Clocks, Drugs and Rock 'n' Roll
We mark the clocks going back with a look at our circadian rhythms: that’s the mechanism by which our bodies mark time and keep our biological processes ticking over. Some drugs work better at certain times of the day, so why isn’t this tested in clinical trials?
In this episode
01:01 - How the body clock affects metabolism
How the body clock affects metabolism
Joe Bass, Northwestern University
For many, the clocks going back this weekend means a welcome extra hour in bed. But, the changing of time zones affects more than just how rested you feel on the 2 days of the year we change between Greenwich Mean Time and “Summer” or “Winter” time. In fact, when the clocks spring forward in March, there is a significant uptick in the number of serious cardiovascular incidents - like heart attacks - and as the clocks fall back in the autumn, rates of mental illnesses like depression and seasonal affective disorder surge.This is all to do with the change having a knock on effect on our internal body clock: the inbuilt timing mechanism which many living organisms use to trigger biological processes to keep them alive. This is also known as our circadian rhythm. James Tytkospoke with Joe Bass at Northwestern University, who has been studying how circadian rhythms not only impact on the ability of animals to know when to fall asleep and when to wake up, but also on their relationship with food…
Joe - Circa comes from the Latin, which is diem, which is about a day. So Circa diem is about a day. And that 24 hour period of our waking up and feeling tired each day corresponds with the rotation of the planet. It turns out that all forms of what we call photosensitive life, which means all life that have the ability to detect light, have evolved a mechanism internally to anticipate the 24 hour rotation of the Earth. This was discovered hundreds of years ago by a biologist in France who took a plant called the Mimosa Plant, which exhibits leaf opening and closing. Every 24 hours, he placed that plant in a dark box and was able to prove that the leaves continued to open and close in the same pattern. In a 24 hour period that matches the rotation of the earth.
James - It's so interesting, and I suppose the question then becomes, how do we utilize this knowledge to our benefit?
乔-正确的。在1970年代早期和晚期1990s, the entire repertoire of genes that regulate timing became known to us and and were available in hand. And once those genes had been identified in the animal kingdom in mice, it became possible for us to begin to ask questions about how this system is intertwined with systems that govern processes such as not only sleeping, but why is it that we get hungry at certain times of day? How does our heart rate change across the day? Now, one of the key moments occurred when such mice were available at Northwestern. These animals had abnormalities in their body weight, and so we began to systematically test whether defects in the molecules that control the sleep system and sleep wake cycles might also control metabolism. And in doing so, we observe that animals that have disturbance in their mechanism for timing have reproducible defects in the control of energy balance, which results in obesity if they're provided high fat diet and in the control of blood sugar, which results in diabetes. We use a variety of different approaches. We can manipulate genes that are in the place in the brain that responds to the sunrise each day, which is called the central clock or the master clock. Or we can get more sophisticated and manipulate that same alarm clock, so to speak in the body, in the cells that regulate energy balance. There may be an alarm clock, so to speak, within our cells that can metabolize nutrition, either store it or burn it.
James - So could you contextualize it, just what sort of impact time restricted feeding has on weight?
Joe - So we had special chambers built, which dispense food by computer systems very precisely corresponding with when the lights go on and off in the environment in which the animal is housed. So here we can control both the light cycle and the dispensing of food that is either normal food or high fat food, and we can compare what are the effects of the change in eating time with regard to the magnitude of obesity that the animal experiences and do the genes that control timing influence the magnitude of weight gain. So using that approach, we were able to definitively show that if an animal eats when it should be asleep, they have a tendency, even if they've eaten the exact same amount that they could eat when they were awake, they gain more weight.
James - Fascinating. And how transferrable are the results you found in mice, in people?
Joe - Well, that's really a million dollar question. Our genomes are 98% conserved across rodents and humans. That doesn't mean that the exact information that we have in hand will in its entirety transfer. It simply means that we've gained inroad into recognition that there's something about the intrinsic timing system and our response to nutrition that needs to be taken into consideration for questions such as, in the situation in which somebody has diabetes for instance, how do we align the delivery of insulin with food? Or what is the effect of eating at different times or shift work on metabolism? And we know that in individuals in which the system's already stressed or pushed by virtue of the development of metabolic disease, these questions become more apparent and immediate from a clinical standpoint. We know, for instance, in the hospital that individuals who cannot eat any longer and are delivered nutrient through a tube, the the tube feedings are often delivered when the individuals are asleep or at night. And almost universally, these individuals develop very severe metabolic complications. They have fat in their liver, they have a requirement for a great deal of insulin. So my hypothesis would be that the reason that misalignment of feeding and light cycles may lead to adverse metabolism, not only weight gain but also the ability to handle nutrients at different times of day, has something to do with the clock system that we have begun to dissect.
08:14 - Chronotherapeutics: timing drug delivery
Chronotherapeutics: timing drug delivery
John O'Neill, Cambridge University
我们刚才听到的生物钟如何影响metabolism, so it's automatically also linked to a range of diseases and, therefore, by extension, to the treatments for those diseases; so should we be giving certain drugs only at certain times of the day; and do we know when? From the Laboratory of Molecular Biology in Cambridge, John O'Neill...
John - It goes in two directions. And number one is that if you disrupt your circadian rhythms, and in most cases that's due to lifestyle disruption, you put yourself at increased risk of a whole range of different aging related diseases. So that's things like neurodegeneration, cardiovascular disease, and diabetes. And on the other hand, because so much of our physiology follows this 24 hour rhythm, the symptoms of many diseases themselves have a daily rhythm. So let's say you've got rheumatoid arthritis pain that you feel tends to be worse in the morning. And so in consequence, if you take anti-inflammatory and steroidal drugs, they tend to be more efficacious when taken in the morning than in the evening. To give you another example, if we consider people with high blood pressure, they might be taking statins. And for a number of those statin drugs, they're only really effective if they're taken before bedtime.
Chris - Why is that?
John - I think it's fair to say that the best understanding is that you get about half of your cholesterol from your diet and then about another half is synthesized in the liver and that largely happens at night. And so the idea is that if you take statins, that inhibits one of the enzymes that helps liver to make cholesterol. If you take it at night before bedtime, you really reduce that internal cholesterol synthesis, but you're still able to get cholesterol from your diet. So you're not in a position where you're getting no cholesterol, you're just reducing the overall level of cholesterol that's being made in the body.
Chris - Is this factored in when researchers do clinical trials to get a drug approved? Do they take this into account?
John - Very rarely for several reasons. Firstly, just ignorance. Many clinicians simply won't be aware that the disease might have regulation by the body clock. Another one is simply the cost of a clinical trial. I mean, these are fiendishly expensive experiments basically. And so rather than just saying, look, you've got one cohort of patients that takes a drug, another cohort of patients that takes the placebo, which is already probably a hundred million pounds or something. If you then say, okay the patient and the placebo group, they have to take it at different times of day, then it massively increases the cost and the administrative burden. But then the third question is whether we would expect a given drug to show a time of day effect, because it's quite clear that many drugs don't show a time of day effect. And it is fair to say that our understanding of, um, circadian physiology is not so advanced that we can predict beforehand which drugs are most likely to show an advantage with giving them at a particular time of day.
Chris - Presumably then you'd advocate for going back over some of the good looking prospects and doing those sorts of studies to see if there is a time dependent effect that might enhance or perhaps even reduce the side effects of an agent.
John - Yeah, and that's a fantastic idea and there are a few examples of that. So Oxaliplatin is the poster child which is an anti-cancer drug which failed its initial clinical trials because it was just considered too toxic. And then another group of researchers took that drug and went back and tried to work out what time of day it might be best tolerated, and then showed that if you give oxaliplatin at the right time of day, it's tolerated much better and you have that beneficial activity against the cancer.
Chris - And does this also apply to giving treatments like cell therapies? Because I think I saw some research showing that if people have bone marrow transplants administered at certain times of the day, they're more likely to have a good outcome than when they're given at other times of the day.
John - So that's quite likely. But I must say that there hasn't been enough research for us to know whether that's going to be born out as a general principle or not. You've gotta bear in mind that the vast majority of research in this area has either been done in cells, in a Petri dish, or in mice, and then the clinical trials very often the time of day variation is noticed anecdotally. And that's the thing that informs the subsequent targeted clinical trial to try and assess what the best time for drug delivery is. So it's difficult to know how you would approach this as a general question. You know, you've got a whole range of new treatments. Can we beforehand work out what the best time of day to try it is rather than trying all possible times of day to work out the most effective.
克里斯-所以你认为really big questions now? Now we've begun to scratch the surface and we've appreciated that these phenomena exist. Where do we need to put most of the emphasis now on understanding this new area?
约翰,有两个主要的挑战。其中的一个is compliance. So let's say we've worked out that this new treatment works best at a particular time of day. What we don't mean is the actual solar time of day, right? What we're talking about is the biological time of day. And of course some of us are larks, really early risers. Some of us are owls and some of us are, in fact most of us are, in the middle. Pigeons, should we say. And if I just tell every patient to take the drug at four o'clock, we're not going to be hitting the same time biologically when we compare the larks and the owls and the pigeons. And so what we need to do is have very, very robust ways of monitoring what time of day your biological clock thinks it is, so that if we know the best time to give a drug, we can make sure it gets delivered at the best circadian time. The other question though is how do you predict the best time of day to take some new treatment? And I think that that's where we probably need to start moving away from mouse models. People have been using mice for years and years and years, but of course they're not small humans. They're nocturnal for a start. They're also much smaller than us and they have very different environmental challenges in their natural environment. And so I think that the future will be using these human organoid on a chip systems. So this is where you've got a micro tissue, let's say a micro liver growing in a microfluidic device. So it's always been fed by something that resembles blood and where you recapitulate the normal daily rhythms in liver function that you would find in a person. And if we could recapitulate that in a dish, then we would have a much better way of before you go anywhere near a patient predicting what time of day the drug is more likely to work
16:07 - Should you booze before you snooze?
Should you booze before you snooze?
Ian Greenlund, Montana State University
One of the most noticeable aspects of our circadian rhythm is the fact that we feel tired at certain times of the day, usually in the evening, and we then spend the next 8 hours sleeping. This happens because a chemical called adenosine builds up in the brain when we are awake and is flushed out when we nod off, so it acts as a sleep signal that makes us feel tired.但睡眠不是一个开/关的过程。在整个night, our brains cycle every 90 minutes or so through phases of lighter and deeper sleep. The lighter sleep is referred to as REM or rapid eye movement sleep and it’s also when we appear to dream. Periods of REM sleep, and hence the richness and complexity of dreaming, also become longer as the night goes on. But why, we have no idea! What we do know is that sleep plays a critical role in health and well-being, and if you disturb the pattern of sleep, both suffer. One very common way that can happen is if you have one drink too many. Although booze can send you to sleep, paradoxically, it robs you of restful sleep, contributing to feeling rough the next day, as Montana State University’s Ian Greenlund explained to James Tytko…
伊恩-酒精是什么,它模仿neurotransmitter in the brain called GABA aminobutyric acid. We're gonna call that GABA for short. And what GABA does is it turns on deep sleep and turns off REM sleep. So if we have a lot of alcohol in our system, in our bodies, while we are trying to initiate sleep, you can see why REM would be inhibited and/or pushed off until further in the night, maybe towards the second half or the last two hours before we wake up or something like that. So you can see when that is circulating, that's definitely going to be disruptive to REM and it's still going to be affected in the second half of sleep as well, because when we're sleeping, alcohol is being metabolized specifically within the liver and within the kidneys. And it's byproducts include two molecules that are called a acetaldehyde and acetate, which then accumulate and can further trigger sleep fragmentation. So one, REM sleep percentage is being decreased, and second REM sleep is also being fragmented. So you're waking up more during REM sleep, which you may or may not remember going into the next morning.
James - And you are interested specifically in binge drinking's effects on sleep and namely on the sympathetic nervous system. I wonder if before we get into what the effects of alcohol will be on the sympathetic nervous system, if we can first start by defining that just for our listener's benefit not, for mine at all, of course.
Ian - Of course. Yes. So the sympathetic nervous system is part of our autonomic nervous system or the part of this nervous system that we have no conscious control over. It's important for us to think about that without the sympathetic nervous system we wouldn't able to be doing simple things such as standing up or it's a very principle regulator of our blood pressure. So while, yes, we need the sympathetic nervous system, when it is overactive it is a large contributor towards heightened blood pressure or hypertension. And we know that alcohol can trigger a more robust activation of the sympathetic nervous system.
James - So that's what happens is it? If you've had a heavy drinking session before you go to sleep, this fight or flight branch of the nervous system is more activated during your sleep and more likely to disrupt that sleep cycle that was so important as we mentioned earlier.
Ian - Yes, that is correct. So during sleep, what you normally want to see is more of an activation of your parasympathetic nervous system to slow brain activity, to bring down blood pressure into a natural resting state for your body to be resting and repairing itself. But with alcohol in the system that is disrupted, you're in a more of a hyper-aroused state that is not conducive to overall restorative sleep.
James - And how do you go about showing this or proving it? How do you go about testing it?
Ian - We've actually dosed men and women with a four to five drink equivalent of alcohol. So this would be like drinking four to five shots of liquor glasses of wine or cans of beer.
James - Is it difficult to find participants for these studies or are there quite a lot of willing people who sign up for these sorts of things?
Ian - It's fairly easy. It's a good study I think to participate in and to be a part of on my side. So it's good for all involved. But what we see with that is then increased sympathetic nervous system activity lasting into the early morning hours, which coincides with, uh, when most cardiovascular events like heart attacks and strokes are most common. And then these mechanisms also help us explain why individuals who struggle with alcoholism and alcohol abuse also present with other cardiovascular diseases such as hypertension.
James - So what about drinking in moderation? How does this impact the sympathetic nervous system? Is it still a significant impact or something much more moderate?
Ian - So light drinking, or maybe drinking one to two drinks, or moderate drinking, three to four drinks, are still associated with some sleep deficits, but it may be fewer than binge drinking as one might expect. But there is some research out there to show light and moderate drinking may help us fall asleep faster and limit nocturnal awakenings, but we still see decreases in REM. So overall that's good news that a small glass of wine prior to bed is likely not impacting our overall sleep quality a great deal, but it speaks to that if we are drinking alcoholic beverages, give yourself some time to decrease blood alcohol content prior to sleep to minimize any potential detriments.
James - Despite what some people might think about maybe a drink, helping them get off a bit quicker and get to sleep sooner. It's not going to have any sort of actual benefit to the quality of sleep. And that's something of a myth.
Ian - That is correct. And majority of the time individuals who struggle with sleep issues and if they do reach for alcohol rather than reaching out to their medical provider first, it's that subjective feeling of falling asleep faster that many individuals associate with getting more quality restful sleep, but they still may be having those detriments to REM sleep. And if the alcohol dose begins to increase as a tolerance is built up to that, it will result in more sleep fragmentation and non-restorative.
23:06 - Sleeping cements memories
Sleeping cements memories
Ken Paller, Northwestern University
People often say that when you've got a tough decision to make you should sleep on it. A good night's sleep seems to be critical for processing information and organising the facts in your mind. Indeed, experiments have repeatedly suggested that people perform better at recalling newly-learned things when they've had a chance to sleep in the interim.But is that better performance just because they're fresh, or is the sleep doing something special to the memory? One way to find out is to record what the brain is doing while we sleep, and this week scientists have reported on how a unique opportunity presented itself to a team at Northwestern University who were able to study patients who had electrodes implanted into their brains to study their epilepsy but it also meant that they Ken Paller could eavesdrop on how newly-formed memories were altering as they slept…
Ken - One of the interesting questions about memory is: how do we actually maintain enduring memories? Because there's so many things we learn every day and yet not everything sticks. So how do memories survive? We call that consolidation, a process where memories are stored in the brain effectively. And a new idea about that is that part of what makes that work is the processing of memories during sleep. We think that memories are revived and processed again during sleep without us knowing that it's happening. In the context of deep sleep, when memories seem to float up things that have happened recently and they accrue to related memories. And all this interactions between memories is part of what makes memories stick because each memory is not just isolated, but it's connected to other memories, other things you've learned earlier. And that's what makes a very solid memory. One that's well integrated with other things you know.
Chris - So what evidence did we have that that is the case?
Ken - Well, the early evidence was comparing people's memory for things they learned some hours earlier and manipulating whether they slept during that intervening time or stayed awake during that intervening time. Now we have a lot of other sources of evidence, including looking at the physiology of sleep that has made the case more strongly. And one of the methods we use in my laboratory is to provoke memory reactivation during sleep and then see what are the repercussions of that. And what we found is that when memories are reactivated, people wake up and they're better able to remember those things that were reactivated while they were sleeping.
Chris - What about actually physically getting inside the brain? Because this week you've published some new data where you've gone inside.
Ken - Yes. We want to understand more about the mechanisms of memory storage and how memories become well consolidated so that we can remember them later. And so we looked at patients who had electrodes inside their brains. And the reason the electrodes were there is because the surgeons were offering the patients perhaps a better therapy for their epileptic seizure disorders. And so while the electrodes are in there, we could also record electroactivity while they're awake and while they're asleep. And so what we'd done in this recent study by teaching each of the patients locations of objects and the objects came along with sounds, a distinct sound for each object like the cat picture came along with a meow sound. So they learn all these locations of objects and then we remind them of a subset of those during sleep by presenting the sound very quietly so we would be sure not to disturb their sleep. And when we presented the sounds, we could then look at the brain activity that's produced in response to the sound and the memories get better when we're reminded of them. So when we wake people up, they were more accurate at remembering the locations of objects that we had reminded them of during sleep. And so now we can see what's happening in certain brain areas in the course of memory change. As memories become stronger through this process,
Chris - How is that reflected in the electrical activity? Because obviously you can test the patients and you're saying they performed better when we asked them to remember where the picture of the cat was, but what happened in their brains when they were remembering the memory of where the cat picture is?
Ken - Yeah, well one of the things we do is we actually presented them two types of sounds. So half of the sounds related to the pictures they had seen in this memory task before they went to sleep. And half of the sounds hadn't been there. So we were able to compare, well what's different about how those two sounds are processed? And we saw larger responses in certain brain areas for those sounds that were connected to the memories they had learned. And furthermore, some of those memories got really a lot better. And we could compare as a function of how much better the memories got for some sounds versus other sounds and see differential activities. Some of the electrodes were in or near an area called the hippocampus. It's known to be very important for memory function because people who have brain damage to this area have serious memory problems as a result. In that area, we would see larger responses to these meaningful sounds that related to their prior memory and predicted how much better their memory would be when they woke up.
Chris - When during their sleep did you do this? And does it matter when during the sleep you do this? Because as we know, sleep is not a static thing. You don't go to sleep, switch off and wake up eight hours later, fully rested. You go through phases of dreaming and not dreaming, deeper sleep, lighter sleep. How did this apply in your patients?
Ken - Yeah, it's a fascinating side of sleep that actually there are different stages. REM sleep for rapid eye movements and non REM sleep of a couple varieties that range from light sleep to deep sleep. And our results were focusing on non REM sleep. So we are looking at deep sleep. It's also called slow wave sleep. And that's when a lot of results have converged to show that this part of sleep, this timing, is very important for memory.
Chris - What are the implications then for as we age and the amount of sleep that we take and the proportion of sleep that's genuine, restful, deep sleep, may change. What are the implications for forming new memories and the function of our memory overall?
Ken - Yeah, that's very important because sleep does change in interesting ways with aging. And one of the changes that starts even in the twenties is that we have less slow wave sleep. And that could be a reflection of sleep not working quite as efficiently. And there are many ideas about how that could be important and be related to age related memory troubles that people have. The general question is: what is good sleep? One of the usual answers is, Well, you have to have enough sleep, seven or eight hours of sleep. And that's a starting point. And then you might say, Well, we also have to measure how much of that sleep is REM sleep versus slow wave sleep. And we're even going further than that because we think, well good sleep quality is about not just how many minutes, but how efficient is the processing and what's happening during that processing. And I think further from the mental side, what kind of memories are you bringing up? Because every day things happen to you and every night you revisit some of those memories. Well, which memories do you revisit? If you're spending some of your time being depressed during the day or maybe having a lot of anxious thoughts, perhaps those are the type of memories that are coming up again during your sleep and exacerbating the issues. So we want to think carefully about good quality sleep and think about, well can we push around sleep to make it better for people so that they wake up, you know, on the right side of the bed. And now that we know it's a little bit malleable, that we can push it around with sounds we present. There's a lot of opportunity here for making sleep better.
Comments
Add a comment