Sickle Cell Anemia, A Molecular Disease - Caltech Work

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.

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.