by Susan Sample

Mario R. Capecchi talks with his hands, often holding a pencil sharpened to a fine point, with which he translates his ideas into lines and letters on a sheet of paper.

"A habit," admits the scientist, who dismisses the marks as "doodles."

But the arrows unraveling from a circle into a straight line aren’t aimless scribbles. They describe homologous recombination, the technology Capecchi pioneered in his molecular genetics lab at the University of Utah that has revolutionized mammalian biology and earned him the 2007 Nobel Prize in physiology or medicine.

"Gene targeting in mice has pervaded all fields of biomedicine," said the Nobel committee in announcing the award at the Karolinska Institute in Stockholm, Sweden, in October 2007. "Its impact on the understanding of gene function and its benefits to mankind will continue to increase over many years to come."

The discovery, however, was almost blocked by the National Institutes of Health (NIH). "Not worthy of pursuit" was the response of reviewers in 1980 when Capecchi first submitted an application to fund experiments testing the feasibility of gene targeting in mammalian cells. But Capecchi, distinguished professor of genetics and biology, co-chair of the Department of Human Genetics at the School of Medicine, and an investigator at the Howard Hughes Medical Institute, had been drawn to molecular biology because of the aura of possibility. He persevered. When he resubmitted his proposal four years later, the NIH reviewers not only enthusiastically approved his grant, but extended an apology: "We are glad that you didn’t follow our advice."

Perseverance is a common theme in stories of great achievements, and adversity can be the incentive an individual needs to forge ahead. Besides, bravado characterized the field of molecular biology when Capecchi entered it as a graduate student at Harvard University in the 1960s. His career, like the new discipline, was nurtured by the legendary figure of James D. Watson, who, along with Francis Crick, determined the structure of DNA.

But Capecchi doesn’t bear the reputedly brash manner of his mentor. He is a quiet-spoken man who contemplates his thoughts before they become words—or sketches on a sheet of paper. He adds no flourishes to the lines of his diagrams, no dramatic descriptions to the narrative of his life. Perhaps it is this sense of understatement that draws one’s attention to the line running down the side of the paper.

Capecchi’s pencil zigzags as he recounts wandering, homeless, for four years from the north of Italy, where his mother had left him with friends before being arrested by the Nazis, to the south, where she found him in a hospital after the end of World War II.

"It is not clear whether those early childhood experiences contributed to whatever successes I have enjoyed or whether those achievements were attained in spite of those experiences," Capecchi told an audience in Japan in 1996 when he accepted the prestigious Kyoto Prize in Basic Sciences. "When dealing with human life, we cannot do the appropriate controls. Could such experiences have contributed to psychological factors such as self-reliance, self-confidence, or ingenuity?"

Capecchi is reluctant to draw a bold line linking these as cause and effect, but neither does he cross them out. He may be a geneticist who uses probability theory to calculate the outcomes of experiments, but he is also an individual whose personal life proves that, while some events are not probable, anything is possible.

In homologous recombination, Capecchi can trace precisely how targeted genes result in physical changes in later generations. In his own life story, creativity and ambition, and a penchant for the unconventional, likewise can be traced back several generations.

Many young women at the turn of the nineteenth century lived out their dreams of moving to Europe through the characters in Henry James’ novels. But Capecchi’s grandmother, Lucy Dodd, was determined to become a painter. The talented young woman sailed from her home in Portland, Oregon, to Florence, Italy, chaperoned by her mother. Her father, who’d gained considerable wealth trading with Japan and China, stayed behind.

Lucy made her name as an impressionist painter in Florence, later hyphenating her signature with her husband’s surname, Ramberg. She had met Walter Ramberg, a German archaeologist, while visiting Nice, France. The couple married around 1900 and, by 1910, had three children: Walter, Lucy, and Edward.

After her husband’s death in 1915—he was conscripted by the German army and accidentally gunned down by his own troops—Capecchi’s grandmother bought a villa in Florence, which became "The Ramberg Villa," a finishing school for girls whom she recruited from the United States. She continued painting, often using her own children as models. The large impressionist canvasses that now hang in Capecchi’s home capture the idyllic childhood of his mother, the young Lucy. In one painting, she and her brother, Edward, share a garden tea party. In another, a young woman picks artichokes in a lush green field near the villa, where the family was cared for by "a nanny, gardeners, cooks, house cleaners, and private tutors for languages, literature, and sciences," says Capecchi.

When her brothers left for Oregon to attend Reed College, Lucy moved to Paris to study at the Sorbonne, where she became an instructor in French literature and poetry. "She had a passion for language. She spoke about 15," recalls Capecchi. "Even if she didn’t know one, in a half-hour, she could pick it up."

Through her love of poetry, which she wrote and published in German, Lucy met the Bohemians, a group of artists opposed to the Fascists and Nazis. "They thought of themselves as extremely powerful," he says. "They thought they could wipe out Fascism and Nazism with a pen." She joined them in northern Italy, where she met an officer in the Italian air force, Luciano Capecchi.

"This was a time of extremes and the juxtaposition of opposites. They had a passionate love affair, and my mother wisely chose not to marry him," says Capecchi, who was born in Verona, Italy, in 1937.

While his mother’s childhood was as playful as light shimmering on impressionist canvasses, the early years of Capecchi’s life became as dark as the boxes of poetry that his mother would seal after the war, never to publish again. He remembers images, some vividly, which, through the years, have been overlaid with recollections of others: his uncle, a scientist who was "prone to understatement," and his mother. "She purposely provided few details, because she wanted to forget," says Capecchi.

For nearly four years, Capecchi lived with his mother in a chalet in the Italian Alps. When World War II broke out, his mother, along with other Bohemians, was incarcerated in Germany as a political prisoner. Anticipating her arrest by the Gestapo, she had sold all her possessions and given the money to friends to help raise her son on their farm.

"It was an interesting life, a real rustic life," recalls Capecchi. "They grew their own wheat, harvested it, and took it to the miller to be ground. From the flour, they made bread dough, which they took to the baker to be baked."

He vividly remembers helping to make wine. "All the kids would get into enormous vats and stomp the grapes. We were squealing masses of purple energy.

"Then, I don’t know what happened. It doesn’t make sense," he says. "Somehow, the money that my mother left me ran out."

He began four years of wandering. He was four and a half years old.

"I headed south, sometimes living in the streets, sometimes joining gangs of other homeless children, sometimes living in orphanages, and most of the time hungry." He spent the last year in the city of Reggio Emilia, hospitalized for malnutrition that would not be cured, since he, like the other children, was given only one cup of coffee and a small crust of bread every day. He wanted desperately to escape. "Scores of beds lined the rooms and corridors of the hospital, one bed touching the next. No sheets, no blankets. We lay naked on those stripped beds," recalls Capecchi.

"The nurse promised me that, if I could go through one day without a high fever, I could leave the hospital. She knew that, without any clothes, I was not likely to run away. By late morning, the high burning fever would return, and we would pass into oblivion."

That is where his mother found him, after a year and a half of searching, on his ninth birthday. She bought him a Tyrolean outfit—"complete with a small cap with a feather in it. I still have the hat," notes Capecchi—and within weeks, the two set sail for America to join his uncle and aunt. His mother had changed enormously. She was unrecognizable, and never did recover psychologically. "She lived essentially in a world of imagination," he says, until she died in Arizona in 1987.

Capecchi made a "huge transition" in 1946, from surviving on the streets of Italy to thriving in a utopian commune near Philadelphia.

His uncle and aunt, Edward and Sarah Ramberg, helped establish the commune, which, by the time Capecchi and his mother arrived, had grown to nearly 65 families. Each had a private home, but the land was held in common. "It was a great place to grow up," says Capecchi, who remembers "lots of kids and lots of activities."

The day after he arrived, his uncle and aunt sent him to the third grade, although he’d never before been to school. Nor did he speak English. "The teachers allowed me to play with paints and make murals, enabling me to learn socialization and the language.

"I was very fortunate to go to Quaker schools," says Capecchi. Later, at the George School, "High school kids were treated liked college students. We had a dialogue between teachers and students. There were no textbooks in some of the classes. It made learning enjoyable."

He became very active in sports, playing on four varsity teams: football, baseball, soccer, and wrestling, where he was team captain his senior year. "Sports are important from a psychological point of view," notes Capecchi, a familiar figure at the University of Utah’s Field House, where he runs 5 to 9 miles every day. "You learn about human psychology, things that you later transfer to relationships: perseverance, pushing yourself beyond certain limits."

The sense of social responsibility permeating the atmosphere at the George School also influenced him. "There was a cognizance of world problems. It wasn’t taught, but it was felt that you could—you should—do something to make this a better world."

At home, most conversations at the dinner table were political. Edward Ramberg was a physicist at the Princeton RCA Research Laboratory who worked out the theory behind the electron microscope and helped build the first one. At the RCA laboratory, he also was involved with making both black-and-white and color televisions. Rather than encouraging Capecchi to go to college, Ramberg used "subliminal indoctrination" to persuade his nephew of the value of science. That, coupled with the Quaker emphasis on social responsibility, convinced Capecchi to study political science.

He selected Antioch College in Ohio because of the work-study curriculum in which students augmented their academic work with practical experiences. But after one political science class, Capecchi found "there wasn’t anything to bite on. There was little science in politics." He switched to science and math, graduating in 1961 with a double major in physics and chemistry.

Capecchi never took a biology class: "I learned about biology in the labs," he says. For his practical experience, he spent several terms at the Massachusetts Institute of Technology (MIT). Once, he worked with Charles "Pop" Kettering, a "very curious man," who dismantled an experimental machine Capecchi had worked three months to construct. Incredulous, Capecchi watched, later admitting, "It was fun watching Kettering and his excitement at seeing how it worked."

Although he liked the "elegance and simplicity" of physics, Capecchi realized from his lab experience that "everything we learned [in physics] was only up to the 1920s. It was still classical education." Physics lacked the excitement that Capecchi sensed in a new science being developed at the time: molecular biology.

"Here, you had a new field being born. The predominant feeling was that anything was possible. You could ask any question. That’s fairly unique," says Capecchi. "It doesn’t occur that often in history."

He knew he would switch to molecular biology in graduate school, but the question was where. On one of several trips to interview at Harvard University, Capecchi asked James D. Watson for his advice. "You’d be f---ing crazy to go anywhere else" was the infamous response.

"I believed him," says Capecchi, who discovered that "doing science in Jim’s laboratory was a blast. He’s a bold person who says anything that comes into his mind. His bravado encouraged self-confidence in those around him. He taught me not to bother with small questions, for such pursuits were likely to produce small answers."

After receiving his doctorate in biophysics in 1967, Capecchi was a junior fellow at Harvard for two years. The next four years he spent on the biochemistry faculty at Harvard School of Medicine, but he came to realize that "science was losing something."

Some 50 universities are located in the Boston area. Yet rather than collaboration, Capecchi felt that thousands of researchers were working in isolation on projects that promised "immediate gratification." "Everyone is so aware of what everyone else is doing," he explains. ‘What’s new?’ was asked every day. That limits you to short-term returns, posing questions that you know can be answered in six months."

In contrast, the University of Utah in Salt Lake City offered "a relaxed atmosphere, where you could work on projects whose outcome may take 10 years. The relative isolation tends to make you more focused on the biological question you’re working on." Plus, he was attracted to the West’s wide vistas. "Space is very important to me. I’m claustrophobic," admits Capecchi. "To be able see to for long distances...that influences the way you think. Once you move out West and go back East, you notice it."

Creativity, so essential to his grandmother’s painting and his mother’s poetry, permeates Capecchi’s science. It also helped draw him to the U, where he sensed "a more creative atmosphere."

The biology department, which recruited him, was being restructured by Gordon Lark, Ph.D., professor emeritus and former chair, who wanted the department to include "representation of all biology—from molecular biology to evolution—under one umbrella. That was an attractive feature.

"My main strength as a scientist is focus: I can think of one thing deeply. But you still want to see how your work fits into all of biology. Just the exposure to a greater diversity of disciplines stimulates you and directs your questions."

The fact that the University’s biology department had only 20 faculty members at that time also was appealing. "If we couldn’t create an atmosphere of creativity with 20," says Capecchi, "then it simply wouldn’t exist.

"It was a good choice," he says of his decision to relocate to the U of U in 1973.

Gene targeting was "inconceivable" while Capecchi was at Harvard, essentially because "the tools weren’t there to even think about it." But with the discovery of recombinant DNA technology, "the stage was set for us."

While injecting DNA into the nucleus of a cell, he noticed, "almost by serendipity," polarity in which the molecules lined up in the same direction. By 1977, he was able to prove that homologous recombination had generated the ordered array of newly introduced DNA molecules in the recipient cells. This implied that all mammalian cells had the machinery to mediate homologous recombination.

"From then on, our objective was to do gene targeting," he says. The experiments started in 1980, despite NIH’s refusal to fund the work. By 1984, Capecchi had clear success. Three years later, he applied the technology to mice. In 1989, he developed the first mice with targeted mutations.

Summarizing Capecchi’s achievements makes his research seem effortless. "From 1977-89 is a long time, but it was a progression. At each step of the way, there were hurdles," he acknowledges. Was he ever tempted to give up? "No, no," is his immediate response.

Retirement isn’t in Capecchi’s vocabulary. He jokes that his wife, Laurie Fraser—who worked many years in his lab and now devotes her time to caring for horses—"envisions me dying in the lab." The 70-year-old does find himself doing a different style of science, however. "Now, it’s managing. My hands aren’t in the experiments themselves."

He also notes a difference in his work cycle. "About every seven years, I would hop into a new area, from bacterial genetics to mammalian cell genetics to recombination to gene targeting to mouse development." But he’s already calculating the length of his next project in decades.

"We are starting a project, which I’m sure will take 20 years," Capecchi noted at the Nobel Prize press conference held on the U of U campus in October 2007. Rather than focus on what is common among organisms, he is now exploring genetic differences among species. "We can become aware of how other organisms solve different problems and, in the process, learn even more about ourselves." Bats and mice, for instance, share many similarities, ranging from size to physiology. Yet by investigating genes responsible for selected differences—for example, bats use echolocation, a sonar-like system to detect objects; mice rely upon their vision—the geneticist hopes to better understand the evolution of complex processes, such as the human auditory system.

Capecchi feels that his life continues to be influenced by the Quaker belief in social responsibility. "It affects how I behave," he says. "Not my research, but how I treat my colleagues and run my lab and raise my family. My wife and I share these ideals." Their daughter, Misha, graduated from the George School. She now studies art and science at the University of California, Santa Cruz.

Genetic technology is raising complex ethical questions, but "for me, they’re almost too specific," says Capecchi. "How should insurance companies behave? That’s not the kind of thinking I like to do."

Overpopulation is of far more concern to the researcher. "In the long run, that will be our most critical problem. It’s going to put enormous strains on this planet. How will we maintain an increasing population base?"

As the earth becomes more crowded, we not only deplete our resources, but also lessen the possibility that we can offer an environment in which all children thrive as well as survive: a poignant concern for Capecchi. His own childhood was "the antithesis of a nurturing environment, which all of us deeply want to believe is a conducive prerequisite for fostering thoughtful, creative human beings."

As Capecchi told the international audience at the Kyoto symposium, "Our only course is to provide all of our children with ample opportunity to pursue their passions and their dreams. Our level of understanding of human development is too meager to allow us to foresee which of the children in our midst will be the next Beethoven, Modigliani, or Martin Luther King."

—Susan Sample is editor of the University’s Health Sciences Report magazine.

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