Dogs collapsing suddenly and mice toppling over to their sides while asleep. Two scientists, pursuing abnormal behaviors seen in very different animals, found orexin, a key substance that regulates sleep and wakefulness. This not only revealed the cause of narcolepsy, but also led to the development of treatments for insomnia and narcolepsy.
On the 11th, the Lasker Foundation said Masashi Yanagisawa of the University of Tsukuba in Japan and Emmanuel Mignot of Stanford University School of Medicine in the United States were selected as co-recipients of the 2026 Lasker Basic Medical Research Award for these contributions.
The two researchers were recognized for discovering a brain peptide called orexin and demonstrating that a deficiency of this substance causes uncontrolled sleep seen in narcolepsy.
The two started from different points. Yanagisawa discovered orexin while studying a brain receptor of unknown function, and Mignot identified the orexin receptor while tracking genes in dogs with narcolepsy.
◇ A substance of "sleep and wakefulness" found while studying hunger
In the late 1990s at the University of Texas Southwestern Medical Center, Yanagisawa was studying receptors on the surface of brain cells whose function had not been determined. Receptors act as an antenna of sorts, receiving signals outside the cell and transmitting them inside.
Yanagisawa's team searched for substances that bind to this receptor and transmit signals. By fractionating extracts from mouse brains through multiple steps, they identified a peptide that stimulates the receptor. When this substance was injected into mouse brains, food intake increased.
The team thought the substance regulated appetite. So they expected that mice lacking the orexin gene would eat less and lose weight. The name orexin also came from the Greek word "orexis," meaning "appetite."
But the results differed from expectations. Mice lacking the gene showed no major differences in food intake or body weight.
While observing mice overnight with an infrared camera, the researchers found an unexpected phenomenon. Mice without orexin were awake and moving around when they suddenly toppled over to their sides. After remaining still briefly, they got up again and resumed activity.
Electroencephalography showed it was not a simple seizure. While muscle tone was lost, the brain was in rapid eye movement (REM) sleep, the dreaming stage. In normal sleep, REM sleep follows non-REM sleep, but in mice without orexin this process appeared abruptly. It resembled sleep attacks seen in people with narcolepsy.
It was the moment it became clear that orexin plays a crucial role in maintaining wakefulness, or "arousal," more than appetite.
◇ The same substance found in "dogs that collapse suddenly"
Around the same time, Mignot was tackling a different problem: finding the cause of genetically driven narcolepsy in certain dog breeds, such as Dobermans and Labrador retrievers.
Dogs with narcolepsy were not only extremely sleepy, but also collapsed as their muscles suddenly lost strength when they felt strong emotions such as joy or excitement. This is called cataplexy.
Mignot tracked canine genes for nearly 10 years. It was not easy because canine genomic information was not well organized at the time. He eventually identified an abnormality in a specific gene in dogs with narcolepsy.
That gene was orexin receptor type 2 (OX2R), one of the orexin receptors. The orexin discovered by Yanagisawa and its receptor were consolidated with the same phenomenon of narcolepsy. The two studies were published in 1999 in succession.
One side found a "substance involved in sleep and wakefulness," and the other found a "gene that causes narcolepsy," and the two studies pointed to the same biological pathway.
◇ Human narcolepsy was also due to orexin deficiency
Their research extended to humans.
Mignot's team measured orexin levels in the cerebrospinal fluid of patients with narcolepsy. They found that orexin was undetectable in many patients. Studies examining the brains of deceased patients with narcolepsy also confirmed a marked loss of neurons that produce orexin.
Narcolepsy is not simply a "sleepy person's disease." Irresistible daytime sleepiness recurs, and in some patients, cataplexy occurs when they feel strong emotions such as laughter or surprise, with a sudden loss of muscle tone. As orexin signaling disappears, the brain cannot stably maintain a waking state.
Why neurons that produce orexin disappear has become another research question. Currently, an autoimmune response in which the immune system mistakenly attacks orexin-producing neurons is cited as an important cause. Researchers are also exploring whether infections or certain genetic factors may trigger such immune responses.
◇ From insomnia drugs to narcolepsy treatments
Research on orexin did not remain basic science. Once it became clear that orexin maintains wakefulness, the idea emerged that blocking orexin's action could induce sleep.
In fact, drugs that block orexin receptors have been developed and are used as insomnia treatments. Unlike conventional sleeping pills that broadly suppress the entire brain, these work by blocking orexin signaling that keeps one awake. Conversely, for narcolepsy, in which orexin is deficient and sleepiness floods in, methods to restore orexin signaling have been studied.
In particular, a drug that activates orexin receptor type 2 has been developed. The U.S. Food and Drug Administration (FDA) in Aug. approved Takeda Pharmaceutical's orexin receptor type 2 agonist Orzeyful (active ingredient oveporexton) as a treatment for adult type 1 narcolepsy.
Longstanding questions about sleep began with "mice suddenly collapsing" and "dogs suddenly collapsing," consolidated into a single molecular pathway, and ultimately led to drugs that treat actual patients.
The Lasker Foundation said the two researchers' discoveries opened the way to understanding the molecular principles that regulate sleep and wakefulness and presented new treatments for narcolepsy and other sleep disorders.
Meanwhile, Michael J. Fox, a U.S. actor who went public with his Parkinson's diagnosis and has dedicated himself to supporting Parkinson's research, was selected as the recipient in the public service category. The awards ceremony will be held on the 17th in New York.
References
Cell (1999), DOI: https://doi.org/10.1016/S0092-8674(00)81973-X
Cell (1999), DOI: https://doi.org/10.1016/S0092-8674(00)81965-0