HomeResearchIntramural ResearchResearch Branches at NHGRIGenetics and Molecular Biology Branch Bodine Lab

David M. Bodine, Ph.D. Chief & Senior Investigator Genetics and Molecular Biology Branch Head Hematopoiesis Section B.A. Colby College, Waterville, ME, 1976 Ph.D. The Jackson Laboratory/University of Maine, 1984 (301) 402-0902 (301) 402-4929 tedyaz@nhgri.nih.gov Building 49, Room 4A04 49 Convent Dr, MSC 4442 Bethesda, MD 20892-4442 Selected Publications

Dr. Bodine's laboratory investigates the genetics of pluripotent hematopoietic stem cells (PHSCs) to improve the effectiveness of bone marrow transplantation and to find better ways to use these unique cells for gene replacement therapy. A major limitation to bone marrow transplantation is the lack of availability of stem cells. His laboratory seeks to understand and control the self-renewal of PHSCs in order to amplify them, thereby improving stem cell transplantation and gene therapy techniques.

PHSCs are found mainly in bone marrow. These cells (and their progeny) proliferate extensively and differentiate into all the cell types of the peripheral blood, a process known as hematopoiesis. PHSCs also can self-renew without differentiating. These two properties allow clinicians to transplant a small number of PHSCs into a bone marrow recipient, where the PHSCs can replicate and completely reconstitute the recipient's blood and immune systems. Dr. Bodine's laboratory is investigating how PHSCs decide whether to differentiate or self-renew when they divide. To this end, he and his colleagues are generating complementary DNA (cDNA) libraries from hematopoietic stem cells and stem cells from other organs to find any differentially expressed genes. They also are investigating the roles of these genes in hematopoiesis with transgenic mouse models to find genes common to stem cells. Their efforts have led to the identification of a gene, HMGB3, which is expressed only in hematopoietic stem cells and is required to prevent PHSCs from differentiating into mature cells. In addition, when the researchers introduce a retrovirus containing HMGB3 cDNA into mouse bone marrow stem cells, the expression of the Hmgb3 protein inhibits both B cell and myeloid differentiation.

Dr. Bodine's laboratory also investigates the genetic causes of acquired and inherited blood disorders. His group has used transgenic mice to demostrate that point mutations in an insulator element of the human ankyrin locus can cause hereditary spherocytosis, a blood disorder characterized by severe anemia that requires frequent transfusions. A similar analysis of a second hereditary spherocytosis mutation has demonstrated where the RNA polymerase complex binds to the red cell ankyrin promoter. Ankyrin has two other promoters besides the one that is active in red blood cells. The Bodine laborabory is now conducting an analysis of the chromatin structure surrounding the three ankyrin promoters to define the sequences required to activate the red-cell-specific ankyrin promoter and to suppress the other two.

Finally, his group is working to perfect the use of PHSCs as a vehicle for gene therapy by identifying and testing novel retrovirus vectors for transferring human genes into these cells. They previously demonstrated that genes can be successfully inserted into mouse and primate PHSCs with retrovirus vectors and, through self-renewal and proliferation, the new genes were passed along to all the progeny of the transduced stem cell. Unfortunately, gene therapy trials with this approach were hampered by the instability of the vectors and the variable expression of gene products in PHSCs. For a treatment approach to be valuable, the transduced gene must be expressed at the appropriate level in the correct cell type. Dr. Bodine's laboratory, therefore, is comparing the relative transduction efficiency of these new retrovirus vectors with conventional retrovirus vectors. In a related study, his group substituted the erythrocyte ankyrin promoter for globin promoters in the retrovirus vectors, and they found that these vectors are stable and produce near therapeutic levels of globin RNA and protein in animal models.

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Last Reviewed: October 14, 2008