SciencePodcast_190201

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1 00:00 Sarah Crespi: This week's episode is brought to you in part by the American Dental Association. Teeth tell a story. We know what ancient civilizations ate, drank, even where they lived, all from looking at their teeth. What story will your teeth tell about you? Your ADA dentist can help you find out and give you the tools to keep your teeth healthy for years to come. Use the American Dental Association's Find-a-Dentist tool to find the right dentist for you. Go to ADA.org/sciencemag today. 00:30 SC: This week's episode is also brought to you by After the Fact, a podcast from the Pew Charitable Trusts. 00:35 SC: Thirty years, why does that number matter? It's been a more than 30 years since a new type of antibiotic has made it to market. Now, you might be wondering why. A stat is only the beginning of a story. To understand the number shaping society's biggest challenges, listen to After the Fact, a podcast from the Pew Charitable Trusts. Available on Stitcher and anywhere else you get your podcast. Visit Pewtrusts.org/sciencemag to learn more. [music] 01:11 SC: Welcome to the Science Podcast for February 1st, I'm Sarah Crespi. In this week's show, I talk with Orla Smith, editor of Science Translational Medicine, about clinical applications of all this microbiome research that we've been hearing so much about. And Meagan Cantwell and Amita Sehgal discuss a gene that induces sleep in fruit flies, that's also linked to fighting off bacteria. 01:36 SC: She's the editor of the journal Science Translational Medicine. Hi, Orla. 01:40 Orla Smith: Hi there, Sarah, great to be here. 01:42 SC: You're celebrating your 10th year of publication with a series of essays that kind of look at different areas of translational medicine and the first is on the microbiome. 01:52 OS: Yes, that's right. We actually launched in October 2009, so 2019 is our 10th year. And we have this focus series, where we've asked leading experts to write about translational advances in their field over the past decade. 02:06 SC: We're talking about the microbiome. What do you think has been the biggest change in this area in terms of translational medicine? Have there been the leaps? 02:14 OS: There definitely have from 10 years ago when it was very descriptive. People were using sequencing to sequence RNA of all the microbial species in the gut, and then were able to say, "Well, the gut microbiota is composed of these different species." So it was very descriptive. 02/02/19 Page 2 of 10

2 02:31 SC: Right. And they were looking at what happens in mice sometimes when you introduce... What is it? Gnotobiotic? 02:37 OS: It's gnotobiotic mice. So indeed, you're right. Those early experiments were actually very clever, because they took fecal microbiota from humans and put them into germ-free mice, these gnotobiotic mice. And then they were able to see what happened when they fed the mice different diets, that sort of thing. And so, it was a very clever way to be able to study the human gut microbiota in an animal model. 03:01 SC: Ten years on, how are we treating with or involve... What kind of treatments involve the gut microbiome? 03:08 OS: So, obviously now, what we're all really interested in is how we can use what we've learnt about the gut microbiota, the gut microbiome to treat different diseases. So probably, I think one of the biggest leaps has been fecal microbiota transplants. 03:23 SC: Right. 03:24 OS: And this is, as it sounds, taking fecal matter from one human and transplanting it into another. 03:31 SC: Apparently, according to the essay here, it was something that was first started in the 4th century. 03:37 OS: I believe it's been around for a very long time. 03:40 SC: Now, doctors are doing it. And what kind of things are treated with this? 03:43 OS: In people with a horrible bacterial infection caused by Clostridium difficile, they become completely debilitated. But a fecal microbiota transplant from what we call a "super pooper," so these are people who have very, very rich fecal microbiota material. In fact, this fecal microbiota transplant can combat their Clostridium difficile. And it's one of the few ways that this bacteria can be vanquished because it is multi-drug resistant. So it's resistant to even tough antibiotics like vancomycin. 04:16 SC: And some day, we may be banking our own fecal matter. So if we do get an infection, we can just get our own stuff back. 04:22 OS: Yes, that's called an autologous fecal microbiota transplant, and obviously does require that there are banking facilities at clinical centers. But in fact, there have been papers and randomized controlled trials where people have received their own autologous fecal microbiota to transplant back after, for example, having a bone marrow transplant, when they were treated with very high levels of antibiotics. And so, they've actually... The doctors have shown that people who get their autologous fecal matter back are able to replenish their gut microbiota rapidly and it helps to improve their survival rates. 02/02/19 Page 3 of 10

3 04:58 SC: Another thing I learned from this essay is that there are prebiotics, probiotics and postbiotics. Now, I've heard of probiotics. That's where you're actually eating bacteria in your yogurt or in a pill. But what about prebiotics and postbiotics? What are those? 05:13 OS: You're quite right about the probiotics. You can buy them off the shelf in the supermarket, and you get them in yogurts, of course, in fermented cultures. Prebiotics are carbohydrates that certain beneficial bacteria like to eat. It's actually like a carbohydrate supplement that can be added to food. And then the goal is that you stimulate growth of the good bacteria in your gut. 05:37 SC: And what about postbiotics? 05:39 OS: Postbiotics are the metabolites, the good metabolites, that certain good bacteria in your gut produce, long-chain fatty acids like butyrate, that have many beneficial qualities. So, the idea of taking a postbiotic is that you just take the good metabolites, the long-chain fatty acids, without having to take the bacteria. 05:58 SC: So you're skipping the bug middleman? 06:00 OS: You are skipping the bug middleman. 06:02 SC: And you're treating yourself with whatever the metabolite that would have helped your health that was coming from bacteria? You're treating yourself with that metabolite? 06:09 OS: That's correct. 06:10 SC: Okay. What kinds of things are treated with pre, pro or postbiotics? 06:14 OS: I think it's still early days for clinical treatments with pre, post and probiotics. As we learn to understand more about bacterial metabolism, about what they produce, about how the bacteria in our guts actually break down drugs or take a prodrug and break it down to the active drug. I think we're going to see much more of an influence of these pre, post and probiotics in medicine. 06:40 SC: I see these probiotics in the grocery store, in my yogurt or in a pill, and I wonder what kind of bacteria are they giving you, how do they know what kind to give you and how effective are they at populating your gut and helping you with your health? Is that something that you can answer, Orla, or have some ideas about? 06:56 OS: Well, I think everybody is obviously very interested about being able to pop a probiotic pill and become more healthy. At the moment, we're still trying to work out which are the good bugs. And there are certain that, like Bifidobacter and Lactobacillus, are beneficial bugs that are in many probiotics. But one of the issues is, we have of course a very populous gut microbiota and so it's not clear how easy is for them to take up permanent residence, or whether they tend to be more 02/02/19 Page 4 of 10

4 transient, in which case you'd probably have to take your probiotic every day or your nice breakfast cereal with yogurt in it. 07:32 SC: I wanna move to the immune system. This has always been amazing to me, this idea that we have bacteria that we're friends with, that our immune system recognizes the way we recognize ourselves. How have we come to understand that relationship better in the last 10 years? 07:48 OS: So this is one of the most exciting areas of gut microbiota research, because it turns out that there is this amazing synergy between our gut microbiota and our immune system. As you probably know, the gut has a very active immune system, and clusters of immune cells in the Peyer's patches. So as it turns out, dendritic cells sample the gut microbiota and then present those microbial antigens to other immune cells to induce tolerance, so that we don't attack our gut microbiota. 08:18 SC: Very cool. And is that something that people are looking to influence for clinical reasons? 08:23 OS: Very much so. Obviously, there are autoimmune diseases and inflammatory diseases, like inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, that involve a dysbiosis in both the gut and the immune system. So this is still quite early clinically speaking, but they are looking at ways to improve the gut microbiota or modulate it to try and ameliorate the symptoms of inflammatory bowel disease. 08:50 SC: Great. Outside of the gut, where else are microbes important? And are people looking to them to help with health? 08:56 OS: Yes, that's a very good question. Obviously, most of the work has focused on the gut because it's easy to obtain fecal matter and... 09:04 SC: So easy. [laughter] 09:05 OS: Yeah, and run sequencing and look at the different microbial species and how the composition changes with diet or with health or with disease. But we have microbiotas in many different tissues, obviously in our mucus membranes, in our nasal passages, respiratory tract, skin. We have our own personal host microbiotas. 09:27 SC: There might even be different microbiomes associated with different organs? 09:31 OS: Yes, we're now beginning to understand that each tissue may have its own microbiota. Although again, it's still very early days and hard to examine. 09:41 SC: What do you think the big hurdles are in this field, translating all this research on the kinds of microbes, where they live, how they change with disease and health and obesity? What's the big hurdle to translating all this descriptive research to the clinic and to treating people? 02/02/19 Page 5 of 10

5 09:58 OS: So the real key will be randomized controlled trials, where you can compare people getting whatever it is, whatever microbiota treatment it is, versus people who are not. We are seeing the start of randomized controlled trials and I think the results of those are going to be very, very informative and are gonna guide us moving forward. 10:19 SC: One thing that I noticed from looking across the literature described in this is that, there's a lot of diversity out there. Is that a problem with translating this stuff into the clinic? 10:28 OS: So, you're absolutely right that the gut microbiota is heterogeneous. It's different from person to person, people who live in different geographical locales, eat different diets. It really varies a lot and so that's one of the big challenges about knowing which specific microbial species are the ones that will benefit all of us. 10:48 SC: So, Orla, what is on the horizon? What's really far out there when it comes to translating microbiome research into the clinic? 10:56 OS: So I think there are certain metabolic diseases, obesity, diabetes, auto immune disorders like the inflammatory bowel diseases that could benefit greatly from a better understanding of our gut microbiota. 11:09 SC: Yeah, I'm also really interested to see how the microbiome of the environment, whether it's hospitals, schools, or where we work, interacts with our own personal microbiomes. 11:18 OS: I think that's a great question. We recently published a paper where the researchers looked at the change in the microbiota in a hospital from the day it opened, when it was brand new, over the course of a year, with patients coming and going with different illnesses and doctors and nurses and it's absolutely fascinating. I think we cannot ignore the microbiomes that's out there all around us. So I would say, watch this space. 11:45 SC: Orla, thank you so much for talking with me. 11:48 OS: Thank you so much, it's really been a great pleasure. 11:50 SC: Alright, I really look forward to the rest of this series. Orla Smith is the editor for Science Translational Medicine. You can find a link to the article we discussed at sciencemag.org/podcasts. Stay tuned for Meagan Cantwell's interview with Amita Sehgal about the link between immunity and sleep. [music] 12:12 Meagan Cantwell: When you're sick, sometimes all you feel like doing for the day is napping. That lethargic feeling is actually not triggered by the infection you're grappling with, but your immune system. I'm here with Amita Sehgal to talk about a gene that links sleep and immune function. Hey, Amita. 02/02/19 Page 6 of 10

6 12:29 Amita Sehgal: Hi. 12:30 MC: First, could you talk a little bit about the processes that regulate sleep. 12:35 AS: The truth of the matter is that we understand very little about sleep. We do know that it occurs with a 24-hour rhythm, a circadian rhythm, and that's driven by a clock, a biological clock that's within us. But we know that there's this other system called the homeostatic system, and the homeostatic system is the system that ensures that you get enough sleep. Usually, the two systems work together to determine when sleep occurs. But the homeostatic system can sometimes override the circadian, so you're up all night, you sleep in the morning, even though your clock is telling you to wake up. We understand a lot about the circadian process, we understand very little about the homeostatic process. What is it that makes us sleepy when we've been awake for a long period of time? 13:24 MC: How did your team approach isolating molecules that modulate sleep and wakefulness? 13:29 AS: We developed several years ago the fly model for sleep. And the reason we did that was because we wanted to really get at molecules and the genetics of sleep, which is harder to tackle in mammalian models. And the fly lends itself beautifully to those types of approaches where you can just mutagenize the animal and then look for ones that have aberrant sleep patterns. 13:54 MC: What was your study trying to figure out that previous studies didn't address? 14:00 AS: In previous studies, we had found genes that affected sleep. But for the most part, we found that those genes were required for the animal to sleep, but they weren't drivers of sleep. So you couldn't increase sleep above the normal sleep amount. And so what we wanted was, "What is the trigger? Is there a gene that when you just increase it, the animal will become sleepy?" And that's what we tried to do in this study. 14:26 MC: Right. And your team was successful in identifying a single gene that induces sleep called nemuri. How were you able to isolate this specific gene? 14:36 AS: So, we basically took different genes across the whole genome and overexpressed them, increase levels of those in adult neurons. And we find that when we turn on this gene so that it then makes protein, the animals sleep. And no other gene from the 12,000 or so that we tested did that. 15:00 MC: So what normally triggers the expression of this gene? 15:03 AS: Normally, it turns out that when the animal has very high need to sleep, if the animal has been awake all night, or if the animal is sick. During sickness, your need to sleep increases 'cause sleep is restorative. 15:18 MC: Is the sleep induced from this protein any longer or deeper or different than normal sleep? 02/02/19 Page 7 of 10

7 15:26 AS: It is deeper and longer. So what happens when we increase expression of this molecule, duration of each episode is increased. Saying they're sleeping more, but they're also sleeping in a better consolidated fashion, so each episode of sleep is longer. Deeper sleep is actually referring to the arousability. So we find that when you overexpress this molecule, if you increase levels of this molecule, that it's harder to wake the flies up. 15:57 MC: How exactly does this gene promote sleep in fruit flies? 16:01 AS: So this particular protein it turns out to be an immune molecule, and it is produced in peripheral tissues in the body, and it actually kills bacteria. But normally, you don't even think of these proteins as being in the brain, although they are. And this particular molecule gets turned on in the brain and it gets turned on in the brain in very few cells, probably just two cells. And what it does is act through the normal known sleep circuitry as in the neurons that normally affect sleep. We don't know how it does it, but it seems to be connecting to that circuitry. 16:39 MC: So in addition to the immune benefits from inducing sleep, it also has other properties that help it boost the immune system? 16:47 AS: It is also promoting immune function. And so we think that when the animal is sick, it has a twofold function. On the one hand, it's killing the bugs. On the other hand, it's increasing sleep, both of which are helping the animal recover from the infection. 17:05 MC: So what was the most exciting part of this discovery? 17:08 AS: The very fact that we could get a molecule that would trigger sleep was really exciting for us. The fact that it was secreted was also really exciting, because the sleep field has long believed in the idea that there are secreted molecules that can increase sleep. So, many, many years ago, these experiments were done where people sleep-deprived sheep and goats, and then they took their cerebral spinal fluid and put it into animals that had been allowed to sleep, and the injected animals became sleepy. They basically were transmitting sleepiness from one animal to the other by just taking fluids, secreted molecules. 17:51 MC: Have there been any other genes discovered that are similar to this gene you found in fruit flies? 17:57 AS: People have tried a lot over the years to figure out what it is that transmits that sleepiness from animal to animal, and it's unclear. For a while, people thought that it might be this molecule called adenosine, which is a breakdown product of energy utilization, but the effects of adenosine on sleep are really restricted to certain parts of sleep, and it's in certain areas of the brain. But importantly, some of the molecules that have been implicated are immune molecules. 18:29 MC: One of the reasons you use fruit flies is because it's easier to isolate the genes than in mammalian models, but what would be a potential approach to figuring out if a gene like this exists in humans? 02/02/19 Page 8 of 10

8 18:41 AS: There are similar classes of molecules in mammals, antimicrobial peptides, molecules that kill bacteria. So for starters, what I would do is work with a mouse or a rat model, and inject them with different antimicrobial peptides that are normally made in those mice and rats and see if they can induce sleepiness. 19:01 MC: Thanks so much, Amita. 19:03 AS: Thank you, Meagan. 19:04 MC: Amita Sehgal is a Musser Professor of Neuroscience, an investigator of the Howard Hughes Medical Institute at the University of Pennsylvania. You can find a link to her research at sciencemag.org/podcasts. [music] 19:19 SC: And that concludes this edition of the Science Podcast. If you have any comments or suggestions for the show, write to us at sciencepodcast@aaas.org. As a reminder, we're looking for a book reviewer, so if you have science and radio experience, please do get in touch. You can subscribe to the show anywhere you get your podcasts, or you can listen on the Science website. That's sciencemag.org/podcasts. To place an ad on the Science Podcast, contact midroll.com. The show was produced by Sarah Crespi and Meagan Cantwell, and edited by Podigy. Jeffrey Cook composed the music. On behalf of Science Magazine and its publisher, AAAS, thanks for joining us. 02/02/19 Page 9 of 10