 Good afternoon. I'm really happy to see so many of you here. So I have been given the kind of challenging task to introduce our presidential speaker today, Professor Fred Turek from Northwestern University in Chicago, United States. It is a challenging task because I rarely get to introduce people with that much of stuff behind their belt. So just listing all the positions he's held and the awards it got received and initiatives he founded and work that would be it would take a lot of time so I will not go into that. So presently, all right, all right, okay let me check the Wikipedia. Now presently he is the director of the Center of Sleep and Circadian Biology and it is important thing that is it's apparently the first place where sleep science and circadian biology are being combined into one which is a really important thing because we need to think transdisciplinary across across the globals also. And he's the Charles and Emma Morrison professor of biology in the Department of Neurobiology in the Northwestern University. But even more daunting than just listing the positions which are indeed that many it would be to try to summarize his publication record over his career because okay let's just say I tried and I figured out that there is a category of scientists for whom you don't count the science papers and nature papers you count those where you made that you are on the cover and because he has several of those and also the covers look very nice so yeah I encourage you to just Google them if you if you would like to so. But also his work has been extremely let's say even mind-blowingly broad in here in in topics so his work in things such as genetics of depression and Parkinson disease aging he's one of the key people who has opened our eyes to the diversity and importance of gut microbiome as well as circadian rhythms to our health and well-being these kind of things that are somehow simple you understand immediately what it is about but you didn't understand that it is how fundamentally important it is for us humans and society until somebody like he came around and just told us and this kind of brings me to the final point I want to make instead of just listing this length of a CV which for many people would be kind of sufficient to highlight the importance I wanted to stop for a second and think what is this to be a scientist there was a discussion recently where there was a question posed what do scientists do in as opposed to engineers entrepreneurs or other people who build things and answer that one comment was the scientists create and produce data and of course that's true but I believe many of you will agree with me that is somehow deeply unsatisfying answer because machines produce data we have we need you need the scientists there to push the buttons to create data but that's not what we do what we are do what we as scientists are doing we are somehow fulfilling the very deeply ingrained need that we as humans have to get more information we are we like other mammals are explorers we need to have more information about the world we want to understand how the world is how we as humans are what makes us human and that's I think is that what what his work is really feeding into his bring information and knowledge insights not that that is interesting not just to those of us who care about the details of how some gene is expressed or another one but this understanding of what does it mean to be a human in the world that we are in and that's I think the most important task of a scientist to bring and feed our dreams about what we could be in the future where we could go literally in places we haven't been and also conceptually to reach something we have not been as a human race so with this small introduction I would invite you to the stage and feed some dreams for us thank you you in Boghna and president grew so I want to thank you for inviting me but it's more than that I mean I the hospitality here has been so fantastic I haven't told you I'm not going home so but before I write to home that I'm not coming back I want to tell you about circadian rhythms in particular and the role that play in health and disease but I want to give you a really good feeling for what has been discovered about the molecular base it's genetic base of the circadian clock system really just over the last couple of decades so let me start by setting up the what I'm what I'm interested in you know we live on this planet and it has distinguishing characteristics that it rotates and to me the way I sort of conceptualize it is that from the beginning you had to take energy from the Sun and use it to create life and to do things that living organisms do and that's what I call fuel metabolism but you can't run your furnace all the time so you had to have sleep and then now it was this for some reason it's this stupid thing is rotating on its axis and it was confusing early life so then they early life came up with circadian rhythms or biological clocks and so these three things have evolved together and they're intimately related to each other and we're making lots of inroads and defining these relationships and what my talk will focus a lot on fuel metabolism and rhythms I will bring in lots of other states that are influenced by the circadian clock so again put it in perspective we live in an environment of where we we control the light dark cycle we're the only species that really controls the light dark cycle and that's it's a relatively recent event I put you know that it's really 120 years since we've had electric lighting and so the question becomes how is this affect humans from we're destroying our biological clock and I'll get to that later after I discuss the sort of the basic mechanisms of the clock and then to put it visually in your perspective this is the NASA composite of the earth from space at night and I think you can see I don't have to point out to you that we live in a world where in the industrial world we are active at night and we're using light and whereas humans in ancient times we're not active at night and the issue here is that our clocks are not always in synchrony with external life and so I particularly focused in and I studied this very hard so if I got it wrong I apologize but there's Okinawa that so it's and by the way I just hit me one time when I was looking at this there's one there's one area in the Asia here that they don't have to worry they don't disturb their biological clock if you look very closely you'll see that North Korea has no light at night so they're an exception and to I'll give us a few examples of the implications of this and I like this one because this was an accident in Chicago in 2014 at O'Hara Airport where the train driver who was coming in on the the metro fell asleep it was two o'clock in the morning and that was the result of falling asleep that's the escalator that takes you from the train up into the into the terminal so it there's it has huge implications but let me give you another really big picture there's been this rapid evolution of circadian field in his role in health and disease and when I say rapid evolution to evolving things at the same time when I started us studying circadian rhythms we were descriptive we were describing rhythmic processes we're describing how animals respond to changes in light dark cycle and then we begin to uncover some of the physiological basis some of the neural areas of the brain that were involved but more recently we began to uncover the genetics and the molecular basis of the circadian clock and much to our surprise and I'll be telling hitting this theme over and over again these clock is tied in with all of habit exaggerate all cellular pathways that's the thing that's kind of blowing us away and the other thing though at the same time when I would try to explain why I was interested in circadian rhythms I talked about shift work jet lag maybe aging but what we the rapid evolution has been uncovering the links between circadian disruption and diseases such as obesity diabetes cardiovascular disease cancer mental disorders and and it's just become a phenomenal basic science moving fast and understanding the health implications moving fast is what I don't want to focus on and just to give you another visual representation of that I'm going to talk about a little bit about the clocks in the digestive system and how that affects things like metabolic disorders and digestive diseases the transportation industry is obviously very much affected by circadian clocks in terms of your hours of service and and the military is very interested because if you got to move deploy forces rapidly across time zones or be awake for long periods of time or operate in an opposition to your biological clock and then I'll be focusing a fair amount on obesity and I probably I will not be talking much about how would we find circadian disruption in depressed patients if the depressed patient here is the man and you can see his clock is out of synchrony with the clock with real time whereas the non depressed person is not now with respect to obesity what I will be talking a fair amount about is that it's really a it might be a ways it's a circadian sleep disorder I'm not saying it's the only cause but it certainly is a major a major cause now as I think most of you know a major event happened a little less than two years ago now which also caused the field to kind of explode which is because the Nobel Prize was given in physiology medicine in 2017 to Jeff Hall and Ross passion and young so why did it was the prize given now well I put I put it into the context of four things the the gene was cloned the first circadian clock gene and I'm gonna tell you more about the genes was discovered in 84 we knew we were gonna discover the gene that's the royal we on this one because we had a mutant fly which was showing a genetic mutation in its rhythms and so it was only a matter of cloning it took 13 years from the time they found the fly till they clone the gene then this was sort of expected we thought the clock genes in the in the molecular clock in the fruit fly would probably be similar to genes and proteins in mammals and that turned out to be true what was unexpected was that the circadian clock genes are in almost all the cells of the body and regulate the timing and expression of 25 to 50 percent of all genes that are expressed in your heart your liver and then totally unexpected in 1984 certainly and really until last 10 years is how this disruption of the clock is linked to multiple mental and physical disorders and I'd like to think we were a little bit prescient I organized that this is one of the thank you for mentioning the cover of science this was exactly almost exactly one year before the Nobel Prize I we were I organized a special issue which was staying on track see the supposed to represent a night worker in England how a circadian rhythm to influence physiology and health so that was one year before the prize and I think it's this combination of the basic biology and the health implications which was played a major role and it certainly is boy when I was on a coming to work and I saw the price had gone I said whoa this is going to really move the field forward and it is the field is just now exploding because it's almost like the Nobel Prize is given this boy this is a serious this is a serious field so it's exciting to be part of it so what we know is we have internal biological clock internal 24 o'clock and I like to show this old slide because it you don't see your rhythm you don't you don't see that you have a rhythm of cortisol you don't see you have a rhythm of body temperature you don't see a rhythm of various metabolites but one you do is your sleep wake cycle and you can feel it so I like this one because it shows a some student who was sleep deprived for 72 hours and if you ever stayed up all night you'll notice how you're getting more and more tired tired tired tired and then around eight o'clock the next day you're not as tired now you haven't slept but you're not as tired as because your clock is telling you wake up let's go and then you can do this for three days and see this 24 hour rhythm in how tired you are so I'm not going to get into sleep because I talked about it a lot yesterday but that's one thing that we can you know we can see we can see that we're our sleep wake cycle is controlled by the circadian clock down the way we study circadian rhythms in various organisms is the major rhythm that's been studied in fruit flies as well as in mammals is activity rhythm why because it's so easy to measure and it's such a great marker of the biological clock so it's like looking at that clock on the wall over there you see the hands that's not the clock the clock mechanism is behind that the running wheel activity is a hands and we use it to infer what's how the clock is functioning and so let me show you a record it's an old one but I like to show up because it's so beautiful it's even pre-pre-computer era it's a record of local motor activity running wheel activity in a hamster on 14 hours of light 10 hours of darkness don't ask me why most people use 1212 but there's reasons we're using 1410 here and you see the animals active during the dark so whenever it's active active you see the black line then then at this point we put the animal in constant darkness we take away all the signals of the from the environment and you can see what happens just look at this look at how beautiful the free running rhythm is the animal wakes up starts running in its wheel 24.2 hours later every day plus or minus one minute I think about that I wonder when I began to tell you about the molecular clock think about this behavioral rhythm how do you translate the molecular clock into such a behavioral rhythm now I'm not going to go into the details but you see I've given a light pulse here that light pulse is occurring one hour here and you'll see instead of the rhythm being where I would have predicted it's been advanced then I go on vacation to the Caribbean for a couple weeks and then I come back and beautiful free running rhythm another light pulse right here and you see I give a delay so all I'm going to tell you without getting into it because it would take way longer than this lecture is that when light at one time of the day speeds up your clock in the morning hours and light at another time of day slows your clock down you think about it if you've got a clock that's 24 and a half hours if it's 24 and a half hours and you just drift through so if you're on a 24 hour like dark cycle you got it you got to slow down your clock if you're free running rhythm is 23.5 you got to speed it up to fit to entrain to the 24 hour day and we do that in what it's called non-parametric entrainment light at one time a day speeds up a clock another time a day slows it down now I just put this one in because it's I want you to appreciate the beauty this is a mouse don't don't worry about the saline injection look at the precision at this is one day two days three days 30 days wakes up every day 23 24.3 hours later and if I asked after president to come up here and tell me when is this animal going to be active the next this day you would draw a line on this and be in trouble if you drew no you hear you can probably draw a line and erase it I did have someone one time we got really excited and drew a line and it was a screen and ruin the screen so just look at the beauty of that rhythm and then of course just what I wanted to show you a record of a mouse that we flew from Paris to Chicago so this is you see the light dark cycle here is here light dark the animals nicely entrained and then when we fly to Chicago it takes you can count one two three four five six about ten days to reentrain to the new light dark cycle I was giving this lecture to master students and I had a student right in the front of the room who said Dr. why why didn't you fly why do you just change the light dark cycle why'd you fly the animal from Paris to Chicago and I said you understand what I'm talking about she understood what was going on now just I just put this in because this is just just came out we know we can fly long long distances the question is can the human in other words the machine the airplane can fly long distances and there's actually studies going on can can humans endure a 19 hour flight so they've just come up with the it's called ultra ultra long flights and I like that picture and it's they're going to see how humans are studies being done so let me just give you the basic properties so that you have them in in your mind the 20 circadian rhythm controlled by a circadian clock the rhythms are self-sustaining indogenous the clock is within the organism the period is about 24 hours and in fact if I looked at a hundred mice there'll be some C 57 black there'll be somewhere between 23 as you'll see 23.5 and 23.9 there the primary synchronizing agent is a light dark cycle the master clock is located in an area of the brain called the supracosmatic nucleus I won't refer a lot to this but I will say I'm not a couple of slides this is an area well I can show it here it's an area that's area in the interior hypothalamus it's two small nuclei that are the master circadian clock this when I say discovered in 72 that was the first indication that's where the clock was located it took about 10 15 years to nail that down but we now know that this is a master circadian clock in that it is entrained by the light dark cycle I talked about this yesterday I won't today I'll just tell you there are unique photoreceptors in your eyes they're not rods they're not cones think about that and when I give this lecture to ophthalmologists they usually leave the room about now because it's there actually are retinal sensitive retinal ganglion cell photosensitive cells so that they project right from the ganglion cell layer to the supracosmatic nucleus and so essentially the the light input system is separate from our visual system I'll leave it at that and now I'm going to tell you though that was fine the story was great but then we had clock shock the clocks are everywhere we did not predict this no way we all thought it's in the supracosmatic nucleus exactly how those neural neurons are coupled together what are the circuits we will discover that but then we found the clocks are everywhere and this was a nice way of presenting it in a paper we had in scientific American a couple of years ago and the clocks within us and the idea of course is that all these tissues if we remove them and put them in a dish once we had sensitive enough methods to monitor gene expression we found the clock was everywhere except for the red blood cells so anything with a nucleus has the clock and then the the the point of the article was that the bodies many cellular clocks in the brain and then it discusses the various diseases if you disrupt the clock the liver the heart the painter is the kidney was that one fat tissue so this opened up a whole new area and then like I said this is still an ongoing it may be tissue dependent but what we use 25 to 50% as all the genes in your heart let's say your heart is expressing 10,000 genes 5,000 of them are rhythmic which means they're good they're high at one time lower another time now if if the circadian clock the molecular clock is regulating the expression of half the genes in your liver what happens when that that circadian molecular machinery becomes disorganized disrupt it how does that lead to health and disease so it really was a paradigm shift in the field with the finding a white reason it took us so long we had to have a marker of the clock before we could look at whether the cells of the liver or the pancreas were rhythmic and that became by by tagging one of the clock genes to Lucifer's reporter gene and this is just to show you so some of some rhythms here's the SCN this is over four days this is skeletal muscle you can see the lung and actually this is this is an early result and now once the tissue culture systems have gotten better I've seen I've seen records of the supracismac nucleus that go out 30 days I've seen the lung I think about 20 days some people play games with it how long can we keep the tissue alive and how long can we see this 24-hour expression so if you look at it from the the big the big overall picture supracismac nucleus there it is right here it's the clock it's getting the light information it's regulating circadian rhythms in all the cells of the brain I'm sorry I didn't put some clocks in the cerebellum sorry and liver kidney so what's going on here is that the SCN is communicating with all the cells of your body either directly or indirectly by that I mean there can be neural connections from the SCN there can be hormonal inputs but also if the SCN regulates the locomotor active the sleep wake cycle and the sleep wake cycle influences many rhythmic processes then it's indirect I call it or if I regulate the feeding cycle then the feeding the feeding rhythm can actually entrain rhythms in the liver so you'd say oh it's not the SCN it's the feeding rhythm no no no no the SCN is controlling the feeding rhythm which is controlling the rhythms in the liver so that's why I call it direct and indirect okay how did we find these genes I've mentioned that we were using one of the genes and that's this that's my favorite part of this wow it's not really my favorite part of the story but it's my favorite beginning part of the story in the early 1990s we had no mammalian clock gene they had the gene in the fruit fly 1984 and we go to meetings and that's why I said we thought there would be some literary because the fruit fly people would get up in an audience like this and go we got genes many of them people would go we got neural structures where's what where's the does the fly have a brain even well it turns out it does and we now know where the neural clock is in the brain of the fruit fly and we know where the molecular clock is in mammals now so the the fields sort of came together now I showed that picture of a hamster in a wheel at the time and this is where you want to be able to adapt your organism we were studying the hamster as our major animal model because it has beautiful rhythms like I was showing you and if I perturbed it with a drug or something if I have a 20-minute phase shift I can pick it up because that rhythm is so precise so beautiful but it turns out the hamster was and is a genetic desert so Joe Takahashi and I in the early 1990s we said let's go after the gene and we actually were talking with Ross Baston Hall we had a very large grant with the three Nobel Prize winners to find genes and mammals and eventually we said let's take the same approach you guys took and we couldn't been done or there were improvements in mutagenesis and I'll tell you what I mean by mutagenesis in a minute which allowed us to go after the the gene but we weren't going to do it in the hamster because we know how many chromosomes there are in the hamster but we don't know the base sequences that we don't know the genes but what's the major genetic organism the mouse and no one was studying rhythms in the mouse so we had two choices we can either bring genetics to the hamster bad idea or we could bring physiology and behavior to the mouse and no one was was was following circadian rhythms in the mouse or very few people were and so we set up a program what I call the mutagenesis and phenotypic screening and by that I've only put too much in the detail you take a male animal you injected with ethonitrate urea it creates a high mutation rate in the germ line creates a high mutation rate in all the cells of the body but I don't care about all the cells of the body and after 10 to 12 weeks of treatment what happens is you kill all the spermatogonia kill all the sperm cells out except for a few spermatogonia you had this was you had to dose this right we didn't get that they were getting it at Oak Ridge in terms of being able to use a chemical mutagen not for clocks but just in general for creating mutations so this we had estimated that maybe one in five hundred one of the thousand genes would be mutated randomly now you remember in about 19 remember when we used to talk about the human and the mouse and that had about 120,000 genes yeah it's amazing now molecular but now we know we got something around 20,000 and most most molecular biologists will they just they waved that they pretend they never said 120,000 so if we thought there were 120,000 genes and we were mutating one in a thousand you can see well it's gonna be hard to pick up so we got fortunate that we lost a hundred thousand genes during the time period and well I'll say that we were told this cannot be done so Martha Vita Turner was a graduate student in my lab I'll keep coming back to her name she's the first author of the science paper she was she was told that's fine for fruit flies but you'll never find a single gene affecting behavior in a mammal mammal behavior is too complex I still get that someone will say oh well that circadian stuff that's simple but I study I study stress I study body weight regulation that involves thousand genes so you won't find one gene isn't that a stupid statement because if I knock out the leptin gene what do I have I got a very obese animal just one gene so this idea that this concept that you could knock out a single gene in the pack of complex physiological behavioral process was not accepted at the time I think it's pretty much accepted today in large part because I think of the circadian story my best one was this was actually told to me by the chairman of my department at the time although I put anonymous correct this is not science what's your hypothesis my hypothesis is I've got to find a gene that's mutated affects the clock that's not a hypothesis she said you're on a big fishing expedition and then I my response was I think it was maybe I made it up over the years yeah but we might catch a big fish and we knew we were getting mutations we know we're getting a clock mutation till we found it let me tell you why I really like this slide I need to get them I can't get a modern version of it because we took it a long time ago mutations many mutations are lethal of course but we were getting we had a two-toned mouse so that's what we must have mutated some gene involved in cold color we had a silver brown mouse cold color and then we had two thumbs mouse so we must have caused some mutation that led to two thumbs and my favorite one and it's really now favorite now that I know you study the balance and the and I was saying earlier we found a mouse with a curly tail so what do we do with the mouse we threw it away had I known that you guys were studying tail and balance I would have saved that mouse and breathe and kept that colony going for 20 years or something like that sorry we couldn't make sure as a per diem so we knew we were getting mutations so the mutation that was really exciting and led to the the the whole now we're going to find the first clock gene in mammals so what we did we would get C57 black put them on a lighthouse these are excuse me remember the the the mutagenized animal then the the offspring so we're testing the offspring and we figured if we tested a thousand animals we might find one mutant animal we were guessing that based upon 120,000 genes and we were guessing there'd be 20 genes involved in circadian this is all hand waving back of the envelope that we did use it back an envelope at the time and then we put the animals in constant darkness and this is a what what night well that's to say all the mice look like and then if you look at a histogram this is the number of animals the period of the rhythm so remember I told you that the period will be somewhere between 23.5 and 24 and if you look at we this is represents 205 mice one mouse okay we did get lucky it was mouse 26 too bad it wasn't mouse 24 but that's okay it was mouse 26 and the standard deviation of this is point one seven we had one mouse that period was 24.8 hours and my statistical mathematician friends tell me given this mean and this standard deviation you'd have to screen about a million animals to find one that would be six standard deviations from the norm well here's our guy like dark cycle then we put the animal into DD at this point DD kinds of constant darkness I didn't explain that and you can see the period is 24.6 24.7 hours now at this point we've got an animal that's got a really abnormal clock and I remember with Jeff Hall because we were meeting with the eventual Nobel Prize winners okay now we knew this already but he said you know maybe maybe the mother dropped it on its head so you got to show that it's genetically transmitted well it was genetically transmitted otherwise I wouldn't be here and we found out that essentially the clock we named the gene clock I wanted to name it time Joe Takahashi wants to name it clock I want to name it time because we could get the cover of Time Magazine but he was very clever by naming it clock then when you talk about clock genes see the link we have a language problem there's one clock gene clock but there's multiple circadian clock genes as I'm going to show you in a minute so if you're carrying one copy because you remember that we only you know we mutilized the male you have a free running period of 24.7 see how greatly different that is if you're tearing two copies we had no idea and it turned out the animals had a period of about 28 hours and then eventually some become a rhythmic you can't even find any rhythm so this allowed us to chase the gene and very quickly because the genetic tools will be coming available MIT was coming out with markers weekly basis actually and the sequencing Joe Takahashi threatened to leave Northwestern unless they bought him a sequencer he wanted a dedicated we have a sequencing facility we'll get your date we'll get your date of two months from now no so eventually we found that the clock gene was on chromosome 5 we knew that pretty quickly based upon looking at what would we call snips today and we were able to sequence that region and find that there was a gene that was I had about a hundred thousand base pairs and one base pair substitution see the a to a t transversion if you have if you're carrying a at this point you have a normal wild type if you're carrying T you have a mutant phenotype as I said this this made me believe in genetics the idea that I could change one base pair out of a hundred thousand in an unknown gene and see such a change in behavior like I said we were working we had a very large program going with the fruit fly people and so they actually they were they were they had the mutant animal that the mutation was in the homology of clock and they were chasing it and when we published our paper and they saw the sequence we beat them to it so when we broke the paper we were able to say we have found the first mammalian clock we said unfortunately we've not found any homologue of the fly genes in humans but we now have the first mammalian clock gene that was it that was almost a joke we it was fortunate for us we had no mammalian homologs of the fly genes because then we could make the claim we had found the first clock gene in mammals but then we then we kept going back and forth and it was like a domino effect I'm not gonna spend a lot of time on the other genes because I focus on the the clock gene but very quickly it was found that clock dimerized with a gene called brain muscle aren't like factor in other words it had been found in the brain and muscle but nobody knew that it played a role in circadian rhythms and then we found that the this and I'll show you in a minute was in a positive negative feedback loop with a couple of genes that are called cryptochrome and pure pure is for period and it was the first that's the gene that was cloned and got the Nobel Prize in 1984 so very quickly the gene for the fly gene homologue for per was found in mammals and mammalian genes were found in the fly and then there was another gene in fly called timeless but then and this should be a question mark anymore I probably have an arrow and says n equals 20 if you ask me to guess how many genes have been identified and how it depends on how you would define a clock gene so very quickly discovered this this positive negative feedback loop that involved transcription translation and some phosphorylation and we found that we titled because we were writing for a liver journal liver has rhythm but this this is me and this is Ravi a lot of who was the student of Mike Ross Bash so the fly people the mainly people were trading if you will and data and then this I'd like this one here because there's some physicists here I know and the cover the number one breakthrough of the year was something not really that important the accelerating universe and but the number one biomedical breakthrough of the year was the finding this sort of clock machinery and flies and and and mammals these were showing universes big clouds and that's why I changed and put the clock in so and in fact the Nobel Prize was given for this discovery in I think 2016 if there's any physicists in the room you can correct me and then the the clock gene in the fruit fly was given a prize a couple years after that so the science was very prescient in predicting it okay what so I've mentioned you know that why now and I want to get to this part here we're where we're finding the clock genes in all the parts of the body but for that I do that I want to show we are also interested in behavioral alterations of the clock so we use genetic manipulations but we can also behavioral manipulations but in other words I can shift the light-dark cycle back and forth back and forth to Paris I'll do to Okinawa back to Chicago Okinawa back to Chicago what effects do I have so we we we work with both genetic and environmental models so let me just tell you the genetic model that of course I used was essentially I at this point I said okay I've got circadian disruption at the genetic level what else is wrong with you and then we I'll go through this rather quickly we found that the it's very important to be observant it was one of my students where she Amy Easton who I wanted her to study aging in the clock mutant animal and she came to me and said I don't want to study aging I don't want to study the clock mutant animal I said first off this is a this is not a democracy why don't you want to study the clock mutant animal she says they get fat and so this led us into a whole I said they get fat maybe we should study why they get fat and Joe Bass had just been recruited in Northwestern a hard core diabetes pancreatic biochemist and I'll just summarize for you that I'll just I could say it clock mutant animals have a regular diet or a high fat diet gain more weight that's what this slide is showing you here now what's interesting is that I always say that what's important if you're trying to move a field like obesity and body weight regulation you've got to get some of the leaders of that field to buy in because no one's going to listen to Fred Turrick and body weight regulation in the field of body weight but something like Bart Stahls who is a hardcore nuclear receptor individual he wrote this very nice commentary when the clock stops ticking metabolic syndrome explodes and he began to link the clock genes with some metabolic genes and then when you alter these metabolic genes we know you alter glucose metabolism crest wall metabolism and then he had one other very clever slide making the point that if you alter the circadian clock system and you alter some of these metabolic genes you're gonna have effects on obesity insulin resistance dyslipidemia hypertension I always like to say that when I go to the dean of the medical school and say I'm studying the biological clock and shift work and jet lag you go when I told him disrupting the clock leads to the metabolic syndrome and cardiovascular disease and diabetes it had much more influence on the what was what what the dean was interested in and then I'm not going to go through the complexities of it and this is really a simplified version eventually it was found that the mammals have three period genes so there's three genes that are homologous to the one fly gene the cryptochromes we have two and only one clock gene and only one female gene and that this transcriptional translational feedback loop affects metabolic genes and we now know the metabolic genes affect the clock genes and so that's a whole area that's worth an hour talk and these these networks are being built and we're finding that the clock genes are not just regulating metabolic genes but they're regulating all kinds of genes that involved in most signal path signaling pathways in the cell so I mentioned that we study genetic models let me show you one very simple environmental model which I like to do simple experiments and in this one we we looked at when we disturbed behaviorally when the animals eat would we affect body weight so this is such a simple study it's one of my favorite studies I had a student Deanna Arbel I said okay let's put the animals on a regular chow let's put them on a high-fat diet when we know they'll gain more weight but let's do this let's let's not they normally eat 70 80% during the dark but let's give them the high-fat diet in the regular diet I'm simplifying it in the dark no food during the light and this is the key group here feed them at the wrong time of day giving them a high-fat diet when they normally don't eat now they have no choice they're either going to starve and die so they got to eat at the wrong time of day and if I say it's so simple this cage had food and this cage had no food so every 12 hours you would come in and just move them here moving back moving back and and the really exciting result was that the animals that were fed on a high-fat diet during the light gained more weight than in the dark and I'll just say I don't need this is not that important but it just is making the point that animals fed at the wrong time of day gain as much weight on a high-fat diet as if they're ad-lib on the wrong time at any time of the day so this led us to this idea we called it wrong and right time feeding the term that's now used as phase restricted feeding so you you restrict feeding eating at a certain time this of course led to an explosion of interest in what about the time of day of eating in humans how does that influence body weight and how does that of course downstream effect conditions related to you know cardiovascular disease and metabolic disorders and let me just say disrupt the clock you increase lethal obesity but let me use this slide to visually have you think about this for a minute so normally we have a clock the SCN in train to the light dark cycle it's regulating the liver and the test in the clocks but it's doing it by regulating feeding time and normally when everything is right we've got food you're eating that's Jesus supposed to be the same time same time same time but in humans we're the only species who does this we can decide to eat at wrong time of day and now the timing of day of feeding has a big influence on liver and I just said the gastrointestinal tract so now you can see the internal organ rhythms are out of synchrony with the light and train one in the super guys Mac nucleus and that's just to emphasize this point I was I was watching a show on baboons when we published that paper and I saw these baboons they what do they do all day they eat all day so I ran back to the lab to the DNR will show me a picture of what a baboon does at night there it is so we've evolved to eat during the day and not at night so what happens when we eat at the wrong time of day so we talk about human body time and body weight regulation it's not only what you eat but also when you eat so in think in terms of thinking about body weight regulation of course we know diet is important and exercise is important what we're bringing we're trying to bring to the forefront is that the clock is involved and yesterday I talked about if I do not allow the animals or humans to sleep normal amount they also gain they they gain weight show signs of the metabolic syndrome so there's these various factors that are involved in body weight regulation and then epidemiological studies have borne this out that the insurances are showing sleep duration and obesity there's huge amounts of epidemiological data now showing that short sleep and little less data disrupted rhythms are involved in body weight regulation now I'm not going to go into the story but it the circadian clock system has major connections with NAD the statuans that whole system which has been linked with a not only body weight regulation but longevity and I just want to I'm going to bring this up because of where I am right now calorie restriction I think you're all familiar with it's one it's the only only behavioral manipulation that's been associated with longevity and I can I don't I'm not in favor of the kind of calorie restriction where you give individual by only 60% of the calorie intake but it it looks like eating obviously eating less is results in a loss of body weight but also isn't related to longevity and I think you may well be aware that there are such things as blue zones and Okinawa is one of the blue zones so I'm bringing this up because of where I am today and blue zone is where there's there's significant evidence that the people live longer in the blue zones and I teach a class on biology of aging and I always show this picture of a boy being fed in Okinawa and I found that one of the things that although I did see a McDonald's and a and a KFC so I'm not sure you guys are things are changing here fast but then I found out that what this is called right Harry Hachi Boo which stands for eat until you're 80% full so and this whole system that's involved in what we think is the sirtuins and the NAD the cock system is involved in that and I just want to say that this is particularly relevant today so to speak the Okinawans most humans forced or they have a low calorie diet the people on this island at least at the time I made this slide had about 70% of the caloric intake as the rest of Japan I don't know what it is today and you have 40 times the incidence of people over a hundred and less diabetes and tumors and today in your newspaper actually was yesterday not that I read the Japanese one but there's an English newspaper and it talked about Japan now I didn't realize this is the of the 204 countries you have more people over the percentage you have more a hundred percent of people over the age of 65 than any other country in the world and Okinawa is at the very the end of that of that probably Belche curve for all of Japan so I just bring that up to point out that the circadian clock system has been linked to the calorie restriction system okay I want to spend about 10 minutes now to get easy book I'm not going to go two and a half hours which was worried about by talking to you about the circadian dysregulation and other things okay so I say ABCD and F because I've been involved in these workshops is what's great about this field of circadian rhythms I can talk about anything I don't know anything but I'm talking about except the circadian rhythm part but I get invited to things like in 2008 the National Institute of Mental Health they took eight or nine circadian people put us in a room with eight or nine people involved in studying depression others maybe other psychiatric disorders and what's the role of circadian dysregulation in mental health so just watch this now that was 2008 2009 Heart Long Blood Institute called the workshop to do the same thing 2010 NIDDK said hey we ought to get into this circadian dysregulation and diabetes and digestive and kidney diseases National Institute on Aging in 2010 had a similar workshop this circadian dysregulation and aging this was a grant we had from the National Institute on alcohol abuse and alcoholism circadian rhythms and alcohol and do tissue damage see the variety of systems I'm trying I'm trying to get that across it's not just metabolic and then this is my one of my favorite ones I was invited to the National Institute of Arthritis and Musculoskeletal and Skin Diseases 2013 that's not that long ago and I'm talking about the circadian clock genes and I know I know nothing about musculoskeletal that's my point I don't know anything about arthritis musculoskeleton but I'm talking with these people and there's somebody in the front row I won't say where he was from but he's chairman of a major department on the West Coast of the United States of a private institution I probably said too much and and he's he's on he's on his computer and I think you know this guy's probably playing some computer game or something he goes Fred did you know there are clock genes in the skin cells now this is the chairman of the department of a major dermatology of a dermatology department in a major institution in 2013 was unaware of circadian clock genes in skin cells I'm not blaming him I'm just saying it wasn't part of the field and all of some of these fields are moving faster than others circadian dysregulation and metabolic disorders moving fast over my right shoulder circadian dysregulation and immune function left shoulder circadian dysregulation in cancer so the field is moving very rapidly into these domains and let me just show you this is a study we did a long time ago but even before the we really had a handle on clock genes and and their role in health and disease very simple experiment essentially have animals hamsters on a light dark cycle and then these were animals I always say Chicago Tokyo Tokyo Chicago every week shifted them back and forth I'm just going to give you this feeling of the breath and then we looked at mortality and this happened to be we were working with a hamster that develops early heart disease and you can see that the animals that were the control animals this is their longevity curve and the animals that were manipulated on a weekly basis obviously had changes in longevity then I got injured I got interested not that I got interested some people in the in the gastrointestinal world came to me and I didn't even know what got leaking this was a few years ago and they said we think that gastrointestinal diseases may be related to circadian disorganization so I said what what what one of your models and they have you can increase gut permeability otherwise known as gut leakiness with alcohol so we put environmentally we shipped at the animals every week like dark cycle boom boom boom boom and you can see they have much more this is a measure of gut leakiness shifted animals the clock mutant animal circadian disruption got leakiness more than the litter made controls so now the gastrointestinal world I'm going to come back to that at the very end then something like pregnancy we did this paper is just a few years old we we took mice on left them on a light dark cycle mice take about 20 days from fertilization to birth so every five days we phase the lead the light dark cycle this is supposed to be dark light so you can see is delaying it and then we had another group we advanced the clock and I was actually looking it was funded by the March of Dimes I was looking for premature birth I thought this is cool this is a good because premature birth is a not that it's cool to have premature birth but it'd be cool to link circadian disruption and premature birth and what we found was not premature birth we found no birth while no birth is an exaggeration this is percent of mice who actually produce litters and the phase shifted we get about this 67 black we use it get about 90 percent success we know that they were that they were fertilized and pregnant because please note that that vaginal plugs if we delayed the animals nine out of 18 gave birth and the phase advances I'm not going to try to go into why advances tend to be more disruptive but you can see this huge decrease in births we're still very fascinated with this question of what role may the circadian disruption play in fertility so you after after intercourse it takes after after fertilization it takes five days before the egg implants and I only found this out recently in mice and in humans before the plants in the human wall so you can imagine if early in pregnancy you're having a disruption of circadian clock system and you may lose you may lose the baby very early and you won't even know that you you know you've lost a baby in the first 30 days you may have a delayed in your menstrual cycle so this is still a just an area that I'm just trying to use that as an example but because we were studying disruption of the of the digestive system we said I don't like microbiota it's too complicated but we decided to look at the microbiota of the animals the clock mutant animals and the phase shift of the animals and I just summarized so I can finish on time and we published a paper in 2014 showing that there was dysbiosis or really there was that means changes in the microbiota which we think are negative there was an increase significant very significant increase in the relative abundance of pro-inflammatory bacteria so this got us into the microbiota world and because I had done things with NASA for many years they I found out about the twins going while the twins study and that was the paper that was just published in science where Scott Kelly went up for one year and his twin who was a former astronaut was on the ground during that time and we had an omics teams somebody was doing proteanomics some was genomics number of people two or three groups were looking at gene expression and and looking at different gene expression profiles we were doing the microbiota and just give you a feeling for the the experiment and remember the way I got involved is because disrupted sleep disrupted rhythms Lisa changes in the microbiota in space they had disrupted sleep they also have disrupted circadian rhythms so I was using that as my link to the microbiota community so this is represent Scott Kelly pre-flight we collected fecal samples two fecal samples about this is about 75 days or 150 days before flight and then during flight we collected samples one two three four times and then these are very complex experiments to do anything with the astronauts takes a lot of a lot of coordination and then we had post flight samples and with Scott Mark Kelly on the ground and and we found that was the paper that we that just came out a few months ago that there were changes in the microbiota with good good bad we don't really know and plus Scott was a sample of one and his brother on the ground was not that good of a control because we didn't control feeding Scott is eating space food Mark is eating real food and sometimes he's in Paris sometimes we didn't get the fecal material when he was traveling we had to collect the fecal material when he was at home in Arizona but we were able to show that there were major changes in various aspects of physiology in our case the microbiota but again it was an of one it had a big splash twin study year in space movies being made so it's it's I tried to you know audition for it but I didn't get any part with that but it got a lot of publicity but it really I'm gonna end by saying that we're doing something now that I think is much more exciting so let me just sort of summarize before I tell you the end of the of the space story let me just summarize what I've tried to tell you so far independent of space circadian disruption in human health in the old days we used to think in terms of jet lab chick black jet like shift work jet lag regulation of the sleep wake cycle but now that we know that all the tissues of the body have the clock it's a new frontier of medicine if we disrupt rhythms how do we impact human mental and physical health what levels are we doing it and now we we're associating at least an animal models and human not so much models but in terms of shift workers and we're finding that people with disrupted rhythms more obese diabetes cardiovascular disease depression Alzheimer's etc. I change this depending upon where I'm talking if I'm talking to gastroenterologists I'll put gastrointestinal diseases there and what I find I like this because I came up with this idea that this reminds me of this drawing of Da Vinci's helicopter he drew the helicopter in 1493 it took 500 years to build a helicopter we have the blueprint of the circadian system now the molecular genetic circadian clock we have the blueprint of how it's interacting not the complete blueprint not so like like this but we've got it so circadian cloud genes and how the blueprint is there how do we then transfer this into a clinical practice that's where the field is is now so I called it a tipping point and thank you the way you introduced me of talking about the future looking at things that big picture future ideas I think we're at a tip of play I called it sometimes I call it circadian medicines and I call it circadian health what is the role and I abused this that I think it's in my abstract for this meeting you know we're bringing time to medicine in the way that Einstein brought time to physics at the beginning of the 20th century I think we're bringing time to medicine at the beginning of this and it really is the beginning so if you one looks in the United States there's about 6,000 sleep clinics there are zero circadian clinics where you would go in and have a circadian profile at there's one there's now one circadian clinic Phyllis he was a postdoc in my lab and become really probably the most prominent sleep circadian human researcher clinician in the world and she's got a couple lieutenants that are working with her but she's established a circadian clinic where she has patients come in and she sees if they got circadian disruption she'll do some profiles on them to look at circadian organization so I consider circadian medicine is really on the next frontier and the journey continues and I'll end it with saying how the journey really is continuing I like that phrase the journey continues I think is in the Star Trek movies they often talk about this the journey continues I already told you about Mark and Scott but what I'm really excited about is a project that this is I have to update this slide it was not newly selected it's been done it's the effects of spaceflight on the gastro intestinal microbiota and mice and now and it turns out that Mark Kelly see Mark Kelly he actually has written a couple books for children mouse journey goes to Mars is one of them and so we really because of the Scott Kelly thing we were selected to do a study of 20 mice in space I'm not going to go into the detail we launched in June on SpaceX 15 it was very very exciting the samples will return the fecal material and all the organs of the body of these mice will return at the beginning of this year this is just to show you a picture of the launch because we you know we love these pictures this is the launch it was a morning launch it was just fabulous to be part of this and and now we have the largest rodent study that's ever been done in space and we can read the and we got control mice on the ground eating the same food I won't go into the details I'll just say we've got well-controlled experiments but I want to end by telling you we've just been selected for a new study which involves Japan it the future study the title of our proposal was impact of the Mars and solar day and gravity on microbiota and mice mechanism and multi-system physiology and the Japanese have a module on the space station and in that module they have a centrifuge for mice the whole idea of having a centrifuge is you can have mice that are in the not centrifuges and moving so they're in zero G you can have one G you can have any G you want but so our proposal is to have the mice on lunar G and Mars and G get a dose response curve and look at the effects on the microbiota and and other physiological system so this is not we've been selected for funding the negotiations are ongoing now between the between I think President Trump and Prime Minister Abe as far as I can tell it's at a very high level of exactly when are we going to fly how many days are we going to get those are details but I'm very excited that we'll be working with this centrifuge so of course I have many collaborators in this work I particularly want to focus on Martha Vita Turner you remember that she was the graduate student who found the clock mutant animal she's still working with me and she's one of the authors on that science paper so we've been we've been working together for a long time and Joe Takahashi who really was the the guy who led the cloning of the gene I went more into looking at effects of the clock gene disruption on physiology and behavior Joe went bar into the molecular biology of it and so but it's a great collaboration so it's been an exciting time to be part of something that was just very fundamental biology 40 years ago and now it's sort of mainstream biology and mainstream biomedicine so thank you very much