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

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

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

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

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 14: Developing A Connection

Dr. Kaltschmidt 0:02
Okay, so it is soft. There was a tiny bit of spice. It’s egg white with some thing spicy on top like paprika pepper or something.

Peter 0:16
Yeah, perfect. That’s exactly what it was. It was some paprika on top. I was looking on your website and you do some work on sexual function. Eggs and reproduction. Eggs are things that develop, wondering you know, try and tie something into.

Hi and welcome back to the Gastronauts podcast. My name is Peter and I’ll be your host. 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 astronauts podcast.

Welcome back. Today we have Dr. Julia Kaltschmidt. Dr. Kaltschmidt is a Wu Tsai Neurosciences Institute Faculty Scholar and an Associate Professor in the Department of Neurosurgery at Stanford Medical School. She received her undergraduate degree in Molecular Biology and Biochemistry from the University of Madison, Wisconsin. She then completed her PhD at the University of Cambridge in the UK, where she trained as a developmental biologist and studied the cellular mechanisms underlying early Drosophila nervous system development in the laboratory of Dr. Andrea Brand. During her postdoc at Columbia University, she began working with mouse as a model system, and became interested in mechanisms that underlie sensory-motor circuit connectivity in the spinal cord. She continued to explore the development and molecular regulation of spinal circuitry as an assistant professor at the Sloan Kettering Institute in New York City. And during this time, the focus of her laboratory expanded to include neuronal circuits that underlie sexual function as well as gut motility. So I want you to tell us a little bit more about your research path. I’d love to hear especially some more about the transition from your PhD to your postdoctoral phases.

Dr. Kaltschmidt 2:44
Hi, Okay, first of all, thank you for having me on this podcast. I’m very excited to be here. As you mentioned, during my PhD, I worked on fly development, particularly looking at neuroblast developmen. And after my PhD, during my postdoc, I have to be very honest, I was very interested in gastrulation, and was heavily invested into looking at labs that study gastrulation. But then decided to interview broadly, and I ended up interviewing a lot of different places all in the United States, and settled on Tom Jessel’s lab at Columbia, where we studied spinal cord circuitry in mice. That, of course, is very different from gastrulation. But I was, you know, I was very much interested in these questions of neuro-circuit formation, which of course, I had a window in during my PhD. And, you know, it was I was very attracted to Columbia to the colleagues at Columbia to the city of New York. So yeah, it was a not straightforward path, via gastrulation. But just to tell you, I thought very broadly, I was not exactly knowing what I wanted at that stage.

Peter 3:57
Yeah, and in retrospect, would you have done anything different now thinking back upon the decision […]?

Dr. Kaltschmidt 4:03
That’s an interesting question. I think all the experiences that you have in life, they shape you who you are. And I think, from that perspective, I think it’s very difficult to say I would have wanted to do something different, because, you know, it sort of made me who I am. And to me, that’s very valuable.

Peter 4:21
Yeah. So could you tell us a little bit more about some of the work that you did during your PhD?

Dr. Kaltschmidt 4:26
So, during my PhD, I worked on neuroblast development, and […] I took the approach of live imaging, which I think at the time was relatively novel. And so I had a GFP marker that would visualize the spindle. And what I noticed, and I remember actually, the moment I noticed it’s that the position of the mitotic spindle rotates during this process of cell division in the neuroblast’s division. And I remember this moment because I printed out my data, it was late at night, and there was a postdoc in the lab. And I printed this out and it was all fuzzy, right? I mean, the picture was, in retrospect, not ideal. But I, I printed it out. And I showed it to him. And I remember him saying, oh my God, do you know what you what you just found? So I found that basically, prior to the division, epithelial cells divide such that the determinants that are localized on one side of the cell get divided up into both cells equally. But for neuroblast, what happens is, is that the division is perpendicular, right? such that the determinants go into only one of the daughter cells. And to mediate that right do you have to have a it’s a 90 degree change in the axes of division. And so what I found is is that the spindle gets assembled as if an epithelial cell would divide. But then during mitosis rotates 90 degrees, and then it’s a quick flip. And then the cell divides in the perpendicular orientation. And this flip was what my PhD was about.

Peter 6:22
That’s really cool. So what I guess I’m trying to visualize what are the implications of this flip? Did you mention that the components of the cell are unevenly distributed after the flip?

Dr. Kaltschmidt 6:32
Correct. So the components you know, they are imagined, I wrote a review on this. And I tried to find a good analogy and it’s a piece of cake, right. So imagine you have chocolate cake was a raspberry frosting and on top of raspberry or a cherry, whatever. And so usually you would divide a few divided right in the middle, both people get the same. However, if you would imagine cutting 90 degrees separate Then one person gets the cake and the other one gets the frosting and the cherry, right. And so that’s the same for the for the neuroblasts. So the daughter cell gets all of the components, which is different from the mother cell.

Peter 7:14
And then understanding the mechanism of why I guess or how this neuroblast divides unequally, what are the implications for this?

Dr. Kaltschmidt 7:23
Potentially? Well, yeah, so then I went on to show that there was a mutant executable, that would not complete this flip, and would divide at a at an angle. And that, of course, then means that the determinants are not any more 100% unequally distributed, but sort of somewhere in between in between, and that has a of course, a change, or an implications for the cell fate of the cells and the cell fate and the determination of I guess, the entire nervous development.

Peter 7:58
Great. So for me gastrulation is a huge process, right? All the organs are developing everything within the body is developing. I know that you focused a bit on the nervous system in particular, was there an emphasis on the spinal cord? Or was the spinal cord something new that you had gotten into?

Dr. Kaltschmidt 8:12
So the spinal cord was something new. To me, the spinal cord is really interesting because it has a direct link to motor output. So studying the circuits of an organ that you can measure its effect directly on locomotion. It’s exciting.

Peter 8:30
Yeah, for sure. And then the other thing was that you had previously done your work in Drosophila as a model system.Then you transition to the mouse. Was there a thought that was going through your head? Were you thinking about I want to work with the mouse model system from now on or tell us some of the pros and cons in your mind about working between these two model systems?

Dr. Kaltschmidt 8:47
Yeah, to be honest, that very interesting question. I was curious about the mouse. And when I started doing my post-doc work, I very quickly realized that at the time, the tools that I was familiar with in total filler could not be translated to the mouse. And that was difficult to realize, because it was basically, you know, I wanted to do X, Y, Z, and I couldn’t do it because it wasn’t, you know, very limited with tools. So I think that was definitely a realization that I had. Of course, that’s also exciting because you can generate new tools, right? So there’s a pro for that. But coming from the fly in that sort of immediate wanting to do things space, there was a setback. But the other thing which, you know, you asked me earlier on about the transition from PhD to postdoc, mice, of course, are more expensive, right? And if you think about, I took them the approach from postdoc to faculty, and I stayed in mice that, of course, is expensive, right? I did not think about that. At the time when I was choosing my postdoc, right? I didn’t think about oh, you know, this might influence my, my expenses downstream. But, you know, some people might think about that. I didn’t, but that’s good. Clearly is a big difference.

Peter Weng 10:01
So what exactly would you say the benefits of working in a mouse model system for what you’re trying to study over within the Drosophila? [The act of] gastrulation is [different] in mouse versus the Drosophila. But studying spinal cord development is very different as well.

Dr. Kaltschmidt 10:15
Right. So I think, you know, of course, the knowledge that we gain from understanding synaptic specificity in the spinal cord of mice, ideally, should be applicable to our understanding of human synaptic specificity, particularly in the realm of, you know, we’re very interested in trying to understand what the molecular underpinnings are of the particular circuits, that knowledge should be beneficial for, for example, spinal cord injury, and you know, regrowth and recurrent activity of the axons. And that actually leads a little bit to what my lab now studies. Since our move to Stanford, it has taken up a lot of studies of the gastrointestinal tract and we have a project that basically links the spinal cord with the GI tract. Because one of the co-morbidities of spinal cord injury actually is colonic dysmotility. And we have a strong interest in trying to understand the interconnectivity of the spinal cord in the gut. And, you know, how that might be disrupted or affected in spinal cord injury.

Peter 11:18
Yeah, that’s really interesting, completely different part of the body that you’re studying the neurons within. I wanted to ask a little bit more about if you could describe your lab’s vision or focus in a sentence or two, what would you say it is? Because the spinal cord is thought of as quite disparate or not really that connected with the gut until now.

Dr. Kaltschmidt 11:37
So I mean, it’s difficult to say that in one sentence.

Peter 11:41
Or as many as just a brief idea what the vision of your laboratory is.

Dr. Kaltschmidt 11:45
So the vision is historically we tried to gain a molecular understanding of synaptic specificity, particular of the inhibitory control of the sensorimotor reflex arc and the spinal cord and more recently, we have come to take the approach of applying the tools and the knowledge that we have gained in the spinal cord to try to understand some of the questions in the enteric nervous system, which is again trying to understand the circuitry of the enteric nervous system and an understanding of that. If we understand what particular cell types do, what’s the effect of manipulating these on the, for example, under pressure ulcers of the of the GI tract? And as I said, there’s this one project, which in the lab currently that connects both.

Peter 12:27
So could you give us a little bit more information for those who are not as familiar with how neurons develop specificity within synapses? How does one neuron within the brain or within the spinal cord decide to form a synapse with another neuron within the enteric nervous system? I know the process is very complex, but from a kind of 30,000 foot view, how do you view these connections?

Dr. Kaltschmidt 12:47
I do not know yet the answer to the spinal cord connection, but I can give you our insight on the sensorimotor, or the gabaergic inhibition of the sensorimotor reflex arc. We know a lot more about that. I’ll give you an example. So very briefly, just to describe the circuits, there are three important synapses, the sensory afferent terminal, which forms a contact with motor neurons. And then there is this gabaergic inhibitory neuron that forms a contact directly onto the sensory afferent terminal. And we’ve asked what these three units, we’ve asked questions about, you know, what mediates that specificity between the gabaergic neuron and the sensory afferent terminal. Why is it not forming a contact onto motor neurons. And so we found an adhesion molecule complex, some parts of those complex are expressed on the sensory afferent terminal and another one on the GABA pre terminal. And if we remove them from either one, you can see that the number of these GABA pre terminals is reduced. So in this case, it’s a sort of an adhesion molecule mediated synapse.

Peter 13:49
And are these the three components that you think are necessary and sufficient? Or do you think there are other components that perhaps may play a role in this?

Dr. Kaltschmidt 13:56
Oh, I think there are other components as well. I mean, there’s data on positional identity. Yes. So I think, right the the other question is, for example, we can have an adhesion molecule for every particular synapse, that’s different, right? So you have to think about different concentrations of different components. So there’s definitely something else that’s going on.

Peter 14:16
So within this gabaergic interneuron, is the specificity the same with all sensory nerves.

Dr. Kaltschmidt 14:25
Great question. So we do know a lot about the sensorimotor connectivity, right, because flexors and extensors have a very particular specificity. And we don’t know very much about the gabaergic specificity besides the fact as I just said that it forms contacts on sensory afferent terminals and motor neurons. And so right, is it that you have a population that acts as an umbrella and every gaba pre terminal, or do you actually have specific effects versus extensor our pre populations that might inhibit one versus the other? And that’s exactly what one of the projects we’re doing in the lab. I’m very excited about this one. That’s exciting. I can’t wait to see you. Thanks for asking that question.

Peter 15:03
No problem. The other thing I’m wondering is whether or not this complex that you’ve seen, because we gabaergic inter neurons throughout our nervous system, have you seen this complex anywhere else outside the spinal cord? And or have you looked in other locations?

Dr. Kaltschmidt 15:17
So we haven’t looked, but it is in other systems in the brain, which makes it of course more applicable.

Peter 15:24
For sure. And then I guess the other thing that goes through my mind, as I think of this relatively naively is before you can even form this connection, you have to get there’s neurotrophic molecules, do you have a good understanding of what the factors that are being secreted that bring these guys together?

Dr. Kaltschmidt 15:39
So again, great question. No, and you’re right. So if you think about the process of synaptic specificity, there is, you know, you can take this, take it apart into different units. And one of the questions is how does the cell know which target regional lamina to go to right, and then once it reaches there, whether it can distinguish In different cell types, for example. The lamina specificity, or the in this case, the regional specificity, which is close to the motor neuron cell bodies, we do not know what mediates that. We would love to know that it’s a process that happens in the first postnatal week. We know that. And we do know that if you remove this, if via genetic surgey get rid of the sensory endings close to the motor neurons, these gabaergic neurons will Project ventually into the spinal cord, but then we retract so they will not form a contact on anything else that is not sensory terminal. So they will not seek out an ultimate target such as the one on or on or another synapse.

Peter 16:40
So there’s, in a sense, this act of constant communication, right? Because if there’s the sensory cell that’s not there, maybe it’s not receiving that signal. The beginning of time, this neuron or this interneuron isn’t really feeling motivated. I guess if we want to anthropomorphize.

Dr. Kaltschmidt 16:53
Yeah, right. Yeah. See, we call this process a stringent specificity, right? Because it’s not it’s not seeking out an ultimate synaptic finding partner, but the point being that it still grows eventually, right? Is something that is not coming from the sensory open terminal, because that’s not there, that attracts the neuron to go there. And the question is what that is?

Peter 17:14
So presumably, there’s two different molecules, right one that is involved in bringing it over, and the other one that gives it that specificity or more, but at least

Dr. Kaltschmidt 17:21
People can think about two steps in that process, at least.

Peter 17:24
Yeah. And is that stringent specificity? I guess? I am always wondering about generalizability of synaptic specificity, and I wondered whether that stringent specificity has been shown in other areas of the nervous system,

Dr. Kaltschmidt 17:36
Not to my knowledge. So in the opposite of stringent specificity, which you could call hierarchical specificity is shown in the fly, right. So you can think of the motor neurons innervating muscles, and also in C. elegans, I would say they are examples of hierarchical specificity. So it’s a no, not yet.

Peter 17:59
I think that makes it interesting. As to why this came about, right? I want to segue a bit more to another aspect of your job. We talked briefly about the gut, but there was another aspect on sexual function. Yeah. What drew you towards understanding sexual function: from sexually specific sensory information? Yeah, and the spinal cord connections there.

Dr. Kaltschmidt 18:18
Yeah, you know, I, it is a my lab website listed as an equal important project. We have, at the moment, no active research in the sexual circuitry, but we did. And we actually see the sexual circuit as an alternate circuit to locomotion. It innervates differently in the spinal court. And so we were using it as a sort of the yin-yang of trying to see how a different functional circuit, right, very different function, how that synaptic specificity is guided or correlated with different function.

Peter 18:56
Okay, can you walk me through a bit about the circuit I guess I’m not that familiar with the parts of it and all the moving components.

Dr. Kaltschmidt 19:03
Right. So all we did basically is we injected into penile muscles. And okay, so the injection is a Cholera toxin subunit B, which is our traditional injection, which we have injected before into a hind limb muscles. What that does is it labels the motor neurons as well as the set of sensory afferent terminals. And so that’s our way of labeling where cell bodies aren’t where the projections are. So yeah, basically what we did is we injected into a couple of penile muscles and what we notice is that the sensory afferent projections do not reach the locomotor muscles directly to the motor neurons. They’re basically innervating the dorsal spinal cord. And we basically use that as a space for comparison. Because the proprioceptive the locomotor, the muscle innovated in you know, we simplified by saying, well, it forms contact on the motor neuron, but it of course also has a dorsal branch. And that is in very close relationship to the penile muscle, sensory branch. And so we had something that was close vicinity and comparable.

Peter 20:04
So in your view, correct me if I’m saying this incorrectly, you’re using this other, I guess, motor system to study synaptic specificity, and it’s, in a way a different validation or a way to see whether a different mechanism of synaptic specificity is being involved. And then we touched upon the gut aspect of it. And you told me that this is something that you’re very interested in. Could you tell me about some of the work that has been done to show this connection between the two?

Dr. Kaltschmidt 20:32
So as I said, we are we are new to the field of the gut. This came about, and I did elaborate on the fact that it just came about because of spinal cord injury, right. It actually came through one of the seminars in the neurosurgery department. I learned that there was this really strong sort of comorbidity of gut dysmotility. And so we look closer and there is not a great understanding of what the connectivity is between the colon and the spinal cord. Is there one, right? I mean, there’s clearly a textbook suggestion that there is connectivity via, you know, sensory neurons going from the colon to the spinal cord and via post ganglionic neurons going to the gut. But we primarily, we were interested in a mapping the sensory integration. And so we basically injected CTB, into the colon to see what we see, that has revealed quite some interesting connectivity aspects.

Peter Weng 21:27
Yeah, that’s interesting, because I think one of the things that our laboratory really talks about is this connection is this drive to find food, right, this patient, it would be interesting in my mind to see whether a) the architecture is there that’s present and then b) can we modulate this architecture?

Dr. Kaltschmidt 21:43
Yes. And if it was, the way I think about this is that, you know, is there an architecture that’s there that we can use to, to drive peristalsis via the spinal cord.

Peter 21:58
And then the other thing that comes to my mind is you were mentioning this comorbidity associated with people who have spinal cord injury and colonic dysmotility. Yeah. I wonder whether or not people who have colonic dysmotility are more susceptible to developing spine injuries?

Dr. Kaltschmidt 22:15
I don’t know whether it is. But I think about it that way around. I mean, think about it the other way around, right? Because you’ve interrupted the spinal circuit, because there isn’t interconnectivity. We are disrupting somehow the motor function. And you’re right, there are other, you know, besides spinal injury, there is Parkinson’s disease, there’s autism, all of those have gi dysmotility phenotypes. Right. And the question is why? I think it has a lot to do with actually the enteric neurons themselves. One question in a lab is whether, you know, autism associated genes are expressed in the enteric nervous system.

Peter 22:52
I think that’s reasonable. It’s just, I guess my thought is whether or not this pathway has the potential to be bidirectional.

Dr. Kaltschmidt 22:58
I see what you mean. Yeah. Possibly

Peter 23:01
It’s an exciting avenue. I feel like there’s a lot out there for us to figure out. And then the other thing that comes to mind is, is there a way to tie together the synaptic specificity between these different motor circuits like the erectile dysfunction with this gut dysmotility? Or is there like any way to tie all these circuits together?

Dr. Kaltschmidt 23:18
Yeah, so that I don’t know. But, you know, actually, if you look at spinal cord injury comorbidities that are listed by patients as wanting to be corrected, or suffering most it is first colonic dysmotility, then its sexual function and then its limb function. So sexual function is clearly also affected. I do not know to what extent there is a link, right. But both circuits could be going through the spinal cord, right.

Peter Weng 23:48
I think intuitively, it makes sense that they are going but understanding I guess, the specificity of how these circuits map. Yeah, very interesting.

I want to ask a bit more about some of your writing actually. So I noticed that you had recently published a preview in neuron titled, chandelier cells swipe right for l1cam. I thought the title was very interesting, right? I, I think it really draws the attention of people who are in kind of modern day society looking at their apps and swiping left or right Why do you think the titles for previews and news and views are so different from the titles in actual articles?

Dr. Kaltschmidt 24:44
Interesting. So first of all, I need to credit my postdoc, Ryan Hamnett for that title. He’s the first author of this preview. And it’s a spectacular writer. Each time I write a preview. I think I am I feel challenged to Come up with a title that is sort of fun and has a second meaning that makes people think. I think it’s there are no real restrictions to that. I personally think that a title for a paper should be very precise. I think every word in that title shouldn’t be visualized in the paper. So right. So when I read the title, I would love to see that reflected in the paper. It’s almost like a mini summary. Why that is? Maybe traditionally so right? I mean, maybe because it doesn’t allow for overstatements.

Peter 25:42
And then I guess what you just mentioned made me think of these graphical abstract abstracts that certain journals have. What do you think the value of a graphical abstract is if your title should give you that image?

Dr. Kaltschmidt 25:53
Well, you know, okay, I personally love graphical abstract. I do spend a lot of time making graphical abstracts. I once taught a class where I also that was one of the assignments doing a graphical abstract. You’re right. That might seem a double effort to summarize the paper. However, I think it has different values. Right? I’m personally a very visual person. So I look at this graphical abstract, and I really get a lot of information out of that. So I think it is perfectly valuable to have both, you know, the the graphic abstract, I think can include more, more content, maybe more detail.

Peter 26:28
Right. So one of the principles that you had mentioned for your title is that it should give you a very precise specific image of what is to come in the paper. Yeah, with regards to creating an image that summarizes your entire paper, are there any principles that you focus on or follow?

Dr. Kaltschmidt 26:43
I’m a very visual person, I was actually accepted to art school originally, and so I had to make this decision between art and science. And I think it has influenced how I make figures for a paper and how I you know, I we have our confocal in the lab and love imaging. So it’s very important to me. And when I think about a graphical abstract, I think trying to make it in a sort of minimalistic style, which still represents the message I think is essential. I’ve done graphical abstracts and I, you know, generally I have too much stuff in my graphical abstract at first and then I think the challenges is to make it clear to sort of minimalize, to sort of conceptualize, I think that’s a challenge. I think it’s not easy to make it graphical abstracts that are actually good. But I think it’s actually um, it’s good also for the person who makes it because it’s, you really have to think about the most, most important things in your your paper.

Peter 27:45
Interesting. One other question that I wanted to ask is, I saw that you are a co-editor in chief for the journal Neural Development. Can you tell us a bit more about this position and why you chose to pursue it?

Dr. Kaltschmidt 27:55
You’re right. So I’m co-editor in chief of rural development lots of reasons why I think this is an important position. First, I want to say, I have really amazing co-editors. It’s wonderful to work as a team. And so if you look at my research, we do molecular neurobiology. If you look at the history of molecular neurobiology, I think, I think it’s an important field that is very important to be continued. And of course, you know, we have functional data added and very valuable additional information. Neural development is a very, I’d say, traditional journal, which focuses on neural development. As such, it is very important to me that it continues to get the attention as a research field. When I was invited to be co-editor, I said yes, because I think it is an interesting challenge nowadays to keep that research field on the on the radar of all minds.

Peter 28:57
You had mentioned molecular neuroscience as being a classic field, I think of at least in my neurobiology courses discrete between molecular neuroscience and systems neuroscience gotten very popular, right? Why do you think molecular neuroscience is important for neural development?

Dr. Kaltschmidt 29:13
I want to make clear that, you know, I think all the other fields are very important to right. But at the end, if we understand how something functions, we understand the systems biology. At the end, I think it is very important to know how these connections are made, right? It’s to me, it is important to know, you know, what are the molecules or the mechanisms or the the rules that make particular synapses personally, to me, that is sort of the the essence of synaptic circuits: how does it interconnect? And so it’s, rather than looking at a bigger entity or building it’s, it’s trying to look at, you know, how does the brick fit in the wall Next to the other brick.

Peter 30:02
Yeah, certainly, I think what I, what I’m hearing is you really like to zoom in to see, there’s this huge system that’s going on. We can only study it if we study it piece by piece and what you’re interested in, is that really the glue that holds the bricks together.

Dr. Kaltschmidt 30:17
Yeah. And it’s, you know, it’s, um, it’s a difficult word than glue, actually, because glue, oftentimes to me means it doesn’t mean specificity. Right. So you have to imagine a glue that only glues certain parts.

Peter 30:30
Yeah, it’s like a lock and key maybe more specific.

Dr. Kaltschmidt 30:33
Exactly what it is right. It’s a lock and key.

Peter 30:35
Yeah, you’re right. Think that’s the classic.

Dr. Kaltschmidt 30:37
Yes, absolutely. Yeah.

Peter 30:38
Really neat. Well, I want to thank you so much for your insights and your time.

Dr. Kaltschmidt 30:43
Yes, it was fun. Thank you.

Peter 30:54
Dr. Kalschmidt walked us through some of her scientific work on what are the molecules, mechanisms and rules that allow neurons to make connections. And along the way, we learned about how she thought about working with a particular model organism and the importance of being precise with our language, and especially in our titles.

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 content, you can follow us on twitter @gutbrains or visit our website @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 Gastraonuts: Dr. Diego Bohórquez and the Bohorquez laboratory.

Episode 13: Curb Your Consumption

Dr. Kanoski 0:00
Definitely fruit. I believe it was an orange and a blueberry, if I had to guess.

Peter 0:10
Yeah, you can open up your eyes. Perfect. It was a bit of a fruit salad. Some of it had fallen out but you got the tangerine and the blueberry exactly what it was the reason why these fruits were chosen, I was looking into some studies to see the effects of certain types of food on cognitive decline. And there have been studies that have shown that strawberry and spinach can be effective as a long term dietary intervention.

Dr. Kanoski 0:33
I actually have an orange tree in my yard in Los Angeles. We have apples oranges all the time, your own oranges.

Peter 0:52
Hi and welcome back to the Gastronauts podcast. My name is Peter and I’ll be your host. 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 astronauts podcast.

Today we have Dr. Scott Kanoski, an associate professor in the Department of Biological Sciences at the University of Southern California. Dr. Kanoski completed his PhD in Psychology at Purdue University in Dr. Davidson’s lab, his postdoctoral fellowship at the University of Pennsylvania and Dr. Grill’s lab and was recruited for a faculty position at the University of Southern California. His research focuses on neural systems that control feeding behavior. And in particular, Dr. Kanoski is interested in studying how dietary and metabolic factors can contribute to cognitive decline, as well as how environmental cues can play a role in controlling feeding.

Could you tell us how you got into studying how consumptions of sugars and fats can be linked with memory deficits?

Dr. Kanoski 2:25
Sure, this was actually part of my dissertation work when I was at Purdue University. There were a few papers coming out at that time showing links between consuming unhealthy diets, so what we would consider to be a quote, Western diet, that’s high in saturated fatty acids and sugar, with cognitive impairments. And what I wanted to do at that time was trying to understand the specific nature of those cognitive impairments that were associated with consuming these unhealthy diets that many of us- I’m guilty of times- myself consume. And it turns out that the hippocampus is a canary in the coal mine in the sense that it’s very sensitive to dietary and metabolic perturbations. So you see, even after consuming these diets for a very short period of time, you see deficits and hippocampal-dependent memory tasks. And this is referring to things like remembering what we did yesterday, or remembering how to get to work. These are memory processes that rely on this brain structure. And more recently in my lab, we’ve been trying to isolate the specific dietary factors that are causing this because a Western diet is different from a healthy diet and in many ways, and we’ve found a role for sugar independent of elevated fat content. However, the effects of sugar on hippocampal dependent memory deficits appear to be exacerbated during early life periods of development, so this is referring to the the juvenile and adolescent phase. So if you consume excess sugar during these periods, at least in rodent models, we see long lasting deficits into adulthood.

Peter 3:59
There was a lot of information there. I want to unpack here a little bit. The first thing I was wondering was how did you stumble on the hippocampus? I know the brain is a very complex region, when you looked at a dietary intervention or a Western diet, did you look at the whole brain and you looked at particular regions that lit up that showed you to focus on the hippocampus? Or did you know-

Dr. Kanoski 4:20
We actually follow the behavior. So psychology is my background. And I tend to start with the behavior and then break it down and get into the brain after that. And what we saw was impairments in memory tasks when animals would consume these diets that were similar to what you would see if you lesion the hippocampus, so starting from the behavior, we noticed a pattern. And then after that, you can look into the brain and try to understand what’s changing in the hippocampus that may be causing these deficits? Yeah.

Peter 4:47
Okay, so behavior was the main focus, and then you went to the brain regions? Interesting. And then the other thing that you had mentioned was that perhaps the brain is particularly vulnerable to these diets at a period in adolescence. Could you tell us some more about how you got into that research or how you identified that?

Dr. Kanoski 5:00
Yeah, we started this project because we thought it was important with regards to human health because if you look at who’s consuming the most sugar, at least in the United States, the highest sugar consumers are children, so they can consume up to 15 to 20% of their entire calories can come from sugar in younger populations. As we get older, we tend to consume a bit less sugar. That was one of the reasons we were interested in studying this developmental period. Just looking at what ages humans are actually consuming sugar in excess.

Peter 5:36
Do you feel that just because we consume more at this adolescent period? If we consumed more at a later period in life, would we see the same effects or is it just because the brain is so susceptible during that period?

Dr. Kanoski 5:49
Yeah, I take caution and extending our Roden data directly to humans. But in rodents, if sugars consumed in excess during adulthood, we don’t see the same pattern of memory deficits.

Peter 6:00
Interesting, well, I guess I’m past that point in my life. So, there’s no hope for me now.
And the other thing that you mentioned was your first interest in the hippocampus started in your graduate studies, your research has really stayed focused on the impact of diet on memory, from your work as a graduate student, to your postdoc to your work as a PI now. How have you been able to navigate the field of academia so that you’re able to distinguish your work that you’re doing now from the work that you’ve done previously.

Dr. Kanoski 6:30
One of the things that we look at that I think is unique in the hippocampus world is, in addition to looking at how the brain is influenced by dietary factors, we also try to understand how the hippocampus controls feeding behavior. And this is a brain region that’s not traditionally linked with the control of feeding behavior. But it is the case that our memory function influences our eating behavior. So we have to remember where we found the food what we consumed, and these memory processes powerfully influencing what we eat, and our overall energy regulation. So that’s one of the things that I think we’re somewhat unique in studying [which] is trying to link memory processes to the control of food intake and bodyweight regulation.

Peter 7:11
I can definitely see how when we were more of a scavenging or a hunter-gatherer society, it’s important to have this memory of where we got the food. And this context will help us define where we’re going to get food easily. Now that food is so ubiquitous, and our rates of obesity are so high, where do you see this kind of translating?

Dr. Kanoski 7:29
Yeah, that’s a good point. So we we don’t have to try really hard to find food now. But what the hippocampus is important for is detecting and interpreting internal cues, not just for navigating the external world. For example, if you lesion the hippocampus in rats, they’re not able to use different levels of food restriction as discriminative cues for some kind of event. It could be a foot shock or a food pellet. And then if you look at humans that have damage to the hippocampus, they also seem to be insensitive to hunger and satiety cues. So if dietary factors lead to hippocampal dysfunction in humans, this may lead to overeating potentially. If individuals are less sensitive to hunger and satiety cues, the default behavioral strategy is generally to eat more and not less.

Peter 8:18
You mentioned these internal cues. Could you give us some example of what specific internal cues? And you said the hippocampus leverages both the external and internal cues. Do we have an idea of how this turns into behavior how this is integrated?

Dr. Kanoski 8:31
We think the neurons in the hippocampus are receiving information about the external world, and then also about the internal world as it relates to hunger and satiety. And then it’s taking these different categories of information and interpreting them to appropriately guide behavior.

Peter 8:49
And are there specific molecules or hormones or mediators of these effects?

Dr. Kanoski 8:53
There are the hippocampus is sensitive and receiving information to a lot of feeding relevant systems. These are hormones, for example, that are secreted during feeding or immediately prior to feeding. Many of these signals act directly in the hippocampus. We think that some of these endocrine signals coming from the periphery from the gastrointestinal tract are in part how this internal information about hunger and satiety is communicated to the hippocampus.

Peter 9:22
Interesting. Could you walk us through, in your head, the process of what happens when we’re thinking about eating, or when we’re consuming food and how- I know this is a huge concept- but how do you think about when we’re going about eating? What factors are involved in signaling to the brain and from the gut as well?

Dr. Kanoski 9:40
We tend to eat based on fixed patterns. Most of us we don’t generally graze throughout the day until we’re full. So the meal is a very important component of how much intake we generally consume. And you can manipulate how much people consume by doing blatant manipulations like having a larger portion size, people tend to eat more. So a lot of our meal regulation is controlled by external factors; we eat three times a day, for example, we eat what’s on the plate. But what’s important is the decisions in terms of what we eat, I think is a very important determinant of how much people consume.

Peter 10:19
So could you tell us a little bit more about what you mean by that? So what we eat is a determinant of what we consume in the sense that if this is a high Western diet or a high carb, high fat diet, will that influence us to consume more to consume less? How exactly does that go?

Dr. Kanoski 10:35
Generally, foods that are unhealthy and are designed to be very palatable. So if you have a donut, for example, most people like donuts, this is high in both fat and sugar and sort of a prototypical element of a Western diet. And when something is more palatable, we’re able to consume more of it. And you get a blunted satiation response because of that positive reward experience of consuming something palatable.

Peter 11:03
Something that’s palatable actually blunts the satiation?

Dr. Kanoski 11:08
That is true. And if that’s been shown biologically in animal models, if they’re maintained on a Western diet, you see impaired signaling that’s called satiation, where we have these biological signals that arise from the GI tract during a meal, whose function is to terminate the meal eventually, we need to stop eating right. And what you see in animals that are maintained on a Western diet is these biological signals are blunted, they’re weaker, they’re less effective in terminating a meal, these satiation signals.

Peter 11:39
And where are these satiation signals coming from?

Dr. Kanoski 11:41
There’s different different signals: mechanical distention of the stomach is one. So just the physical expansion of the stomach by the food that we’ve consumed. There’s also intestinal hormone signals. One of the classic signals his cholecystokinin or cck, which is secreted from the intestines during eating. This signal acts in part to try to increase satiation and terminate feeding. And both of the two I just described, their effectiveness is blunted in animals that are maintained on an unhealthy yet palatable diet.

Peter 12:16
Interesting, we just came to my mind is sometimes our lab will bring leftovers from dinner or something and put them in our lab meeting room. And there’s it’s oftentimes unhealthy food. And it’s just because it’s there. I don’t really consider the unhealthy nature of it, but I just go about and start eating it regardless. And I was wondering, how does this play into the fact that we have these strict three time a day meals, but like, we also do this grazing when we just present we kind of impulsively just eat at it. How do you correspond these two thoughts together?

Dr. Kanoski 12:49
I’m interested in both, so I studied how the brain controls normal feeding behavior, meal frequency meal size, but you mentioned impulsivity and that’s something that that my lab is very much interested in. In fact, we just had a publication come out a few months ago on a neural circuit. So how the brain is causing individuals to be impulsive, and in this case it was impulsive, responding for palatable, rewarding foods as you just described.

Peter 13:18
And can you unpack the circuit a bit more is it part of the hippocampus is a different part of the brain?

Dr. Kanoski 13:21
It is part of the circuit. So the circuit that we identified, it originates with a neuropeptide. It’s called melanin concentrating hormone. And it’s produced in the hypothalamus, the lateral hypothalamus. And this neuropeptide communicates throughout the brain but one of the strong targets of these neurons that produce the peptide is the hippocampus, the ventral region. And what we found which was interesting if you manipulate this MCH to hippocampus pathway, the animals were more impulsive for food, but it didn’t increase their free feeding behavior. It didn’t increase appetite didn’t increase their motivation to work for the food. It was very selective to that impulsive response.

Peter 14:03
And how exactly do you determine impulsive behavior in a rodent system?

Dr. Kanoski 14:08
That’s a good question. There’s a couple ways you can do that. One is a task where the animals learn to press the lever for a palatable food, donut hole, if you will, for equivalents. And they have to learn to refrain from pressing again for a 20 second period to get the next pellet. And then ideally, the animal would press every 20 seconds and get a pellet every 20 seconds. But what animals do is they can’t wait 20 seconds, they might hit it at say 15 seconds into that period, and that’s resetting the 20 second clock. So if the animal hit the lever every 15 seconds, they wouldn’t get any food at all. That’s one of the ways the other way is a more classic task is called delay discounting. And the human equivalent, you’ve probably seen videos where you have a kid, a toddler, a small child, who’s given a marshmallow and told you can eat that marshmallow now or if you wait for. Five minutes when I come back, I’ll give you two marshmallows. There’s a task that’s comparable to that in rodents, where they, they have two levers to choose from. One gives them a small but immediate reinforcement. And the other one gives them a larger reinforcement, but after different delay periods, and it’s always advantageous to take the large reinforcement lever, but what animals do is as that delay increases, they go for that short immediate reinforcement. So these are two different impulsivity tasks. One is an impulsive response. The first one the second is an impulsive choice. And we found that this mth brain system is increasing impulsivity for both of those tasks.

Peter 15:42
Forgive my naiveness, I’m not a behavioral scientist, but I was wondering what came to mind here was addiction in some sense. So it seems like if I’m wrote in presses more frequently for a pellet, could it also be addicting and what exactly is the distinction between addiction and impulsivity?

Dr. Kanoski 16:01
Yeah, I try to avoid that term. There’s a lot of controversy with regards to whether food certain foods can be addicting. I try to stay out of that controversy. But it is the case that there are common brain circuits that are involved with both food reward, and with drugs of abuse, cocaine, heroin, for example. So they are tapping into similar circuitry, but via widely different mechanisms. I’m not one that would promote the idea that food itself is addicting.

Peter 16:28
Okay. Good to know. I was also wondering, with this idea of this melanin concentrating hormone being sent from the hypothalamus to the hippocampus. Is it in the sense that these levels are upregulated or increased during impulsive behaviors? Or are they decreased? Or is there a way to change the gain on this?

Dr. Kanoski 16:49
Yeah, that’s a good question. And we had some really surprising results. So we found via different mechanisms, if we drive up the system, the animals are more impulsive. So if we wanted to drive down system, you would predict? What would you predict?

Peter 17:03
They would be less impulsive.

Dr. Kanoski 17:04
That’s what we thought too. But that’s not what we found. We drove down the system via multiple means. And every time we did that the animals were again more impulsive. So we think of it as there’s a healthy tone of the system that keeps impulsivity in check. And if you perturb that tone in either direction, you get a release on that check on impulsivity.

Peter 17:27
What pops to my mind is, is there a way to decrease impulsive behavior, but that is very complicated now that you think that there’s this physiologic setpoint. So whenever it goes up, right to try and turn it down.

Dr. Kanoski 17:37
Or it could be an impulsive, individual that that tone is too high or too low in that potentially it could be corrected with pharmacological approaches, but it’s not. We’re not there yet.

Peter 17:48
Yeah, well, I can’t wait to see what you guys do in the near future. I wanted to transition a bit more to some of your career paths. W hen someone is becoming a new PI or someone who’s making that transition from a senior postdoc to a PhD position, what advice would you give to someone who’s just starting a laboratory?

Dr. Kanoski 18:05
Good question. For me, that was seven years ago, almost to the day. I started at USC in January of 2013. And it’s a very overwhelming thing to start a lab. But you have to just take it one day at a time. And one of my initial strategies was to not put all of my eggs in one basket, but rather have two or three different very different research projects. When I started the lab, my rationale was, NIH funding is hard to predict, right? And you may have a project that at one point was something that NIH would generally fund, but the winds blow in different directions with the funding agencies. So if you put all of your effort into one project, you’re at a risk of not getting that project funded. So what I did was try to start three different, somewhat overlapping but very different projects early on, and they’ve all slowly developed into funded projects, fortunately.

Peter 19:02
And how do you know what the magic number of projects is? If you can envision yourself doing- is three, is the magic number five?

Dr. Kanoski 19:12
I have probably five right now, you know, some people work better with more than that fewer than that. I think it’s it’s unique to each individual.

Peter 19:17
Do you think it’s also dependent on the starting size of your lab? Do you have the physical human power to go about that?

Dr. Kanoski 19:23
Yeah. And that’s going to be reflective of your your startup package, how much funding you’re given how much space you’re given when you start the lab. Another thing that I get asked about a lot is how do you hire people? Do you hire someone for a certain skill? Or do you hire someone based on a personality? It’s really difficult to describe, and we all make mistakes in that arena. But I generally try to hire people that aren’t necessarily bringing in a skill but that I find are really engaged in the research that we’re doing. I call it the fire in the belly. So if rotation student doing technically everything right in the lab, but I don’t see that enthusiasm for the research or not bringing papers to my office and excited about it, then I don’t think that’s generally a good fit for me.

Peter 20:13
And do you think your hiring practices have changed? I guess what I’m thinking is the first person that you hire often is a very big decision point for you. And do you think your thoughts on what is valuable for personnel in your laboratory has changed from this first hire to now?

Dr. Kanoski 20:27
I do, because at that point, I was just it was just me, right. And I needed to order stuff and set things up. And now I have a much larger lab. So it does change as the lab changes.

Peter 20:41
One thing that you touched upon earlier was NIH funding is really hard to predict. And you have been incredibly successful. You’ve had three aro ones recently funded and congratulations on that. I was wondering, do you have any advice [for] younger investigators trying to get this grant funding is there a particular avenue that they should approach or there’s what goes through your head when you’re trying to give someone advice for-

Dr. Kanoski 21:05
Tricks of the trade for grant writing? Certainly. Yeah. One thing that is always helped me is to focus a lot on the specific aims page. Because if you lose the reviewers there, that’s it, you’re done. So I consider that page, it has to be a masterpiece. It has to tell a story be somewhat redundant, but not too redundant. has to really connect with the reader. So I spend probably a solid month on that one page before I write the rest of the grant. And I don’t move on until that’s at least from my perspective, as close to perfect as I can get it.

Peter 21:39
Yeah. So really hone in on that specific games.

Dr. Kanoski 21:40
I think it’s critically important. Yeah. And another thing for, particularly for younger investigators trying to get fellowships, and I think we all know this, but it’s worth pointing out to get a funded template that’s close to your area of research. And you get this by reaching out to colleagues and sometimes you have that within the lab that you’re in, but it’s useful to have some kind [of] recently funded template, this is a grant for that same mechanism you’re trying to get that was successfully funded.

Peter 22:10
But then at the same time you have to differentiate-

Dr. Kanoski 22:21
Of course. It’s not that you’re using that research, but it just it’s to get you the feel of what a successful grant for that funding mechanism looks like.

Peter 22:17
That’s really great advice.

Dr. Kanoski 22:18
And you’ll find that people are generally collegial, and will share that with you.

Peter 22:23
Yeah, with this whole talk of grants, where we’re thinking where the research is going, where do you see your lab going? Or where do you envision the five projects that you’re working on? Do you see any way to consolidate them? Or do you see them as five separate projects moving into the future? I know, we’ve probably touched upon two or three of them.

Dr. Kanoski 22:40
They’re all connected in some way most of our projects focus on on some elements of hippocampus, not all of them. But to be honest, I don’t look too far ahead. I try to focus on the data. That’s what drives me. I try not to look too far beyond the data. I mean, you have to to some extent to write a grant, you have to imagine some experiments that you might do. But the nice thing about the NIH model is that it’s not a contract. You don’t have to do those experiments, you have to do something that’s somewhat related. But it allows you to follow your data, make discoveries, find unexpected results, and then go in a different direction based on those results.

Peter 22:21
Really neat. One of the other things that I think about is oftentimes we look at research and we feel it’s very removed from our day to day practice. A lot of the work that you’re doing is something that is fundamental to our day to day practice. Eating is something that we do every day and understanding what motivates our decision to go after food or when to eat is something that I think about on a daily basis. And I was wondering how your research has impacted your day to day life or are your thoughts on eating?

Dr. Kanoski 23:46
Well, I’m a vegan, and it’s probably related to what I study, but I do tend to think carefully about what I eat probably more so than people that aren’t energy balance researchers per se and it’s not unique to me, you know, a lot of my colleagues are foodies. And are chefs.

Peter 24:08
Do you mind me asking what went behind the decision for you to become a vegan? Or have you always been a vegan?

Dr. Kanoski 24:13
I’ve been a vegetarian for about 20 years and just thought I would try a strict vegan diet a couple years ago. And it’s not for everyone, but it worked pretty well for me, so stuck with it so far.

Peter 24:24
And have you looked at the effects of a vegan diet on the hippocampus? Or is there any research that you could call to?

Dr. Kanoski 24:32
Well, the problem with that is rodent diets aren’t vegan. So the baseline isn’t [there]. But it’s not something I’m interested in studying directly.

Peter 24:40
And then the other thing you mentioned was you associate with people who are foodies, not intentionally, but just by nature of the trade. And I was wondering, does your lab do food outings or do you go as a lab to go try out different types of food is food a big part of your lifestyle as well?

Dr. Kanoski 24:57
Not necessarily. I mean, personally, it is. But as a lab we do outings together, we have activities, but they’re generally not focused on food. For example, we went ziplining on Catalina Island. Recently, we’ve done a few escape rooms. We’re going to go drive ATV vehicles at Lake Arrowhead. So we do that kind of thing. But we do have a Christmas lunch at the same Thai restaurant every year. Yeah, that’s our only food activity.

Peter 25:26
Sometimes the public perception of scientists is that of people who are in white coats doing research all the time, in my kind of experience has been very different, right? We have all these lab outings, we have these activities that allow us to bond and I was wondering what do you think the value of these lab outings is for team cohesiveness or even your science in general?

Dr. Kanoski 25:49
I think the lab is version of a family. So I don’t think it’s healthy if the only way that people are interacting is in the trenches of the lab. And I try to keep things light in my lab and and not just to always talk about the data.

Peter 26:21
You mentioned earlier that someone has to have kind of a fire in the belly for you to want them to really be a part of your laboratory. What else are you looking for in graduate students? And what do you hope to instill in these graduate students as you are a mentor to them across their training?

Dr. Kanoski 26:39
I want them to enjoy the science. I think it’s important, for example, to one to plug your own data, right? I don’t want to have to tell someone, you’re falling behind. I need to see this. If someone’s really enthusiastic about the research. I don’t have to nag them about anything.

Peter 26:56
So kind of this inner drive or this inner motivation, and how do you go about instilling that in your trainees? Or is it something that someone just naturally has?

Dr. Kanoski 27:05
Yeah, I mean, I don’t know if there’s an exact recipe for how you instill that enthusiasm. I think some of its inherent, but some of it comes through seeing your project succeed, or finding an unexpected but exciting result that led you in a different direction.

Peter 27:20
Have you had any of those experiences yourself that have led you to pursue a field that’s different than what you thought you were going to go into?

Dr. Kanoski 27:27
Yeah, I guess you could say that I joined Terry Davidson’s lab at Purdue, not because I was interested in feeding behavior, but rather I was interested in the hippocampus and what types of memory processes that brain region is regulating. But at that time, there were a lot of feeding related researchers at Purdue, including some that studied the gut brain axis, the vagus nerve and their thought was really influencing my thought at the time and we started to think about how the hippocampus and memory processes influence feeding behavior because at the end of the day, that’s a very important behavior for for organisms. How do you acquire food? What are you consuming? Yeah, certainly. So I got into feeding by by accident, it wasn’t my intention.

Peter 28:11
That’s nice. Just follow the research, follow the data, what you’d mentioned earlier. And you’ve talked about the vagus a bit. This is one of the projects we hadn’t talked about earlier. Could you tell us a little bit more about this vagus project that you’re talking about potentially linking the hippocampus into vagus in the gut?

Dr. Kanoski 28:26
Yeah, so the vagus nerve is 10th cranial nerve, and it’s a conduit of neural communication between the gut and the brain. So this nerve has cell bodies located outside of the brain, the nodose ganglion, and the sensory fibers of this nerve innervate, the gastrointestinal tract, other organs as well, but we’re focused in my lab on the GI tract. And one of the signals that’s carried by this nerve is something I referred to earlier, the satiation process, which leads to the termination of feeding. And that’s really the classic way that
this nerve has been studied in the context of feeding is the communication of these satiation signals. But there’s also a connection between gut derived signals the vagus nerve and the hippocampus. And we knew that before we got into this project based on some functional neuroimaging results, where if you expand the stomach, for example, you see a high level of neural activity in hippocampus. In humans, there was a study that stimulated the gastric branch of the vagus nerve. And somewhat surprising to the investigators at that time this was in 2006, was that the activity the blood flow activity, using fMRI was the highest in the hippocampus of anywhere else in the brain. So there’s this mysterious connection, but the function of that connection had not been studied in depth. And this is a project where we found that if you selectively eliminate the guts sensory nerve that innervates the upper gut, so the stomach and the intestines, you see severe impairments in memory processes that rely on the hippocampus. And we’re really interested if there’s a functional connection there. And what we then did is to try to map the pathway through which these gut signals are eventually getting to the hippocampus. And when I say map the pathway, we’re looking at what endocrine signals might be involved, what neurotransmitters might be involved, and what are the connections in the brain through which this information is getting there.

Peter 30:25
That’s really neat. Do we know like what the exact pathway is? And does it go through the hypothalamus and other regions that you had talked about earlier and whether or not this is associated with impulsive eating? Is the Vegas associated with impulsive eating as well?

Dr. Kanoski 30:38
I don’t know any links between the vagus and impulsivity off the top of my head, but we do know a bit about the pathway. But it doesn’t seem to go through the hypothalamus. In this case, there’s a connection we identified through the medial septum, which is interesting because this region connects to the hippocampus and this is one of the regions that’s most affected by Alzheimer’s disease, this colon urge acceptable input to hippocampus. And in fact, Alzheimer’s medications largely target cholinergic septal input and so we’ve identified a pathway from the gut through the medial septum to the hippocampus that we’re now studying.

Peter 31:18
That’ll be really interesting [to see] whether or not an ingestible can be derived or some pharmaceutical that targets that gut specifically to maybe perhaps lower risk of Alzheimer’s.

Dr. Kanoski 31:29
Yeah, we’re actually studying that now. Very early in the project, but we’re interested in if you amplify the gut vagus signal in models of Alzheimer’s in rodents, can we attenuate some of the cognitive deficits? That’s something we’re slowly starting to get into now.

Peter 31:46
Yeah, that’s really exciting. I can’t wait to see what you guys find out from that. Well, great. Thank you so much for your time.

Dr. Kanoski 31:51

Peter 32:03
Dr. Kanoski taught us how the hippocampus, an area of the brain that is traditionally thought to govern learning and memory, can control feeding behavior and energy regulation, reminding us that seemingly separate areas of our body are perhaps more closely linked than we think and may work together to regulate our behavior. Similarly, when starting up a laboratory, it is key to pursue parallel avenues of research that may seem unrelated initially but may tie together in time. 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 content, you can follow us on twitter @gutbrains or visit our website @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 Gastraonuts: Dr. Diego Bohórquez and the Bohorquez laboratory.

The Gastronauts Podcast Season 2

Season 2 Transcripts

Episode 14: Developing A Connection (Julia Kaltschmidt, Stanford)

Dr. Kaltschmidt tells us how neurons in the spinal cord form connections with other nerves.

Episode 13: Curb Your Consumption (Scott Kanoski, USC)

Dr. Kanoski tells us how the hippocampus is involved in feeding behavior.

Episode 12: Mind The Microbes (Carlotta Ronda, Columbia; Martina Sgritta, Baylor)

Dr. Ronda tells us about how she thinks about modifying microbial communities in our gut. Dr. Sgritta tells us about how a particular bacteria can be used to treat autism spectrum disorder.

Episode 11: Jumpstart Your Career (Natale Sciolino, NIEHS & Sofia Axelrod, Rockefeller)

Dr. Sciolino tells us about how a region in your brain thought to regulate stress also governs eating. Dr. Axelrod tells us about how circadian rhythms work to govern our lives.

Episode 10: Food For Thought (Gary Schwartz, Einstein)

Dr. Schwartz tells us about how he thinks about researching how our body makes sense of food.

Episode 9: Beyond The Hypothesis (Hans Clevers, Utrecht)

Dr. Clevers shares both his research experiences and how he thinks about the scientific process.

Episode 8: Translating Disease Models (James Bayrer, UCSF)

Dr. Bayrer shares his work on intestinal organoids and irritable bowel syndrome and how we can optimize time management.

Episode 7: Developing Our Creativity (Gary Wu, UPenn)

Dr. Wu shares his experiences as both a physician and scientist and how we can develop the skills to think creatively and communicate effectively.

Jun 2018 – Robert Heuckeroth

Dr. Robert Heuckeroth, M.D. Ph.D. is a Professor of Pediatrics and practicing pediatric gastroenterologist at The Children’s Hospital of Philadelphia- Research Institute. His research aims to better understand enteric nervous system anatomy and development to translate into clinical pathology. One of the diseases he studies is Hirschsprung’s disease, a disease in which the distal portion of the bowel is aganglionic due to defective nerve cell migration. This lack of nerve cells prevents the bowel from working correctly causing significant obstruction. Dr. Heuckeroth has provided insight into how the enteric nervous system develops and what external factors affect its development. Hirschsprung’s disease is commonly associated with RET mutations, as RET signaling is critical for enteric nervous system proliferation, migration, and network formation. Dr. Heuckeroth’s work has identified glial cell line-derived neurotrophic factor (GDNF) as an important molecule in establishing enteric nervous system structure and function. His lab has also identified external, prenatal factors that promote proper enteric nervous system development. Vitamin A is essential for enteric nervous system development. Additionally, they have shown that maternal usage of ibuprofen slows migration of enteric nervous system precursor cells and predisposes for Hirschsprung’s disease. They will continue to investigate the internal and external factors that contribute to enteric nervous system development with hopes of both preventing childhood bowel motility disorders.

Apr 2018 – Sean Adams

Metabolomics and xenometabolomics: Applications to study metabolic health

Dr. Sean Adams is the Director of the Arkansas Children’s Nutrition Center where his research aims to understand the molecular processes that underlie metabolic disease and obesity. Although it is well known that health status affects the microbiome and that the microbiome affects health status, molecular signals linking gut microbes and host pathophysiology remain largely unknown. His lab applies metabolomics to gut microbiome metabolism, which they call xenometabolomics. During his talk, Dr. Adams focused on two topics. Firstly, how does microbial metabolism impact host physiology? To investigate this question, they have studied nitrogen, kidney, and liver metabolism in the context of an altered microbiome. They have found that dietary manipulation of the gut microbiome alters the host liver metabolome; there are reduced hepatic amino acids and urea cycle metabolites in mice feed a high starch diet. The same diet fed to experimental mice in a chronic kidney disease model ameliorates the kidney disease. They believe that the high starch diet increases the density of beneficial bacteria which then act as a nitrogen sink to reduce the nitrogen load on the kidney. Further, they reason that the changed metabolites from the changed microbiome reduces uremic solutes. Second, Dr. Adams discussed how host physiological states impact the microbe population and biochemistry. In a study of adult human women, they found that xenometabolites—specifically, cis-3,4-methylene heptanoyl carnitine and aminomalonic acid— change with both acute exercise and with weight loss. They have also found the microbiome and xenometabolomics distinctively change during diabetes progression in a rat model. In fact, performing a “xenoscan” of the cecal metabolites can discriminate severity of disease in a rat model. Knowing this, his group hopes to investigate how we can use these altered metabolites to treat or identify disease. In summary, Dr. Adam’s group has shown that host microbiome cross talk involves a two-way street. They will continue to investigate the molecular factors involved in this communication and work towards improving our metabolic health by studying microbiota ecology and xenometabolism.