Link post for Orexin and the Quest for more Waking Hours

A week ago I was skeptical about the prospect of radically reducing human sleep needs. After reading John Boyle’s Cause area: Short-sleeper genes, I decided to research the area more deeply and updated to believe that it’s more likely that we can reduce human sleep needs without significant negative side effects. It might increase risk-taking which has both positive and negative effects. The one friend I have that has short-sleeper genes is a startup founder.

Boyle suggested that one of the best actions to attempt would be using orexin or an orexin agonist as a drug, but that there’s currently a lack of funding for doing so.

Given the way the FDA and EMA work, drugs only get approved when they are able to cure illnesses, with an illness being anything that has an ICD code. According to that notion, people who suffer from having to sleep more than four hours don’t have an illness and thus drugs can’t be approved for that purpose. In practice, this results in the NIH not being interested to fund the research of Ying-Hui, about people who need a lot less sleep and are still well rested, that Boyle discussed.

DEC2-P384R and orexin biology

The DEC2 gene produces prepro-orexin, which is 131 amino acids long. People with the DEC2-P384R mutation produce more prepro-orexin and have a reduced need for sleep. From prepro-orexin our body generates orexin A, which is 33 amino acids long, and orexin B, which is 28 amino acids long. Orexin A is highly conserved and has the same molecular structure in humans, mice, rats, and cows, while human orexin B differs from rodent orexin B. While orexin B doesn’t cross the blood-brain barrier, orexin A does. I didn’t find information on whether or not prepro-orexin passes the barrier, but it likely doesn’t given its size.

According to Uniprot:

Orexin-A binds to both OX1R and OX2R with a high affinity, whereas orexin-B binds only to OX2R with a similar high affinity.

The literature is sometimes unclear when they use the term orexin about whether the author means prepro-orexin, orexin A, and orexin B or a mix of them. Hypocretin is an alternative name in the literature for orexin, hypocretin-1 for orexin A, and hypocretin-1 for orexin B.

Do we get a free lunch?

From an evolutionary perspective, it seems beneficial to have a lower sleep requiremen...