Mario Capecchi and Oliver Smithies of the United States and Martin Evans of Britain won the 2007 Nobel Prize for Medicine for their work in creating "knockout mice," the 21st-century test bed for biomedical research. The trio, who worked independently of one another, were honored for discovering how to genetically manipulate mouse embryonic stem cells, leading to lab rodents that replicate human disease.

    Their "groundbreaking discoveries concerning embryonic stem cells and DNA recombination in mammals ... led to the creation of an immensely powerful technology," the Nobel jury said.

    The discovery is technically called gene targeting but is commonly known as gene "knockout."

    Engineered mice provide researchers with a lab model that yields insights into the fundamentals of diseases ranging from Alzheimer's to cancer and the response to new drugs. Thanks to their work, scientists can now determine the role of specific genes, a breakthrough that has "revolutionized life science," the Nobel jury said. "Gene targeting in mice has pervaded all fields of biomedicine. Its impact on the understanding of gene function and its benefits to mankind will continue to increase over many years to come."

    The trio already shared the Albert Lasker Award for Basic Medical Research in 2001 for their work.

    To date more than 10,000 mice genes-approximately half of the genes in the mammalian genome-have been knocked out.

    Disabling, or knocking out, a gene is a two-step process.

    The first is to snip out a functioning gene from the animal's genome, using chemical "scissors" such as an enzyme. The next is to replace that gene with the modified one-the gene whose flaws will cause the disease to be studied.

    The big challenge is coaxing this introduced stretch of DNA to find the corresponding slot in the chromosome and then fit in snugly.

    Just a little over two decades ago, the prevailing wisdom was that the task was impossible in mammalian cells and that the DNA would insert itself in the chromosome almost randomly. But the Nobel laureates found a way to do this. In the 1980s, Evans isolated mice embryonic stem cells-the all-purpose master cells whose manipulation could create in theory any mutation of choice. In the meantime, Capecchi and Smithies, working separately, found a way to target genes by a technique called "homologous recombination."

    "Homologous" means that the introduced DNA sequence lines up with its mirror target sequence in the mouse chromosome, while "recombination" means the incoming and target sequences break and then rejoin.

    "The award is very exciting and particularly appropriate," observed Steve Brown, a leading scientist at the Mammalian Genetics Unit of Britain's Medical Research Council. "Our ability to knock out-to lose the function-of a gene in the mouse genome has been absolutely critical in understanding the genetic basis of human disease in all areas."

Dream come true

    Evans, who has been knighted in Britain, said the prize was "a boyhood dream come true."

    "I'm very pleased that British science is being honored in this way. It is a pleasure and it is the highest honor in science," said the director of the School of Biosciences and professor of mammalian genetics at Cardiff University. "This is the peak achievement of a career. It is absolutely wonderful."

    Evans said the trio's research had a wide-ranging impact on biomedicine. "Essentially it has provided for the understanding of the human genome," he said.

    Italian-born Capecchi, a human genetics and biology professor at the University of Utah, said the prize a "marvelous honor." He said he hopes to expand his genetics research into other organisms.

    "I plan to keep working in the lab for the next 20 years. I've begun a project that will probably take 20 years, so I hope so," he said. "Right now we do all our work in mice," he explained. "I would like to see whether I can extend this technology to other organisms that are much more difficult to study. How do we fight diseases through our immune systems? Some organisms do that much better than others and how do they do that?"

    Capecchi spent part of World War II living on the streets of his hometown of Verona and begging for food after his mother was arrested by the Gestapo and placed in the Dachau concentration camp.

    "It's actually a rather peaceful feeling of culmination of a life of science," said British-born Smithies, who said he was inspired to become a scientist after reading about an inventor in a comic strip. "There was a comic strip that had an inventor in it and I thought that was neat stuff and I'd be an inventor. And that's what I've been," Smithies once said in an interview. He said he was seven or eight years old at the time, and "as long as that, ever since I can remember, I wanted to be an inventor."

    A professor of pathology at the University of North Carolina, Smithies said he is currently studying kidney function and hopes that his Nobel-winning research can be used to "correct a gene in a useful way to help humans."

    "I would like to be able to see us use it, for example, to take bone marrow from a person who has a cell disease and correct the gene and then return the bone marrow to the person to help them get over their disease," he said. M

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From mice to men

Can "knockout" rodents knock out diseases?

 

Marlowe Hood, Agence France-Presse

 

PARIS

One mouse is called Methuselah. Another is called Frantic. A whiskered cousin of theirs goes by the less poetic name of p53.

    These and thousands of other genetically altered-or "knockout"-mice play a critical role in health research today. Researchers depend crucially on these unsung rodents to decipher disease, devise new treatments and explore the mysteries of the genetic code.

    "Most of our profound understanding of how genes cause disease in humans has come by identifying particular genes in the mouse, knocking them out, and then looking at what disease develops in the mouse and how it develops," said Steve Brown, head of the Mammalian Genetics Unit of Britain's Medical Research Council.

    "Without this toolkit, we would be considerably hampered," said Brown, a specialist on the genetics of deafness, who described the technique as a "grand, groundbreaking achievement."

    In the 1980s, Mario Capecchi, Oliver Smithies, and Martin Evans devised a technique to remove a functioning gene from the mouse's genetic code and replace it with a flawed counterpart to replicate human disease.

    Knockout mice have been used as a model for various cancers, heart disease, diabetes, Parkinson's, Alzheimer's, and scores of other conditions.

    "Methuselah mice," which enjoy extraordinary longevity for rodents, are helping to find the keys to ageing, while so-called "Frantic mice" are shedding light on the genetic roots of anxiety. Others carry the name of the disease-causing gene, such as the p53 cancer gene.

    The targeting technique is so smart that engineers can choose to manipulate a gene that is a notorious culprit in one disease, or a selection of genes that play a supporting role in a harmful molecular cascade.

    "You can knock out one gene and observe what happens, or introduce two or three copies of that gene, to get a more subtle picture of what occurs in the proteins controlled by the gene," said Nadine Bouby-Bouzidi of France's National Institute for Medical Research, who worked on diabetes with Smithies.

    "Ongoing international efforts will make 'knockout mice' for all genes available within the near future," the Nobel jury said.

    "We are now on the cusp of being able to knock out every gene in the mouse genome," said Brown, who is part of an international consortium of European, US, and Canadian scientists working toward this end.

    Knockout mice, while extremely useful, have their limitations as a mirror of what happens among humans, which are more complex creatures. "But in terms of their fundamental developmental processes-their biochemistry, their physiology-the two organisms are extraordinarily similar," said Brown. M

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"Bring out the freak"

Hamsters on Viagra take center stage at Ig Nobel awards

 

Stephanie Schorow, Agence France-Presse

 

CAMBRIDGE, Massachusetts

Scientists who discovered that (sildenafil) Viagra helps hamsters overcome jet lag and a Japanese researcher who extracted vanilla flavoring from cow dung won top honors at the 17th annual Ig Nobel Awards.

    The awards, a tongue-in-cheek homage to their Scandinavian counterparts, were announced during a raucous ceremony at Harvard University in Massachusetts that shone a bright light on obscure and often bizarre research and inventions.

    The Igs, as they are known, are chosen by the Annals of Improbable Research magazine to highlight scientific achievements that, in the words of editor Marc Abrahams, "first make people laugh and then make them think."

    Among the winners were a British-US duo for a penetrating report on the effects of sword swallowing and a Spain-based team who answered the question of whether rats can discriminate between Japanese and Dutch spoken backwards.

    "It was a surprise, it was the last thing we expected," said Nuria Sebastian-Galles, one of the Barcelona team of scientists, of the findings. The awards, she said, "bring out the freak inside most scientists."

    Seven of the 10 winners this year paid their own way to accept the awards, which were handed out by six real Nobel Prize laureates. Although pelted by paper airplanes, as per tradition, each winner expressed delight at receiving the small trophies affixed with a chicken and an egg.

    Asked why chickens were chosen as this year's theme, master of ceremonies Abrahams looked astonished and said only: "How could you not?"

    Some scientists have complained that the satirical awards unfairly tarnish legitimate research. Others say a sense of fun humanizes scientists.

    "I don't take it as an insult at all," said Brian Witcome, a British radiologist who won the medicine prize for his sword-swallowing research. "Humor adds to research," he said. His coauthor, US scientist Dan Meyer, even gulped down a short sword before thanking the whooping crowd with the hilt between his teeth.

    Past winners who showed up included the creator of the pink plastic flamingo, the inventor of a hiding alarm clock, and a researcher who reported the first known case of homosexual necrophilia in the mallard duck.

    Research highlighted by this year's awards ranged from a study of how sheets wrinkle and how the word "the" causes headaches for indexes, to why humans can't stop eating when presented with an apparently endless bowl of soup.

    Some winners tried to explain their research but if they talked for more than 60 seconds they were interrupted by an eight-year-old girl who repeatedly intoned, "Please stop, I'm bored."

    Nonetheless, Dutch scientist Johanna van Bronswijk managed to describe why she is doing a census of the mites, insects, spiders, and other creatures with which humans share their bed. "I found that you never sleep alone," she said.

    Diego Golombek, the Argentine who found the cure for hamster jet lag, thanked his assistants "for going to the store to get the Viagra for us."

    Also honored was a Taiwanese man who patented a device to net bank robbers, but who could not attend the ceremony because he has apparently vanished. "Someone in Taiwan suggested the man is trapped inside his machine and is there to this day," Abrahams said.

    The highly coveted peace prize was given to a US Air Force laboratory for researching what the committee dubbed the "gay bomb"-a chemical weapon that would make enemy soldiers become sexually irresistible to each other.

    No one showed up to collect the award but a disco ball dropped over the stage and Abrahams said the bomb would be demonstrated before an official censor of the evening's activities intervened.

    Japanese researcher Mayu Yamamoto, who received the chemistry Ig for her work extracting vanilla flavor from cow dung, got an additional honor: a local ice cream shop created a new flavor, the "Yum-a-Moto Vanilla Twist," in her honor.

    Yamamoto said she first learned of her award by e-mail and thought it was a joke but decided to go to the ceremony because "I want everyone to know about my research."

    As if further levity were needed, the ceremony was punctuated with goofy "Moments of Science" and a contest to win a date with a Nobel laureate billed with the slogan: "He's shapely, he's sassy, and he's smarter than you." M

 

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