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The award of the 2007 Nobel prize in physiology or medicine to three gene technologists has been widely applauded by biologists. They believe that the three scientists' achievements will play a major part in revealing the extent of genetic influences in human disease.
Rather less enthusiastic is the animal rights lobby. The work for which Mario Capecchi, Martin Evans, and Oliver Smithies were awarded the prize led to the development of the quaintly but aptly named “knockout mouse.” Now an essential tool of laboratory research into the role of genes, its creation reversed a fall in the number of experiments carried out each year on animals.
The Nobel citation talks of the trio's discovery of “principles for introducing specific gene modifications in mice by the use of embryonic stem cells.” Working independently, Professor Capecchi, of the University of Utah, and UK born Professor Smithies, of the University of North Carolina, showed how such modifications could be brought about by using homologous recombination, the natural process by which our maternally and paternally derived chromosomes are able to swap sections of their genetic material.
The outcome of these exchanges is an increase in the genetic variation in a population, fostering the emergence of new characteristics through which natural selection brings about evolutionary change.
Professors Capecchi and Smithies showed that this recombination mechanism could be exploited to incorporate completely new DNA—new genes, in other words—into a genome.
It was work by the third of the trio, Professor Evans, of the University of Cardiff, that allowed this principle to be exploited in the production of genetically modified animals.
Working with stem cells from early mouse embryos, Professor Evans first showed how to grow them in culture. He went on to inject stem cells of one mouse strain into the embryo of a different strain, then implanted the embryo into a surrogate mother. The mice born from this procedure turned out to be a mosaic of cells: some of one strain, some of the other.
He then used a retrovirus able to integrate its own genes into mouse DNA to genetically modify mouse embryonic stem cells. This time the resulting mice were a mosaic of normal cells and of others carrying the viral DNA. Further breeding allowed him to produce mice in which the germ line had been altered, so ensuring that all cells in all their offspring carried the alien genetic material.
In the 1980s the technologies devised by the three researchers were brought together to create animals with specific genetic abnormalities.
The great strength of the new technique lies in the possibility it offers for gene targeting. In essence this involves using a length of DNA to inactivate a particular gene: to “knock it out.” This allows researchers to investigate the effects of single genes. The method is already telling us much about the role of genes in health and disease and during processes such as development and ageing.
The first knockout experiments were reported in the late 1980s. Researchers were quick to realise their potential, and some 10000 mouse genes have already been targeted. Scientists have produced more than 500 mouse models of human illnesses through which to study disease mechanisms and test possible treatments.
Commenting on Professor Evans's contribution, Martin Rees, president of the Royal Society, described the award as fitting recognition for groundbreaking research. “He is a world leader in mammalian genetics, and his research has undoubtedly increased our understanding of human diseases,” said Lord Rees. “Stem cell research has immense potential. It is a field where UK scientists . . . have made pioneering contributions and maintain a powerful presence.”