by Thomas Hager
The enzyme scheme, so much in line with Pauling's idea about antibodies, was just the beginning. Soon he was theorizing that the senses of taste and smell might work because of a complementary fit between the sensed molecule and specific sites in the body (a theory still in favor among odor researchers). The behavior of viruses, too, an odd form of matter that seemed halfway between a crystallizable protein molecule and a living organism (Pauling called them "a gene that has escaped from the control of the parent organism"), might also be explained on the basis of complementarity.
Pauling speculated that genes were probably large, complex protein molecules capable of making precise copies of themselves, a process called autocatalysis. His 1940 paper with Delbruck had already touched upon a possible general mechanism for genetic replication; now, between 1945 and 1947, Pauling thought more about the idea in the context of complementarity. By 1948 he had devised a general model of the simplest way a gene could replicate. "The detailed mechanism by means of which a gene or virus molecule produces replicas of itself is not yet known," he told an audience during one of the many talks he gave on complementarity during the period. "In general the use of a gene or virus as a template would lead to the formation of a molecule not with an identical structure but with a complementary structure. It might happen, of course, that a molecule could be at the same time identical with and complementary to the template upon which it is molded. ... If the structure that serves as a template (the gene or virus molecule) consists of, say, two parts, which are themselves complementary in structure, then each of these parts can serve as the mold for the production of a replica of the other part, and the complex of two complementary parts thus can serve as the mold for the production of duplicates of itself." This prescient vision of a possible duplex nature of the gene was articulated four years before the discovery of the double helix structure of DNA.
Having done nothing less than propose a structural basis for most of molecular biology, Pauling turned to medicine. During the war, his medical interests expanded from kidney diseases, antibodies, and plasma substitutes to preliminary thoughts on the structure of drugs, the effects of nutrition, even an idea that several degenerative diseases might be caused by the clumping of red blood cells. At one point he gave thought to developing an institute for fundamental medical research in conjunction with Caltech, a place that could function as a test site for his ideas about the structure and function of biomolecules. And here, too, he thought molecular complementarity could play an important role.
Toward the end of the war, he had been asked to serve on the Palmer Committee, a group of medical experts—Pauling was the only nonphysician—convened at the behest of Office of Scientific Research and Development (OSRD) head Vannevar Bush to come up with ideas for the postwar funding of medical research. During a dinner meeting of the group in the spring of 1945 at New York's Century Club, the talk among the doctors turned to a little-known blood disease called sickle-cell anemia. A Harvard medical professor, William B. Castle, explained that the disease got its name by de-forming the red blood cells from flattened discs to misshapen crescents. These sickle-shaped cells would then clog small blood vessels, leading to the clinical effects of the disease: pain in the bones and abdomen caused by reduced oxygen, blood clots in the lungs, kidney, and brain. One odd thing, Castle said, was that the sickled red blood cells appeared more in the venous blood returning to the lungs than in the more highly oxygenated arterial blood.
When Pauling heard that, something clicked. He knew from his hemoglobin work that red blood cells contain almost nothing except hemoglobin and water. If the presence or absence of oxygen played a role in the flattening of the blood cells, then hemoglobin, the molecule that binds oxygen, was probably involved. As the other committee members talked and smoked around the table, Pauling sat back quietly for a moment, imagining hemoglobin molecules, globular proteins, he knew, slightly elongated in one direction, like short, thick cylinders. Say something changed them so that a new shape was formed on the surface of the molecule, a shape complementary to an area on another hemoglobin molecule. The hemoglobins would then stick to each other. If the spots were on the ends of the molecules, they might stick together end to end, creating long chains inside the red blood cells. If enough of these chains aggregated with each other, they might form something like a hemoglobin crystal, twisting the blood cells out of shape, making them sickle. But how was oxygen involved? Binding oxygen to the hemoglobin, Pauling thought, must change the shape of the molecule enough to distort or hide the sticky spots. Add oxygen and inhibit sickling. Take oxygen away and sickling is enhanced. Thinking out loud now, Pauling explained his ideas to the group, asked Castle a few more questions about the disease, then asked if the physician had any objections to his running a few experiments comparing normal and sickle-cell hemoglobin when he got back to Pasadena. Castle did not mind. It is unlikely that many of the other physicians, whose training in structural chemistry would have been minimal, understood much of what Pauling was talking about.
Perhaps because of his own bout with Bright's disease, medicine stayed near the forefront of Pauling's mind during this period, the themes of blood and healing becoming intertwined with his new organizing principle of complementarity. Complementarity might even explain the action of drugs. In 1940, a British researcher had proposed that sulfa drugs stopped bacterial infections by masquerading as a needed food source, taking the place of the needed metabolite and essentially starving the bacteria to death, a process that worked in theory because the drug was closely related in structure to the metabolite. Pauling, like many researchers, thought that this competition of two substances for a specific binding site on a living cell could be a central concept in designing new drugs. In October 1947 he told an audience at Yale University: "When it has become possible to determine in detail the molecular structure of the vectors of disease and of the constituents of the cells of the human body, it will be possible to draw up the specifications of a specific chemotherapeutic agent to protect the body against a specific danger, and then to proceed to synthesize the agent according to the specifications."
By then Pauling was convinced that complementarity was a sufficient explanation for all of biological specificity. He had found a way to explain the essence of life in the standard lexicon of chemistry. At a stroke, he provided a reasonable explanation for everything from enzyme action to genetic replication and eliminated the need to seek new physical laws to explain life. Life was, at its root, a matter of precise molecular structure. Pauling's down-to-earth vision, his chemical explanation of the phenomenon of life, marked one of the most profound insights in twentieth-century science. It was an affirmation of the centrality of molecular structure and an essential signpost on the path to molecular biology—a field of study that would be predicated, as Pauling foresaw, on the interaction of complementary molecules.
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At the time, however, no one seemed to be listening; or, rather, most listeners did not grasp the importance of what he was saying. They were not trained to understand. Biologists in the late 1940s had only a passing acquaintance with physical chemistry. Chemists, for the most part, did not think of proteins in terms of chemical substances. "The average biochemist of the day," said molecular biologist Alexander Rich, "didn't know what a van der Waals interaction was, didn't know about hydrogen bonds or electrostatic potentials." Pauling was leaping over so many disciplinary boundaries, mixing so many different scientific languages, that only a handful of other researchers could follow him.
Then, too, what he was saying was still untested. No researcher had as yet defined the sequence of amino acids in any protein, nor had any structural chemist or crystallographer even roughly outlined the sorts of complementary shapes Pauling was talking about. The detailed shapes of proteins were still a mystery. The only vaguely related structures known in three-dimensional detail were the few amino acids and peptides Pauling's group had worked out. No one knew what a gene was made of (protein was th
e odds-on favorite of the day) or how one was built, much less how it worked. Hard data on the specifics of enzyme action were just beginning to be published. In the absence of specific facts about protein structure, there was too much room for conjecture and plenty of reasons to withhold judgment. Pauling realized this, too, and generally ended his talks by noting the vital importance of learning more about the specifics of how proteins were structured. Until that was done, he limited the expression of his ideas to speeches rather than major papers in refereed journals, works that might have had the influence, say, of his papers on denaturation or antibody formation. Those would come only after his general ideas had been substantiated by further experiments. Pauling set Niemann to work on proving his enzyme hypothesis in the immediate postwar period, but the younger researcher soon lost interest and moved on to other things. Pauling also kept his eye out for someone to put on the sickle-cell hemoglobin project.
In the meantime, however, he remained convinced that he was on the right track. "The evidence for the theory that specific biological forces result from complementariness in structure is very strong," he said in 1947, "and I think it highly likely that this is the only mechanism of biological specificity which has been developed in living organisms." By 1948 he was telling audiences, "I believe that we can understand these properties of living matter and that we do know what the nature of life is (apart from consciousness), in terms of molecular architecture."
Life at the Top
Pauling and Beadle exemplified the optimism and success of science in postwar America. World War II left the United States the world's undisputed leader in basic research. The German scientific community had been decimated by Hitler, and the war had damaged or demolished many of Europe's great scientific centers. Those that remained intact, like the great Cavendish Laboratory at Cambridge, were aging and relatively impoverished. Basic science was a low priority in nations dealing with bread lines and bombed-out cities.
But in America postwar scientists were showered with money and acclaim. They were national heroes, inventors the rockets and radar and bombs that had helped the Allies win, and they were lionized during the euphoria that followed. Scientists—especially atomic scientists—were profiled in magazines and newspapers, asked to give speeches to clubs, and made the center of attention at Capitol Hill cocktail parties. It was a heady time.
The grateful U.S. government, bewitched by dreams of a new age of plenty fueled by unlimited atomic power, was ready to keep the money flowing. Formerly unaffordable multimillion-dollar big-ticket items—atom smashers and nuclear reactors topped the list—were suddenly available to researchers. Who knew what other wonders the scientists could conjure up on short order if provided enough funds?
One of the first things Harry Truman did after assuming the presidency upon Franklin Roosevelt's death in 1945 was to ask Vannevar Bush, the man who had organized the scientists' wartime efforts as head of the OSRD, to prepare a report on the needs of postwar science. Bush saw an opportunity. He made what could have been a simple bureaucratic response into a tool to change the face of postwar science. He convened panels of experts—including the Palmer Committee on medical research, in which Pauling participated—to make recommendations for different areas of research, and melded their ideas into a long, comprehensive, and persuasive document that he called "Science—The Endless Frontier." Anchoring the plan was a proposal to create a National Research Foundation through which tax moneys would be distributed by panels of scientists, a device that would make possible the funding of science without any attendant political pressure. Only in this way, Bush argued, with scientists doling out the money to scientists, could basic research be freely pursued with government funds. Congressional critics called it a lack of accountability and gasped at the sums Bush proposed: $33 million for science the first year alone, rising to more than $120 million annually by year five. One congressman quickly dubbed it "Science—the Endless Expenditure."
Pauling enthusiastically supported the Bush plan. He was concerned especially about the interruption the war had created in the production of young scientists—by 1945 the combined junior and senior classes at Caltech included only six chemistry majors—and believed that government involvement was warranted to fix it. If something was not done, and done quickly, there was a chance that there might not be enough scientific talent to accomplish the huge tasks of the postwar years. Pauling even talked about drafting the youth of America into science training programs instead of the army. More realistic was the likelihood of using the proposed research foundation to shift money into science education while avoiding the back-room influence and mediocrity he believed characteristic of many governmental programs. Pauling joined a national "Committee to Support the Bush Report" and, after Bush turned his plan into a congressional bill, helped organize support meetings and letter-writing campaigns.
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Pauling was rapidly becoming one of the most visible and influential scientists in the postwar world. Before the war, Pauling's ideas on the nature of the chemical bond had been beyond the reach of most chemists. But now, thanks to the growing influence of The Nature of the Chemical Bond, they were catching up with him. His book had become required reading for postwar graduate students and young researchers, especially those interested in molecular structure.
Pauling complemented it in 1947 with what would become an even more influential undergraduate text, General Chemistry, a one-volume survey of the field that would mark a milestone in chemical education. General Chemistry was the first introductory college text based firmly on a foundation of quantum physics, the first to take its readers logically from general theoretical principles—beginning with his valence-bond approach—to an abundance of real-world examples, and the first to use the concepts of chemical bonding and molecular structure as organizing principles. Written with Pauling’s usual clarity and zest, the book also made the molecular visible through its pioneering use of illustration, including dozens of precise drawings of chemical structures made under Pauling's supervision by the illustrator Roger Hayward. In this book, molecules were not abstract notions. They were individual characters, with sizes and shapes and peculiarities. They came alive.
The book helped revolutionize the teaching of college chemistry. Pauling's reputation ensured wide early adoption, and when teachers saw how effectively it worked, the book became wildly successful—but not for its intended audience. Pauling based General Chemistry on his lecture notes for Caltech freshmen chemistry, which meant that much of the material was too advanced for first-year courses at other universities. After a few years, it found its niche as a best-selling text for more advanced undergraduate students, selling so well in its various editions that it propelled its relatively unknown San Francisco publisher, W. H. Freeman and Co., into the leading ranks of textbook publishers and made Pauling's name synonymous with modern chemistry for the tens of thousands of new college students who flooded campuses after the war.
Royalties from the book also gave Pauling his first taste of wealth. He was now able to make some outside investments and indulge in some luxuries, including a large in-ground swimming pool for the yard of his mountainside home—the pool that General Chemistry built, his children called it. And he traveled. As his health strengthened and his fame increased, as he responded to speaking invitations and attended more meetings than ever, his children saw less and less of him. His work schedule was back at a formidable level, and he made it clear that even at home he was not to be disturbed for anything other than meals. The degree of domestic organization required to accommodate his work bordered on the bizarre. A typical day started with his immediately going into his study after waking while Ava Helen fixed breakfast for the children. When they were done, she rang the doorbell to call Pauling to breakfast. He would eat and leave for Caltech, sometimes driving the children to school on the way. He returned home in the mid-afternoon, sometimes picking up a child from school on the way, then again retreated to his study, where
he would work, read the newspaper, or listen to the radio news until Ava Helen rang the doorbell to call him to dinner. After helping with the dishes, he went back to his study until after the children were in bed.
This went on weekday and weekend alike. Practically the only time the children talked to him was on their drives to and from school, when he would quiz them about their studies. He was impressed with young Crellin, who seemed quite bright and who surprised his father one day by telling him that he figured out that September had fifteen days in it. "How do you know that, Crellie?" Pauling asked. "We learned it in a poem," the little boy answered. "'Thirty days half September.'" Crellin would have loved to have a father like other boys, someone who would play games with him and take him places on weekends. But this was not to be. Instead, he spent his afternoons creeping up to Pauling's study door and listening to him dictating into a machine on the other side. That, Crellin remembered, was his foremost memory of his father from early childhood: "He came home and talked to 'Comma' on the dictaphone."
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At the same time Pauling's fame was increasing, the old generation of leaders in chemistry was passing away. Roscoe Dickinson—the man who had patiently taught Pauling x-ray crystallography—died at an early age in 1945. The following year, Pauling's mentor, role model, and friend G. N. Lewis was found crumpled at the foot of his lab bench, struck dead in the middle of an experiment—"a great blow to me," Pauling said. Only one year after returning to Caltech following his wartime service, Richard Tolman died of a cerebral hemorrhage in 1948.
