Thomas Ryan, Ph.D.
|McCallum Basic Health Sciences Building
1918 University Blvd
Birmingham, AL 35294-0005
Lab Research Focus: Stem Cell Therapies in Animal Models of Human Disease
The research in our laboratory is focused upon understanding basic mechanisms of gene regulation in order to develop and subsequently cure animal models of human disease. Knowledge gained from our studies of the high-level, tissue-specific, and temporally regulated expression of human globin genes in transgenic mice have enabled the generation of mouse models of sickle cell disease and beta thalassemia that faithfully mimic and reproduce most if not all of the pathology of the disorders.
Embryonic stem (ES) cells have multiple qualities that make them invaluable for the production of genetically modified mice. These same characteristics also make them an ideal tool for future cell based therapies. Namely, ES cells can be propagated in a pluripotent state indefinitely, genetically modified site-specifically by homologous recombination, clonally isolated, expanded to great numbers in culture, and directed to differentiate in vitro to numerous cell types.
We are developing ES cell based therapies to model the correction and cure of inherited genetic disease utilizing our mouse models of beta thalassemia and sickle cell disease. ES cells derived from somatic cells of diseased mice are corrected by homologous recombination and differentiated in vitro to hematopoietic stem cells for transplantation back into the diseased animals. The long-term goals of this project are the development of therapeutic methods that are efficient, reproducible, safe, and translatable to human therapy. Consequently, the laboratory is also modeling some of these methods in one of the federally approved human ES cell lines (WA01).
We have recently initiated a mutagenesis screen in mice to identify genetic modifiers of sickle cell disease. This phenotype driven approach utilizes ES cells derived from our knock-out transgenic and knock-in animal models of sickle cell disease. Sickle ES cells are chemically mutated with N-ethyl-N-nitrosourea (ENU), subcloned into mutant cell lines, and cryopreserved. After thawing, sickle mice are produced from the mutant ES cell lines and examined for variation in their disease severity. Additionally, mutant sickle ES cell lines harboring mutant genes of interest are identified by screening DNA purified from our mutant ES cell library. This prescreening for mutations allows the production of sickle mice for study that have known mutations in genes of interest.
Thomas M. Ryan (b. 1956) received B.A. degrees in Biology and Chemistry from Humboldt State University (Arcata, CA, 1982). Dr. Ryan received his Ph.D. in Microbiology in 1990 from the University of Alabama at Birmingham for his studies on human globin gene expression, synthesis, and switching in transgenic mice. These studies defined the functional importance of regulatory sequences in the locus control region of the human beta globin locus. Linkage of these sequences to the human alpha, gamma, and beta globin genes enabled the production of the first transgenic animals that synthesized functional human hemoglobin and the first demonstration of human fetal to adult hemoglobin switching. Post-doctoral research (1991-96) in the Biochemistry Department at the University of Alabama at Birmingham in the laboratory of Tim Townes led to the development of the first animal models of beta thalassemia and sickle cell disease. Continuing these studies in the Biochemistry and Molecular Genetics Department as a Research Assistant Professor (1997-2003), Dr. Ryan produced the first knockout-transgenic animal model of sickle cell disease. Dr. Ryan became an Assistant Professor in Biochemistry and Molecular Genetics in 2003 and the Graduate Program Director in 2004.