Two scientists have been awarded the Albert Lasker Basic Medical Research Prize for their work identifying the cause of narcolepsy, a neurological disorder characterized by sudden sleep attacks and episodes of muscle weakness. The prize, announced last Wednesday, recognizes research conducted in the 1990s that uncovered the underlying mechanisms behind the disorder and significantly advanced the field of sleep science.
Professors Emmanuel Mignot and Masashi Yanagisawa, working independently through different methods, arrived at complementary conclusions pointing to the absence of a brain chemical called orexin—also known as hypocretin—as the root cause of narcolepsy. Their findings revealed that narcolepsy is related to a deficiency or dysfunction in orexin signaling, a breakthrough that has reshaped medical understanding of sleep regulation.
Prof. Mignot, affiliated with Stanford University School of Medicine, focused his research on hereditary narcolepsy in dogs. After a decade of studying the canine genome, he identified a genetic mutation responsible for the disorder. In affected dogs, while orexin is still produced, a mutation prevents it from binding properly to its receptor, effectively disrupting normal wakefulness.
Meanwhile, Prof. Yanagisawa from Tsukuba University in Japan discovered the neurotransmitter orexin itself and initially linked it to appetite regulation. Subsequent experiments demonstrated that mice lacking orexin exhibited symptoms identical to narcolepsy, marking an important parallel to the human condition.
The combined work of both researchers established that in narcoleptic humans and animal models, orexin-producing neurons in the hypothalamus are either absent or nonfunctional. This insight transformed sleep research, revealing for the first time the genetic basis of a sleep disorder and opening avenues for targeted therapies.
Decades after the initial discoveries, the implications of this research continue to influence treatment options. This year, a drug addressing orexin deficiency in patients with Type 1 narcolepsy received approvals in the United States, China, and Japan. Prof. Mignot described the medication as a “game changer” that has restored quality of life for many patients, allowing them to resume activities they had previously abandoned due to disabling symptoms.
Additionally, orexin antagonists have been developed to aid patients suffering from insomnia by dampening the neurotransmitter’s wake-promoting effects, illustrating orexin’s broader role in sleep-wake regulation.
Despite these advances, some aspects of narcolepsy and sleep physiology remain unclear. Prof. Yanagisawa noted that while the brain mechanisms governing the transition between sleep and wakefulness are better understood, the precise triggers initiating that shift remain a “real mystery.” Similarly, questions persist regarding the underlying cause of orexin neuron loss in humans with narcolepsy. Prof. Mignot is currently investigating the hypothesis that an autoimmune response, possibly triggered by influenza virus infection, leads to the destruction of these neurons.
Another unresolved phenomenon concerns the sudden sleep episodes often triggered by strong emotions in people with narcolepsy. “We don’t really understand why they fall asleep when experiencing emotions like laughter or surprise,” Prof. Mignot said, highlighting the ongoing complexity of this neurological disorder.
The Lasker Prize marks the latest recognition of their contributions, following previous accolades including the 2023 Breakthrough Prize, underscoring the profound impact of their research on the field of sleep medicine.