When Emmanuel Mignot opened the door, a black-and-tan dachshund bounded into the basement room at Stanford University's Sleep Research Center, its nails scrabbling the concrete floor. The dog looked around, shook itself with a flapping sound, and wagged its tail excitedly. Across the room, a dozen men and women exchanged nervous glances. They had seated themselves carefully in chairs against the wall, and now they watched as Mignot's associate, Seiji Nishino, reached for his research tools: a can of dog food and a spoon.
‘In less than two years I suspect we’ll
have good drugs in development for
narcolepsy and sleep disorders in general’
“Allez beau teckel!” said Mignot, a native of Paris, as he knelt to rub the dog’s belly. Beau seemed an excitable but ordinary dog. His regular food was dry pellets, Nishino told the visitors. But today, Beau would get some nice, aromatic, canned dog food—a special treat. Nishino rapped the spoon against the can. The visitors went silent. They remained completely still in their chairs as Nishino opened the can. He spooned the wet food onto the floor, and Mignot cooed, “C’est de la bonne viande.” Beau perked up, trotted happily to the food, sniffed, rolled his eyes in pleasurable anticipation—and dropped to the concrete, limp as an empty sock. His chin hit the floor with a thud.
Mali Einen tries to keep her emotions in
constant check, fearing a moment of
excitement could prompt her to suddenly
collapse in a heap just like the Dobermans
on the previous page. “It would almost be
better to have a severed limb,” she says.
“People would be more understanding.”
The visitors, members of a narcolepsy support group from California’s East Bay area, laughed, then caught themselves and awww-ed in sympathy. One of the most dramatic symptoms of narcolepsy, the disorder in which sleep instantly overwhelms a person during the day, is collapse triggered by excitement or strong emotions. So what happened to Beau, a narcoleptic dog, did not surprise the people in the room. “He knows we’re laughing at him,” said a handsome, silver-haired man, as his wife reached down, lifted Beau’s head, then gently set it down again. “It feels like a dead weight, just like your body does,” she said.
Mignot’s purpose in occasionally inviting people with narcolepsy to meet Beau is to give them hope. As a physician, Mignot has been working with narcoleptics for 13 years and knows all too well how physically and emotionally debilitating the disease can be. As a lab researcher with a Ph.D. in molecular pharmacology, he believes he has finally discovered the key to understanding—and maybe someday curing—narcolepsy. Last August, Mignot announced that he and others experimenting with a colony of narcoleptic dogs at the Stanford Sleep Research Center had identified the gene that causes narcolepsy. A few weeks later, in one of those odd coincidences of medical science, molecular geneticist Masashi Yanagisawa and his colleagues at the Howard Hughes Medical Institute and the University of Texas Southwestern Medical Center announced they had found a closely associated gene in mice. Both groups of scientists believe their discoveries could soon lead to an effective treatment for the disease, which afflicts more than 135,000 Americans.
A RESEARCH TWOFER
Molecular geneticist Masashi Yanagisawa once said that the human brain controls only three important things: eating, sleeping, and sex. Now it appears he has identified a single molecular mechanism that affects two of the three: eating and sleeping.
Yanagisawa and his colleagues at the University of Texas Southwestern Medical Center wanted to observe feeding patterns in mice, so they genetically engineered a strain of mice that lacked a certain brain hormone affecting appetite. With an infrared camera, they taped 300 hours of nocturnal mouse activity and then began the tedious job of watching the tapes. They saw mice eating, running around, playing, grooming, and—surprisingly—passing out, waking up, and passing out again.
Yanagisawa wondered why. “It was very striking, bizarre behavior,” he says. To find out more, he and his colleagues inserted needlelike electrodes into the brains of the mice. He found that the mice weren’t having seizures, suffering hypoglycemia, or experiencing electrolyte disturbances. Instead, the creatures were deep in REM sleep—just as narcoleptic humans or dogs are during an attack of instantaneous paralysis. And the mice were missing the same molecules that Emmanuel Mignot and his colleagues at the Stanford University Sleep Research Center had identified as a key factor in dog narcolepsy: hypocretins, also referred to as orexins. “We didn’t aim at, or expect, sleep to be involved,” says Yanagisawa. “But these mice have exactly the same disturbances as the dogs.”
Now, Yanagisawa says, many researchers—including those at drug companies—are looking for mutations in human orexin-receptor genes. He agrees that the research could lead to improved sleep-control drugs. “Barbiturates generally silence your neurons and create an abnormal state of sleepiness, and they shorten the REM period, which is not good,” he says. “So moderating the orexin system and directly regulating only the sleep might lead to a better, more natural form of sleep and a longer REM period.” And yes, he confirms, he also found subtle differences in the mice’s eating patterns. They ate less. So it’s no surprise that researchers are already looking for ways of making antiobesity drugs that work on the orexin system. —Jack McClintock
Narcoleptics are not the only ones for whom the new findings offer cause for hope. Ultimately millions of Americans, including everyone who has insomnia or is overweight, could benefit. “In less than two years,” Mignot says, his optimism visible on his face, “I suspect we’ll have good drugs in development for narcolepsy and sleep disorders in general.” And the potential doesn’t stop there. Sleeping and eating are linked both behaviorally and evolutionarily. “When you start to become hungry, you shouldn’t curl up and sleep—you should go hunting,” says Yanagisawa. “When you’re full of good food, you’re sleepier.” Now it appears that eating and sleeping are linked genetically as well. When Yanagisawa found the sleep gene in mice, he was studying a gene for eating. They turned out to be the same (See “A Research Twofer,” right). As a result, the identification of the gene could also lead to the creation of drugs to suppress appetite and fight America’s rampant obesity. Drug companies are already working on it.
In the faulty gene Mignot and Yanagisawa uncovered, a straightforward biogenetic mechanism has gone awry. A normal cell has chemical receptors on its surface that link up with specific molecules generated by the body and control the timing of such functions as eating and sleeping. If the receptor genes don’t work (as in narcoleptic dogs), or if the chemical isn’t produced (as in the mice), things go wrong. The challenge is to discover how the mechanism breaks down in narcoleptic humans and then to develop drugs that correct it.
Until Mignot and Yanagisawa announced their findings, narcolepsy mystified the medical profession. In fact, researchers say, most narcoleptics remain undiagnosed. One man was 73 before he learned he had it, and by then his reputation for laziness was legendary. “It’s difficult to diagnose,” says Mignot, “because sleep is so natural, the last thing to complain about.” It doesn’t help that some doctors aren’t aware the disorder exists. Narcolepsy is characterized by extreme daytime sleepiness, involuntary sleep attacks, paralysis, hallucinations and, in its most severe and disturbing form, episodes of cataplexy in which a person—usually in the grip of strong emotion—suddenly loses muscle tone and goes limp. That’s what happened to Beau when he sniffed that dog food. Strangely, the disorder doesn’t appear to shorten lives. Narcoleptics get a normal amount of sleep in a 24-hour period; it just happens to be broken into uncontrollable and disabling pieces.
Narcolepsy usually shows itself during adolescence or in the early twenties, “a really tough time,” Mignot notes. “At an age when narcoleptics want to conform, they get so excited they fall down.” In their private lives, many narcoleptics face unhappy choices: Do I sit in the dark, or risk climbing a high ladder to change the burned-out bulb and maybe have an attack and fall? I’m getting married today; shall I skip my antidepressant so I can perform sexually on my honeymoon, or take a pill so I won’t pass out during the ceremony? Am I too hungry to sleep, or too sleepy to eat?
In one study of 500 narcoleptics, 85 percent said the disorder had reduced their job performance, 33 percent said their medications reduced their sex drive, 15 percent were permanently disabled, and many reported impaired memory and concentration. “I can’t even read a children’s book to my kids,” says a 48-year-old man. “The first complete sentence my daughter said to me was ‘Daddy, wake up.’ ”
Narcoleptic attacks often provoke nervous laughter among observers, but the condition is anything but funny. Yes, narcoleptics have fallen asleep in their spaghetti, but they have also caused serious auto wrecks. In its worst form, the malady can destroy a person’s life. “Without medication, I can hardly do anything,” says Mali Einen, 38. She discovered she was narcoleptic at age 24 when her baby daughter, Kelsey, said something funny during a Christmas celebration. At that moment, Mali suddenly went limp. Her jaw fell open, her muscles turned to yarn, and she collapsed “like a puppet with its strings cut, right into the Christmas tree.”
Stanford's Center for Narcolepsy home page: www.med.stanford.edu/school/Psychiatry/narcolepsy.
For a history of sleep research, and of the Stanford University Sleep Research Center: www.stanford.edu/~dement/history.html.
More about Masashi Yanagisawa's research can be found at www.hhmi.org/news/yanagisawa.htm.
Years later, relaxing in the sunny lounge of a Palo Alto research lab, Einen appears cheerful. Blue-eyed and attractive, she lives in a million-dollar house in upscale Menlo Park with her daughter, now 16. But her life has changed. She was a single mom with a successful career as a hedge-fund money manager, her earnings doubling, then tripling. But as her narcolepsy grew worse, she had increasing difficulty coping with it at work and at home. Since that Christmas years ago, she has fallen asleep unwillingly thousands of times, at the most awkward possible moments, with her eyes rolled back, her jaw slack. She has hallucinated—dreamed she ate and woke up feeling full, dreamed she’d been touched and woke up with the feel of a stranger’s fingers on her skin. Once, passed out and dreaming that someone had broken into the house, she woke up, dialed 911 and screamed, then had to explain what had happened to the police. She hasn’t worked or dated in years, and only medication keeps her—sometimes just barely—alert enough to get through the day. She and Kelsey live alone.
Sudden excitement at the sight of a scoop
of dog food causes Blitzen, a narcoleptic
Doberman, to collapse at Mignot’s feet.
When people with narcolepsy suffer similar
attacks, they may remain conscious but
find themselves unable to either move or talk.
“I really don’t have friends,” she says. “I’m exhausted all the time. I took a 10-minute nap before coming here. It’s been lonely,” she says resignedly. “Life is lonely.”
As Beau vividly illustrated, the disorder’s most conspicuous feature is cataplexy, which can range from a mere sagging of the jaw and buckling of the knees to full, severe, and instantaneous rag-doll limpness that can last for minutes. “Cataplexy feels like all the joints and bones in your body collapse at once,” says a 12-year-old girl who experiences it. “It’s a struggle for my mind to regain strength and reownership of my body. My mind feels numb.”
What we call narcolepsy was first noted by French physician Jean-Baptiste Edouard Gelineau in the 1880s. Normal people remain wakeful during the day, then pass through three stages at night: wakefulness, non-rem sleep, and rem sleep—in that order. rem sleep, named for the rapid eye movements that accompany it, is the active, dreaming stage of sleep, in which the body is paralyzed and the mind is dreaming. In narcoleptics, however, rem sleep arrives out of order. Usually triggered by emotion, it abruptly follows the wakeful stage, and the person slumps into a waking dream.
So far, even the best available drugs treat only symptoms. Amphetamines and other stimulants keep the narcoleptic awake; antidepressants fight off cataplexy. Just finding passably useful medications can be time-consuming. Einen took Ritalin for a year, then found she was building a tolerance to it. So she switched to Dexadrine, an addictive stimulant she has relied on for 10 years. One man has taken it daily for 40 years. While Einen was employed, the amphetamine helped her keep moving, but it never had the same benefits as a nap, she says. In addition, she’s taken a succession of antidepressants over the years to curb her cataplexy. Without them, she would have been bedridden. “But they seemed to make my disrupted nighttime sleep so much worse, which made me more tired, which led to more stimulants—yuck!” Now she’s taking an experimental drug, gamma hydroxybutyrate, which she says knocks her into a deep, restorative sleep, but only for two or three hours. Then she has to get up and take another dose. “I still need naps,” she says. As a way of life, it’s far from perfect.
For a narcoleptic, even jokes are dangerous. Heading for the basement lab, one of the East Bay narcolepsy support group members—the handsome, silver-haired man—had ventured a small wisecrack as he neared the yelping dogs. “They don’t sound sleepy,” he said. The others laughed, but carefully. The man was feeling good, so he risked another sally of wit. “Want to see something funny?” he said. “A party of narcoleptics!”
He was taking a chance and so were the others, merely by listening and laughing. Narcoleptics don’t listen to comedy routines. They tend to avoid humor for fear it will set off an attack. Experience teaches a narcoleptic to control his or her emotions, to filter experience, to dampen personality, to suppress passion. “You know, if I thought something was funny, it’s a toss-up whether I’d tell you, even while I was medicated,” said Einen. “The combination of being assertive and witty is sometimes just too much.”
It is hoped that Mignot’s research will bring more cheer into the lives of all narcoleptics. He came to the United States in 1986 to test a French narcolepsy drug on the Stanford sleep center’s colony of narcoleptic dogs, mostly Doberman pinschers and a handful of Labrador retrievers and dachshunds bred for the disorder. Psychopharmacology is “one of the last fields where there’s a lot to discover,” he says. Unraveling the mysteries of narcolepsy was frustrating at first. “We were not finding the initial defect.” So after three years, he decided to look for the gene itself, and his enthusiasm for the research was eventually rewarded. “The beauty is that you can find something completely new, something that no one knew was involved in sleep,” he says. “That’s why it’s so exciting. It has a human side, and at the same time it goes to the core of what it is to sleep.”
Mignot thinks it probably
takes a defective gene
and a trigger, like stress
or even a virus, to
Dogs inherit narcolepsy much like human beings do; some siblings get it and some don’t. For a decade, Mignot and his colleagues have scrutinized the dogs’ dna, bit by bit, comparing it with that of normal littermates until, in 1998, they narrowed the defect down to a single chromosome. The gene turned out to be the same in both breeds of dog, although abnormal in different ways: a bit more dna added in the Doberman pinschers, a bit of dna altered in the Labradors. All the complex set of symptoms that add up to narcolepsy results from these tiny changes in that single gene, a receptor in the dogs’ brains intended to receive molecular signals from chemicals called hypocretins, also known as orexins.
Think of brain cells as rooms with locks called receptors on their surfaces and a hypocretin as a key that is also a stimulant. In a normal animal, the hypocretin hooks up with the lock, opens it, and stimulates it to increase electrical activity—to be alert and awake. Without the receptor gene, however, the key won’t open the lock and can’t stimulate the brain cell. That’s what’s wrong in the dogs. In Yanagisawa’s mice, the exact opposite is true. The receptor is present but the hypocretin isn’t. In other words, the lock has no key. But the effect is the same.
The question is, will it be the same in humans? And can we use the information to help narcoleptics? Mignot thinks so. But locating defective genes hasn’t resulted in any remedies for disease. Scientists years ago found the gene responsible for cystic fibrosis, but so far that hasn’t helped prevent or cure the disease. Although narcolepsy appears to be genetically based in humans, simply having the defective gene doesn’t mean a person will have the disorder. Mignot thinks it probably takes a defective gene and a trigger, like stress or even a virus, to cause narcolepsy. But finding the hypocretin-receptor gene in humans could lead to a far better, more specific treatment.
“If we’re lucky,” Mignot says, “we’ll find in humans a genetic receptor for a natural molecule like hypocretin. Such receptors are natural targets for drug development. “It’s easy to find drugs that can replace or block or mimic the effect of the molecule,” Mignot says. The benefits of such drugs would extend far beyond the treatment of narcolepsy. For narcoleptics and insomniacs alike, sleep isn’t really the problem—timing is. “A lot of people would love to have narcolepsy, but only at night,” Mignot says with a smile. “This may [lead to] a very good sleeping pill.”
“You can imagine a flurry of work now,” Mignot tells his touring group from the East Bay, adding cheerfully: “We’re going to be overwhelmed with competition.”
“You’ll figure all this out in our lifetime, right?” asks one of the women.
“I hope so,” Mignot tells her.
So does Mali Einen. Her daughter, Kelsey, is old enough to spend some time on her own, and Einen is tired of staying in the house, tracking her investments on-line. She has decided to look for a job. “I need to go to work,” she says. “I’m capable. I’m bright. But I’m scared to death.” She’s taking her medication, waking in the middle of the night to take more, grabbing 40 winks whenever she must during the day. She’s easy to spot, she says: “I’m the weirdo in the Burger King parking lot with the doors locked and the seat pushed back, taking a nap.”