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Dr. Mario Capecchi and his science that changed the world

 

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Dr. Mario Capecchi is a researcher at the University of Utah and Huntsman Cancer Institute, as well as a distinguished professor of human genetics and biology at the university. He is also the institute’s only researcher with a Nobel Prize.

The work for which Capecchi won the prize is so landmark that newspapers called him a “genetics giant” and said his research “could have enormous implications for medicine” and “may well help to define the 21st century”.

His Life

Capecchi's mother
Capecchi's mother at their chalet before her arrest

Capecchi was born in October of 1937 in Verona, Italy at a time when “Fascism, Nazism, and Communism were raging through the country”. His father was an Italian aviator and his mother was an American poet and scholar who published poetry in German—the language of her father—and taught literature and languages at a university in Paris. His parents never married, and Capecchi lived on a chalet with his mother until the age of three.

He writes, “In the spring of 1941, German officers came to our chalet and arrested my mother. This is one of my earliest memories. My mother had taught me to speak both Italian and German, and I was quite aware of what was happening. I sensed that I would not see my mother again for many years, if ever. She was incarcerated as a political prisoner in Germany.” He believes she was imprisoned in Dachau.

Before her arrest, his mother had suspected she may be arrested for her activities with a group of anti-Fascist artists called the Bohemians, and had sold everything she owned to pay for him to live on a farm. But, after a year, he was left on his own at the age of 4. He lived on the streets for three years, sometimes joining street gangs of other homeless children. They stole food from open-air markets to survive, and slept in bombed-out buildings in the war-torn country. Capecchi was arrested several times and sent to live in hospitals or orphanages, which were sometimes worse than living on the streets.

He ended up in a hospital for abandoned children about 160 miles away from the farm. He stayed there for over a year. His malnutrition was treated with only a daily cup of coffee and a piece of bread. He likely also had typhoid. The hospital workers kept him from running away by stripping him naked, knowing he wouldn’t leave without his clothes. He spent most of that year in a feverish delirium.

When Dachau was liberated in 1945, Capecchi’s mother started looking for him. She found him a year later in that hospital. He writes, “As an example of her flair for the dramatic, she found me on my ninth birthday, and I am sure this was by design.” Despite this, she was never the same. Of those years on his own, Capecchi has said, “My recollections of those four years are vivid but not continuous, rather like a series of snapshots. Some of them are brutal beyond description, others more palatable…Her experiences were undoubtedly more horrific than mine. She had aged beyond recognition during those five years of internment. Following her release, though she lived until she was 82 years old, she never psychologically recovered from her wartime experiences.”

Capecchi's uncle
Capecchi's uncle in his physics lab

After finding Capecchi, his mother took him to Rome where he had his first bath in six years. From there, his uncle Edward paid for their passage to the United States. They lived in a Quaker commune which Edward had started. He began school in the third grade the day after they arrived, despite the fact that he spoke no English and had never been formally schooled.

 Edward and his wife raised Capecchi, because his mother’s time imprisoned during the war left her unable to do so herself. Edward was a physicist at Princeton. He developed the first electron microscope and his work was principally important to the invention of television, which he was less proud of. Capecchi says television was not allowed in the home.

He went to college at Antioch in Ohio, originally intending to study political science. It combined social responsibility—a dedication born of his Quaker upbringing—and science—a respect resulting from his uncle’s work. He writes, “I carried the charge of making this a better, more equitable world for all people. Most of the problems appeared to be political, so I started out at Antioch majoring in political science. However, I soon became disillusioned with political science since there appeared to be little science to this discipline, so I switched to the physical sciences—physics and chemistry.”

For graduate school, Capecchi was attracted to molecular biology, a totally new field of science at the time, because he could ask any question. “Everything was new. There were no limitations. The guiding principle was that the most complex biological phenomena could, with persistence, be understood in molecular terms.”

James Watson
Capecchi's mentor, James Watson, with a model of DNA

He chose Harvard, and was educated under the mentorship of James Watson, one of the discoverers of DNA’s double helix structure and a Nobel prize winner himself. Describing Watson, Capecchi said, “He personified molecular biology. His bravado encouraged self-confidence in those around him. His stark honesty made our quest for truth uncompromising. He taught us not to bother with small questions, for such pursuits were likely to produce small answers…I could not be kept out of the lab.”

Watson later said “Capecchi accomplished more as a graduate student than most scientists accomplish in a lifetime”. Capecchi said it wasn’t work, but “sheer joy”.

He did his post-doctoral work at Harvard, and served as a professor there for a short time before coming to the University of Utah to teach and pursue research of a nature that was too long-term to be done at Harvard.

 

Capecchi's Work

Capecchi’s primary interest was gene targeting: how to change the genetic make-up of mammalian cells. It’s fundamentally a “method of changing any gene in any conceivable manner in an organism”. When the entire human genome was sequenced in the early 2000’s, and the order of every A, T, C, and G was known, that project was landmark. However, it meant little without the ability to discover what each gene does. Gene targeting would allow, among other things, the inactivation of a gene to discover its function. Today, Capecchi describes it as taking a part out of a car, then subsequently watching how the car’s function changes in order to infer the role of the part.

Capecchi could remove a gene from a cell. That technology had existed for years. The problem was that cells have two copies of each gene. He needed not only to remove a gene and insert a manipulated version of it into the break but also trick the cell into converting its second copy of the original gene into the newly inserted one. This must always be done, because cells possess incredible repair mechanisms that would put him right back at step one. The cell can use the second copy of the original gene to destroy and replace the inserted gene with a copy of itself. If he could overcome this obstacle, he would have achieved his goal of selectively changing the genetic make-up of a cell.

The other problem would be how he could change the genes of an entire mammal like a mouse, rather than just a cell. 

In 1980, Capecchi submitted a grant request to study these questions to the National Institutes of Health. They denied his request. In their letter, they wrote that his idea was “not worthy of pursuit”. They felt the two problems were insurmountable and the research could not go forward. He continued the project by redirecting research funding from other projects. This was an incredible gamble. Had it failed, he likely would have lost all his funding, and his career as a scientist would have ended.

The gamble paid off. In 1984, he had more proof that his idea would work. When he applied for a grant again, the approval letter said “We are glad you didn’t follow our advice.

It took years of work. Capecchi didn’t develop the first mice with targeted genetic changes until 1989. All told, it took him about 10 years to come up with the ideas and develop the technology to do it. He calls his mice ‘knockout mice’.

Mario and a knockout mouse
Capecchi with one of his knockout mice

 

As in Capecchi’s car analogy, knockout technology can be used to study normal biological processes. However, most importantly to his research at Huntsman Cancer Institute, it also allows researchers to make animal models of human disease. He can make mice with diseases like high blood pressure, cystic fibrosis, and cancer. The technology give scientists a remarkable amount of precision in manipulating genes. It’s been said that “the ability to remove or mutate genes to assess their function has forever changed the fields of biology and medicine”. This is the accomplishment for which Capecchi was awarded the Nobel prize in Physiology or Medicine in 2007.

 

Capecchi being awarded the Nobel prize

 

His Love of Science

In 1996, after being presented an award in Japan for lifetime achievement in the betterment of humanity, he said, “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.”

He believes that, “Despite the complete absence of an early nurturing environment, the intrinsic drive to make a difference in our world is not easily quenched and that given an opportunity, early handicaps can be overcome and dreams achieved.”

For Capecchi, science is the stuff of those dreams.

“I think of the process of science as a series of concentric circles where the small circles in the centre are where most people are working. As you move further and further out to the edge of the larger circles you approach science fiction. What you have to do is find the circle in which you are comfortable. I like to work near the edge of the largest circle and hope that I don’t step over that edge, because then I would be wasting my time. I like to go out there and work on things that require not only thinking about the problem, but often developing the technology needed to solve the problem, which is why the problem is way out there.”

“I do some of my wildest thinking starting around 2:00am. In my excitement, I nudge my wife. She awakens and says “What?” And I begin my story. By 5:00am I am satisfied that I have provided sufficient details to make the story compelling and then promptly fall to sleep. As I wander off into dreamland, I hear her whisper, 'My God!'"


Sources

"Biography 41: Mario Renato Capecchi (1937 - ) :: DNA Learning Center." DNALC Blogs. Cold Spring Harbor Laboratory, n.d. Web. 1 June 2017.

Capecchi, Mario R . "Mario R. Capecchi - Biographical." Nobelprize.org. Nobel Media, n.d. Web. 1 June 2017.

Gumbel, Andrew. "Mario Capecchi: The man who changed our world." The Independent. N.p., 8 Oct. 2007. Web. 1 June 2017.

Kain, K. "The first transgenic mice: an interview with Mario Capecchi." Disease Models and Mechanisms 1.4-5 (2008): 197-201. NCBI. Web. 1 June 2017.

"Knockout mice as models for human disease." 2001 Albert Lasker Basic Medical Research Award. Albert and Mary Lasker Foundation, n.d. Web. 1 June 2017.

"The Birth of Gene Targeting: Mario Capecchi." iBiology. iBioMagazine, 03 Oct. 2016. Web. 1 June 2017. 

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