History and Geography

Sickle-cell anemia has been traced back to at least 1670, where it was noted to be present in the Krobo tribe in Ghana. This disorder was first described clinically by James B. Herrick, a Chicago physician, in 1910. During the 10 years following Herrick's report, three cases of sickle-cell anemia were reported. Thirteen years later, J. G. Huck reported a series of 14 patients and first noted the reversibility of sickling. In 1939 J. Bibb and L. W. Diggs described irreversibly sickled cells, and in 1946 M. Sherman demonstrated that hemoglobin S has an ordered structure. This finding encouraged Linus Pauling to investigate the physical chemistry of hemoglobin S by electrophoresis. On the basis of his findings he reasoned that the genetic basis of sickling was due to a single gene. V. M. Ingram, using peptide mapping techniques, then demonstrated that the condition resulted from a single amino acid substitution of valine for glutamic acid. M. Murayama noted that this change resulted in the loss of two negative charges and postulated that noncovalent interactions took place, resulting in hemoglobin stacking. In 1949 A. B. Raper noted the high incidence of sickle-cell trait in areas endemic for malaria and suggested that the trait protected against infestation. But it was not until 1954 that geneticist A. C. Allison correlated sickle trait with regions in which falciparum malaria was or had been endemic.

Further analysis of this observation showed that this gene change was the result of a genetic principle known as balanced polymorphism. Generally a gene such as the sickle-cell gene, which results in severe morbidity and mortality, dies out in a population unless certain conditions result in a more favorable survival. Such is the case with the sickle-cell gene. Africa and the Mediterranean are areas endemic for the parasite Plasmodium falciparum, which causes a malignant form of malaria. But when persons with sickle-cell hemoglobin are infected with malaria, the infected cells tend to sickle and are selectively destroyed by the body's immune system. Therefore, the sickle-cell gene promotes survival in persons infected with a disease that is potentially fatal and, paradoxically, prolongs survival. In parts of the world such as the United States where P. falciparum is no longer endemic, the sickle-cell gene becomes the sole determinant of morbidity and does not prolong life. This explains why the frequency of the sickle-cell gene has decreased in much of the Americas.

Georges C. Benjamin

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