Nobel Prize For Medicine Goes To Scientists Working In UK And US

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Main Category: Stem Cell Research
Also Included In: Genetics
Article Date: 08 Oct 2007 - 12:00 PDT

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The Nobel Prize in Physiology or Medicine for 2007 this year has gone to three scientists working in the US and the UK for their work on the genetic modification of embryonic stem cells. Their discoveries led to the creation of powerful "gene targeting" technologies that are now used extensively in research and therapy.

The three Nobel Laureates are:

• Mario R Capecchi, born in Italy in 1937 and now working at the University of Utah, Howard Hughes Medical Institute, Salt Lake City, USA.
• Sir Martin J Evans, born in the UK in 1941 and now working at Cardiff University in the UK.
• Oliver Smithies, born in the UK in 1925 and now working at the University of North Carolina at Chapel Hill, USA.

The Nobel Prize, which is awarded by the Nobel Assembly at Karolinska Institutet in Sweden, was for their discoveries of "principles for introducing specific gene modifications in mice by the use of embryonic stem cells".

Since their discoveries, more than 10,000 mouse genes (nearly half of all the genes in the mouse genome) have been selectively "knocked out" in order to find out how they contribute to embryo development, adult physiology, diseases and aging. As more international work progresses in this area, it is likely that very soon "knockout mice" will be available for every gene in the mouse genome. (A "knockout mouse" is a genetically engineered mouse that has had a specific gene switched off).

There are now over 500 types of genetically engineered mice ("mouse models") with DNA patterns that model human disorders, including cardiovascular illnesses, neuro-degenerative diseases, diabetes and cancer.

It has been nearly 50 years since bacteriologist Joshua Lederberg was awarded the Nobel Prize for his discovery of the process of "homologous recombination" which Capecchi and Smithies used to modify genes in mammalian cells.

Homologous recombination is where sections of DNA are exchanged between the set that came from the father and the set that came from the mother.

When a mammalian egg is fertilized and starts to grow into an embryo, cells "obey" instructions that decide the form, development and physiology of that organism in their DNA which is held in chromosomes in the cell nucleus. One set of chromosomes comes from the father and the other from the mother. But a curious thing happens during the life of cells. The chromosomes exchange strands of DNA with each other. Thus after a while, pieces of DNA that came with the father's chromosomes end up in the the chromosomes that came from the mother and vice versa.

Capecchi showed that homologous recombination could also occur between introduced DNA and the DNA that was already in mammalian cells. And he showed that faulty genes could be repaired this way. Smithies showed that it was possible to target all genes using homologous recombination. However, although they were able to show homologous recombination worked, they were not able to create gene targeted animals because the cells did not pass on the DNA modifications when they divided.

This is where Evans' work comes in. Evans was working with mouse embryonal carcinoma (EC) cells, which although they came from tumours, he found they gave rise to almost any type of cell, they were like a "master cell". At first he tried to use EC cells to bring new genetic material into the mouse germ line. But he didn't succeed because the EC cells had abnormal chromosomes. He then found that early mouse embryos could be used to develop chromosomally normal cell cultures and these became known as embryonic stem (ES) cells.

Evans then took embryos from one strain of mice and injected them with ES cells from another strain. These became "mosaic embryos", they had ES cells from two strains of mice. These embryos were born and eventually mated and their offspring were shown to have genes from the injected ES cells. This proved it was possible to introduce genetic material using ES cells that is then inherited by the next generation of the organism.

He then used retroviruses to genetically modify the ES cells. Thus Evans was able to put all three steps together: modify the ES DNA using retroviruses, introduce the genetically modified ES cells into a mouse strain, and show that the offspring of that mouse inherited the genetically modified DNA. This was effectivey homologous recombination in ES cells.

So, now we have on one side Capecchi and Smithies showing that you could target specific genes using homologous recombination in cultured cells (ie cells derived from ES cells), and Evans showing you could use homologous recombination to make sure genetically altered ES cells passed on their alteration to the next generation of the organism.

Reports of studies using homologous recombination in ES cells to generate gene-targeted mice started to appear in 1989. Since then the number of knockout mouse strains that are available has risen exponentially and the technology has advanced enormously. It is now possible to activate genes in specific organs or cells and to switch them on at a designated time in the development of the organism or life of the adult.

Later, Capecchi went on to discover how genes affect organ development in mammals and how they contribute to the "body plan". His work has uncovered the genetic causes of many congenital defects.

Evans has developed mouse models for many human diseases, including cystic fibrosis, and he has used them to test many disease mechanisms, including the effects of gene therapy.

Smithies has also developed mouse models of human diseases, including one for the inherited blood disease, thalassemia and others for hypertension and atherosclerosis.

The Nobel Prize press release summarized the contribution and impact of the three 2007 Laureates as:

"Gene targeting in mice has pervaded all fields of biomedicine. Its impact on the understanding of gene function and its benefits to mankind will continue to increase over many years to come."

Click here for more information about the Nobel Prize.

Written by: Catharine Paddock
Copyright: Medical News Today
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