Return to the audio for How to Science Episode 4, with scientist Orie Shafer.
Monica Dus: Today with me is Orie Shafer.
Orie Shafer: I’m Orie Shafer. I’m currently an associate professor in the Department of Molecular, Cellular, and Developmental Biology at the University of Michigan in Ann Arbor.
Orie, thank you so much for being here with us today. I’m gonna ask you about your science story. How did you get to where you are today?
OS: Thank you for having me, first.
How did I get where I am today? I don’t really know why, but I developed a really strong interest in science starting in high school. I grew up in a really small, fairly…“backwards” is probably too strong a way to put it, but it was a very un-diverse place, in many ways. Un-diverse in the way we typically think about diversity, but also intellectually, it lacked diversity.
Where was this?
OS: This was a small town in Indiana. Since I’m not saying particularly positive things about it, I’ll leave it at that...
I grew up Catholic in a really small town in Indiana. We were by far the minority denomination. It was a very rural, very Protestant place. There were a couple of students in my high school who were very energetically Baptist, who decided it would be a great project to try to convert the Catholics to a Protestant affiliation.
I began to engage these people in debate, which was not something that happened much in this part of the country. People in this part of the country typically try to avoid confrontation; we’re very passive-aggressive.
We communicate our displeasure much more subtly. Like saying, “Oh, that’s nice,” and moving on. But these people really wanted to engage in a really energetic conversation about why the church I was going to on Sunday was wrong, and theirs was right. And I took great offense to this. I didn’t like it, and I noticed that people who tended to do that behavior clustered with all kinds of really nasty things like racism and antisemitism.
And I noticed in my conversations with them that two things that drove them absolutely crazy were the Big Bang and one guy: Darwin. You could just mention these two things, and these people would go absolutely crazy.
They’re taboo topics.
OS: Yes. They just would go nuts. Absolutely nuts.
And it never made much sense, because here we are surrounded by cornfields and soybean, so this is not a place where Darwinian theory really has much sway on daily life, and they would go absolutely crazy about this. So I thought, “Hmm, this is great.”
It just really started this sort of ammunition for getting these people as worked up as possible.
And then I just became fascinated by science. So I took all of the science classes that were available–I ran out of them. And I asked my biology teacher if I could create my own, which just consisted of my senior year sitting in the library and reading about cosmology and evolution.
So that’s really where it started.
During this time, were your science teachers helpful mentors, or guiding you, or were they just a presence?
OS: They were absolutely terrible. Uniformly terrible. That’s why I really don’t know where this deep interest in science came from.
The only thing my biology teacher was really interested in discussing was amplexus, where the male frog squeezes the eggs out of the female frog to fertilize them, and he just worked amplexus into every single conversation that he possibly could. He was also my football coach. He brought this up in football practice as well; it was the strangest thing.
And I had a physics and chemistry teacher who on the first day of class, said, “I really wanted to be a research chemist, but I couldn’t. So now I’m teaching you.” That was his introduction to the class.
So it wasn’t a very inspiring place to study.
What about when you went to college, then? Did you find it a much more inspiring place?
OS: Yes, absolutely. When I went to college–at Purdue University in West Lafayette, Indiana–I started as a pre-med major, because in my little town, people who were smart did one of two things: They were lawyers or doctors. And people who were interested in science were doctors.
I really had no idea that one could do this for a living. I mean, when I chose that university and I chose to major in biology, I had no idea that one could do what we do for a living. So meeting people that were doing it, and having a chance to start doing it immediately, just completely blew my mind.
So is that what you did? You started doing research pretty early on when you started college?
OS: Yeah, so I started as a pre-med major, majoring in evolution and ecology, and I took a class in the evolution of behavior from this amazing ecologist named Peter Waser. And most of it was more of a mathematical, ecological approach to behavior, like game theory and Why is it adaptive for an animal to have this particular behavior?
And then I think the last two lectures he spent on neurobiology, and he covered this work on Tritonia, where people in the Puget Sound up in the Northwest were trying to figure out how this beautiful sea slug–this very strange organism, this intertidal organism–how it goes from slowly and peacefully crawling across the floor of the ocean, eating seaweed, to detecting a predator–which in their case is a sea star–detecting their presence, and then shifting very rapidly to this really hilariously inefficient escape swim.
But what they had done was amazing. Dennis Willows is one of the people who did this work. They’ve mapped out the circuitry involved in everything: in walking, detecting the sea star, switching from grazing mode to the escape mode. They figured out–through many techniques that seem very modern–acute activation of neurons, acute inhibition of neurons and behaving animals. They worked out how this decision was made. They figured out the structure of the brain, they figured out how neurons were talking to each other, and they placed it in a real-world context–like a real-world, fight-or-flight, Darwinian fitness situation. It was absolutely astounding.
I decided that term, based on those two lectures, that I wanted to double-major. I wanted to double-major in ecology and evolution and take all the neuroscience courses. And there was one person on campus doing sharp-electrode electrophysiology. It was Dr. Christie Sahley, and she was working on simple forms of memory in the medicinal leech. So my first model system was the leech.
And I started just spending all of my time in the lab there, trying to get my head around what questions were being asked and how people ask them, and just immediately fell in love with that life. And I knew then that medical school was not what I should do. Now that I discovered that one can actually do this for a living, that this is what I should do.
So what made you fall in love with it?
OS: That’s a great question. I was just really amazed. I was never a particularly strong student. I didn’t perform well in class. I had a bit of an anti-authoritarian streak in me, and so I would often read the same subject matter–in physics class, I would read Stephen Hawking–but I wouldn’t actually do my homework or…
The textbooks.
OS: The textbooks and that sort of thing. And so I wasn’t a particularly strong student, and before I left that little town, I thought that science was something that was done by Newton, Einstein…
The elite?
OS: The absolute outliers in human intellectual endeavor. That these were the people who were capable of thinking on another level, building and operating incredibly complicated…
The geniuses.
OS: Yes. They were just like from another planet.
And so I never imagined that I could, for example, walk into a lab, and after a few months of washing dishes, and showing that I was serious, and that I had attention to detail, that in very short order, I could read enough papers, I could talk to enough people, and I could learn enough skills to actually ask a new question.
And it slowly began to dawn on me that that was really what was happening. It was just asking a series of simple questions, one after another, and accepting the answers as they come, and changing your mind about how things work to get a better picture. It’s just that simple. That’s really what we’re talking about here–we’re not talking about sophisticated machines and techniques and geniuses operating on high levels. We’re talking about just knowing enough to ask the next question.
And yeah, being intelligent enough to learn the best way to ask that question. I guess I was just really intoxicated by the fact that here I was, talking to this woman who was a brilliant neuroscientist, trying to figure how memory worked in the brain. And very rapidly, I could bring her news. I could bring her answers to questions that she was interested in that nobody knew, you know? And so I was hooked.
I want to go back to that question, because it seems really relevant for the rest of your career. It seems that you’ve really been fascinated and focused on one really big question. I was hoping you could tell us about why you picked that question. What was so fascinating that you chose to continue pursuing it? What was your course? In your Ph.D., in your postdoc, and now what you do in your lab?
OS: My career’s a little unique in that, from graduate school on, I stuck with the same question.
So at Purdue as an undergraduate, I worked on neural degeneration and regeneration in response to injury. And then, when I went to graduate school, I wrote my applications stating that I wanted to study the evolution of nervous systems, which a lot of people were doing. They were comparing brains from different species, and I found that very boring. I was more interested in population biology, and how the variation that’s out there could be the subject of selection, and how that shapes the brain. Kind of esoteric and not particularly interesting to the listeners, probably.
It was really in the course of trying to find a project as a graduate student that I discovered circadian rhythms. And the reason I did that was because of–again–a really fascinating ecologist. His name is Ray Huey, and he was interested in Drosophila, which we’re probably going to talk a lot about.
The flies that we study came from Africa. And at very different times in history, they invaded other continents–they invaded Europe, they invaded North America, and they invaded South America. And then, as they spread north and south in all of those climates, they had temperature changes, challenges that you experience at one latitude that you don’t at another.
And he had this wonderful collection of flies, based on collecting single, fertilized females from all along the latitudinal range of South America. His field season, as far as I could tell, was to go to a beautiful place in South America, order a beer, drink the beer until there was a little bit left, and wait for female flies to show up. And then he would aspirate them, and chances are, they were fertilized.
And so he brought these collections of flies back from South America that represented small samples of populations from the entire latitudinal range. He was interested in how they evolved heat tolerance and alcohol tolerance.
My advisor, Dr. James Truman, had been a real leader in the field of circadian rhythms. That’s what I study: the body clock, our sense of time. And there were theories out there about the clock that predicted how the clock should vary as a function of latitude. For example, day length is very different at the equator than it is at the tip of Patagonia, depending on the season, right? There were predictions about that, so I thought, “Well, this is my opportunity to do population biology in the nervous system.” Because I knew the brain was where the clock resided, and so I decided that this would be a promising beginning to doing population biology in the brain.
And there was nothing there. None of the predictions that I had, none of the experiments that I did on Ray’s flies, panned out. It was a spectacular failure. But in the process of testing them, I met really interesting people from the field of circadian rhythms and realized that there were even simpler questions to ask. And ever since, I’ve been fascinated by these clocks. I don’t foresee leaving them. I’m really very, very interested in them.
You mention adversity, and it feels like we have some things in common–that we’re both maybe very romantic about science. When I talk about science, I just really love it, and it seems that it’s the same for you. But you talk about adversity and the failure when all your hypotheses are wrong and there was just negative data. Can you talk about another defining moment in your science career where there was adversity, and how that shaped your path in science, or your vision of it?
OS: I guess I don’t mean to be discouraging, because I absolutely love what I do for a living, but adversity and failure is really a daily...you usually don’t know what’s going on. Your experiment usually doesn’t work, right? And that’s because the universe is an amazingly complicated, beautiful, fantastic place, and we’re one mind in trying to understand it.
So I guess it is not surprising that, when I was 20 years old, and I thought I knew exactly what was going to happen–that it didn’t. Right? And that really happens to everybody at every stage in their careers, because figuring this out–it's an amazing thing that we can, right? So when I think of adversity and failure, I think that’s just part of daily…
Like the constant poke.
OS: Yes, it’s a constant, “Oh, I was wrong.” “Oh, no that didn’t work.” From the really small things to the really big ideas, we’re wrong all the time. And I think you would agree that even our best, our most successful scientific studies–they’re all provisional. They’re all going to be replaced eventually by something that captures what’s actually happening even better.
So I think, to me, the real revolution for me, was understanding that that’s the strength of science–that we’re willing to be wrong over and over and over and over again. We’re willing to fail over and over and over again, knowing that every once in a while, we actually get this wonderful glimpse into how things probably work. So really, what a fantastic way to live and a fantastic way to approach anything–even outside of science–is to just accept that failure as a part of everyday existence. To not be so bothered by it, and to persist, and get this glimpse at how the universe and the living world actually works. It’s fantastic.
I think the understanding that–first, it’s a shocking understanding. That this is mostly failure, but that’s what makes it so fantastic. I mean, how many other people do you know who can so freely admit that they don’t have a handle on exactly what’s happening? And you know what? They don’t succeed most of the time. And yet, this is actually by definition how you succeed in science.
Yeah, and in many aspects, the true caliber of a scientific question is how many other questions it generates, rather than how many it really answers.
OS: It’s true. It’s about not knowing. It’s about what we don’t know. And I think if more people worked that way…
We have a very formalized version of: Ask a simple question, accept the answer that you get, and be willing to change your mind.
If everybody lived that way–if everybody stopped believing that the universe should operate according to their own idea of how things operate, and just actually interrogate, ask questions, and change their mind, it would be a better world.
Right; it would be very free.
OS: What I love about science is that we have a very rigorous way of doing that every single day, but it’s something that can and should be applied everywhere.
Do you feel that this experience you have with science has changed the way you are as a non-scientist, or in your daily interactions with people?
OS: Yes, I think so. I was never a particularly confident person, especially when it came to intellectual things, but I have to say one of the other great things about science is it’s much easier to apply this in a formal and intellectually rigorous way, rather than in politics or what’s the best way to live one’s life. It’s much easier to apply these things in the lab than it is, because we have our stubborn beliefs. We have things that we think with no evidence. We’re very hesitant to do experiments in our lives.
Well, you know, I think that getting up at 6 AM every morning is the best way to be productive. Well, maybe it's not. Why don’t you get up without an alarm clock for a few days and see how many pages you write and compare? We can all do it, but we’re very hesitant to do that in real life. It is something I’ve been trying to do more. My real life has to catch up with my lab life in some ways, but I am trying to apply that everywhere.
So, since you hinted there are free-running clocks, I feel this is a good time to talk about your research, and what your lab studies, and what you’re interested in studying in the future.
OS: I study circadian timekeeping, and most of us are aware of circadian timekeeping based on the fact that we tend to do the same things at the same times in the same places every day. We really have…
Like we used to meet for coffee…
OS: I was thinking of the same thing.
I walk in; you walk out.
OS: With amazing regularity. As it turns out, most of us don’t need alarm clocks or tight schedules to maintain regularity. We know this because the sleep-wake cycle is the best known “output” of the clock. We tend to sleep at the same time every day and wake up at similar times every day, and that’s because in our brain, we have a clock that controls when we wake up and when we get sleepy. We know this because if you take people and you isolate them from cues from the environment, that they continue to show a real pattern of waking up and going to sleep. It’s very, very regular.
What is fascinating about that rhythm is that if you put them deep underground, for example–these are the original experiments, deep down in a bunker underground–that they continue to have sleep-wake cycles, temperature rhythms. They eat with a rhythm, but their clock now runs too slow.
Chuck Czeisler at Harvard thinks, based on really good evidence, that the human clock actually runs with a schedule of 24 hours and 11 minutes a day. So the clock is about 11 minutes slow, on average. Which, if you imagine having a wristwatch that you were using to schedule your life, and it was 11 minutes off every single day, it wouldn’t take many days for that watch to cause trouble.
So the clock that we have in our brain is this fascinating timekeeping device that controls almost every aspect of our existence: behaviorally, physiologically, metabolically…
Emotionally?
OS: Emotionally, intellectually...We think better at some times of the day than others. We’re stronger at some times of the days than at others. Based on this endogenous clock, it doesn’t need the sun to come up and go down. It doesn’t need temperature to go up and go down. It’s there, and its precise–very precise. Each of us has a clock that runs at a certain speed, and that clock is very precise, but it is inaccurate. Ours is too slow. And every day, we use cues from the environment to “entrain” it–to reset it, to push the minute hand forward 11 minutes.
So what are those cues?
OS: The most important cue is certainly light. You can take that nearly 24-hour rhythm and turn it into a perfectly 24-hour rhythm or turn it into a 26-hour rhythm or turn it into a 23-hour rhythm by giving light-dark cycles on those schedules. So light is really the most important.
But almost any cue–when delivered in isolation with a schedule, social interactions, temperature changes, magnetic field changes, all kinds of things–have been shown under certain conditions to entrain the clock. To turn your nearly perfect 24-hour clock into a 24-hour clock.
That’s, in a way, a very democratic process, right? Because each of us is slightly different, but by these external forces, like temperature and light and when we eat and so on, then we kind of get pushed together into being more similar?
OS: Yes, but here’s the interesting thing: It’s also well known that there are people who are programmed through their circadian system to be early risers. These are people that are up, maybe before the sun comes up, they are hard at work at 8:00 being very productive.
And then there are night owls. There are people who are clearly biologically predisposed to wake up at 11:00 in the morning, noon, and stay up very, very late at night. And they feel better when they’re able to do that.
Now, the problem is that we have a society that is built for the early bird. Our society is based on getting up, being at work by 8:30 or 9:00, and as it turns out, if you are biologically a late type, and like most people, are forced to live as an early type, you’re much more likely to be obese, to abuse drugs and alcohol, to smoke, and to be depressed.
So that natural variation, not only in how fast the clock runs, but also in how things are phased–what’s the timing, what’s your schedule within that day–that there are people that really struggle to stay on early-bird time, which is really what society, at least in the United States, is based on.
So it’s more like a dictatorship then, for some people.
OS: The rise of the early types, yes. They tend to run the show.
But if you think about school: Most people who end up being teachers, you would really struggle if you weren’t an early type. You have to get up early, and early types tend to think being an early type suggests motivation, intelligence, and diligence, right?
You mentioned increased risk of obesity, diabetes, depression, and other things. Do people know how that works?
OS: The idea is, Till Roenneberg is one of the real proponents of this idea–it’s a brilliant idea–of social jetlag. So of course, every day of the week is not the same. We have five days of the week where we are forced to live according to the early-bird schedule. That’s the work week.
And then we have two wonderful days where we really have no responsibilities; we have a so-called “free day”. And so he and others have studied the way that sleep works in late types who were forced to live an early-type existence. What you find is–not surprisingly, because the clock controls when you get sleepy, and the clock controls when you wake up–that late types struggle every single day to force themselves to wake up at a time when their internal clock–when their brain–is telling them that they should be asleep. This probably accounts for why they smoke more and why they drink more caffeine.
I think it was also linked to likelihood of income, essentially.
OS: Probably, yeah. And then the clock–one of the things that the clock does for us is that right after that afternoon slump, when you begin to feel really tired, because you’ve built up sleep debt, you haven’t been sleeping for a while–your circadian system kicks in and says, “You know what? We’re gonna stay up for a lot longer.” Well, that system is at play at 10:00, 11:00, 12:00 at night for the late type. So they’re trying to get to sleep, they’re like, “Oh, I’ve gotta get up at five in the morning tomorrow.” But their circadian system is saying, “No, we need to stay up and work. We need to stay up and be productive.”
And so what they do is they develop what we call a sleep debt. And when you fail to get enough sleep, you have to pay it back. When you are sleep-deprived, and you have an opportunity to sleep again unmolested, you will sleep longer. You will pay back that debt.
You rebound, essentially.
OS: It’s a sleep rebound; exactly. So these late types, who are forced to spend five days a week acting as early types–they build up a sleep debt. They’re not sleeping enough. They sleep less than they should all week, and so on the weekend, they pay that back, and the effect of that is that everything happens much, much, much later in the day. They wake up later, they begin their day later, they do their activities later, and they get sleepy later. And if you look at the timing of how they live on the weekends, and the timing of how they live during the week, it's like getting in a plane and flying three or four time zones away!
So it’s like they are jet-lagged essentially–chronically.
OS: Chronically jet-lagged, back and forth. Imagine you work in Boston all week long, and then Friday night, you hop on a plane to L.A., and you live for two days in L.A., and you fly back Monday morning or Sunday night to Boston. I don’t think it is surprising to anyone that that would be really, really bad for you.
Yeah, and affect your health profoundly.
OS: And that is all because our sense of time is not just a passive response to the cycles–the very profound cycles in the environment. Light, sound, social interactions–they all happen with a 24-hour rhythm, but that’s not where this comes from. This comes from an internal clock that has real power over our lives, and setting it back and forth and back and forth like that is really bad for you.
So correct me if I’m wrong, but the first “individuals” that were discovered to have different periods of perceived or internal time of day were actually fruit flies. Is that true?
OS: I believe that is true, and these were not natural variants, right?
That’s right.
OS: So my approach to this question starts with that experiment you are describing. Ron Konopka’s isolation of three mutants and the fruit fly Drosophila melanogaster. And it was a spectacular success. I teach this paper every chance I get.
Seymour Benzer had done really pivotal work on the nature of heredity–the encoding of genes–and he got fascinated, as many people did, with the brain and behavior.
#SeymourShouldHaveGotANobel.
OS: Two of them, at least!
Well actually, as it turns out, it was Ron’s idea to look for mutants whose clocks did not run properly, because Ron had known about circadian rhythms for quite some time, and he was very, very interested in rhythms, and of course, this was really what Seymour was doing.
He had a fantastic research program involving the discovery of mutants that didn’t behave properly. So Ron decided he was going to find mutations in the circadian system. So he mutagenized flies, and he looked for flies that didn’t keep time properly. And he found three mutants: period short, period long, and period zero. And this was a fly whose clock ran too fast–18 hours per cycle, instead of 24. A fly whose clock ran too slow, at 27 hours per cycle. And a fly whose clock appeared to be broken.
And the idea, of course–the great hope from the beginning–was that if you identify a mutant, you have identified potentially a gene, and potentially a protein that is expressed in certain places and does a certain job that produces that behavior. And of course this has been spectacularly successful. Based on that original discovery, we now know how the human clock works. As it turns out, it works on the gene period, the one that he discovered in flies. It’s been a spectacular success story in science and neurobiology and science in general.
And I feel it’s also truly a science story that talks about why it’s important to do this kind of basic fundamental research, because you never know where the great discoveries are going to come from, right? Now we talk a lot about CRISPR–that came from people studying why bacteria get the flu. And so I know that you are a big advocate for basic research, and both you and I have pretty much spent our entire career working on fruit flies. Maybe we can talk a little bit about the importance of basic research, what it means, why it’s important.
OS: Absolutely. The fruit fly has a spectacular history of informing us about very, very important things. I mean, what could be more fantastic than the fact that all animals start off as a single cell that somehow turns into a functional organism? We go from no patterning to this amazing pattern. We have two arms, we have two legs, our vertebrae are these beautiful chain of bones that protect our spinal cord.
Well, this was another fundamental question in biology that was in part answered through a very similar approach in flies. Let’s look for flies whose patterning is wrong. Well, now we know about the Hox genes. The Hox genes pattern us. They pattern you. They pattern me, right?
And so the fly has this amazing genetic tractability. It’s just a beautiful genetic tool that we can use to ask very basic universal questions about life on this planet, and it has never stopped informing us of really important things about ourselves.
And speaking to this importance: In fact, a lot of Nobel Prizes were given for researching fruit flies, like the discovery of the body plan, for example, immune genes and processes...I feel like we should have a tiny crown and put it like on top of the fruit fly. I also want to talk about something else I know that you really care about, and I know you’re an amazing educator and you do a lot of outreach.
OS: Thank you.
Can you tell us more about why you do outreach and why you feel it’s an important mission of scientists to do it?
OS: Absolutely. I mean, I think I was lucky. I mean, I wasn’t a good student, but I was a fairly intelligent guy. I thought that anybody who was slightly interested in biology had to become a general practitioner. I mean, I really didn’t know that one could do this.
So I think it’s important that, particularly in places that don’t have access to good biology, physics, chemistry, math–people who don’t have an opportunity to talk to people who are excited by this–maybe they’re the next Einstein. Maybe they are the next outlier that’s going to really transform science and humanity by their discoveries, but maybe they never hear about it. I think that fundamentally is what it is.
I also think it’s really fun to talk about it, and I learn a lot by teaching. First and foremost, I think we’ve got a real problem with access. There’s a really uneven access to just basic knowledge about science–what’s been discovered. But also the opportunities that people have to contribute to this.
This is how progress is made. This is why jet airplanes fly and magic carpets don’t. This is progress. We understand the universe better. We can do things that we couldn’t do before.
And you have organized some specific activities to really get to that issue, right?
OS: Well, the first big one starts this summer. We’re going to have a neuroscience camp for junior high school kids at the Natural History Museum here.
“Here” is Ann Arbor.
OS: Yes. The idea that I’m most excited about is we’re going to use the fly–we’re going to use insect preparations–to teach some fundamental aspects of how the nervous system works. But in addition, we’re going to expose students, who maybe have never heard of neuroscience before, to cutting-edge technology. We’re going to have them do optogenetics. We’re going to have them excite neurons in…
Mind control.
OS: Mind control, right? So they’re going have an opportunity to not only talk to scientists and students here and see labs, but really start to play around with the things that we do here.
And realize that they might also become scientists one day, right?
OS: Well, I hope so. If they’re interested.
If they’re interested. If they want to.
OS: But at least they’ll know.
Well, this sounds really awesome. I’m really excited to learn more about that. So do you want to talk about anything else?
OS: Oh, not on the microphone!
All right; I just really want to thank you for this amazing conversation and for being part of this.
OS: Thank you very much for the invitation. I was happy to do it.
Return to the audio for How to Science Episode 4, with scientist Orie Shafer.
