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Biologists Claim Nobel Prize with a Knock-Out : Nature News 11/22/09 10:03 PM

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Biologists Claim Nobel Prize with a Knock-Out : Nature News 11/22/09 10:03 PM Biologists claim Nobel prize with a knock-out : Nature News 11/22/09 10:03 PM Published online 9 October 2007 | Nature | doi:10.1038/449642a News Biologists claim Nobel prize with a knock-out Architects of mutant mice are rewarded for their work. Alison Abbott The architects of a technique that has allowed biologists to identify the function of genes easily have been rewarded for their efforts with this year's Nobel Prize in Physiology or Medicine. The technique allows researchers to generate 'knock-out' mice -mutant strains in which specific genes are disabled. These can be used to establish what role specific genes have in health, development and disease, and to create animal models of human diseases. "Virtually no field of biomedicine has been untouched by one knock- out strain or another in a significant way," says Jeremy Berg, director of the National Institute of General Medical Sciences in Bethesda, Maryland. Oliver Smithies Mario Capecchi from the University of AP Photo/Karen Tam Utah in Salt Lake City, Martin Evans of Cardiff University in Wales and Oliver Smithies of the University of North Carolina at Chapel Hill, share the €1.1- million (US$1.5-million) award. As is now often the case with this Nobel prize, the trio's work had previously been recognized with a Lasker award, in 2001. Thousands of strains of knock-out mice Mario Capecchi have been generated since use of the AP Photo/Douglas C. technique was first reported in 1989. Pizac More than 500 of these are models for specific human disorders such as cardiovascular and neurodegenerative diseases, and cancer. The technology's origins lie in a natural phenomenon called homologous recombination, which cells are thought to exploit to repair damaged DNA. Chromosomes, which package DNA, exist in pairs — one inherited from each parent — and during homologous recombination fragments of DNA can be exchanged between the two. Capecchi and Smithies found that artificial DNA of known sequence could engage in homologous recombination with mouse DNA, and exploited this to target specific mouse genes. Martin Evans Evans provided the key element of heritability that eventually led to the development of knock-out mice — strains in which a gene remains knocked out in future generations. He had the idea of using mouse embryonic stem cells to introduce genetic material http://www.nature.com.ezproxy.library.wwu.edu/news/2007/071009/full/449642a.html Page 1 of 5 Biologists claim Nobel prize with a knock-out : Nature News 11/22/09 10:03 PM generations. He had the idea of using mouse embryonic stem cells to introduce genetic material into embryos from a different strain of mouse. When he injected the stem cells into the embryos, their chromosomes, as expected, combined. The mosaic embryos created could be brought to term in a surrogate mother. When the pups were mated, their offspring contained genes derived from the stem cells. Evans then began modifying the stem cells before injecting them into the mouse eggs, using retroviruses to integrate new genes into their genomes. These new genes could then be transferred into the embryos and their offspring. Combining this technique with artificial homologous recombination led to the development of the first knock-out mouse. Important refinements to the technology — particularly the development of 'conditional mutants' — have made knock-outs even more valuable for biologists. A system, known as Cre-lox, has been developed in mice by Klaus Rajewsky, now of Harvard Medical School, to allow the targeted gene to be switched off at a chosen time after birth. This is important both because up to 15% of genes are essential for embryonic development and a knock-out would not survive to birth, and because some genes may become relevant for a particular disease only later in life. Smithies told Nature that the prize was "not unexpected, given the calibre of the work". Celebrating with ice-cream, he confessed to "being pleased". What thrills him most, he says, is opening journals to find so many papers that rely on knock-out mice. "It's quite clear that the homologous- recombination method has contributed deeply to our understanding of the genome," he says. "We may have the sequence, but knock-outs help us understand how it functions." Knock-out mice In recent years, Capecchi has helped elaborate the role of particular genes in embryonic development. His work has focused particularly on body organs and the way the body plan is formed — vital to ensuring that all of an animal's body parts are in the correct places. Evans has developed many mouse models of important human diseases, such as cystic fibrosis, and has used these to study disease mechanisms and to try to find ways to repair defective genes. Smithies has also developed a cystic fibrosis mouse as well as models of common diseases including high blood pressure and atherosclerosis. Now that the mouse genome has been sequenced, a ADVERTISEMENT worldwide effort has been launched to knock out every single one of the animal's genes. "The impact of the technology on the understanding of gene function and its benefits to mankind will continue to increase for many years to come," says Evans. Comments Reader comments are usually moderated after posting. If you find something offensive or inappropriate, you can speed this process by clicking 'Report this comment' (or, if that doesn't work for you, email [email protected]). For more controversial topics, we reserve the right to moderate before comments are published. http://www.nature.com.ezproxy.library.wwu.edu/news/2007/071009/full/449642a.html Page 2 of 5 Biologists claim Nobel prize with a knock-out : Nature News 11/22/09 10:03 PM How many examples exist of good, valid scientific papers which have been and are still rejected or discriminated because of presumed (or real) differences between mouse and human species? How to explain this discrepancy? Thanks, Antonio Brunetti, MD, PhD Univ. of Catanzaro "Magna Græcia", Catanzaro Italy Posted by: Antonio Brunetti 09 Oct, 2007 Is there any standard by which the results found with knockout mice can be evaluated with a human perspective? Posted by: losiana nayak 10 Oct, 2007 Last year’s awarding of a Nobel Prize in Physiology or Medicine to discoverers of RNAi caused a surge of complaints because not only RNAi is a reinvention of RNA interference wheel but also a tiny aspect of the broad scope discovery on epigeneics. This year’s Nobel Prize in Physiology or Medicine went to researcher extending the discovery of transgenic mice with the creation of knock-out in embryonic cells but the pioneer(s) making precedent greater discovery of transgenic mice were noticed but not awarded. Why this most respected scientific award went so often to trivial and late scientific extensions but left behind grand earlier breakthroughs under-appreciated? (full-length free at http://im1.biz/albums/userpics/10001/TW2007V2N2A12_Nobel2007Med.pdf) Posted by: Shi Liu 10 Oct, 2007 Congratulations to Mario R. Capecchi, Ph.D., Sir Martin J. Evans, Ph.D., DSc., FRS, and Oliver Smithies, D.Phil., FRS, all former recipients of the March of Dimes Prize in Developmental Biology, on sharing this year’s Nobel Prize in Physiology or Medicine. Dr. Capecchi and Dr. Smithies shared the 2005 March of Dimes Prize, and Sir Martin was a co-recipient of the 1999 March of Dimes Prize. We are proud to have honored their achievements in gene targeting. The March of Dimes Prize in Developmental Biology has been awarded annually since 1996 to investigators whose research has profoundly advanced the science that underlies the understanding of birth defects. Five former March of Dimes Prize recipients now have gone on to win a Nobel Prize. The previous ones were Sydney Brenner, D.Phil., FRS, and H. Robert Horvitz, Ph.D., who shared the 2002 Nobel Prize in Physiology or Medicine for their discoveries on genetic regulation of organ development and programmed cell death. For more information, visit the March of Dimes Web site at marchofdimes.com. Posted by: Michael Katz 10 Oct, 2007 In the table of contents, there's a link to the PDF version of this article. It doesn't reach it. What did you do with the PDF version? Posted by: Jean SmilingCoyote 10 Oct, 2007 This years award is indeed well deserved. But it is a bit too much to go about knocking out every mouse gene. It is O.K. so long as it stops at the mouse but how justified are we in extending it to humans ? Prof S.L.N.Rao Posted by: SLN Rao 10 Oct, 2007 It is true that transgenic mice creation was the initiation but expanding on the gained understanding, knock outs brought too many robust end point clarity at the cause-effect scenario. Often sparks are ignored and the large blazes drwas attention. Indeed knock-out concept was novel and brought out vast gene function information that dwarfed the transgenic creation. http://www.nature.com.ezproxy.library.wwu.edu/news/2007/071009/full/449642a.html Page 3 of 5 Biologists claim Nobel prize with a knock-out : Nature News 11/22/09 10:03 PM information that dwarfed the transgenic creation. Posted by: Robin Mukhopadhyaya 11 Oct, 2007 Hearty congrats. But then all our efforts are with hardware and not software of the organism. An organism is a natural biocomputer with hardware and software. Hardware is the chemical structures and software is the biological program stored on the chromosome as we store our programs and data on our computer disc. The program is invisible or intangible agreeing with the view of Wilhelm Johannsen who first proposed the term gene and who cautioned that gene is not particulate.
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