As a model system for investigating the feasibility of performing genetic engineering in humans, mice with hereditary anemias will be cured by the genetic manipulation of their pluripotential blood stem cells. The genetic defect causing the anemia will be overcome by the introduction (using DNA transformation techniques) of a normal wild type gene into the defective stem cells. The "genetically engineered" stem cells will be returned to the mouse mutants where they will multiply and replace the deficient stem cells. There are 17 inherited red blood cell dyscrasias in the mouse with defects including decreased production of alpha-globin chains, hemolysis of red blood cells, and inadequate proliferation of stem cells. In some of these mutants, a "cure" of the anemia has been effected by the introduction of blood stem cells from genetically wild type congenic mice. The normal stem cells appear to replicate more rapidly than the defective stem cells and thus have a selective advantage in the anemic host. Mutants which can be cured by these methods are excellent candidates for genetic engineering and will be used in the following experiment. Defective stem cells from mice with a blood cell anomaly will be concentrated and exposed in vitro to wild type genomic DNA in the form of recombinant DNA, high molecular weight DNA, or chromosomes isolated from normal mice. The genetically manipulated stem cells resulting from this procedure will be reinjected into the mouse mutants and the normal transformants with a selective advantage may be expanded in the host. The expression and maintenance of the transferred genes will he monitored in the differentiated red blood cell progeny of the transformed stem cells. Expression will be defined as the synthesis of a specific product or an overall improvement or cure of a mutational defect in the recipient. Maintenance will be defined as the continued expression of the trnasferred gene. In addition, dominant mutations for drug resistance will be induced in stem cells. Stem cells will be exposed to successfully higher doses of antineoplastic agents in vitro. Surviving stem cells will be injected into lethally irradiated mice and the mutagenized cells will be maintained under selective pressure. Drug resistant stem cells may provide another selective mechanism to improve the acceptance of transformants in drug sensitive mice.