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Sickle Cell Anemia, a Molecular Disease
"Sickle Cell Anemia, a Molecular Disease" is a 1949 scientific paper by Linus Pauling, Harvey A. Itano, Seymour J. Singer and Ibert C. Wells that established sickle-cell anemia as a genetic disease in which affected individuals have a different form of the metalloprotein hemoglobin in their blood. The paper, published in the November 25, 1949 issue of ''Science'', reports a difference in electrophoretic mobility between hemoglobin from healthy individuals and those with sickle-cell anemia, with those with sickle cell trait having a mixture of the two types. The paper suggests that the difference in electrophoretic mobility is probably due to a different number of ionizable amino acid residues in the protein portion of hemoglobin (which was confirmed in 1956 by Vernon Ingram), and that this change in molecular structure is responsible for the sickling process. It also reports the genetic basis for the disease, consistent with the simultaneous genealogical study by James V. Neel: those with sickle-cell anemia are homozygous for the disease gene, while heterozygous individuals exhibit the usually asymptomatic condition of sickle cell trait.
The paper introduced the concept of a "molecular disease", and is considered a major impetus to the development of molecular medicine. The paper helped establish that genes control not just the presence or absence of enzymes (as genetics had shown in the early 1940s) but also the specific structure of protein molecules. It was also an important triumph in the efforts of Pauling and others to apply the instruments and methods of the physical sciences to biology, and Pauling used it promote such research and attract funding.〔Kay, Lily E. ''The Molecular Vision of Life: Catltech, The Rockefeller Foundation, and the Rise of the New Biology''. New York: Oxford University Press, 1993. pp. 256–260.〕
==Caltech work==
Linus Pauling was a prominent physical chemist at the California Institute of Technology (a main focal point of Warren Weaver's efforts to promote what he called "molecular biology" through Rockefeller Foundation grants). In the mid-1930s, Pauling turned his attention to the physical and chemical nature of hemoglobin. In 1946, he set graduate student Harvey Itano (who had been previously trained as a physician) the task of finding differences in hemoglobin that might explain sickle cell disease. After failing to find any differences in size, weight, or acid-base titration (despite the advanced instruments available at Caltech), Itano found that oxygen could inhibit the sickling process while various reducing agents could speed it up; this was the basis of Pauling and Itano's first publication on the disease. Itano also found that the globin portion of sickle cell hemoglobin had a barely detectable difference in electrical charge.〔Hager Thomas. ''Force of Nature: The Life of Linus Pauling''. New York: Simon & Schuster, 1995. pp. 333–334.〕
In order to measure this difference precisely, Pauling assigned graduate student John Singer to work with Itano and another medical researcher, Ibert C. Wells, on using a "Tiselius Apparatus" to perform free-boundary electrophoresis, before leaving in early 1948 for a guest lectureship in England. Using the electrophoresis technique, Pauling's researchers were able to estimate that molecules of sickle-cell hemoglobin had about three more positive charges than normal hemoglobin.〔〔 They also estimated that blood from those with sickle cell trait was a mixture of 60 percent normal hemoglobin and 40 percent sickle-cell hemoglobin.〔 Near the end of the project, they learned of parallel results by geneticist James V. Neel, who demonstrated the inheritance pattern of the disease by traditional genetic methods; both Neel's work and that of Pauling's group were published in the same issue of ''Science''.〔
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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