168 



HARVEY A. ITANO 



and normal adult hemoglobin, and hemoglobins S and A are present (Pauling, 

 et al., 1949). Apparently the gene-controlled mechanism for the synthesis of 

 hemoglobin A is more efficient than that for S; sickle cell trait blood invariably 

 contains more hemoglobin A than S (Itano, 1953a). 



Sickle cell hemoglobin C disease and sickle cell hemoglobin D disease are 

 genetic analogues of sickle cell trait in which the gene for an abnormal non- 

 sickling hemoglobin replaces the normal allele. The existence of these variants 

 of sickle cell disease was brought to light as a result of electrophoretic and 

 solubility studies of hemoglobin in cases which did not fit the classical descrip- 

 tions of sickle cell anemia and trait (Itano and Neel, 1950; Itano, 1951). As 

 shown by the solubility studies, to be described, the hemoglobin mixtures in 

 these two diseases form more stable aggregates than do the A-S mixture of 

 sickle cell trait. Sickling is of the filamentous type, but the cells show less intra- 

 vascular sickling than those of the anemia (Kaplan, et al., 1951; Sturgeon, et 

 al., 1955). In sickle cell thalassemia disease one sickle cell gene and one thalas- 

 semia gene, which blocks partially or completely the synthesis of normal 

 hemoglobin, are present (Sturgeon, et al., 1952). The red cells produce more 

 hemoglobin S than A, and the net effect is to increase the ability of the cells 

 to sickle. Hematologic observations which reflect differences in sickling tend- 

 ency have been summarized in Table I. Although the results are given in 

 qualitative terms, the differences are usually quite evident to the trained ob- 

 server. 



Recent observations at high altitudes have illustrated dramatically the effect 

 of oxygen tension and of hemoglobin composition on sickling (Smith and Con- 

 ley, 1955). The pathological effects of sickle cell disease can be ascribed to the 

 presence of sickled cells in circulating blood. As an apparent effect of their 



TABLE I 



Relationship of the sickling properties of red blood cells to their hemoglobin 



content and solubilities 



1 These figures are for samples which correspond to the solubilities shown. Percentages of 

 Hb S falling a few per cent outside these ranges have been reported. 



2 The solubilities in grams per liter of amorphous ferrohemoglobin were determined in 2.24 

 molar phosphate buffer at 25°C. (Itano, 1953c). 



