The Fabric And The Chain

Pauling's protein model was not the only one generating interest during the 1930s. The same year that he and protein researcher Alfred Mirsky published their ideas on denaturation, a brilliant and unconventional British scientist gained worldwide attention with her own, very different, ideas about proteins.

Dorothy Wrinch, the first woman to receive a doctorate in science from Oxford, was in many ways ahead of her time. She spoke her mind (often with an acid tongue), smoked cigarettes, believed in independent careers for married women, and forcefully pursued her own. Trained as a mathematician, Wrinch believed that all scientific progress grew directly out of pure logic; she found her greatest success applying that approach to biology.

In the early 1930s, Wrinch was an intellectual gypsy, separated from her physicist husband, traveling through Europe with her young daughter, apprenticing at biological laboratories to learn about embryology, genetics, and protein structure. Her mathematical approach attracted the attention of the Rockefeller Foundation's Warren Weaver, who in 1935 gave her a grant to fund her work for five years.

She used the time to devise an intriguing set of ideas about protein structures. Starting with the then-popular (but mistaken) idea that many proteins were composed of subunits numbering exactly 288 amino acids, Wrinch constructed models that were not long chains, like Pauling's, but fabrics formed by amino acids connected in more complex ways. Her favorite was a honeycomb of hexagonal rings that could be folded around on itself to make a cagelike structure of exactly 288 amino acids. She called it a cyclol.

Wrinch's cyclol was appealing because it had a three-dimensional shape with an outside and an inside, a general configuration that many protein researchers believed was likely for a lot of important proteins. But Pauling was skeptical. He did not believe that nature dictated any "magic numbers" such as 288 amino acids for proteins, and did not think that the types of chemical bonds that Wrinch proposed for cyclols were likely to exist. After talking with Wrinch and discovering how little she knew about protein

Dorothy Wrinch (right) shows a model of her cyclol structure to two colleagues. Pauling was skeptical of her work and published a paper demolishing Wrinch's arguments.

chemistry, he wrote Weaver a stinging report that concluded that Wrinch's "arguments are sometimes unreliable and her information superficial."

Still, because so little good evidence was available about protein structure in general, there was no direct proof that Wrinch was wrong. Free to theorize, she continued to make her case through the late 1930s, earning the support of some well-known scientists and even appearing in front-page news items in which reporters called her the woman Einstein.

To put an end to what he saw as a distraction from more valuable lines of inquiry, Pauling and fellow protein researcher Carl Niemann in 1939 published a paper marshaling all the chemical evidence in favor of their chain theory of protein structure and against Wrinch's arguments. Its impact was devastating. After it appeared, no one would take Wrinch's cyclols seriously again.

Pauling and Niemann turned out to be right—mostly. Pauling's chains would prove the rule in nature, cyclols the extremely rare exception. Pauling would go on to win world acclaim, Wrinch to spend the rest of her life in scientific obscurity, arguing for her structures, reminding anyone who would listen how Pauling had undermined her work and calling him "a most dangerous fellow."

Linus Pauling text continued from page 69

blood proteins that had the unique ability to recognize and latch onto specific targets like viruses and bacteria, clump them into masses, and help clear them from the body.

Antibodies, Landsteiner told Pauling, posed an intriguing puzzle. They were all proteins, all roughly the same size and shape, and all made of roughly the same mix of amino acids, yet each was also very different in the way it attached to one and only one target molecule, or antigen. An antibody to a certain virus would not attach strongly to anything else. Landsteiner had found that a single animal could form thousands of different antibodies, including new ones tor synthetic chemicals never found in nature.

Knowing of Pauling's work on denaturation, Landsteiner asked for his help. Could Pauling, with his knowledge of structural chemistry, explain how similar proteins could recognize and bind to so many different antigens in this bafflingly precise way?

Pauling had no quick answer. He bought a copy of Landsteiner's book on antibodies, quickly read it, and spent time thinking. His first assumption was, of course, that molecular structure had to be involved. The shapes of antibodies would determine their specificity. But how?

In 1940, Pauling published a brilliant answer. Each antibody molecule, he theorized, was formed by the body as a denatured chain, stretched out, without hydrogen bonds, with no specific shape. One end would then come into contact with a foreign molecule, an antigen, and begin to shape itself around it. It would be held in place by weak bonds: hydrogen bonds, the attraction of oppositely charged areas on the surface of the antigen and antibody, and so forth. Like soft clay being pressed onto a coin, the antibody would take on a complementary shape, and when that shape was good enough, the fit close enough, the sum of all the weak links would be great enough so that antibody and antigen would stick together. The same thing could happen at the other end of the antibody chain, making a "bivalent" molecule capable of latching onto two foreign molecules at once, explaining how antibodies could clump their targets together.

It was a wonderful theory, but it was in part very wrong. The idea that antibodies are created as denatured proteins that become specific by adapting their shape through direct contact to antigens would prove to be mistaken. But the underlying concept of key-in-lock complementary shapes causing an antibody to stick to a target was right.

For 15 years, however, until a new, more powerful theory of antibody formation was put forward, Pauling's idea led the field. His antibody work again expanded his growing reputation as a master of many fields.

But at the height of his success, his world began to fall apart.

In the late 1930s Pauling, like many other American scientists, began to receive increasingly desperate letters from colleagues in Germany. The researchers, many of them Jewish, were seeking someone, anyone, who could help them escape the Nazis by obtaining a visa for travel to America. Pauling, who personally knew many German researchers through his European travels, became keenly aware of the anti-Jewish, antiscience attitudes of Hitler and his government. By 1939, Pauling was convinced that Hitler had to be stopped.

With Ava Helen's encouragement, he began speaking out about the issue and joined a group called Union Now that proposed joining all the democracies in the world into a federation modeled on that of the United States. At first Pauling was a bit uncomfortable speaking on political topics, but he soon found he enjoyed it. When Germany attacked France and then Britain, he began speaking passionately in junior high school auditoriums and local living rooms about the need for America to help. "Should not our country help Britain now to fight off the thing which is attacking her and will probably attack us when she is polished off?" he asked his audiences. "This means going to

Linus Pauling

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