Linus Pauling's success as chairman of the Caltech Division of Chemistry and Chemical Engineering was due in no small part to a steady flow of funding from the Rockefeller Foundation. Warren Weaver, the foundations director of funding for natural sciences, had focused Pauling's attention on the new field of molecular biology and had given him large sums of research money through the late 1930s. The funding was provided to study the structure of biomolecules, the enzymes and genes, antibodies and hormones that had such profound and mysterious effects in the body. Weaver capped his support in 1936 with a magnificent gift: a quarter of a million dollars to staff and equip a new Caltech building devoted to bio-organic chemistry. The new facility's spacious laboratories, equipped with the latest and most expensive equipment, and the outstanding scientists who came to work there would be under Pauling's command.
This new building was named the Crellin Laboratory, after Edward Crellin, a retired steel magnate who had given millions to Caltech. Pauling was so pleased with it that he and Ava Helen named their fourth child, born just as the building was nearing completion, Edward Crellin Pauling.
"Crellie," as he would be called, would be the last of Linus and Ava Helens children, joining older brothers Linus, Jr., and Peter and sister Linda. To accommodate the growing tribe, Pauling built a large, rambling, ranch-style home on a hillside overlooking a beautiful arroyo outside Pasadena. It was a house that reflected the man, designed for comfort, not show. There were two large wings, one for the children and another for the adults, joined in the middle at exactly the angle formed by carbon atoms in benzene, and fronted with adobe brick. There were bookcases everywhere, a big fireplace in the living room, an octagonal study for Pauling, a garden space for Ava Helen, and plenty of room for the children to play.
As the 1930s ended, the Paulings' lives took on a routine. Pauling had breakfast with the family and left for the laboratory, sometimes driving the kids to school on the way. Ava Helen tended house. After a morning's work overseeing his laboratory, doing minor administrative work, and attending meetings, Pauling would eat lunch at home or at the Athenaeum, Caltech's elegant faculty club. In the afternoon, he would return to his office, handle major divisional matters, and write grant requests and papers. He always spent suppertime with the family. When it was over, Pauling would disappear into his study, where he would listen to the news on the radio, read scientific journals, popular magazines, and newspapers, write a bit, and dictate letters and memoranda until going to bed at about 11:00.
On the weekends, Pauling spent almost all his time in the study. He would emerge only when he heard Ava Helen ringing the doorbell to call him to meals. The children, under strict orders not to make noise or bother their father, saw little of him. Crellin remembered when he was little, listening through the study door as Pauling dictated letters on the other side and wondering who the person was named "Comma" that his father always talked to.
Pauling worked terrifically hard, twelve hours a day, seven days a week, including most holidays, but it did not seem like hard work to him. He was doing what he loved and, like any artist, he found that the hours he spent thinking about new discoveries passed quickly. He loved reading and was proud of his ability to keep abreast of the latest developments in many fields, not only chemistry and physics but now, as his interests turned to molecular biology, in biochemistry, the study of enzymes and viruses, and research into blood molecules. All this he stored away in his capacious memory, ready to be called upon when needed to make new connections.
When Pauling had new ideas—and sometimes he had two or three per day—he usually jotted them down in a short memo and passed them on to a growing group of research assistants, postdoctoral fellows, and graduate students for verification in the laboratory. When, as was usually the case, his ideas were found to be right, a paper would appear in the scientific press, in which Pauling shared credit with his many coworkers.
The results seemed almost magical. No one had Pauling's wide range of knowledge and his nearly intuitive understanding of how atoms liked to join together. No one had yet mastered his technique of model building guided by strict chemical rules. With these tools, Pauling was able to produce an enormous body of work in the late 1930s, on everything from the structure of ice to the magnetic properties of hemoglobin, from the significance of resonance in molecules to the nature of metals, from the uses of electron diffraction to a theory of the color of dyes.
But of all Pauling's work during this period, nothing was more important than his attempt to understand the structure of some of the most complex and important molecules on earth: the proteins. Hair and feathers, skin and muscle are proteins, as are the major parts of nerves and the chromosomes that carry the secret of heredity. Enzymes, biomolecules that have a strange ability to speed certain reactions, are proteins; antibodies that fight off infections are proteins; the hemoglobin that carries oxygen in the blood is a protein. Proteins are involved in every major reaction and form an important part of every major structure of the body.
It was here, at the level of proteins, Pauling and many others believed, that dead chemicals somehow were transformed into moving, breathing organisms. Whoever discovered how proteins were built and worked, the thinking went, would discover the secret of life. Pauling intended to do just that.
But proteins were a nightmare to study. Proteins appeared to vary widely in size, and some were gigantic, consisting of tens of thousands of atoms joined into molecules that were orders of magnitude larger than anything Pauling had studied before. They were so huge that Pauling estimated that solving even the simplest would take 50 years using X-ray crystallography alone. They were also difficult to purify and easy to mangle. Even modest heating, mild treatment with acids or alkalis, or just mechanical agitation like beating eggwhites with a fork could be enough to change a protein's properties and kill its activity. This process was called denaturation.
Denaturation made proteins difficult to study, but it also offered a doorway to understanding them. Pauling was interested to read the work of two Rockefeller Institute scientists who had found that some proteins could be denatured by gentle heating, but then could, if cooled properly, regain their original activity. Higher heat, however, irreversibly denatured the molecules, seemingly broke them into pieces so that nothing would return them to an active state.
This characteristic meant that denaturation was a two-step process. It also gave Pauling an idea. The two steps in denaturation—the first, reversible step caused by gentle
Pauling in his Caltech laboratory in 1940. Despite the many demands made on his time as the head of the chemistry department, Pauling continued to conduct groundbreaking research on his own.
heat and the second, irreversible one caused by higher heat—could mean the involvement of two kinds of chemical bonds: the first, relatively weak bonds easily broken and re-formed and the second, stronger bonds, harder to break and impossible to remake.
Pauling had a guess about the weaker bonds. In his reading he had come across a description of a so-called hydrogen bond, a very weak link in which a hydrogen atom acted as a bridge between two others. The original work with the hydrogen bond had been done with water molecules, and no one thought it was important in any other setting. But Pauling saw that the estimated strength of the hydrogen bond fit the data about the first level of denaturation. He then began thinking about how hydrogen bonds might work in proteins.
It was already known from the work of the German organic chemist Emil Fischer that proteins also contained strong covalent bonds formed by the equal sharing of pairs of electrons between two atoms. If these stronger bonds were broken, the protein would fall into pieces. Covalent bonds would take more energy to break, and when broken, could not easily be re-formed. This might represent the second level of denaturation.
To test his ideas, Pauling lured Alfred Mirsky, one of the Rockefeller scientists studying proteins, to Pasadena and started him working on a series of studies designed to measure carefully the energy needed at each step of denatura-tion. Mirsky liked Pauling's ideas, which meshed nicely with Fischer's theory that proteins were made of long chains of amino acids linked end to end. Each time one amino acid linked to another, a water molecule was given off and a specific kind of covalent bond, which Fischer called a peptide bond, was formed. Long strings of amino acids could be formed, which Fischer called polypeptide ("many peptide") chains. These chains could be looped or twisted around, Pauling thought, and pinned into specific shapes through the formation of weaker hydrogen bonds between different parts of the chain.
Pauling and Mirsky published their ideas in a 1936 paper that became a milestone in the history of protein science. "Our conception of a native protein molecule (showing specific properties) is the following," they wrote. "The molecule consists of one polypeptide chain which continues without interruption throughout the molecule. . . . This chain is folded into a uniquely defined configuration, in which it is held by hydrogen bonds." This, they wrote, was the basic structure of all proteins.
Their idea explained the two levels of denaturation. The first step consisted of breaking hydrogen bonds, which would unfold the protein strings, leading to a loss of native activity. As long as the strings were in one piece, however, the hydrogen bonds could re-form, returning the molecule to its original shape and activity. Treat it more harshly, however, and the covalent peptide bonds along the string would break, leading to irreversible denaturation.
This analysis cleverly explained denaturation, but it did more. Pauling and Mirsky were proposing that all proteins were basically the same at one level—they were all long chains of amino acids—but differed in their abilities because of their final shape. It was the shape of the protein that determined its specific properties, they argued: Molecular shape was the secret of life.
But what were those shapes, and how did they confer on proteins their amazing abilities? How did an enzyme's molecular form explain its ability to catalyze one, and only one, specific chemical reaction? How did a gene's shape explain its ability to make exact copies of itself?
These were big questions, and Pauling began searching for answers in a variety of ways. He thought first of building a model of proteins, working upward from what little was known of the structure of amino acids, the basic units of protein chains. He set a hard-working, meticulous assistant, Robert Corey, to work using X-ray crystallography to discover the structure of the simplest amino acid, glycine. When Corey quickly succeeded—becoming the first person ever to describe with precision how an amino acid is built— Pauling put him to work on a two-amino-acid molecule called diketopiperizine. The goal here was to determine for the first time the precise length and angle of the peptide bond. Pauling had a hunch that this particular bond would prove critical to understanding protein structures, because he theorized from what he knew about amino acids that it held the atoms on either side of it in a very specific, quite rigid way. If that was true, it would reduce greatly the possible number of ways in which protein chains could fold and twist. Corey's work confirmed Pauling's prediction.
While the two learned more about these building blocks, Pauling was also working to understand more about the properties of whole proteins. In the spring of 1936 Pauling had met Karl Landsteiner, a distinguished, silver-haired, Austrian-born researcher who had won a Nobel Prize for discovering how to make transfusions safe by testing for blood types. Landsteiner's passion was immunology, the study of the body's defense mechanisms against infection and disease, with a special focus on antibodies, which were text continues on page 72
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