The 2026 Albert Lasker Prize for Basic Medical Research has brought to light a discovery that changed scientists’ understanding of the mechanisms of sleep and wakefulness, after scientists Emmanuel Mineo and Masashi Yanagisawa were honored for uncovering the orexin system and its role in maintaining wakefulness, and proving that a deficiency in its signals causes uncontrolled sleep in narcolepsy.
The story of the discovery brought together two scientific paths that seemed far from each other. Yanagisawa searched for the function of new molecules in the brain, while Mineo tried to solve the mystery of narcolepsy by studying dogs that were genetically affected by the disease. After years of work, the two paths converged at the orexin system, and experiments on mice, dogs, and then humans revealed that this molecule plays an essential role in maintaining alertness.
Emmanuel Mineo, professor of sleep medicine at Stanford University and director of the Stanford Center for Narcolepsy, said in exclusive statements to Al Jazeera Net via email: “The main discovery was when we found that we could not measure the levels of orexin in the cerebrospinal fluid of most narcolepsy patients. The result was published on January 1, 2000. This was the cause of narcolepsy in humans.”
This result came after research on animals had linked the orexin system to disease. Previous studies have shown that changes in the genes responsible for orexin or its receptors cause narcolepsy in animal models, including the Mineo team’s study on dogs in 1999, which revealed that their hereditary disease results from a defect in the orexin receptor No. 2 gene.
The Lancet journal published the human study referred to by Mineo, and showed that hypocretin-1, also known as orexin A, was not detectable in 7 of 9 patients with narcolepsy, which provided direct evidence of a disorder of the orexin system in humans. Later studies confirmed that orexin deficiency is primarily linked to type 1 narcolepsy, which is usually characterized by cataplexy, that is, a sudden loss of muscle tension while remaining conscious.
The honoring of the two scientists coincides with the approaching announcement of the Nobel Prize in Physiology or Medicine for the year 2026 tomorrow, Monday, October 5, bringing the story of orexin back to the circle of scientific interest during Nobel Week. The Nobel Committee does not announce the names of the nominees for the prize, as nomination information remains secret for 50 years, so Mineo and Yanagisawa’s winning of the Lasker Prize does not represent an announcement of their nomination for the Nobel, but rather an independent honor for a discovery whose impact extended from the laboratory to the treatment of patients.
A molecule searching for a function
One strand of the story begins in the lab of Masashi Yanagisawa, who is currently director of the International Institute for Integrative Sleep Medicine at Tsukuba University in Japan. In the 1990s, his team was searching for natural molecules that bind to receptors in the brain whose functions were unknown.
In 1998, Yanagisawa and his colleagues published in the journal Cell the discovery of two new neuropeptides called orexin A and orexin B. They found that the cells that produce them are concentrated in the hypothalamus, a small region located near the base of the brain that participates in regulating sleep, wakefulness, hunger, body temperature, and a number of hormonal functions.
Researchers initially focused on the possibility of orexin being related to regulating food intake, but another, more important function began to emerge.
The surprise was revealed when Yanagisawa’s team developed mice that did not produce orexin. The animals began to exhibit sudden bouts of loss of movement, and researchers initially thought they were convulsions, before recordings of brain activity revealed that they were linked to a severe disturbance in the transition between wakefulness and sleep and the emergence of characteristics resembling narcolepsy.
The team published its results in 1999 in the journal Cell, providing strong evidence that loss of orexin causes a disturbance in the stability of sleep and wakefulness.
Dogs lead to the same result
Mineo took a different route to reach the same system. In 1989, the search for the genetic cause of hereditary narcolepsy in Doberman pinschers and Labradors began, at a time when the canine genome had not been sequenced and even a preliminary, integrated genetic map had not been developed.
The researchers observed dogs that showed sudden episodes of loss of muscle tone, especially with excitement, in addition to sleep disturbances, a picture similar to some of the symptoms of narcolepsy in humans.
Mineo tells Al Jazeera Net: “Masashi’s work in mice and our work in dogs showed that orexin is linked to sleep and narcolepsy. The appearance of the result by different researchers and in two different species, dogs and mice, was the best evidence that the result was correct. Otherwise, we would have had to wait for another researcher to repeat it.”
The concurrence of Yanagisawa’s results in mice and Mineo’s in dogs strengthened the finding, before human studies later confirmed that orexin deficiency is associated with type 1 narcolepsy.
How does orexin maintain alertness?
Orexin helps multiple nerve networks in the brain maintain and stabilize a state of alertness, so its role cannot be reduced to being a “sleep-preventing” substance. It helps the brain to remain in a stable state, reducing sudden and inappropriate transitions between wakefulness and sleep.
This function explains many aspects of narcolepsy. The problem is not limited to extreme sleepiness during the day, but rather extends to disruption of the boundaries between sleep and wakefulness, and may appear in the form of cataplexy, sleep paralysis, hallucinations when sleeping or waking up, and disturbed sleep at night.
Research has shown that people with narcolepsy type 1 lose most orexin-producing neurons in the hypothalamus. Researchers believe that an autoimmune process contributes to the destruction of these cells in people with a genetic predisposition, while the details of this process are still being researched.
A treatment that compensates for what patients miss
Understanding orexin changed the way of thinking about treating sleep disorders. In insomnia, drugs that block orexin receptors are used to reduce alertness signals, while in narcolepsy, researchers have headed in the opposite direction, by developing drugs that activate its receptors to compensate for the missing signal.
Mineo tells Al Jazeera Net: “Orexin receptor-stimulating drugs represent a major shift in the treatment of type 1 narcolepsy, because they compensate for what these patients lack. But we believe they have many other applications in medicine.”
One of the most notable applications came with the drug “ofiborexone”, an oral drug that selectively activates the orexin 2 receptor.
In September 2026, the New England Journal of Medicine published the results of two phase III trials, which showed that the drug improved the ability to stay awake, and reduced daytime sleepiness and cataplexy attacks in people with type 1 narcolepsy, compared to a placebo. Mineo participated among the researchers in the study.
A placebo means a substance that is similar to the drug used in the study, but does not contain the active ingredient. Researchers use it to compare and ensure that the improvement results from the treatment being tested.
The publication of these results was preceded by an important step on August 5, 2026, when the US Food and Drug Administration approved Orzeyful, which contains oviporexone, for the treatment of adults with narcolepsy type 1, becoming the first approved drug that works directly to restore lost orexin signals that lie at the basis of the disease.
Why do we care about sleep?
In an article published in the New England Journal of Medicine on the day the Lasker Prize was announced, Dutch neurologist and sleep medicine researcher Sebastian Overeem and Danish researcher Birgitte Kornum described Mineo and Yanagisawa’s research as pivotal work in discovering the orexin system and its role in narcolepsy.
The article explained how this research moved from a basic discovery in neuroscience to understanding a disease mechanism, then to developing drugs targeting the defect itself, a path that took more than a quarter of a century since the discovery of orexin.
Today, Mineo continues to study the genetic, immunological, and neurological aspects of narcolepsy at Stanford University, while Yanagisawa and his team in Japan continue to research the mechanisms that determine when the brain sleeps and when it wakes up.
At the end of his speech to Al Jazeera Net, Mineo says: “It is really nice for sleep to be recognized as an important physiological phenomenon. We spend a third of our lives sleeping, yet only a small number of people study it.”
His phrase summarizes the story of research that began with dogs suffering from a mysterious disorder and mice that lost a small molecule in the brain, and then reached humans and a drug that compensates for the missing signal. Mineo and Yanagisawa did not discover the “sleep button” in the literal sense, but they did uncover one of the most important systems that helps the brain stay awake when it should be awake.