The fundamental defect responsible for sickle-cell disease was recognized by Pauling and his co-workers' as a mutated hemoglobin. A single genetic change2 leads to the synthesis of hemoglobin S which contains a valine residue (instead of glutamic acid') at position 6 of the 13-chain.4-8 Hemoglobin S (Hb S) is thus composed of two normal a-chains and two modified 1-chains and may be written a! A 6v&l 8 In contrast to a normal red blood cell, a sickle cell loses the characteristic biconcave disk shape upon deoxygenation. The distortion in cell shape is caused by gel formation of the deoxyHb S in the cell. The phenomenon may also be observed in stroma-free deoxyHb S solutions.9 Certain hydrocarbons (methane, ethane, and propane) reverse gel formation from deoxyHb S solutions and unsickle sickled cells. On this basis, Murayama'0 proposes hydrophobic bonding as the driving force for the association process. Sickle-cell anemia is a serious disease, its sequellae arising from the abnormal behavior of the sickled cells in the circulation. Individuals afflicted with the disease (perhaps 40,000 in the United States alone) are subject to anemia, recurrent crises, and early death.I Occasional transfusions are the only generally useful supportive measure.12 Drastic techniques like chronic carbon monoxide poisoning,'3 raising the blood pH,'4-'6 oxidation of part of the Hb S to methemoglobin S,17 or supposed inhibition of glucose-6-phosphate dehydrogenase with phenothiazines'8' 19 have little or no clinical value. We have suggested that the introduction of glutamic acid residues into Hb S (a transformation) might diminish the ease of gel formation.a We now report that the solubility of Hb S (Itano2l) can be augmented in the predicted way. Glutamic acid residues can be introduced by reaction of the protein with the Ncarboxyanhydride of glutamic acid.22-24 With a sufficient number of added glutamic acid moieties, the solubility of the modified deoxyHb S exceeds that of deoxyHb A (normal hemoglobin). Methods and Results. -Bloods were drawn from outpatients at Bronx Municipal Hospital Center and Lincoln Hospital, Bronx, New York. All patients were SS and had not been transfused for at least five months. Hb S solutions were prepared from bloods by removal of plasma, washing cells with isotonic buffer, lysis with an equal volume of water, shaking after addition of half a volume of toluene, and separation of the Hb S solutions by centrifugation at 17,000 g. Concentrations were determined spectroscopically with a Cary model 14 spectrophotometer (em8 14,200). All Hb S solutions were maintained at 40 until use. The N-carboxyanhydride of glutamic acid, 1 (NCA 1), was generously supplied by Drs. Ralph Hirschmann and Robert Denkewalter of the Research Laboratories, Merck, Sharp and Dohme, Inc., Rahway, New Jersey. The NCA 1 was transported and stored at -80°. For utilization in the experiments, the stored material