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One Peptide, Two Names: How Two Labs Found Orexin and Hypocretin in 1998
In February 1998, two research groups published the discovery of the same pair of peptides within weeks of each other, in two journals, with two different names. One team called them orexins, from the Greek word for appetite. The other called them hypocretins, because they come from the hypothalamus and resemble the gut peptide secretin. Both names are still in use.
Key takeaways
- Orexin A has 33 amino acids and orexin B has 28; both come from the same precursor.
- One group, led by Takeshi Sakurai and Masashi Yanagisawa, found them as the missing partners of orphan receptors.
- The other, led by Luis de Lecea and J. Gregor Sutcliffe, found them by looking for genes active only in the hypothalamus.
- Within two years, orexin was linked to the sleep disorder narcolepsy in dogs, mice and people.
- The story shows how peptides can turn up from two directions at once.
The hunt for orphan receptors
By the 1990s, gene sequencing had revealed hundreds of receptors for which no natural ligand was known. They were called orphan receptors. Sakurai and Yanagisawa, then in Texas, used orphan receptors as bait: they made cells that carried an orphan receptor and tested extracts from brain tissue to see which would activate it. One extract did, and the active material proved to be two related peptides. Because injections into rat brain increased feeding, they called them orexins.
The other way in
At almost the same time, de Lecea and Sutcliffe at the Scripps Research Institute took a different approach. They searched for messenger RNAs that were made only in the hypothalamus. One of them coded for a precursor that contained two peptides that looked similar to secretin. They named them hypocretins. The two papers appeared within weeks of each other in early 1998.
The sleep surprise
The feeding effect proved modest. The big finding came in 1999, when Emmanuel Mignot’s group showed that a form of narcolepsy in dogs was caused by a mutation in an orexin receptor, and Yanagisawa’s group showed that mice lacking the orexin gene had sleep attacks that resembled narcolepsy. Studies of human brains then found that people with the most common form of narcolepsy had lost most of their orexin-producing neurons. Orexin neurons turned out to act as a switch that keeps wakefulness stable.
From peptide to drug target
Because the peptides themselves are poor drug candidates, pharmaceutical researchers designed small molecules that block orexin receptors. One of these was approved in 2014 for insomnia. That repeats a familiar pattern, seen in the octreotide story: a peptide points the way, and chemists then design something more practical.
Why the story is useful
- Orphan receptors can lead to peptides, and peptides can lead to receptors.
- Two groups can find the same molecule and name it differently, so sequence and receptor data matter more than names.
- Short hypothalamic peptides are processed from larger precursors.
- Sleep research has a long history with peptides, from the sleep substance hunters to our DSIP overview.
The bottom line
Orexin is one of the most important peptide discoveries of the 1990s. It reminds researchers to look at the same molecule from more than one angle. See more peptide stories in our history of peptide drugs and the Research Library.
Related reading
- The sleep substance hunters
- DSIP and sleep architecture
- The endothelin story
- Browse the full Research Library
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.