Mind & Brain / Animal Intelligence

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.

“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.”

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.”