Mind & Brain / Animal Intelligence

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.

“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.

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.

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.