Specificity in the Interaction of Sickle Cell 

 Hemoglobin Molecules 



Harvey A. Itano 



National Institute of Arthritis and Metabolic Diseases, National Institutes of 

 Health, Bethesda, Md. 



STUDIES OF THE PHYSICAL PROPERTIES of the humaii hemoglobins have 

 provided much information concerning how a specific molecular inter- 

 action in a living organism can cause a particular group of inherited 

 anemias. The normal hemoglobins of man are fetal (F), present in fetal life 

 and in early infancy, and adult (A). Electrophoretic studies have disclosed the 

 existence of a number of abnormal forms which are inherited modifications of 

 the adult hemoglobin (Pauling, et al., 1949; Itano, 1955). The adult form and 

 its modifications are probably determined by a series of allelic genes (Itano, 

 1953a), so that a person can have either one or two of these forms, depending 

 upon whether he is homozygous in one of the genes or heterozygous; he can 

 have no more than two since an individual can have only one pair of genes at 

 any allelic site. The production of hemoglobin F is under separate genetic 

 control, and this form may be present in addition to the adult forms, not only 

 during infancy but also in later life in certain chronic anemias (Singer, et al., 

 1951; Itano, 1953b). 



Hemoglobin S, the hemoglobin of sickle cell anemia, has the striking property, 

 not possessed by the other forms, of aggregating and of becoming very insoluble 

 when deoxygenated (Harris, 1950; Perutz and ]\Iitchison, 1950). The specific 

 structural abnormality which causes hemoglobin S to aggregate, and to do so 

 only when deoxygenated, is not known. The tendency to aggregate cannot be 

 correlated with any of the other known properties of the molecule. In spite of 

 an abnormal net charge (Pauling et al., 1949), its amino acid composition 

 (Schroeder, et al., 1950; Huisman, et al., 1955) and antigenic behavior (Good- 

 man and Campbell, 1953; Chernoff, 1953) are very similar to those of hemo- 

 globin A. Its solubility when oxygenated is the same as that of oxyhemoglobin 

 A (Perutz and Mitchison, 1950), and its oxygen equilibrium behavior is normal, 

 even in the presence of aggregates of its deoxygenated form (Allen and Wyman, 

 1954). The second abnormal hemoglobin, hemoglobin C, is more abnormal in 

 electrophoretic mobility (Itano and Neel, 1950) and amino acid composition 

 than is hemoglobin S (Huisman, et al., 1955); but its solubility when deoxygen- 

 ated is closer to that of A (Itano, 1953c). Hemoglobin D has the electrophoretic 



166 



