SPECIFICITY IX SICKLE CELL HEMOGLOBIN MOLECULES 171 



with 40 per cent hemoglobin S is less soluble than the corresponding A-S mix- 

 ture. The last result is consistent with observations that the cells of sickle cell 

 hemoglobin disease sickle more readily than those of sickle cell trait and that 

 S-C mixtures gel at a lower total concentration than A-S mixtures containing 

 the same percentage of hemoglobin S. 



The composition of the hemoglobin mixture in sickle cell hemoglobin D 

 disease cannot be determined since hemoglobins S and D have the same electro- 

 phoretic mobility. The hemoglobin in this disease has a total solubility in 

 phosphate buffer that is less than that in sickle cell hemoglobin C disease and 

 greater than that in sickle cell anemia. Hemoglobin D has not been obtained 

 in the homogeneous state; naturally occurring mixtures of hemoglobins A and 

 D have nearly the same solubility as hemoglobin A alone. Thus, there is in- 

 sufficient information to decide whether the relatively low solubility of S-D 

 mixtures is due to a stabilizing interaction in the aggregated phase or to the 

 presence of a high percentage of hemoglobin S. 



Briefly summarized, the basic factor in the production of sickle cell disease 

 is the presence of an abnormal hemoglobin molecule which aggregates when 

 deoxygenated and produces a rigid, distorted cell. The sickled cell is more 

 susceptible to destruction and is capable of causing tissue damage by blocking 

 blood vessels. The effectiveness of the abnormal molecule in causing disease is 

 modified by several factors. When an individual has only genes for hemoglobin 

 S, a severe anemia called sickle cell anemia occurs. When genes for hemoglobins 

 A and S are present, the resulting hemoglobin mixture always contains more 

 A than S, and sickling is inhibited to such an extent that no anemia results. 

 If, in addition, a gene for thalassemia is present, hemoglobin A synthesis is 

 inhibited; consequently the red cells contain more S than A, and anemia occurs. 

 In sickle cell hemoglobin C disease the average proportion of hemoglobin S 

 is higher than the average in sickle cell trait; in addition, sickling is enhanced 

 by the increased stability of S-C aggregates. On the other hand, the aggregates 

 are not as stable as those of hemoglobin S alone, and the sickling tendency and 

 anemia are less than in sickle cell anemia. 



In conclusion, I wish to point out that in order to simplify the discussion 

 and illustrate the basic factors which characterize the variants of sickle cell 

 disease, the average findings in each variant have been considered. As is evi- 

 dent from Table I, the proportion of hemoglobin S varies in each of these con- 

 ditions, and overlapping of values between different conditions occurs. Other 

 factors which determine the final effect on the individual, such as the ability 

 of his body to compensate for blood destruction by increasing blood formation, 

 have not been discussed. The factors involved in any human disease are so 

 numerous that we are indeed fortunate in having for study a group of condi- 

 tions in which the actual molecules responsible for the disease process can be 

 isolated in large quantities for controlled investigations. 



