Pathways of innovation: a history of the first effective treatment for sickle cell anemia.

The promise of molecular medicine is the prevention and treatment of illness. Understanding the mechanism of the disease should allow one to "fix" it. For sickle cell anemia, however, knowledge of the biochemical basis of the disease was only partly responsible for finding a means of treating the disease--of equal value were hypotheses and conclusions generated from clinical observations. This article describes the research path that led to the first effective treatment for sickle cell anemia, hydroxy-urea. Rather than exemplifying the "bench-to-bedside" model commonly used to describe the process of therapeutic innovation, this history of this research reveals that the critical advances for the development of treatment came not from basic research, but instead from clinical and patient-oriented research. Given that the linear approach is the prevailing paradigm of therapeutic innovation, this history is important because it indicates the inadequacy of this approach for a relatively straightforward single-gene mutation disease such as sickle cell anemia and suggests the need for multiple models of innovation for more complex diseases. Thus, this article questions the expectations of molecular medicine and the dominance of a linear model of therapeutic innovation, which often excludes or subordinates other models of developing treatments.

Sickle cell anemia and antisickling agents then and now.

Sickle cell anemia is a genetic blood disorder arising from a point mutation in the beta-globin gene that leads to the replacement of glutamic acid residue by valine at the sixth position of the beta--chain of hemoglobin. At low oxygen tension, the mutant hemoglobin, sickle hemoglobin, polymerizes inside the red blood cells into a gel or further into fibers leading to a drastic decrease in the red cell deformability. As a result, micro-vascular occlusion arises which may lead to serious, sometimes fatal, crises. The present article reviews the historical, genetic, molecular, cellular, and clinical aspects of the disease. A review for the development and design of drugs to treat sickle cell anemia is presented. Anti-sickling agents are classified, based on the target to be modified, into three classes: the gene, the sickle hemoglobin molecule, and the red cell membrane modifiers. In spite of the full understanding of the pathology, physiology, and the molecular nature of the disease, and the development of large number of antisickling agents, a cure for sickle cell anemia still is unavailable. Strategies to treat sickle cell anemia since the early times of the disease state discovery in 1910, has focussed mainly on prophylactic measures to alleviate the painful crises. The article addresses clinical approaches used then and now to treat the disease, and the rationale of their use. Currently in clinical practice, hydroxyurea is the most commonly used agent to treat the disease, and it has been recently approved by the united states Food and Drug Administration as a drug for that purpose.