Of Mice, Men and the Nobel Prize for Medicine

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The 2007 Nobel Prize in Physiology or Medicine was announced this morning. The prize was awarded to three men for a series of discoveries regarding embryonic stem cells and DNA recombination in mammals that led to the creation of a technique for manipulating mouse genes called gene targeting. Today, the technology is being applied to virtually all areas of biomedicine.

The three men, Mario R. Capecchi, age 70, at the University of Utah in Salt Lake City, Sir Martin J. Evans, age 66, at Cardiff University in Wales and Oliver Smithies, age 82, at the University of North Carolina in Chapel Hill, will share the 1.54 million prize.

Gene targeting allows researchers to inactivate or modify specific genes in the germline of mice and to raise offspring that express the modified gene. This lets them study how those genes affect health and disease. The technique is often used to inactive or “knockout” single genes in order to identify its role in development, physiology and disease.

According to the Nobel committee [1], the technique of gene targeting:

… has revolutionized life science and plays a key role in the development of medical therapy.

As of 2004, the curated Mouse Knockout & Mutation Database listed 2,669 unique genes that have been knocked out [2]. Hundreds of mouse models of human diseases have been produced, including models of cancer, cardiovascular and neurological diseases, and diabetes.

The mouse as a model organism

The mouse has developed into the leading mammalian model system for genetic research because of its genetic and physiologic similarities to humans [3]. Like humans, mice naturally develop diseases that affect the immune, endocrine, nervous, cardiovascular and skeletal systems. Additionally, many diseases that don’t afflict mice, including cystic fibrosis, diabetes, osteoporosis and glaucoma can be induced by altering the mouse genome using gene targeting. Almost all mouse genes have homologs (meaning the genes are related by descent from a common ancestral DNA sequence) and the mouse genome supports targeted mutagenesis in specific genes in embryonic stem cells.

The ability to knockout a gene in embryonic stem cells and mice was developed in the late 1980s [4]. It’s based on a naturally occurring process called homologous recombination, whereby segments of DNA within a cell are exchanged between chromosome pairs during meiosis. Homologous recombination is responsible for genetic variation in the population.

Using gene targeting, all three researchers have made important contributions regarding the role of genes in development and disease. Capecchi’s research has identified the roles of genes involved in mammalian organ development and in the establishment of the body plan [5-7]. Evan’s work has developed several mouse models for the inherited human disease cystic fibrosis [8-9]. Smithies also used gene targeting to develop mouse models for inherited diseases such as cystic fibrosis and the blood disease thalassemia. In addition, he has also developed numerous mouse models for more common human diseases such as hypertension and atherosclerosis [10-13].

References

1. Advanced Information — Gene modification in mice. The Nobel Prize in Physiology or Medicine 2007.
2. Austin et al. The knockout mouse project. Nat Genet. 2004 Sep;36(9):921-4.
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3. Background on Mouse as a Model Organism. National Human Genome Research Institute. Reviewed 2007 Sep 17.
4. Goldstein JL. Laskers for 2001: knockout mice and test-tube babies. Nat Med. 2001 Oct;7(10):1079-80.
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5. Chen and Capecchi. Paralogous mouse Hox genes, Hoxa9, Hoxb9, and Hoxd9, function together to control development of the mammary gland in response to pregnancy. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):541-6.
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6. Wellik and Capecchi MR. Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. Science. 2003 Jul 18;301(5631):363-7.
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7. Boulet et al. The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev Biol. 2004 Sep 15;273(2):361-72.
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8. Colledge et al. Generation and characterization of a delta F508 cystic fibrosis mouse model. Nat Genet. 1995 Aug;10(4):445-52.
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9. Ghosal et al. Sodium channel blockers and uridine triphosphate: effects on nasal potential difference in cystic fibrosis mice. Eur Respir J. 2000 Jan;15(1):146-50.
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10. Koller et al. Toward an animal model of cystic fibrosis: targeted interruption of exon 10 of the cystic fibrosis transmembrane regulator gene in embryonic stem cells. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10730-4.
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11. Krege et al. Angiotensin-converting enzyme gene and atherosclerosis. Arterioscler Thromb Vasc Biol. 1997 Jul;17(7):1245-50.
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12. Pandey et al. Hypertension associated with decreased testosterone levels in natriuretic peptide receptor-A gene-knockout and gene-duplicated mutant mouse models. Endocrinology. 1999 Nov;140(11):5112-9.
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13. Caron et al. Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3420-5. Epub 2007 Feb 20.
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