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Who Is Mario Capecchi? Disease Models & Mechanisms 1, 197-201 (2008) doi:10.1242/dmm.001966 A MODEL FOR LIFE The first transgenic mice: an interview with Mario Capecchi Mario Capecchi recently won the Nobel Prize for contributions to genetics that have catapulted the mouse to the status of the most valuable of all animal models. He has a personal story that is as rich and interesting as his science. Here, he discusses the journey that led him to gene targeting and his vision for the future. The ability to remove or mutate genes to My thought was that the cells were using assess their function has forever changed endocytosis, where cell membranes engulf the fields of biology and medicine. A exogenous material, to internalize the pioneer of this technology, Mario Capecchi DNA. Cells usually do this with the intent was shaped by a unique childhood that of shuttling the internalized material to taught him persistence and self-reliance. He lysosomes to degrade it, and then use what- was born in Italy during World War II. ever is useful to them. So, my thinking was When he was only 4 years old, his American that most of the DNA in those early exper- mother was imprisoned in a German con- iments ended up being degraded and that DMM centration camp and soon after he found very little of it was delivered to the nucleus himself homeless and fending for himself where it could function. I thought that if I on the streets of Italy. After 4 years alone, he made very small hypodermic needles and was reunited with his mother and they stuffed the DNA directly into the nucleus moved to the USA. He quickly developed a itself maybe the efficiency would be much passion for physics and his early work with higher. I did it, and it turned out that effi- James Watson further influenced his scien- ciency was much higher. Now one in every tific mind. His discoveries leading to gene three cells, rather than one in a million cells, targeting are rapidly unlocking the myster- incorporated the gene into its genome in a ies of the mammalian genome. functional form. That was interesting and important, but didn’t answer the question In 2007 you won the Nobel Prize for your of how the DNA was inserted into the role in developing the process of gene genome. targeting, in which homologous recom- Wigler and Axel were using a lot of DNA, bination is used to replace an endoge- and what they did was mix plasmid DNA nous gene with one that has been modi- containing their gene of interest with Disease Models & Mechanisms fied. What inspired you to approach such salmon sperm carrier DNA, which was a monumental challenge? cheap to buy, to get the DNA concentration There was a paper by Wigler and Axel [in high enough to form the precipitate. inserted into the genome in the same ori- Cell, 1977] in which they formed a precip- Because I was injecting individual mole- entation. DNA has an orientation, just like itate of DNA and calcium phosphate on top cules, I could choose to put in 1, 10 or 100 reading a text. If I started by putting all of of cells and found that the cells took up the molecules. When I put the needle into the the separate DNA copies into the nucleus DNA. These cells started out lacking a par- nucleus, the solution that I was injecting and they ended up incorporated into the ticular gene that was necessary for survival had a distinct refractive index so I could genome at a single locus in the same orien- in a chosen medium, but if the cells stably watch the solution spread out in the tation, then this process couldn’t happen incorporated the gene into their genome nucleus. I used that information to measure randomly. then they survived; the efficiency was the volume I was adding to the cells. So, I One possibility is that the cell picks up a roughly one cell in every million. Further, could control how much I was injecting and piece of DNA and uses it as a template, like they showed that the added DNA was ran- then I could also control the concentration a sausage machine, to synthesize more domly incorporated into the host cell of DNA that I was injecting and, conse- copies of the DNA in a process that would genome. quently, how many molecules were being end up producing DNA copies all in the injected. I found that the DNA was ran- same orientation. This would be a synthetic Mario Capecchi is the Distinguished Professor of domly incorporated into the genome, but way of generating the observed head-to-tail Human Genetics and Biology at the University of if I put in 10 copies or 100 copies, or even concatamers. The other possibility was that Utah and an investigator in the Howard Hughes Medical Institute 1000 copies, of the same DNA sequence the DNA copies are put together by ho- (e-mail: [email protected]) into the nucleus, all of the molecules were mologous recombination, a naturally oc- Disease Models & Mechanisms 197 A MODEL FOR LIFE Mario Capecchi curring process in which similar DNA se- The reason that somatic cells use ho- 2007 Nobel Prize.) I asked if I could come to quences on chromosomes can exchange in- mologous recombination is that every day his lab and learn how to work with ES cells formation with each other. Since homolo- each of your cells receives about 10,000 right then and there. He was very generous gous recombination always maintains se- insults to its DNA. The insults arise from to let my wife, Laurie, and I visit his lab. quence orientation, the DNA that has been oxygen radicals produced in the cells, or When I arrived he said to me, “Nobody newly inserted by homologous recombina- from sunlight, or from everything else that’s seems to be interested in my cells” and I told tion would also be in the same orientation. happening to your poor cells. Often, a DNA him, “They will be, just wait!” I could readily distinguish between these strand gets broken. When it breaks, you not two potential models and showed that only lose the gene at the breakage point, but After you developed this new technology head-to-tail concatamers were generated by upon cell division you lose all the genes that there were limitless genetic unknowns homologous recombination. are no longer associated with a centromere. available for study. Why did you choose At that time, people knew about the The first thing a cell wants to do is stick to focus on the HOX gene family? process of homologous those two pieces of It was timing. At that time, Walter Gehring recombination but they DNA back together so in Switzerland had just characterized HOX thought it was primarily I am a very gene-centric that, rather than losing a genes in Drosophila. As Ed Lewis had restricted to myosis (i.e. guy. Not because genes do thousand genes, it just shown, these genes are responsible for spec- during the formation of everything, but because loses one gene. Once ifying segmental identity in Drosophila. sex cells, sperm and that is done, the Walter Gehring and others showed that eggs). When sperm and genes are the easiest place damaged DNA at the these genes contained DNA-binding egg come together you to be able to dissect junction is tagged and domains called homeo boxes. Amazingly, have chromosomes complex biological the cell can use the copy they also showed that HOX genes not only derived from your phenomena with great of the gene from the existed in Drosophila, but also in frogs, DMM mother and father, but other homologous chro- mice and humans. This story was breaking these chromosomes are precision mosome to repair it. For at the same time as we were thinking about not intact chromosomes example, if the maternal which gene to tackle with our technology derived from one maternal or paternal copy is broken, then the paternal copy can for modifying mouse genomes. grandparent. Rather, the chromosomes that be used to repair the damaged gene. This was all happening in the mid-1980s. you received from your mother or father are Homologous recombination is the machin- All of a sudden, these HOX genes were extensive mixtures derived from both of your ery that mediates this repair. Every cell in being characterized at the DNA level and maternal or paternal grandparents, respec- your body has to have very efficient homol- identified in many species. Up until then, tively. The extensive exchanges between the ogous DNA repair machinery or it could people knew that, for example, the citric pairs of chromosomes derived from your not survive. acid cycle was going to be the same in all grandparents are mediated by homologous Since the machinery is there in every cell species from plants to humans, so they recombination. This process generates I asked, ‘how can we fool Mother Nature to thought of metabolism as being conserved, much, much greater variation in the DNA use this machinery for our advantage?’ but they didn’t think that the genetic cir- content that is present in each of your chil- What if I could convince the homologous cuitry responsible for development would dren than if your sperm or egg contained recombination machinery that I’m present- be the same among disparate species. The intact copies of chromosomes obtained from ing the ‘good copy’ of the gene to the cell, conservation of HOX genes among many Disease Models & Mechanisms one grandparent or the other.
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