Mario Capecchi, Ph.D.
Capecchi Wins 2007 Nobel Prize in Physiology or Medicine
Learn More About Mario Capecchi's Research
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 Capecchi, 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 was almost erased by the National Institutes of Health (NIH).
In 1980, when Capecchi submitted a grant application to the National Institutes of Health that included experiments testing the feasibility of gene targeting in mammalian cells, peer reviewers were skeptical about the probability of success for this part of his proposal and thought that other experiments he planned would be more fruitful. But Capecchi, distinguished professor of human genetics at the School of Medicine, investigator at the Howard Hughes Medical Institute and distinguished professor of biology, had been drawn to molecular biology because of the aura of possibility. He received NIH funding for all of the projects, which enabled him to carry out the mammalian gene targeting experiments, and persevered.
Perseverance is a common theme in stories of great achievements. 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 zigzagged as he recounted wandering, homeless, for four years from the north of Italy, where his mother left him with friends before she was deported to a Nazi concentration camp, to the south, where she found him after World War II in a hospital.
"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 when he accepted the prestigious 1996 Kyoto Prize in Basic Sciences for his discovery of gene targeting. "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 also is an individual whose personal life proves that, while some events are not probable, anything is possible.
A heritage of creativity and ambition
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 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: Lucy Dodd-Ramberg. She had met Walter Ramberg, a German archaeologist, while visiting Nice, France. The couple married in 1905 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, she picks artichokes in a lush green field near the villa. "A nanny, gardeners, cooks, house cleaners and private tutors for languages, literature and sciences," as Capecchi described their life.
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," recalled 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. She joined them in northern Italy, where she met an officer in the Italian air force, Luciano Capecchi.
"This was time of extremes and the juxtaposition of opposites. They had a passionate love affair, and my mother wisely chose not to marry him," said Capecchi, who was born in Verona, Italy, in 1937.
Early childhood in Italy
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 pieces of poems that his mother would seal after the war, never to publish again.
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 sent to Dachau 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," recalled 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," becoming "squealing masses of purple energy."
"Then, I don't know what happened. It doesn't make sense," said Capecchi. "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 Emelia, hospitalized for malnutrition that would never 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," said 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 was where his mother found him on his ninth birthday after a year of searching. She bought him a Tyrolean outfit, "complete with a small cap with a feather in it. I still have the hat," noted Capecchi. Within weeks, the two set sail for America to join his uncle and aunt. His mother "had changed enormously. She wasn't recognizable." Nor did she ever recover psychologically. "She lived essentially in a world of imagination" until she died in Arizona in 1989.
Growing up in Quaker Pennsylvania
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," said 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 him to "learn socialization and the language."
"I was very fortunate to go to Quaker schools," said 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. 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," noted Capecchi, a familiar figure at the University's Field House where he runs 5-9 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 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 Quaker emphasis on social responsibility, convinced Capecchi to study political science.
He selected Antioch College 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.
From physics to molecular biology
Capecchi never took a biology class; "I learned about biology in the labs." For his practical experience, he worked 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 that "it was fun watching Kettering and his excitement at seeing how it worked."
Although he "really liked physics--its elegance and simplicity," 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: 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," noted 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-- crazy to go anywhere else" was the infamous response.
"I believed him," said Capecchi, who discovered that "doing science in Jim's laboratory was a blast." Watson is "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 earning 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 the Harvard School of Medicine, but realized that "science was losing something."
Some 50 universities are located in the Boston area. Rather than collaboration, Capecchi felt that the thousands of researchers were working in isolation on projects that promised "immediate gratification." As he explained, "Everyone is so aware of what everyone else is doing. '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.
"It was a good choice," said Capecchi of his decision to relocate to the U of U in 1973.
Genetic research in Utah
Creativity, so essential to his grandmother's painting and his mother's poetry, permeates Capecchi's science. It also drew him to Utah, where he sensed "a more creative atmosphere." The biology department was being restructured by Gordon Lark, Ph.D., former chair, who wanted to have the department 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," said Capecchi, "then it simply wouldn't exist."
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.
"If we could harness this machinery to mediate homologous recombination between a DNA molecule of our choice and the same DNA sequence in the living cell genome, then we would have the ability to mutate any gene and even decide ahead of time what kind of mutation to introduce into the chosen gene," explained Capecchi. Such a capability would revolutionize biology.
"From then on, our objective was to do gene targeting," he said. 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 acknowledged. Was he ever tempted to give up? "No, no," was his immediate response.
"We realized homologous recombination wasn't a simple problem, so we designed our tools to pick up rare events. That was the reason for our success," said Capecchi. Others "thought we were biting off a big problem. Their question was: would we ever get there?
"Once you have a signal, you try to improve it. We could see a signal with these techniques. We weren't waffling around in the dark."
At home in the canyon
Tree-studded mountain ridges fade to distant blue from the deck of the home Capecchi shares with his wife, Laurie Fraser, and their daughter, Misha, at the top of a canyon in Salt Lake County.
"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."
Although many of Capecchi's neighbors use their homes as summer getaways, he and his family live there year-round. When snow covers their 17 acres, they must hike up the narrow dirt road. "I like the transition, especially in the winter. With seven, eight feet of snow, it's really isolated."
In anticipation of being snowbound, Capecchi set up a computer station in an alcove off a bedroom. It remains shrouded in plastic covers; the snow and ice have yet to deter him.
The rustic three-level home, paneled in pine, was built originally as a geodesic dome, but collapsed the winter before they bought it in 1979. "There's only one right angle," explained Capecchi, who recently had to find space for an antique corner hutch he'd inherited. The couple has added onto the house in stages, so the spaces complement the eclectic decor.
Like the diversity Capecchi values in science, their home is a fascinating blend of art. Green and orange papier-mache fish that Misha made dangle above a long wood chest dating from the 15th century, which the family inherited from The Ramberg Villa in Florence. A Bali mask Capecchi brought back from a scientific trip hangs on a nearby wall, while whimsical sculptures of a racoon and porcupine not only adorn the loft, but "actually hold up the roof."
Musical accompaniment inside the home is provided by two parakeets and two cockatiels, who live quite peacefully with four cats, one dog and two rats. Fraser's horse--she specializes in dressage--is stabled in Draper, since their property is so steep.
"My wife wants to live somewhere she can have lots of horses," said Capecchi. "But she thinks I'll never retire. She envisions me dying in the lab."
Retirement doesn't seem to be in Capecchi's vocabulary, although he does find himself doing "a different style of science. Now, it's managing. My hands aren't in the experiments themselves. But I haven't put thought into what will be the next phase of my life."
Genetic engineering and human potentiality
World peace was more than an ideal to Capecchi's uncle, Edward Ramberg. A founder of Scientists for Social Responsibility, Ramberg lived his belief that peace was possible. Until his death in January 1996, the 88-year-old scientist walked three-and-a-half miles every day in Philadelphia to volunteer at the American Friends Service Committee.
His nephew doesn't claim to be "too religious," but feels that his life continues to be influenced by the Quaker belief in social responsibility. "It affects how I behave," said Capecchi. "Not my research, but how I treat my colleagues and run my lab and raise my family. My wife and I share these ideals. We're strongly thinking of sending Misha to Quaker camp."
Genetic technology is raising ethical questions as complex as those surrounding world peace, but "for me, they're almost too specific," said 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."
First published in the University of Utah Health Sciences Report
Author: Susan Sample