Science of Sleep

01 October 2013
Presented by Chris Smith, Priya Crosby.

What's the best way to catch 40 winks? We investigate the science of sleep, including why we need it and why do some people fall asleep at the wrong times? Jason Rhiel tell us how he investigates what makes us sleepy using zebrafish and Mick Hastings explains the effects of shift work on our health. Plus, in the news, nanoparticles deliver vaccines without needles, the 4,000 year old body perfectly preserved in a bog, an animal that can keep track of tides, a new nose grown on a forehead, and nurturing new neurones to treat Parkinson's...

In this episode

01:34 - Inhalable viral vaccines

Vaccination using hypodermic needles might be replaced by a breathable nanoparticle vaccine, new research suggests...

Inhalable viral vaccines

Researchers have developed a new kind of breathable vaccine, a paper released in the journal Science announced this week.

When most of us think of a vaccine, we think of a needle shot in the arm. However, it has been suggested that this might not be the best method of vaccination for many Needlediseases.

The fact is that most viruses do not naturally enter the body through cuts and grazes - as occurs with a hypodermic needle - but are breathed in from the air or even eaten. Because of this, our body is much better evolved to mount an immune response to something that is eaten or inhaled than to something that is injected. This means that, if we can introduce a vaccine into the body in a more natural way - for example, by breathing it in - it might be more effective than if injected.

The problem is that most small particles that are inhaled - including the weakened viruses used for vaccination - are cleared from the airways without ever entering the body or encountering the immune system. This means that they are not around for long enough for the body to develop an immune response to the virus and so are mostly ineffective.

However, a group at the Massachusetts Institute of Technology (MIT) might have found a way around this problem.

The group, which was led Darrell Irvine, created a multi-layered fat capsule which could surround the weakened virus used for vaccination. Although still extremely small - only nanometers across - the drops are larger than the weakened virus alone and their fat composition make them more likely to be taken up by the body.

When compared to inhalation of the weakened virus alone - without the nanocapsule -  or to injection of the virus in nanocapsules, the results of vaccination using inhalation of these nanocapsules were impressive.

Mice vaccinated using inhalation of the nanocapsules almost invariably survived subsequent challenge with the real live virus. In contrast, mice which had been vaccinated using the other techniques did not.

Although this technique has only been tested in mice so far, it provides real hope as a possible new method of vaccination against a variety of diseases in the future.

04:08 - Rotating antibiotics stop superbugs

A new technique to block antibiotic resistance in bacteria has been discovered by scientists in Denmark...

Rotating antibiotics stop superbugs

A new technique to block antibiotic resistance in bacteria has been discovered by scientists in Denmark.

With the drug development pipeline E. coli bacteriaat an all-time low, there couldn't really be a worse time for rates of microbial resistance to be steadily rising.

Policy makers in many countries, including the UK's Chief Medical Officer Dame Sally Davies are even warning that, within a matter of a decade or so, the antibiotic arsenal will be on its last legs.

So the announcement this week from Technical University of Denmark researchers Lejla Imamovic and Morten Sommer of the discovery of a new way to prevent resistance - but using only existing rather than any new drugs - might be just the shot in the arm that the sector needs.

Published in Science Translational Medicine, the Danish duo's approach depends upon a principle termed "collateral sensitivity".

Put simply, in order to become resistant to one class of antibiotic drugs - call it drug A, bacteria often have to drop their guard and become super-sensitised to another antibiotic - drug B. This can happen because the clusters of genes that are activated to defend against A can switch off the very genes needed to fortify the bacteria against B. And thus, the first bugs to die when exposed to drug B would actually be the very ones that were showing resistance to drug A.

So, Imamovic and Sommer reasoned, if the right antibiotics are administered in the right order, it should be possible to prevent the establishment drug-resistant bugs in the first place.

To test this theory, cultures of E. coli bacteria that were individually resistant to one of 23 different antibiotics were tested against the other 22 antibiotics to see which, if any, of the drugs they were more or less sensitive to.

Seventeen of the 23 drugs tested showed the theorised collateral sensitivity to a second antibiotic ranging from them being two- to eight-fold more vulnerable to the drug compared with non-resistant bugs.

Using this information, the researchers were able to draw up over 200 drug cycles - sequences of 2, 3 or 4 antibiotics - that if administered successively over a short period to bugs with resistance to a given drug should destroy those bugs and thus prevent further resistance developing.

Tested on two clinical strains of E. coli that were resistant to 8 of the 23 antibiotics studied, the drug cycles successfully destroyed all of the bugs as predicted.

According to the researchers, "This study provides proof of principle that an underappreciated side effect of resistance, collateral sensitivity, can be used to target drug resistance when selected drugs are cycled optimally."

They go on to speculate that collateral sensitivity cycles like those established by their study could be effective for treating a wide range of E. coli pathogens, which are now a leading cause of hospital-acquired multi-drug resistance infections...

07:40 - Mind Boggling Bog Bodies

A mummified body known as the Cashel man was recently found to be the oldest so called ‘bog body’ with intact skin anywhere in the world.

Mind Boggling Bog Bodies

A mummified body known as the Cashel man was recently found to be the oldest so Tollund Mancalled 'bog body' with intact skin anywhere in the world. Here's your quickfire science on how wetlands can preserve ancient human remains with Kate Lamble and Matt Burnett

- A bog is an area of wetland covered with sphagnum moss and peat or partially decayed vegetation

- Hundreds of bodies preserved in these areas have been uncovered across Europe. Several have been found in Ireland including the Cashel man in County Laois.

- If a body is buried in a bog soon after death the lack of oxygen, low temperatures and high acidity of the environment mean that bacteria cannot begin to decompose the body, preserving internal organs, clothes and even hair.

- However over time, bodies are often crushed under the weight of the peat and the acidic conditions dissolve the calcium in the deceased's bones, making them either floppy or completely vanish.

- Not all bogs preserve bodies equally well. Lower levels of acidity and higher water flow can turn some remains into skeletons rather than mummies.

- Once removed from the bog Cashel man needs to be sprayed with non-ionised water to prevent it from decaying at room temperatures. In the long term, bodies are preserved by soaking them in a water soluble polymer and then freeze drying the remains.

- Radiocarbon dating suggests that Cashel man is around 4,000 years old, dating from the early Bronze Age. This is earlier than most bog bodies which date from the Iron Age  

- However we don't know if how closely he is related to the current Irish population as the preservation process also destroys DNA material.

- Bodies are typically uncovered by those digging for peat to use as fuel. The first recorded discovery of a bog body was in the 17th century and for the next two hundred years bodies were typically buried in graveyards as it was presumed they were modern victims.

- A high number of bog bodies have been found to have died of violent wounds, leading archaeologists to speculate that some may have been sacrifices. Cashel man's spine was broken several times, and there was evidence of a sword or axe cut on his arm.

10:05 - The Tidal Clock Keeping Marine Life Safe

Researchers at the Universities of Aberystwyth and Cambridge have discovered a marine animal that has a tidal clock as well as a body clock

The Tidal Clock Keeping Marine Life Safe
with David Wilcockson, University of Aberystwyth

Scientists have known for a while that probably all living things, us included, have a 24 hour body clock ticking inside them that keeps track of the time so they know when to wake up and when to go to sleep.

But this week, researchers at the Universities of Aberystwyth and Cambridge have discovered a marine animal that also has a tidal clock. As well as the time of day, it can also tell when high tide is due!

David Wilcockson is the senior author on the paper in Current Biology...

David -   Hello, Chris.

Chris -   So, what is this creature?

David -   It's a small crustacean, lives on sandy shores around the UK, and it's called Eurydice pulchra. It's a speckled sea louse. It's only about 5 mm long and it's a marine relative of the wood louse.

Chris -   Why does it need to know when the high tide is coming?

David -   This animal lives buried in the sand when the tide is out.  When the tide comes in, it comes out of the sand to swim.  And so, it needs to know so that it can gear itself up to swim for two or three hours and burry back into the sand before the tide goes out.  And so, it doesn't get stranded in the inappropriate points on the shore.  It stays in its preferred position.

Chris -   So, how did you discover that this organism has this tidal clock?

David -   We've known this for quite some time.  In fact, one of the authors on the paper, Mike Hastings did his PhD on Eurydice way back in the '80s and we know that it has rhythmic behaviour, swimming rhythm with a 12.4-hour or a tidal period.  But what we didn't know is how this 12.4-hour activity was governed, whether it is simply a daily or 24-hour clock that was running a different speed or whether it's a unique tidal clock.  And this is what we've been working on to really uncover how these 12.4-hour rhythms are driven.

Chris -   How have you done that?

David -   So, we've used modern molecular biology as well as some - I think a quite elaborate behaviour of experiments where we manipulate the light regime the animals are exposed to. What we've done is we've sequenced lots of the genes that we know were involved in daily rhythms in other organisms.  We've sequenced those from Eurydice.  One of the things we've done is, we've actually knock down the expression of one of these genes.  That has disrupted daily colour changes in the animal and actually left the 12.4-hour swimming rhythm intact.  So, we've removed the daily clock, but left intact the tidal clock.

Chris -   I see.  So, what you're doing is, you're saying, there are some things that this animal does everyday according to the time of day and that's driven by its normal body clock.  If you dismantle the body clock using various tricks which you've done, then those daily things go away, but it still has this swimming activity every 12 hours, showing it's keeping track of tides in a separate way to the way it keeps track of normal time of day.

David -   That's exactly right.  So, what I just said is, when it's having its 12.4-hour swimming activity, the animals that changes from dark to light on a daily basis with the light dark changes of night and day.  And also, when it's having a high tide at night time, it swims more than it does during a high tide day time.  So, it's a daily modulation of the tidal swimming.  We can actually reduce those by knocking out the daily clock, but we cannot influence, we cannot change the 12.4-hour rhythm of swimming.  So, we've disentangled or disassociated these two clocks.

Chris -   The fact that it's got two different clocks running in its brain, do you think that's unique to this creature or are there many other creatures perhaps even humans included that have other clocks other than our daily body clock?

David -   That's a really important question.  The answer is that, it's definitely not unique to Eurydice.  This is our model organism for non-circadian for tidal rhythms.  But we know that there's many other marine organisms that also have 12.4-hour rhythms of activity and also, lunar rhythms and semi-lunar rhythms of reproduction for example.  There's a paper published at the same time as ours on a small marine worm that has lunar rhythms of reproductive cycles.  They've shown also that they can disentangle a circadian or daily clock and their lunar clocks.  So, they've come up with similar results but in different organism.

Chris -   But you don't yet know what this clock is or how it runs?

David -   Well, that's the next big question really is, what's the nature of this clock and how is it orchestrated, how this 12.4-hour rhythm orchestrated at the molecular and cellular level.  And that's something that we're getting close to having an answer on and we're working on it very hard at the moment.

15:08 - New Brain Cells for Parkinson's Disease

Stem cells that can turn into dopamine-producing neurones might be a future treatment for Parkinson's disease...

New Brain Cells for Parkinson's Disease

Scientists at Kyoto University are developing an exciting new treatment which might one day provide a treatment for sufferers of Parkinson's disease.

Parkinson's is a degenerative disease in which the sufferer finds it increasingly difficult to carry out smooth, controlled movements. Famous sufferers include Mohammad Ali and Michael J. Fox.

The problem in Parkinson's disease is that the sufferer slowly loses a type of brain cell which produces the chemical dopamine - so-called dopaminergic neurons. It is these neurons which are implicated in executing controlled movement.

The Japanese group, led by Jun Takahashi, have been using stem cells to try to overcome this problem, as explained in a paper published in the journal Stem Cell Reports this week.

The study used a group of monkeys from each of which they took a sample of cells, either from their mouths or from their blood. These cells were then grown in the lab, where they were induced to return to the stem cell state - the state in which a cell is undecided and can divide to form any other type of cell in the body. The cells were then persuaded to divided to become dopaminergic neurons, such as those lost in Parkinson's Disease.

These dopaminergic neurons were then grafted back into either the brain of the monkey from which they were derived or into the brain of a completely different monkey. The monkeys were then left for 3.5 to 4 months.

After this time, the researchers noted that both types of cell graft had survived in the brain, although those cells Nerve_cellswhich were derived from same monkey did slightly better than those from a different monkey. However, the survival rates of both types of cell graft were extremely significant.

This provides us with an interesting new avenue for Parkinson's treatment. Previously, it was thought that this kind of graft might only be really effective if the cells were derived from the same animal into which they were grafted. However, this study suggests that it might be possible to have a more generic treatment for Parkinson's, where the same type of stem cell-derived dopaminergic neurons could be implanted in to the brains of all Parkinson's patients. This has a significantly lower cost than a personalised graft.

There are clearly still many other things that need to be tested - we do not currently know if the grafted cells are able to restore the function of the missing dopaminergic neurons. However, this is still very interesting as a potential future treatment for Parkinson's disease.

17:58 - On-Site Nose Reconstruction

A Chinese man looks like he has a nose growing on his forehead after surgeons worked to replace his nose damaged in an accident...

On-Site Nose Reconstruction
with Nakul Patel, Addenbrookes Hospital

Now, you might have seen in the newspapers this week, pictures showing an individual in Nose grown on ForeheadChina who has a new nose apparently growing on his forehead. The story goes that some time last year this man was involved in a car accident, and that led to an injury to his face. He then succumbed to an infection in the skin and soft tissues of his nose and this infection destroyed the cartilage of his nose and led to profound disfigurement. So doctors in China in the Fujian province where he lives have resorted to a fairly radical and clever way to repair. 

Chris Smith spoke to plastic surgeon Mr Nakul Patel from Addenbrookes Hospital to find out more about the procedure...

Chris - Why would they have grown the nose on his forehead and what's the sort of plastic surgical intervention that is going on here, Nakul?

Nakul - Sure. So, they've used the forehead as a flap, as a block of tissue that's moved down to reconstruct the nose. But prior to that, they've actually used the cartilage from the patient's own ribs to reconstruct the framework that will form the shape of the nose and then thereafter, as a subsequent procedure, they'll transfer this to recreate the nose.

Chris - So, why not just put the cartilage straight onto the face and borrow some skin from somewhere else and build the nose in situ? Why go through this rigmarole of growing a nose up there?

Nakul - It's quite a novel way of doing things. The standard way would be exactly as you've described and they've just tried to differentiate. I think the media has caught the wrong end of the stick in some parts. They've suggested that this new nose has been grown whereas actually it's not necessarily that it's been grown. However, it's just that it's been shaped and placed into the forehead prior to the next operation which is going to be to move it into its correct place.

Chris - How will they do that?

Nakul - So, they take a strip of the forehead tissue, all the way up to the hair line. This technique is well-established.  It was sort of described as early 700 BC and then they place it onto the nose. They leave it attached for a period of about 3 weeks. By which time, it has sufficient blood growth from the edges, such that tissue is likely to survive.

Chris - When you say leave it attached - you mean, leave it attached so it's like on a stalk from the forehead and you trim it out and rotate it down. In that way, it takes its bloody supply with it.

Nakul - That's exactly correct. Once it's got its new blood supply from its new home on the nose, they're then able to divide this stalk and place the remainder of the stalk back onto the forehead.

Chris - Why use forehead skin to do that? I mean, apart from the fact there's a blood supply there, is there any benefit of using that part of the body as opposed to any other?

Nakul - Very good question. The forehead skin is a really good match to the rest of the skin of the nose. That's why this procedure that's been done such a long time ago, it's stood the test of time. So, yeah, we continue to use it to this day.

Chris - Is this likely to be successful for him?

Nakul - Looking at the pictures in the media, I think he's got a good reconstruction with regards to the shape of the nose and I'd hope that if all of that survives, he'll have a nice reconstruction.

Chris - What problems could he succumb to when they try to do the final movement?

Nakul - The worry would be, if any of that cartilage doesn't have a sufficiently good enough blood supply, if any of that gets resorbed. In which case, it will lose its shape.  If there's any infection, again, the same problem could occur.

Chris - What about closing up the forehead where the nose is at the moment? How will they close the skin together so that you don't leave a gaping nose-sized and shaped hole on the man's forehead?

Nakul - Most of the lower part of our forehead, up close to our eyebrow can be closed directly. So, that will leave a straight line scar. You might well leave a small area on the forehead which is quite high up to heal on its own or place a small skin graft on that.

22:26 - Why Do We Need To Sleep?

Some animals spend over 80% of their lives asleep. But why? What’s the purpose of sleep and why does it become a problem for some people?

Why Do We Need To Sleep?
with Tim Quinell, Papworth Hospital

Onto our main topic for the week: sleep. We spend a third of our lives doing it; in fact some animals spend over 80% of their lives asleep.

But why? What's the purpose of sleep and why does it become a problem for some people?

Priya Crosby spoke to Tim Quinell, who is a consultant at the sleep centre at Papworth Hospital...

Tim -   Sleep is about a transition from when we're fully alert and interacting sleeping commuterwith our immediate environment.  When we go to sleep, consciousness gradually drops.  There are several levels of sleep and types of sleep.  So, very light sleep isn't always perceived by someone, but fairly rapidly, at the beginning of the night, we'll go into quite deep non-dreaming sleep and it's called slow-wave sleep because the brain waves slow down.  And that's, if you like, the big money sleep that fills up the sleep bank, pays by the debt of wakefulness.  The chief drivers to sleep is how long you've been awake beforehand.  So, we're going to deep non-REM sleep and after a cycle of sleep lasting about an hour, our sleep will lighten and we will go into dream sleep and that's called rapid eye movement sleep or REM sleep.  So, that's a different type of sleep and in fact, when they've looked at brains with special imaging, during dream sleep, the brain is as active as wakefulness, but we are nonetheless asleep.  And then once we've had some dreaming, we'll go back to non-REM sleep again and the cycles continue through the night.  As the night proceeds, there is less deep sleep because the sleep bank is being filled up if you like, the debt is being paid off and there's more dream sleep.

Priya -   Roughly, how long is any one of these cycles went to a cycle of non-REM and then REM sleep?

Tim -   It's about an hour and a half to 2 hours, but it varies greatly through the nights and between individuals.

Priya -   And so, we've got a concept of what normal sleep looks like.  How do we define a sleep disorder?  I mean, a lot of us will have a night or a few nights when we struggle to sleep, but when does that what I would call normal inability to sleep become a disorder?

Tim -   All of us can have a bad night now and again.  Perhaps if we've got something big happening the next day, we might not sleep so well.  If it becomes more deeply entrenched to that, so perhaps if there's a reason to not sleep well one night, but then that reason has happened the next day, but the sleep problem persists, that might be starting to become a disorder.  It's when it becomes every several weeks or months.  That's really what I'm really talking about there is typically insomnia which is commonly experienced where people can't sleep very well at night.  But there are other disorders which typically gradually develop and they are specific disorders of breathing or where the brain's control of sleep and wake becomes dysfunctional.

Priya -   So you mentioned insomnia.  Do we know exactly what happens when someone has insomnia, we have an impression that they struggle to sleep, but do we know what's going on at a sort of more neurological level?

Tim -   There's not a lot known about why people have insomnia.  There's some evidence that people with insomnia seem to be hyperaroused.  When you look at their brainwaves during sleep, they seem to not be having such a deep solid sleep.  But there's no clear understanding as to why.  There are some other sleep disorders which present as insomnia.  For example, there's a condition called restless leg syndrome where legs are fidgety particularly later in the night when people are tired and finally lying down to go to sleep.  Their legs become uncomfortable and there's an urge to move them.  And that can disrupt sleeping causing insomnia.  And then there are other disorders of breathing where we stop and start breathing without necessarily knowing about it, but what the patient can be aware of is of poor sleep because they're constantly interrupted by the breathing pauses.

Priya -   You mentioned there problems with breathing as a disruption of sleep.  What exactly happens there?

Tim -   Sure.  So, obstructive sleep apnoea is what I'm talking about and that's probably the commonest breathing disorder during sleep aside from insomnia.  What happens with obstructive sleep apnoea is that the throat relaxes and closes or becomes very narrow, so that breathing becomes obstructed.  And so, if you like, the person suffering from obstructive sleep apnoea is choking themselves awake repeatedly during the night.  Usually, they only wake up for a few seconds so they don't remember it.  But what that means is that their sleep is peppered by brief awakenings.  And so typically, what happens if it's frequent enough is that they wake up unrefreshed by their sleep and they're sleepy during the day.

Priya -   What could they do if someone has obstructive sleep apnoea?

Tim -   People can have suggestive symptoms and we have to take them forward for test to confirm the diagnosis.  And they will look at how bad their symptoms are and how much apnoea it's occurring, how many times they stop breathing every night.  It may be that simple lifestyle measures would improve the situation.  So, mild sleep apnoea may respond to weight loss because that's a major risk factor for the development of sleep apnoea.  Sometimes it only happens when someone's lying on their back, so we can talk about measures to avoid sleeping on their back and that can do the trick.  Sometimes if sleep apnoea is more severe, then they need specific treatments.  One way of treating it is to wear a mask called CPAP which stands for Continuous Positive Airway Pressure.  This is a mask connected to an air pump which blows air through the throat to provide a pneumatic splint to the airway to stop it from flopping shut.

Priya -   If someone thinks that they might have insomnia, what options are there out there to treat or manage the condition?

Tim -   Well, many bouts of insomnia settle spontaneously so it will be short-lived and it may well relate to something that's going on in someone's life.  But if it becomes protracted as about taking a step back and looking at what things you might be doing, but aren't helping the situation - has someone got into the bad habit of working very late and then switched their lights straight out, having caffeine in the evening, or that sort of stuff, it's looking at their sleep environment, is it appropriate, is it quiet, dark, comfortable, that's sort of thing.  And also, what does happen with insomnia is it tends to feed on itself.  So, even if the initial stressor that's triggered the insomnia has been dealt with and resolved, the concerning anxiety about not being able to sleep tends to feed it.  The worst thing that can happen for insomnia is to be worried about sleeping because if we do that, then it gets worse.  And that really is something that probably most of your listeners will recognise.  If they are having a night where they're thinking about something important the next day, they're worrying about that then they realise they're not sleeping and they start worrying about that.  Sleep becomes even more elusive.

Priya -   Thanks to Tim Quinnell from Sleep Centre at Papworth Hospital.  The best thing for insomnia is actually to stop worrying about it.  Easier said than done in my own experience, I find that if you've struggled to sleep to find yourself getting into loop and you get more and more worried about it, and it stops you sleeping altogether.

Chris -   What did you think stopped you sleeping then?

Priya -   Worrying about not sleeping.

Chris -   So, what do you think got it going in the first place?

Priya -   I think shifting sleep, I think I have to get up early for a few things, and you then start thinking, well, I'm going to have 5 hours or I only got 4, and it just rolls in itself pretty much.

Chris -   I know what you mean though because when I've been in situations where you worry because you've got a big day ahead, and then you worry because you're not sleeping because you got a big day, and you are worried about being lethargic entirely the next day and then actually, worrying about not getting enough sleep takes over, doesn't it?

Priya -   Exactly.

29:35 - Experiencing Narcolepsy

One serious sleep disorder is narcolepsy; sufferers regularly fall asleep because they can’t regulate their sleep patterns...

Experiencing Narcolepsy
with Julie Flygare

We've touched on the problem of insomnia, where people can't get to sleep, but a more serious sleep disorder is narcolepsy; sufferers regularly fall asleep during their daily lives because they can't regulate their sleep patterns properly.

Julie Flygare writes a blog about what it's like to have the condition...

Julie -   For me, the first thing was, I was laughing about a joke.  My knees justA sleeping boy slightly buckled.  It was like the strangest feeling.  Like almost like I melted inside.  But then my friends said she doesn't she anything, so I thought, okay, I don't know what that was.  That weakness became worse and worse over a few years, only when we're laughing at jokes or I was annoyed then my body would start giving out on me.  I asked my doctors about that and around the same time, I was also in a law school and I just started law school and I was having such a hard time being awake through all my classes.  Some of my notes from class would have words from dreams, like mixed in with the lecture and like celebrity names and then half sentences.  So, I was conscious, but not really actively engaged in my classes. 

I really didn't think of it as a sleep disorder for a long time.  I just thought it was like my personal problem and it wasn't until one morning that I was trying to drive to school after getting my full night sleep, I got to school and I woke up in a parking lot.  I didn't remember having arrived there.  So, that's when I thought, maybe I had a sleep disorder.  So, I went to see different doctors and it took a while, but eventually found narcolepsy with cataplexy as my diagnosis.  Once I was diagnosed, like I thought I would take medication and go back to my life, the way it was before.

I take medication twice a night to help me get into a better form of sleep because we've spent too much time in REM dream sleep.  I mean, not getting stage 3 restorative sleep and then I take daytime stimulants during the day.  But even with all that, I still nap twice a day and that's really unpredictable. 

I feel pretty energetic and then slowly, I lose my ability to really concentrate and think straight and make the decisions.  If I'm in a conversation with friends, all at once, I might say something that has nothing to do with the conversation.  It's almost like I almost entered like a little bit of a dream and then my friend will be like, "What did you say?"  And then I'll be like, "What?  Oh, I don't know.  What did you say?  What did I said?"  I just kind of fizzle out and that happens once or twice a day.  So, as soon as I start feeling that way, I try to take a nap.  I still have that cataplexy where my body gives out. 

It's not nearly as bad like before I received treatment.  If I hadn't gone to treatment, like I would end up in a wheelchair.  I got so bad that I was completely collapsed to the ground paralysed for a minute or two and there's another symptom of hallucinations so, when I wake up from a nap or sometimes during the night, I really think things are happening to me that someone has come into my apartment.  Maybe it's a burglar or someone's going to attack me.  I really feel like I could see them and hear them, and feel touched, but they're not really there, and that still happens to me quite often.  That's also because the boundary between dream sleep and consciousness are kind of broken.  So, aspects of dream sleep are happening while I'm too conscious.

Priya -   Julie Flygare who writes the blog julieflygare.com, describing her experience of narcolepsy.

33:43 - What Can Zebrafish Tell Us About Sleep?

How can we probe what’s going on in the brain of someone who has a sleep disorder? Jason Rihel uses zebrafish to learn more about sleep...

What Can Zebrafish Tell Us About Sleep?
with Jason Rihel, University College London,

How can we probe what's going on in the brain of someone who have a sleep A zebrafish, zebra daniodisorder? Chris Smith and Priya Crosby spoke to Jason Rihel, from University College London, about how he uses zebrafish to learn more about sleep.

Chris - How on Earth do you understand sleep from watching fish?

Jason - So, the first thing we can do is very simply watch a fish with a video camera. In fact, we can watch thousands of fish at once. And then what we can do is we can manipulate them genetically or we can add drugs into the water and ask, how does their sleep patterns change? And then from there, we can try to understand what's happening.

Chris - Are fish a good representation of the patterns of sleep and the systems in the brain that control sleep in even more complicated animals including us?

Jason - Yes. So, this concept of non-mammalian sleep is a relatively new one. It's only been about the last 12 or 15 years when scientists have reached a consensus that most organisms including fruit flies and fish have a sleep-like state. And in the fish in particular, not only do drugs that regulate or manipulate sleep in humans, also give the same effect in the fish. But also, many of the neurons including those neurons that are lost during narcolepsy also are present in the fish and seem to have many of the same kinds of neuronal connections that are present in mammalian brains. And also, some of the same functional consequences that we see in mammalian brains as well.

Chris - So, you can do many, many parallel experiments watching these fish and you can put chemicals into the environment the fish are in to see if they change their sleep behaviour. Have you discovered anything that can manipulate sleep?

Jason - So, in fact, one of the things that we did was we can do a screen because we can do so many at once, we can do a screen of thousands of small molecules. In fact, we did a screen for several thousand small molecules and we identified hundreds of different compounds that regulate sleep, either upregulating or downregulating various parts of their behavioural experience. The other thing I should say is that the larval zebra fish are also optically transparent. So, another thing that we can do is, we can use calcium indicators which will respond to when neurons are active. We can actually watch the fish brain while they're sleeping or while they're awake, and ask what neurons are doing during different behaviours.

Chris - How old are these fish because we know that if you study a human, a baby spends the majority of its life asleep whereas an elderly person spends half the night awake because they can't drop off - So, are your fish therefore a good model for a human in that regard?

Jason - One thing to realise is that when we talk about larval zebra fish, the comparison to mammalian models is a little bit overly simplistic. So, one problem for example is that the larval fish - so, they go from one cell to a fully patterned animal in about 24 hours. And then at 4 or 5 days post fertilisation, they can actually do complex behaviours including, they can learn, they can hunt. So, in some ways, they're more on their own very early on. So, they're not necessarily like a human baby per se, they're more like an adolescent maybe.

Chris - We heard just before you from Julie Flygare and she's been describing her experiences of the condition narcolepsy. What can your fish reveal about why she's having those symptoms?

Jason - Narcolepsy is a syndrome that is accompanied by loss of these very specific neurons deep in the hypothalamus of our brains that produce a peptide called hypocretin or orexin. That peptide gets secreted and through mechanisms that were very complex and somewhat not well understood yet seems to promote arousal. One of the things that we've done in the zebra fish is be able to manipulate the orexin hypocretin system. We can make mutations that eliminate that function or we can kill those neurons just like in the human patients and then this is one of the things that we're doing right now actively is, we can then test say, some of the drugs that we identified from our previous screen and ask, now these fish, they have no hypocretin signalling. How do they respond to these drugs?

Chris - Have you got any leads? Do you think you're going to be able to come up with some compounds that will help people with narcolepsy better than the present agents which all have many side effects that they're currently forced to take?

Jason - Well, it's very early days. So, I'm reluctant to say too much, but I think we're hopeful that we could screen a large enough compound set that maybe we'll be able to find something.

Priya - Jason, you were talking about sleep in baby animals and larval zebra fish earlier. I've got a question in from one of our listeners, David Stovel and he's asking about sleep in the foetus in the womb and he says, "When a foetus is developing in the womb, does it wake up for the first time, or does it go to sleep for the first time?" I think what he's asking here is, when do we start to see sleep and wake cycles in a baby human?

Jason - So, I know from studies in rodents that you can in fact, by measuring brain activity, identify what appears to be a sleep-like state during late foetal development. I don't know exactly when in humans that kicks on, but certainly in other species, you can identify a sleep-like state during development.

39:52 - Disturbing Our Sleep With Shift Work

How does disturbing our sleep patterns by working shifts affect us?

Disturbing Our Sleep With Shift Work
with Mick Hastings, MRC Laboratory of Molecular Biology

Most of us only have our sleep disturbed when we get jet lagged or start working An old style alarm clockshifts at really odd hours. To find out how this affects us, Priya Crosby spoke to Michael Hastings from the MRC Laboratory of Molecular Biology in Cambridge who works on understanding our 'body clocks' or circadian rhythms.

Priya - So, we all get tired if we're suddenly asked to do a night shift, but people who do it regularly seem to adapt to these strange alternate hours. Can you tell us, how do our bodies accept this new kind of timing.

Michael - Well, you mentioned it yourself in the introduction that we have a clock in our body. In fact, we have probably innumerable clocks in our body. There's principal clock in the hypothalamus, something that Jason mentioned earlier which is called the suprachiasmatic nuclei. That is basically the conductor to a whole orchestra of other clocks spread right across the body. So, there are clocks in the liver, there are clocks in the stomach, the immune system, you name it, it's all rhythmic, and nature programme us to operate on a normal 24-hour day. That 24-hour day because the suprachiasmatic nuclei are connected to the retina of the eye, they know as it were when it's day and when it's night, and then they can relay that information to all of the other body clocks right across our body.

Of course, the problem arises is that nature never intended us to jump on airplanes and travel across time zones. So that when we do that, in fact, the capacity of our body clock system to adjust to a change in the light dark cycle is very limited. At the time we're trying to catch up with the changing light dark cycle, this beautiful programme that normally controls our physiology and behaviour is completely scrambled and that's why we feel lousy and we're confused, and we can't concentrate.

Priya - How long does it take our body, roughly, to adapt to this new cycle?

Michael - Yes, so the rule of thumb and you can demonstrate this in people, you can also demonstrate it in experimental animals. The rule of thumb is that for every hour difference in time zone, it takes about one day to readjust. So, you know when the clocks go forward or back in spring and autumn, that's a one hour difference, so it's not too much of a problem for people. But of course if I were to fly from here to New York, it's a 5-hour time zone difference. It would probably take 5 days for me to adjust to New York time and then when I come back, I've got another 5 days of readjustment to Cambridge time.

Priya - So, it's quite a long time to shift between these two cycles. Are there any problems, perhaps not so much with jet lag which is quite rare, but if someone shifts a lot, for example if they're doing shift work and they change between working days, and nights, would there be problems with doing that kind of thing?

Michael - Absolutely. I'm sure that many of listeners have work shifts or have experienced it. It's not a pleasant thing to do. From the point of view of the body clock, we can have animals for example and change their light dark schedules and mimic the effects of shift work. And if for example, you have let's say a mouse, which is a type of mouse which has got problems with its heart, if you then mimic shift work changes on the light dark cycle, that will aggravate the cardiovascular disease that we see experimentally.

You can then jump from those experimental observations to look at people, and if you do epidemiological studies, so you look across a large number of people trying to correct for all the different potential confounding factors, one finds that people who have had a working life on rotating shift work. So, they are forever trying to jump from one clock zone to another, they've got a let's say 20% increased chance of getting certain forms of cancer or indeed cardiovascular disease. So, there is a real life cost to people, trying to work against their natural body rhythm.

Priya - We've got a question in from one of our listeners here from Anthony Gortastic. He says that he's a shift worker. Every 21 days, he does 7 nights and he wants to know what's the best thing to do eating wise. Should he eat meals through the night as if it were a day or should he just have lots of light snacks?

Michael - I mentioned there's a clock in the liver and that controls when the liver produces the various digestive enzymes. The clock in the liver is actually responsive to meal times. In an experimental animal, if you change a time when they can eat, you see that their rest activity, their sleep wake cycle stays the same, but the clock in the liver gets pushed out of sync with it. So, meal times are very potent stimulus for this internal synchronisation.

In terms of what your listener says, given that he's spending most of his time - if it's 7 days out of 21 and you've got 14 days out of 21 on normal schedules. So, I think the best thing - my personal view would be, it's better for him when he on the shift to stick to the meal times he has when he's not on a shift, to stick to his normal routine rather than trying to change things for 7 days and then have to change them back again after 7 days.

Is there any benefit of having "power naps"?

Michael Hastings - Two separate questions. The purpose of sleep, aside from withdrawing from the world, and rebuilding your body and repairing damage, and taking time out as it were, the principle purpose of sleep is for the consolidation of memories. So, when you sleep, you encode the information which you've taken on during the day. Obviously, for children, nothing can be more important for a developing brain than to correct the process, all the new experiences that children have as they grow up. So, short sleep times in children is potentially going to have consequences for their cognitive abilities and probably with their mood as well. I think most parents recognise that.

Why do some people talk in their sleep?

Jason Rihel - So, I am a sleep talker, but no one in my family over 30 some years of talking in my sleep have ever found me to say anything coherent whatsoever. So, I'm not certain if it's a subconscious way of trying to answer or say things that we otherwise wouldn't. It may just be just like when our eyes start rotating during dreams through REM sleep, Rapid Eye Movement. Perhaps when we're talking, it's also just kind of an automatic response like that.

Is it possible not to dream in months?

Jason Rihel - Yes. In fact, it's possible not to dream for as far as we're aware, years. So, some patients that take certain kinds of anti-depressants and anti-psychotics, actually have a massive suppression of REM sleep which is the dreaming sleep. They seem to have no obvious cognitive impairments due to the lack of REM sleep which comes to the question, what is REM sleep for and what are dreams for? We don't really know, but one idea is that it's a way to prepare the brain for wakefulness. The brain becomes active again after being in this strange slow wave sleep phase and then perhaps it's just a way to prepare the brain to be active.

Why are dreams so often forgotten?

Jason Rihel - So, one thing to keep in mind is that even though sleep seems to be important for consolidation of memories, it's not necessarily tied to the dreaming stage of sleep. In fact, many of the studies that link memory to sleep actually point it to being particularly important during the non-REM sleep phase. So, it's not necessarily true that the dreams are the part that are the memory replay and consolidation. Now, why you often forget your dream, I think that's probably an adaptation for exactly what you said, how do we know that a dream isn't reality? If we remembered our dreams too thoroughly, perhaps we would begin to become confused about what is reality and what was a waking experience.

Does digestion make you sleepy?

Jason Rihel - So, my experience is, it's been always a glass of warm milk that makes me sleepier, but yes, there are definitely foods that can make us less tired or more awake. In fact, many people have experienced for example, after a large meal in particular, sleepiness. That's actually a period of sleep called postprandial sleep which is after eating sleep. If you look throughout the animal kingdom, think of the mighty lion for example, feasting on a zebra carcass and then just going off for a big long nap.

Why is coffee so good at giving a boost?

Jason Rihel - So, that is because of what's in coffee which is caffeine and caffeine is an adenosine receptor antagonist.

So, in order to understand how this works, one concept for the timer for what maintains wakefulness is thought to be in fact adenosine which is a small molecule that gets progressively secreted in the brain and builds up during wakefulness. In certain areas of the brain, it's thought that adenosine is triggering, "Hey, it's time to go to sleep now." Caffeine is thought to directly interfere with that signal that it's time to go to sleep and give in fact a boost to wakefulness.

Why is it so hard to stay awake in class?

Jason Rihel - Yeah, so that's a very good question and I see it in my students and I see it among the faculty when they have a seminar at even once that they are particularly interested in. I think it's a combination of sleep deprivation. So, you're not sleeping perhaps enough and then during a lecture, you're getting a period of quiet restfulness. Maybe the lights go down, and those are all being triggers to say, "Hey, maybe you should go to sleep now. You didn't get enough sleep last night."

Why do I wake 4 hours after going to sleep?

Michael Hastings - Short sleeper I guess. We're trying to find out, we and other people, to discovered the genes. Obviously, one approach is mainly using mice as your experimental model and zebrafish as well. We need to find the genes behind this because it's a common feature of people from individual to individual, to have different lengths of sleep, just the same as people have got different eye colour and height. But we know very little about the genes that control the length of sleep as opposed to the genes that control the timing of sleep.

52:02 - Does the moon cycle affect human physiology?

Does a full moon affect your sleep? And if so, is there a biological rationale for this?

Does the moon cycle affect human physiology?

Hannah - To answer Martin's sleepless question, we turn to clock doc, John O'Neil from the Laboratory of Molecular Biology in Cambridge where he works on circadian rhythms. But what exactly are circadian rhythms and how is it relevant to Martin?

John - Your circadian rhythm is the approximately 24-hour biological clock that ticks away in every cell of your body, priming us for wakefulness in the morning and making us feel sleepy at night.

Hannah - Aha! So, could the moon cycle or atmospheric pressure changes affect our circadian rhythms in some way and disturb sleep. Let's start with atmospheric pressure. What's the data on that?

John - I'm afraid there is very little that's known about the effects of high atmospheric pressure on human sleep.

Hannah - That's disappointing. Okay, well what about the moon? Is there any data linking the lunar cycle to Martin's reports of disturbed sleep and wild dreams?

John - When it comes to lunar cycle, beyond the historical folklore, the moon very much continues to influence modern day human cultures. But despite a persistent belief that our mental health and other behaviours are modulated by the phases of the moon, until very recently, there has been no solid evidence that human biology is in any way regulated by the lunar cycle. It has been speculated however, that just like with the circadian clock which synchronises to the cycle of day and night, there may exist in humans a lunar rhythm that synchronises with the phases of the moon, as has been observed in certain marine organisms. So, just last month, Anna Wirz-Justice and colleagues performed a retrospective analysis of human sleep data, collected under stringently controlled laboratory conditions with neither the participants nor the investigators being aware of the lunar phase. They found that during the full moon, on average, participants experienced a 30% decrease in deep sleep, otherwise known as NREM sleep, a 20-minute reduction in total sleep, and that it took 5 minutes longer to fall asleep even though they didn't know it was the full moon. This implies that lunar rhythms do exist in humans and it would seem reasonable to expect that some individuals such as your listener perhaps are more sensitive to them.

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