7 Steps To Health Linus Pauling

The Triple Helix

On the morning of Tuesday, August 7, 1945, Linus Pauling stopped at a Pasadena drugstore to buy a newspaper. He would remember the next few moments for the rest of his life. The newspaper headline read, "Tokyo Admits Atomic Havoc." A new type of American bomb had just been dropped on the Japanese city of Hiroshima. An enormous fireball had killed or injured tens of thousands of Japanese. Much of the city, the report said, was destroyed in an instant. J. Robert Oppenheimer's experiment, the Los Alamos project he had tried to talk Pauling into joining, had been a success. Science had created the atomic bomb.

Three days later, Pauling read that another of the new weapons had destroyed the city of Nagasaki. Shortly after that, Japan surrendered. World War II was over. Americans danced in the streets, and Pauling and his family joined in the general euphoria.

But when the excitement wore off, Pauling and many other scientists were left with difficult questions. They began gathering in small groups, in private homes and faculty clubs, to talk about the social and political implications of the new bomb. A few dozen of these devices, delivered

A mushroom cloud rises over Nagasaki after an atomic bomb was detonated there on August 8, 1945. The power and destruction caused by this new weapon spurred Pauling and other scientists into political action to limit its development and use.

by airplanes, could destroy an entire nation, wiping out its armies and cities in a single day. Didn't the power of these weapons now make war obsolete? It made sense to have military secrets in wartime, but now there was peace. Should the workings of the atomic bomb remain military secrets, or should they now be shared, like any other scientific discoveries, with the rest of the world? Atomic energy could also be used to make electricity. Didn't scientists owe it to the war-ravaged planet to make that process available to everyone?

As more details about incinerated cities, terrible burns, and radiation poisoning became public, a sense of guilt was added to the scientists' other concerns. Wasn't it immoral to develop this weapon? What had they done?

Pauling joined a discussion group of concerned professors and students in Pasadena and was among the first to understand that the new bomb also meant a changed role for scientists. "The problem presented to the world by the destructive power of atomic energy overshadows, of course, any other problem," he wrote a fellow researcher less than two months after Hiroshima. "I feel that, in addition to our professional activities in the nuclear field, we should make our voices known with respect to the political significance of science."

This approach was something new, because scientists usually steered clear of politics. They were trained to be objective, to analyze data critically and fairly, and to come to conclusions uncolored by personal prejudice. But politics was messy, personal, and often rooted in emotions and partisanship. How could scientists be objective if they were taking political stands?

Pauling's answer, and that of hundreds of other scientists in the months just after the war, was that they must add their voices to the public debate over the bomb. Their objectivity and technological know-how was required to inform the political debate. The new bombs were complicated scientific discoveries that also had enormous political effects. The public needed to understand both how they worked and what they were capable of—as well as the positive side of the possible development of atomic power— if there was to be a rational use of this powerful new technology. Scientists were needed to explain all of this.

The Pasadena discussion group talked for hours over beer and pretzels in the basement of the Caltech faculty club about all these issues, including the inescapable reality that the United States would not long have a monopoly on the atomic bomb. As Albert Einstein said, "What nature tells one group of men, she will tell in time to any group interested and patient enough in asking the questions." If the Soviet Union and other nations developed the bomb, as Pauling was certain they soon would, what was to prevent a worldwide holocaust?

The answer, hundreds of scientists nationwide agreed, was logical. No one nation could keep atomic secrets, so they should be shared with all. As Einstein began pointing out, the new bombs were a signal that humankind needed a new form of government, a cooperative world body that would not only oversee the peaceful development of atomic power but quash any individual nation foolish enough to threaten atomic war.

Pauling and many other scientists began to speak out on these issues. Dozens of scientists' discussion groups coalesced into a national organization, the Federation of Atomic Scientists (FAS), which lobbied Congress to keep atomic energy under civilian rather than military control. Pauling joined the FAS and raised his voice in favor of civilian control.

To help further involve the public in atomic energy issues, Einstein and a small group of other leading researchers formed the Emergency Committee of Atomic Scientists to raise money for public information campaigns. Pauling was happy to join when asked, especially because

I Linus Pauling

Pauling in 1949 at Caltech's faculty dub, the Athenaeum. Pauling's increasing involvement in antiwar activities would isolate him from many of his colleagues at Caltech.

it offered him the chance to visit more with Einstein. Einstein's repugnance for the bomb and passion for peace were coupled with an ability to speak from the heart that had a great effect on Pauling's own approach to the atomic issue.

But there was an even more important person in Pauling's decision to move toward political action. Ava Helen believed even more strongly than her husband did that citizens had an obligation to speak out where they saw injustice. She had convinced Pauling to join Union Now, an anti-Nazi, pro-democracy group before the war, and had gotten him interested in fighting the internment of Japanese-American citizens during the crisis. Ava Helen, too, felt that the atomic bomb was the most important issue of the day. She was always at Pauling's side during his meetings with Einstein and in the front row at his public talks,

Pauling in 1949 at Caltech's faculty dub, the Athenaeum. Pauling's increasing involvement in antiwar activities would isolate him from many of his colleagues at Caltech.

encouraging him, critiquing his speeches, urging him to ever greater involvement.

With her help, Pauling became a powerful and popular speaker. His years of teaching had given him the ability to clearly explain technical matters. Through 1946 he made speeches about the physics and technology of the bomb to business clubs and women's associations, high school assemblies and scientific organizations. Later he began adding political content, talking about the insanity of atomic war and the need for world government. In 1946 he and Ava Helen began joining nonscientific political groups that advocated worldwide cooperation and open communication with all other nations, including the Soviet Union.

For a year after the war's end, Pauling's views were not unusual. The FAS succeeded in convincing Congress to take the oversight of atomic energy away from the military and give it to a civilian agency, the Atomic Energy Commission. In 1945 the United Nations was formed—a first step, some thought, toward world government. For a while, President Harry Truman and his advisors openly talked about sharing atomic secrets with other nations, including the Soviet Union.

In the fall of 1946, however, things began to change. The Russian leader Joseph Stalin sealed off Eastern Europe, brutally suppressing democracy there and forcing those nations to adopt communism as their political system, drawing closed what British prime minister Winston Churchill called the Iron Curtain. In China, communist rebels began threatening the government. Alarmed by the rising tide of worldwide communism, U.S. voters began electing anti-communist politicians who rejected the idea of world government, encouraged a tough line with the Soviet Union, and pushed for a build-up of atomic weapons. By late 1947 all talk of sharing bomb technology ceased, and soon anyone who spoke in favor of world government or cooperating with the communists was suspected of actually being a communist. It was the beginning of a long period of silence and fear in America. It was the beginning of the cold war.

During these years Pauling made political speeches because he felt he should, but he continued his scientific work because he loved it. His work with antibodies had confirmed for him the simple but powerful idea that much of the specific activity of biomolecules in the body could be explained through the close fitting of large molecules. Shape and structure were everything—precise, hand-in-glove fitting of molecule to molecule—which he called "detailed molecular complementarity."

He now felt confident that the idea of these close-fitting, complementary shapes was sufficient to explain how antibodies latched onto their target molecules. His own research had shown that the preciseness of the fit between antibody and antigen was incredibly exact, so that even a single atom out of place could significantly loosen the attachment. And he felt that the same could be true of other biological molecules. Through the late 1940s, in a series of brilliant lectures, Pauling outlined the case for complementarity as the core principle of molecular biology. This matching of shape to complementary shape, he said, could explain everything from an enzyme's specificity for a certain substrate to the nose's ability to distinguish between different smells (the theory being that only certain-shaped odor molecules would fit specific odor receptors).

Complementarity could even, Pauling believed, explain the greatest mystery in biology: how living organisms replicated themselves. By now it was known that small units of inheritance called genes carried the instructions for new generations, but their chemical nature was entirely unknown. Pauling, like most scientists, believed that genes were most likely made of proteins.

But how could genes make the precise copies of themselves needed to create new cells and new generations? Pauling had a theory: "In general, the use of a gene ... as a template would lead to the formation of a molecule not with an identical structure, but with a complementary structure," he said in 1948. "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 the 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 can thus serve as the mold for the production of duplicates of itself." This was a fair description of the DNA molecule—four years before its structure was discovered.

Pauling felt he was on the right track, but he refrained from publishing his ideas because he had no proof to present. No one knew for certain what genes were made of, much less how they were shaped, nor had anyone even a crude idea of the detailed structure of any of the proteins. Pauling, intent on solving this last problem, wanted to become the first to publish the precise structure of a protein, and he had a good candidate for the task: keratin.

Keratin, a common protein, is the stuff of hair, fingernails, and animal horn. A good deal of X-ray work had been done on keratin in England, where it was found that hair is made of very long molecules with a structure that repeats itself every 510 picometers along its length. (A picometer is one-trillionth of a meter; for comparison, 100 picometers is roughly the distance from a hydrogen atom to an oxygen atom in a water molecule.) Most of England's leading researchers, and Pauling as well, thought the X-ray data indicated that keratin had some sort of kinked, zigzag structure that accounted for hair's ability to stretch when wet as the molecular kinks straightened out and then shrink back when dry. The 510 picometers were thought to be the distance between each kink.

Using what his lab had discovered about the structure of amino acids and the nature of the peptide bond, and adding in his ideas about hydrogen bonds, Pauling set about building a mental model of keratin. But nothing he tried in the form of a kinked ribbon seemed to work. He could not devise any reasonable structure that obeyed the rules he set himself—especially the rigid peptide bond—and also matched the X-ray data.

Then, during a long visit to England in early 1948, Pauling heard about another approach. British researchers were saying that, instead of a kinked ribbon, keratin and other proteins might have a molecular structure more like a spiral or, as some called it, a helix.

Shortly after learning this, the damp English weather put Pauling to bed in his house in Oxford with a severe sinus infection. "The first day I read detective stories and just tried to keep from feeling miserable, and the second day, too," he later remembered. "But I got bored with that, so I thought, 'Why don't I think about the structure of proteins?'" Gathering paper, a ruler, and a pencil, he began sketching out a string of amino acids, measuring to make the proportions as precise as he could, marking the peptide bond with double-thick lines to indicate where the atoms were held rigidly in place. He organized the amino acids so that any side chains would point outward, away from the center of the molecule.

Then Pauling started folding the paper so that the amino acid chain formed a spiral. In a few moments, much to his surprise, he came up with a structure that maintained his planar peptide bond, had reasonable angles for other connections, and easily formed hydrogen bonds between each rise in the spiral. "Well, I forgot all about having a cold then, I was so pleased," he said.

Pleased, that is, until he took out his ruler to measure the distance between each rise of the spiral. It would take months of careful model building to try to confirm the point, but even without that it appeared that the distance between one turn of the chain and the next above it was not close to the 510-picometer repeat found in the X-ray data. There was no way Pauling could see to stretch or compress his model to make it fit. Clearly, something was wrong.

He went back to bed. Pauling told no one about his doodles, filing them away for further study when he returned to California. For the moment, he felt, all he had was "just a piece of paper."

And he went on to other things. When asked once how he had so many good ideas, Pauling answered, "I have a lot of ideas and throw away the bad ones." His fertile mind continued to generate a variety of new ideas through the late 1940s. Some he pursued on his own—protein structure, the nature of the chemical bond in metals, the quantum states of oxygen, a continuing interest in antibodies, the writing of highly influential textbooks for college students—but most he continued to jot down for his research assistants, postdoctoral fellows, and graduate students to follow up.

One of these seemingly offhand ideas turned into an extraordinary advance for medicine. Toward the end of the war, Pauling had been asked to join a committee charged with outlining the postwar funding needs of U.S. medical research. At a committee dinner one night, the talk turned to a rare blood disorder called sickle-cell anemia. One of the members, a physician expert in the disease, described how the red blood cells in these patients were twisted into sickle shapes instead of flat discs. This distortion clogged small blood vessels in the body. The result was joint pain, blood clots, and often death. The disease particularly affected black Americans, this physician said, and there was one more unusual thing: The sickled cells seemed to appear more often in blood in the veins, returning to the lungs, than in the more oxygenated blood found in arteries.

Pauling knew that red blood cells were essentially tiny bags stuffed with hemoglobin. If the cells were sickling, it was likely that hemoglobin was somehow involved. What if the hemoglobin molecules were altered in sickle-cell patients in a way that caused them to stick to each other, clumping up and distorting the cell? This could happen if the surface shape was altered even a little, just enough to create an area complementary to a neighboring hemoglobin. If that happened, the molecules would stick together like an antibody sticks to its antigen. He knew, too, that when oxygen bound to hemoglobin it changed the molecule's shape, perhaps enough to reduce the "stickiness" and lower the amount of sickling.

This was an idea that perhaps could have occurred only to Pauling, but to prove it he would have to find differences in structure between normal and sickle-cell hemoglobin. He gave that job to Harvey Itano, a young physician who was earning his Ph.D. under Pauling. Itano, joined later by a postdoctoral fellow, John Singer, worked for a year trying to find the structural difference Pauling had predicted, but they could not find anything. The hemoglobins were the same size, same general shape, and had the same reactions to tests; in short, they appeared to be identical.

But Itano and Singer kept at it. Finally, while Pauling was in England, they put the hemoglobins through an extremely sensitive new technique called electrophoresis, which separates proteins by the electrical charges on their surfaces. And here they found their answer: The sickle-cell hemoglobin carried a few more positively charged atoms on its surface. The difference was not great, but there was in fact a structural difference.

This was astounding—a slight change in the electrical charge of a single molecule in the body meant the difference between a healthy human and one with a deadly disease. Never before had the cause of a disease been traced to an alteration in a single molecule, and this discovery—

Pauling called it history's first "molecular disease"—caused an international sensation. Itano and Singer's follow-up work demonstrated a pattern of genetic inheritance for the disease and added to its importance as one of the cornerstone discoveries in modern medicine.

By the end of the 1940s, there seemed no scientific height that Pauling could not scale. There was talk of a Nobel Prize after the sickle-cell discovery in the late 1940s. In England he was awarded honorary degrees from that nation's three major universities—Cambridge, Oxford, and London—the first American, he was told, ever so honored. At home he was nominated for the presidency of the National Academy of Sciences and elected president

Pauling and his assistant Robert Corey, with a model of a molecule.

of the American Chemical Society. But still the greatest prize eluded Pauling: to discover the precise structure of a protein.

After his return from England, in the winter of 1948, Pauling quietly assigned a visiting professor of physics named Herman Branson the job of rechecking his idea about keratin helixes. The instructions he provided Branson were somewhat open-ended. Ignore the X-ray data for the moment, he directed, but use the limiting factors of known amino acids' dimensions and the planar peptide bond, and look for structures that maximize hydrogen bonding to pin the helix in position. Given those limits, how many stable helixes could be devised? After a year's work, Branson came up with just two, one being the same that Pauling had sketched in England. He gave Pauling detailed calculations for the parameters of both—one more tightly wound, called the alpha helix, and a looser one, the gamma helix—and went on to other research.

Again Pauling was confounded. Neither of Branson's two stable helixes matched the 510-picometer repeated distance along the axis that the X-ray data said should be there. The tighter spiral came close, at 540 picometers, but not close enough.

And again he hesitated to publish the findings. "I felt so strongly that the structure must explain the X-ray data that I took a chance by waiting," he remembered. Perhaps, he was beginning to think, it would take 50 years of work to solve protein's structure after all. Pauling let it sit for a year until he was jolted into action by a scientific paper published by Sir William Bragg, the X-ray pioneer, whom Pauling had beaten to the structure of silicates 20 years before, and his research group at the Cavendish Laboratory in Cambridge. Pauling had visited there, finding it a place where protein research was both well-funded and surprisingly advanced. If anyone had a shot at beating Pauling to the structure of keratin, it was Bragg's group. The some what unfocused paper by Bragg that Pauling read in 1950 was all about protein structures. But because the British did not pay enough attention to the idea of a rigid peptide bond, which Pauling believed to be absolutely necessary, they twisted and bent their theoretical structures in ways he believed impossible. No wonder Braggs group concluded that none of the 20 kinked chains and spirals they proposed was quite right.

One of their forms, however, came very close to Pauling and Branson's alpha helix, a near miss that was enough to get Pauling back in the game. Feeling forced into action by the British advances, Pauling decided to ignore the contradictory X-ray evidence and publish his ideas anyway. He and his assistant Robert Corey, an expert in the painstakingly precise art of interpreting X-ray crystallography data from proteins, wrote a short note in the fall of 1950 outlining their two spirals. Then Pauling and Corey threw themselves into the hard labor of pinning down the position of every atom in their models.

They were aided by some unexpected good news. A British manufacturer of artificial fibers announced that it had created synthetic protein strands very much like keratin by joining glycine amino acids with peptide bonds. This artificial protein formed itself into a spiral with roughly the dimensions Pauling predicted for his alpha helix. That was encouraging. But even better was the news that the X-ray pattern from this synthetic protein did not show the 510-picometer repeat found in natural keratin. Pauling was very excited by this result. Perhaps the confounded X-ray data had nothing to do with the essential spiral structure at all but was simply an artifact of how the spirals interacted with each other in natural proteins.

Pauling and Corey worked feverishly now, expanding their ideas beyond the two helixes to additional structures for silk that they called pleated sheets. They also explored more complex structures for the proteins in feathers,

H Linus Pauling muscle, and collagen, a common protein found in bone, cartilage, and tendon.

On February 28, 1951, his 50th birthday, Pauling sent to press an extremely detailed complete description of the two helixes he and Corey had started with. He then spent the following weeks working on his other structures. "I am having a hard time keeping my feet on the ground now," he wrote a former student, "I have been working night and day, neglecting almost everything else."

The result was one of the most extraordinary sets of papers in 20th-century science. Seven appeared together, dominating the May 1951 issue of the Proceedings of the National Academy of Sciences. There was a detailed description of the pleated sheet for silk. There was a new model for the protein in feathers, and new ideas about the structure of artificial proteins, globular proteins, and muscle.

THE STRUCTURE OF PROTEINS: TWO HYDROGEN BONDED HELICAL CONFIGURATIONS OF THE POLYPEPTIDE CHAIN

By Linus Pauling, Robkrt B. Corey, and H. R. Branson*

Gates and Crellln Laboratories of Chemistry, California Institute op Technology, Pasadena, California t

Communicated February 28, 1951

During the past fifteen years we have been attacking the problem of the structure of proteins in several ways. One of these ways is the complete and accurate determination of the crystal structure of amino acids, peptides, and other simple substances related to proteins, in order that information about interatomic distances, bond angles, and other configurational parameters might be obtained that would permit the reliable prediction of reasonable configurations for the polypeptide chain. We have now used this information to construct two reasonable hydrogen-bonded helical configurations for the polypeptide chain; we think that it is likely that these configurations constitute an important part of the structure of both fibrous and globular proteins, as well as of synthetic polypeptides. A letter announcing their discovery was published last year.1

The problem that we have set ourselves is that of finding all hydrogen-bonded structures for a single polypeptide chain, in which the residues are

The May I95I issue of the Proceedings of the National Academy of Sciences wos dominated by several revolutionary articles by Pauling on the structure of proteins.

There was what Pauling called an "astounding structure" for collagen, a complex of three of his alpha helixes wound around each other to form a cable.

Taken together, Pauling's protein papers constituted an amazing event, a leap from knowing nothing about the detailed structure of any protein to knowing a great deal about many of them. It raised the stakes for protein researchers worldwide, who now had to detail their structures to the level of precisely placing each atom if they wanted to match Pauling.

Not everything in these papers was correct, of course. It was later proved that Pauling and Corey's ideas about several proteins, including collagen and muscle, were wrong, and others needed refining. The looser, gamma, helix was never found to be important in nature.

But none of this could eclipse Pauling's towering achievement. His alpha helix was soon confirmed to be the structure of keratin and was found as well to be an important component of many other proteins of widely varying types. By using his wits, his model building, and his belief in the rules of chemistry, Pauling had succeeded in jumping to an understanding of the correct structure for a protein years before anyone else might have.

And yet Pauling had not solved the mystery of life. His alpha helix was an important structural feature of many proteins, but it could not explain how the important ones worked. Apart from hair and horn, Pauling's alpha helix seemed to explain nothing about protein activity. To make an antibody, for instance, sections of alpha helix would have to bend and twist to create an area complementary in shape to the target molecule. Pauling's model did not account for bends, nor did it predict in any way how the alpha helix could create the fantastic variety of shapes necessary for proteins.

At the same time, it was becoming clear that the real chemical secret of life—the stuff that made genes—was not text continues on page 95

Linus Pauling

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