Background

With the benefit of hindsight, we can pick out observations that, if properly interpreted, would have suggested the genetic relationship between sickle-cell anemia and sickle-cell trait, and a functional relationship between hemoglobin and the sickle cell trait. Diggs et al. (1), for example, noted in 1933 that the proportion of sickled erythrocytes was greater in people with anemia than in people with the trait. They also noted that sickling was time-dependent under a sealed cover slip. From those observations one might have deduced a genetic relationship and the idea that oxygen consumption (equate with hemoglobin deoxygenation) promoted sickling. However, at that time the idea of "one gene, one protein" had not been conceptualized and biochemists knew very little about the chemical nature of proteins (2,3).

Linus Pauling (4), perhaps the most impressive scientist of the 20th century, made the connection, formulated a hypothesis, tested it, and described the results in the article you are about to read. Why would Pauling, a chemist who received two unshared Nobel Prizes (Chemistry and Peace), be the person to make the discovery of hemoglobin S, arguably a discovery worthy of a Nobel Prize in Medicine?

Although Pauling gained stature for his monumental work on the nature of chemical bonds, he had an interest in the chemistry of hemoglobin. In the 1930's he proposed a new structural and mathematical model for cooperative binding of oxygen by hemoglobin (5). He demonstrated that the spectral changes in hemoglobin, attributed to oxidation and reduction of hemoglobin by Stokes (6), were due to the change in electronic spin states of heme iron when liganded to molecular oxygen (7). In 1951 on theoretical grounds, he proposed the a-helix (8), a regular structure later found to represent 70% of the polypeptide chain in hemoglobin. Given Pauling's familiarity with hemoglobin, his deduction that the sickling of red blood cells which occurred at low oxygen tension must be due to a hemoglobin with distinct properties seems almost obvious in retrospect. What is surprising is that no one before Pauling made the same deduction. Shortly before his death in 1994, Pauling described the flash of insight which came to him almost half a century before (9).

Given the prominence of Linus Pauling, his life is well documented by several books (10-13). The Pauling library at Oregon State University maintains an extensive web-site on Pauling.  Pauling kept detailed notebooks that should be an example for all scientists to follow. All of Pauling's 46 bound notebooks are digitized and available on the Internet from Oregon State University, Pauling's alma mater. They are cataloged and referenced by topic. For example, if you would like to read the thoughts, experiments, and calculations Pauling did in preparation of his article with Coryell on the magnetic suseptability of oxy- and deoxyhemoglobin in 1936 (7), they are in Notebook No. 13 (follow links to hemoglobin). You can see his calculations for the redox potentials of hemoglobin on May 11, 1935. In addition, there is an extensive web-site devoted to Pauling's facination and studies with hemoglobin.