by Thomas Hager
Linus junior, however, seemed to be doing fine. He surprised his parents that fall by announcing his engagement to Anita Oser, the great-granddaughter of both Cyrus McCormick and John D. Rockefeller and heiress to one of the nation's largest private fortunes. Theirs had the trappings of a fairy-tale relationship—the quiet son of a respected scientist and the beautiful, charming daughter of America's financial elite—and the engagement was well covered in the newspapers. They were married in a simple ceremony on the lawn of the Pauling's Sierra Madre house that September. This, too, was pleasing to Pauling; it fit his vision of how the world should work. He had labored hard his entire life to achieve the American Dream, and here, spread out on the velvet lawn of his mountain home with a crowd of the wealthy and renowned drinking toasts under the brilliant Southern California sun, it seemed that he had succeeded.
In late December, Linus, Ava Helen, and their three other children took the train to New York City, where they were due to embark on the Queen Mary the day after Christmas. They celebrated the holiday by exchanging gifts in a midtown Manhattan hotel room and were delighted to look outside and see snow falling, giving the Paulings their first white Christmas. They all bundled up and ran outside, Pauling and Ava Helen, too, scraping up snowballs and throwing them at street signs.
But by the next morning it had turned into too much of a good thing. A blizzard had buried the city in snow. With nothing moving on the streets, their ship set to sail in a few hours and Pauling growing nervous, they finally found a cabbie willing to try to get them to the dock—for an elevated fee. They made it.
The children were having the time of their lives. While the captain delayed departure to pick up late-arriving passengers, they explored the ship from end to end. Even their modest accommodations—Pauling had saved money by sailing third-class—seemed exotic and exciting. Finally, with a great blast on the steam whistle, the Queen Mary pulled away from the dock through the densely falling snow.
After the ship cleared the storm, the crossing was fairly calm, with the family afflicted only slightly by seasickness. Pauling spent his time on the top decks, where he ran across a fellow scientist, Erwin Chargaff, an expert on nucleic acids, who tried to interest him in a recent observation he had made about the ratios of the molecule's chemical subunits, something about the rough equivalence of purines and pyrimidines. Pauling might have been slightly interested if he had not been on vacation and had Chargaff not struck him as rather too loud, too pushy, and too full of himself. He cut the conversation short and fled back to his cabin. "I didn't pay enough attention to what he was saying," Pauling later remembered. It was a rare moment when Pauling's restless mind did not light upon and file away new information. It was a moment he would later regret.
- - -
After taking a week to settle in a London flat and enroll the children in local private schools, Pauling began what he would later remember as "one of the happiest years of my life." He was the archetypal Yank at Oxford, tall, thin, energetic, clever, and funny, his black robes and thinning hair, streaked now with gray and worn quite long for an American, flying behind him as he strode through the ancient arched and crenellated campus. Students and professors flocked to hear him. "He was a sensation. The lecture hall was too small to hold all the students who wished to attend his lectures; there was standing room only," remembered one lucky enough to get in. "I have never heard anyone quite like him, with his jokes, his relaxed manner, his seraphic smile, his slide-rule calculations, and his spontaneous flow of ideas."
In the evenings the Paulings picked through a pile of dinner and party invitations or went to plays or lectures or musical events. Pauling met an array of researchers, dignitaries, industrialists, and politicians and found that as long as the topics discussed turned on either politics or science, he could charm them all. He was showered with more honors and awarded doctorates from Oxford and the University of London as well as Cambridge—the only person at that time, he was told, to have been so honored by all three.
The British Chemical Society sent him on a lecture tour of the United Kingdom, including appearances at the University of London and a special series of three talks at Cambridge. His theme was most often molecular complementarity, which he made more dramatic by showing his audiences a standard molecular ball-and-stick model. "Here, if atoms were really this big, two or three inches across, then at the same scale, a man looking at them would be 250,000 miles high," the distance from the earth to the moon, he would tell his listeners.
This became a favorite image in his talks, the man as tall as the moon, and he used it in a number of different ways to illustrate the challenges facing scientists interested in working out the structure of molecules. He had his audiences imagining themselves 250,000 miles tall. Now the earth is the size of a billiard ball to you; you can pick it up in your hand and turn it around. Say you were a scientist and you wanted to study this odd little ball, especially the tiny dot, barely visible to the naked eye, that is New York City. Aided by a conventional microscope, you could see things about a thousand feet wide: Central Park, say, or Rockefeller Center. With one of the new electron microscopes you could make out the shape of the Empire State Building—although nothing of its interior structure—and cars would show up as little dots. You could measure the sizes of the cars with semipermeable membranes or ultracentrifuges. But then would come a gap. The next step would be to use x-ray crystallography or electron diffraction, techniques so incredibly precise that you could determine the shapes of bolts, rivets, and gears, but nothing bigger.
There was a hole in the seeing, a blind spot between what could be discerned with the electron microscope and what could be worked out with x-ray diffraction. To the 250,000-mile man, this would eliminate the chance of determining the shapes of things between about one foot and ten in size, including the makers of Central Park and the Empire State Building and the cars: the humans. Take the same problem back to normal scale and you find that this "dark area of the unknown," as Pauling put it, extending across the size range of proteins and other giant molecules. It was this unexplored region that now required concentrated examination.
In February 1948 he was asked to give one of the Royal Institution's Friday night lectures, a formal monthly affair attended by the cream of British science and society. Founded by Michael Faraday in 1825, the lectures were an artifact from the days when the sciences were patronized like the arts; they originally offered the wealthy of London a chance to be amused by the latest in scientific research. But now they had become much more. Only the most significant work was afforded a hearing on Friday nights—it was here, for instance, that J. J. Thomson had announced the discovery of the electron. It had become for researchers the scientific equivalent of playing Carnegie Hall. "The members are connoisseurs who have an artistic appreciation of a good discourse," remembered a regular audience member. "The traditional way in which it is conducted, with lecturer and audience in evening dress, all helps create the right atmosphere."
For his Friday night Pauling carefully prepared a talk of the requisite and precise one-hour length. The evening began with a formal dinner, after which Pauling was ushered into the carefully maintained antique office of the great Faraday himself, the father of electrochemistry, and left alone to gather his thoughts before taking the stage.
He emerged an hour later, suitably inspired, entered the small, ornate auditorium, and faced a select audience of men in black tie and women in furs and jewels. Reminding himself of the lessons he had learned in oratory at Oregon Agricultural College, Pauling took a deep breath and began:
As I look at a living organism—at one of you or myself—I see reminders of many questions that need to be answered. . . . What is skin, fingernail? How do fingernails grow? How do I feel things—how are nerves built and how do they function? How do I see things? How can I smell things, and why does benzene have one smell and iso-octane another? Why is sugar sweet and vinegar sour? How does the hemoglobin in my blood do its job of ca
rrying oxygen from the lungs to the tissues? How do the enzymes in my body break up the food that I eat, burn it to keep me warm and to permit me to do work, and build new tissues for me from the food fragments? Why do I catch cold when exposed through contact with an ailing person, get pneumonia, and then recover after treatment with a specific antiserum or a sulfa drug? How does penicillin carry out its wonderful function of fighting disease? Why am I immune to measles, whooping cough, poliomyelitis, small-pox, whereas some other people are not? And finally, why is it that my children, as they grow and develop, become human beings, and show characteristics similar to mine, and their mother's—how have these characteristics been transmitted to them?
The basic answers to all of these questions are not to be found in books. Even though Chaucer said, "For out of olde feldes, as men seith,/ Cometh al this newe corn fro yere to yere;/ And out of olde bokes, in good feith,/ Cometh al this newe science that men lere," he was before long corrected by Francis Bacon: "Books must follow sciences, and not sciences books."
To understand all of these great biological phenomena we need to understand atoms, and the molecules that they form by bonding together.
Having gathered in his audience by mixing scientific questions, images of everyday experience, and quotes from British literary and scientific heroes, Pauling went on to outline his idea of complementarity as the central paradigm for understanding the action of biological molecules. While other Friday night speakers generally stood stock-still and read their notes, Pauling lectured from memory, pacing the theater stage, chalk in hand, scribbling out illustrations of antibody formation and enzyme action on a blackboard. He had his listeners imagine themselves as tall as the moon. He made them understand that the question of the structure of proteins was the central problem in biology. It was a flawless, seemingly spontaneous performance. And it had the desired effect. At a party given after Pauling's speech, Sir Ian Heilbrun, head of the Imperial College, remarked, "When we hear Linus giving one of his lectures, we think of a genius thinking out loud."
The Cavendish
Protein structure was also on the mind of one of the most illustrious members of the audience that night, William Lawrence Bragg. In the twenty years since Pauling had outraced Willie Bragg to the invention of a set of rules for determining complex silicate structures, the two men's professional lives had followed parallel upward trajectories. Bragg had emerged from his mental breakdown in the early 1930s seemingly stronger and more confident than ever, and he made his Manchester x-ray crystallography laboratory the most theoretically innovative in the world. His efforts were rewarded in 1938 by the call to succeed Rutherford as head of England's greatest center for physics, the Cavendish Laboratory at Cambridge. Three years later, he was knighted.
By 1948, he had made the Cavendish into the world's foremost center for x-ray crystallography. But here the two men's interests diverged. While Pauling was interested in the results of x-ray crystallography, Bragg was interested in the process: the perfection of equipment and mathematical techniques needed to interpret the x-ray patterns. It was the variety and power of his machines, the cleverness of the young men he attracted, and his ongoing interest in the theory of the technique that made the Cavendish Laboratory great. The molecular structures themselves Bragg left mostly to his workers. Much of their effort was spent on minerals, alloys, and small organic molecules, but there was also, when Bragg arrived, a little group led by Austrian émigré Max Perutz that was engaged in what Bragg called "a valiant attempt" to figure out the structure of hemoglobin. Bragg was not much interested in proteins when he first arrived—he never understood biology very well and thought that proteins were in any case much too large and complex to attack with x-rays—but Perutz was a tireless and optimistic worker with enough promising results to interest Bragg in proteins as an x-ray-analysis challenge, a sort of supermineral puzzle. By the time Pauling arrived in England, Bragg had secured enough funding to sustain Perutz, a young coworker, John Kendrew, and two research assistants, and their results were beginning to show the broad structural outline of the hemoglobin molecule. This was not the only British group making headway with proteins. At other universities, Dorothy Crowfoot Hodgkin was starting her second decade of studies on insulin, and J. D. Bernal and his coworkers were beginning to pick apart the enzyme ribonuclease.
The more Pauling heard about the British work, the more concerned he became about losing the race to become the first in the world to determine the structure of a complete protein. While he had been attacking proteins from the bottom up, carefully pinning down the structures of single amino acids and small peptides as a way of building larger structures from their subunits, the British had been working from the top down, analyzing the x-ray diffraction patterns of whole proteins. Pauling had thought proteins too large, their x-ray patterns too complex, for the top-down approach to work in any reasonable length of time. But after talking with Bernal and Hodgkin, he realized that the British seemed to be getting uncomfortably close to cracking some structures.
So he began thinking again about the theoretical attack on the parent of all proteins, the keratin chain, the structure that he had tried to solve in 1937. He had failed in trying to build a protein chain that matched Bill Astbury's x-ray data and had assumed at the time that his ideas about amino-acid structure or bonding were wrong. But everything that had been done in the years since, including Corey's careful amino-acid studies, had shown him that he had not been wrong. The dimensions were all roughly as he had assumed, and the double-bond character he had predicted for the peptide bond—the factor that prevented rotation and held the atoms on either side in a plane—had been confirmed by Corey's work with diketopiperazine. He had not been off by more than a few degrees or a few hundredths of an angstrom anywhere. Why had he failed ten years earlier?
In the spring of 1948 he returned to the problem, this time with a new guiding principle. In the 1930s a structure like a spiral staircase had been proposed for long-chain starches, and in 1943 Pauling's old collaborator Maurice Huggins (the scientist with whom he had done some of the early work leading to the idea of the planarity of the peptide bond) had theorized that the same shape might be important in proteins. In Huggins's model the amino-acid chain, rather than looking like Astbury's flat, kinked ribbon, spiraled up and around like a bedspring; Huggins hypothesized that it was held in shape between turns of the chain by hydrogen bonds.
This was an exciting idea and had already become a topic of discussion among British crystallographers. It helped to explain some things. While you would expect Astbury's flat ribbon to chemically reflect a ribbon's two-sided nature, protein chains actually behaved as if they were the same all around, consistent with a spiral's overall cylindrical shape. There were theoretical arguments in favor of spirals, too: As Francis Crick, then a graduate student in Perutz and Kendrew's laboratory, put it, "It was well known that any chain with identical repeating links that fold so that every link is folded in exactly the same way, and with the same relationship to its close neighbors, will form a helix." Whether called a helix or a spiral, Huggins's idea had an important influence on the Cavendish group. Soon it seemed that every protein researcher in Britain was looking for spirals. Dorothy Hodgkin, for instance, with whom Pauling had several long conversations during his Oxford visit, had been on the lookout for evidence of the shape in her insulin molecule.
Then a week or two after his Royal Institution lecture, Pauling fell ill, the damp British spring contributing to a severe sinus infection that put him in bed in his flat. "The first day I read detective stories and just tried to keep from feeling miserable, and the second day, too," he remembered. "But I got bored with that, so I thought, 'Why don't I think about the structure of proteins?'" More specifically, he decided to make another stab at keratin, this time using the idea of a spiral. He gathered some paper, a ruler, and a pencil and began sketching out a chain of amino acids, drawing the atomic bond lengths and angles from memory. He followed a three-step pla
n: Draw out a chain using the known dimensions of amino acids; line the elements up in space so that hydrogen bonds could form easily and peptide bonds were kept planar; then see if the resulting model explained the x-ray data. He drew the basic carbon-carbon-nitrogen backbone of each amino acid, then a heavy line where they linked to show the peptide bond; this he would keep flat on the page. The side chains that distinguished each type of amino acid from the others he pointed outward, away from the center of the spiral, figuring that in that way they would not interfere with construction of the repeating structure that had to exist at the center.
Then he started folding, keeping the peptide-bond area flat on the page, making turns only around the single carbon in the amino-acid backbone that was not involved in the peptide bond, the one spot he thought rotation could take place. When he folded here, he tried making the angle roughly that of a tetrahedron, the most logical choice for a carbon bond. He worked his paper around, trying to line elements up so that as many hydrogen bonds as possible could form. In a few moments, much to his surprise, he came up with a spiral that looked surprisingly good. It had planar peptide bonds, roughly correct bond angles and lengths, and allowed reasonable hydrogen bonds to form between each turn. "Well, I forgot all about having a cold then, I was so pleased," he said.
It was a classic example of his stochastic method, using a few decisively limiting chemical rules to create a reasonable model. But Pauling's happiness faded when he realized that the likely x-ray pattern produced from his model would not match the patterns Astbury and others had been getting. The actual keratin pattern showed a strong reflection at 5.1 angstroms, a distance thought to be the basic repeat unit along the length of the chain—in the case of a spiral, this would mean the distance between one turn of the chain and the next above it. It would take months of careful model building to confirm this, but it appeared from his crude sketch that Pauling's spiral measured out to a different repeat distance. Playing by his own set of rules about the peptide bond and hydrogen bonding, Pauling found: "There was no way I could stretch my structure or compress it."