Archive for the ‘Men and Women of Science’ Category


And it goes 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”

Mario R. Capecchi, born 1937 in Italy, US citizen, PhD in Biophysics 1967, Harvard University, Cambridge, MA, USA. Howard Hughes Medical Institute Investigator and Distinguished Professor of Human Genetics and Biology at the University of Utah, Salt Lake City, UT, USA.

Sir Martin J. Evans, born 1941 in Great Britain, British citizen, PhD in Anatomy and Embryology 1969, University College, London, UK. Director of the School of Biosciences and Professor of Mammalian Genetics, Cardiff University, UK.

Oliver Smithies, born 1925 in Great Britain, US citizen, PhD in Biochemistry 1951, Oxford University, UK. Excellence Professor of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA.

Their discoveries led to the creation of an immensely powerful technology referred to as gene targeting in mice . It is now being applied to virtually all areas of biomedicine – from basic research to the development of new therapies.

Our DNA is packaged in chromosomes, which occur in pairs – one inherited from the father and one from the mother. Exchange of DNA sequences within such chromosome pairs increases genetic variation in the population and occurs by a process called homologous recombination.
Mario R. Capecchi demonstrated that homologous recombination could take place between introduced DNA and the chromosomes in mammalian cells. He showed that defective genes could be repaired by homologous recombination with the incoming DNA.

Oliver Smithies who worked on Blood diseases, initially tried to repair mutated genes in human cells by correcting the disease-causing mutations in bone marrow stem cells. (Bone marrow stem cells give rise to all blood cells.) In these attempts Smithies discovered that endogenous genes could be targeted and modified by homologous recombination .

The cell types initially studied by Capecchi and Smithies could not be used to create gene-targeted animals. This required another type of cell, one which could give rise to germ cells. Only then could the DNA modifications be passed on from the parent cell to the daughter cells.

Martin Evans worked with the technology of modifying Embryonic Stem cells from mouse cells genetically and for this purpose chose retroviruses. Retroviruses have the machinery to integrate their genes into the chromosome of cells they infect.
He demonstrated transfer of such retro viral DNA from Embryonic Stem cells, into the mouse germ line. Evans also applied gene targeting to develop mouse models for human diseases. He developed several models for the inherited human disease cystic fibrosis and has used these models to study disease mechanisms and to test the effects of gene therapy.

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.

A “KNOCK-OUT ” mouse is one in which a certain gene has been selectively inactivated. The inactivation is achieved byhomologous recombination of the mice embryonic cells with a small segment of genetic material we artificially insert into it using retroviruses.

How do we benefit?

The technology opens the opportunities to selectively shut-up mutated genes that are known to cause diseases in mammals. This helps us to study what exactly is the function of the “disease gene”. Gene targeting has helped us understand the roles of many hundreds of genes in mammalian fetal development by creating mouse models for human diseases in labs.

Gene targeting has already produced more than five hundred different mouse models of human disorders, including cardiovascular and neuro-degenerative diseases, diabetes and cancer.
Mario R. CapecchiMartin J EvansOliver Smithies

Source: nobelprize.org

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