Richa Saxena, PhD: The Biology of Sleep

Most of us know from experience the difference that getting enough sleep can make  in our health and wellbeing, and good sleep has become big business with everyone from mattress companies to mindfulness apps promising to help you get better sleep. But despite all the attention that sleep gets these days, the biology of sleep and its function is still not well understood. 

Dr. Richa Saxena, a sleep researcher in the Department of Anesthesia at Mass General is working to change that. Richa and her team have been studying the human genome to better understand sleep. To date they have identified dozens of genes related to sleep and are finding along the way that many of these genes are related to other health problems as well, like cancer, psychiatric disorders, and diabetes. 

Richa hopes that uncovering the biology of sleep can lead to better treatments for not only sleep disorders, but the many health problems affected by sleep and sleep genes as well. 

So, welcome Richa.

A:  Thank you.

Q:  I wanted to start off by talking about this fact that we don’t really understand sleep. We know that it’s important and that we need it. But can you explain a little bit about why scientists don’t have a better understanding of sleep?

A: Sleep still remains a bit of a mystery. The function of sleep hasn’t really been well, studied and it’s only been in the last like 10 or 15 years that people have started to understand why we sleep. Because it influences the whole brain and the body there are many processes going on during sleep that we don’t fully understand. 

Really the reason we don’t understand sleep so well is sleep is always understood in the context of other diseases or health, but not really taken as a huge body of research to be examined on its own until the past 20, 30 years. And there measures of sleep have been very difficult that many both environmental and genetic factors influence sleep. We have many different stages of sleep. There are many influences of how we behave, especially as societies have become industrial, that lead to different outcomes of sleep.

So, since there are so many different facets of sleep, there is sleep quality, sleep quantity, sleep timing, sleep physiology that involves both the brain and the body, and both good health and poor health can lead to sleep disturbance. So it’s a very complex systemic process.

Many researchers have tried to study sleep in simpler organisms. But the problem there is that it’s not clear how much of sleep evolves through evolution of life such that how much of what humans experience is actually related to the sleep processes going on in other organisms. So there has been huge amount of strides in understanding of brain circuits involved in sleep in model organisms, but how much of that really translates to people hasn’t been well understood. 

Further there are many different types of sleep disorders that might be underlying either diseases or generally present in the population and these have not been well diagnosed or well defined, so you really don’t have any understanding of what is leading to a particular sleep disturbance in people that can be well-defined.

And also a lot of technologies that would measure sleep more accurately are very intensive and so they are only used for very short periods of time, not really getting a very dynamic understanding of sleep. It’s only been in the past five to 10 years that sleep is coming to be recognized as being so important in medicine and disease.

Q: In the past you said five to 10 years, sleep has really come to fruition as a topic of study. What accounts for that? Why have people started to really appreciate or focus on sleep?

A:  I think there have been many different factors that have led to sleep emerging as an important research and medical-related topic. I think one is it’s been recognized how much sleep deprivation influences society. Generally sleep deprivation has been known to be responsible for many different accidents in the workplace, in pilots, in residents, in the medical system, and sleep researchers have done beautiful, elegant studies that show the impact of sleep loss on performance. And so that has brought sleep to the forefront.

In terms of sleep research, there have been several breakthroughs over the last 10 to 20 years and these involve understanding more of the mechanisms that drive sleep. It’s known that there are both internal circadian rhythm processes that determine sleep, as well as the time spent awake that ends up leading to the need for sleep. And research in model organisms such as flies and mice have led to really fundamental insights about how circadian rhythms influence many different rhythmic processes

And by looking at sleep regulation in model organisms, we have been able to understand more about the critical function of sleep.

Also there have been key epidemiological studies as well as human experimental studies that have shown how critical sleep disorders and sleep loss are in determining risk for future cardiovascular diseases and cognitive decline and as well as cancer and psychiatric neurodegenerative diseases.

Q:  And I know a lot of your work has been devoted to understanding the biology of sleep. What does it mean when you’re looking at the biology of sleep?

A: When you’re looking at the biology of sleep, you’re trying to understand what is happening in the brain and the body when you sleep, and therefore the deeper measures of looking through the brain’s point of view or the muscles’ point of view or the heart’s point of view or the lungs’ point of view when you’re sleeping. That’s where you’re trying to understand what the biological processes are that are ongoing when you sleep.

For my particular case we are very interested in looking at what are the drivers of the molecular processes that are ongoing when we sleep and why are we really sleeping at all? And is it so that we can restore our physical and mental health? Is it so that we are clearing metabolic waste from all the activity that we have had during our waking time? Is it helping us with immune function? Iis it, why are we sleeping and what exactly goes on in our brain and body when we sleep?

 Q:  How are you approaching that question?

We start actually by looking at sleep patterns of people across either normal populations or looking at people with or without sleep disorders, and we examine their entire genetic makeup. So, we look at how genetic variation across the genome actually correlates with the presence of a sleep disorder or whether people with early or late timing of sleep or people with good quality or bad quality sleep or people with long or short sleep have differences in their genetic makeup that highly correlate with that and therefore could causally contribute to these behavioral patterns and differences.

It’s trying to understand their sleep patterns across large groups of people and then linking those sleep patterns to genetic differences so that we can find and locate the specific genes that are regulating molecular processes in the brain or the body that are eventually leading to these sleep disorders.

 Q:  And so then what are some things you have found? What have you learned about sleep in doing this work?

A:  So, we have learned a lot of different things. In fact, we were very fortunate to actually have access to this very large database of almost 500,000 people with description of their sleep patterns and with or without sleep disorders. And based on this, we have found the first robustly associated genetic variants for sleep. We found unequivocally hundreds of places in the genome that actually suggest genes in those places are involved in sleep.

And so for example, we have found genetic differences near the Orexin Receptor, which is sleep regulating gene that was found first in dogs with narcolepsy and is very important in sleep/wake regulatory circuits identified from animal models as well as is a key component of disturbances in narcolepsy. And we found that is involved in influencing how much we sleep and whether we nap or not. 

And then we found hundreds of genes that are related to circadian rhythms that influence whether we’re night owls or early birds. We found many genes related to connections, synaptic connections between neurons that determine how much we sleep on a daily basis.

And so we are starting to find the many different genes that determine different aspects of sleep that were just not at all known in people before.

 Q:  Have you been surprised as you find all these things, like I think back to the night owl versus early bird, I think most people would assume that that is maybe a personality trait or a habit that you have gotten into over time, so to find out that it’s actually connected to something in our genes to me is really surprising, but I’m wondering for you as a geneticist who have really been immersed in this world is it surprising to you that all these things are tied to our genes?

A: It’s in some ways surprising how many genes contribute to both our early bird/night owl behavior, but it’s not surprising to me that genes contribute to this. And actually it’s known that people with extreme morning or evening preferences actually have family members who have the same types of behaviors. And in the last 10 years, a few small studies in extreme people had found these types of tendencies, so we knew that there would be a genetic component there.

As I said, we were surprised that there are so many genes that determine this and they may be related both to the circadian clock mechanisms, but also to inputs of light into the system as well as outputs of the behavior as well.

The other components that we see related to morning-ness/evening-ness preference may also have to do with the amount of how our pressure to sleep builds up and how our pressure to sleep dissipates. And that, too, shows up as our morning and evening-ness preference. So, actually, a large part of our work is separating what is it, which processes are really contributing to this overall behavior that we end up seeing as either early morning or late evening preference. Really dissecting which component, which genetic factors, which molecular circuits are actually driving which aspect of this behavior is something that we can do now based on understanding these genes.

Q:  And as you are discovering all these genes and factors that are related to sleep, are you finding there is a “best” sleep or an optimal sleep? Or is it really just a matter of each of us has individual unique sleep needs?

A:  I think those are some of the things that we are starting to explore. There is actually a quite strong genetic tendency maybe we focus first on the early bird/night owl scenario, where each of us has a particular tendency and it is actually a very strong tendency and it’s whether we live by that tendency or live against that tendency based on our society that may really be related to our future disease risk.

Genetics helps us understand better what our internal preference is and it might be that it’s actually the misalignment. And a lot of research has shown that it might be that us not living in concert with what our internal tendency is that ends up leading to us not having the optimal health.

For example, what we see is that there is a bit of a link between being a night owl and having more mental health problems, and this might be because night owls have a more difficult time in our society to maintain their natural sleep rhythms, and therefore they are living slightly more against their clock than morning people.

There is a lot of beautiful epidemiological and experimental data in humans has actually shown already that there seems to be this optimal amount and quality of sleep that is needed, but exactly is it quantity of sleep, how does it relate to the quality of sleep, and how much does each person need based on their genetic makeup and how they live in accordance with or without their genetic makeup, and then also with the influence of all sorts of technologies in today’s society and staying up late and the demands and stresses of work, as well as exposure to light-related technologies late into the night can all lead to sleep problems. In terms of genetics helping us understand whether each of us has an individual need, we think there is really potential for genetics to help us understand that.

It’s really about both the better understanding of sleep in the population and also understanding then how these genes we have identified actually work in influencing the different aspects of sleep and sort of untangling that will help us understand this better.

Q:  It’s interesting. As I’ve been listening to you talk the thing I’ve been thinking about is, you know, I do think we’re in this moment where people are very focused on sleep and getting the best sleep and whether it’s you need these sheets or meditate or use this app, but I’m struck by hearing it’s more about,  matching our habits to what our body needs and that might not be the same for me as it is for you.

A:  Yeah. I think that that’s very much the case. I think that is where maybe there is an underlying realization in the research community as well that there is a need to mesh the biology with the society. And not only that, in medicine there is a recognition that sleep disturbances and sleep impact of disease, or sleep as a marker for disease are all components that need to be considered. So your sleep may actually be telling you something about how well or how unwell your body is. That I think in the general population may be, may be understood as a more, a need for better mattresses or better this or that, but it may not be as simple as that. There may be some underlying reasons that have to do with your disease process that influence your sleep. 

Q:  It’s making me feel better. I’ve always been a night owl, and I think sometimes there might be some feelings of “Oh I’m not responsible enough” or  “I should behave in this other way”, so in some ways it’s a little bit empowering to say, “This is my biology and it’s okay.”

A:  I have to say I think that has been a very gratifying part of our work is that knowing that people can feel comfortable being who they are, and the genetics of the behavior suggest that there is the biological component that we have to respect. I think the science now has really beautifully teased apart that there are many aspects of our physiology that have a rhythm, including our sleep behavior.  

Q:  Are there other things that you have found about sleep or sleep differences that have been really surprising to you?

A: I think other things that have been surprising to us are that some of the sleep disturbances or sleep disorders don’t end up being related to the same processes that are involved in regulation of the quality/quantity/timing of sleep, but are in themselves different disorders related to different gene mechanisms and different processes, for example for insomnia, which is a disorder that has not been very well understood at the molecular level and we have and other researchers have recently really made some headway into understanding the genetic basis for that, and what we find is specific subsets of neurons that seem to be dysregulated that are not necessarily the same structures that are involved in sleep regulation more globally.

We have also been surprised at how sleep is so central to every single process. So, once we start looking at how sleep genetics or sleep might be causal to other disease processes, we keep finding more causal links. And in some cases we find bidirectional links so that sleep may cause a disease, may contribute in a causal way to a disease, and then the disease itself may impact sleep. And then there is a viscous cycle. 

So, sleep can be a modifying lifestyle factor that enhances your risk of disease as well as that sleep in itself is a problem for your functioning. 

I think it’s just it’s been surprising to me how central sleep is and in some way it should not be surprising, because sleep is such an integral function. It’s highly conserved through evolution and without it we cannot live.

 Q:  And if our sleep is so tied to our genes does that mean that, I guess is it impossible to change our sleep habits? Or do we need to change our genes to change our habits? How does that work?

A:  No, I think an important thing I need to emphasize is that it’s not really that our genes determine how we sleep at all. So, our genes, I would say, determine about 10 to 30% of the variability in our sleep patterns, but it’s really our behavior that determines and our environment, our lifestyle choices, all of that. 

Finding our genes is important, because it shows us what processes drive different aspects of behavior, and it shows us where we might be able to intervene therapeutically to fix sleep problems or related diseases, but it’s not at all deterministic. And that’s the beauty of studying sleep as well is that it’s modifiable.

And I think a focus in the research and medical community now really needs to be in specific, personalized interventions that improve sleep. 

Q: I’m wondering as I listen to you talk about all of the work you have done within sleep, what about your own personal relationship with sleep? Has it changed your sleep habits?

A:  So, this is really interesting. Yes, it has changed my sleep habits quite a bit. So, I as a researcher have been used to my whole life working very late at night, and I am also a night owl, so I love to work late at night and sort of dig into the data and really try to understand what my data are trying to tell me. And I’ve been known my whole life to stay up until like 2:00 in the morning trying to figure everything out. And since I started working on sleep, I realized how much I was actually influencing adversely my own health. And I can feel it. 

I think some people are more sensitive than others to sleep deprivation, and I think I am very sensitive to it. So, I would function poorly the next day and I recognized it more when I started actually looking at the genetics of sleep. 

Then second when I had my son, it was a very different feeling as well. I had my son almost at the same time that we started the lab. And so he grew up while I had been getting more and more exposed to sleep, so I think he has had better sleep habits than I would have had if I had a child at the time before learning about sleep. So I think it has really influenced our sleep habits in our family and I’m happy to say we love to sleep and we enjoy it and we take our time for it during the weekend, especially.

Q:  And through all of the learnings that you have had along the way are there things that you wish people understood about sleep or misconceptions about sleep that you wish we could correct?

A: I think it’s very important to understand that missing or curtailing your sleep either acutely, very few hours of sleep a few nights in a row, or chronically having less sleep than your body needs is really poor for your entire system. I mean it has an impact on your performance on your body, and on your brain that lasts. And I think that message has really come out already and I think it is borne true with all the research that is going on. 

I think the research and medical community need to add the evidence in their work to really objectively understand how sleep fits into the disease that is being studied. 

Q: Thank you so much, Richa. This has been wonderful. Before I let you go I have my final five questions. 

Q:  If you weren’t a researcher what would you be?

A:  I love to read, so I would love to think about history and philosophy through the ages and really love to understand that more. And so I would probably have been a scholar of some type that way. 

The other thing that I really like is yoga and, and Eastern medicine, so I would have liked to sort of investigate that further. I really feel the power of nature, so I would love to do something like that would be like, even yoga doing something like that in nature would be a beautiful thing for me. 

Q:  What advice would you give your younger self?

A:  Advice to my younger self would be, not to be fazed by people who judge you in a particular way, and to continue to pursue what you think is important.

 Q:  What is the best decision you ever made?

A:  The best decision I ever made was to come to the States for college. I grew up in India in the Middle East, and was in boarding school in Cyprus. There was an opportunity to stay in India and, or through Cyprus go to the UK and study there, but I really loved science and I wanted to do science, and so I came to the States for college and then grad schoo.

Q:  What was your first job? 

A:  My first job was actually counting seeds for my dad who is an agricultural researcher, and so I would count chickpea seeds from experimental research station and, and it was almost like a little research assistant job.

 Q: What do you consider your superpower to be?

A:  My superpower I think is persistence. If I really want something and want to know or really strongly believe in an idea or a goal then I try to make it happen and I am able to keep pushing until it does.

Q:  Thank you so much. It’s been a pleasure having you here today and I’ve learned a ton about sleep.

A:  Thank you.