A conversation with Nobel laureate Mario Capecchi, George School class of 1956, on resilience, risk-taking, and the long path to scientific discovery.

Mario Capecchi arrives in a black blazer, quiet and unhurried. He settles into his seat and waits for the questions. He is not the kind of Nobel laureate who fills the room; he is the kind who makes you lean in.

What he has to say, though, is anything but quiet.

Mario, George School class of 1956, won the Nobel Prize in Physiology or Medicine in 2007 for a breakthrough that transformed the way scientists study human disease. But long before Harvard, long before George School even, there was a small boy alone on the streets of postwar Italy — no parents, no home, no food, and certainly no education— learning to survive in a chaotic world. In an interview upon his return for the Alumni Weekend, Mario reflected on the road between those two moments: a journey shaped by risk, resilience, and, above all, the willingness to begin again.

Early Life in Postwar Italy

Whenever Mario talks about his childhood, he describes it with a lightness and humor. “I went essentially from the streets to civilization,” he said. “It wasn’t gradual — it was a huge shift.” 

However, the backstory is almost impossible to hold in the mind all at once. His mother, Lucy Ramberg, was an Italian-American poet and political activist who had openly opposed Fascism and Nazism in prewar Europe. In the spring of 1941, German officers came to the family’s chalet in the Italian Alps and arrested her. Mario was three and a half years old.

His mother had anticipated the arrest and left money with an Italian peasant family in Tyrol to care for him, but the money ran out after a year. At age four and a half, Mario was on his own. 

He spent the next several years moving between the streets, gangs of other homeless children, and orphanages — hungry most of the time, feverish and malnourished. When his mother finally found him on his ninth birthday in 1946, he was in a hospital in Reggio Emilia, admitted for typhoid and malnutrition. They soon moved to the United States after his uncle Edward Ramberg, had sent them money to buy two boat tickets to America.

A Community of “Sixty-Five” Parents

By the time Mario reached George School, he could not speak English, could not read, and could not write. Some of the teachers told the adults caring for him not to bother — that the window for learning literacy had already closed, and he should just go to a trade school instead.

“That was pretty silly,” Mario said with a smile, with characteristic understatement. 

What George School gave him, he said, was not just an education in the academic sense. It gave him community — and for a boy who had been entirely self-reliant since toddlerhood, that meant something almost incomprehensible. “I went from being completely alone to suddenly being part of a community — with essentially 65 ‘parents’ instead of none. That transition was enormous.”

There was also something simpler that George School provided, something most students take entirely for granted: time to play. “A child spends a lot of time playing, but because I had to take care of myself from age three to nine, I never really played,” he said. “So George School gave me the opportunity to do that, and I think that was very important.”

“Even in animals, when they play, they’re actually learning the skills they’ll need as adults. The same idea applies to people. During playtime, you learn how to be social, how to function in a community.”

During his four years at George School, Mario had not yet found his passion in science. He was catching up on everything else. “I was more interested in girls and sports,” he said, laughing. “Those were my main interests because I hadn’t had the chance to develop relationships or play sports earlier.” He went on to letter in five varsity sports starting his freshman year because of coordination and strength built from years of hard physical survival.

The Making of a Scientist

Science came later, in college, through an unusual program at a small university in San Antonio that alternated academic quarters with working quarters. Over five years, Mario spent roughly half his time doing hands-on research.

 “I gained an enormous amount of lab experience,” he said. “About two and a half years working in labs all over the country — Boston, New York, Ohio, and so on. So by the time I went to graduate school, I already had a lot of hands-on experience.” A quarter at MIT, as he described in his autobiography, was where he first encountered the then-newborn field of molecular biology. 

By the time Mario arrived at Harvard for graduate school, the results of that foundation were already visible. “In my first year, I was already running many experiments, and I even had my own lab and a technician — resources that most graduate students, even at Harvard, didn’t have.”

James Watson — of Watson and Crick, the pair who decoded the structure of DNA — who was his mentor, would later say that he accomplished more as a graduate student than most scientists do in their entire careers.

“Doing things you’re interested in is a great way to learn what a field is really like and whether you enjoy it,” he said. “That helps you choose your vocation, and I made the decision to become a scientist.” 

The Long Game: Gene Targeting

The research that earned Mario the Nobel Prize was not a quick triumph. It was a decade-long wager on a question most of the scientific world thought was not worth asking.

“I knew gene targeting might take ten years — and it did.” Mario said.

In the early 1980s, Mario became interested in whether it was possible to use a cell’s own internal machinery — a process called homologous recombination — to make precise, targeted edits to the DNA of living mammals. The idea was to “knock out” specific genes in mice, creating animals that could serve as models for human diseases caused by genetic mutations.

The scientific establishment was unmoved. Funding agencies like NIH were unwilling to support the work. “People said it was impossible, so I couldn’t get funding for it,” Mario recalled, still with a smile, he said “I had to use money from another grant.”

He also knew that Harvard, for all its resources, was the wrong place for a ten-year project. “At Harvard, people constantly ask, ‘What’s new?’ That encourages projects with quick results.”

Moving to the University of Utah gave him the space, open nature, and most importantly, “the freedom to work differently”. 

“Synergy”

The project demanded answers to a chain of questions, each one unlocking the next. The first was fundamental: homologous recombination — the cellular process he wanted to exploit — was known to occur in germ cells, the eggs and sperm that pass genetic information between generations. But did ordinary body cells, somatic cells like skin or muscle, have that same machinery? 

“That was the first thing I needed to find out,” Mario said. The answer, when it came, was yes. “Once I knew that, the next step was figuring out how to use that machinery to do what I wanted.”

Solving the recombination problem was only half the puzzle. Even if he could modify a cell’s DNA precisely, he still needed a way to take that modified cell and use it to grow an entire living mouse. That required a different technology altogether — one being developed, at that very moment, by a researcher in England who was working on embryonic stem cells, which have the rare ability to become any cell type in the body. 

“So I called him and asked if the rumor was true. He said yes. I asked if I could come learn how to make those cells. He said, ‘Sure.’”

What followed was a collaboration that bridged continents, something Mario calls “synergy”. 

“He had half the solution, and I had the other half,” he said with a smile. “By collaborating, we solved the problem much faster than if we had competed. Two minds are always better than one.”

“The race wasn’t against other scientists — it was against time.” Mario had roughly four years to produce results before his funding ran out.

The resulting technique, gene targeting, has since been used to create thousands of mouse models of human disease, accelerating research into cancer, heart disease, neurological disorders, and more.

Risk, Failure, and Learning

When asked how he kept going after all those rejections, Mario paused for a moment. 

“Theres no way of getting away without risk,” he said. “You don’t know whether something will work, but the only way to find out is to try.”

For Mario, failure is not an endpoint but part of the process. “In science, most things don’t work,” he said. “So you have to design experiments in a way that you learn as much from failure as you do from success — often even more.”

“In failures, you have to do enough controls to be able to say why you failed. Then, it’s a learning process, and you can’t lose. ”

This philosophy applies to his entire life as well as his scientific journey. “You learn only through challenges. Challenge it, and it has infinite capacity.”

New Field, New Beginning

Today, Mario has turned his attention to neuroscience — specifically, the biology of anxiety. “Anxiety is like a hub,” he explained. “Many other psychiatric disorders, like depression or schizophrenia, can develop from it.”

Starting a new field in life, Mario said, requires humility. “You start from the bottom again, as a student, and work your way up.” At the same time, “Being naive can also be an advantage,” according to him, “because I can ask questions others are not thinking about.”

The field is still in its earliest stages, he acknowledged, with enough unresolved questions to occupy researchers for generations.

“The brain is so complex that I could work on it for the next 30 years and still have more to do,”Mario said. “And this might be the last new area that I go into.”