This year we have turned our attention to the disease Paroxysmal Nocturnal Hemoglobinuria. This disease is an acquired disorder in which red cells and other blood elements become abnormally sensitive to the lytic action of complement. It is believed that this represents a clonal disorder in which an individual clone of cells in the bone marrow becomes disordered, proliferates and takes over a portion of the marrow, forming cells with abnormal membranes. Others have shown in the past several years that these cells are missing a complement regulatory protein termed """"""""decay accelerating factor"""""""" (DAF). Our preliminary experiments during the course of the last several years suggested to us that in fact bone marrow precursor cells which give rise to the cells which act as PNH cells do not have the PNH defect. This is a radical idea and represents an entirely new concept of the pathogenesis of PNH. To test the validity of this idea we have obtained bone marrow from patients with Paroxysmal Nocturnal Hemoglobinuria and use the fluorescent activated cell sorter with specific antibody to DAF to separate cells into precursors that have DAF and those that do not. The majority of the cells in the bone marrow in PNH patients are DAF negative--that is, abnormal cells. We find that all of the progeny that grow and, therefore, all of the cells that represent primitive stem cells are DAF positive. There are no stem cells in the DAF negative population. Moreover, direct test of the progeny of these DAF positive cells shows that many are DAF negative. The results indicate that the precursor cells in the bone marrow that give rise to PNH cells do not have the PNH defect. This represents a completely new concept of the disease.