There are important questions concerning sickle cell disease which cannot be explained by the well-known property of gel formation of deoxygenated sickle hemoglobin. The sequence of events leading to vaso-occlusive crises has not yet been defined. Complete details of the molecular mechanism of red cell sickling and a method for preventing sickle cell crises have not yet been established. In addition, specific drugs have not yet become available to prevent sickling. We have investigated these problems using various new biochemical and biophysical techniques including the turbidimetric method for studying the kinetics of the polymerization of sickle and non-sickle hemoglobins in concentrated phosphate buffer, a new method for the accurate measurement of the solubility of hemoglobin, the spin-label method, the mechanical shake method, and the use of an automatic apparatus to measure oxygen equilibrium curves of red cell suspensions. We have also measured the amount of denatured hemoglobin inside erythrocytes. Much progress has been made in studies on the mechanism of the gelation of sickle hemoglobin. Using this method, we found that non-sickle hemoglobins such as Hb A and Hb F polymerize in a manner similar to that of Hb S. We have also screened several potential anti-sickling agents that prevented red cell sickling in vitro. The molecular mechanism of the effect of these drugs was investigated thoroughly.
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