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Their Duty Done,The Drowsy DogsCan Doze Off Again
Stanford Pack Helped SolveMystery of Narcolepsy;Now It's Up to Zebrafish
By RON WINSLOW
 March 15, 2007; Page A1
PALO ALTO, Calif. -- For three decades, Stanford University researchers kept a colonyof narcoleptic dogs to study the mysterious disorder that causes people to becomeexcessively sleepy in the middle of daily activities.When excited by a favorite treat or roughhousing withone another, the dogs -- mainly Doberman pinschersand Labrador retrievers -- would suddenly crumple tothe floor, limp as rag dolls. Over the years, the dogs became a powerful scientific, educational and public-relations resource. Live performances were a mainstayof psychiatrist William Dement's popular Sleep andDreams course at the medical school. The dogs wereeven on the "Today" show.But the menagerie, which at one point numbered 80dogs, has gradually been disbanded. Today, only Bear, a black energetic schipperke, remains. Scientists now relymostly on smaller research animals -- includingzebrafish -- which are cheaper and more suited togenetics research."The colony just isn't useful anymore," says Emmanuel Mignot, director of the Center for  Narcolepsy here. Narcolepsy is a debilitating conditionthat affects about one in 2,000 people.It typically arises during adolescence,though it often goes undiagnosed for years. Symptoms include abnormalities in dream sleep and, often, attacks of cataplexy, asudden muscle weakening that can cause people to collapse in a sleeplike paralysislasting from a few seconds to several minutes. The attacks tend to be triggered by positive emotions.
Emmanuel Mignot and Bear Dr. Mignot from Stanford University's Center for Narcolepsyshows two dogs with narcolepsy who can't play withoutperiodically losing muscle strength and falling asleep.
 
Stanford's first narcoleptic dog was a French poodle donated to Dr. Dement in 1973. "Wenamed her Monique," he recalls. But when they bred her with other narcoleptic dogs, theoffspring didn't develop narcolepsy, indicating that Monique's disorder wasn't inherited.Then, in the late 1970s, the laboratory received two litters of narcoleptic pups --Dobermans and Labs -- that did appear to have a genetic form of the disorder. They became founding animals of the colony.Lewanne Sharp, a researcher experienced in breeding dogs, was hired to develop andmanage the colony. "It was a definite challenge trying to get two narcoleptic dogs to breed," she says. "When the male would get excited and mount the female, invariably hewould fall asleep."
Personal Connection
Still, Ms. Sharp managed to produce about 30 litters. Pups were named according tothemes: Paris was from the capital cities litter; Zeus was one of the gods. Sleepy andDopey were from the Seven Dwarfs litter.Even in research papers, Dr. Mignot referred to the dogs by name, not number. "We reallyfelt we had a personal connection with the dogs," he says.The search for a cure took a leap in 1999 when Dr. Mignot, a Howard Hughes MedicalInstitute investigator, and his colleagues discovered a gene in the Stanford dogs' DNAthat causes narcolepsy."The dogs laid the foundation for much of our current thinking about narcolepsy," saysThomas Scammell, a sleep researcher at Harvard Medical School and Beth IsraelDeaconess Medical Center, in Boston.
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•Stanford's Center for Narcolepsy
The landmark paper describing the discovery of the narcolepsy gene was published in the journal Cell in August 1999; a picture of a Doberman pinscher was on the cover, with"Prancer" (from the Santa's reindeer litter), inscribed on his collar.In many cases, the dogs were needed for just six months to a year, so the lab found people to adopt them. When Jeremiah Hall of San Francisco visited the colony inresponse to a newspaper ad, a Labrador retriever named Goofy caught his eye. "I bentdown to say hello and she immediately went narcoleptic," Mr. Hall, a senior vice president at public-relations firm Feinstein Kean Healthcare, recalls. "She had to comehome with me."Ice cream and games of fetch were reliable triggers for Goofy, as were walks in the city.When Mr. Hall got home from work, Goofy would run to the door in anticipation of a
 
walk and then "fall asleep at the door," he says. Attacks typically lasted just a fewseconds.Goofy died in December at age 13. "We always thought of it as endearing, not adisability," Mr. Hall says.Ms. Sharp, who left Stanford in the mid-1990s after budget worries prompted adownsizing of the colony, still has a Lab named Sorbet (from the Popsicle litter, so named because it was conceived with frozen semen), whose cataplectic episodes are triggered by picking up a tennis ball.Publication of the paper announcing the gene discovery capped a decade of painstakingwork by Dr. Mignot and his colleagues that involved close to 100 litters of animals tohome in on the location of the gene.It also appeared just two weeks ahead of a report from researchers led by MasashiYanagisawa at University of Texas Southwestern Medical Center, in Dallas, who foundthe gene in mice. Both papers linked the disorder to a problem with a protein calledhypocretin. The Stanford dogs Dr. Mignot studied lacked a functioning receptor for hypocretin, preventing the protein from doing its job; the narcoleptic mice lacked nervecells that produced the hypocretin itself.It then didn't take long for Dr. Mignot and a group from University of California at LosAngeles to show that people with narcolepsy were severely deficient in hypocretin.Solving that mystery holds the potential for new treatments for people. But the findingsrevealed that the biology of the disease was different in dogs than in humans, meaningthe colony would be of little further use in studying narcolepsy in people. The dogs hadserved their purpose, and the colony was disbanded.
Big Mystery
Still, important questions remain. "The big mystery is why the hypocretin cells are dying"in people who develop narcolepsy, Dr. Mignot says. "The only way we are going tofigure out the whole story is to study simpler animal models."To that end, he says, "We have created a narcoleptic zebrafish." The common household-aquarium fish is emerging as an especially useful model to study developmental biology.Like humans, it has a hypocretin system.How do you know a zebrafish is asleep? "They have a certain posture -- the tail will dropa little bit," says Philippe Mourrain, a researcher in Dr. Mignot's laboratory.But the dogs have played roles no zebrafish will ever fill. Just last month, Bear appearedin a huge Stanford classroom filled with 600 students, for Dr. Dement's Sleep andDreams class. Researcher Seiji Nishino laid out a mat and scooped out several spoons of 
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