We are still waiting for that happy ending. Even if I could get my hands on a vial of orexin-A or orexin-B, how would it get into my brain? Swallowed in solution, the enzymes in my gut would make short shrift of it, plucking off the amino acids like beads off a necklace. Injected into muscle or the bloodstream, not enough would make it through the blood–brain barrier. There have been some experiments on a nasal delivery, suggesting that sniffing orexins may be a way to smuggle some of them into the hypothalamus via the olfactory nerve, but there has been relatively little investment in this approach.

This does not mean that the pharmaceutical industry has ignored the discovery of the orexin pathway. Far from it. Within just 15 years of the Cell publication by Mignot and colleagues that linked a loss of orexin to narcolepsy, Merck had received US Food and Drug Administration (FDA) approval for suvorexant (or Belsomra as it’s known in the trade), a small molecule capable of getting through the blood–brain barrier and blocking orexin receptors.

A drug that promoted sleepiness was not the application that most people with narcolepsy were looking for. By preventing the orexins from binding to their receptors, Belsomra effectively creates an acute case of narcolepsy, but where the fog, ideally, will have started to lift by the morning.

Sleeping pills commonly used to treat insomnia tend to work by depressing the central nervous system as a whole, says Paul Coleman, a medicinal chemist who works at Merck’s laboratories at West Point, Philadelphia, and who was instrumental in the development of Belsomra. “What’s so exciting about Belsomra is that it is very selective for blocking wakefulness, so it doesn’t affect the systems that control balance, memory and cognition,” he says.

In his career, Coleman has developed drugs to treat a range of different infections, illnesses and disorders, but the orexin system stands out. “Narcolepsy has given us a thread we can pull on to unravel a lot about what underlies the systems that govern wakefulness and sleep,” he says.

Lucy Tonge, who lives with narcolepsy

© Daniel Stier

“Wakefulness is a pretty central process for everybody, whether you are a healthy person or have narcolepsy or insomnia. It’s the most exciting thing I’ve had a chance to work on.” The applications of Belsomra may be wider still, with clinical trials proposed to investigate its potential to help shift workers sleep during the hours of daylight, improve the sleep of Alzheimer’s patients, help those suffering from post-traumatic stress disorder, combat drug addiction and ease human panic disorder.

I am delighted to see these developments, but the millions of us with narcolepsy are still hoping for a drug that could work in the brain to rouse rather than silence the orexin system.

This has been a long-term project for Masashi Yanagisawa, who was in the race with Mignot to link the orexins with narcolepsy 20 years ago. But designing and synthesising a compound that will make it through the gut intact, that has what it takes to find its way from blood to brain, and that boasts the perfect configuration to activate one or both of the orexin receptors is “a very, very high challenge” he says, one that is “significantly” greater than finding a compound to interfere with the receptor as Belsomra does.

Earlier this year, Yanagisawa and his colleagues published data on the most potent such compound to date, a small molecule called YNT-185. Injections of this molecule into narcoleptic mice significantly improves their wakefulness and cataplexy and reduces the abundance of the REM stage of sleep in which most dreaming occurs (one of the characteristics of narcolepsy). This, says Yanagisawa, is a “proof of concept”. Although the affinity of YNT-185 (how strongly it binds to the orexin receptor) is not great enough to warrant a clinical trial, Yanagisawa’s team has already hit upon several other potential candidates. “The best one is almost 1,000 times stronger than YNT-185,” he says.

While the symptoms of narcolepsy can vary wildly from one person to the next, the underlying pathology – the absence of orexins – is still the same. “If this compound works, it’ll work for all those patients,” he says. “In that sense, it’s a relatively simple clinical trial compared to many other disorders.”

A still more futuristic avenue involves stem cells. Sergiu Paşca has the office next to Emmanuel Mignot at Stanford and in 2015, he and his colleagues developed a way to take induced pluripotent stem cells (fashioned from skin cells) and direct them towards a new life as brain cells. “You can use this system to derive various brain regions and like a Lego game, assemble them to form circuits in a dish,” he says.

Recently, his lab has developed methods to do something similar for people with narcolepsy, starting with a skin cell and ending up with a fully functional orexin neuron. In theory, it should be possible to transplant this into the brains of people with narcolepsy and restore some of the function. This is, however, not something to be taken lightly. For a start, the cells themselves are unlikely to be exactly the same as orexin cells, inserting a needle into the brain is not a risk-free exercise, and there’s always the possibility that the immune system might make another assault on the transplanted cells.

So, will the tale of the orexins really have a happy ending? The translation of basic research into the clinic is notoriously difficult and expensive, says Casper. (The cost of the current best available treatment for narcolepsy – sodium oxybate, or Xyrem – is such that it is not routinely available for adults in England, even though it could transform the lives of many.)

There is a widespread perception that narcolepsy is a rare disorder with a small market, so any pharmaceutical research and development in this area would be unlikely to reap a significant return. This ignores the fact that narcolepsy is probably undiagnosed in many people, and that someone who develops narcolepsy in their teens and lives into their 80s would need some 25,000 doses over their lifetime.

Even more compellingly perhaps, the orchestrating role that the orexins play in the brain suggests the market for such a drug would go far beyond narcolepsy. Something that tickled up the orexins would be useful for any condition where excessive daytime sleepiness is an issue, not to mention the myriad other situations where low levels of these messengers may play a role, including obesity, depression, post-traumatic stress disorder and dementia.

There is, I believe, one other reason why this story has not yet reached its conclusion. For too long, sleep has been undervalued, seen as an inconvenient distraction from wakefulness. With this mindset, research into the neuroscience of sleep does not seem like it should be a priority. Nothing could be further from the truth. There is now abundant evidence that poor sleep can have devastating consequences for physical, mental and psychological health. Sleep is not incidental. It is fundamental, a matter of serious public health. Investing in sleep research is not just about the few with demonstrable sleep disorders. It is about everyone.

Henry’s book Sleepyhead: Neuroscience, narcolepsy and the search for a good night will be published by Profile Books in March 2018.