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Article Source: New York Times
Art by Jonathon Rosen; Photographs: Fish, Peter DaSilva for The New York Times, Dog, Grant Delin, Other Images Courtesy of Tom Recchion From the Album 'Sweetly Doing Nothing'/SchoolMap (Italy)
From Faithful Dogs and Difficult Fish, Insight Into Narcolepsy
By: INGFEI CHEN
October 23, 2007
On a sun-drenched morning this month, a small, black, bushy-haired dog trotted out from the animal care center at Stanford. The Belgian schipperke, Bear, soon veered off to lift a hind leg over a shrub.
He was, clearly, oblivious to the gravitas of the day. Bear had spent nearly seven years in the underground kennels as part of a colony of narcoleptic dogs studied by Dr. Emmanuel Mignot, director of the Stanford Center for Narcolepsy.
Dr. Mignot had just signed papers to adopt the dog, the last of the colony. Bear’s freedom ended 30 years of investigations that led to the discovery of the importance of a neurochemical called hypocretin in human and animal narcolepsy, and in normal sleep.
Bear will now be a pet. And Dr. Mignot has turned to less huggable research subjects, like wet, cold-blooded and, unexpectedly, less cooperative zebrafish.
Investigators now understand that narcolepsy arises from a deficiency of the brain cells that make hypocretin, similar to the way that Parkinson’s is caused by the loss of dopamine-producing neurons.
Dr. Mignot, who has devoted his career to studying narcolepsy, has been “a real pioneer in this,” said Giulio Tononi, a sleep researcher at the University of Wisconsin, Madison. Pivotal contributions also came independently from scientists in Dallas and Los Angeles.
The normal boundaries between wakefulness and slumber fray in narcolepsy, which plagues 135,000 Americans. Symptoms include overwhelming sleepiness during the day, insomnia at night and hallucinations or muscle paralysis while dozing off. Laughter or strong emotions like elation and anger can set off sudden muscle weakness. One good joke, and patients can find their knees buckling or heads sagging. But they remain awake.
In the early 1970s, a sleep scientist at Stanford, William C. Dement, diagnosed narcolepsy in a French poodle. He tracked down Doberman pinschers and Labrador retrievers with an inherited form of the disorder, establishing a breeding colony in 1976. The dogs shared a striking trait: collapsing in attacks of muscle weakness when excited by their favorite food.
Dr. Mignot began studying the colony in 1986. Born in Paris, he received his M.D. from the René Descartes School of Medicine in 1984, in tandem with doctorate pharmacology studies at Pierre and Marie Curie University. After a psychiatry residency, he faced a year of mandatory military training, or he could practice medicine for 16 months in Africa or Asia.
Dr. Mignot, who said he was “a nerd of the greatest dimension,” sought a different path. Intrigued by the enigma of sleep, he persuaded a French company to send him to Stanford to test its experimental narcolepsy drug on the dogs. Dr. Mignot arrived in Palo Alto, Calif., in 1986.
The medication, modafinil, reduced sleepiness but had no effect on paralysis attacks, Dr. Mignot found. In 1988, he became head of the Center for Narcolepsy and decided to hunt for the canine narcolepsy gene. “At that time,” he recalled, “there were no maps of the dog genome.”
It took 10 years and breeding nearly 200 Doberman and Labrador puppies to succeed, working with a psychiatry professor, Dr. Seiji Nishino, and others. (Animals were later put up for adoption.)
In August 1999, Dr. Mignot’s team announced the culprit: a flawed gene for a receptor protein that binds to hypocretin. In a surprise, Dr. Masashi Yanagisawa, a geneticist at the University of Texas Southwestern Medical Center, reported that month that deleting the gene for hypocretin caused narcolepsy in mice.
Those genes are normal in most human narcoleptics but they still lack hypocretin, according to separate studies by Dr. Mignot’s group and a team led by Jerome Siegel, a neuroscientist at the University of California, Los Angeles. The reason is that patients have lost 90 percent of the brain cells that make hypocretin.
In a report in May, Dr. Siegel said that in late-stage Parkinson’s disease, as well, the hypocretin-producing cells were missing, 62 percent of them. Daytime drowsiness and poor night sleep are common in Parkinson’s patients. “Long before they’re diagnosed,” Dr. Siegel said, “these individuals are sleepy.”
Hypocretin was the first protein directly linked to a true sleep disorder, and many labs jumped into deciphering its role in normal sleep. “I think hypocretin is a key molecule that helps you stay awake when you start to be sleep deprived,” Dr. Mignot said.
Scientists know that a small set of hypothalamus neurons secrete hypocretin, activating brain circuits to promote wakefulness. Research also suggests that hypocretin is involved in regulating muscle tone, metabolism and feelings of pleasure.
Initial hopes for improved narcolepsy medicines that replace hypocretin have faded, because studies showed that the molecule did not readily cross the blood-brain barrier. It may be possible to find an oral hypocretinlike drug, Dr. Mignot said.Many patients rely on modafinil, approved in 1999, and other stimulants. To suppress paralysis, patients take antidepressants or sodium oxybate, found in the date-rape drug. None of the medicines influence the hypocretin system.
Dr. Mignot is now asking why hypocretin neurons die in narcoleptic people. The best hypothesis is that the immune system destroys the cells, but no one has direct evidence of that, Dr. Mignot said.
His group has been studying rodents, tinkering with genes in their hypocretin cells to see whether damage or symptoms result. But diagnosing narcolepsy in mice is tricky. “Sometimes,” he said, “they collapse, but you don’t really know why.”
He has turned to zebrafish, which possess hypocretin and hatch rapidly. Computer analyses of fish videos convinced him that the animals do sleep. Snoozing fish drift to the tank bottom and stop. “Their tail kind of droops,” he said.
In a study published last week in PLoS Biology, the researchers reported on an effort to breed a colony of narcoleptic zebrafish by obtaining mutant fish that lacked hypocretin receptors. “I was hoping that they would collapse, like the dogs,” Dr. Mignot said. But the fish did not flop over. They were no sleepier during the day, and they were evening insomniacs.
Their hypocretin cells, it turns out, are not wired like those in mammals. Dr. Siegel concluded that zebrafish would not open major insights into hypocretin's role in narcolepsy; the sleep system “is just very different.”
Although disappointed by the findings, Dr. Mignot mused that one could learn as much from negative results as from positive. He still plans to explore the cell biology of zebrafish hypocretin neurons.
By studying fish and other animals, Dr. Mignot said and Dr. Siegel agreed, researchers could reap knowledge about the evolution of sleep across species.
Dr. Mignot is optimistic about cracking the immune-system connection in narcolepsy soon. “I don’t care actually even if it’s going to take a long time,” he said. “I’m ready to cross deserts.”
Dr. Tononi said Dr. Mignot was ideally suited for that, adding: “This is what is good about Mignot. He is relentless.”
New York Times: Science: Scientist at Work | Emmanuel Mignot
October 23, 2007
On a sun-drenched morning this month, a small, black, bushy-haired dog trotted out from the animal care center at Stanford. The Belgian schipperke, Bear, soon veered off to lift a hind leg over a shrub.
He was, clearly, oblivious to the gravitas of the day. Bear had spent nearly seven years in the underground kennels as part of a colony of narcoleptic dogs studied by Dr. Emmanuel Mignot, director of the Stanford Center for Narcolepsy.
Dr. Mignot had just signed papers to adopt the dog, the last of the colony. Bear’s freedom ended 30 years of investigations that led to the discovery of the importance of a neurochemical called hypocretin in human and animal narcolepsy, and in normal sleep.
Bear will now be a pet. And Dr. Mignot has turned to less huggable research subjects, like wet, cold-blooded and, unexpectedly, less cooperative zebrafish.
Investigators now understand that narcolepsy arises from a deficiency of the brain cells that make hypocretin, similar to the way that Parkinson’s is caused by the loss of dopamine-producing neurons.
Dr. Mignot, who has devoted his career to studying narcolepsy, has been “a real pioneer in this,” said Giulio Tononi, a sleep researcher at the University of Wisconsin, Madison. Pivotal contributions also came independently from scientists in Dallas and Los Angeles.
The normal boundaries between wakefulness and slumber fray in narcolepsy, which plagues 135,000 Americans. Symptoms include overwhelming sleepiness during the day, insomnia at night and hallucinations or muscle paralysis while dozing off. Laughter or strong emotions like elation and anger can set off sudden muscle weakness. One good joke, and patients can find their knees buckling or heads sagging. But they remain awake.
In the early 1970s, a sleep scientist at Stanford, William C. Dement, diagnosed narcolepsy in a French poodle. He tracked down Doberman pinschers and Labrador retrievers with an inherited form of the disorder, establishing a breeding colony in 1976. The dogs shared a striking trait: collapsing in attacks of muscle weakness when excited by their favorite food.
Dr. Mignot began studying the colony in 1986. Born in Paris, he received his M.D. from the René Descartes School of Medicine in 1984, in tandem with doctorate pharmacology studies at Pierre and Marie Curie University. After a psychiatry residency, he faced a year of mandatory military training, or he could practice medicine for 16 months in Africa or Asia.
Dr. Mignot, who said he was “a nerd of the greatest dimension,” sought a different path. Intrigued by the enigma of sleep, he persuaded a French company to send him to Stanford to test its experimental narcolepsy drug on the dogs. Dr. Mignot arrived in Palo Alto, Calif., in 1986.
The medication, modafinil, reduced sleepiness but had no effect on paralysis attacks, Dr. Mignot found. In 1988, he became head of the Center for Narcolepsy and decided to hunt for the canine narcolepsy gene. “At that time,” he recalled, “there were no maps of the dog genome.”
It took 10 years and breeding nearly 200 Doberman and Labrador puppies to succeed, working with a psychiatry professor, Dr. Seiji Nishino, and others. (Animals were later put up for adoption.)
In August 1999, Dr. Mignot’s team announced the culprit: a flawed gene for a receptor protein that binds to hypocretin. In a surprise, Dr. Masashi Yanagisawa, a geneticist at the University of Texas Southwestern Medical Center, reported that month that deleting the gene for hypocretin caused narcolepsy in mice.
Those genes are normal in most human narcoleptics but they still lack hypocretin, according to separate studies by Dr. Mignot’s group and a team led by Jerome Siegel, a neuroscientist at the University of California, Los Angeles. The reason is that patients have lost 90 percent of the brain cells that make hypocretin.
In a report in May, Dr. Siegel said that in late-stage Parkinson’s disease, as well, the hypocretin-producing cells were missing, 62 percent of them. Daytime drowsiness and poor night sleep are common in Parkinson’s patients. “Long before they’re diagnosed,” Dr. Siegel said, “these individuals are sleepy.”
Hypocretin was the first protein directly linked to a true sleep disorder, and many labs jumped into deciphering its role in normal sleep. “I think hypocretin is a key molecule that helps you stay awake when you start to be sleep deprived,” Dr. Mignot said.
Scientists know that a small set of hypothalamus neurons secrete hypocretin, activating brain circuits to promote wakefulness. Research also suggests that hypocretin is involved in regulating muscle tone, metabolism and feelings of pleasure.
Initial hopes for improved narcolepsy medicines that replace hypocretin have faded, because studies showed that the molecule did not readily cross the blood-brain barrier. It may be possible to find an oral hypocretinlike drug, Dr. Mignot said.Many patients rely on modafinil, approved in 1999, and other stimulants. To suppress paralysis, patients take antidepressants or sodium oxybate, found in the date-rape drug. None of the medicines influence the hypocretin system.
Dr. Mignot is now asking why hypocretin neurons die in narcoleptic people. The best hypothesis is that the immune system destroys the cells, but no one has direct evidence of that, Dr. Mignot said.
His group has been studying rodents, tinkering with genes in their hypocretin cells to see whether damage or symptoms result. But diagnosing narcolepsy in mice is tricky. “Sometimes,” he said, “they collapse, but you don’t really know why.”
He has turned to zebrafish, which possess hypocretin and hatch rapidly. Computer analyses of fish videos convinced him that the animals do sleep. Snoozing fish drift to the tank bottom and stop. “Their tail kind of droops,” he said.
In a study published last week in PLoS Biology, the researchers reported on an effort to breed a colony of narcoleptic zebrafish by obtaining mutant fish that lacked hypocretin receptors. “I was hoping that they would collapse, like the dogs,” Dr. Mignot said. But the fish did not flop over. They were no sleepier during the day, and they were evening insomniacs.
Their hypocretin cells, it turns out, are not wired like those in mammals. Dr. Siegel concluded that zebrafish would not open major insights into hypocretin's role in narcolepsy; the sleep system “is just very different.”
Although disappointed by the findings, Dr. Mignot mused that one could learn as much from negative results as from positive. He still plans to explore the cell biology of zebrafish hypocretin neurons.
By studying fish and other animals, Dr. Mignot said and Dr. Siegel agreed, researchers could reap knowledge about the evolution of sleep across species.
Dr. Mignot is optimistic about cracking the immune-system connection in narcolepsy soon. “I don’t care actually even if it’s going to take a long time,” he said. “I’m ready to cross deserts.”
Dr. Tononi said Dr. Mignot was ideally suited for that, adding: “This is what is good about Mignot. He is relentless.”
New York Times: Science: Scientist at Work | Emmanuel Mignot
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Eric Suchy, Email: [email protected], last updated: May 15, 2010
