In 1999, two scientists independently uncovered the function of orexin and published papers about it. Dr. Masashi Yanagisawa, a molecular biologist and physician now at the University of Tsukuba in Japan, came across orexin while studying the interaction of receptors and chemicals in the brain. Dr. Emmanuel Mignot, now the director of the Stanford Center for Narcolepsy, homed in on orexin while studying narcoleptic dogs. (His Chihuahua, named Watson, has narcolepsy, and he previously had another dog with the condition, named Bear.)
Yanagisawa told Live Science that, at the start of his research career, he didn't expect to end up studying sleep. Mignot, on the other hand, had an early interest in understanding narcolepsy so that better treatments for the neurological disorder could be developed. Live Science spoke with Mignot about the discovery of orexin and how the field might progress in the future.
Dr. Emmanuel Mignot: There were three things that attracted me to narcolepsy: Number one, it was a human problem. It was already known [at the time] that it was not super rare. I'm not saying it's super common, but 1 person per 3,000, 0.03% — it's reasonably common. And nobody cared about it. I would talk to neurologists and they'd say, "Oh, I've never seen one case in my entire life." So I would say, "Yes, of course; you miss them all." That was the state of the play at the time.
The third thing that made me ready to go there was that it was tractable. A lot of problems are not tractable.
EM: I studied the pharmacological basis because I was trained in pharmacology, and as a psychiatrist, and I discovered how this drug modafinil [a stimulant-based narcolepsy treatment] was working. But quickly, I realized I'm not going to find the cause by doing pharmacology. I'm only going to explore what's known.
After narcolepsy was described — the dog gene — suddenly narcolepsy became much more famous.
EM: The guy at Stanford that started the sleep program was called Dr. [William] Dement. He was a graduate student in Chicago in the 1950s, when [Eugene] Aserinsky and [Nathaniel] Kleitman discovered REM sleep. He had the foresight to understand that this was an important discovery.
That dog had already been euthanized, but it still gave him the idea that these dogs have narcolepsy — maybe we should try to get some. So he went to a lot of veterinarians to talk to them about it, and they identified a whole series of dogs, including the first poodle, Monique, who had narcolepsy. And they started this little colony of dogs. Initially, they tried to breed them, but most cases of narcolepsy are actually not genetic. Then, in 1977, they got a whole litter of Dobermans, and then Labradors, that had some form that was genetic.
NL: At that time, it's not like you had a complete dog genome. Did that make studying their genetics challenging?
It took me 10 years. I had times where some people didn't believe that the dogs had narcolepsy. There were a few depressing moments, but I was convinced that was the right thing to do.
Orexin (pictured) is a peptide in the brain that promotes wakefulness. (Image credit: theasis via Getty Images)EM: I was lucky. Honestly, I had no idea. I got enamored with genetics because what I love [about it] is you can find something without any hypothesis. You just search for it, and what you find tells you what it is. You have no prerequisite for knowing what you would find.
Then, it turned out to be immediately applicable to humans. That, too, was a lot of luck; let's be honest. I was just trying to find the cause of one thing and one step at a time; it could have been something very complicated. It turned out to be simple.
NL: Do you recall what the reception was like when the initial finding was published?
But after narcolepsy was described — the dog gene — suddenly narcolepsy became much more famous. And what happened is that people started to pay attention to narcolepsy, and we started to see kids. In kids, the picture is so much different. They gain an enormous amount of weight; it's very abrupt. It's a little bit different than what you see in adults, where they have adapted to it.
The second thing that happened is, all the drug companies started to develop hypnotics [sleeping pills], trying to block the orexin. They developed hypnotics relatively quickly, and they are very effective. They are probably safer than benzos [benzodiazepines] and so forth.
EM: We know that the orexin definitely drops during sleep, so blocking it is definitely a way to recapitulate that drop; that's true. It's an awake-promoting system, so if you remove something that makes you more awake, it's safer than inducing sleep by shutting down the brain.
EM: It's not something I 100% discovered. In 1983, before I came to study narcolepsy, there was a guy in Japan who I met, called Yutaka Honda. [Editor's note: Honda's research linked narcolepsy to the human leukocyte antigen (HLA) region of the genome, which helps regulate immune responses.]
When I came, that was already known. But then people really looked and tried to see if the disease was autoimmune, but they couldn't find anything — no autoantibody, nothing. It was all negative.
I'm very proud of that study because I think it's the first time that people used human diversity to actually map down a genetic factor more precisely, which now is used commonly. It's called transethnic mapping.
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It's going to have a lot of other applications [beyond narcolepsy]. Some people think it's going to be very helpful for ADHD; some people think it could be very helpful for depressed people with excessive sleepiness. We don't know, really; there's a lot of possibilities.
You don't know until you try, but I'm sure it's going to have other applications.
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