Two Americans and a Briton won the 2007 Nobel Prize in medicine yesterday for developing the immensely powerful “knockout” technology, which allows scientists to create animal models of human disease in mice.
The winners, who will share the $1.54 million prize, are Mario R. Capecchi, 70, of the University of Utah in Salt Lake City; Oliver Smithies, 82, of the University of North Carolina in Chapel Hill; and Sir Martin J. Evans, 66, of Cardiff University in Wales.
Other scientists are applying their technology, also known as gene targeting, in a variety of ways, from basic research to the development of new therapies, said the Nobel Committee from the Karolinska Institute in Stockholm that selected the winners.
The knockout technique provided researchers with a superb new tool for finding out what any given gene does. It allows them to genetically engineer a strain of mice with the gene missing, or knocked out, then watch to see what the mice can no longer do.
After the first decoding of the mouse and human genomes in 2001 yielded thousands of new genes of unknown function, knockout mice became a prime source of information for making sense of these novel genes.
Most human genes can also be studied in this way through their counterpart genes in the mouse. Mice have been likened to pocket-size humans, because they have the same organs and their genes are about 95 percent identical in sequence. Scientists have developed more than 500 mouse models of human ailments, including those affecting the heart and central nervous system, as well as diabetes, cancer and cystic fibrosis.
Scientists can now use the technology to create genetic mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal, the Nobel citation said.
Gene-targeting technology can knock out single genes to study development of the embryo, aging and normal physiology. So far, more than 10,000 mouse genes, or about half of those in the mammalian genome, have been knocked out, the committee said.
Researchers can also make conditional knockouts, mice in which a gene of interest can be inactivated in a specific tissue or part of the brain, at any stage in life. Another important variation is to tag a normal gene with a so-called reporter gene that causes a visible color change in all cells where the normal gene is switched on.
Knockout mice are so important in medical research that thousands of strains are kept available in institutions like the Jackson Laboratory in Bar Harbor, Me.
“The technique is revolutionary and has completely changed the way we use the mouse to study the function of genes,” said Dr. Richard P. Woychik, the lab’s director. “When people come across a novel human gene, one of the first things they think about is knocking it out in a mouse.”
The three laureates, who are friends but work independently, also shared a Lasker Award in 2001. They began their work in the 1980s, and the first reports that the technology could generate gene-targeted mice were published in 1989. The reports involved a rare inherited human disease, the Lesch-Nyhan syndrome, in which lack of an enzyme causes fits of self-mutilation.
The prize was particularly rewarding for Dr. Capecchi, who said he lived as a street urchin in Italy during World War II and later had to prove his scientific peers wrong after they rejected his initial grant to the National Institutes of Health in 1980, saying his project was not feasible.
Dr. Capecchi’s mother, the daughter of an American, had lived in a luxurious villa in Florence and had become a Bohemian poet, writing against Fascism and Nazism. She refused to marry his father, an Italian Air Force officer with whom she had had a love affair.
When young Mario was not yet 4, the Gestapo came to their home in Tyrol, in the Italian Alps, to take his mother to the Dachau concentration camp — an event he said he remembered vividly.
Because she knew her time of freedom was limited, she had sold all her possessions and given the proceeds to an Italian farming family, with whom Mario lived for about a year. When the money ran out, the family sent him on his way. He said he wandered south, moving from town to town as his cover was exposed. He wandered, usually alone, but sometimes in small gangs, begging and stealing, sleeping in the streets, occasionally in an orphanage.
At the war’s end, the malnourished boy was put in a hospital for a year. During that time his mother, who had survived Dachau, searched hospitals and orphanages for him. A week after she found him — on his birthday — they were on a boat to join her brother in the home of a Quaker family in Pennsylvania.
The family put Mario in the third grade, where as a means of communication his teachers told him to draw murals. As he did, he slowly learned English. Because of the street smarts he developed in Italy, he became a class leader and the boy who beat up the bullies.
He went on to study political science at Antioch College, alternating periods of work and studies. Then he went to the Massachusetts Institute of Technology and Harvard, where he worked in the laboratory of James Watson, the Nobel Prize-winning co-discoverer of the structure of DNA.
When he decided to leave the Harvard faculty in 1973 because members of the department did not get along, he said, and did not recruit sufficient younger scientists, Dr. Capecchi went to Utah. Colleagues told him, he said, that he was “nuts” to leave Harvard’s Ivy League splendor. But Dr. Capecchi said Dr. Watson told him he could do good science anywhere.
Dr. Capecchi said the main advantage was that he could work on long-term projects more easily in Utah than at Harvard, where there was a push to get results quickly.
Dr. Capecchi said that when he reapplied to the N.I.H. in 1984 for the grant it had rejected in 1980, he was told, “We are glad you didn’t follow our advice.”
After learning he had become a Nobel Prize winner, Dr. Smithies told Agence France-Presse that “it’s actually a rather peaceful feeling of culmination of a life of science.”
Dr. Smithies has credited his interest in science to his boyhood love for radios and telescopes, and for a comic-strip inventor whom he wanted to emulate. He earned a scholarship to Oxford, then dropped out of medical school to study chemistry before moving to the University of Wisconsin. Because of a visa problem, Dr. Smithies worked in Toronto for about seven years before returning to Wisconsin. He became a geneticist and moved to the University of North Carolina 19 years ago.
Dr. Smithies is a licensed airplane pilot and is fond of gliding.
Dr. Evans had planned to have an “ordinary day” off work cleaning his daughter’s home in Cambridge, England, where he was visiting when he learned he won the prize. It was “a boyhood dream come true,” Dr. Evans told Agence France-Presse.
Like Dr. Capecchi, Dr. Evans said his scientific career was an upward struggle. In an interview with the Lasker Foundation, Dr. Evans said recognition was important to him because he often was a lone scientist who cried out against the consensus. In applying for grants, he said he was told many of his ideas were premature and could not be done.
“Then five years later,” he said, “I find everyone is doing the same thing.”
Nicholas Wade contributed reporting.
By LAWRENCE K. ALTMAN
GENETIC PIONEERS Three scientists won this year’s Nobel Prize in medicine for work on creating “knockout mice.” The larger one lacks a gene that limits muscle growth. From left, the Nobelists are Martin Evans of Cardiff University, Wales; Mario R. Capecchi of the University of Utah; and Oliver Smithies of the University of North Carolina at Chapel Hill.
No comments:
Post a Comment