The science of sleep: Finding a cure for narcolepsy
One of my first jobs was to keep a lookout for lions.
There are some occupations that are not suitable for someone with untreated narcolepsy and this is probably one of them.
I was 22, a recent zoology graduate studying meerkats in the Kalahari desert in South Africa. We worked in pairs, one of us on foot, walking with meerkats, the other in the jeep scanning the horizon for signs of leonine danger. On many occasions, I awoke with the imprint of the steering wheel on my forehead, realizing that meerkats and colleague had wandered out of sight. I would look for signs of life and, as the panic grew, signs of death.
I can tell this story now only because nobody got eaten.
I have not always been like this. For the first 20 years of my life, I had a healthy relationship with sleep. Shortly after my 21st birthday, though, I began to experience symptoms of narcolepsy, a rare but not-so-rare disorder thought to affect around one in 2,500 people.
If people know one thing about narcolepsy, it’s that it involves frequent bouts of uncontrollable sleepiness. This is true, but the condition is so much more disabling, often accompanied by cataplexy (where a strong emotion causes loss of muscle tone and a ragdoll-like collapse), trippy dreams, sleep paralysis, frightening hallucinations and, paradoxically, fractured night-time sleep.
There is no cure. Yet.
What there is, though, is overwhelming evidence that the most common cause of narcolepsy is an autoimmune attack, where the body’s immune system mishandles an upper respiratory infection and mistakenly wipes out the estimated 30,000 neurons in the center of the brain.
In an organ of up to 100 billion cells, this might not sound like too much to worry about. But these are no ordinary cells. They are found in the hypothalamus, a small, evolutionarily ancient and unbelievably important structure that helps regulate many of the body’s basic operations, including the daily see-saw between wakefulness and sleep. The cells in question are also the only ones in the brain that express a type of protein called orexins (also known as hypocretins) that regulate wakefulness.
The answer to my problems appears to be simple — I just need to get the orexins (or something similar) back inside my brain. So why am I still waiting?
Every dog has its day
In April 1972, a toy poodle in Canada produced a litter of four. Eager families were quick to snap up the cute puppies, but one of them, a silver-grey female called Monique, soon developed what her owners described as “drop attacks” when she tried to play.
When vets at the University of Saskatchewan observed Monique, they suspected these were bouts of cataplexy, and hence figured this might be a case of narcolepsy with accompanying cataplexy.
As luck would have it, Monique’s diagnosis coincided with the arrival of a peculiar circular from William Dement, a sleep specialist at Stanford University in California. He was on the lookout for narcoleptic dogs. The Saskatchewan vets wrote back to him immediately. When Monique’s owners were persuaded to relinquish their pet, Dement managed to convince an airline to fly her to California.
Word began to spread, and soon Dement and his colleague Merrill Mitler were looking after Monique alongside several other narcoleptic dogs, including a Chihuahua-terrier cross, a wire-haired griffon, a Malamute, Labrador retrievers and Doberman pinschers. The fact that narcolepsy appeared to be more common in some breeds than others suggested there could be some kind of genetic basis to the disorder.
Then came the breakthrough: a litter of around seven Doberman puppies, all of them with narcolepsy and cataplexy. It turned out that in Labradors and Dobermans, the disorder was inherited.
Dement made the decision to focus on Dobermans and, by the end of the 1970s, he was the proud custodian of a large colony and had established that narcolepsy in this breed was caused by the transmission of a single recessive gene. By the 1980s, methods of genetic analysis had advanced just enough to contemplate an effort to hunt down the defective Doberman gene.
I can never reconstruct the combination of factors that led to the onset of my own narcolepsy, but the stage was set at the moment of my conception in 1972, at around the time of Monique’s birth in Saskatchewan.
My one-cell self inherited a particular version of a gene, known as HLA-DQB1*0602, that forms part of a set that helps the immune system distinguish friend from foe. HLA-DQB1*0602 is pretty common — around one in four people in Europe boasts a copy — but it plays a key role in many cases of narcolepsy, and is present in 98 per cent of those with narcolepsy and cataplexy.
On top of this genetic background, there may have been some bad timing too.
People with narcolepsy are slightly but significantly more likely to be born in March (as, indeed, I was). This so-called birth effect is seen in other autoimmune disorders and is probably explained by a seasonally variable infection at a particular moment in development. In the case of narcolepsy, it seems that those of us born in March are just a little bit more vulnerable than others.
While other infections during my childhood, hormonal fluctuations and emotional stress may also have played a part, it was in late 1993 that I probably encountered a key pathogen — an influenza virus or Streptococcus perhaps. It was this that took me to an autoimmune tipping point and resulted in the rapid dismantling of my orexin system.
On the hunt
Around this time, the Doberman project in Stanford was on the verge of unraveling the genetic basis of narcolepsy in this breed. The man tasked with hunting down the mutation responsible was Emmanuel Mignot, who subsequently succeeded Dement as director of the Stanford Center for Sleep Sciences and Medicine.
Back in the 1980s, the idea of locating the gene for canine narcolepsy was off-the-scale ambitious. Breeding narcoleptic Dobermans is harder than it sounds, as the afflicted tend to topple over mid-coitus, temporarily paralyzed by a cataplectic thrill (an “orgasmolepsy” that can occur in humans too).
This impracticality aside, there was also the task of locating a gene whose sequence was not known, in a genome that was, at the time, a no man’s land. “Most people said I was crazy,” says Mignot. In a sense, they were right, because it took him more than a decade, hundreds of dogs and over $1 million. And he was nearly beaten to it.
In January 1998, after more than a decade of painstaking mapping, and just as Mignot’s team was closing in on the gene, a young neuroscientist called Luis de Lecea at the Scripps Research Institute, San Diego, and colleagues published a paper describing two novel brain peptides. They gave them the name “hypocretins” — an elision of hypothalamus (where they were found) and secretin (a gut hormone with a similar structure). They appeared to be chemical messengers acting exclusively inside the brain.
Just weeks later, a team led by Masashi Yanagisawa at the University of Texas independently described the exact same peptides, though called them “orexins” and added the structure of their receptors into the bargain.
Back at Stanford, Mignot heard about the two papers, but there was no reason to imagine this new pathway had anything to do with narcolepsy or sleep. By the spring of 1999, however, he and his team had worked out that the recessive mutation had to lie in one of two genes. One was expressed in the foreskin. “It didn’t look like a candidate for narcolepsy,” says Mignot. The smart money was on the other gene, which encoded one of the two orexin receptors.
When he got wind that Yanagisawa had engineered a mouse lacking orexins that slept in a manner characteristic of narcolepsy, the race was on.
Within weeks, Mignot and his team had submitted a paper to the journal Cell, revealing a defect in the gene encoding one of the orexin receptors. “This result identifies hypocretins [orexins] as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients,” they wrote. Kahlua — one of a litter of Dobermans all named after alcoholic beverages — lay sprawled across the cover of the issue.
Yanagisawa and colleagues added their experimental evidence to the mix just two weeks later, also in Cell.
From discovery to drugs
The orexin neurons are a very big deal, and not just for those like me who’ve lost them. Present in every major class of vertebrate, they have to be doing something seriously important.
We have found out a lot, particularly thanks to optogenetics, a technique de Lecea helped pioneer. By deploying a virus, a promoter and a gene found in blue-green algae, it is possible to render a particular population of neurons sensitive to light.
Using optogenetics and other methods, de Lecea has been able to show that the orexins have a powerful effect on many important neurological networks. In some settings, they act like neurotransmitters, crossing gaps in neurons to activate target neurons that release a chemical called norepinephrine throughout the brain’s cortex.
In other settings, the orexins act more like hormones, working further afield in the brain. This is how orexins influence other brain chemicals, including dopamine (essential for the processing of reward, in planning and for motivation), serotonin (strongly associated with mood and implicated in depression) and histamine (an important alerting signal).
“In most other neural networks, there are parallel and multiple layers of security,” says de Lecea, but in the case of the orexins, however, there appears to be little or no backup at all. “It is a brilliant model for understanding neural networks more generally,” says de Lecea.
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.
However, 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 synthesizing 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. 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.
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.