“I’M STILL alive.” These are the only words that appear in a diary entry I made on 1 September 1994. I flip back a page to find a vivid account of a death-like paralysis that had gripped me the night before. “My mind awoke but my body was still sleeping,” it read. “I could feel myself suspended as if caught between two worlds. It felt, I imagined, like inhaling one’s first breath of water when drowning.”
Although I had no idea at the time, this was one of the first clear indications that I had narcolepsy. If you’ve heard of this condition, which most people have, thanks to an abundance of voyeuristic TV documentaries, you will probably know that it is characterised by a frequent and overwhelming need to sleep. But a narcoleptic will also often have sleep paralysis – waking up unable to move – hallucinogenic dreams and cataplexy, in which laughter causes them to lose muscle tone, crumbling to the floor in a manner that resembles Obi-Wan Kenobi’s collapse at a sweep of Darth Vader’s light sabre.
In 1994, precious little was known about this disorder, and it took a while before I found a doctor who took my symptoms seriously. Thankfully, even although the cause of narcolepsy was still a mystery, there were drugs available. They have helped with my sleepiness and put a complete stop to the other symptoms. I think it’s because of this pharmaceutical assistance that I had never looked into the strange goings-on in my brain, despite becoming a science writer. But so much has been discovered about narcolepsy in the past few years that I figured it was time to take a look. What I discovered was surprising – not least that millions of people could soon be deliberately inducing narcolepsy in themselves, and benefiting greatly as a result.
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I begin my journey by boarding a train to Cambridge en route for the annual meeting of Narcolepsy UK, a charity that brings narcoleptics together to raise awareness of the condition. There is a dedicated “snooze room” at the back of the auditorium, and several delegates doze off during the lecture I have come to see. None of this fazes Emmanuel Mignot, director of the Stanford Center for Sleep Sciences and Medicine in California, who has spent the past 25 years trying to understand narcolepsy. Talking to the pathologically sleepy is something he has done before.
To figure out the basis of human narcolepsy, Mignot began by studying a rather unusual lab animal: the Dobermann pinscher. In the late 1970s, the founder of the Stanford sleep centre, William Dement, had studied the pattern of inheritance of narcolepsy in these dogs and concluded that a single gene was responsible. When Mignot arrived in Dement’s lab in 1986, he soon set his sights on tracking it down. “I reasoned that if I could identify the gene responsible for narcolepsy in these dogs, it would lead me to the cause of narcolepsy in humans,” says Mignot.
There were plenty of hurdles to cross. Like Dement before him, he had to establish a pack of narcoleptic Dobermanns, which was even harder than it sounds, as dogs with narcolepsy tended to topple over while mating, temporarily paralysed by a cataplectic attack. It was also necessary to find dozens of volunteers to take in the pups churned out by the programme. Then there was the titanic task of locating a gene about which nothing was known in a genome that was, at the time, “a no-man’s-land”. “Most people said I was crazy,” says Mignot.
“Establishing a pack of dogs with narcolepsy was not easy, as they tend to topple over while mating, temporarily paralysed”
In January 1998, just as Mignot’s team was closing in on the gene, another team published a paper describing two previously unknown hormones in the brain of rats and mice. They gave them the name “hypocretins”. Just weeks later, a different group independently described the same hormones. They called them “orexins” instead and also identified the structure of the receptors that detect their presence (). Both groups speculated that the hormones might have something to do with stimulating feeding.
Mignot’s team saw something else in the results. They had the mutation responsible for narcolepsy in dogs pinned down to a small region on chromosome 6, and one of the receptors discovered in the orexin research was within this region. Team member Ling Lin suspected that the mutation might be in the orexin receptor – and her hunch eventually turned out to be spot on.
Orexins, then, are “stay awake” hormones, though they have other effects too. They are released by some cells in the brain, mainly during the day, and are detected by other brain cells with an orexin receptor. The faulty orexin receptors in the Dobermanns prevents orexins from spreading their stay-awake message throughout the brain, resulting in narcolepsy.
So is this it? Am I like a narcoleptic Dobermann, with a mutation in my orexin receptors? Several lines of evidence make it clear that the answer has to be no. I, like most people with narcolepsy, have not always been this way. Sleep only took hold of my life in my early 20s. It is also rare for identical twins both to have narcolepsy, despite their identical genetic make-up. As if this weren’t convincing enough, the genetic sequence encoding the human orexin receptors is entirely normal for the vast majority of narcoleptics. In humans, the receptors are fine – it is the stay-awake hormones that are missing.
How did this happen? Aged 20, I was quite normal, with some 70,000 specialised neurons in my hypothalamus happily churning out orexins. A little over a year later, these cells had vanished, emptying my brain of these magical little hormones.
A clue comes from the strong association between narcolepsy and a particular variant of a protein that plays a part in the immune system deciding what is dangerous and what is not. I have this variant, known as DQB1*0602, but so do a lot of people – about 1 in 3 in fact. Only 1 in 3000, though, develop narcolepsy. So something else is needed. It seems that when people with this variant are exposed to some environmental trigger, it can occasionally prompt an immune response that destroys the orexin-producing neurons in the hypothalamus.
There is now compelling evidence that narcolepsy is an autoimmune disorder, with the smart money being on the immune system mishandling a respiratory infection. A vast set of data from China shows that people tend to develop narcolepsy in the spring more often than in the summer. I know I did: a fit of hysterical laughter in April 1994 triggered a cataplectic attack that laid me flat on the floor of a friend’s bedroom.
This seasonal pattern suggests that a winter infection of the upper airway, such as flu, can trigger narcolepsy. By chance, the swine flu pandemic of 2009 provided strong support for this hypothesis (see diagram). In the spring following the initial spread of the virus, there was a threefold increase in new narcolepsy cases in Beijing (). I can’t recall whether I was bedridden with flu during the winter of 1993-1994, but that would be the prediction.
All this is getting us closer to the sequence of molecular events that results in narcolepsy. If we can get to grips with the underlying cause, there might be ways to prevent it, says Mignot. And for people who, like me, already have narcolepsy, this new understanding could lead to better treatments.
I take amphetamine-like pills, which save me from incapacitating somnolence, but my sleep patterns are still far from normal. I would happily kick the drug habit in a nanosecond if there were some way to give my brain a fix of orexin.
Towards the end of his lecture, Mignot suggests what that might be. If human narcolepsy were caused by a dysfunctional orexin receptor, as it is in dogs, it would be extremely difficult to repair the faulty gene. But as my receptors are in perfect working order, all I need is an orexin substitute. “In the next five years it’s very likely this drug will be available,” Mignot says.
I am just digesting this exciting news, when it is followed by something of an ironic bombshell. The discovery of the orexin pathway certainly caused widespread excitement among pharmaceutical companies, Mignot tells us, but all their efforts have gone into finding a way to block rather than stimulate the orexin receptors. It takes my orexin-deficient brain a few seconds to process this volte-face. What possible reason could there be for wanting a drug that would effectively induce narcolepsy, not treat it?
The answer, of course, is insomnia. As a narcoleptic, this is a condition that I haven’t lost a lot of sleep over. In fact, I have felt a quiet envy of the insomniac mind, one not incessantly disturbed by sleep.
I resolve to find out more, and once I’m home after the meeting, I call Actelion, a Swiss company that was one of the first to realise the potential of drugs that block the orexin receptors (). Talking to Jed Black, a consultant for Actelion who treats and studies people with sleep disorders at the Stanford Sleep Medicine Center, it doesn’t take me long to realise that insomnia would be no better, and possibly far worse, than narcolepsy. Long-term insomnia is a 24/7 process, says Black. “It can be really awful.”
Inducing sleep
At present, the drugs used to treat insomnia either block the action of excitatory neurotransmitters or stimulate the action of inhibitory neurotransmitters. Although these agents work, they may not produce the most natural of sleeps, and come with all sorts of side effects, such as addiction. But it could well be that most cases of insomnia are a result of an overactive orexin system, Black says, in which case blocking the orexin receptors could offer a more powerful treatment with far fewer side effects. “Theoretically, the individual may feel like they are getting not a drugged sleep but a more natural sleep.”
In the race to develop orexin blockers, Actelion has now been overtaken by Merck. By screening for small molecules that bind to orexin receptors, Merck’s researchers hit on a compound now called Suvorexant. With phase III trials in the bag, .
“This is some of the most elegant, beautiful science I’ve ever been involved in,” says Darryle Schoepp, a senior neuroscientist at Merck, who has followed Suvorexant’s rapid progress through the development pipeline. The perfect drug for insomnia is one that is safe for long-term use, puts people to sleep, keeps them asleep but allows them to function normally the following day, he says. “Suvorexant has actually delivered those things,” he claims.
“The perfect drug for insomnia puts people to sleep, keeps them asleep but lets them function normally the next day. Orexin blockers will deliver this”
We will soon find out if regulators agree with his assessment. If orexin blockers do live up to their promise, the millions of people who suffer from insomnia might not be the only ones to benefit. There has also been , including schizophrenia, depression and addiction. “It’s very early days,” says Schoepp. “Having a good molecule like Suvorexant will give us the opportunity to start exploring this possibility.”
Where does this leave my quest for some substitute orexin? Why not just knock up a bit of orexin in the lab? Making it is a cinch, Mignot had told me during a canteen lunch after his lecture. In fact, synthetic orexin has already been used to of their narcolepsy – but this required inserting a tube into their brains to carry the hormone to the hypothalamus. The problem is that orexin molecules are large, and do not reach the brain if swallowed or even if injected into the blood. Nasal administration has more of an effect, but not enough to treat people this way.
It might one day be possible to generate cells to replace my long-lost orexin-producing neurons, but there is a fair chance they would suffer the same autoimmune fate as the ones I was born with. So the best hope of replacing my orexins is to find a small molecule that mimics their effect, as Mignot had suggested.
Both Actelion and Merck assure me that this is work in progress, but it won’t be easy. A hormone and its receptor work like a key and lock. Blocking a receptor involves finding a small molecule that will lodge itself into part of a receptor and stop the hormone getting in – like jamming a lock with chewing gum.
Activating a receptor, on the other hand, means finding a small molecule that fits perfectly – a key that can turn the lock – which is much more difficult. “There’s a reason why orexin is so large,” Schoepp says. Its specificity is linked to its size.
But what about Mignot’s prediction that an orexin mimic would be on the market within five years? I call him at Stanford. “It will happen,” he tells me, but he is frustrated that the drug companies have not ploughed more resources into the hunt. “Of course it’s difficult to do, but when they say they are trying, they are not trying very hard,” he says. “They are missing the boat. We are much more in need of safe stimulants than sleeping pills.”
I know I am, but I can wait. For every narcoleptic like me, there are at least 150 people with crippling insomnia and my genuine excitement that they may soon be able to get some proper rest takes me by surprise. I suddenly realise that this journey into my brain has cured me of my ill-informed envy of insomniacs. I now appreciate that narcoleptics and insomniacs are probably both fighting against a common enemy – a faulty orexin system – and at this newfound sense of solidarity, I smile.
