Concept 41 DNA is only the beginning for understanding the human genome.

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Mario Capecchi developed a technique to target and mutate genes in mice using homologous recombination. Brian Sauer adapted the cre/lox recombinase system from phage for mammalian gene knock outs.

In 1980, Mario Capecchi faced an uncertain future. Reviewers deemed the research proposal he sent to NIH "not worthy of pursuit," so Capecchi gambled and diverted money from other projects into the new research. If the gamble didn't pay off, Capecchi risked losing all his research funding, a death sentence for researchers in today's publish-or-perish universities. But for a man who spent five years as a homeless orphan on the streets of war-torn Italy, the risk probably seemed insignificant.

During the first four years of his life, Capecchi lived with his mother, Lucy Dodd-Ramberg, a poet. Lucy joined a group of artists opposed to fascism in northern Italy, where she met Mario's father, an officer in the Italian air force. Capecchi says they had a passionate love affair, but she wisely refused to marry him.

When World War II started, Mario's mother, along with the other Bohemian artists, was arrested by the Gestapo and sent to Dachau. Lucy anticipated the arrest and arranged for Mario to live with friends with the money she received from selling all her possessions. After a year, however, the money ran out - or was stolen by Mario's father - and the five-year-old was left to fend for himself.

Mario headed south and joined gangs of other homeless orphans, stealing food from open-air markets and sleeping in bombed-out buildings. The police captured him again and again and sent him to orphanages and hospitals, but life there was worse. In the hospital, a cup of coffee and a piece of bread once a day were used to treat his malnutrition, and Mario spent the days lying naked on a stripped bed in a feverish delirium.

After the war, Capecchi's mother was released from prison and searched Italy for a year before finding Mario in a hospital in Reggio Emelia, a city near Bologna. The woman didn't look like the mother he remembered, but she promised to take him from the hospital, so he traveled with her to his uncle's Quaker commune outside Philadelphia in the United States. Edward Ramberg and his wife, Sarah, struggled to tame Mario, now 9, when it became clear that Lucy was too psychologically scarred from the war to care for him.

Mario entered third grade at the local public school without knowing English and spent most of his time beating up his classmates. By high school, he had been socialized, partly through his participation in sports. Capecchi thinks playing on the school's football, baseball, soccer, and wrestling teams taught him lessons in human psychology that he eventually transferred to later relationships.

In college at Antioch, Capecchi began studying for a political science degree to combine his esteem for science with his sense of social responsibility. But he found little science in politics and abandoned it for physics and chemistry. Before he graduated in 1961, though, he knew he would make another switch to molecular biology in graduate school. The field was so new that anything was possible and you could ask any question.

Capecchi's graduate advisor at Harvard, James Watson, steered Mario away from small questions that were only likely to produce small answers. By 1967, Capecchi had his doctorate and, in 1968, joined the biochemistry faculty at Harvard Medical School.

Even though there were thousands of researchers and potential collaborators in the Boston area, Capecchi felt he needed more isolation to freely pursue the big questions in his head. In 1973, he moved to the University of Utah in Salt Lake City where he had 20 colleagues in a department that covered everything from evolution to molecular biology.

The professional gamble Capecchi took with his research funding in 1980 paid off, and he was on his way to harnessing the machinery of mammalian cells to precisely mutate any gene he wished. The technique not only helps researchers generate mice with human diseases for study, but it may be used in future gene therapies to correct disease-causing genes. When he reapplied to NIH in 1984, the reviewers admitted their goof: "We are glad that you didn't follow our advice." Capecchi, Evans and Smithies were awarded the 2007 Nobel Prize in Physiology or Medicine for their work.

Mario Capecchi is currently a professor of Human Genetics at the University of Utah and lives with his wife and daughter in a remote house in the mountains near Salt Lake City. In 1996, he received the Kyoto Prize honoring his lifetime achievement in the betterment of humanity.