Emmanuel Mignot, MD, PhD, came to the United States to study a colony of narcoleptic dogs at Stanford in the 1980s. Since then, he has grown our knowledge of pharmaceuticals, genetics, and immunological aspects of the sleep disorder.
When sleep scientist and clinician Emmanuel Mignot’s dog ran along the Pacific shoreline on a beach near Palo Alto, Calif, the dog became so excited by the salty air and the sand beneath his paws that the experience triggered a cataplexy attack. Suddenly, his body went limp, and he fell snout-first into the sand.
Cataplexy, a symptom of narcolepsy type 1, leads to temporary loss of muscle tone. Up until then the dog, named Bear, had lived all his life in a kennel at Stanford, where Mignot, MD, PhD, searched for causes and therapies for the sleep disorder.
“The first time we took Bear to the beach, he was so happy to be running like crazy on the sand that he just collapsed,” says Servane Briand, Mignot’s wife. “It gives you a lot of empathy for people who have narcolepsy because it is quite disabling.”
This scenario of a dog experiencing cataplexy is something that Mignot, director of the Stanford Center for Sleep Sciences and Medicine, is all too familiar with since his research career began with him studying narcoleptic dogs more than 30 years ago. Since then, many of his colleagues would agree, his work has transformed the scientific world’s understanding of the physiology and treatment of narcolepsy. He is most famous for discovering a cause of narcolepsy, but he also has contributed a vast number of research articles leading to a greater understanding of how to best treat the disorder pharmacologically.
“He is the leader in the study of narcolepsy,” says Thomas E. Scammell, MD, professor of neurology at Harvard Medical School. “He is energetic, intense, gets things done, and brings a lot of curiosity to his research.”
Some of Mignot’s earliest research projects uncovered how the now commonly used narcolepsy drug modafinil works to increase extracellular dopamine in the brains of narcoleptic dogs.1 Another notable discovery is his identification of a new use for venlafaxine (Effexor), a selective serotonin and norepinephrine reuptake inhibitor, to diminish cataplexy.2 In another research project, in which he was a coauthor, Mignot found that sodium oxybate could be safely administered to pediatric patients for daytime sleepiness.3
“His work set the foundation for how we think about narcolepsy medicines now,” says Scammell, a neurologist at Beth Israel Deaconess Medical Center in Boston.
Mignot’s research continues to inform the work of other scientists and influence the development of new pharmaceuticals. Specifically, Mignot discovered that narcolepsy type 1 (with cataplexy) stems from the destruction of the neurons in the brain that produce hypocretin, a neuropeptide also called orexin that regulates arousal and wakefulness.
In recent years, pharmaceutical companies have made a push to develop new drugs to stimulate or replace the function of hypocretin, says Scammell.
One example of this was presented in September at the World Sleep 2019 Biennial Congress in Vancouver, Canada, where researchers from Takeda Pharmaceuticals shared results of a Phase 1 clinical proof of concept study on a compound called TAK-925.4
The researchers explained that the compound, a selective hypocretin type-2 receptor agonist, promotes wakefulness in people who experience narcolepsy with cataplexy compared to a placebo. The data presented during the meeting showed that the compound was well tolerated in this population during a randomized, double-blind, placebo-controlled study. “The company presented data that looked quite encouraging,” says Scammell.
A Brief History of Narcolepsy Research
While narcolepsy was first described in the late nineteenth century in Germany and France, much of the research on this sleep disorder has been conducted at Stanford University, beginning with William Dement, MD, PhD, and Christian Guilleminault, MD, DM, DBiol, in the ’70s, according to an article by Mignot, published in the journal Immunologic Research.5
Mignot carried on this legacy of narcolepsy research at Stanford after completing his medical degree in psychiatry at the French public research institution Paris Descartes University and his doctorate in pharmacology at Pierre and Marie Curie University.
He came to California from Paris as a visiting scholar to study narcoleptic dogs at Stanford in the 1980s and he never returned home, carrying narcolepsy research into the future and becoming a leading researcher in the field.
The first project he worked on at Stanford involved an investigation into the effects of modafinil in dogs. Over the years, the colony of dogs at Stanford expanded and contracted. At times, researchers there were handling four or five litters of puppies at once.
One of them, Bear, was lucky enough to find a new home with Mignot, who adopted the dog. When Bear passed away about five years ago, the family was heartbroken, but then received an unexpected call from a dog breeder in Vermont who had a Chihuahua that likely had narcolepsy and wanted to know if Mignot would take the animal in. Tentative at first, Mignot accepted and traveled to the opposite side of the country to pick up “Watson,” who continues to live with the family today.
The Genetic Search
By the late ’80s, after making great developments in pharmacological interventions for narcolepsy, Mignot’s drive to help his patients led him in a new direction.
Drugs, he thought, would only ease the symptoms but never get to the root cause of the disorder. Since he wanted to find the cause, he knew he must move in a new direction in the next chapter of his research career. “That’s when I started to search for the gene for narcolepsy in dogs,” he says. “Everyone told me that was totally crazy. They said I would never succeed.”
Despite the skeptics, Mignot pivoted his research to focus on genetics in the early ’90s. Over the course of a decade, he spent many long hours in the lab, where he used a technique called positional cloning to locate a disease-associated gene on the chromosome. He searched from chromosome to chromosome, looking at sub-regions on the chromosomes, trying to narrow his search. Years went by with no results.
“It was horrible. I couldn’t have a girlfriend because I was smelling like a dog. I’m joking, but actually it is not completely wrong because I was really smelling like dog because I was working with dogs a lot,” he laughs. “It’s stressful. You have nothing to show for all your work until you find the gene. You go 10 years without any results.”
Then, finally, a breakthrough happened.
He isolated a mutation in the hypocretin receptor 2 gene that he believed would lead to narcolepsy in dogs. Worried that he had made a mistake, the first thing Mignot did after making the discovery was to ask a student to repeat the experiment to confirm his results. Results confirmed, he then got to work on publishing the results in the journal Cell.6
“I remember that moment, there was a bit of happiness, but also a bit of stress,” he says. “We have it now, and we really need to publish it as soon as possible.”
From that moment on, he knew he could start to test humans to see if there were any similarities in the ways in which narcolepsy is caused.
In a study, published in Lancet, Mignot and collaborators found that many humans who experience narcolepsy with cataplexy have no hypocretin in their cerebrospinal fluid. The researchers found that hypocretin was undetectable in seven out of nine people with narcolepsy, indicating abnormal hypocretin transmission.7
“That was a big discovery in 2000. We were really excited,“ he says. “It was a little different from the dog but still the same pathway.”
This research fueled even more research. He started to suspect that maybe there was an immune component to narcolepsy in humans, shifting his focus to research in the area of immunity.
This shift led to the discovery that human narcolepsy can be spurred by an autoimmune response that can lead to the destruction of the brain cells that produce hypocretin.
The study, published in Proceedings of the National Academy of Sciences, also provides a specific example that demonstrates the theory in immunology called molecular mimicry, that autoimmunity is the result of the immune system mistaking healthy cells in a person’s body for proteins within infectious pathogens.8
The research revealed the mechanism behind how the immune system can confuse the hypocretin neurotransmitter that is responsible for wakefulness with a protein present in some strains of influenza and in some versions of the swine flu vaccine.
“It is really pretty remarkable that he has fearlessly been able to change his scientific approach to narcolepsy as the situation demands,” says Scammell.
Over the course of his career, Mignot has been a co-author of more than 200 original scientific publications. He has received numerous research grants and accolades, including National Sleep Foundation and National Institute of Health Research Awards, Howard Hughes Medical Institute Investigator and McKnight Neuroscience awards, the Narcolepsy Network professional service award, and grants from Wake Up Narcolepsy. He is a member of both the National Academy of Sciences and Medicine.
“It is a life of constant learning. Emmanuel is an extremely curious person, someone who has a very wide range of knowledge,” says his wife of more than 30 years, Briand, who is a visual artist. “He has a constantly active mind.” Even at home, his mind keeps churning. “Living with him, I am never bored because there are always interesting topics of conversation and things to discover,” she says.
With all these accomplishments under his belt, Mignot is still certain that his work is not over yet. There are many large narcolepsy research questions that still need to be answered. In the meantime, he continues to teach courses at Stanford and treat patients, but not without the help of Watson, the Chihuahua, who sometimes accompanies him to the sleep clinic.
“Emmanuel loves to put [his patients] at ease and make them laugh. Seeing the dog is really fun for them,” says Briand.
Also a professor, Mignot teaches a course at Stanford called “Sleep and Dreams” and with Watson’s help, he is able to give a live demonstration of what cataplexy looks like—just as Bear inadvertently demonstrated on a beach all those years ago.
Lisa Spear is the associate editor of Sleep Review.
- Mignot E, Nishino S, Guilleminault C, Dement WC. Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep. 1994 Aug;17(5):436-7.
- Mignot E, Nishino S. Emerging therapies in narcolepsy-cataplexy. Sleep. 2005 June;28(6):754-63.
- Plazzi G, Ruoff C, Lecendreux M, et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health. 2018 Jul;2(7):483-94.
- Evans R, Tanaka S, Tanaka S, et al. A phase 1 single ascending dose study of a novel orexin 2 receptor agonist, TAK-925, in healthy volunteers (HV) and subjects with narcolepsy type 1 (NT1) to assess safety, tolerability, pharmacokinetics, and pharmacodynamic outcomes. Abstract at World Sleep 2019.
- Mignot EJ. History of narcolepsy at Stanford University. Immunol Res. 2014 May;58(2-3):315-39.
- Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999 Aug 6;98(3):365-76.
- Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000 Jan 1;355(9197):39-40.
- Luo G, Ambati A, Lin L, et al. Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12323-E12332.