Scientists who discovered cause of narcolepsy win Breakthrough Prize

Emmanuel Mignot and Masashi Yanagisawa won the 2023 Breakthrough Prize in life sciences for their discovery of the molecular mechanisms in the brain that cause the sleep disorder narcolepsy  

By Grace Wade

Masashi Yanagisawa and Emmanuel Mignot won the 2023 Breakthrough Prize for their discovery of the cause of narcolepsy

Breakthrough Prize / Masashi Yanagisawa and Emmanuel Mignot

Emmanuel Mignot and Masashi Yanagisawa have won the 2023 Breakthrough Prize in Life Sciences for discovering the cause of narcolepsy, a lifelong disorder in which people suddenly fall asleep and experience extreme daytime drowsiness.

Each year, the Breakthrough Prize awards $15 million across five prizes to top researchers working in the fields of physics, mathematics and life sciences.

Emmanuel Mignot at Stanford University in California and Masashi Yanagisawa at the University of Tsukuba in Japan each discovered the mechanism behind narcolepsy independently.

In the 1980s, Mignot and his colleagues started cross-breeding narcoleptic dogs in an attempt to identify genes related to the condition. “When I started to do this people were saying it was crazy because the human genome had not even been sequenced yet,” says Mignot. “And indeed, it was so crazy it took me 10 years, but it paid off.”

The gene his team ended up identifying coded for two membrane receptors in the brain. Membrane receptors sit on the lining of cells and detect molecules outside of it. Certain molecules activate receptors, triggering a cascade of responses, often leading to changes in an organism’s behaviour. It wasn’t clear to Mignot, though, what the function of these new-found receptors was, let alone which molecules they responded to.

Around the same time, Yanagisawa and his colleagues were working to identify the roles of hundreds of receptors by seeing which protein-like molecules, called peptides, activated them. They did this by extracting peptide mixtures from animal brains and refining them until they were able to isolate which specific peptides activate a certain receptor. Their first hit was for the receptor Mignot was also looking at, which they found responded to two previously unknown peptides now called orexin-A and orexin-B.

Yanagisawa and his team then disabled the gene that produced orexin in mice and saw that these animals, which are normally nocturnal, periodically collapsed into bouts of sleep at night, similar to narcolepsy. When they injected orexin into the brains of these mice at night, they were able to stay awake.

Together, these discoveries revealed not only the membrane receptor implicated in narcolepsy, but also the two types of orexin that normally bind to this receptor to induce wakefulness. Further research confirmed that people with narcolepsy don’t produce orexin.

“So that was a very dramatic, exciting convergence of the two laboratories coming from completely different directions,” says Yanagisawa.

While its isn’t entirely clear why people with narcolepsy don’t produce orexin, Mignot’s more recent work has found it may be an autoimmune condition in which the body’s immune system attacks and kills orexin-producing cells in the brain.

Mignot and Yanagisawa’s discovery was awarded the Breakthrough Prize as it has improved our understanding of sleep and spurred the development of new drugs to treat narcolepsy, which is estimated to affects around 1 per cent of the global population. While none have been approved so far, many are in various stages of clinical trials. “If everything goes smoothly, then within maybe three or four years, there will be a clinically available drug treatment,” says Yanagisawa.

This year, there were two other Breakthrough Prize awards given in the life sciences, including to Demis Hassabis and John Jumper for the development of AlphaFold and to Clifford Brangwynne and Anthony Hyman for their discovery of a fundamental mechanism in cellular organisation.

In mathematics, Daniel Spielman won for his contributions to theoretical computer science and the fundamental physics prize was shared among Charles Bennett, Gilles Brassard, David Deutsch and Peter Shor for their work in quantum information.

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