Pathology & Lab Medicine
Area of interest
Research is centered on two main themes: the correction of genes with mutant pathologies (gene therapy) and the construction of animal models of human genetic diseases to facilitate better studies of the resultant pathology, and the development of new modes of treatment (by gene therapy and/or by more classical approaches).
(1) He and his associates are carrying out a series of studies to assess the possible use of gene targetting (homologous recombination between exogenous DNA and a target chromosomal gene) as a means of correcting sickle cell anemia and the beta-globin thalassemias. Currently they are attempting to use gene targetting to correct the defect in a deletion type of beta-globin thalassemia. The cells chosen for study are mouse erythroleukemia cells that they have modified so that they carry a single copy of the human chromosome 11 from the thalassemia patient. The correcting DNA will be introduced into these cells by micro injection, and cells in which correction has been obtained will be identified by a polymerase chain reaction protocol designed to amplify only DNA from a corrected beta-globin gene. The expression of the corrected gene will be studied in the erythroleukemic cells. Comparable experiments will be carried out with cells that contain a sickle cell beta-globin gene.
(2) An extensive series of experiments is underway aimed at allowing the modification of genes in the germline of mice. Embryonic stem cells (from the inner cell mass of blastocysts) can now be propagated on feeder layers in tissue culture. Dr. Smithies' group has demonstrated that they can modify a specific gene in the ES cells either to restore its function (if it was defective) or to abolish its function (if it was normal). The resulting ES cells have been reintroduced into normal blastocysts and chimeric animals have been obtained. Some of these animals are chimeras in the gonads, and so transmit the modified gene to their progeny. Thus, they are in a position to obtain germline corrections of gene defects or to produce inherited models of genetic defects of their own choice. Currently they hope to use this technology to construct animal models of human sickle cell anemia, of atherosclerosis (in collaboration with Dr. Nobuyo Maeda), and of cystic fibrosis (in collaboration with Dr. Richard Boucher). They anticipate using the same techniques to study the effects of derangements of genes thought to be important in development. Dr. Smithies' group has inactivated the gene for the beta 2 microglobulin chain of class I MHC antigens, in order to assess the general significance of the class I antigens.
Awards and Honors
2005 March of Dimes Prize
2007 Thomas Hunt Morgan Medal for lifetime contributions in the field of genetics