In sickle cell disease pathogenesis and crises arise as a result of the polymerization and gelation of deoxyhemoglobin S into long fibers that distort and rigidify red cells and inhibit or prevent their passage through the microvasculature. Clinical consequences depend on the polymerization kinetics and are highly mutable when small changes in conditions produce large changes in kinetic rates. We suggest that the mutability of rheological properties such as viscosity, elasticity and solid-like behavior may also be determining factors in pathogenesis. Because of these relations between physical chemistry and clinical disease we plan to study (a) the kinetics of polymerization and its changes with conditions which may change within the red cell, (b) rheological properties of hemoglobin S gels, (c) the effects of shear, which can occur within red cells, in accelerating kinetics greatly and on rheology, and (d) the structural bases of each of these phenomena. In respect to structure, we will examine the distribution of fiber lengths and other properties and also fiber alignment and the existence and number of domains. Measurement of microheterogeneity and fiber length distributions, previously employed for other rod-like polymers but not for hemoglobin S, offers evidence on the kinetic mechanism of fiber assembly which is complementary to that obtained from the progress of average properties during gelation. Fiber lengths are also critical in the development of rheological properties and hence may have direct bearing on clinical events. The methods to be used include electron microscopic measurement of fiber length distributions and other properties, viscometry and related rheological techniques, light scattering and polarizing microscopy for observation of reaction progress and the latter for study of domains and other higher order structures as well. By relating structural and rheological observations (as functions of time) and kinetics we hope to gain a fuller understanding of mechanisms of rheology and kinetic assembly of fibers and of the structural and physical chemical bases of disease.