Capecchi, Smithies and Evans share the Nobel

Researchers are honored for developing genetic techniques for making knockout mice

Oct 5, 2007
Edyta Zielinska
Mario Capecchi of the University of Utah, Sir Martin Evans of Cardiff University in the UK and Oliver Smithies of University of North Carolina, Chapel Hill, will share this year's Nobel Prize in Physiology or Medicine for their work in gene manipulation that let to the development of knockout mice. Learning this morning that he had received the award filled him with a "sense of peace," Smithies told The Scientist. "It was a nice finale to a life's work."Since the first knockout mouse publications in 1989, the technique has become ubiquitous in mammalian biology, allowing researchers to investigate gene function and to create animal models for diseases."People have been expecting this since the 1990s," said Jeremy M. Berg, director of The National Institute of General Medical Sciences. "The surprise is that they hadn't won it before."The trio started from different lines of research, but in the 1980s, their work began to converge. Evans' research used a cell line derived from embryonic carcinoma that could differentiate into cancer tissue. In a 1975 publication, he demonstrated that the embryonic carcinoma cells could be inserted into embryos and the embryos could then be carried to term by a surrogate mother.Working separately, Capecchi and Smithies each advanced techniques for inserting specific DNA fragments into mammalian cells. Capecchi improved on a homologous recombination technique developed by Richard Axel by using a glass pipette to inject DNA directly into the nucleus in 1980. Others quickly recognized the potential of combining this method with Evans' work enabling mouse embryos to be transformed with foreign genetic material. Meanwhile, Smithies, who had a medical background, was investigating homologous recombination as a tool to repair genes responsible for hereditary diseases. He focused on using the technique to correct a deficiency in the enzyme HPRT (hypoxanthine-guanine phosphoribosyltransferase), responsible for Lesch-Nyhan Syndrome, in a mouse model. Smithies contacted Evans to obtain a sample of embryonic stem cells that he could manipulate for the experiment. "[Evans] brought a sample of his embryonic stem cells in his own pocket," said Smithies. "It was science in its best form." Smithies then took defective embryonic stem cells with the HPRT deletion and injected the corrected DNA on a plasmid. To select for correctly transformed cells, he used a medium in which only those cells with a functioning HPRT gene could survive.Capecchi's lab, which had also begun working with HPRT, developed a different selection strategy. In his 1987 paper demonstrating targeted mutagenesis in mouse embryo cells, which has been cited more than 1200 times, he wrote that the method "will provide the means for generating mice of any desired genotype." "Capecchi and Smithies developed clever tricks," to isolate cells that had properly recombined, said Berg.In 1989, several labs used the methods developed by Evans, Smithies and Capecchi to create mice in which genes for proteins had been knocked out. Two years later, Smithies used the technique to create the first mouse model of a human disease by knocking out the gene responsible for causing cystic fibrosis in humans.The trio received the Lasker Award in 2001 for their work. "The concepts developed in Martin's, Mario's and Oliver's laboratories allow researchers worldwide to examine gene activity in mice and other organisms," said Allan Bradley, Director of the Wellcome Trust Sanger Institute in Cambridge, UK, who worked in Evans' lab for many years. Edyta Zielinska mail@the-scientist.comLinks within this article:Mario R. Capecchi http://capecchi.genetics.utah.edu/contact.htmlMartin J. Evans http://www.cardiff.ac.uk/biosi/research/genetics/staff/evans.htmlOliver Smithies http://www.pathology.unc.edu/common/smithies.htmV.E Papaioannou et al., "Participation of cultured teratocarcinoma cells in mouse embryogenesis," J Embryol Exp Morphol, 44:93-104, 1978 http://www.the-scientist.com/pubmed/528871C. Bahls, "Mario R. Capecchi," The Scientist, March, 2004 http://www.the-scientist.com/article/display/14469/K. Morgan, "Eighty ears in the making," The Scientist, April 1 2007 http://www.the-scientist.com/article/display/53011/M.R. Capecchi, "High efficiency transformation by direct microinjection of DNA into cultured mammalian cells," Cell, 22:479-88, 1980. http://www.the-scientist.com/pubmed/6256082J.W. Gordon et al., "Genetic transformation of mouse embryos by microinjection of purified DNA," PNAS, 77:7380-4, 1980. http://www.the-scientist.com/pubmed/6261253Lesch-Nyhan Syndrome http://www.ninds.nih.gov/disorders/lesch_nyhan/lesch_nyhan.htmT Doetschman et al., "Targetted correction of a mutant HPRT gene in mouse embryonic stem cells," Nature, 330:576-8, 1987. http://www.the-scientist.com/pubmed/3683574KR Thomas and MR Capecchi, "Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells," Cell, 51:503-12, 1987 http://www.the-scientist.com/pubmed/2822260D. Bruce, " 2001 Lasker Award Winners announced," The Scientist, September 17, 2001 http://www.the-scientist.com/article/display/19901/