Sickle Cell Anemia, a Molecular Disease
"Sickle Cell Anemia, a Molecular Disease" is a 1949 scientific paper by
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.[2] 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.[3]
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.[4]
To measure this electrical difference precisely, Pauling assigned graduate student John Singer to work with Itano and another medical researcher, Ibert C. Wells, before Pauling left in early 1948 for a guest lectureship in England. Using a "Tiselius Apparatus" to perform
Follow-up work
Following the 1949 paper, Itano left the Pauling laboratory to work with Neel; in the following years Itano and Neel used electrophoresis to identify a number of other human hemoglobin variants, including some associated with other diseases. At Caltech, a comparison of the amino acid content of normal and sickle cell hemoglobins showed that there were several differences in chemical makeup, but did not explain the difference in electric charge that made electrophoretic separation possible. The cause of this difference was pinpointed in 1956 and 1957, when Vernon Ingram used protein fingerprinting (a combination of electrophoresis and chromatography) to show that the key difference between normal hemoglobins and sickle cell hemoglobins was a single difference in one chain of the protein: a glutamic acid residue on the normal hemoglobin in place of a valine residue on the sickle cell hemoglobin.[5]
The molecular disease concept put forward in the 1949 paper also became the basis for Linus Pauling's view of evolution. In the 1960s, by which time it had been shown that sickle cell trait
Notes and references
- ^ PMID 15395398.
- S2CID 90232736. Retrieved 2008-12-30.
- ^ a b c 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.
- ^ a b Hager Thomas. Force of Nature: The Life of Linus Pauling. New York: Simon & Schuster, 1995. pp. 333–334.
- S2CID 4167855.
- ^ Evolution and Molecular Disease, accessed January 5, 2009.
- ^ Eugenics for Alleviating Human Suffering, accessed January 5, 2009.
External links
- It's in the Blood! A Documentary History of Linus Pauling, Hemoglobin and Sickle Cell Anemia — Oregon State University Library
- Sickle Cell Anemia, a Molecular Disease — reproduction of the paper