Episode 19: Forming Gut Circuits

Peter 0:15
Hi, and welcome back to the Gastronauts podcast. My name is Peter, and my name is Reem hasnah. And we’ll be your hosts. Here at Gastronauts we are committed to exploring communication throughout the body with a focus on the crosstalk between gut and brain. We invite speakers in this field to share both their research and their life journeys. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts Podcast.

I want to introduce Dr. Piali Sengupta. She received her PhD from MIT where she studied pheromones signaling and yeast in Brent Cochran’s laboratory. She then did her postdoc at UCSF where she identified genes that encode how olfactory receptors are encoded in C. elegans with Corey barman. She was then recruited to Brandeis University in 1996, and she is currently a professor of biology at Brandeis University, and is recently elected as a fellow in 2019. For her pioneering work on the molecular genetics of chemical communication and thermo sensation in C. elegans. Her lab work has two primary research focuses. One is the cilia squad, which is focused on the mechanisms by which cilia form and function. And the other is this axis of taxes, which is aimed at uncovering how thermal and chemical stimuli are sensed by C. elegans.

Reem 1:53
I’ll introduce Dr. Brian. So Dr. Brian received his PhD from the University of Colorado Health Science Center, where he studied chemoreceptor cells. He is currently an associate professor in the physiology department at Michigan State University. The focus of his lab is to understand how inflammation in the nervous system, neuroinflammation leads to long term changes in the neuronal circuitry. So welcome Dr. Brian.

To make this episode easier for you. We wanted to try something new this time around and give you some context for some of the terms and words introduced later in the episode. First, Hirschprung’s disease is a disease, which is a condition that affects the large intestine the colon and causes problems with passing stool. That condition is present at birth, as a result of missing nerve cells in the muscle of the baby column. Then, glia. Glia can be called as glial cells or neuroglia, which are non neuronal cells in the central nervous system, and the peripheral nervous system that do not produce electrical impulses. They maintain the homeostasis. Finally, cilia. Cilia are fine hair like projections from certain cells, such as those in the respiratory tract that helped to sweep away fluids and particles.

Winston 3:29
Hi, I’m Winston Liu, I’m from Duke University. Really great talks from both speakers today. Thank you guys for coming. My question is for Dr. Sengupta. As I guess I was thinking about your talk, you know, for example, we have chemo sensation, you know, things that we prefer that are innate, like, you know, loving, sweet things, avoiding better things, for example, versus some things we learn over time. And I’m wondering for something like a C. elegans, do you see the same types of things? Are there sort of innate categories and learn categories? And there’s some insights you can draw about how those things are determined in the field against?

Dr. Piali Sengupta 3:59
Yeah, thank you for that question. So yes, the answer is yes. So there are innate chemicals, obviously, like for. So for example, for not us specifically, but for mammals. Some of the innate responses obviously, are to toxic chemicals to things like pheromones. So worms actually also have all of those responses. So worms actually, and I can talk about this for an hour. But worms actually produced like 150 different types of pheromones. And they have the most amazingly complex responses to those pheromones. So those are what we consider innate behaviors. And a lot of the responses that I was talking about, again, just like for toxic chemicals, they’re also innate, there are learned behaviors. So there are chemicals that can be you know, they’re generally indifferent to it. But if you’re associated with food, they can become attractive, for instance, so there is that kind of associative plasticity as well. So yeah, so the short answer is there are both types of responses.

Winston 4:56
Thank you.

Reem 4:56
Talking about innate and learned, I have a question. Do we make memories of these different experiences and different stimuli that alter the future of sensory behavior?

Dr. Piali Sengupta 5:08
So it’s funny you asked that question, because this is not our work at all. But there is actually now recent work from a number of labs, specifically Coleen Murphy’s lab at Princeton. So worms, when I say the bacteria, they actually a lot of the bacteria, as you can imagine, are pathogenic, make them sick. And so once they’ve actually eaten a pathogenic bacteria, and so initially, they don’t know that it’s pathogenic, they like it, they eat it, they get sick. And then when you expose them to the same bacteria, now they run away from it, which makes sense, right. And so, Callie’s lab has actually shown recently, in some some very nice papers, where that avoidance of a pathogenic bacteria can actually be transmitted through generations through its progeny, it actually is mediated so the worm eats it, it’s in the gut, there’s a small RNA from this pathogenic bacteria that it senses, the signal goes from the gut, to the germ line to the neuron, and that information is passed down through five generations. And then those project even though they’ve never seen that pathogenic bacteria will avoid it. So it’s super cool. There might be other behaviors that are also passed down transgenerationally, but hasn’t been looked at.

Reem 6:18
Dr. Brian, what do you think of glial cells? Do they make memory also of the different stimuli? Or they just forget as it comes over and over?

Dr. Brian Gulbransen 6:30
That’s a great question. I, I’m not aware of any work really showing memory in the gut, necessarily. I mean, there’s a lot of work showing neural plasticity in the circuits. And most of that is in the context of inflammation. So if you perturb the system in some way, you know, the properties of the neurons and the glia change over a long time course. And I don’t know if you necessarily call that learning, but with the glial cells, they’re very plastic, I could imagine that if you, you change the circumstances in any way that glial cell is going to adapt to maintain homeostasis, because that’s their main function. So I think that they would probably display some types of, I guess you could call it sort of learning, I guess, in in terms of how the circuit responds and how the circuit adapts and the glial cell adapting to that circuit. But yeah, I don’t know if we all cells would do anything really what we would call learning, necessarily,

Peter 7:20
When you find some things that are being secreted or released by cells, how do you choose which one to focus on? I know that you mentioned that this octopamine story was the one that you focused on there, Piali. But I guess both of you like you focused on ATP, Brian.

Dr. Piali Sengupta 7:37
So I think for us, it’s actually pretty straightforward, because a lot of our work is based on genetics. So we just screened through a lot of mutants. And then if you have a phenotype, we essentially focus on that one. So a lot of these neurons are expressed multiple neurotransmitters that express multiple neuropeptides. But it’s very straightforward for us to just read through them and look to see if there’s a defect in behavior.

Dr. Brian Gulbransen 7:58
Yeah, I mean, for us, we we focused on purines and acetylcholine to begin with anyway, because those are two of the main neurotransmitters and excitatory circuits in the gut, there’s probably every neurotransmitter that’s in the brain and the gut. And so once you get into, you know, the effects of all these, it could probably get complicated. And there, there are probably many, many more that have effects. But these were two of the most likely candidates. And so we started with them, just because nothing else was known.

Maya Kaelberer 8:22
Hello. Yeah, my name is Maya Kaelberer. And I’m interested to know, the worm has such a reduced nervous system, I should say, fewer neurons. And in a lot of these models, there’s a lot of redundancy in the system. So at some point, if you were to silence this neuron saying, Go this way, or go or don’t go this way, will you eventually have a different circuit that will pick up that signal?

Dr. Piali Sengupta 8:47
That’s a really good question. And so there’s sort of two short answers to that, that I’ll give. So one of them is that so if you continuously either optogenetically or chemo genetically silence or activate a given neuron, eventually that neuron will stop responding just because it’s sort of adapts to the whole process. Right. But then as soon as you release that inhibition, it’ll actually continue to respond again. Your second question is actually sort of a very deep question is about this whole the small nervous system? And so one, if you don’t mind, if I sort of rephrase it, are there circuits that are sort of dedicated to specific tasks? And then so if you get rid of that circuit, for example, with something else kick in? And that’s a really interesting question, because this sort of is an issue of degeneracy in circuit function, where you can actually have multiple circuit components giving rise to the same output. This has been described in many different small nervous systems, for instance, and in fact, we actually find that so if you get rid of a specific set of neurons, you can have a defect in behavior, but then depending on how long you’ve gotten, so suppose you’ve got like you have genetically a blade a set of neurons, there are behaviors for which a completely different set of neurons will kick in and managed to generate that same behavior. But if you acutely block that specific neuron, genetically or optogenetically, then the second set of neurons, it doesn’t give it enough time to kick in. So there’s actually plenty of degeneracy in the system, which actually gives the system a lot of flexibility in terms of generating behaviors. And it’s a very interesting question that we’re looking at, as well.

Maya Kaelberer 10:24
Can I just follow that up? So that’s so cool. So if you get rid of the neuron, another neuron mites will come in and take its place, do you find that its structure then mimics the structure of the neuron that, you

Dr. Piali Sengupta 10:36
No, when I say another neuron, I actually mean a circuit. And so essentially, another circuit can compensate for it. But the way it compensates for it can be very different from the way the original circuit was actually doing that specific function. We don’t fully understand it, but it’s something that’s starting to come up in a couple of months of different experiments. And so people are starting to look at it.

Maya Kaelberer 10:57
Thank you.

Peter 10:59
That was really fascinating. Yeah, it just made me think of like, we used to use knockout models a ton, we knockout and we assumed that that’s the only thing that happens, and there’s so much compensation that occurs. And there’s so much learning, I guess, if we want to use that term,

Dr. piali sengupta 11:11
what is known about the lineages of some of these glia if they actually are sort of circuit specific, and they come from, like, some common lineage, or they come from completely different ones?

Dr. Brian Gulbransen 11:20
Yeah, that’s a great question, you know, so most of them come from neural crest, and they migrate into the gut along with the neurons. And then there, there are some of these precursor cells that have a glial potential. And there’s, there’s others that have a neuron potential. And then there’s some that have this remaining neuron glia potential, and the has done great work describing this population and how the gut patterns itself with these populations of precursor cells. But some of the really interesting work coming out now is about these schwann cell precursors. And these actually are later population of cells that comes in along these extrinsic nerves and populates the gut. And in some of the models of hirschsprungs, these cells are actually able to repopulate the gut and actually form new new enteric neurons and glia. And since in enterically in schwann cells are so similar, and they’re driven towards a similar phenotype in the same environment, it would be very difficult to tell if some of these cells in the myenteric ganglia are actually derived from the schwann cell precursors as opposed to the neural crest cells that come in early in development. And so I think you may actually have a mix of cells of different lineages possibly.

Peter 12:28
So we have another question from Brad.

Brad 12:31
Hi there. I have a question for Dr. Gulbransen, about what sort of effects you’ve seen with stimulating glia and the effects that it has on motility. And also some of this discussion on the lineage of these cells and Dr. patchiness, his work? Are there any opportunities there to treat some of these motility disorders that we see in the gut? Whether it’s a short term motility disorder, or something that’s more long term genetically linked like Hirschsprung? Or something like that?

Dr. Brian Gulbransen 12:56
Yeah, that’s a great question. I, you know, we definitely hope so something like chronic constipation, we could see where, you know, activating glial cells and potentially eating the activity of these circuits might be beneficial, because that would be a prokinetic at that point. So we would hope that, you know, something like that would come out of this. Mustafa was also working on a project on chronic intestinal pseudo obstruction. And there we’ve been doing some collaboration with Roberta de Georgia we found there is that glial bio lipid signaling is impaired. And that if you blocked by a lipid signaling in mice, it gives you a phenotype where you develop these intestinal obstructions. And so, you know, potentially, by restoring that kind of signaling mechanism and the glia, you might be able to restore some of the function in some some of these severe motility disorders like Cpo. Also, another part of the research in the lab right now is on visceral pain. And so several of the people in the lab […] working on visceral pain. And she has been studying how glial cells potentially ate the visceral nociceptors in the context of inflammation. I think that’s another really promising area where modulating glial cell activity could benefit. visceral pain in people with IBS

Brad 14:08
Vry interesting. Thank you.

Peter 14:09
I was really interested in this, I guess the cross generational learning that we had talked about, this made me think whether or not there would be any sex differences. And we actually have a question from Amy Shephard calling in from Boston.

Amy 14:23
And I think your sex differences, Brian in the responses to the ascending and descending neurons in response to glia are really fascinating. I wondered if you saw any when you were doing your more specific call, no joke and courage. Was that true for both sexes? Or did you see sex differences there as well?

Dr. Brian Gulbransen 14:41
That’s a great question. Thanks. Thanks, Amy. That sex differences I think we’re really interesting because, you know, we started doing these stimulations. We weren’t really sure if we would pick up any sex differences in the circuits because, you know, we’ve never looked at this before. And, you know, we thought maybe organ level maybe, but maybe not the circuit level. Actually.What we saw most of the time was that the populations of neurons and glia, that responded were similar, at least the magnitude of the sizes of the cohorts of cells that responded as seemed like there was similar. So it seemed like the the circuitry was wired in a similar way in males and females. But what we saw in the females was consistently the neurons and glia responded with larger calcium responses to anything, so that the female neurons and glia were just amped up, they responded, much larger than the neurons and glia. In males, that was consistent in all our experiments, whether we were doing a fiber track stimulation, the field stimulation, or with the drugs, the drugs seemed like they affected the males and females in a similar way, you know, altering the cohorts of neurons and glia that responded, but just the magnitudes of those responses were different in the calcium responses.

Amy 15:51
Any idea? Why do you have any favorite?

Dr. Brian Gulbransen 15:54
That’s? That’s a good question. I mean, there are probably many, many things that could cause this, you know, I don’t know if it has something to do with the endoplasmic reticulum being different in females or something about calcium release being different in the females at this point, your guesses is probably as good as mine, or better.

Reem 16:10
As a follow up, does age have an effect on the cells?

Dr. Brian Gulbransen 16:14
Yeah, so actually, it does. So what one of the things we’ve observed with age is that there’s a drop off in these connection 43 channels expressed by the glia, the glia seem like they’re less able to respond and less able to convey that response to the neurons. And so we think that this probably is involved in the slowing of gut motility with age and you lose this potential rating effect of having the glial cells recruited by neurons. And we see similar things when we knock out connexin-43 channels and younger animals as these old animals with lower connexin-43 expression.

Paula 17:05
Hi, I’m Paula also from Duke University. And so since we were speaking about innate and learned responses, so I was just curious is the like, lifespan of these worms, and now for us to study all these differentiators in made and like learned? And how do we do that? Just curious.

Dr. Piali Sengupta 17:23
So the typical lifespan of of wild type C. elegans is about 30 days or so. And in any kind of associative conditioning experiments that people have done, that’s actually very fast. So it only happens, like, you know, takes a couple of hours at most. So whether a young warm and an older worm, if they have sort of different responses to different stimuli, they do. But it I think, in that case, it’s a little bit hard to sort of differentiate between whether that’s been learned over time, or whether they’re age dependent, independent, age dependent, changes in the responses. So I don’t know if I can, I don’t know if I can actually directly answer your question of whether over the lifespan there is learning that’s happening that’s changing that responses later.

Paula 18:09
I see. Thank you.

Peter 18:11
To Brad’s question on, I guess translational impact made me think a lot of times, some of the work that we do feels a little bit removed from the direct clinical effects that we can see. And I was wondering, really taking like a 30,000 foot view. How did you get into studying glia? Brian, and how did you get into studying C. elegans purely and how did you choose to really start on this field of research?

Dr. Brian Gulbransen 18:33
Sure. So I actually started studying the enteric nervous system. When I was an undergraduate at the University of Wyoming, I had gone there. I was interested in wildlife biology, and didn’t know what kind of research I wanted to get into was wandering around the halls and the Waluigi department ran into this lab that had a poster outside that was on the enteric nervous system. And I said, hey, that’s pretty cool. I should go in there and talk to that guy. And so I went in there it was Paul Wade, who now works at Takeda. He gave me a job in there doing some research and I studied aging in the gut as an undergrad, then as a graduate student, I wanted to see what else was out there. So I studied chemo reception in the nasal cavity. But it was also communication between non neuronal cells and neurons in the periphery. I knew after doing my PhD work that I wanted to get back into doing in tech neuroscience. And I had also had this experience with signaling between non neuronal cells and neurons. And so I had talked to Keith Sharkey, and he was doing some work on enteric glia, and was interested in glia to neuron signaling and, you know, communication between neurons and glia. As I said, that’s a great fit and what they’re for my postdoc loved it, and just kind of stuck with it from from then on.

Dr. Piali Sengupta 19:38
For me, I mean, as you mentioned, I was a as a graduate student, I also worked on pheromone signaling and yeast, and it sort of became really interested in seeing how animals respond so precisely to their environment. And then, you know, use doesn’t have a nervous system. So as a postdoc, I wanted to find an organism where I could really connect specific genes to behavior.And I think this is something like C. elegans flies, I mean, mouse. Now, of course, also, I guess, absolutely, I still find it absolutely amazing that you can mutate a single gene and see this amazingly dramatic effect on behavior. And then especially in worms, you can, you can actually follow it all the way from the effect of the gene on a specific neuron through the circuit all the way to exactly how the behavior is being altered. And that just even after three decades of this never ceases to amaze me. That’s, I think there’s so much to learn. Just it’s I think it’s a really exciting area. So both of you really study a very interesting area.

Reem 20:37
Not only this, I can see that you have really interesting lab websites. So how did you determine what to publish on your website? Why did you choose to have these illustration in your websites? And why did you choose to put these things and these lab websites?

Dr. Piali Sengupta 20:54
Yeah, so my website is actually set up by a graduate student in the lab, Lauren Tresco, who is went around the lab, and I think just chose the most beautiful pictures that she could find. So I think a lot of the appeal of a website, of course, is the visual appeal, the part of my lab that I didn’t talk about the cellular biology part, they generate a lot of very beautiful pictures. And so I don’t think this was a particularly reasoned decision. I mean, I had a little bit of input, but I basically let them design the website on their own.

Dr. Brian Gulbransen 21:25
Yeah, I kind of did the same thing I you know, I’m sure mine is very outdated at this point, I need to update it, because I’m the one that’s maintaining it. And I usually get around to doing that maybe once a year. So I should probably update it. But I did the same thing and shows, you know, some nice images, some some videos and things that would be kind of eye catching. And then just basically bullet point types of information of what we do. And who’s here.

Peter 21:48
Just as a quick follow up, I thought it was really neat. I was taking a look on your website, Brian, I don’t know if a lot of labs really published, I guess, the methodological detail, and you have like methods for each one of the protocols out there. And then I think, Piali, I thought it was really neat that you have like this section on lab values, and core values in your laboratory. And what was the motivation behind putting this information out there? And why did you feel it was important to share?

Dr. Brian Gulbransen 22:13
It’s, you know, in the efforts to be more transparent, and to have data be more reproducible. I mean, we’ve been trying to publish more than methods, get more of that out there. Eventually, we want to be able to have a part of the labs website actually devoted to a lot of the transcriptomics work that we’re doing right now, and have searchable databases on there. So we can have some of these glial databases all together. So it would be a tool for the community, you know, we don’t want to be operating in a vacuum and kind of with this in this black box, we want to let people know what we’re doing. So they can trust the data. And if other people want to repeat the experiments, they can do it exactly how we did it.

Dr. Piali Sengupta 22:48
So that’s actually that’s really great. I think that I should, we should look into doing that as well. I mean, we tend to actually, for some of the journals, if they allow it, we do tend to upload our Excel spreadsheet, which has all the raw data for every single figure that we’ve generated. But to put in the details of the protocols are actually on the website is a really good idea. I mean, in terms of the core values for my lab, I mean, so like many of your labs, my lab is fairly diverse. I have people from all over the world, from very different backgrounds. And I, myself am an immigrant, I came to this country when I was 18. And so I think it’s really important for me to specify upfront, what are the things that I value, and what I hope that my lab will have in terms of respecting everyone’s opinions, respecting their the diversity and having this having sort of shared values of collaboration, of interaction, and also, very importantly, the scientific ethics. And I think I wanted to just put it up there so that it’s just very obvious to anyone who’s interested in joining my lab. And it’s a conversation that I also have with individuals as well as a group.

Reem 23:59
They’re interesting. I see science, communication nowadays is a very important aspect of science. Because when we communicate science in a better way, we can have science spread all around the world. So thank you so much, both of you for joining us.

Dr. piali sengupta 24:16
Thank you so very much. This was super fun. Thanks for inviting me.

Dr. Brian Gulbransen 24:19
Yeah, thank you so much for the opportunity to share some of our work is this is great.

Peter 24:23
Yeah. Thank you so much.

Reem 24:35
Thank you all for listening, and we’ll see you on the next episode. For more of our content, you can follow us on Twitter at the gut brain matters, or visit our website thinkgastronauts.com. The gastronauts podcast would be impossible without our incredible team. Meredith Schmehl, our producer and theme music composer and a special thanks to the founder of Gastronauts Dr. Diego Gohorquez and the Bohorquez laboratory

Apr 2021 – David Virshup & Judith Eisen

On Stem Cells and Neurodevelopment In the Gut

Dr. David Virshup is the director of the Programme of Cancer and Stem Cell Biology at Duke-NUS Medical School as well as a professor of pediatrics at Duke University. He Received his MD from Johns Hopkins, followed by a residency in Pediatrics and a fellowship in Pediatric Hematology/Oncology. He established his independent laboratory at the University of Utah, where he was an endowed chair at the Huntsman Cancer Institute. In 2007, he moved to Duke-NUS in Singapore to help establish the Cancer and Stem Cell Biology programme. He is Elected to the: American Association for the Advancement of Science and the Association of American Physicians. His research focused on signal transduction, with an emphasis on both Wnt signaling and circadian rhythms, and his laboratory has collaborated to develop a small molecule inhibitor of Wnt secretion that is now being tested in human clinical trials.

Dr. Judith Eisen is a Professor in the Institute of Neuroscience at the University of Oregon. She completed her PhD in neurobiology from Brandeis University where she worked  in the lab of Eve Marder, where she studied circuit neuromodulation in the stomatogastric ganglion. She later joined the laboratory of Dr. Monte Westerfield at the University of Oregon as his first post-doc, where she developed methods to label and track individual neuron progenitors in the zebrafish. She then was hired by the University of Oregon as faculty, and her lab has been focused on studying how neuronal diversity is generating during development, how these neuronal circuits are wired up and how host-associated microbiota and immune systems work together to influence the development of the nervous system. Dr. Eisen has authored over 150 publications, has been awarded the Gugenhein Memorial Foundation Fellowship, and is both a fellow of the Association for the Advancement of Science and the American Academy of the Arts & Sciences. 

Mar 2021 – Lori Zeltser & Alexandre Caron

The Chilling Side of Hunger

Dr. Zeltser is an Associate Professor in the Naomi Berrie Diabetes Center and the Department of Pathology and Cell Biology at Columbia University. she graduated from Princeton University and received her Ph.D. from The Rockefeller University. She continued her research training in developmental neurobiology and did her postdoctoral fellowship in the laboratories of Andrew Lumsden at Kings College London and Claudio Stern and Thomas Jessell at Columbia University. Currently, Her laboratory studies developmental influences on the formation and function of neuronal circuits regulating food intake and body weight, they explore how developmental influences exert lasting impacts on body weight regulation. 

Dr. Caron is an Assistant Professor at Laval University. He completed his PhD at Laval University with Drs. Denis Richard & Dr. Mathieu Laplante where he studied how an mTOR interacfting protein was involved in energy balance. He completed his post-doc at UTSW with Dr. Joel Elmquist, where he focused his efforts into studying how leptin is produced and where it functions through pharmacogenetics and transgenic approaches. His lab’s current goals are to understand the mechanisms by which the brain controls energy metabolism and develop pharmacological strategies to treat metabolic diseases and disorders.

Feb 2021 – Nicholas Betley & Daniel Drucker

Sensing Nutrients, Secreting Peptides

Dr. Betley received his Ph.D.,from  Columbia University, in 2010, where he worked with Thomas Jessell and investigated the developmental programs that determine synaptic partners during circuit formation. For his post doc he worked in Janelia Research Campus with Scott Sternson where they examined the structure and function of neural circuits that influence feeding behaviors.currently he is an Assistant Professor of Biology at the University of Pennsylvania. His lab is interested in understanding how the brain processes information from the external world to facilitate appropriate behavioral responses that are necessary for survival. 

Dr. Drucker is an Endocrinologist and Professor of Medicine in the Division of Endocrinology at the University or Toronto. He was trained in Internal Medicine and Endocrinology at the Johns Hopkins Hospital in Baltimore and the Toronto General Hospital, University of Toronto and completed a research fellowship in Molecular Endocrinology (1984-87) at the Massachusetts General Hospital. He has conducted pioneering work that has furthered our understanding of glucagon and GLP-1 and has authored several hundred publications, and issued 33 US patents covering various novel therapeutic aspects of peptide hormone action.

Episode 18: Our Greatest Challenge

Peter 0:13
Hi, and welcome back to the Gastronauts Podcast. My name is Peter and I’ll be your host. As many of you know, here at Gastronauts, we are committed to exploring communication throughout the body, with a particular focus on the crosstalk between gut and brain. We invite speakers across the globe to share both their research and their life journeys. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts Podcast.

Today, we have a panel of four incredible rising stars in their respective fields. Dr. Kara Marshall is a postdoctoral fellow at Scripps Research in San Diego, California. She studies the nerves that control our bladder. And recently she found out that Piezo2, a molecular channel that senses mechanical forces, in fact works to control our peeing.

Dr. Kara Marshall 1:23
Thanks.

Peter 1:24
Dr. Dafni Hadjieconomou is a postdoctoral fellow at the Imperial College of London. She studies how neural circuits in the gut of a fly, or these enteric neurons, are altered during pregnancy. And she has found that these enteric neurons are key to increasing food intake of the mother and enhancing reproductive success.

Dr. Dafni Hadjieconomou 1:45
Thank you.

Peter 1:46
Dr. Marcelo Zimmer is a postdoctoral fellow at Yale and the Federal University of Rio. He studies how certain neurons in the brain of a neonatal mouse respond to maternal separation. Activation of these neurons induces ultrasonic vocalizations or USVs to encourage the mother to return to the pup, so she can continue providing care.

Dr. Marcelo Zimmer 2:08
Thank you.

Peter 2:09
And lastly, Dr. Yuuki Obata, is a postdoctoral fellow at the Crick Institute of London. He studies how bacteria in our gut talk to neurons in our gut to change intestinal motility and control the rate at which food moves through our intestinal tract.

Dr. Yuuki Obata 2:25
Thank you.

Peter 2:26
Science is a global endeavor, and we can tell from this conference with people calling in from all over the world. It’s really great seeing so many excited and engaged scientists, but it has to start small- from the groups with the people that you work with, with the mentorship that you provide different people who are just, you know, trying their first time in science. Now that you all are transitioning from the postdoc to perhaps an independent investigator, what mentoring principles Do you guys hold? Or what are you looking for in a trainee?

Dr. Kara Marshall 2:56
I mean, I’ll start I mean, I’m not a PI yet. But I actually think about it a lot. Because this is the huge jump that we have to make, right? We go from being bench scientists to all of a sudden being mentors, and it’s a completely different job. So I think about it a lot now to be like, how can I prepare and do a good job. And I think that one of the things that I’ve learned the most is that, you know, just like anything else, it is a skill. And unfortunately, I think a lot of people don’t consider that as you know, a skill that they can build and should try to build. And like, there is known information out there about how to be a good manager, and scientists are not concerned with that, right? Because we’re all excited about the science. And so we all focus on just like let’s get the science done. But um, yeah, as a PI, like, you have to manage people, that’s kind of your number one job. And so I think that, you know, I was talking to someone not too long ago about how she actually just hired someone in the business world to teach her how to hire people, and how to manage people, because it’s like, these are not unknown things, and scientists just kind of like, wing it, you know, and ends up being it ends up making for really, sometimes unprofessional environments, and then also environments where really, people aren’t doing their best science because they don’t feel like they’re being managed appropriately. And so I don’t know, I guess just having a growth mindset. That’s kind of cheesy, but it’s true, right? Like, you can learn these things like there’s, you know, data out there. And so trying to actually just learn the skills that are needed to manage people, I think, and just listening to people and actually really listening to what each individual needs and not just trying to one, one fits all solution. That’s my goal.

Dr. Dafni Hadjieconomou 4:29
Yeah, I would really also second that, I guess, for me, with a little bit of mentorship that I have given and what I have experienced, I think this the you should never think that one fits all is the take home message for me. You know, because I have also tried to be the mentor I wanted but this doesn’t always work. So I guess it’s going to be a lot of trial and error and there will be biases, you know, for for the mentor you wanted to have always or you had and you really loved or you had an you really hated. And I guess this is why what you’re saying care there is is important, perhaps we have to really work on this as a muscle that has to grow actively. And I guess also, again, get information as we do with everything else get information from people that have done it a while back. And we respect for instance, I guess this is how I plan to do it.

Dr. Marcelo Zimmer 5:25
Yeah, I definitely agree with Dafni, I think we need to learn from people who are already in the lab mentoring people, because as Kara said, we don’t know how to manage people, and then we suddenly we are being mentored to mentor people. So it’s a rapid transition. As a mentor, if I’ll be a mentor, one day, I’ll try to use my experience during my PhD, to do the same that I that I received while I was a practitioner to the students. And I think one of the best ways to do science is being always highly motivated. You need to motivate your students, we know that motivation plays a critical role in continuing science, because we’re going to fail all the time, failure will be a part of the process during our studies. So I think having a highly motivated mentor, they allow us to do anything that you wanted. I think that is the key, in my opinion.

Dr. Yuuki Obata 6:18
Yeah, I think I was very lucky to have great mentors. So what I learn from them in my future career. And also I have experience to teach some students in the lab, and they’re also great, and they really like science and think about trying to addressing the question not just for the job. So then the very good relationship was built. So yeah, that’s I think that depends on the motivation, the science and yeah.

Peter 7:02
We have a question from Lihua.

Audience 7:04
Dr. Zimmer, my question is: early life isolation that used in your model, your mouse model have been known to induce irritable bowel syndrome in the mouse. I’m just conscious curious, like, whether you finding has anything that related to the symptoms that developed in mouse models later in their life, like, increase of visceral sensitivity, and difference in the enteric motility and whether you’re finding will have anything connection to that

Dr. Marcelo Zimmer 7:39
Thanks for the great question. It’s something that people usually ask for us, if you follow the facts of the material separation later in life, and we never follow actually. So I don’t know. I don’t know if they actually they could be contributing for the development of the irritable bowel syndrome, but it’s definitely like at a very important question to try to evaluate the future for sure. Thanks for the question.

Peter 8:04
Next, we have Julia Davis.

Audience 8:06
I’m calling him from Boston. And I just had kind of like a more general question. Earlier this week, I was just looking at some literature and kind of like the gut brain axis and its relationship with neuro-inflammation. And I was wondering, like, if any of you kind of have thoughts on that, or like the mechanisms for how that might influence other disorders like delirium, or Alzheimer’s disease, which are often linked to neuro inflammation, and just kind of like, if you think that there is kind of value in going down that path, and seeing if there’s the microbiome does can play a role in our understanding of those diseases that are still kind of a little bit unclear.

Dr. Dafni Hadjieconomou 8:41
I think it’s pretty exciting. And I guess we don’t have the tools perhaps, or the understanding yet on how this works exactly. But, you know, and this is what I sort of wanted to put out there with my introductory bit that is so complicated, because we just beginning to understand that this microbiome does a lot of very different things. And, you know, Yuuki presented one of these aspects, but I guess it’s out there that this is all regulated and there is a link for sure with with the brain, and then all of these disorders could be coming from the microbiome, and then they are linked directly to the brain or their local inflammation in the gut that then link looks back to the brain. And I guess all of them could have a little bit of that. And something we don’t quite understand yet. But sure, sure. Is it an exciting way forward to think about that?

Audience 9:43
Hey, everyone, my name is Maya Kaelberer. I’m at Duke University. So my question is actually for Dafni, and Yuuki: how’s the microbiome changing during pregnancy? And is it known if these changes are actually affected some of the food intake right so I’m assuming that pregnancy does a lot to the body. I’m just wondering does it change the microbiome? And can you actually change your food intake that way?

Dr. Dafni Hadjieconomou 10:06
Thank you. I think I’m gonna let Yuuki go first. I’m not a microbiome expert.

Dr. Yuuki Obata 10:13
I’m not sure about this. And we know maternal microbiota is very important for the development of the immune system and nervous system have in the offspring animal. But in this case, I’m not sure how pregnancy affected it. I can imagine there are many changes to hormonal change can affect the microbiome, but I don’t know.

Dr. Dafni Hadjieconomou 10:33
And if we take it back to the fly, I guess there there are differences in general, with the microbiome and the colonization, and so on, as surely when flies lay eggs, they do also lay a bit of anti-microbials. So there might be changes. Sure. We don’t know if these do affect the way the flies eat? Not to my knowledge. I don’t know that. But yeah, very interesting question, Maya, for sure.

Peter 11:08
Yeah, I think it’s a really great question. And it made me think of, I guess, technological developments, and how we think about technology changing over time, and a lot of our studies are done really at a specific time point, or at a specific location, right? How do you expect your findings to translate across time or at different stages during development? I think each one of our talks today had a little bit of this theme, right? With Marcelo’s Agrp neurons having a different function early on in life. Dafni during reproduction, you have, you know, this innervation that has a differential effect. And Kara, right, when you mentioned, specifically like these Piezo2 neurons and piezo and urinary issues happened primarily when we’re older. So I was curious as to, just to reiterate, like how you expect the findings that you have to translate across different times? Or is this something that you’re interested in moving forward?

Dr. Dafni Hadjieconomou 11:57
Yeah, absolutely. I think, you know, this audience is already already unique, that, you know, we do think of other bits of the other organs, not only one, like people normally really focus on one neuron in the brain or one year, in their favorite place, or, and here, we’re talking about inter organ signaling. But I think also, yes, absolutely. For me, the timing is a very important element, because we you look at this ms neuron that I described, and it’s very different after mating, animated female. And I have also seen that it’s, it’s quite different after different food in food to being presented with different dietary challenges, let’s say. So this is also what I plan to do, I plan to see what happens in different challenges internally, but also in different times. So developmental is one thing, and how that shapes its function in the adult, for instance, because now what I presented, you were specifically adult neurons, right, that were manipulated for a few hours in the adult body. And that’s the beauty again, of the fly. But you can do the manipulation the other way around and look later on what happens. So for me, absolutely.

Dr. Marcelo Zimmer 13:14
I think that one of the biggest reasons that I’m doing this research in infants is trying to understand how the new secrets which neural secrets involve, and which neural secrets regulating behavior, because what we know from the literature is that any type of early life stress in an infant, and we’re talking about many types of mammals, including humans, leads to long term consequences. So if you at least start to tracking which are the newest they are, they are sensitive, when the animals are isolated with animals are exposed by like stress, we can actually benefit us understand if the neighbors were involved in this long term consequences that we see when we isolate all the animal is exposed to like stress.

Dr. Yuuki Obata 13:58
Yes, time is a very important factor for for our system as well. Actually, we are recently interested in the effects of the time of the day in the in the physiology of the enteric nervous system. As you can imagine, it’s it has a circadian rhythm in the activity of chronic peristalsis. And also, the number and composition of microbiota shows circadian rhythm as well. So we we are actually interested in how changing their time affect the physiology. Of course, we also are interested in the developmental time period or embryonic stage. This is a very important topic to study.

Dr. Kara Marshall 14:44
Yeah, I kind of touched on it. I totally agree that given the role of aging and kind of how aging ends up corresponding with a lot of issues in the urinary tract, it’ll be interesting to see how these circuits change how the sensors change, and then Development here. I mean, both sides of the equation are really fascinating.

Audience 15:02
Hi, hello, I’m Elaine Snell, I’m from London, does Piezo2 naturally diminish with age? And in which case, does that explain the high rate of urinary dysfunction in people of an older age group? And would that be or is it already a target for for treatment or strategy for treatment to kind of replace that if that’s possible?

Dr. Kara Marshall 15:25
Excellent question. And it’s something that I can’t answer directly, because we don’t know if the protein expression changes during age in the system. But I’ll answer it from the perspective of what we know about the skin because we know a lot more about touch receptors in the skin, which are also mechano-sensitive. And we do know that with age people do lose these sensory neurons. So your innervation, density goes down, and you become less touch sensitive. And so it’s very possible that this happens internally as well. And again, I think that this is an entire area that could be really interesting to understand how internal innovation changes with age, and maybe it’s diminished in the same way that our skin innovation has diminished. And all of the sequela that come after that, right? You know, neuropathy, diabetic neuropathy, which of course, diabetes is very common, and that leads to degeneration of some of these, some of these innervation. And it could have, you know, similar effects in the skin as it does inside, so you might get all of the reflexes, all of the sensing, if that’s gone, you know, that could absolutely cause dysfunction. And so I don’t know yet, but there’s definitely a precedent for that in other organs. So it’d be interesting to see. And then as far as therapeutics, you know, I’m a big believer and understanding the basic science and molecules of how things work, give us targets. Right now, we don’t have good pharmacological tools to target this ion channel, in particular. It’s proving to be actually quite difficult, because unlike a lot of other ion channels, these respond to tension in the membrane. And so how do you make a drug that targets that- it’s not clear that we’re going to have great like a lock and key mechanism where we can get something to bind. And so that hasn’t been very easy to find so far. In the future, though, it would be wonderful if it could, because I sort of touched on in the beginning that this, this protein is involved in so many different sensory functions. And so it would be great to have a pharmacological tool. But you know, if not pharmacological, you know, maybe there’ll be something else, some sort of genetic tool, or even estimate stimulation protocols, or something that we could do to help in the future. It’d be really interesting.

Peter 17:21
Next, we have a question from Valentina.

Audience 17:24
I’m calling in from Boston. And I have a question for Kara. I was wondering if you looked at the role of sex hormones in your model. And if you think, or if you observed any differences in your knockouts between males and females. I guess I’m just wondering if sex hormones might potentially regulate Piezo2 and these different patterns for urination?

Dr. Kara Marshall 17:47
Yeah, that’s interesting. So I haven’t looked at this at all. But it’s an interesting question, because we do know that some of these lower urinary tract pathologies are very different between men and women in terms of what kinds of pathologies they get, and how they manifest. And part of this is simply anatomical, males have much longer urethra. So they’re less prone to say UTIs but then there are other problems that come with having a prostate. And so part of these anatomical differences kind of designate what the pathologies are later in life. So I haven’t looked at sex hormones in particular, but it’s also possible that kind of overlaid on top of the anatomy has some role. But I don’t know the answer to that yet. I will say that I did do full cohorts of males and females in all of my studies. And to the extent to which the responses are slightly different because of the anatomy. All of the other phenotypes were exactly the same. So I saw the same deficits in males and females, they saw the same remodeling. But again, you know, males, because they have, especially in mice, their ureters are so small and so long, that the coordination is particularly important for them to go. So I think the remodeling was maybe worse for them. But overall, it seemed like the result was the same in males and females. Thanks for the question.

Peter 18:57
Yeah, that’s interesting, this sex difference question reminded me of some of the things that Dafni talked about with the MS neurons. And I was wondering, do the sensory neurons of urinary control change during pregnancy? Like what are the parallels between the enteric nervous system and the bladder?

Dr. Kara Marshall 19:11
Yeah, I’d say that it’s all open. You know, I don’t know, I hadn’t really considered looking during pregnancy. But of course, that is a- that is a time of like, massive change. So it’d be interesting to know if some of the innovation changes to I don’t know.

Dr. Dafni Hadjieconomou 19:25
Yeah, I don’t know. This is why I thought, you know, it would be very interesting to see if the neurons change or the epithelium changes with both of them, and what happens at the molecular level, because, you know, somehow this body needs to cope. it undergoes under increasing pressure. And I guess in the mouse model, you might have more or less pups, and that also might change. So I think it’s very exciting to just have a look. Yeah, and I would imagine that there are changes, but then yeah.

Dr. Kara Marshall 19:59
I also wonder how different it is between mice and humans, given that humans are upright, and so much of that gravitational pull has a huge effect. And in mice, I wonder if I’m being this direction means that that is different. And you know, the the two horn of the uterus, maybe they actually are spared some of the issues that humans go through. I don’t know, though, be interesting to find out.

Peter 20:21
This is really interesting. Moving on, we have another question for Dafni. So the fly mid gut is like the primary site for food digestion & absorption, what is known about neuronal innervation in the fly mid gut? How are the enteric neurons affecting intestinal motility? absorption?

Dr. Dafni Hadjieconomou 20:40
Yeah, thank you. So not a lot was known. And the truth is that not a lot is known. So in fact, Irine’s lab really did bring home this. So she was one of the founders, I guess, in it, and there are enteric neurons and the fly. And the paper, the first paper of the lab described some of this innovation in our paper, the recent paper also gives a bit more information about the integration of the medical and especially the anteromedial, which is, I guess the question goes for that, where a lot of the digestion is happening now for the function. So we do know, for specific lineages, some of the aspects of the function that do go to the mid gut, and the neurons that I talked about today go to the mid gut, as well as the crop. And now for peristalsis, for the midgut. Specifically, I guess we don’t know exactly how they. So their motor, so the motor output is for specific types of neurons. If you talk completely paralyzed, of course, the gut. Yeah, there is a problem. But it’s just the beginning of this. So similar to the mammalian lineages, we did not we didn’t know so much about them, I guess, what is nice is that we can manipulate small subsystems of them and uncover what their function is.

Peter 22:05
Great- I actually had like a relatively broad question for all of you is really interesting seeing the different model systems that you all use. Marcelo, you mentioned that you’re planning to do some future work in guinea pigs, Dafni, you’ve been working flies; Kara, you’ve done some human studies, and Yuuki, you’re doing work in a nice. So I was wondering, how do you choose which animal system to use? And then in your future work do you plan on continuing to use the same animal models? Are you planning to diversify what systems you’re going to be studying?

Dr. Kara Marshall 22:32
I will say that it was actually a really fortunate thing that we were able to include the humans in the study with the mechanistic mouse models. And I think there was a bit of luck there, I mean, to have this group of patients was, we were incredibly fortunate because of course, you don’t always get that with any particular gene that you’re studying. So I would love to do more of that in the future. But I think it it sort of depends on, you know, wonderful collaborators, being open to open to working with us. And I think that that’s a general lesson in science, that if people are open to collaborating, especially across disciplines, like with clinicians, because of course, the science is very different, that the story becomes so much stronger. And so I mean, I would love it, if that could happen in the future again.

Dr. Dafni Hadjieconomou 23:13
I do plan to work on flies and, and actually collaborate or anything else. So my drive is really coming from basic discovery in basic science. So I think the fly is a powerful model for understanding genetics, and really basic mechanisms. And then the conservation of this, you know, other people that I can collaborate with can do in, in higher mammalian systems, let’s say that being the mouse or humans, for instance, I will be very excited to work with people along along the way. But my drive is really this basic mechanisms, and I plan to work on flies for the rest of it.

Dr. Marcelo Zimmer 23:57
I think, really the purpose of our long term goals. But I think as a scientist, we always try to contribute to the well being of the human being and to humans. But the reason I choose to move towards minipigs is that I’m really interested interested in the infant’s perspective of interaction with the mother. Whereas we know a lot of researchers in a lot of studies doing the maternal behavior in mice, right. So we don’t know much about how the infant’s they communicate how they how they interact the mother, most likely most because these infants they are born in a three show state, so they are really mature. So we cannot really evaluate the behavior of the infants during this first few days of life. Whereas the green epic the infant is born in precocious states, so the animals are much more active, much more mature. So using this animal model, I think we are able to at least understand better when do me think about your secrets that are involved in the infant direction to the mother.

Dr. Yuuki Obata 24:57
So for me, the reason I’m here using the mouse, so it’s just it’s very, very well organized, it’s very established model. But I’m also interested in the other other models, including a human, or even Hydra they, or zebrafish, because each each model has on advantage and disadvantage, a bad combination these studies helps us to understand different aspects of physiology by using different techniques.

Peter 25:28
Yeah, it’s really great to hear all of your perspectives on the pros and cons of different model systems, how sometimes it’s due to collaboration has sometimes it’s due to chance.

Audience 25:38
Hello, I’m yeah, I’m Alistair McDonald. And I’m calling from Exeter in the UK. And my question is for Dr. Marshall, I’m interested to know how much of the Piezo2 pressure sensing is, is mediating intrinsic kind of bladder or spinal to bladder versus integrating top down control from the brain. So you have some looks like full urination in the middle of the cage. So maybe properly initiated, but just at the wrong point, how much of that sensory detection is useful for the brain?

Dr. Kara Marshall 26:09
Yeah, so all of the functions I was showing with regard to cystometry and the urethral reflexes, these would be spinal reflexes, right? So these are mediated by spinal pathways. And, you know, we think the sensory neurons, of course, are directly conveying information, the bladder goes to the urethra, and the urethra actually goes to the bladder. So you know, you want when your bladder is ready to contract, you want it to contract against a relaxed urethra. And then similarly, when your rethrow has fluid flow go through, it sends signals back to increase bladder contraction. So these kind of are classical reflexes that have been defined for a while. So we think that definitely Piezo2 sensory neurons are mediating the initiation of these reflexes. But we haven’t looked at all as to you know, how this sensory information is integrated in Barrington’s nucleus, which is the nucleus that controls top down urination. And I’m so glad you brought it up, because it is really important. And in fact, people who study urination, primarily study these brain mechanisms that are critical for release of urination and of course, in humans and other animals. We have tight control over this and we don’t, you know, we only are supposed to go at appropriate times. And this is very important. And so I don’t know yet how Barrington’s integrates this information, but certainly it must right it It knows when your bladders full, and otherwise you don’t have that kind of urge. So yeah, I think it’d be really interesting to understand in the future, what those neurons are sensing.

Peter 27:51
We have a question from Jorge Villalobos.

Audience 27:54
Hey, I’m Jorge. I’m calling from Duke University. And I have a question for Dr. Zimmer. So Dr. Zimmer, what would happen if you play a recording of ultrasonic vocalizations on one side, then if you have a pup on the other side, would the ultrasonic vocalization would be like a stronger stimuli for the dam to prefer that side? Or would the olfactory cues from the pump would be a stronger signal and then the mother would go to the other side?

Dr. Marcelo Zimmer 28:23
Yeah, that’s a great question. We’ve never done this type of experiment, we try to evaluate whether only playing record user playback system in which we would play the record off of error mode in which we activate the newest compared to animal that is a control animal to see the model prefer one side over the other. And we are not capable of having like a final result, we realize that odor cues are super important. So not only visual cues, because once the mother realizes there is no neonates that are there she stopped, she stopped directing, but there are so we never done that. But if I have to guess I would say the daughter queues and this stage, they will play a higher role will be more important for a preference of the monitors, either the odor queues or the auditory cues.

Peter 29:14
Thank you. And we have another question from Amy Shepard.

Audience 29:18
Yeah, hi, I’m calling from Boston. And my question is for doctors around the USVs. I was wondering if not only does the number of calls change, but just the quality or complexity of those calls change. I’m only really familiar about USVs in adults, which I know have, you know, like a lot of variation. I wonder if you looked at that and those parts as well.

Dr. Marcelo Zimmer 29:38
That is a great question. Yes, we look at and indeed change change the part of the cause the animals they elicit different types of syllables. So in neonates, the list of 11 types of syllables that we know and when we quantify the number of vocalizations, in which syllables we find their activation of these neurons, the indeed increase some of the syllables One that we found was a channel was it was a charity organization. So we are trying to identify whether this has any meaning for the mother and look and talk about the spectral temporal features of the vocalizations, it does have a decrease in the duration, it seems to lead to change the new frequency distribution. So, yes, there’s a change.

Peter 30:20
Thanks for the question on communication, like USVs are ways neonates communicate, and I was wondering, you know, broadly about communication. We don’t communicate with USVs. So I was wondering, how do you think about communicating your work to fields very disparate from your own? How do you think about communicating to form collaborations and communication in general to inform the general public?

Dr. Marcelo Zimmer 30:42
Yeah, that’s not an easy question. What we can try to communicate the general public is that we see the vocalizations of the infants as a form of crying of the animals. So the way that we try to communicate that we are trying to identify one of the most innate behavior that we see not only in mice, but also in humans, which is a crying behavior. So this is the way that we try to communicate for general public our findings.

Dr. Kara Marshall 31:07
It’s kind of weird to study your nation. And I think as a neuroscientist when people say, Oh, you do neuroscience, what do you study? It’s, it’s something that kind of takes people back when you’re like, oh, urination. And it’s because I think societally, it’s not something people talk about, like when again, I was really stunned by the epidemiology. And you can pretty much bet if you’re talking to an older person, they’ve had some issue with their urinary tract. And so I think it’s actually, it’s been really neat to see that by studying these kind of basic functions, it opens the public up to talk about things that maybe they wouldn’t normally talk about, or even honestly, for adults to know that they’re not alone, that this is actually really common, and that they should seek out help for some of these issues, when you know, it’s sort of not not discussed very often. So I would say that, in some ways, urination is great and easy, because everyone does it and really connects to it because it’s a normal part of their lives, and lots of things go wrong. But on the broader scale, I think, for so long, especially in touch research, and like doing very basic science research about ion channels and stuff, it felt disconnected from the public. And I think that what’s been nice is kind of being able to really teach people the importance of just basic science. And I’m sure Dafni has strong feelings about this working in flies, because, I mean, I see the gorgeous, like, whole gut images, like there’s so much you can do in flies. And I think that, you know, conveying to the public that like figuring out these really fundamental questions, like answering fundamental questions is just about, like, how does this system work, even if it’s in, you know, a simpler model organism or something is really just like an important foundation. And I think that it is so critical to convey to the public, like basic science research is how we get to this translational stuff. And, you know, you don’t always know where that will come from. So you have to have a really broad foundation of basic science research in flies, and then, you know, mice.

Dr. Dafni Hadjieconomou 32:59
I do feel like that. And I think, just being in the business for a bit longer, you just sort of know, to filter down the information that you give to people, you know, people just ask yourself, what, what excites you and what are you working on? And you can start by saying, Hey, you know, I worked to understand how the brain works. And so you know, of course, everybody’s kind of interested in the brain. And then people are interested to find out that their neurons in your gut, which you know, and it’s a surprise to a lot of people still and I guess, then if you talk to them and bring it home, that if something doesn’t go really well, with that, you you might have an eating disorder, let’s say so I think you always have to link things, as Kara said, as, for instance, with the older people with something they have experienced and remove the jargon as much as possible. It’s not very easy. I think, if you just get better with the more you do it.

Dr. Yuuki Obata 33:55
Yeah, this is very difficult. But yeah, very important to communicate with the public. So in my experience, I have contributed to make a documentary film about gut physiology in collaboration with TV programs. So they they’re professionals. So we don’t we just provided the concept and the beautiful image of the gut. So that was, that did work very well, in terms of the delivering the message to many people.

Peter 34:24
Just speaking of like, things in the public. One of the things really just coming up to public perception now is the importance of science with the global pandemic that we’re having and coronavirus. What do you think the biggest hurdle or issue that our generation of scientists is up against?

Dr. Marcelo Zimmer 34:41
So I think we are not trained to communicate, so we don’t know how to communicate why we’re doing so that’s why I think we have this, this, this difficulty to talk to people. I mean, we don’t have any training to communicate what we’re doing to show the importance of why we’re doing. I would say for you Peter, it really depends well where you are as well, because I can I can say right now we have the opposite. People still don’t believe in science even more right now, because we have people that don’t think the vaccine is like this the cure for the COVID. So we have two problems in my vision, the first that we don’t know how to communicate. And there’s also political views about science, depending on the country, where you are.

Dr. Kara Marshall 35:20
Yeah, I agree. I mean, I’d say that I feel like in the US, politicians have been pretty good about like, continuing to fund the NIH, for example, even though there might be anti-science rhetoric in general, they kind of come through with some funding. But we need to be better not only about communicating the excitement of science, but just like how beneficial it is, like, I think these advances are so slow, you know, what’s coming on the market now might have been researched 10 years ago, or 15 years ago. And so it’s hard for a person and this is especially true in the private sector to look at this and say, Oh, you know, what you’re doing now is going to definitely economically benefit me and benefit humans. And so I think like, having a better narrative around these processes, and how they are slow, and it takes kind of people coming at questions from all different angles, which takes a lot of money. And I think that showing people that output and like the Human Genome Project was this moonshot. And it was it worked. And it actually like, has generated so much value, not only economically, but also just for knowledges sake, I don’t know, I think there’s like the two pronged argument could be made. So maybe scientists need to be better about communicating that.

Dr. Dafni Hadjieconomou 36:27
Yeah, absolutely. I think, you know, communication is a big thing. But I guess we’re also facing, perhaps an economic crisis I had, and that is going to impact science for sure. Across the board, so some countries will be more or less affected, I guess. So I guess this is where somehow we have to come together. And for more collaborations, perhaps and, and, you know, perhaps think of different ways of doing science, which is very hard, because careers are, you know, need to still be shaped. And it’s a it’s a hard one. But I guess you know, our generation could be perhaps more open. I don’t know, it’s a hard one. I think if I have to just find one that is going to be the most difficult hurdle to overcome. For our generation of scientists, I guess we are quite a lot at the moment, and very excited and the funds are might run thin for a wide base, I mean, or not, we’ll see.

Dr. Kara Marshall 37:27
I was just noticing someone asked about diversity and inclusion. And I was gonna say that one of the plans or hopes that I have in the future is, you know, of course, to have a really inclusive and diverse environment. But I think one of the ways to do this is really make sure that a broad range of undergrads get a chance to be in love. Because I think that’s the time at which most of us get our first experience with research. Like, I didn’t know anything about being a scientist, when I was an undergrad. I mean, I liked science. But I think that just making sure that a broad range of undergraduates that you know, may or may not have been exposed to science at all, like have the chance to go through lab. And what that can do is really allow us to practice mentorship at all the different levels, right, if you have grad students, mentoring undergrads and postdocs, mentoring graduate students, and like making sure that not only is everyone welcome in lab, but also people practice mentoring a diverse set of you know, others, right, and it’ll, you know, maybe people when they’re undergrads decide they don’t like it. But at the very least giving that opportunity and making sure that people from a broad range of backgrounds have the chance to access that is good. The other thing is outreach, I think is really fun. And we had talked about communication. But outreach to local schools is something I’ve always done wherever I am. And that’s also a really great way to introduce kids to the idea that scientists are real people. And it’s a manageable, fun career that you can actually pursue. And it’s not, I think it feels very kind of elitist if you’re not, you know, introduced to a scientist or whatever. So I think that encouraging communication, encouraging your lab members to seek out events where you go to schools and communicate science is a really good opportunity to both increase diversity and inclusion, but also to train people on communication and mentorship. So it’s like two birds with one stone.

Peter 39:07
Yeah, that’s really great. I think that question was from Yeka Aponte. I don’t know if you had a follow up.

Audience 39:12
Yes. I’m very delighted to be here today. I mean, thank you, Diego for inviting me. So I’m Yeka Aponte. I’m a tenure track investigator at the NIH. And Kara, your answer was a stellar because it’s about time that you know, especially when we think about gender, and we think about diversity & inclusion, that’s what he makes us stronger. And I think that we all have to when to reach, you know, the PI level to feel that we have a voice, you know, and that’s something that as you guys all said, no one teaches us how to be a manager we have to learn by doing. And I think that that’s kind of challenging. The other thing is that I recently became the director of the diversity and inclusion at the NIH, NIDA. And, and I think the one of the hardest and more challenging things is that, you know, expectations are really high when we join a lab. Interns, summer students, you know, and you have to understand when you have these kids that come from underrepresented backgrounds, they didn’t have the same privilege that most of us had, and the same training. So you have to put an effort to really, really get these kids to that level. And as Kara very nicely stated it, you have to start from like the undergrad level. I mean, if it were up to me, I would start, you know, for like, elementary school, but at least we have to start somewhere. And I think that this is the advice that I give all the investigators that you know, you have to be patient, you have to understand that perhaps in the first year, you’re going to want to get any data from that student, but the reward that you’re going to get one, that kid that perhaps is the first generation going to high school and college came out of your lab, you will feel so proud. I said, that’s my child, you know, that kid became a doctor because of me, because the training in my lab, so on a team that, you know, it’s about time that we educate ourselves about our conscious and unconscious biases, because we all have them, even if we don’t know. And, you know, this is something that, you know, I tell my lab members, we have to stop being bystanders, and you know, speak out & loud. I mean, I’m sure you’re all aware about this horrible paper that came out two weeks ago, and how female scientists not being good mentors, you know, I mean, on top of dealing with my background as diverse, I also have to deal with my agenda just to show people that yes, I can be a good mentor. It has nothing to do with my gender. So yeah, those are the comments that I just wanted to ask. But thank you, Kara, for just stating this at the level of you know, the trainees. So it was really enlightening for me to hear that.

Peter 41:37
Yeah, I don’t know if there’s any better way to close than that. I feel very empowered. I feel like we have to keep pushing the ball forward. We have to continue advancing science. And I really wanted to thank everyone here for coming to this Gastronauts Bite Size Summit. We really enjoyed your presence and we really valued your opinion. Thank you all so much for listening! Science is all about this open communication and how we can continue to advance it. If you can think of any other ways for how Gastronauts can improve, please feel free to reach out to us. If you feel like you’ve got something from this today, we’d love if you’d share this with a friend or a colleague and just get more people in the know-how about Gastronauts and about science. Thank you so much for joining us and thanks so much to our speakers.

Peter 42:48
Thank you all so much for listening and we’ll see you on our next episode. For more of our content, you can follow us on Twitter @gutbrains or visit our website at thinkgastronauts.com. The Gastronauts Podcast would be impossible without our incredible team. Meredith Schmehl is our producer and theme music composer, and special thanks to the founders of Gastronauts: Dr. Diego Bohórquez and the Bohórquez laboratory.

Episode 17: What Bugs Us

Peter 0:15
Hi, welcome back to the Gastronauts podcast. My name is Peter. And my name is Reem Hasnah, and we’ll be your hosts. Here at Gastronauts, we are committed to exploring communication throughout the body with a focus on the crosstalk between gut and brain. We invite speakers in this field to share both their research and their life journeys. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts Podcast. Today, we have two great scientists Dr. Mary Estes and Dr. Dylan Dodd.

Reem 1:06
Dr. Mary Estes is a professor of biology and microbiology in the Department of Medicine at Baylor College of Medicine. She’s a member of the National Academy of Science, the past president of the American Society for biology, a fellow of the American Association of the advancement of science, and has authored over 400 articles. She’s a molecular biologist whose research is focused on understanding viral infections of the gastrointestinal tract. Her research group focus is to study how the viral proteins interact with receptors of the intestinal cells. Welcome, Dr. Mary.

Dr. Mary Estes 1:41
Thank you very much.

Peter 1:42
Dr. Dylan Dodd is an assistant professor at Stanford University. He received his training as a physician scientist at the University of Illinois in Urbana Champaign. his PhD work was done in Professor Isaac Khan’s laboratory, where he looked at the molecular mechanisms that were involved in how energy is captured by gut bacteria. And then he worked in Dr. Sonnenberg laboratory where he studied how gut bacteria contribute to small molecules that impact host physiology. He has leveraged his research to co found a company that engineers bacteria to modulate the immune system. And his research group’s focus is to uncover the chemistry underlying host microbe interactions in the gut.

Reem 2:24
Dr. Mary and Dr. Dylan. So what was the motivation behind you both going into research and studying these microorganisms like the microbiome and the viruses?

Dr. Mary Estes 2:36
So I originally had thought that I would go to medical school because I didn’t know that there were was another career that you could do research. And when I went to undergraduate college at a small girl school, we had a visiting prior graduate from the college come and give a talk. She was doing research in microbiology, and I had liked biology, I thought that I wanted to do immunology and I suddenly discovered that there was this whole other area of research. So I applied to graduate school. And then when I took my first class in microbiology, I learned about viruses. And I was hooked from then on. I worked on different viruses, tumor viruses initially, and then once I came to Baylor, I still worked on tumor viruses for a while, and then changed into gastrointestinal viruses after a few years.

Reem 3:27
So the carrier started with a spark.

Dr. Mary Estes 3:29
Yes.

Reem 3:32
Yeah. And you Dr. Dylan?

Dr. Dylan Dodd 3:34
Yeah. So I also was very excited about immunology, I actually joined MD PhD program straight out of undergraduate, because I knew I wanted to try to do science that could more broadly impact patient health. Unfortunately, you know, as graduate school goes, sometimes the lab you wanted to go to, there aren’t openings. And so I ended up going to microbiology, which I had never even studied as an undergrad. And I was captivated by it actually worked on trying to identify new enzymes for biofuels, if you could imagine, and the best place to look for enzymes that break down grass and lignocellulose is really the cows for stomach, the rumen. And so I did my PhD in rumen. microbiology. And it was very surprising for a lot of people that were my cohort and MD PhD. They said, Why are you studying the cow, but I immediately made connections between the metabolic activities within the cow’s stomach and what’s happening in our gastrointestinal tract. And so then I switched over to studying human colonic microbiota and their metabolic properties.

Peter 4:46
That’s super neat. It’s just so interesting how people get into their path into science and there’s just so many different paths to it. I guess for me, I had never thought I’d be studying the gut either. I never thought I’d be working on a podcast or the session with Reem. So I think it’s All about that spark.

Reem 5:02
It’s a small world Peter.

Peter 5:05
We’re really excited about the audience being really interested in asking questions. And we are going to start having people in the audience who have typed their questions ask their question,

Reem 5:15
Dr. McCann.

Dr. McCann 5:17
My question is for Dr. Dodd. I’m a research staff scientist in the Rawls lab. And we’re also really interested in microbial metabolism along the gut. And I was just curious actually what you thought about your sample set diversity. I know the Sonnenberg lab has access to tons of diversity as far as fecal samples go, but for your blood metabolites. I know, for instance, we have a hard time in really finding diverse populations and sample sets to look at for microbial metabolites. And I was curious about what you thought about that access? And how important it is?

Dr. Dylan Dodd 5:51
Yeah, thanks. That’s a great question. And I fully admit that our sample is not really capturing great diversity. It’s just capturing sort of the cultural background of the Bay Area, and especially tech companies. And in fact, we don’t have the metadata to say what the background is, or do we have any information on diet? So yeah, as you mentioned, you know, Justin Sonnenberg also at Stanford, in fact, my former mentor, has been studying the hodza, which is a sort of hunter gatherer population. And he’s got extensive metabolomics data that he’s working on in different populations across the world. And, you know, I think he definitely sees large changes in metabolomic profiles that vary across people. And so I think it’ll be really interesting as we start to build up datasets from culturally diverse as well as geographically diverse, as well as people taking diverse diets.

Dr. McCann 6:54
Thanks.

Peter 6:54
With regards to the diversity is that we experienced with our diverse diets and what not married, are you aware of how this diversity affects infections to viral gastroenteritis?

Dr. Mary Estes 7:06
I actually don’t know the answer to that question. Maybe there’s another a bile acid person that studies that this more broadly in different populations, or Victoria, do you have an answer?

Victoria 7:18
I think we’ve had this question, at least with individuals who have deficiencies in bile acid production. They’re more or less susceptible, but I don’t think we have an answer

Peter 7:28
Moving on, we have actually a question from Roy.

Roy 7:32
Hi, Dr. Dodd. I’m a student in Dr. Mary Estes lab, also joining us today. So I was wondering, my question is short, so I was wondering if the caffeine level you’ve just mentioned is now indulgence, right? So [I was wondering] you have some topic to say related to coffee or tea consumption and how affects maybe metabolite composition?

Dr. Dylan Dodd 7:58
Yeah, so I didn’t even mention it. I had caffeine on the far right of my plot of metabolites. And, you know, one, one point I like to make about that is actually 25% of individuals in our population had undetectable levels of caffeine. And that corresponds roughly to the caffeine consumption that we know, for, you know, typical individuals in the population. So 75% of people were positive, and then their concentrations ranged about as dramatically as the microbial metabolites. And so I just like to make that comparison to orient people and then also to say that, you know, that microbial metabolites are drug like molecules, essentially similar to caffeine. And their concentrations are varying as much in the population.

Roy 8:43
And may i ask one more question. So you just mentioned that there’s some potential limitations in metabolomics. So I’m wondering, are people developing a new technique to try to detect all undetectable metabolites so far, or that technique is improving?

Dr. Dylan Dodd 9:02
Yeah, that’s an important question. And, you know, if you look at, say, David Wishart’s group, who has the human metabolome database, you know, when they publish their papers, they go extensively into their samples with multiple different methodologies. And they may get very trace molecules that we would be unable to detect. So, you know, we’re, I do believe that we’re just kind of scraping the surface. But you know, mass spectrometers are sort of the workhorse of metabolomics. They have linear dynamic range on the order of four to five orders of magnitude. So I think it’s a really good approach right now, but I’m sure as we get interested in molecules that are at lower concentrations, we’ll have to change our methodology.

Roy 9:48
Okay, thank you.

Reem 9:49
So people are subjected to several medication and several foods and nutrients. And so how do you establish a stable set of microbial metabolites And how are they altered by pharmacological intervention? So what do you think?

Dr. Dylan Dodd 10:06
Yeah, that’s that’s a great question. It’s such a complex microbial community. And production of these molecules isn’t linear. It’s not one microbe acting on its own to produce these chemicals. It’s the microbial community interacting, exchanging electrons, transferring substrates. And so really, it’s, it’s incredibly challenging to tell how a dietary perturbation is actually going to influence a molecule like an amino acid metabolite. If you give fiber to people, you might actually see an increase in some of these protein metabolites. And it’s really difficult to understand. So I think to get at that, what we really need to start doing is human studies that are, you know, essentially longitudinal, studying each individual and how their metabolism changes over the course of a day over the course of different diets. And if we were able to do large scale studies of those sort of longitudinal analyses, I think we’ll learn an incredible amount about how diet influences microbial metabolites.

Reem 11:12
Yeah, that’s great. What do you believe is the most critical lack in our understanding of the host microbe interaction, to help us get into the precision of us having transplanted microbiome and then getting over specific diseases?

Dr. Dylan Dodd 11:30
Well, I mean, in the in the context of therapeutics, we don’t really know what dictates whether a microbial community will stay after transplantation. So it’s community dynamics, that really we don’t understand. We know that if you do a fecal microbiome transplant, you can actually track donor strains. And you can also track the original strains from the recipient. And you get some sort of mixture of that as assemblage over time. And so I just think that it’s going to be more of these very careful, multi omic types of analyses of FMT, that is going to allow us to understand more about the mechanisms and the dynamics of microbial interventions at the community scale.

Dr. Mary Estes 12:17
I think that what you said is absolutely true. I think the other big challenge at the moment is having technologies to be able to really address host micro biome interactions. I mean, one of the ways we’re doing that is with these cultures, we can put the cultures in anaerobic chambers, and we’re now making platforms or we can add the microbiota. And we do have a few examples. Now we’re putting microbiota in with a virus. microbiota can enhance viral replication, or in other cases where it can reduce viral replication. Now, that’s all in vitro, it’s reductionist, but that may be a way to that to begin to understand some of these more complex communities, perhaps in a simpler system. And then you would certainly have to go back ultimately and tested in animal models or perhaps people

Peter 13:08
Really neat. Andrea Marciniak.

Andrea 13:11
Yes. Hi, I’m a graduate student from the University of Virginia. And I had a quick question for Dr. Dodd, I’m actually studying how microbial metabolites are impacting the CNS. And have been thinking about this question a lot recently, of how likely is it that we will be able to modulate microbial communities long term to mediate their metabolism in chronic disorders? So I’m thinking things like, you know, depression or mood disorders? And is it likely that our work might be used in the future just for drug discovery? And that will actually be using these small molecules in a pill form?

Dr. Dylan Dodd 13:45
Yeah, I think if you look at sort of the biotech space, you know, they’re very much used to working on small molecules. But having biological entities like a microbe that’s anaerobic, and its entire suite of pathways, as well as its interactions with other strains, is really challenging to conceptualize and to bring through sort of the market. So I think the low hanging fruit are the small molecules that have specific receptors that you can actually dose. But a lot of the case in the microbiome is you want to actually deplete some molecules that potentially have a deleterious effect. And in that case, you might be able to block the receptor. But another strategy would be to make a fecal microbiome transplant, if you will, and potentially a synthetic FMT to actually replace the microbes in the community with ones that don’t produce that molecule or take the molecule the substrate down a different pathway. So there’s a lot of approaches people are taking, and I think all of the ones I’ve described, at least a few companies are working on. And so it’ll be super exciting to see what ends up working. And the the nice idea about the fecal microbiome transplant is you could potentially affect a long term change, if you could replace somebody’s microbiome with a synthetic community, but that has yet to be shown to be possible.

Andrea 15:31
Okay.

Maya 15:31
so my name is Maya Kaelberer. I’m here at Duke University. So we care a lot about good bacteria and bad viruses, if I’m going to generalize. What about good viruses? Are there symbiotic viruses that are symbiotic with like, maybe even the host, the human or even the bacteria? And how is their role different than bacteria? Or is it similar?

Dr. Mary Estes 15:53
I’ll give you two comments about good viruses. One are viruses that infect plants. So the tulips that you enjoy in the spring, and if you go to the Netherlands, there will actually be production facilities, in a greenhouse where a particular plant virus is added to make the white stripes on a red tulip or something. So that’s one example of a really good virus, I think.

Maya 16:18
Beautiful virus, yes.

Dr. Mary Estes 16:21
The other area where people are looking carefully now our bacteria are phage that actually come from infecting bacteria. But they may have some positive effects in the intestine. They’re not fully understood yet. But there’s some suggestion that the levels of phage may be important in outcomes of colitis. I think some of that is from animal models. I don’t know that we have good data in people yet. But I think that’s an area that’s going to be looked at, like carefully and there are beginning to be more and more stories where there are interactions between hosts genetics, bacteria and viruses that can either make disease worse, or trying to they I don’t know that I know of one that’s potentially better, but I think we’ll learn about those in the future.

Dr. Dylan Dodd 17:09
Are you interested in the bad bacteria?

Maya 17:14
I guess that’s true. My, my question was very one sided. But what about the bad bacteria?

Dr. Dylan Dodd 17:20
Yeah, I mean, we like to think a lot about beneficial microbes. And there are a lot of them, but not all microbes are commensals. And I mean, there’s opportunistic pathogens, which we know a lot about, especially esbl, for immunocompromised individuals, that can lead to enteric and systemic infections. But I think, you know, as we learn more about microbial metabolites, there are contexts where those molecules and their signaling pathways are beneficial. And there’s contexts where the same molecule on signaling pathway could actually be detrimental. And I think as we learn more about those specific interactions, we’ll learn about you know, what is sort of a beneficial context and one patient population versus another.

Dr. Mary Estes 18:04
I do know, so there are people in Houston that are studying Cryptosporidium, they also had done volunteer studies, and they had found that the levels of indle in the large intestine actually seemed to protect against crypto infection there are now doing experiments to try to understand exactly how that’s working. But that would be potentially an example where if you had the right bacteria making that you might be resistant to an infection.

Reem 18:33
We have a follow up question.

Elaine 18:35
hi. This is the Elaine Snell from England, London, about to go into lockdown. Question for Mary. So thank you and thank you both actually for your excellent presentations. I really enjoyed them. And Mary, I was immediately struck by the fact that you were talking about norovirus as a pandemic, the G 242 three strains that cause a pandemic that that norovirus kills 200,000 people globally every year. Well, you know, in the current circumstances, with Coronavirus, claiming all the attention whilst I’m not asking you a political question about how it’s been dealt with, I mean, you must have a view on you know, the the ways that norovirus is communicated and managed and lessons that can be learned for, you know, this other virus Coronavirus that also kills hundreds of thousands of people this year, I can imagine it must be quite frustrating for you to see the way it’s being managed in many respects, but I don’t want to put words in

Dr. Mary Estes 19:42
I mean, I think we know how to manage it. The question is whether the population will until we have a vaccine or prevented therapeutics. You know, you need to wear masks social distance. Wash your hands and actually those are the same Same rules for norovirus. So this is a virus that used to be known as the cruise ship virus. I think maybe that’s now taken over by our new pandemic Coronavirus. But it’s the same principles. When you get people in closed semi closed environments. You may have one person come on a cruise ship that’s sick. And if they don’t use good personal hygiene and go around touching surfaces, this is fecal oral spread. They’ll spread the virus very readily and you and you can have thousands of people on a cruise ship that will get sick with this. There have been ships that have been denied entry into ports in the last several years, because so many people are infected. So the principles are the same. I hope that if people will become educated about infectious agents, and how do you handle them, really probably could reduce the level of infection globally for many of these organisms. I mean, even the Coronavirus seems to be having an enteric phase and many people, it’s not clear that it’s actually spread through the feces but it certainly can infect the intestine. There’s been some suggestion that it may cause a pro inflammatory response in the intestine that may actually get into the circulation and affect other organs. That’s not fully proven, but as a hypothesis.

Elaine 21:23
Thank you.

Peter 21:24
Yeah, this is just having me think Reem and I were having a discussion earlier. I think every time before we have our meetings, we talk about how is COVID affected you? Are you doing okay in the time of Coronavirus? I was wondering, a lot of times these research in norovirusi and I guess research in the microbiome is not quite made it to the same degree of the public as Coronavirus has, and I was wondering how do you apply these findings from your research into your personal your day to day lives?

Dr. Mary Estes 21:49
I try to use good personal hygiene to prevent getting the infections and I think in terms of in the era that we’re in with Coronavirus. I think we’re trying to apply all the expertise that we have to maybe trying to answer a question about Coronavirus. So there’s been a lot of discussion about whether Abo blood type may be important or Coronavirus, infections. And there’s you’ll read one report that says that there is another that says it isn’t we have actually submitted a proposal to try to look at that, using our culture’s were so the histo blood group antigens are part of the Abo blood type system. And we have these cultures now that we’ve well characterized, we know what kinds of glycans are on them. And we’re proposing to try and use them to infect with Coronavirus to see if in the in vitro system, we can actually get a clear answer. And if we can to determine what part of the spike protein might be binding to the glycan where it might be binding and see if that might be able to be blocked in some way.

Dr. Dylan Dodd 22:55
Yeah, I can chime in on you know, how we use the microbiome and the metabolites that we’re studying in our day to day lives. You know, I have a six year old, and my wife and I, you know, are conscious about what we eat, and especially coming from Justin Sonnenberg lab, we have a copy of the good gut, on our shelves. And so we incorporate we try to incorporate more fiber into our diet. He’s a huge proponent of that. And there’s a lot of evidence that increasing your fiber intake is beneficial. We actually have a lot of fun picking that recipes randomly from the book. So I encourage you to take a look at it if you haven’t seen it already. It’s just a lot of fun. Justin and Erica Sonnenberg have done an amazing job with that.

Peter 23:36
I feel like the research that we do just definitely lends itself to, you know, impacting our personal life, especially if we study the gut, or viruses that infect our gut or viruses in general means basically like our understanding of our personal hygiene, how we live our daily lives-

Reem 23:52
and also the decisions we make on a daily basis. So whatever we learned in the lab, actually influenced our decisions in the future. I would like to thank our amazing audience who without them, we wouldn’t have this great discussion or these questions. Also a huge thank you from the Gastronauts family, to our guests, Dr. Mary Estes and Dr. Dylan Dodd, thank you for your precious time, and for taking part of today’s discussion.

Dr. Mary Estes 24:16
Thank you for inviting us. It was great to be here.

Dr. Dylan Dodd 24:19
Thank you so much.

Reem 24:33
Today we had a great episode, and a great discussion. And we knew that our body is far more complex than what we expect or know. Thank you all for listening. And we’ll see you on the next episode. We are really excited to announce that Gastronauts Global will take place this year and will start May 11! See you all in the virtual Gastronauts global. For more of our content, you can follow us on Twitter @gutbrainmatters or visit at our website thinkgastronauts.com. The Gastronauts Podcast would be impossible without our incredible team. Meredith Schmehl, our producer and theme music composer, and a special thanks to the founder of Gastronauts: Dr. Diego Bohórquez & the Bohórquez laboratory.

Episode 16: Tracking Our Behavior

Peter Weng 0:15
Hi, and welcome back to the gastronauts podcast. My name is Peter,

reem hasnah 0:19
and my name is Reem hasnah.

Peter Weng 0:22
And we’ll be your hosts. Here at gastronauts we’re committed to exploring communication throughout the body with a focus on the crosstalk between gut and brain. We invite speakers in this field to share both their research and their life journeys. So come join me as we explore the steps that go into shaping a scientist on the gastronauts podcast.

Today, we have two great scientists, Dr. Yulong Li and Dr. Michael Krashes. Dr. Li is a professor at the School of Life Sciences in Peking University. He received his PhD at Duke University, where he utilized single molecule techniques to understand the role of specific proteins in neurotransmitter release. He then pursued a postdoc at Stanford University in the lab of Richard Chen, where he developed a genetically encoded pH probe to monitor activity dependent release of neurotransmitters. And now his lab has expanded on his previous work and developed advanced imaging probes to untangle the exact chemical signals that neurons are using to communicate in specific circuits. And using these probes, Dr. Li’s lab has worked to identify new receptors and neurotransmitters and characterize their roles in specific neural circuits.

reem hasnah 1:49
I’ll be introducing Dr. Michael Krashes. He’s a section chief at the an ID DK at the National Institute of Health. He received his PhD from the University of Massachusetts Medical School, his work focused on memory circuits and older memory processing and Drosophila. His lab currently focuses on how the brain brings together information sense from the external environment and its own internal states, including the memory. Welcome, Dr. Michael to this episode, I would love to know why both of you have really been motivated to be in the science field. So I know that’s Michael, I heard an interview that he went into science because of your mother. So why did she influence this?

Dr. Michael Krashes 2:36
Yeah, so I mean, I think my mom was a chemist, and was, you know, very heavily involved in the sciences, and just was always very curious. And I fell in love with biology, kind of in high school. And then in college, I kind of just messed around and didn’t really get a lot of science background in college, and then kind of after graduating college, I kind of just kind of kicked around for three years before going back to graduate school. And it was really my mom, my mom that pushed me to do so. But again, you know, Scott, who’s on this call, was my graduate advisor, so he can he back this up, I really had no idea what I was getting into. As far as going to graduate school, I thought I would just go get my PhD, become a professor and be rich, that turns out not to be what happens. I didn’t know what a postdoc was before I started graduate school. In fact, probably not until about two years into graduate school, but it was really, you know, being pushed by my mom to at least get into science, but then having incredible mentors, throughout my my career and support from others in the field. I mean, Scott was just wonderful to me, and really directed my research. He knew what my interests were, I was actually going to leave and go into industry after after graduating from his lab, but he kind of knew that that’s not where my heart was, and pushed me to my postdoc advisor, who was Brad Lowe, who was very big in like the energy balance field. And again, just tremendous mentoring by him, and just the support that I’ve received from the two of them. But again, you know, people that I mean, I can see people in this phone call, I mean, from trainees to, you know, people that have interacted that were graduate students that were postdocs. I see p eyes here, you know, all people whose research I’m so motivated, inspired by, I think that’s what really kind of pushed me to where I am now.

reem hasnah 4:27
And yulong What was your motivation behind being a scientist and a person who develop techniques?

Dr. Yulong Li 4:34
I think I’d love to find since out, you know, the curiosity that was sort of with me since childhood, but I was from a small town in China and my parents been practical and I think my father actually wants me not to go to high school, Senior High School. By going to the professional school, because there was graduate, you can find a very secure job, just in our small town. And around then I, I just I refuse I was like, now this small town is so small, you know, 15 minutes biking, you know from one end to the other end. And so I was sort of just, you know, thinking I need to go to senior high school and then go into the college. And I think, fortunately, even though my parents are practical, and but they all value my own opinion. So they respect my opinions, I, if I decided to go to sort of senior high school and then go into this college entrance exam to apply for colleges, they say, well, we give our best advice. But if you choose to go to your way, good luck, and they still support me so. So that’s part of the way. But I also found that being a scientist or study, including now supervising students, I think has the same sense of financial stability. Okay, probably not expect to be enraged, but at least have some sort of enough support will also assure people that they can sort of focus during research. And you don’t want a career that people are worrying about whether they can go by every day and still concentrate, and doing research. So So I think, have steady and secure support for, from grad student to postdoc, and also to two faculties, which junior faculty will brief good, so people can focus on the important part of science, rather than worrying about their own division.

Peter Weng 7:00
Yes, I think one of the key things from you and Michael, about what they said here was the importance of finding a good mentor, find a good good team of people, whether they have something that you see that you want to do in the future, whether they have the financial security, it’s something that you can look and aspire to be. And that’s been really important. And it was a recurring theme. From what Lisa had mentioned in the previous episode, just reach out to these people who you really want to be.

reem hasnah 7:24
I have a question for Dr. Michael actually have an interest of mine is memory and memory that we make for food? Do you think this memory is created in utero so that the pregnant moms eat different kinds of food and the babies would make memory of what they are eating?

Dr. Michael Krashes 7:42
Yeah, yeah. So I mean, a lot of this kind of beauty studies have been actually done, where the moms, for example, are given exposure to a high fat diet. And then that response is then translated down to pops. work from Young’s burnings group, has shown this really, really nicely. A lot of the changes that happen in the dopamine circuit can occur by just feeding the mom the high fat diet. So yeah, I think it actually predisposes the offspring as well.

reem hasnah 8:13
So you think our guts makes memories since day zero?

Dr. Michael Krashes 8:17
Did I mean, I think I think it definitely is involved.

Peter Weng 8:21
super interesting. Michael, I have a brief follow up. One of your previous papers, you mentioned the challenges of using optogenetics to study agrp neurons in the presence of food. And I was wondering, this optic stimulation is just such a blunt and like aggressive tool to really activate the cells. I guess this is both for you. And you long, how can technology be developed, and additional studies be performed to more accurately mimic physiologic hunger,

Dr. Michael Krashes 8:48
some of the approaches that have been done, you know, in the last couple of years, have been able to kind of record neural activity and then feed back that activity directly to those particular neural subsets. Most of this has been done in the prefrontal cortex or you know, where you can kind of get a large swath of neurons and record their activity. And then you can kind of this is like, it’s like holographic imaging, but then you can then playback exactly kind of that signal, and hopefully induce the exact same behavior that you would see that occurs when the animals actually perform that behavior.

Dr. Yulong Li 9:24
So I think that technology in a way, for example, calcuim imiging, really lower the bar for neuroscientists to study the brain, in a way study the brain activity, and previously, probably only physiologist or electrophysiologist, using sophisticated inaturalist that they can sort of detect, spiking and then study the sort of activity of the brain with precisions but calcium imaging and use You can, for example, really sort of allowed one to look at a single cell type, and a variety of animal systems. And Southland that, there’s just no easy ways to do it, I throw into the brain. So I think the technology and increase of the convenience of lectures and sensitivity or to really allow a larger group of scientists, including your scientists to really assess the uncharted territories, and our neuromodulators sensors, as well as some of the colleagues in the field, in the same way is also trying to make the boundary lower to the bar for people to study is the important signaling molecules. And I think calcine, what did you add? Those are good, but they are still incomplete, and a neuromodulator, with different chemical majors. By Design, they are quite critical. And, and therefore it’s important to measure that dynamics.

reem hasnah 11:04
So I have a question along these lines for both of you, actually. So before we make a statement of that the role of cell type x is modulating behavior, why we need to make sure that this tool that we’re using is repeated can be repeated by different people and repeated by different labs. So how you go through choosing the tools that you use in your labs, and for the experiments, especially with food derived experiments, it gets harder and harder.

Dr. Michael Krashes 11:30
Yeah, so I mean, for the first part, like looking at specific cell types, I mean, this is one of the reasons why I can’t kind of separate myself from agrp neurons. And moving on from saying agrp neurons. I mean, I do honestly think there’s still so much more to discover. But it is a population of neurons that I know if anyone use these tools that I’m using, or that labs using to kind of activate or inhibit or record from, you know, every lab is going to see the same thing. So this is very reproducible. And, and again, that to me is the most important thing about science is that any lab can do this and see something similar. And then when you kind of build on top of that knowledge, that’s how you make progress. And then as far as the tools, I mean, it’s true there is I mean, I’m not a tool developer, I’m one of the people that actually throughout my, my scientific career has taken advantage of the really smart people that have actually developed the tools, whether it was my work in Drosophila, where you know, I use trip a one, which is a heat sensitive way to kind of activate neurons and just saw flat or trip, I’m eight, which is as you know, the menthol receptor, but then can be expressed in flies, and we can change neural activity in that manner, whether it was Shiri into software, or using optogenetics, and human genetic methods in mice, I think the idea is, you know, you obviously know a good tool when you can, when it’s seen in publication after publication after publication, there are a number of tools that, you know, you see once published in a methods paper. And, you know, I think those tools may, they may or may not work as advertised. But I think the the tools that you see published the most are probably the ones that most people are using, and there’s a reason that they’re using them because they work really well and do what they’re supposed to do. And again, reliably across, you know, neurons regardless of what type of neurons or even glial whatever cells people are working with. But if they’re supposed to do what they’re supposed to do, I think that’s why people have kind of continued to use that. So that’s why you see the G camp, you see these new sensors that you Yulong developing these grab sensors, you’re seeing the D light, and you’re you know, these are, these are the tools that are highly used over and over again, because of their efficacy for actuallyworking.

Dr. Yulong Li 13:53
So, again, I think a lot more people use and as a way, they can validate the performance of distances. So for our group, as Michael Krashes set, for example, our intense group from UC Davis also developed D Ly, although a medium D one receptor, and we are using a D two receptor, so that sort of principle actually are sort of corroborated by a different group. And also we share those to us in advance to different groups to test in different scenarios, and also get a feedback and then going through the iterative improvements. Indeed, there’s a difference in terms of you know, the species the temperature might be different, and the cell type might be different for the virus. So there are a lot of parameters cannot easily just be tested by us in the lab. So we, again, we try our best to, to validate our own hands but also distribute to people in different groups to to validate And also I think making to us, test in vivo is critical. And I love tools and we make them. And I admire Roger Chen, who make those tools. And now also a lot of tools published by Cambridge, geneticist. But I think, for neuroscience, probably the most important thing is to test it in vivo, which is more challenging. And a lot of people demonstrate proof principle in cultured cells. And my own group, we want to publish since at least when I was telling my students, we want to have the in vivo evidence, and we want it to work in vivo, before we publish this, and so I think that has a higher power in a way that if you have the in vivo signal to noise ratio, and usually in other conditions, that it should be more robust, for example, in the slides, or in culture systems.

Peter Weng 15:58
Yeah, I think a really neat point that you own brings up is the importance of collaboration, you’ve shared some of those sensors with our laboratory. And it’s been really great to hear about collaboration, we actually have a question from Daria,regarding collaboration.

Daria 16:12
So I am a doctoral student in the Department of Nutrition at the University of North Carolina, and I do sort of translational work in the gut microbiome and diabetes. And I have really a general question for you. I have been involved in some limited research collaborations with collaborators in China. And I was wondering if you could speak to sort of the environment that would or would not allow for continued efficient collaboration between China and the US, given all the really great work that’s being done in both countries? And sort of, I’m wondering how you see this playing out in the future? You know, given some of the challenges that have arisen recently?

Dr. Yulong Li 16:52
Yeah, I think it’s really a good question. You know, I spent 11 years in the states from my high school and postdoctoral training, and then I have my own lab in Beijing for more than seven years. I think the scientists are open. And at least for me, I have a very pleasant collaboration with scientists around the world, including a lot of labs in the US, I think the geopolitical issues are, indeed host constraints. That is certainly worrisome. And there are different cultures and different systems, I think, one of the ways to have the collaboration could be that laying out the the collaboration in a more open tense that in case and, you know, given to the political competition or issues between the governments, so if the parties can lay out attempts, more transparent to stairways that might ease the issues, for example, you know, the why heard is that, you know, they’re, especially the Chinese Americans, some of the friends they worry about the compliment the US government might, you know, might be treated in such a way that they are an export of the sensitive information. So, at least as best I can think of, and but but generally, among scientists, I actually have quite pleasant sort of feedbacks and experience, and also the US scientists that I encounter and interact and collaborate. They’re also worrying about the political environment at my limit, and have fallen soundly to the faithful and completing reports system to disclose the collaboration in advance, and also timely, and that can sort of reduce the concern, I think.

reem hasnah 19:16
So we have a question from Elaine.

Elaine 19:18
Hello, thank you. Question for Michael Krashes. Thank you very much indeed for your really interesting talk. I was wondering, though, is the overriding desire for high calorific food do with the evolution of survival? So in other words, do we sort of instinctively need to eat more sort of high calorie, high energy food when it’s available if we don’t know where the next meal is coming from? Obviously, that’s much less of a problem now for most of us, but you know, for the mice and rats that you were talking about, and perhaps for humans, way back when meals weren’t Simply available.

Dr. Michael Krashes 20:01
Yeah, I mean, I, I can’t tell you the exact reason for it. But that’s precisely how I think about it is that is that we’re attracted to the energy dense foods because we’ve just evolutionarily conserved to try to go after, you know, the most calories for the the limited time that we have. Because again, we were we used to forage for food, you know, so that we were able, then. So I think that we try to get as many calories as we can, in a short amount of time as we can. And you know, in particular, fat is really involved in the actual evolution of the human brain. And it’s why the brain became bigger and bigger as as evolved was because of the fat that we consume from our food. So I think fat in particular, is extremely, you know, attractive to us humans. And I think that’s conserved and unfortunately, yes, as you mentioned, in you know, an obesogenic environment that we’re kind of many of us live in now, that can have a very detrimental effect. Yeah.Thank you.

Along the similar lines. Another question from Michael, about willpower and the ability to resist cravings.

Michael 21:11
Yeah. Hi. So I am Michael from the Air Force Research Labs, actually, it says a question to Dr. crashes, some people seem to have more willpower to to not eat these high density out high energy foods. Is that is that more of a learned response? Or is that? I mean, how do you sort of reconcile those those sorts of things?

Dr. Michael Krashes 21:31
Yeah, I mean, so I don’t think there’s a good answer to that. What I will say is that, that mice, just like humans, really show a tremendous variability when they are exposed to these high fat diets. On average, these animals are gaining quite a bit of weight over the the experimental period where they’re exposed to high fat diet. Again, on average, these animals are completely ignoring the standard diet, because now they’re just eating a high fat diet. But in reality, just like humans, you know, there are annoying people that can eat like crap, and not gain much weight at all. And what we noticed is that it didn’t matter how much body weight these animals gained over that exposure period, we always saw that those animals showed that devaluation for the standard diet, both in their home cage and even when we did the experiments where we fasted those animals and gave them a standard diet back that those animals were still they still did not want to eat the standard diet. So I do think there’s, you know, there’s, there’s a number of factors that I’m sure that are involved in the production disposition of how the body actually reacts to to like a palatable diet. And I think that’s what we’re trying to figure out exactly what those factors are. But again, I think it’s going to be many factors and working together. So to identify, you know, particularly one of those is going to be really difficult. Thank you.

reem hasnah 22:51
So we have one more question for Michael from Hilary.

Hilary 22:55
Hi, my name is Hilary ship. I’m a postdoc at Stony Brook University. My question is about how chemo sensory cues interact with feeding. So I noticed that the animals fed the high fat diet avoided the standard pellet, like right away. And so I’m wondering if they use taste or smell cues rather than the post ingestive cues? And if so, how do those chemosensory cues then, like reach and modulate the agrp cells?

Dr. Michael Krashes 23:22
What is such a great question? And actually, we have something that we is in review right now, because we had that same question, which is basically what role does you know, olfaction play in this kind of rapid preference, and then prolonged preference and devaluation? So the preference for the high fat diet and the devaluation standard diet. So we did these gain of function and loss of function experiments where, you know, we positioned animals to be able to say, smell the high fat diet in their home cage, but never eat it. So they, you know, they, they kind of make the Association, the smell of the high fat diet, but they could never eat it. And they actually never showed devaluation for standard diet. So it would suggest that they would have to actually consume it. It’s smell alone is not sufficient for them to kind of show devaluation. And then on the opposite end of the spectrum, we actually ablated the olfactory bulb, so we did these Baalbek dummies, so you know, render the mice and cosmic, and even in anomic mice, they very rapidly made the decision that they just wanted to eat the the high fat diet as opposed to the standard diet. So at least olfaction itself, you know, of course, we took this reductionist approach, at least the faction itself doesn’t seem to be heavily involved in that process. We were looking to do some experiments on taste. Unfortunately, there’s not kind of a really nice knockout model in mice for tastes, but there are some experiments you can do by entering say the stomach or entering the calories before it’s actually absorbed into the digestive tract, to kind of look at the role of two One thing I do want to point out, and I’m glad that I can do this in this question is, when we published this study, recently, another study came out from Zack Knight’s lab, it was driven by Lisa Butler, who has her own lab now at Northwestern. And what they showed very, very nicely, I mean, we also did some infusion experiments where we directly infuse calories directly into the gut to kind of bypass all their chemosensory information that you’re, you’re talking about. But I think they did a much better job. And they went even further to show that it was actually this specific macronutrient of high fat diet is is the one that’s kind of devalued at the level of agrp neurons. And that happens presumably through through cck, like this signaling peptide cck in response to fat, so I think I think there’s still questions out there to be answered, but at least on the surface, what I can tell you from our recent work is that olfaction does not seem to be involved in this process.

Hilary 25:56
Cool. Thankyou.

reem hasnah 26:09
Thank you all for listening, and we’ll see you on the next episode. For more of our content, you can follow us on Twitter. At the gut brain matters or visit our website think astronauts calm, the gastronauts podcast would be impossible without our incredible team. Meredith is our producer and theme music composer. And special thanks to the founder of gastronauts Dr. Diego Bohorquez forecast and the Bohorquez laboratory

Episode 15: Shaping Our Appetite

Peter Weng 0:09
2020 has truly been a turbulent year and brought forth a new set of challenges on how we live and how we communicate. And as such, we have needed to find ways to adapt and grow. we’ve adapted our podcast to be a live stream through zoom. We’ve brought a new co host onboard. So everyone please give a warm welcome to Reem hasnah, a graduate student from Sidra medicine in Qatar,

reem hasnah 0:31
it’s a pleasure for me to be the new member of the Gastronauts family. Hi everyone.

Peter Weng 0:37
And we are so excited to continue diving deep on gut brain matters and learning about the scientists Behind the Science. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts podcast.

Hi, everyone, we would like to welcome you all to our sixth year of Gastronauts. For those of you who have been with us from the beginning, we would like to thank you all for your commitment. For those of you just tuning in, we are happy to have you join our community. Here at Gastronauts. Our ambition is to foster discussion and spread knowledge on gut brain matters. What started as a seminar series led by Dr. Diego Bohorquez in 2015, has now expanded into an international symposium and a podcast aimed at exploring the scientist Behind the Science. Today, we invite you to join us in thinking and talking about why we eat. My name is Peter and I along with Reem Hasnah will be your hosts. So without further ado, let’s introduce our speakers. Dr. Lisa Beutler is an assistant professor of medicine at Northwestern University Feinberg School of Medicine. She is a physician scientist aiming to study how the gut and brain communicate with each other to maintain body weight. Dr. Beutler received her MD and PhD from the University of Washington where she studied how input from NMDA receptors onto medium spiny neurons, inhibitory neurons in the basal ganglia are critical for learning and Dr. Richard pomodoros laboratory. She then proceeded to specialize clinically in endocrinology, and began studying how a subset of neurons in the hypothalamus these AGRP neurons are involved in regulating hunger in Dr. Zachary Knight’s lab, and she is currently studying how obesity affects the ability of these neurons to detect certain nutrients.

Dr. Anthony Sclafani is a professor of psychology at Brooklyn College at the City University of New York. He has had a truly distinguished career of over 50 years and studying the neurochemical circuits that govern learn taste preferences. He has served as the past president of both the Society of the study of adjusted behavior and the obesity society, and has authored over 300 publications. Dr. Sclafani began his research into ingestive behavior in Dr. Pete Grossman’s laboratory where he developed a wire knife to dissect neural pathways involved in an obesity syndrome generated from damage to the hypothalamus. From there he has pioneered studies that have helped answer how specific features of food promote appetite, and the brain reward systems that are activated from the consumption of palatable foods.

Sometimes eating is not a reward. So what do you think of this?

Dr. Anthony Sclafani 3:35
So that’s a very good question. I mean, one way to look at it is that the brain is basically turned on by food almost all the time. And if the food is satiating, then it generates signals that temporarily turn us off. Or if we accumulate too much fat, we have long term signals like leptin, that keeps our appetite somewhat limited. But when you look at the behavior of these shame, feeding animals, for example, whereas a normal rat, when food deprived, would drink, maybe 10 ml of a sugar solution, if you lead to sugar fall out of its stomach, in the 30 minute period, you test it and might drink 50 or 60 ml of the solution. So there’s no inhibition and it seems to be just permanently driving this reward system. You know, there are situations like with anorexia nervosa or with animals that hibernate and they show cyclic changes in their approach to food, that the brain may be turned off to food but it might be a good biological bet that if there’s food there, and it’s a nutritious and it tastes, we’ll eat it when you can.

Dr. Lisa Beutler 4:49
Food is certainly always rewarding to me.

reem hasnah 4:52
Me too.

Dr. Lisa Beutler 4:54
I think I think I overall agree with that. But I will say that one of the reasons why I got it To this field, I think there’s a there’s a few reasons why I was interested in studying feeding and setting obesity. One is very related to my medical school experience in my life experience with obese people and wanting to figure out why they were obese, because it just makes their life so much harder for something that is really not within their control. But the other reason that I really got into this is because I personally come from a family where about half of us are complete food maniacs, and the other half of us really, you know, eat to survive, you know, dinner at dinner, they eat because it’s like Time to eat dinner. And so they eat a small meal, and then they can stop. And so I think that there’s like, people are probably tuned differently as to how rewarding food is and to how far they will go. And I think, you know, kind of related to that, if you look at an average healthy, like 25 year old guy will go eat a burrito the size of his head, and feel really great afterwards and kind of learned nothing from the experience that maybe that’s overnutrition and not great. But you take that same person at the age of 40, or 50, or whatever, at some later age. And probably at some point part of the way through the burrito, they’re going to be like, Whoa, if I eat more than this, I’m gonna feel not great later. So I think that probably breaks maybe get put on more in general later in life and are also on at different levels and different people.

Peter Weng 6:23
Do you think that sensing and ingesting behavior is altered with the aging process? So as we age, we tend to have new circuits new neuronal circuits or less of the effect of a specific sugar or a specific nutrients on our food preference?

Dr. Anthony Sclafani 6:41
That’s a good question. We certainly know with aging, the sensitivity of the olfactory system declines. And that could interfere with the appetite of elderly people. And unfortunately, many COVID patients have a lot of primarily odor, and that interferes with their attraction to food. We have not looked at aging animals for their post oral nutrient response. I think that’s an excellent question. And someone should write up an r1 application for that project.

Dr. Lisa Beutler 7:13
I totally agree. I think we don’t know from any of the models that we use, what aging does we just know, kind of from the human experience, and from mouse models, what Tony said about the olfaction going down? I think an interesting question is whether the homeostatic setpoint for body weight changes in aging people, does it get lower? Are we supposed to get skinnier? Does Britain think we should be skinnier when we’re older? Or do the negative consequences of eating too much just begin to alter our behavior? And hopefully in the coming years, we’ll find out the answer to that question.

Peter Weng 7:44
Has having a career in science of feeding altered your own food choices?

Dr. Anthony Sclafani 7:49
I’m not so sure I mean, I’ve been experimenting with some some recent developments in nutrition, there are these rare sugars called isomaltulose and allulose that have been promoted. Because I so multilocus is a sucrose type molecule that’s slowly digested. So it doesn’t produce a spike in blood glucose. And we’ve actually shown that mice will drink it. But they show let’s have a conditioning response to it. And allulose is a fructose molecule that’s not digested. It’s not metabolically use, you could buy cereal products that contain this fructose molecule that allows them to save the sugar, the cereal contains no sugar, because you can’t use it. And I’ve actually purchased the cereal. But it wasn’t particularly tasty to me. So I haven’t pursued that very much. But, you know, I’ve haven’t experimented with some products such as sweet taste inhibitors. But I’m not sure it really is changed my long term nutritional inputs.

Dr. Lisa Beutler 8:59
I think probably working in the field that I do, both in science and in medicine should have changed my eating behavior more than it has. But I think overall it has not. I think maybe if I’m being generous to myself, I would say that working in the feeding and in the obesity fields has at least made me try to focus on eating foods that I actually really love. And not eating foods simply because they’re available, but I still eat way too much.

reem hasnah 9:28
A question that I really want to ask you, Lisa. So as both we are females in science, how do you think your work might have been affected if you were in the field 50 years ago?

Dr. Lisa Beutler 9:40
Oh, man. I don’t know if I don’t know if I would have been in the field 50 years ago. To be honest, I don’t know how my life would have been different 50 years ago, but I’m very grateful to be doing science now. God I’ve not ever been asked quite this question. I will say that I count myself as someone who’s enormously privileged there are a large number of scientists and physicians in my family, my great grandmother on my dad’s dad’s side was a physician. And so I feel like I’ve experienced less barriers than many, many women. And many, many, certainly women of color have experienced and getting into science and medicine. So I want to start by just one expressing my gratitude and saying that I think that comparatively, I’ve had it fairly easy. But as I’ve transitioned to being a PA, and I have women trainees, I noticed the ways that they’re conditioned to behave differently than men still. And I’ve feel like I’ve worked to overcome some of that over the last 15 years. And my hope is that I can take my privilege and pay that forward to the next generation of women. Because I like if it had been 50 years ago, I may not have gone into science. And I hope that in another 50 years, it’s it’s easier still and more equitable still, for women and other groups.

Peter Weng 11:01
These times have been really changing. And hopefully, we’re going to make a lot more progress in the coming years for both, I guess the diversity and inclusion efforts and thinking about the changes that we have in our society has also made me think about the technological advances and how things are developing at a blistering pace, really, some of the work that you Dr. Sclafani started out as were these course dissections and creating lesions in the hypothalamus. And now we can actually target really specific neuronal populations, through light or through chemicals. How do you leverage the implementation of these latest technologies against methods that you have developed in your laboratory that, you know, are tried and true? And how do you go about including or incorporating collaborative efforts for things like this?

Dr. Anthony Sclafani 11:44
Right, I am in total, or of the work that’s being done today, in manipulating the brain with the super sophisticated procedures when I was in graduate school 55 years ago, which by the way, I don’t recall how many women we had in our class, I think it was very few. At the time, we were manipulating the brain by putting a wire in the brain and passing electricity and destroying 1000s and 1000s of cells. My PhD advisor, was one of the first scientists to actually put drugs into the brain to manipulate the activity of chemospecific ways. But at that time, believe it or not, we were putting the drug in the brain in crystal form, we didn’t have the technique to inject solutions. So we just stuck a crystal at the end of a stainless steel tube. That’s how crude it was. So in my lab, I never developed these super sophisticated techniques, we were manipulating the gut, and lucky to be able to get shamed, feeding animals and self infusing animals. And that gave us a lot to keep us busy. But I just loved the work that’s being done today by both men and many women.

Dr. Lisa Beutler 13:00
Can I add something to that? Even even as like looking on a shorter timescale, I had basically a five year interruption and doing science between when I finished my graduate work. And when I started my postdoctoral research, because I was finishing my clinical training. And even in those five years between 2011 and 2016, I got back into science and was like, holy crap, this is really, really different than how I left it. I was pivoting fields as well. So that was certainly a component. But really, the actual tools and technologies available had just completely exploded in the last five years. And it was both, inspiring and terrifying. So I think that this is an exponential process. And we’ll see we’ll see how it continues going. But also, from my perspective, as a pretty Junior investigator, I learn so much by going back to some of the old literature, not like, you know, when when somebody brings me a paper and says this is really old, and it’s from 2001, or something like that. But really going back to when people were thinking and only had the tools to study the very most fundamental aspects of biology, or much more fundamental aspects of biology. I think you can learn a lot and save a lot of reinventing some wheels, and generate a lot of really cool questions by looking at these older studies.

reem hasnah 14:39
If you could offer your graduate students, any self advice of wisdom of what you gained throughout your expertise and throughout your career, what would it be and why?

Dr. Anthony Sclafani 14:49
Well,I think you have to be willing to change fields as needed and utilize the most latest techniques but one early experience that I had that was very instrumental. When I first came up with the idea that there was a Nā Pali Coast tatse, I submitted an NIH grant, it was rejected. And I resubmitted the grant, and it was rejected a second time. And in those days, the good old days, you could submit it a third time. And I submitted the grant a third time. And I think I worm him out, because I asked for four years of funding, but they only gave me two. And then, in those two years, I had already collected so much private, you know, private data, I finally had a breakthrough and showed convincing evidence. And they subsequently supported the grant for 30 years, and no, they had a problem, you know, getting funded. But if I gave up too soon, I don’t know where I would have been. So if you think you have a good idea, don’t give it up too soon. Give it a try couple of times,

Dr. Lisa Beutler 15:58
as a trainee, rather than focusing on the duration of your training, or how close or far you are, from your next goal. Focus on whether you like going to work everyday or not. Because if you like going to work on more days than you don’t like going to work, I think you’re probably doing something right. And this is a it’s a long path for all of us. So don’t get too too hung up on the number of years, you are from your next thing, just enjoy what you’re doing. And use that as your barometer for whether you’re doing the right thing.

Peter Weng 16:31
That’s really great advice.

reem hasnah 16:33
Yeah,

Peter Weng 16:33
I think that’s something I’ve been doing with myself lately. Like, how many days do I wake up? And I’m happy doing what I’m doing,

Dr. Lisa Beutler 16:38
right

Peter Weng 16:39
And if the answer is less than 50%, and maybe need to change my career path or something,

reem hasnah 16:44
maybe not change your career, change your team, the team plays a huge effect. So when you have a great team of people, and then you want to wake up every morning just to have coffee with them, and just talk science,

Peter Weng 16:57
where do you see the field of gut brand communication going in the future? And how do you want to be a part of this?

Dr. Lisa Beutler 17:04
I think I see it as really turning into more than just one field. I don’t know that I consider gut brain communication to be a totally unified field. My focus is on body weight maintenance. Tony’s focus is on development of taste preference. Are those two things related? Yes, but Tony’s built, and I’m building an independent career on two aspects of this thing that are completely different. I think that the direction that I’m probably overall most excited about and hope to contribute to is understanding how genetics lead to differences that promote or protect from obesity, why body weight maintenance succeeds in some people and fails and others is what keeps me up at night. And I think that the way we’re going to ultimately understand that from a gut brain perspective, is to really drill down the molecular aspects of this genetic aspects of this,

Dr. Anthony Sclafani 18:04
we need much more translation in our research. Because while it’s very easy to condition, a mouse in rakk, with intragastric confusions, it’s much more difficult to demonstrate food learning and adults, adult humans, although children seem to learn much, much more readily, there’s something missing. And part of it is the complexity of the human environment and the foods that we eat. But there may be differences in how rapid humans form development, you know, developmental responses to gi changes. So some of our experiments have been have to be safely translated to human work and see how we can understand the difference between humans and rodents in this regard, because it’s easy to make animals obese and maybe prevent them becoming from obese obviously, in a clinical situation, it’s much more difficult.

Peter Weng 19:01
Yes,certainly, a lot of the goals with regards to obesity are not particularly for mice would be great if we never had any obese mice. But we want to translate this impact to humans in the socially complicated diseases like obesity and anorexia. What is the biggest barrier to communicating this information to the public?

Dr. Anthony Sclafani 19:19
Well, it’s very difficult. Every week, you’ll read the New York Times The Washington Post or some magazine, and they’ll highlight a recent study that came out and it sounds like you know, it’s the best thing since whitebread was invented. And it turns out they overhype the results. So the results were based on a small group size or some cases it’s based on limited number of human subjects in an experiment. So it’s very difficult for the news media, I think, to do a good job in presenting the data because they’re always looking for the hottest headline too, and then people they don’t pay attention to it. Because the story keeps changing. So now we have, you know, artificial sweeteners cause overweight, sugar causes overweight. But what should people do? They don’t know what to do.

Dr. Lisa Beutler 20:10
I think that overhyping is a huge, huge issue. And I think some people respond by not listening. But I think that unfortunately, some fraction of the population might respond by listening too much, and get really fixated on ideas that were sold to them as being potentially like a really great cure, but are either not practicable or not going to be effective, and it leads to kind of recurrent disappointment, and really doesn’t help anyone. And I think another another problem with communicating to the public is just that, you know, this is my job. And it’s really, really hard to stay on top of the amount of literature that’s coming out on this. And for somebody who doesn’t do this as their career, and even for the media to keep up on the literature as it really is, I think, is probably borderline impossible.

Peter Weng 21:03
Yeah, I think I’ve talked to some friends who are not really in the scientific fields. And a lot of times, they’ll be like, Oh, I thought we cured that disease already. And it’s just like, No, we’ve just learned more and more about it. But there’s still a lot of work to be done, to transition a bit about our communication to the public communication amongst scientists. And I really want to thank you both for participating in this new experimental seminar type format. And I’m curious to hear how you felt the dissemination of scientific knowledge has changed over the past 20 to 50 years, from an era before PowerPoint presentations, Dr. Sclafani to a time of now we have these virtual conferences, what principles have enabled the presentation to be so memorable or having a long lasting impact? And how do you think these types of presentations or dissemination of knowledge will continue to evolve?

Dr. Anthony Sclafani 21:53
Well, I think these new methods are very effective. We used to take as a weeks to prepare our slides for a slide talk. Now we could do everything almost instantaneously include the latest data, when I was a graduate student at the University of Chicago, we literally had to go to the library, and look in index medicus, or psych abstracts to find out what the research was today, on your telephone, you could look up PubMed and find out what the latest news is. But the latest news doesn’t always tie back to the oldest studies. So you know, you have to be very careful and looking at what’s the latest brightest thing and try and put everything in context. But as far as communication wise, I’m, I just love these new forms of communication.

Dr. Lisa Beutler 22:45
And I think that’s something that stayed consistent. I mean, I don’t I can’t speak from experience from 20 or 30 years ago. But something that has stayed the same, at least at the level of the literature, and as long as I’ve been on in science, is that whatever the technology is, that is used to disseminate new scientific stories, the key to doing so successfully is to tell a story. And the science that I read, and the science that sticks with me, and the presentations that stick with me, are those that really succeed in telling a story and answering the why, and then proceeding logically through the how and what it showed. And in fact, that’s how I came to be in neuroscience, which is a field that I when I was younger I swore I would never go into.

reem hasnah 23:29
For people who are considering to be a part of this field, what advice do you give them for young scientists, graduate students, or just high school students that might have listened to us?

Dr. Anthony Sclafani 23:42
My advice is, it’s to me. It’s been an exciting way of life. I spent 50 years or more in the laboratory. I was fortunate, however, to be funded, a little nervous if I was in a new student, what the funding situation is going to be. But it’s, it’s, you know, it’s exploration. Science is just wonderful to increase your understanding of the universe.

Dr. Lisa Beutler 24:10
As a young investigator, I am nervous about the funding situation and where my career is gonna be in five years. But as I alluded to, before, I like going to work every day like I look forward to going into the lab and seeing my students and talking to them and talking to my technician. And that’s I can’t think of a better barometer for choosing a career than that. And I guess my other advice, which I think is easier advice to give than probably to take, but something that I would advise young scientists or young people thinking they want to get into scientists is to not be afraid to reach out to us because as you can probably tell, we really love talking about what we do and answering questions and talking to young scientists and young people who want to do science is one of the highlights of what I get to do. So if you’re curious, send an email. If we don’t respond, send another email, we won’t get mad at you. And just keep at it and keep trying to get your your foot into the door. Like I said, that’s easier for me to say than to do. And that also comes from a fair amount of privilege. But hopefully, if this can get to some ears, that were reluctant to actually send an email because they don’t want to be a bother because they don’t know if it’s appropriate. It is, and do it.

Dr. Anthony Sclafani 25:28
I agree.

reem hasnah 25:29
Thank you, guys. A huge thank you from the gastronorm family to the audience who attended today’s episode, your presence matters the most to us. Also, we would like to thank our speakers, Dr. Buetler, and Dr.Sclafani, who gave us from their precious time to share with us their science and knowledge. A final remark. I’m really thankful and excited to be the newest member of the gastronorm family, and to be co hosting these episodes with Peter. See you in our next episode. Stay tuned. Thank you, everyone.

Dr. Anthony Sclafani 26:02
Thank you. It was a pleasure.

Peter Weng 26:03
Thank you all.

Dr. Lisa Beutler 26:04
Thank you very much.

reem hasnah 26:10
Dr. buechler. And Dr. Sclafani taught us many fascinating things. But the major highlights of this podcast is what we eat shapes how we eat, and that different nutrients activate different receptor and as a consequence, different pathways. Also, in this episode, we received a great advice that in science never stopped trying and keep on going, knock many doors and send too many emails. with that. I want to thank you all so much for listening, and we’ll see you on the next episode. For more of our contents, you can follow us on the new Twitter account gutbrainmatters, or visit our website thinkgastronauts.com the Gastronauts podcast would be impossible without our incredible team. Meredith is our producer and team music composer. And the special thanks to the founders of Gastronauts Dr. Diego Bohorquez, and the Bohorquez laboratory.

The Gastronauts Podcast Season 3

Season 3 Transcripts

Episode 15: Shaping Our Appetite (Lisa Beutler, Norhtwestern & Anthony Sclafani, Brooklyn College)

Dr. Beutler and Dr. Sclafani share with us the neurons and gut cells that govern our desire to eat.

Episode 16: Tracking Our Behavior (Michael Krashes, NIDDK & Yulong Li, Peking University)

Dr. Krashes and Dr. Li share with us how we can leverage the latest technology to not only enhance our research but define our careers.

Episode 17: What Bugs Us (Mary Estes, Baylor & Dylan Dodd, Stanford)

Dr. Estes and Dr. Dodd get personal with the bugs in our gut.

Episode 18: Our Greatest Challenge (Kara Marshall, Scripps, Dafni Hadjieconomou, Imperial College, Marcelo Zimmer, Yale & Rio & Yuuki Obata, Crick)

We talk about what got us into science & how we see the future of science.

Episode 19: Forming Gut Circuits (Piali Sengupta, Brandeis University & Brian Gulbransen, Michigan State University)

We talk about how the circuits in our gut can direct our behaviors.

Jan 2021 – Piali Sengupta & Brian Gulbransen

The Gut That Moves Us

We kicked off the new year with a virtual discussion with Dr. Piali Sengupta & Dr. Brian Gulbransen on January 12, 2021.

Dr. Sengupta received her PhD from MIT, where she studied pheromone signaling in yeast Brent Cochran’s laboratory. She then did her post-doc at UCSF, where she identified genes that encode how olfactory receptors are encoded in C. elegans with Cori Bargmann. She was later recruited to Brandeis University in 1996. Dr. Sengupta is currently a professor of Biology at Brandeis University and was recently elected as an AAAS fellow in 2019 for her pioneering work on the molecular genetics of chemical communication and thermosensation in C. elegans.Her lab work has two primary research focuses: one is the cilia squad, which is focused on the mechanisms by which cilia form and function, and the other is the axis of taxis: which is aimed at uncovering how thermal and chemical stimuli are sensed by C. elegans

Dr. Gulbransen received his Ph.D. from the University of Colorado Health Science Center, where he studied chemoreceptor cells. He is currently an associate professor in the physiology department at Michigan State University. The focus of his lab is to understand how inflammation in the nervous system (neuroinflammation) leads to long-term changes in gastrointestinal function with a particular focus on the intercellular communication between glia, neurons and immune cells.