Stanford sleep doctor’s breakthrough in narcolepsy began with dogs

When Dr. Emmanuel Mignot returned to Stanford from Europe last week — where he had won the Lasker Prize, one of medicine’s top prizes, for his work in sleep research — he was greeted enthusiastically by Watson, his chihuahua.

Watson is black and white and the size of a small cat, and when he is eager to see Mignot, he dances until Mignot rocks him like a baby. Watson licks Mignot’s face and presents his belly to rub. And once placed, the dog collapses. His legs give out, or his body, or he falls asleep.

Watson suffers from narcolepsy, a sleep disorder that causes humans and dogs to feel excessively tired and paralyzed when they get too excited. In the United States, it is usually diagnosed in children and affects approximately 200,000 people.

Watson and dozens of other dogs over the years have been an inspiration – and sometimes research partners – for the work of Mignot and his colleagues. Studying narcoleptic dogs helped them identify the cause of the disease and, eventually, a treatment approved by the Food and Drug Administration last August.

And after decades of work and a little luck, Mignot can imagine being able to cure, or even prevent, narcolepsy in the near future. This work could also help scientists understand other disorders, not just those related to sleep.

Mignot’s research “transformed the field of sleep medicine and gave hope to the millions of people living with narcolepsy around the world,” Dr. Lloyd Minor, vice president for medical affairs at Stanford, said in a statement after Mignot won the Lasker Prize.

Mignot, a professor of sleep medicine at Stanford, shared the Lasker Prize with Dr. Masashi Yanagisawa, who also studies sleep, at Japan’s University of Tsukuba. The men did not work together, but made two key discoveries by chance that unlocked the mechanisms behind narcolepsy.

By studying a colony of narcoleptic dogs at Stanford, Mignot was able to find a gene that seemed to play a central role in this disease. The gene controls a receptor for a neuropeptide, which is a chemical messenger that acts in the nervous system. When this neuropeptide is blocked, narcolepsy develops.

Meanwhile, Yanagisawa had identified the neuropeptide orexin – which happened to be the same neuropeptide controlled by Mignot’s gene. Both men published papers in the late 1990s suggesting that narcolepsy was caused by a disruption of orexin.

“We found that when you didn’t have this orexin or this orexin receptor, you had narcolepsy,” Mignot said. “He made his discovery almost at the same time as we found the gene. It was like we had converged.”

Scientists quickly discovered that they couldn’t just give people orexin to treat narcolepsy, because they had no way of getting it into their brains where it could do its job. It took two decades to develop a treatment, a drug that helps restore the brain’s ability to use orexin.

Mignot continued to treat patients with narcolepsy and further explore the mechanisms of the disease. He found evidence that at least one type of narcolepsy is an immune disorder, perhaps similar to type 1 diabetes. In diabetes, the body attacks insulin-producing cells; in narcolepsy, the target is orexin-producing neurons. Indeed, Mignot’s laboratory discovered approximately 70,000 orexin-producing neurons in the hypothalamus of healthy human brains studied posthumously; the brains of people with narcolepsy did not have them.

He also discovered that in some cases this immune attack can be triggered by the flu. In fact, working with colleagues in China, Mignot found that narcolepsy diagnoses followed a seasonal pattern, with an uptick in cases about six months after the peak of flu season.

This discovery could one day help scientists prevent narcolepsy, perhaps through a mechanism found in the flu vaccine, Mignot said.

“My goal is to one day be able to modify the flu vaccine so that people are protected,” Mignot said. “And there will be no more narcolepsy, and I will finally be able to die in peace. I think I will. I’m close.”

Mignot also believes that some of the secrets revealed in narcolepsy could lead to treatments for other illnesses, such as Parkinson’s disease or depression. “Maybe it’s another way to stimulate the brain,” he said.

Mignot, 66, was born in Paris, the youngest of six children. He was shy and a little wild, he said, but he always loved science. In his youth, he went digging in the Paris basin, rich in fossils. He still has much of his childhood collection, including a 50 million-year-old Campanile giganteum, a sea snail fossil larger than Watson.

He studied psychiatry and molecular pharmacology, earning both his medical degree and a doctoratebut didn’t know much about the science of sleep until he enrolled in a program at Stanford in the late 1980s. There he met Dr. William Dement, who had opened one of the world’s first sleep clinics. Dement, who died in 2020, had also created a colony of dogs with narcolepsy to help him in his research.

Mignot took over the colony when Dement retired and spent a decade researching the narcolepsy gene. There were about 20 dogs in the colony, and most lived in a kennel at Stanford. Some dogs came from families of Dobermans or Labradors with a genetic form of narcolepsy. Others were collected from breeders, who had no use for puppies who collapsed when overexcited.

Research on the dogs ended years ago and the animals were adopted, Mignot said. He had a narcoleptic dog named Bear. Shortly after Bear’s death, Mignot received a call from a breeder about a narcoleptic Chihuahua. Mignot no longer studied dogs and “for me, a chihuahua is not really a dog,” he said with a laugh.

But the dog’s previous owner had abandoned him and Mignot couldn’t help but take him in. Watson’s small size is convenient, Mignot said, because he’s not too heavy “and we can carry him when he’s sleepy.” Watson’s narcoleptic episodes are most often triggered by good food — he loves chicken — or play time, Mignot said.

Sometimes he brings Watson with him to his clinic, where he has great success with the children he treats for narcolepsy, “and as it turns out, the poor guy is so drunk.”

Holding the animal on his lap one afternoon at his home in Palo Alto, Mignot humored it by rubbing its belly and scratching its chin. “You are very kind, my little animal,” Mignot said to him in French. “So beautiful.”

He put Watson down, and Watson trotted over to his bed and fell asleep.