Fire said his 1998 breakthrough with Mello, when the two scientists published their discovery of a mechanism that could silence signals sent from malfunctioning genes, was the result of years of brainstorming. "We first started talking to each other about some of the experiments we were doing because we were both interested in this question of what happens when you put DNA into cells," Fire said. "We would throw about crazy ideas at meetings, we would talk on the phone and swap emails. Sometimes we'd veer off in totally different directions, and sometimes we'd be quite close together. "It's been a long-term collaboration."

    But the science is very new and analysts caution that technical problems and safety concerns remain to be resolved before RNAi therapies enter the medical vocabulary.

Poor research funding

    Just as soon as he got wind of the news, Mello deplored poor funding of medical research as a waste of precious time and costs human lives. "The consequence of not acting is we are sentencing people to death when we could be helping" with new drugs and therapies, he said. "We have a great opportunity and I am sad to say they are not spending enough money on that medical research."

    "I want to get right back to work," Mello said. "I feel like we have a mission that we are accomplishing, we are on the right track. I think because of the genome project and many of these other technologies that allow us to know the causes of diseases, there are tremendous opportunities to develop new drugs."

    "In every disease, there is related gene expression," he said, referring to the instructions from the DNA, at the heart of the cell, to the cell's protein-making machinery. "We are rapidly learning more about the underlying genetic cause of diseases and with technologies like RNA interference, technologies could be used ... to understand the underlying genetic base of the diseases and once that is understood, you can develop drugs, traditional molecular drugs as well as RNA therapeutic drugs, that will target these diseases."

    Mello said there were a vast number of potential applications from their research, and a number of projects are now underway.

    Fire and Mello will each receive a gold medal and a diploma and will share the prize sum of US$1.37 million. The formal awarding of the prizes will take place on December 10. M

 

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Shooting the messenger

With mRNA, doctors may soon have a sniper's rifle to train at numerous diseases

Richard Ingham

Agence France-Presse

 

 

PARIS

Gene silencing, whose discovery earned two US researchers the world's paramount prize in medicine, holds out the entrancing vision of a cure for disease by the virtual flick of a switch.

    Barely eight years have elapsed between the time when Andrew Fire and Craig Mello reported on RNA interference (RNAi) and when the Nobel Committee awarded them this year's prize for medicine on Monday.

    By the traditions of the Nobel Prize, where a young scientist can become snowy-haired waiting for the phone call from Stockholm, this is remarkably brief and by itself highlights the almost religious fervor for gene silencing.

    From the pair's initial publication in Nature, gene sleuths have worked swiftly, exploiting the phenomenon of RNAi in order to expose the mechanisms of human genome. Medical researchers are using it in the lab to explore the specific genetic switches that control HIV, polio, Huntington disease, cancer, and viral infections.

    The first generation of therapies targeting blindness in old age and a form of cancer, are already being cautiously tested on humans.

    The target for RNAi is an unsung molecule called messenger RNA, or mRNA. It is mRNA's task to convey instructions from the DNA, at the heart of the cell, to the cell's protein-making machinery. Proteins comprise, repair and destroy the body's tissue and the instructions for making them come from the genes on the double-helix DNA code.

    In work on the humble earthworm, Fire and Mello discovered that mRNA molecules whose genetic code is identical to that of a short, double-stranded type of RNA are degraded by the cell's biochemical arsenal. This process exists naturally-it is an ancient defense mechanism to control genes so that protein levels are properly regulated.

    Researchers were quick to realize that gene silencing really could be golden. Instead of blunderbuss weapons that block the action of cells (and often cause collateral damage while doing so), they could in theory get out a sniper's rifle to shoot the messenger, thus turning off the genetic cause itself.

    In the lab, scientists have used gene silencing to turn off the main proteins in HIV and the poliovirus, preventing the viruses from replicating within cells and infecting others.

    In June this year, researchers led by Beverly Davidson used gene silencing to turn off, in mice, the flawed gene behind Huntington's disease, an inherited single-gene disorder that causes progressive cognitive breakdown. When injected into the mice's brains, double-stranded RNAs reduced levels of the protein huntingtin, which causes the disease and improved the animals' behavioral symptoms.

    Clinical trials were launched in 2004 by a US firm, Acuity Pharmaceuticals, among half a dozen people suffering from macular degeneration, a blinding disorder in which a faulty gene causes blood vessels to grow across the retina.

    A Danish biopharmaceutical company, Santaris Pharma, is carrying out larger-scale human trials for RNAi therapy against a form of cancer called chronic lymphocytic leukemia.

    Novartis and Alnylam Pharmaceuticals of the United States are working on a prototype RNAi vaccine that, if it works, would not only protect against bird flu but across the whole range of influenza strains.

    The idea of a simple switch-off is especially exciting given that the other avenue of gene therapy-replacing a flawed gene with a normal one-has proved to be far more complex and problem-ridden than thought.

    A US teenager died in 2000 after being treated with gene-replacement therapy for a rare condition in which toxic ammonia builds up in the blood, while in France, three children who were given gene-replacement therapy for severe immune deficiency developed leukemia.

    These setbacks have given the aura of a false dawn around gene replacement. And they reinforce the message of caution to the RNAi true believers before the words "RNAi therapy" step from the realm of medical jargon to that of everyday speech. M

 

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FLIPSIDE OF GENIUS

Headache-immune woodpeckers, picky dung beetles win IgNobels

 

 

CAMBRIDGE, Massachusetts

Scientists who answered questions such as why woodpeckers don't get headaches, whether dung beetles like their diet, and if rectal massage can cure hiccups have at last been recognized for their work.

    The IgNobel Prizes, a tongue-in-cheek alternative to their more formal Scandinavian counterparts, were presented by genuine Nobel Prize winners on October 5 at an annual ceremony at Harvard University.

    The two-hour ceremony was geek-turned-chic as scientists traded their labcoats for tuxedoes and roared with laughter whenever someone uttered the word "inertia"-the evening's theme.

    "This is probably the only place in the world where fractal geometry gets applause," said audience member Bill Card.

    Ivan Schwab of the University of California Davis and the late Philip May of the University of California Los Angeles received the ornithology prize for their pioneering work on the ability of the humble woodpecker to avoid head injury.

    Wasmia Al-Houty of Kuwait University and Faten Al-Mussalam of the Kuwait Environment Public Authority took home the nutrition prize for showing that dung beetles are in fact finicky eaters.

    Winners had one minute to deliver acceptance speeches, with the time limit strictly policed by an outspoken eight-year-old girl.

    Audience members bucked new security regulations intended to curb an IgNobel tradition: throwing paper airplanes. Over the course of the evening hundreds were hurled at the stage, where Harvard physicist Roy Glauber dutifully swept them up, as he has for the last 10 years. Glauber joined the ranks of Nobel laureates in 2005 but still insisted on retaining his sweeping duties for the 16th annual ceremony this year.

    Despite the gala's irreverent tone, the awards are taken increasingly seriously in the scientific community, with eight of the 10 winners this year paying their own way to attend the ceremony.

    One of those unable to attend the ceremony for family reasons was Howard Stapleton of Merthyr Tydfil, Wales, who was awarded the peace prize for inventing an electromechanical teenager repellent. The device makes an annoying noise designed to be audible to teenagers but not to adults. He later used the same technology to make telephone ring tones that are audible to teenagers but not to their teachers.

    Three American scientists-Lynn Halpern, Randolph Blake, and James Hillenbrand-won the acoustics prize for conducting experiments to learn why people dislike the sound of fingernails scraping on a blackboard. Audience members squirmed as Nobel laureates recreated the jarring sound using handheld slates and gardening tools.

    And two researchers from Australia's Commonwealth Scientific and Research Organization received the math prize for working out how many photos you need to take to ensure that nobody in a group photo has their eyes closed.

    Not to be overlooked, Francis Fesmire of the University of Tennessee accepted the medicine Ig in person for his report "Termination of Intractable Hiccups with Digital Rectal Massage."

    In his acceptance speech, Fesmire recalled booking a trip to Stockholm upon first learning of the award-only to realize later that he wasn't receiving a Nobel but rather an Ig. "My first reaction was shock, then depression," Fesmire joked, waving at the audience with a rubber glove on his hand.

    Physics laureates Basile Audoly and Sebastien Neukirch of Paris University were honored for their insights into why dry spaghetti tends to break into more than two pieces.

    And while the conclusions of a group of scientists from Valencia University and the University of Illes Balears in Spain were not immediately clear, the judges deemed their study "Ultrasonic Velocity in Cheddar Cheese as Affected by Temperature" worthy of the chemistry prize.

    Also honored for cheese research, Bart Knols from Wageningen Agricultural University in the Netherlands won the biology award for his part in research showing that female malaria mosquitoes are equally attracted to limburger cheese and human feet. "Beat malaria, eat limburger," Knols said in his acceptance speech.

    Former winners who participated in the ceremony were Don Featherstone, creator of the plastic pink flamingo; Kees Moeliker, who reported the first scientifically recorded case of homosexual necrophilia in the mallard duck; and Stefano Ghirlanda, coauthor of the study "Chickens Prefer Beautiful Humans."

    In his closing remarks, host Marc Abrahams sent recipients home with a backhanded compliment: "If you didn't win an Ig Nobel this year, and especially if you did, better luck next year." M AFP