefeller money and what he planned for the future. His top priority, he said, was an attack on the structure of organic molecules, and he tantalized Weaver with a mention of future investigations of chlorophyll and hemoglobin. These hints and promises were not good enough for Weaver. He liked Pauling and thought he had great promise, but he also had to sell the value of his research to the trustees. He told Pauling bluntly that structural work in general organic chemistry would not be funded; money would flow only for work with a direct bearing on biology.
Pauling listened. When he made a formal application at the end of 1933 for a three-year grant extension, his proposal prominently mentioned biological molecules. Weaver thought he should get the money, but there was so little completed biologically related work to point to that he found it hard to convince his board. He ended up comparing Pauling to Louis Pasteur, whose abstract interests in chemical structure in the 1850s eventually led to great discoveries in biology and medicine. Even so, the board approved funds for only one additional year. Weaver broke the news to Pauling gently, telling him that economic conditions had made it "unwise" to offer longer-term support and again underlining the Rockefeller Foundation's expectations: "The possibility for favorable consideration of your request has depended largely upon the fact that your work has now developed to the point where it promises application to the study of chlorophyll, hemoglobin, and other substances of biological importance."
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Although biology was interesting, Pauling was not ready to orchestrate his scientific life around it. His background in organic chemistry was minimal, and he had never taken a biology course in his life. He was self-confident enough to tackle almost anything, but a move toward biology would take him out of an area of proven success and into a research field with a different set of expectations and a new group of scientists judging his success. It was risky. Besides, he felt he was close to developing a set of general rules underlying the structure of sulfide minerals, a task he felt he could complete given just a little more time and money. Early in 1934 he asked the Geological Society of America's Penrose Fund to support his research on sulfides.
The group turned him down, a surprising rejection he felt as a slap both to his research agenda and his ego. He suddenly realized just what the Rockefeller money meant. Pauling had expanded his laboratory with Rockefeller money, and the assistants and postdoctoral fellows and graduate students that he brought in and equipped with the help of that money had made him dependent on a new way of working, one in which he came up with ideas or problems to solve, handed them out for lab work, then helped to analyze the results and cowrite the paper. The system kept him out of the laboratory and in his study, where he did his best brainstorming; it expanded his reach and allowed him to indulge his wide-ranging curiosity by tackling a variety of subjects at once. Every paper he published in 1934 was cowritten, usually with someone paid with or equipped by Rockefeller money. The Depression was a long way from being over, and there was little chance of significant funds coming from other sources.
He followed the money. "It seemed pretty clear to me that I would have difficulty in getting further support from the Rockefeller Foundation unless I became interested in chemistry in relation to biology," he wrote. He dropped some of his mineralogical investigations and shifted his attention to biological molecules. "The foregoing episode," he later noted dryly, "suggests that granting agencies can influence the progress of science."
Blood
He may have been slow in starting, but once Pauling began attacking problems in organic chemistry and the structure of biological molecules, he devoted to the matter all of his usual energy and imagination. On the theoretical side, he and his student George Wheland extended their resonance ideas to important organic structures, such as the carboxyl group of organic acids and the aromatic free radicals. Lawrence Brockway now had the electron-diffraction apparatus up and running, and a stream of papers on the structures of small organic molecules began to appear. Among them was a description of one of the subunits of hemoglobin.
Hemoglobin was an attractive target for laboratory study for a number of reasons. It was, first and above all, a protein, the most important
class of molecules in the body. Hair and horn and feather, skin and muscle and tendon, were proteins, as were the most important parts of nerves and blood. Enzymes, with their unexplained ability to catalyze specific reactions, were proteins; so were antibodies and the better part of chromosomes, the tangled complexes of protein and nucleic acid that carried the secret of heredity. Proteins were involved in every reaction and formed an important part of every major structural component of the body. If there was a secret of life, it was thought, that secret would be found among the proteins.
In the early 1930s no one knew how proteins worked or even what they looked like. Yet proteins were the engines driving vital processes; it was here, at the level of these molecules, that cold chemicals became moving, breathing organisms. Discovering the secrets of the "giant protein problem," as Weaver called it, was the most important item on the Science of Man agenda.
From a practical standpoint, however, proteins were a nightmare to work with. The early data indicated that they were huge molecules, sometimes including tens of thousands of atoms—orders of magnitude larger than any molecular structure Pauling had ever solved. They were hard to purify and easily destroyed. Modest heating or treatment with acids or alkalis was enough to change a protein's native shape and kill its activity—"denaturation," it was called. Simply whipping a protein with a fork was sometimes enough to denature it, as a beaten egg white demonstrates.
Hemoglobin at least offered some advantages. It was easy to gather in bulk and in almost pure form from the red blood cells of cattle or sheep. Better yet, it could be crystallized, which meant that it had a regular, repeating structure of some sort. Anything that could be crystallized at least offered the possibility of being solved with x-ray diffraction.