This Q&A is cross-posted from the Stanford Neuroscience Institute.
Dr. Emmanuel Mignot is a professor of psychiatry and behavioral sciences and the director of Stanford’s Center for Sleep Sciences and Medicine. He is best known for discovering the cause of narcolepsy.
Your lab has used a variety of approaches over the years; how would you describe your scientific discipline?
The scientific community often wants to put you in the box of neuroscientist, immunologist, etc. I consider myself just a scientist. The distinction between disciplines isn’t important—the question is what is important. Broadly speaking, I study why we sleep and what happens in the brain while we sleep. I am always ready to try new techniques to answer my questions; this keeps me flexible. I even force myself to go to scientific conferences outside of my field, such as cancer conferences. These give me ideas about my work.
What is your approach to studying sleep?
I began by searching for a clinical disorder that could inform us about sleep. Narcolepsy was the perfect starting point because it has a clear, objective phenotype: patients fall into REM (“Rapid Eye Movement”) sleep faster than controls. This phase of sleep is associated with vivid dreaming, brain activity similar to waking states, and muscle paralysis. REM sleep normally occurs 90 minutes into sleep and reoccurs every 90 minutes, but the timing is dysregulated in narcoleptics. I began studying narcolepsy by investigating how the drugs used to treat narcoleptic patients work, namely amphetamines and Modafinil. Our work with narcoleptic dogs, along with Nora Volkow’s elegant human work, demonstrated that Modafinil acts as a dopamine re-uptake inhibitor, which was controversial at the time.
Dogs are far from a common model organism. What informed your choice to study narcolepsy in dogs?
I cannot take the credit for this one. My mentor—William Dement, who just retired at 88 years old—was working with dogs when I came to Stanford. At one of his talks in the 1970s, someone in the audience mentioned that he may have a dog with narcolepsy. So Dr. Dement advertised in the newspaper and found a French poodle named "Monique" that had narcolepsy. These dogs had the hallmarks of narcolepsy and a related disorder called cataplexy—they had REM abnormalities and immediately fell asleep once excited or aroused. After these initial cases, we found a few cases that were genetic because they transmitted through the family.
In 1992, we discovered an immune-related gene that predisposes humans to narcolepsy. However, this discovery didn’t reveal the mechanism behind the disorder. I hypothesized that human narcolepsy was directly related to the canine narcolepsy we studied. It was a risky bet! A lot of my colleagues said it was infeasible to clone a gene in dogs; and others, including grant reviewers, said the finding would have nothing to do with human narcolepsy. However, my hypothesis turned out to be correct: We discovered that canine narcolepsy is caused by a mutation in the hypocretin receptor (subtype 2) gene. This discovery clued us into the nature of human narcolepsy—we discovered that humans are completely missing hypocretin, the brain peptide that interacts with the hypocretin receptor! In narcolepsy, it turns out that the immune system actually destroys the neurons that produce hypocretin. The story didn’t have to unfold this way; we were a little lucky.
Breeders select for certain traits, such as size and hair color. Do you think narcolepsy was indirectly selected for during this process?
Yes, of course, especially because of inbreeding. Initially we found a family of Labradors and Dobermans that show familial inheritance of narcolepsy. These families have a mutation in the same gene because breeding an affected Labrador with an affected Doberman results in offspring with narcolepsy. Now the question was: Did the mutation come from an ancestral breed common to both Labradors and Dobermans? Surprisingly, no. These breeds actually have different mutations in the same gene. In genetics, when different mutations in the same gene lead to the same phenotype, this is more proof that the mutation is causative. We were doing this work long before the dog (or even the human) genome had been sequenced, so it was a very long search.
It’s important to think long-term in science. I tell my students: —"You don't go anywhere if you don't know where you're going."
So, where are you going these days?
These days my direction is applying techniques from the emerging “big data” field to a combination of EEG, wearable biosensor, and genetic datasets. I work with electrical and bioengineers from Denmark who developed a machine learning algorithm to detect different sleep stages with much finer resolution than humans can. With these data, I believe we will detect mini-arousals throughout sleep, and the clinical and genetic correlations to these arousals will be really novel and interesting.
Another one of our goals is to complement our studies on narcolepsy with understanding the genotype and sleep patterns of individuals on the opposite side of the sleep spectrum: “short sleepers” who are hyper-vigilant and don’t need a lot of sleep. Finally, we are working on a very rare disorder called Kleine-Levin Syndrome in which patients, usually teenagers, sleep for about 20 hours a day.
Can you give us a peek into the sleeping habits of the director of Stanford's sleep science and medicine?
I used to sleep very well, but I don't sleep as well now that I’m older. I fall asleep easily, but usually wake up in the middle of the night. Fortunately, waking up doesn't bother me much, so I don't stress about it, and I fall back asleep. I'm not sleepy during the day, so what else could I ask for?
To finish up, do you have tips for our readers for a good night's sleep?
You have to sleep enough, but not too much. There is a sweet spot for everyone. If you try to sleep too much then your sleep becomes fragmented. If you are a night owl but must work in the morning, then you can help shift your rhythms by going outside or exercising outside in the mornings to expose yourself to light. When you travel, you need outside light to reset your circadian rhythm. The lights inside are too dim, even though we may perceive them to be bright. These are relatively simple tricks!