Dream­ing of a cure: the bat­tle to beat nar­colepsy

The Guardian Australia - - Science - Henry Ni­cholls

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.

In the Kala­hari, back in 1995, I was new to th­ese symp­toms. I had lit­tle sense of the in­cal­cu­la­ble toll that fight­ing a never-end­ing bat­tle against sleep would take on mind, body and soul. I was not alone. Few fam­ily doc­tors had heard of the con­di­tion, let alone en­coun­tered a sufferer. Some neurologists knew what to look for, but many did not. Not even sleep spe­cial­ists could ex­plain why this dis­or­der would sud­denly strike, with peak on­set at around 15 years of age.

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 the­cen­tre 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).

Yet while there are drugs that can help man­age the worst of the symp­toms of nar­colepsy, none of th­ese comes close to re­pair­ing the un­der­ly­ing brain dam­age. It is re­mark­able that the lack of a chem­i­cal re­sults in such a be­wil­der­ing con­stel­la­tion of symp­toms. 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?

In April 1972, a toy 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 full­blown 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.”

Mitler is now a foren­sic ex­am­iner based in Washington DC, spe­cial­is­ing in lit­i­ga­tion aris­ing from fa­tigue-re­lated ac­ci­dents. I ask him 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 cata-

plexy. “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 HLADQB1*0602) that forms part of a set that helps the im­mune sys­tem dis­tin­guish friend from foe. HLADQB1*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.

On top of this, 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 so­called “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 dis­man­tling of my orexin sys­tem. In short, most cases of nar­colepsy are prob­a­bly the re­sult of an un­for­tu­nate com­bi­na­tion of events.

Around this time, the dober­man project in Stan­ford was on the verge of un­rav­el­ling the ge­netic ba­sis of nar­colepsy in the breed. The man hunt­ing down the mu­ta­tion 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 mid­coitus, 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 no­man’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, 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 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 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. Yanag­i­sawa and col­leagues added their ex­per­i­men­tal ev­i­dence to the mix just two weeks later, also in Cell.

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.

Thanks to op­to­ge­net­ics, a tech­nique De Le­cea helped pi­o­neer, much has been dis­cov­ered. 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.

De Le­cea brings up a video on his lap­top. There is a mouse in a cage that has been en­gi­neered so its orexin neu­rons will fire in re­sponse to light. There is a thin fi­bre­op­tic ca­ble run­ning into its brain. “The mouse is asleep,” he says. The op­tic ca­ble comes alive, a pulse of bluish light flash­ing for pre­cisely 10 sec­onds. The light-sen­si­tive orexin neu­rons re­lease their neu­ropep­tides and, all of a sud­den, the mouse wakes up. When the light goes off, it falls asleep as rapidly as it woke.

Us­ing op­to­ge­net­ics and other meth­ods, De Le­cea has shown that the orex­ins have a pow­er­ful ef­fect on many neu­ro­log­i­cal net­works. In some set­tings, they act like neu­ro­trans­mit­ters, cross­ing gaps in neu­rons to ac­ti­vate tar­get neu­rons that re­lease a chem­i­cal called nor­ep­i­neph­rine in 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, 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. So, ma­nip­u­lat­ing this sys­tem pro­duces the kind of clear-cut re­sponse that sci­en­tists can work with. “It is a bril­liant model for un­der­stand­ing neu­ral net­works more gen­er­ally,” says De Le­cea.

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.

Even if I could get my hands on a vial of orexin, 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 (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.

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

This has been a long-term project for Yanag­i­sawa. 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. 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 the same. “If this com­pound works, it will work for all those pa­tients,” he says. “In that sense, it’s a rel­a­tively sim­ple clin­i­cal trial com­pared with 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 a type of stem cell and di­rect it to­wards a new life as a brain cell. “You can use this sys­tem to de­rive var­i­ous brain re­gions and like Lego, as­sem­ble them to form cir­cuits in a dish,” he says.

Re­cently, his lab has de­vel­oped meth­ods to do some­thing sim­i­lar for peo­ple with nar­colepsy, 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 risk­free 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 have a happy end­ing? The trans­la­tion of ba­sic re­search into the clinic is no­to­ri­ously dif­fi­cult and ex­pen­sive. 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, 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. 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 Ni­cholls’s book Sleepy­head: Neu­ro­science, Nar­colepsy and the Search for a Good Nightwill be pub­lished by Pro­file in 2018.

This is an edited ver­sion of an ar­ti­cle first pub­lished by Well­come on Mo­saic and is re­pub­lished here un­der a Creative Com­mons li­cence.

Breed­ing nar­colep­tic dober­mans is harder than it sounds, as the af­flicted tend to top­ple over mid-coitus

Nar­colepsy af­fects about one in ev­ery 2,500 peo­ple, but has no cure. Pho­to­graph: SIpho­tog­ra­phy/Getty Images/iStockphoto

Dober­man dogs suf­fer­ing from nar­colepsy played a vi­tal role in the search for a cure for the con­di­tion. Pho­to­graph: Teri Pengilley

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