Deciphering Sleep: Our Interview with David Rye

Why do we need to sleep? In all of human biology, few questions are more persistent – or more mythologized – than this one. Almost as puzzling as sleep itself are sleep disorders like narcolepsy and insomnia, which make us wonder why some of us need so much more sleep than others do.

David Rye, a neurologist at Emory University’s School of Medicine, thinks he may finally have some answers to these age-old questions. While studying hypersomnia, an unusual disorder characterized by long yet unsatisfying sleep, David and his co-researchers discovered a new brain chemical that may not only be responsible for hypersomnia, but could help explain why we need to sleep at all.

As soon as I read David’s paper, I knew I had to call him up and talk in more detail. I think you’ll agree that his ideas could turn out to have big implications for all of us. –Ben
Ben Thomas: How’d you get interested in studying hypersomnia, David? Was there a particular patient…?

David Rye: Any sleep physician will see hypersomnia patients from time to time. I’ve been doing this since 1992, and you sometimes run into patients like this: They’re fairly young, but they’re just addicted to sleep. They sleep for long periods of time, and they’re very efficient sleepers – they tend to sleep deep, and they can sleep through alarms and fires and sometimes even bombs. But despite sleeping all that time, they wake up very unrefreshed and they’re still sleepy during the day.

BT: And you’ve pointed out that this pattern is different from what we see in narcolepsy.

DR: Hypersomnia has been labeled with so many inappropriate names, and “narcolepsy” is the biggest one we hear. But narcolepsy has been classified very precisely into several categories – for instance, Type I narcolepsy, which is characterized by the loss of this neuropeptide chemical known as hypocretin. And narcolepsy – the literal translation is “to be seized by sleep.” Narcoleptics don’t actually sleep more than healthy people over an average 24-hour period; their disorder is characterized by sudden attacks of sleepiness. So to characterize a person with hypersomnia as “narcoleptic” is really a disservice to the language.

BT: What are some unique features of hypersomnia?

DR: Hypersomnia patients don’t really respond to traditional stimulants – they can still sleep for hours even after taking a large dose of caffeine, or an amphetamine. And what they usually describe is that these stimulants make them feel physically awake, but they never quite wake up mentally – they feel as if they’re in a fog. Academics at sleep centers around the country agree that they’ve seen these patients, but no one knew exactly how to treat them.

BT: Could there be such a thing as “hypersomnia with narcoleptic symptoms,” or are these two disorders completely distinct?

DR: I think it’s closer to the former, which makes the process of diagnosing these disorders even more confusing. There are people who are labeled “narcoleptic” because they fall asleep during the day and go right into a dream – and this is characteristic of the “genuine” narcolepsy I was just mentioning. But in reality, recent research has found that many narcoleptics are more like our hypersomnia patients – they sleep for long periods of time during the day.

BT: So how do you distinguish these diagnoses in the clinic?

DR: Well, see, that’s what makes this even trickier: Patients don’t come into a clinic complaining that they fall directly into dream states – that’s just not a complaint you’d hear. So my question is, why are we classifying patients as “narcoleptic” based on whether or not they fall into a dream state when they have a nap during the day? As physicians, we start diagnosing a new disorder based on clusters of signs and symptoms, rather than on underlying biological processes – but as time goes by and we come to better understand the biological basis for a particular disorder, we update our diagnostic criteria so we can more accurately categorize the patients we see. And that’s been a huge uphill battle for these sleep disorders, because we’re only beginning to understand their biochemical causes.

BT: Do we have any idea, neurochemically, why hypersomnia symptoms are so unusual?

DR: I think we’re putting our finger on it with this research. The traditional approach is sort of a “Western” approach – what I mean is, when Western neuroscience deals with a problem, we have a bias to characterize the problem as “something’s missing.” In this case, that plays out as, “This patient’s wake-up system isn’t working properly,” so we say, “Give it more stuff to make it awake.”

BT: But that’s focusing on the wrong issue.

DR: Right. By analogy, we’re pushing the accelerator pedal – but the problem isn’t that we need more gas; it’s that the parking brake is still on. The “parking brake” is gamma-aminobutyric acid (GABA), which is an inhibitory neurotransmitter chemical that helps promote sleep. And that parking brake needs to be disengaged before we can hit the gas and hope to actually get moving.

BT: And in this study, you looked at substances that interact with GABA receptors, and isolated a chemical that’s strongly correlated with hypersomnia.

DR: Exactly. We’ve characterized this chemical quite well – in fact, when we submitted our paper to the New England Journal of Medicine, they told us they were impressed with the level of detail in our pharmacological analysis of this chemical’s interaction with GABA receptors. The real question now is, is this biological agent unique to the types of hypersomnia we studied, or might it also be a factor in other known types of narcolepsy that we didn’t look at? Or might it be part of a general-purpose pathway to sleepiness, common to all human brains? That’s actually the explanation we’re leaning toward, though you can’t make that claim from our data in this particular paper.

BT: There’s been a lot of media blitz around this study since you announced your results. Why do you think this work resonates so strongly with the general public?

DR: I think it speaks, first of all, to our culture’s traditional and literary fascination with sleep. There’s Sleeping Beauty, Rip Van Winkle – for centuries, we’ve been enamored with stories of people who sleep for long periods of time. It’s also the opposite side of the coin of insomnia, which is something a lot of us struggle with. When I talk to reporters about hypersomnia, one comment I hear a lot is, “Can you give me a dose of that?” They’re jealous! So I think it speaks to a lot of topics that puzzle and intrigue us.

BT: It sounds like people find the actual experience of hypersomnia difficult to relate to, even if they’re jealous of it.

DR: And yet, what our data really seem to suggest is that hypersomnia is just one end of a spectrum – a bell curve – that includes all of us. The majority of us sleep for seven and a half, eight hours – and what we’re showing here is that even people who need to sleep nine or ten hours are probably just less extreme variants from the center of that curve. So my wife and I joke that we can definitely relate to this – when her family come to visit for the holidays, they can sleep for nine hours and take a two-hour nap in the afternoon.

BT: So this data could give us insight into why some people are fine with six hours of sleep, while others are drowsy if they get less than nine.

DR: I think that’s the point. Beyond the direct implications of being able to treat hypersomnia, we’re getting some good insights into how normal sleep is generated – and maybe even why we need to sleep at all.

BT: That question’s always intrigued me – it’s definitely one of the all-time great science mysteries.

DR: Well, if we know what this molecule is, and what chemical pathways it’s involved in, and we can make specific statements like, “It accumulates in excess under these certain conditions,” I think we’re gonna be pretty damn close to understanding why we sleep.

BT: That’ll be really interesting to see. I’m excited to hear about where that research goes.

DR: We’ve actually gathered quite a bit of sleep-related data that didn’t make it into this paper, so we’ll be publishing more about our findings in the near future. So stay tuned.

I definitely will, and I’ll do my best to keep all of you in the loop, too. Thanks for joining us – we’ve got lots more exciting interviews coming up soon!

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