Paul Shaw, PhD, a neurobiologist and an associate professor of neuroscience at Washington University at St. Louis talks about how fruit flies are helping researchers learn how sleep heals the brain.
Interview conducted by Ivanhoe Broadcast News in May 2016.
Can you tell me what’s your focus?
Shaw: Yes, my ultimate goal is to understand why we sleep. We spend a third of our lives doing it and we don’t know why. We know if we don’t get enough sleep we feel horrible, we know if we do get sleep we feel good but no one has any idea what sleep is actually for.
What are some of your hypothesis, is it to heal?
Shaw: I have a kind of general view of what sleep does. I have a saying all my friends are tired of hearing me say which is, “anything that tastes good tastes better fried.” Also this theory which is basically, anything a neuron needs to do, sleep can make better. Sleep is kind of like a jack of all trades, so you think about, if you don’t get enough sleep; you feel bad. We know that if you don’t get enough sleep you have heart problems, you have cardiac problems, you can’t think properly; you don’t really know exactly why but we know without sleep your brain doesn’t work. With sleep your brain can do some amazing things. I think what sleep does is it helps your brain do what it needs to do in a way that, that you can’t live without.
Tell me about your line of research? What are you looking at right now?
Shaw: We have this crazy idea. We thought, okay, sleep is good for the brain. Let’s test the limits of what sleep might be able to do. I worked on sleep in fruit flies because they’re generally trackable. You can take genes out, you can put genes back and they’ve been studied for a very long time. There are countless levels of prizes being won off identifying critical pathways in flies because they are relevant for humans. One of the pathways that people look at are genes that are involved in memory. Some very important people have identified genes in circuits and flies. They seemed to be required for the flies to form a memory. We’ve asked a simple question, if sleep is good for the brain can we take these animals that are broken, that are missing genes not fix the gene, just make them sleep and then can they learn? We can do this with a host of different mutant flies that are missing critical multiple molecular pathways that are important for memory. We can even take on structures in the fly brain which are important for memory, like our hippocampus and surprisingly we can break the brain in a lot of ways and see if we can fix all these circumstances.
Can you walk me through it on how you’re doing it? What would we see in your lab?
Shaw: What you’ll see in my lab is one of the beauties of working with the flies is that we have a big community that has been working on interesting ideas for a long time. There’s a guy, Dr. Tollee, who has identified several different mutants. These flies are incapable of learning, he maps the genes, he knows what they are. Dr. Ron Davis, at the Scripts, again the number one leader in the field as well, and they have identified all these mutants and they know these animals are deficient. They know that the genes are broken and they don’t work properly; that the flies are incapable of forming a proper memory. These important people have identified critical genes which are important, we now understand more about human memory because a lot of these genes are conserved in mammals and in humans. What I was able to do is contact these guys and say can I get these flies, these mutant flies, these stupid flies and they came to my lab, because you can do this. They shipped them to the lab and I asked, okay well great, are they stupid in my lab too. They didn’t get any better, by the trick you never know. We have these stupid flies and they’re broken in profound ways and then we can make the flies sleep using three different techniques. One is a drug that we have identified as being a powerful six month drug in flies. It was the first, in my mind the first one ever identified for flies. Then we have two other genetic traits where we can activate subset neurons, remotely, so we can actually make them sleep when we want and for how long we want. We take these flies that are broken so we simply make them sleep for two days, just two and after two days they behave as if they were normal; as if that gene was back or if that brain structure was back and it’s not. These animals are still broken, the genes are still missing, the brain structure is still gone. But, somehow sleep has allowed the brain to adapt and to do interesting things and giving an example, we all know we go to sleep at night we try to solve a problem and we wake up the next morning and then we have that solution. Your brain isn’t just remembering things that you’ve done it’s not just consolidating memories, your brain is extracting information from the world allowing you to problem solve ways that it’s hard to do sometimes during waking. Well, we’ve heard stories of people who tell of a dream. They went to sleep at night and they had a dream and they woke up the next morning with a solution they’ve dreamed about. In some ways, when you go to sleep your brain is doing this interesting thing. It’s actually extracting information from the world trying to solve the problem. We think that when we make our files sleep their brains are broken but we are allowing the brain then to kind of figure out other pathways to solve the problem. It sounds like magic, but we know and we’ve known for a long time, ever since humans have been bonking each other in the head since the time of the caveman. We know that brain damage causes deficits. We know that often times you can recover from that, from stroke, from brain damages; maybe not as well as you would like to, but we know it is possible. There’s recovery of function something that our brains can do, so what we think sleep is doing is somehow tie in those basic mechanism of letting your brain do what your brain is supposed to do, which is to solve problems, extract information and provide insight and seek augment them.
You said that you got the flies and you’re doing different things, three different ways to make you sleep, what will we see in your lab?
Shaw: Well you see, we take flies, we take files and we put them in individual tubes, we can monitor their activity and like a lot of animals, when they are awake they move. Us we can sit and watch TV and not move forever because we’re lazy. But, most animals when they move their awake, they move around; they just can’t help themselves. When animals are awake they move and so we can monitor that, when they go to sleep they stop moving. We can verify that by using a bunch of other independent metrics but especially when they stop moving they tend to be asleep. We either give our flies those drugs, they eat it spontaneously and then if they go to sleep, and sleep. It’s not abnormal, they go to sleep for 20 minutes and then they wake up and go about their business. Then they’ll got back to sleep again during the day and then at night they sleep longer but they don’t look abnormal. If it’s a drug, they eat the drug that makes you go to sleep with our genetics tricks we can activate these neurons either with heat or white and turn those knobs on and we do that and then the animals just stop in their tracks, go to sleep.
How do you make the leap from fruit fly?
Shaw: It’s actually an easy thing and it turns out that I’m not the first so that makes my life a lot easier. As I mentioned, there are several levels of prizes that has been given to software researchers because they have direct relevance to human health and so the case has already been made for me and often times. For example, I can take a human gene that is involved in the same pattern of your hand. I can take that human gene and it in the flies and I get a wing. The same gene, the human gene in the fly it’s important for that wing formation, for example. I can take human insulin receptors and I can put them into flies and they work perfectly well. I can swap genes in and out, human gene into a fly, and the gene works perfectly well. This is all done by people that are a whole lot smarter than me and I kind of proved it beyond a shadow of doubt. In my lab we take advantage of this knowledge bases and we are more bolder than we try to accomplish. For example, what we can do we can try to identify genes that are important for sleep loss. One of my goals in my lab is to identify biomarker of sleep loss, so we can then bring out a point of care test. When you go to the doctor’s office, you can say I don’t feel well, and the doctor can give you a tablet to say that you’re not getting enough of sleep. Why you may not be getting enough sleep is a whole different question, at least the doctor can say go to the clinic. If you are a school bus driver, or a truck driver, if you’re a surgeon, airline pilot and you’re sleepy, that’s a bad thing and there’s no independent test when you’re tired, so my logs is trying to find these. Now when we start off in the fly, we can do these tricks, we can find flies that are awake and tired or awake and not tired. We identify these candidates and we ask do these changes humans and many of them do. You go directly from the fly to the human, simplified humans behave a lot like simplified flies all the way down to the molecules and they are modified by sleep loss. Then we do something even crazier; we went from the human back to the fly. We find things first in the human and found those things that we didn’t know were changed in flies were also changed in flies.
All the practical implications?
Shaw: I think that in the end sleep is important, so I think my work is augmented that idea that not all sleep pods are bad, but to know is bad. Because if you don’t sleep, you get ugly, stupid and fat, that’s just the way it happens. What does this do for you? We can now make animals sleep when we want so we can identify what is good happening. The ramifications are far reaching and for example, we can express human Alzheimer’s genes in flies. They don’t learn just like humans don’t learn and their memory gets impaired. We can make them sleep and we can offset those problems. If you think about, about sleep and what sleep can do for us in terms of health, it can delay Alzheimer’s perhaps, and we have the Chair of Neurology here at Washington University, Dave Holsman is working on this intensely in humans and in rodents, and his data is pretty compelling. But if you think of all the disorders that impact us as human beings, many of them might be slowed, reversed if you get a good night’s sleep.
How far down the road is this?
Shaw: Well, I guess there are two answers to that question. The first answer is if you know up front that good things can happen if you sleep. I think it might be easier for us to convince the population at large to actually pay attention to their sleep. It’s one thing to say bad things are going to happen if you don’t sleep, but if you know that good things happen if you do sleep and we can be working on that from kind of a public health issue. Now in terms of final call what can we do if manipulate sleep in humans? It’s very complicated and there are receptors that activate sleep centers are diverse, and complex, and so a lot of the sleep drugs that works in humans also have side effects. Can we find a drug in humans that might be able to activate sleep without the side effects? I think increasingly with the new technology we have in genetics in mammals that’s becoming even more likely than before and so I’m optimistic. I see new papers coming out in mice all the time, where they are identifying new groups in neurons that have been ignored before because the technology wouldn’t support their involvement. But yet they are involved, and as we identify these neuron we began to target them specifically instead of trying to target all of the brain.
Is there anything that I didn’t ask you that you that you want people to know about what you’re doing?
Shaw: You know, I think the important thing to remember is that sleep is fundamental. That you need it and if you don’t get it bad things will happen but importantly good things happen if you do sleep.
END OF INTERVIEW
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