Orexin's discoverers win the Lasker basic-science award a month after the first agonist approval

"We never thought we would end up in sleep," Masashi Yanagisawa told Live Science, calling the work "a kind of biochemical fishing expedition" ^[17]. His lab was screening G protein-coupled receptors whose activating chemicals nobody had identified, the ones the field called orphans ^[13]. The design was blunt in a productive way: isolate peptides from rat brain tissue, present them to orphan receptors, and watch for one that fires. The fifth or sixth receptor tested gave a hit, and the trail led to two closely related peptides and a second, related receptor ^[14]. The peptides came from the hypothalamus, a region already tied to eating behaviour, so the team named them orexins, after the Greek word for appetite ^[15]. Despite the name, the peptides' main job is holding wakefulness open, not appetite ^[3].

What turned this into a story about sleep was a phenotype. Mice without working orexin genes fell over and lay immobile for a minute or two, and recordings showed them dropping straight into REM sleep, the abrupt intrusion also seen in people who have narcolepsy with cataplexy ^[16]. Mignot had come from the clinical end, chasing the causes of narcolepsy, and found orexin deficiency behind a canine form of the disease before pursuing the mechanism in patients ^[4]. Two independent designs landed on the same molecule, and the deficiency showed up in three settings: engineered in mice, spontaneous in dogs, and absent in people with some forms of the disorder ^[1]. "It became, suddenly, a very, very convincing story," Yanagisawa said ^[18]. That convergence is what does the causal work. Before it, sleep regulation was studied by damaging parts of an animal's brain and watching what changed, with no molecular or genetic account of the mechanism ^[19].

Translation then ran in both directions. Antagonists that block the receptors became a class of insomnia drugs, promoting sleepiness by turning wakefulness down, and agonists became narcolepsy drugs ^[5]. According to STAT, Takeda began on the agonist side more than a decade ago and won the first approval of one last month, in a type of narcolepsy ^[6]; Alkermes and Eli Lilly, which entered by acquiring Centessa, are working on rare sleep disorders ^[20].

How far the pathway reaches into the indications that would make it commercially large remains unproven. STAT reports drugmakers exploring depression and Alzheimer's, where patients feel sleepy, and emerging research suggesting the orexin system also touches attentiveness, cognition and mood ^[22]. In narcolepsy the missing peptide is the lesion the drug addresses ^[1]. In those other conditions, sleepiness is only a symptom, the agonist is a hypothesis, and the deficiency biology does not settle it.

The other two prizes come with less detail on the record. Live Science identifies the clinical winners as three scientists affiliated with the Japanese drug maker Chugai Pharmaceutical, credited with a hemophilia treatment, without naming the treatment or describing how it works ^[2][7]; STAT's Lasker item covers the orexin award only ^[8]. The public service prize went to the actor Michael J. Fox for Parkinson's advocacy that has helped advance research ^[10], awarded by a foundation established in 1942 by Albert and Mary Lasker, philanthropists and health advocates themselves ^[12]. Each award carries a $250,000 honorarium ^[11], $750,000 across the three ^[21]. The screen that started all of this was built to find ligands for orphan receptors, not to treat a sleep disorder ^[13].