Their Duty Done, The Drowsy Dogs Can Doze Off Again

Stanford Pack Helped Solve Mystery 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 colony of narcoleptic dogs to study the mysterious disorder that causes people to become excessively sleepy in the middle of daily activities. When excited by a favorite treat or roughhousing with one another, the dogs -- mainly Doberman pinschers and Labrador retrievers -- would suddenly crumple to the floor, limp as rag dolls. Over the years, the dogs became a powerful scientific, educational and publicrelations resource. Live performances were a mainstay of psychiatrist William Dement's popular Sleep and Dreams course at the medical school. The dogs were even on the "Today" show. But the menagerie, which at one point numbered 80 dogs, has gradually been disbanded. Today, only Bear, a black energetic schipperke, remains. Scientists now rely mostly on smaller research animals -- including zebrafish -- which are cheaper and more suited to genetics research.

Emmanuel Mignot and Bear

"The colony just isn't useful anymore," says Emmanuel Mignot, director of the Center for Narcolepsy here. Narcolepsy is a debilitating condition that 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, a sudden muscle weakening that can cause people to collapse in a sleeplike paralysis lasting from a few seconds to several minutes. The attacks tend to be triggered by positive emotions.
Dr. Mignot from Stanford University's Center for Narcolepsy shows two dogs with narcolepsy who can't play without periodically losing muscle strength and falling asleep.

Stanford's first narcoleptic dog was a French poodle donated to Dr. Dement in 1973. "We named her Monique," he recalls. But when they bred her with other narcoleptic dogs, the offspring 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 and manage 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 he would fall asleep." Personal Connection Still, Ms. Sharp managed to produce about 30 litters. Pups were named according to themes: Paris was from the capital cities litter; Zeus was one of the gods. Sleepy and Dopey were from the Seven Dwarfs litter. Even in research papers, Dr. Mignot referred to the dogs by name, not number. "We really felt 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 Medical Institute investigator, and his colleagues discovered a gene in the Stanford dogs' DNA that causes narcolepsy. "The dogs laid the foundation for much of our current thinking about narcolepsy," says Thomas Scammell, a sleep researcher at Harvard Medical School and Beth Israel Deaconess Medical Center, in Boston. MORE • 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 in response to a newspaper ad, a Labrador retriever named Goofy caught his eye. "I bent down 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 come home 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 few seconds. Goofy died in December at age 13. "We always thought of it as endearing, not a disability," Mr. Hall says. Ms. Sharp, who left Stanford in the mid-1990s after budget worries prompted a downsizing 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 painstaking work by Dr. Mignot and his colleagues that involved close to 100 litters of animals to home in on the location of the gene. It also appeared just two weeks ahead of a report from researchers led by Masashi Yanagisawa at University of Texas Southwestern Medical Center, in Dallas, who found the gene in mice. Both papers linked the disorder to a problem with a protein called hypocretin. The Stanford dogs Dr. Mignot studied lacked a functioning receptor for hypocretin, preventing the protein from doing its job; the narcoleptic mice lacked nerve cells that produced the hypocretin itself. It then didn't take long for Dr. Mignot and a group from University of California at Los Angeles to show that people with narcolepsy were severely deficient in hypocretin. Solving that mystery holds the potential for new treatments for people. But the findings revealed that the biology of the disease was different in dogs than in humans, meaning the colony would be of little further use in studying narcolepsy in people. The dogs had served 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 to figure out the whole story is to study simpler animal models." To that end, he says, "We have created a narcoleptic zebrafish." The common householdaquarium 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 drop a 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 appeared in a huge Stanford classroom filled with 600 students, for Dr. Dement's Sleep and Dreams class. Researcher Seiji Nishino laid out a mat and scooped out several spoons of

canned dog food. As if on cue, Bear approached the treat, fell to the mat, recovered and managed a mouthful before collapsing again. The students cheered. "Bear is truly a star," says Dr. Mignot. Dr. Mignot himself plans to adopt Bear, but he's also hoping the dog will be available for one more test. Unlike the dogs with inherited narcolepsy, Bear has a version that closely resembles the acquired human malady. "If I found a drug that mimics the effect of hypocretin, one of the first things I would try would be to give it to Bear," he says. "Trying it in just one dog would help a lot." Write to Ron Winslow at ron.winslow@wsj.com

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