The Search for the Molecular Helix

In the late 1920s, the world's wealthiest philanthropic organization, the Rockefeller Foundation, decided on a new venture. Under the direction of its new head of the natural sciences division, Warren Weaver, the Foundation began supporting investigations into a new type of biology. Weaver believed that biology was about to undergo an epochal transformation thanks to recent advances in chemistry and physics. New techniques such as x-ray crystallography and chromatography would lay bare the nature of the molecules of life, especially proteins, making it possible for researchers to directly study the germ plasm, the basic material of life itself.

The Rockefeller Foundation began awarding significant grants in this area. Linus Pauling, however, was not an early recipient. His work focused on the crystal structure of inorganic molecules, and he had shown little interest in biological substances. Nevertheless, impressed by the reputation Pauling was earning among chemists, Weaver visited Caltech and offered Pauling research support in hopes that he could shape the young chemist's research interests. Lured by Rockefeller money, Pauling in the early 1930s turned his attention to the structure of biomolecules, especially proteins such as hemoglobin and antibodies.

Determining the structure of proteins at this time was an enormous problem. Most proteins were difficult to purify, easily degraded, and hard to characterize. Proteins appeared to be not only gigantic molecules comprising hundreds or thousands of atoms--structures much too large to determine directly with x-ray crystallography--but were also relatively fragile, losing their function (denaturing) after even slight heating or mechanical disturbance. No one at the time was even sure that they were distinct molecules--one popular theory held that proteins formed amorphous colloids, gels that did not lend themselves to molecular study.

But once Weaver had convinced him to take on the challenge, Pauling succeeded by his hard work, his deep understanding of simpler chemical structures, and his model-building approach. To solve the problem of protein structure, Pauling first directed his laboratory coworkers to find the precise structures of several amino acids, the building blocks of proteins. This effort resulted in a far better understanding of these important components.

Following on the ideas of the German biochemist, Emil Fischer, Pauling correctly theorized that amino acids linked to one another end-to-end, through relatively rigid bonds that would hold them in certain positions. From this initial understanding of amino acid bonds, he built up his ideas about larger-scale protein structures. Working with Alfred Mirsky in the mid-1930s, Pauling discovered that the denaturing of proteins was the result of breaking weak bonds, called hydrogen bonds, that pinned the amino acid chains into specific shapes and allowed them to function biochemically. Through the 1930s he used his lectures and persuasive writing to criticize rival theories of protein structure.

In May 1951, he wrote a celebrated series of seven papers detailing the structures of a number of proteins at the level of individual atoms, including the structure of the single most important basic form of protein chain, the alpha helix (a hydrogen-bonded helical chain that is a structural component of most proteins). It was an astounding breakthrough, and it opened the door for an understanding of biology at the molecular level.

Pauling's strategic approach to his research, as well as his specific discoveries, established him as a founding father of molecular biology. First, he worked to understand the structures of the subunits that make up the larger molecules. Then he determined how they could link together. He used the basic rules of chemistry and physics to limit and guide his hypotheses. Finally, he built models to test and elaborate his ideas. By using this approach, Pauling was able to make fundamental advances in determining the shapes of biomolecules, and this achievement then allowed him to investigate how chemical structure determines biological function.

For Pauling, though, determining the structure of DNA was the prize that eluded him. In 1952, he proposed a three-chain helical structure for DNA. Hampered by inadequate data, he was mistaken. The following year, armed with better experimental results, James Watson and Francis Crick used Pauling's strategic approach and came up with the correct, double-helical structure. After years of hearing her husband answer questions about how he missed this essential discovery, Pauling's wife Ava Helen asked him--only half in jest--"If that was such an important problem, why didn't you work harder on it?"