Editorial Note: In Pandemonium and Pandemrix the question was when and what basis is it possible to agree with an obviously smart women, as AM is, that there must be a link between the Pandemrix she was given and the narcolepsy she ended up with. No one really tackled this head on.
The answer has to be that if she and other smart people figure there is a link in their cases, there likely is. There are other factors that can be taken into account, such as whether anything else happening at the time might have played a part, but for the most part sensible people are largely right when it comes to adverse effects.
But rather than go with AM’s hunch, we turn to epidemiologists or other merchants of doubt to tell us whether there could be a link or not. This post covers another way into the issue.
In a Guardian article two months back Dreaming of a Cure Henry Nicholls wrote:
Sleeping on the Job
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 danger. On many occasions, I awoke with the imprint of the steering wheel on my forehead, realising 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 no one 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 disorder thought to affect about one in every 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.
A lot has changed in 20 years. There is now overwhelming evidence that by far 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 centre of the brain. In an organ of up to 100bn 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 important structure that helps regulate many of the body’s basic operations, including the daily seesaw between wakefulness and sleep. The cells in question are also the only ones in the brain that produce orexins (also known as hypocretins).
The Doberman Guide to Narcolepsy
In April 1972, a poodle in Canada produced a litter of four. One of them, a silver-grey female called Monique, soon developed what her owners described as “drop attacks” when she tried to play. These did not look like sleep; they were mostly partial paralyses: her hind legs would go weak, her bottom would slump to the floor and her eyes would become still and glass-like. At other times, particularly when fed, Monique would be struck by a full-blown attack.
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.
“Monique is very likely to collapse when she’s eating something she especially likes, or when she smells a new flower outside, or romps around,” Dement’s colleague Merrill Mitler told the Associated Press for a story that ran in dozens of US newspapers. “We hope to discover exactly where in the brain the dysfunction occurs that causes narcolepsy,” Mitler said soon after Monique’s arrival at Stanford. “This could be the first step towards developing a cure.”
I ask Mitler if the story of the discovery of narcolepsy is really as good as it appears. “In a word, yes,” he says. “In the 70s, we didn’t know what we didn’t know about narcolepsy.” There is simply no way anyone could have anticipated how profitable the research into Monique and other dogs would turn out to be. The plan at that stage, he admits, was simply to use the animals to test new drugs that might improve treatment of the symptoms and to carry out autopsies in case there were some obvious physical changes to the brain.
Word began to spread, and soon Dement and Mitler were looking after Monique and several other narcoleptic dogs. 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. “Within 24 hours or less we saw the first of the litter and then the last of the litter all collapse,” says Mitler. “There was a large group of us at Stanford and we collectively had our chins on the floor.”
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. I 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 has a copy – but it plays a key role in many cases of narcolepsy, and is present in 98% of those with narcolepsy and cataplexy.
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 dismantling of my orexin system. In short, most cases of narcolepsy are probably the result of an unfortunate combination of events.
How do Cataplectic Dogs… ?
Most people with narcolepsy also have cataplexy – a state were a strong emotion from laughter to fear can cause a paralytic response so that the person might slump to the floor for instance leaving others thinking they have had an epileptic attack. They also have hypnogogic and other hallucinations – which is where the featured image comes in.
Around this time, the doberman project in Stanford was on the verge of unravelling the genetic basis of narcolepsy. The man responsible was Emmanuel Mignot, who 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 paralysed by a cataplectic thrill (a so-called “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. It took him more than a decade, hundreds of dogs and more than $1m. 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, Luis de Lecea, at the Scripps Research Institute, 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.
A team led by Masashi Yanagisawa at the University of Texas independently described the same peptides, though they called them “orexins” and added the structure of their receptors into the bargain. They speculated that the interaction of these proteins with their receptors might have something to do with regulating feeding behaviour. “We didn’t even think about sleep at all,” admits Yanagisawa, now director of the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan.
By the spring of 1999, Mignot and his team had worked out that the recessive mutation had to lie in one of two genes. When he got wind that Yanagisawa had engineered a mouse lacking orexins that slept in a manner characteristic of narcolepsy, the race was on.
In weeks, Mignot and his team had submitted a paper 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. Yanagisawa and colleagues added their experimental evidence to the mix two weeks later in the same journal.
Under normal circumstances, a chemical messenger and its receptor work a lot like a key and lock. A key (the messenger) fits into a lock (its receptor) to open a door (cause a change within the target cell). In the case of Mignot’s Dobermans, a massive mutation had effectively jammed the lock of the orexin receptor, rendering the orexin useless.
Whether it’s the lock that doesn’t work, as in this case, or that the keys are missing, as they were in Yanagisawa’s mice, the upshot is the same. The door won’t open. The orexin system is broken. In human narcolepsy, there are many ways to break the orexin system. Occasionally, a brain tumour or head trauma is sufficient to do the damage. In most cases, however, narcolepsy is caused by the series of unfortunate events outlined above.
The orexin neurons are a very big deal, and not just for those like me who have lost them. Present in every major class of vertebrate, they have to be doing something seriously important.
When mouse neurons release orexin, all of a sudden, the mouse wakes up. When they stop, it falls asleep as rapidly as it woke.
In most other neural networks, there are parallel and multiple layers of security, so if something isn’t working properly, there are systems that can step in and pick up the slack. In the case of the orexins, however, there appears to be little or no backup at all.
What we now know about orexins also helps explain why losing just a few tens of thousands of cells should result in a disabling, multi-symptomatic disorder like narcolepsy – something that messes with wakefulness and sleep, body temperature, metabolism, feeding, motivation and mood. These proteins are giving us a privileged insight into how the human brain does what it does.
The pharmaceutical industry has not ignored the discovery of the orexin pathway. Within just 15 years of the publication that linked a loss of orexin to narcolepsy, Merck had received FDA approval for suvorexant (Belsomra is the trade name), a 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.
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.
Editorial Note: This second section comes from other sources
In an attempt to battle the 2009 swine flu pandemic, two separate pharmaceutical companies developed vaccines for the causative H1N1 strain: Pandemrix, produced by GSK, and Focetria, created by Novartis. Following Pandemrix use there was arise in cases of narcolepsy that didn’t happen after Focetria, which was manufactured using a different H1N1 strain. The association was too strong for even GSK to ignore.
According to a new study the vaccine can trigger the generation of antibodies that targeted both the virus and a population of brain cells critical to the regulation of sleep-wake cycles.
This finding supports ideas that narcolepsy may be the result of an autoimmune reaction, where the body accidentally attacks itself. These suspicions were aroused after scientists discovered that a significant portion of disease sufferers possess a genetic variation within a family of immune molecules that distinguish foreign invaders from the self. Additionally, narcoleptics seem to generate higher levels of antibodies to pathogens following infection.
Another important observation is that the brains of narcolepsy patients seem to have fewer neurons responsible for the generation of a signaling chemical called hypocretin that, when attached to its corresponding receptor, helps maintain wakefulness. Consequently, narcoleptics also have less hypocretin in their brains.
So what could it be that is joining all of these dots? It turns out that a chunk of one of H1N1’s proteins closely resembles a portion of the hypocretin receptor. While this protein was found in both vaccines, it was present in significantly higher concentrations in Pandemrix.
This suggests the antibodies generated as a result of the vaccine could be cross-reactive, meaning they stuck to both their viral target and the hypocretin receptor. If this turned out to be the case, it could mean that the antibodies were triggering an autoimmune reaction.
To probe this hypothesis further, the researchers examined the blood of 20 individuals who developed narcolepsy following immunization with Pandemrix and compared them to six controls vaccinated with Focetria. Piecing together the clues, they found that 17 of those in the Pandemrix group had abnormally high levels of hypocretin receptor antibodies, whereas the controls did not.
The suggestion therefore is that in those genetically predisposed to the condition, the H1N1 protein that was present in high levels in Pandemrix, but not Focetria, successfully triggered the production of antibodies to the virus, but that these also bind to the hypocretin receptor. This could ultimately drive a targeted immune response towards the hypocretin cells, triggering their destruction, disrupting the regulation of sleep-wake cycles.
Editorial Notes: So why this detour through biology? In cases like AM’s outlined last week, the story should convince most people in its own right – down to the benefits of Prozac. Prozac and other SSRIs are hugely helpful for the cataplexy that is an integral feature of a lot of narcoleptic syndromes. Facing Prozac in a narrative like this though, people will mistakenly wonder about the mental stability of the person affected. In this case the Prozac detail helps confirm there is nothing mentally wrong with AM.
But we doubt individuals these days and rather than work with them, we look to outside sources. Governments and others turn to epidemiologists, who specialise in pointing out that smoking couldn’t be causing cancer because people are smoking more and living longer now (in the 1960s) than they were in the 1920s. There will always be an annual incidence of narcolepsy in which any new cases can be hidden.
This turn to doubt is unfortunate not only because of the harm it does to AM but also because we will ignore what she is showing us about ourselves – who knew that our dreams can go on for forty minutes or more and end in a gift shop on the second floor.
Life and healthcare would be very different if everyone who walks in through the door was a potential researcher – or a research couple: AM and her partner – rather than a burden.