Editorial: Sickle cell disease.

Although sickle cell disease was designated by a number of onomatopoetic native names in Africa for centuries ( 1 ), it was clearly described as a distinct hematological and clinical entity in the United States in 1910 (2). During the next three decades, a considerable body of descriptive, clinical, and genetic data was slowly accumulated; but progress accelerated after protein chemists such as Pauling and Itano and later Ingraam, indentified the molecular defect in sickle hemoglobin. The far-reaching significance of the delineation of the basic molecular defect in sickle cell anemia can hardly be overstated, for it has been decisive in the delineation of the mechanisms of gene action and a deciphering of the genetic code. It is now possible to describe a fairly precise sequence from the substitution of base pairs in DNA which ultimately results in the clinical symptomatology of the patient. From the point of view of biochemical genetics and protein chemistry, sickle cell disease is one of the best understood of human diseases. Unfortunately, this sophisticated information has made little impact on the management of the patient with sickle cell anemia. A substantial number of patients die in their first five years, and survival beyond the third decade is unusual. In addition, recurrent painful or vasocclusive crises, for which there is no specific therapy, plague the life of the sickle cell patient. Treatment of sickle cell anemia has progressed very little during the past 25 years. Symptomatic management including hydration, analgesia and blood transfusions remain the mainstays of therapy. More specific treatment has been elusive, but recent events in this area are of considerable interest. Studies of molecular aspects of the sickling phenomenon have indicated the importance of intramolecular hydrophobic bonds (3). Hydrophobic bonds can be disrupted by concentrated solutions of urea, and this fact led Dr. Robert Nalbandian to believe that urea might be a therapeutic modality. He infused concentrated solutions of urea into several patients experiencing painful sickle cell crises. Apparent clinical improvement was noted following these infusions. Objections to this therapy were immediately raised. First, in order to disrupt hydrophobic bonds, the concentration of urea must approach 1 M. In a patient this is equivalent to a blood urea nitrogen of over 5000 mg/100 ml! Blood levels accomplished during urea infusions were less than a tenth of this concentration. Clinicians experienced in the management of sickle cell disease have long recognized the extreme variability of the painful sickle cell crisis. This makes controlled observations crucial before judging efficacy of any form of therapy. The history of sickle cell disease is studded with scores of therapies which were originally described as being of great benefit, but when suitable controlled studies were performed, they were found to be of no consistent value.