Three Scientists to Share 2007 Nobel Prize in Physiology or Medicine

Abstract

Three scientists—2 Americans and 1 from the United Kingdom—will share this year’s Nobel Prize in Physiology or Medicine. The new Laureates—Dr Mario R. Capecchi, Sir Martin J. Evans, and Dr Oliver Smithies—made a series of groundbreaking discoveries concerning embryonic stem (ES) cells and DNA recombination in mammals. Their discoveries in homologous recombination led to the creation of an immensely powerful technology referred to as gene targeting in mice, a technology that is now applied to virtually all areas of biomedicine, from basic research to the development of new therapies. Dr Capecchi is the Howard Hughes Medical Institute Investigator and Distinguished Professor of Human Genetics and Biology at the University of Utah, Salt Lake City, Utah. Born in 1937 in Italy, he received a PhD in Biophysics in 1967 from Harvard University. Sir Evans is the Director of the School of Biosciences and Professor of Mammalian Genetics, Cardiff University, United Kingdom. Born in 1941 in Great Britain, he received his PhD in Anatomy and Embryology in 1969 from University College in London. Dr Smithies, an American citizen, was born in Great Britain in 1925. He is the Excellence Professor of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill. He received a PhD in Biochemistry in 1951 from Oxford University. Drs Capecchi and Smithies both had the vision that homologous recombination could be used to specifically modify genes in mammalian cells. Capecchi demonstrated that homologous recombination could take place between introduced DNA and the chromosomes in mammalian cells, and showed that defective genes could actually be repaired by such homologous recombination. Smithies initially tried to repair mutated genes in human cells. He hypothesized that certain inherited blood diseases could be treated by correcting the disease-causing mutations in bone marrow stem cells. In these attempts, Smithies discovered that endogenous genes could be targeted irrespective of their activity, suggesting that all genes may be accessible to modification by homologous recombination. However, the cell types initially studied by Capecchi and Smithies could not be used to create gene-targeted animals. This would require another type of cell, one that could give rise to germ cells. Only then could the DNA modifications be inherited. Martin Evans had worked with mouse embryonal carcinoma (EC) cells, which, although originating in tumors, could give rise to almost any cell type. He had the vision to use EC cells as vehicles to introduce genetic material into the mouse germ line. His attempts were initially unsuccessful because EC cells carried abnormal chromosomes and could not therefore contribute to germ cell formation. Looking for alternatives, Evans discovered that chromosomally normal cell cultures could be established directly from early mouse embryos. These cells are now referred to as embryonic stem cells. The next step was to show that ES cells could contribute to the germ line. Embryos from 1 mouse strain were injected with ES cells isolated from another mouse strain. These mosaic embryos (composed of cells from both strains) were then carried to term by surrogate mothers. The mosaic offspring was subsequently mated, and the presence of ES cell–derived genes were detected in the pups. These genes would now be inherited according to Mendelian distribution. Evans then began to modify the ES cells genetically and for this purpose chose retroviruses, which integrate their genes into the chromosomes. He demonstrated transfer of such retroviral DNA from ES cells, through mosaic mice, into the mouse germ line. By 1986, all the pieces were at hand to begin generating the first gene-targeted ES cells. Capecchi and Smithies had demonstrated that genes could be targeted by homologous recombination in cultured cells, and Evans had contributed the necessary vehicle to the mouse germ line—the ES cells. The next step was to combine the two. For their initial experiments, both Smithies and Capecchi chose a gene (hprt) that was easily identified. This gene is involved in the rare inherited human disease Lesch–Nyhan syndrome. Capecchi refined the strategies for targeting genes and developed a new method that could be generally applied. The first reports in which homologous recombination in ES cells was used to generate gene-targeted mice were published in 1989. Since then, the number of reported knockout mouse strains has risen exponentially. Gene targeting has developed into a highly versatile technology. It is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal. The Laureates received their award in Stockholm on December 10, 2007.