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The Linus Pauling Papers

The Molecular Basis of Disease

[Linus Pauling speaking in a lecture hall]. [ca. 1967].
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Toward the end of World War II, Vannevar Bush, the head of the U.S. Office of Scientific Research and Development, contacted Pauling. Bush was seeking to restructure the way in which scientific research was conducted and funded in the United States. He formed several committees to work on the best institutions for postwar research; and he asked Pauling to serve on the one devoted to medical science. The 1945 report Bush eventually created from his committees--grandly titled "Science: The Endless Frontier"--would fundamentally change the role of the U.S. government in scientific research and help create both the National Science Foundation and the modern form of the National Institutes of Health.

Pauling was the only non-physician on Bush's medical research committee--a nod to his growing reputation outside of mainstream chemistry. He enjoyed talking with the physicians, relishing the chance to add a fundamental research perspective to their more applied approach. At a committee dinner one night in the spring of 1945, talk turned to a rare blood disorder, sickle-cell anemia. One of his dinner companions, an expert in the field, described how red blood cells in the victims were twisted from their normal disc shapes into dangerous sickle shapes. The distortion hindered the blood cells' transport through capillaries, resulting in joint pain, blood clots, and even death. The disease primarily affected Africans and African Americans. Pauling was struck particularly by one fact described at this dinner: sickled cells appeared most often in bluish venous blood, rather than in the more oxygenated red blood found in the arteries.

From his previous work with blood, he knew that red blood cells were little more than bags filled with hemoglobin, the molecule that carried oxygen from the lungs to the body. If the sickled cells had changed shape, perhaps it was because the hemoglobin had been altered in some way, making it clump and stick to one another, as antigens stick to antibodies. Pauling had already shown that hemoglobin changed shape slightly when it was oxygenated. So perhaps adding oxygen to this altered form of hemoglobin reduced the stickiness by changing the molecule's shape back to something approaching normal.

In the fall of 1946, Pauling presented his ideas as a research problem to Harvey Itano, a young physician who was then working on a Ph.D. in his laboratory. Itano, later joined by postdoctoral fellow John Singer, worked for a year trying to see if sickle-cell hemoglobin was shaped differently from normal hemoglobin. At first they found no detectable differences in any of the tests they devised. But finally, in 1949, using an exquisitely sensitive new technique called electrophoresis that separated molecules by their electric charge, they found their answer: sickle-cell hemoglobin carried more positive electric charges on its surface.

This was an astounding discovery. A slight change in the electrical charge of a single type of molecule in the body could spell the difference between life and death. Never before had the cause of a disease been traced to a molecule. This discovery--to which Pauling attached the memorable title "molecular disease"--received widespread attention. Itano and Singer's subsequent work demonstrated a pattern of inheritance for the disease, firmly wedding molecular medicine to genetics.

The positive response to this discovery--there was even talk of a Nobel Prize for Pauling--spurred him to greater effort in the medical field. He had long proselytized for greater use of basic chemical research in medicine, and for more physicians trained in basic research. In the late 1940s and early 1950s, he spearheaded an effort for joint biological/chemical research at Caltech, sought funds for more medically related research, and began immersing himself in the data on the health effects of nuclear weapons. He encouraged M.D./Ph.D. candidates, hired physicians to work in his laboratory, and began focusing his own research on medical problems, including developing a new theory of anesthesia.

In the 1950s, Pauling extended his concept of molecular disease to the brain. He read about phenylketonuria (PKU), a condition in which a mental defect can be caused by the body's inability to metabolize an amino acid, phenylalanine, leading to a buildup of that substance and others in the blood and urine. Pauling theorized that the problem might be caused by a defect in an enzyme needed to break down phenylalanine. PKU, in other words, might be another molecular disease. Now interested in the possibility of a range of molecular mental defects, Pauling visited a local mental hospital, saw other patients whose diseases seemed hereditary, and decided to seek support for an investigation into the molecular basis of mental disease. In 1956 the Ford Foundation awarded him $450,000 for five years' work--a vindication of Pauling's approach and a tribute to his reputation. The grant, however, yielded little in the way of immediate results, with much of the funding going toward testing his theory of anesthesia, which ultimately turned out to be mistaken.

Pauling's focus on the macroscopic effects of molecular changes led to a significant scientific success during the 1960s. He and his colleague Emile Zuckerkandl developed a theory of a molecular evolutionary clock. By comparing the structures of similar biomolecules--such as hemoglobin--found in different species, one could gauge how divergent these species were from one another, and, with some estimate of the rate of molecular mutation, one could come up with a "clock" to time evolutionary divergence. The molecular clock idea has proven important in evolutionary biology.