PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Nobel Prize in Physiology or Medicine 2007: A closer look by Manu Lopus, PhD This years Nobel Prize in Physiology or Medicine went to Mario R. Capecchi, Martin J. Evans, and Oliver Smithies, "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells". The technology, commonly called as 'gene knockout', has revolutionized the life sciences research especially the fields of genetics, physiology, developmental biology, and pathology. Let us have a closer look at the contributions of these eminent scientists that won them the Prize. Martin Evans, along with Matt Kauffman, identified, isolated, and cultured embryonic stem cells from mouse blastocysts, and reported their findings in 1981, in an article titled 'Establishment in culture of pluripotential cells from mouse embryos' in Nature. Prior to this, Evans used a mouse strain called 129 Sv to establish the culture of embryonal carcinoma cells as this strain has high frequency of a kind of cancer called testicular teratoma. This embryonal carcinoma cells was shown to be capable of growing on a fibroblast feeder layer and is able to differentiate into different kinds of cell type including skin, nerve cells and also cardiac cells. However, the fact that these cells are cancerous in origin limited its application for clinical purposes. Evans overcame this challenge with the help of Kauffman, an embryologist, by combining cell culture and embryo manipulation. To quote them from the paper in Nature: "Their [i.e. ES cells] use as a vehicle for the transfer into the mouse genome of mutant alleles, either selected in cell culture or inserted into the cells via transformation with specific DNA fragments, has been presented as an attractive proposition. In many of these studies the use of pluripotential cells directly isolated from the embryos under study should have great advantages." In addition, Evans developed 'chimeric embryos' by introducing new genes into cultured embryonic stem cells, and this successful germline transmission was also published in Nature in an article titled 'Formation of germ-line chimeras from embryo-derived teratocarcinoma cell lines'. Capecchi and Smithies independently made it possible to produce specific alterations in endogenous genes through 'homologous recombination' (the discovery of which earned Joshua Lederberg Nobel Prize in 1958). It may be interesting to note that the proposals of specific gene targeting from Evans to the UK Medical Research Council, and Capecchi to the National Institute of Health, USA, were turned down - the latter for its extreme unlikelihood, and the former, for being 'over-ambitious'. Capecchi, however, pursued his idea and showed that such gene targeting is possible; he repaired a defective neomycin resistance gene (neor) by introducing a functional neor gene. Smithies demonstrated the 'Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination', as the title of his paper in Nature reads, in 1985. These findings provided experimental medicine necessary tools and sufficient insights for studying the hypotheses related to gene modifications for treatment of a variety of deceases including cystic fibrosis, heart diseases, and cancer. Nowadays, almost all research in experimental medicine as well as the drug discovery process makes use of gene targeted models. The use of 'predictable designer mutations' in mouse genes is continually providing deeper understanding on the genetic basis of development, diseases and often, potentials for cure. References Evans MJ, Kaufman, M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154-6. Bradley A, Evans, M., Kaufman, M.H., Robertson, E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature. 1984:255-6 Thomas KR, Deng C, Capecchi MR. "High-fidelity gene targeting in embryonic stem cells by using sequence replacement vectors". Mol Cell Biol. 1992, 12 (7): 2919-2923. Smithies O, Gregg, R. G., Boggs, S. S., Doralewski, M. A., Kucherlapati, R. S. Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature. 1985;317:230-4. www.nobelprize.org www.wikipedia.org Dr. Manu Lopus is an NIH post-doctoral fellow, investigating the mechanism and regulation of microtubule dynamics in neurodegenerative diseases and cancer at the department of Molecular, Cellular and Developmental Biology & the Neurosciences Research Institute, University of California, Santa Barbara. He may be reached at: manu.lopus@gmail.com ### << Previous Next >> [ View All Perspectives ] |
|