Belfast Telegraph

Thursday 17 April 2014

Mario Capecchi: The man who changed our world

He lived as a feral child after the Nazis sent his mother to a death camp. His 'unworthy' ideas were rejected by the scientific establishment. Yesterday, he was awarded the Nobel Prize for a medical revolution

The genetics research that won Mario Capecchi a share of this year's Nobel Prize for medicine may well help to define the science of the 21st century. But the man himself was marked, in extraordinary ways, by the turbulent history of the century before.



Mr Capecchi's grandfather, a German archaeologist, was accidentally gunned down by his own men during the First World War. His father, an Italian aviator, perished in the Second World War. He himself spent that war destitute in northern Italy after his American mother was arrested and sent to the Dachau concentration camp – a survival tale all the more remarkable for the fact that he was just four years old when his mother was taken away.



One might imagine, after a start like that, that he would develop into an artist wrestling with his demons – one thinks of Roman Polanski, who survived the Warsaw Ghetto – or a political campaigner. Indeed, Mr Capecchi first intended to study political science when, at length, he got around to a university education.



Instead, though, he came to embody the very best of the can-do spirit of that defining 20th century nation, the United States, and, with his quiet manner and rigorously methodical mind, rose to the top of his chosen field in the medical sciences.



Yesterday's prize recognises work which could have enormous implications for medicine. Mr Capecchi, of the University of Utah in Salt Lake City, shares the £755,000 award with another naturalised American, British-born Oliver Smithies, of the University of North Carolina at Chapel Hill, and a Briton, Sir Martin Evans, of Cardiff University.



Mr Capecchi was lucky enough to study at Harvard under James Watson, a pioneer of DNA research, and devoted himself to the field of genetics long before it became popular or even obviously useful.



His area of interest, gene targeting, involved injecting DNA into the nuclei of cells and trying to change their genetic make-up. From the start, the dream – now rapidly turning into a reality – was to be able to control the mutation process and effectively take control of genetic change in mammalian cells.



When Mr Capecchi first applied for a grant from the National Institutes of Health (NIH) – the main US government health research agency – he was told his ambitions were "not worthy of pursuit". That was in 1980. Four years later, Mr Capecchi had pressed ahead with his experiments regardless, and demonstrated that the technology for gene mutation he had developed – something called homologous recombination – was clearly successful.



He applied for an NIH grant a second time, and this time his application was greeted enthusiastically. "We are glad that you didn't follow our advice," the approval letter read.



By 1987, Mr Capecchi was far enough advanced to apply his technology to mice. By 1989, he had developed the first mice with targeted mutations – the breakthrough for which the Stockholm committee ultimately rewarded him.



Mr Capecchi has often been asked about the impact of his childhood on his later achievements, and his answer has always been the quintessential response of a professional scientist.



"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 told an audience in Japan in 1996, when he collected the Kyoto Prize in Basic Science. "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?"



It's a good question. In Mr Capecchi's case, he had the advantage of a colourful family background. His grandmother, Lucy Dodd, bucked all convention by sailing from her home in Portland, Oregon, to Italy to pursue a career as a painter. It was there that she met the German archaeologist Walter Ramberg and had three children before the First World War ripped the family apart.



His mother, Lucy Ramberg, was a poet who fell in with an anti-fascist group of artists calling themselves The Bohemians. She had a torrid affair with Luciano Capecchi, an Italian airman, but never married him, preferring to live quietly in a chalet in the Italian Alps instead.



Mario was born in Verona in 1937 and managed nearly four years of normality. His mother was keenly aware that she risked arrest for her political beliefs and made arrangements for him to be raised by friends on a nearby farm in case anything should happen to her. She sold most of her possessions and built up a fund for her son to give him a chance at survival on his own.



When the Gestapo came for her in 1941, Mario went to the farm as planned. But after about a year something happened – nobody has survived to explain exactly what – and he was left to fend for himself. For three years he lived as a street urchin, getting by as best he could.



"I headed south," he once told an interviewer for a newsletter at the University of Utah, where he has been based since 1973. "Sometimes living in the streets, sometimes joining gangs of other homeless children, sometimes living in orphanages. Most of the time hungry."



He wound up in a hospital in Reggio Emilia along with a ward of abandoned children, who were given one cup of coffee and a crust of bread every day. He dreamed of escaping but was beset by fevers and had no clothes in which to walk out the door, even if he had been strong enough.



He stayed at the hospital for a year and might well have perished there, were it not for the miraculous survival of his mother. As soon as the Allies liberated Dachau in 1945 she set out to find her son. It took her a year to track him down, but she finally found him, on his ninth birthday.



She bought him a Tyrolean outfit, complete with feathered hat. "I still have the hat," said Mr Capecchi. And the two of them headed towards Naples, where they boarded a ship and set sail for America.



They moved in with Mr Capecchi's maternal uncle, who lived in a commune near Philadelphia inspired by the Quakers. His mother was deeply marked by her experience and, as Capecchi later recounted, was never the same. "She wasn't recognisable," he said. "She lived essentially in a world of imagination."



Mr Capecchi himself, though, thrived in the communal environment, where he could pick his friends from the children of 65 other families who lived there. The day after he arrived, he started attending a Quaker school, even though he had never received a day's formal education in his life and spoke no English.



His schooling turned out to be excellent and he was an adept pupil, inspired, above all, by his uncle who was a physicist at Princeton who helped develop the first electron microscope.



He did his undergraduate degree at Antioch College in Ohio, then transferred to the Massachusetts Institute of Technology (MIT) to pursue graduate work in physics and maths. He knew then that he wanted to work on genetics, but had to find a way to make the switch since he had never taken a biology class in his life. MIT was just down the road from Harvard, where James Watson gladly took him under his wing. When Mr Capecchi asked him whether Harvard might accept him to work on molecular biology, Watson memorably replied: "You'd be fucking crazy to go anywhere else."



Mr Capecchi spent six years at Harvard, only to conclude that the pressure to come up with quick research results was too great. The University of Utah provided a more relaxed atmosphere, "where you could work on projects whose outcome may take 10 years". He has been there ever since.



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