Respectful Insolence

The Nobel Prize for Physiology or Medicine

No IgNobels here, the 2007 Nobel Prize for Physiology or Medicine has been awarded to Mario R. Capecchi, Martin J. Evans, and Oliver Smithies for a technique that is so incredibly important to modern biomedical research that it’s a wonder they didn’t get the prize before:

This year’s Nobel Laureates have made a series of ground-breaking discoveries concerning embryonic stem cells and DNA recombination in mammals. 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.

Gene targeting is often used to inactivate single genes. Such gene “knockout” experiments have elucidated the roles of numerous genes in embryonic development, adult physiology, aging and disease. To date, more than ten thousand mouse genes (approximately half of the genes in the mammalian genome) have been knocked out. Ongoing international efforts will make “knockout mice” for all genes available within the near future.

With gene targeting it is now possible to produce almost any type of DNA modification in the mouse genome, allowing scientists to establish the roles of individual genes in health and disease. Gene targeting has already produced more than five hundred different mouse models of human disorders, including cardiovascular and neuro-degenerative diseases, diabetes and cancer.

It’s hard to overstate how important this technique has become. Using this genetic engineering technology, it is possible to produce mice with a gene or genes specifically knocked out. It is possible to introduce a gene into stem cells and produce mice with that gene’s expression cranked up to high levels. Scientists can then observe the resulting phenotype. The entire process is illustrated below:

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I’m actually familiar with Mario Capecchi’s work and have read many of his papers. This is because one of my long time research project involves studying homeobox genes, and Capechhi is known for using this gene targeting technique to produce mice with specific HOX genes disrupted in order to demonstrate their function by observing the phenotype of the resulting mice. He played a major role in working out the “HOX code” in vertebrates. Capecchi’s work with vertebrate HOX genes demonstrates the power of gene targeting to produce transgenic mice.

In the study of human disease, the applications of this technology range from cancer to heart disease to–well, pretty much any disease with a major genetic component. All I can say after seeing this award is: What took the Nobel Prize committee so long?

Comments

  1. #1 Marcus Ranum
    October 8, 2007

    I notice that it involves sticking needles into things. Did they adequately control for the fact that the needles might be what’s making the mice feel better?

    … heh. Just kidding.

    I wish I understood this stuff better. I’m glad that there’s really smart people out there pushing the boundaries of science while the rest of us push the speed-bumps of stupid.

  2. #2 Abel Pharmboy
    October 8, 2007

    Orac, given your admiration of Capecchi and work on combating Holocaust denial, I thought you and your readers might be interested in a heartcrushing story by Daniel Cressey at Nature’s The Great Beyond blog that I learned from the WSJ Health Blog:

    Capecchi’s life story is humbling. Born in Verona in 1937, he was the product of a brief relationship between Lucy Ramberg, a poet, and Luciano Capecchi, an Italian air-force pilot. Nearly four years later, his mother — who was one of the Bohemians, a group of artists outspoken in their opposition to the Nazis — was taken away by the Gestapo and interned in the Dachau concentration camp.

    Before her arrest, Capecchi’s mother sold all her belongings and used the money to arrange for a peasant family to care for him. But for reasons Capecchi has never understood, the cash soon ran out. At just four-and-a-half years of age, he was turned out onto the streets. Although he is happy to talk in general terms about his early life, Capecchi refuses to be drawn into the grim specifics. “The reality was brutal and there is little to be gained from recounting the details.”

  3. #3 Coin
    October 8, 2007

    It’s a little surprising to me because I’d heard of “knockout mice” a zillion times before, but I’d never heard this described as a “stem cell” technique until I started seeing the articles about this this morning. Looking at the procedure outlined here though that does appear to be the correct way to describe it.

  4. #4 khan
    October 8, 2007

    Implanted into a mouse!

    What instruments are used to implant a blastocyst into a mouse’s uterus?

    Is there a diagram or video of this procedure?

  5. #5 Uncle Dave
    October 8, 2007

    What about multiple roles or codes within single genes?
    Forgive my ignorance on this subject, but isn’t there a complex role that yet needs to be understood within each individual gene? Identifying a so called aging gene for instance is but only a part of that particular genes function?

  6. #6 John
    October 8, 2007

    “Implanted into a mouse! What instruments are used to implant a blastocyst into a mouse’s uterus?”

    Forceps, a needle, and a pipette.

    “Is there a diagram or video of this procedure?”

    http://ourworld.compuserve.com/homepages/TheBroons/tnp2.htm

  7. #7 Jesse
    October 8, 2007

    Good point, Coin. To make a genetically altered mouse- i.e., knock out or knock in- the initial DNA recombination occurs in a stem cell and then that cell is used to create a whole animal through blastocyst implantation or tetraploid aggregation. Very neat stuff.

  8. #8 Brian
    October 8, 2007

    And yet, almost 20 years later, we still have never been able to create a knockout rat. Why? Nobody knows. Still.

  9. #9 sparc
    October 9, 2007

    To make a genetically altered mouse- i.e., knock out or knock in- the initial DNA recombination occurs in a stem cell and then that cell is used to create a whole animal through blastocyst implantation or tetraploid aggregation.>/blockquote>
    Seemingly, ozgene (http://www.ozgene.com/) has a technology that allows homologous recombination in fertilized oocytes. Unfortunately, they did not publish it and their “Cobra – beyond ES cells” page is still under construction.

  10. #10 W. Kevin Vicklund
    October 9, 2007

    And yet, almost 20 years later, we still have never been able to create a knockout rat. Why? Nobody knows. Still.

    May, 2003: the first knockout rat is created. (actually, that’s probably the publication date)

  11. #11 Doc Bill
    October 9, 2007

    What, no word from your pal Egnor?

    I thought he said that there was NO connection between evolution and medicine.

    Nope, none whatsoever. Not a smidgin’. Totally u.s.e.l.e.s.s.

    Maybe he was runner-up for the Prize. Hopefully he’ll enlighten us on the travesty of justice in an upcoming essay on the DI’s Whine and Cheese site.

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