Linus Pauling and the Structure of Proteins: A Documentary History Narrative  
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A Sickled Cell
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When he resumed life at Caltech in the late summer of 1948, Pauling found himself diverted from protein spirals by much more exciting work being done in his laboratory.

It had started at the end of the war, when Pauling served on a select committee charged with designing postwar funding for medical research. At one of their dinner meetings, the conversation turned to a little-studied blood disease called sickle-cell anemia. Another committee member, Harvard medical professor William B. Castle, described how the disease deformed the shape of red blood cells from flattened discs to distorted crescents, which then clogged small blood vessels, leading to the painful symptoms suffered by its victims. One odd thing, Castle added, was that the misshapen blood cells were more common in venous blood than in the more highly oxygenated blood in arteries.

When he heard that, Pauling had an insight. He had studied hemoglobin, the oxygen-carrying protein inside red blood cells, and had published a paper on how oxygen bound to the molecule. What if, he thought, hemoglobin was at the heart of the disease? Perhaps the red blood cells were deformed because something happened to the hemoglobin when oxygen was released from it. In the fall of 1946 he had hired a young physician-turned-chemist, Harvey Itano, to explore the differences between normal and sickle-cell hemoglobins. Sickle-cell anemia is more common among blacks than any other American racial group, so Itano and Pauling had tried to get samples from physicians in the Los Angeles black community. When that failed to turn up enough, they had sickle-cell blood shipped from Tulane University in Louisiana.

But all their attempts to find some difference between normal and sickle-cell hemoglobin had failed. Just before leaving for England Pauling had hired a postdoctoral fellow, John Singer, to help. Singer was more experienced than Itano in the chemistry of large molecules, and he knew something about a new piece of protein-separation equipment that might help them.

By carefully comparing the behavior of the two hemoglobins in the new apparatus, Itano and Singer were able to show that, as Pauling had guessed, there was a measurable difference in the electrical behavior of molecules of normal hemoglobin versus the same substance from sickle-cell patients.

This was an astounding finding. A slight change in the electrical charge of a single type of protein out of the thousands in the body meant the difference between sickness and health. In some patients it meant the difference between life and death.

"Sickle Cell Anemia, a Molecular Disease," published in the fall of 1949 (with Pauling's name ahead of Itano's and Singer's), was a landmark paper. It not only traced human disease definitively and for the first time to a single molecule in the body, but went on to link this finding firmly to a genetic pattern.

People began talking about a second Nobel Prize for Pauling, this time in Physiology or Medicine, to reward this important insight. It was no wonder he paid little attention to the keratin bedspring he had sketched in London.

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Audio Clip  Audio: Itano, Singer and Wells' Work on Sickle Cell Anemia. November 1970. (2:18) Transcript and More Information

Video Clip  Video: Sickle Cell Anemia, a Molecular Disease. 1977. (2:02) Transcript and More Information

See Also: "Difference in Electrophoretic Behavior of Sickle Cell Hemoglobin and Normal Human Hemoglobin." April 27, 1949. 

Click images to enlarge 

Pastel drawing of sickled Hemoglobin cells, 1964.

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"Sickle Cell Anemia, A Molecular Disease." 1950.

"I think that we shall be able to get a more thorough understanding of the nature of disease in general by investigating the molecules that make up the human body, including the abnormal molecules, and that this understanding will permit...the problem of disease to be attacked in a more straightforward manner such that new methods of therapy will be developed."

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