Episode 19: Forming Gut Circuits

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

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

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

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

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

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

Winston 4:56
Thank you.

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

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

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

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

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

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

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

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

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

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

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

Maya Kaelberer 10:57
Thank you.

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

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

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

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

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

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

Brad 14:08
Vry interesting. Thank you.

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

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

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

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

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

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

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

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

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

Paula 18:09
I see. Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

Peter 24:23
Yeah. Thank you so much.

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

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 16: Tracking Our Behavior

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Hilary 25:56
Cool. Thankyou.

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

Episode 15: Shaping Our Appetite

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

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

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

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

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

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

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

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

reem hasnah 4:52
Me too.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

reem hasnah 16:33

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

Dr. Lisa Beutler 16:38

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Anthony Sclafani 25:28
I agree.

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

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

Peter Weng 26:03
Thank you all.

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

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

The Gastronauts Podcast Season 3

Season 3 Transcripts

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

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

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

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

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

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

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

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

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

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

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.

Episode 12: Mind The Microbes

Peter [0:13]
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 particular focus on the crosstalk between gut and brain. We invite experts in this field to share both their research and their incredible journeys. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts podcast.

We have two more young scientists who have been incredibly successful in studying how microbes or bacteria in our gut can affect our brain. First up, we have Dr. Carlotta Ronda, who is a postdoctoral researcher in the department of systems biology at Columbia University in Dr. Harris Wang’s lab. She received her PhD from the Technical University of Denmark in Dr. Alex Toftgaard Nielson’s lab, where she designed new genetic engineering tools to accelerate the development of biosustainable cell factories. She is currently a Simon’s Society Junior fellow and her research focuses on engineering tools to modulate or modify the gut microbiome.

So thanks so much for being on Dr. Ronda. So the first thing I want to ask about is to [have] you elaborate a little bit more on the two things that I introduced and tell us a little bit about some of the projects that you’re working on.

So as you know, the gut microbiome is inhabited with a variety of different bacteria and a lot of them are not very readily amenable to manipulations or genetic manipulation. So it’s very difficult to try to understand the physiology of the gut without considering our microbiomes. It can be skin, it can be gut. And so if we want to really understand this, given these microbial communities, we need to be able to cultivate them or manipulate them and try to assemble their functions. And so what I’m doing is trying to devise methods that allow us to unravel or deconvolute this complexity. The ability to create tools that allow us to shine some light on their functions and their physiology and how they interact with the host, which is us. It’s really important to really understand the physiology. And so like, my work is trying to devise new methods to understand how these communities behave, and how these communities interact with the host, and allow us to better understand their functions and their role in the human physiology.

Peter [3:20]
So I really want to take a […] 30,000 foot view step back. So we’ve talked a lot about the microbes within the gut. Are there bacteria living on other organ systems within our body? What made you choose to focus specifically on the gut microbes?

Dr. Ronda [3:35]
So yes, there are other microbiomes: we have skin microbiomes, we have eye microbiomes […] we discover new microbiome everywhere every every day […] they even discussed about a potential brain microbiome which is kind of very controversial. The reason to delve into the gut is because it’s one example of a microbiome that has been already extensively studied. And so people are very interested in understanding it, because its role in physiology in disease has become extremely evident in the past like five to 10 years. So that’s why I’ve decided to work on the gut. But I will expand my work and my tool are expandable [to other] microbiomes.

Peter [4:31]
The gut microbiome is the most densely enriched population of microbes throughout our entire body. We may have these bacteria living on different organs, but the gut is the most well studied and the most number of bacteria live on the gut. Could you speak a little bit to the stability and the transient nature of our gut microbiome and how you will potentially target those populations?

Dr. Ronda [4:52]
The gut microbiome is extremely dynamic and it constantly changes: with the circadian rhythm, it changes based on the food we eat, the place we live, so it’s a very dynamic system. And so, it is very difficult to really engineer them and have them stably maintain the same community as at the beginning, unless you have a specific fitness advantage that you can compare to specific spaces. So you can give, for example, if you want to select for specific members of the community, you can provide them specific stress substrates that they grow on and give them a fitness advantage to persist within the community and to bloom within a community and change their abundance within the community. So if you want to modulate the community, not at a specific genus or species level, but at the genetic level, then it’s a completely different matter. Because at that point, the reprogrammed function that you want to give to the community is genetically encoded and when it is genetically encoded, it can be hosted by different species. And it’s not necessarily linked, you can make it to be broad and hosted by different species and not directly linked to a one single populations. And so, in that scenario, you want to give genetic stability to reprogram functions that you engineer within the community. So engineering the community, it’s actually a very broad term, but it involves multiple levels, you can work at that populations, the genus and species level and their fluctuations within the community. You can work at the genetic content.

Peter [6:54]
And is a lot of your work on the engineering focused on modifying it at the genetic level- not so much on the species level or population level. You’re more interested, your work is currently more focused on genetic reprogramming or targeting wide variety of species just based off of their genomes. Is that correct?

Dr. Ronda [7:10]
Yeah. So right now I’m working on genetic reprogramming, because you have more stability on genetic programming. And it’s not a trivial problem to give an increase of fitness or like you provide a fitness advantage to specific spaces because the gut microbiome has incredible metabolic capacity and plasticity. So it’s very difficult to find molecular metabolites that are unique, and you can use [these] as a driving force […] to give the populations [we] are interested in a fitness advantage […]

Peter [7:50]
To allow us more tight control essentially.

Dr. Ronda [7:52]
To get more tight control and also allow the reprogramming function [to be] more pervasive. Because you can target multiple spaces, so the reprogram function will be propagated within the populations and not restricted to only one species. So if you have a beneficial function and you want to enhance your microbiome capacity, and you want to have […] a substantial difference from your baseline in terms of like production, and maybe one species is not enough to drive that enhancement. So if you actually reprogram the functions within multiple species, then you can increase [and] propagate it and you can increase the performance. So you can increase the enhancement if you want to reprogram in the function.

Peter [8:49]
So by genetically reprogramming, you’re introducing kind of a new type of DNA into this bacteria to give it a fitness advantage or to allow it to produce a particular metabolite- is that correct?

Dr. Ronda [9:02]
So the best scenario would be to to link the fitness advantage with a specific function you’re interested in. Let’s assume that you want to increase the serotonin level and instead of taking antidepressant you want to increase the serotonin level [through the gut]. So the gut isactually the major producer of serotonin. And so a [depressed] person doesn’t produce it that much and you want to increase the productions and use it as an alternative to antidepressant-

Peter [9:40]
Are you focusing on any particular bacterial populations? Or do you just see it as just increasing the total amount of serotonin for this example?

Dr. Ronda [9:48]
So microbiome engineering is a very broad term and it is actually composite of multiple nuances. And it depends on the question you’re asking or what you’re looking for. And so, if you are looking for just an increased production from one single species, then my suggestion is, which I have other projects that I’m working on where you engineer a single probiotic, which is specialized to produce that specific molecule. And then you give […] a single entity that is optimized for the production of the molecules and you will have a lot of release. But the problem with these specific probiotics is that they cannot stay, they cannot stick in the microbiome, they cannot colonize. They just will be washed out pretty fast […] It’s a major factor when we’re discussing about probiotics. So if you reprogram your own microbiome to a certain function, then you don’t have this colonization problem. And then you can have a constant release. So […] you can modulate the time of release of your of your drug, and the and you can maintain the release of your drug. Okay, let’s assume that you eradicated completely species, which can happen extinction of a species in your microbiome, those have died because of abuse of antibiotics, then how can you perform their functions? How can you try to reintroduce those species? You’re not sure they will engraft because you already have your own community, and they might not engraft. So if you want that function to be performed, you can just record it in and deliver it and reprogram already existing spaces to actually do that […]

Peter [12:04]
So this genetic engineering is more like a personalized approach as opposed to using one probiotic to give to everyone you change your individual microbiome.

Dr. Ronda [12:12]
Exactly. The idea is to try to go towards a personalized approach where you don’t take a generic probiotic, you don’t take other people’s microbiome. Getting microbial community from other individuals has been shown to be an extremely effective system for C diff infections. And so it is a very powerful and effective treatment, but there are still open questions if it’s the best approach because there’s so many things unknown about the process [that can be] more controlled with genetic engineering. Yeah, and also what is the best microbiome to give you we don’t know. Like, there are super donors where the microbiome of those super donor seems to be more effective and to be able to colonize better, but what are the rules that make a super donor a super donor? We don’t know them yet. There are efforts in trying to understand what is the holy grail of microbiome to cherry-pick specific bacteria and create like a perfect for microbiome, but you never know […] Sorry, I have to correct myself. We don’t know, at this point, what can happen in the host because there is also host genetic changes as well, [and] host physiology and genetic can have an influence […] the colonization process and the shaping of the community but also into specific species. So these are still open questions that we haven’t we haven’t addressed yet.

Peter [14:04]
It’s an exciting place [to be conducting research]

Peter [14:08]
So we’ve definitely talked a lot about the uncertainties with regards to the whole microbiome sphere currently, which makes it such an appealing avenue for people to do genetic engineering, for people to study what exactly in these microbial populations is beneficial. And I was wondering, as you start to transition to running your own laboratory, what are some of the big questions that you want to answer with are using microbial and genetic [engineering]?

Dr. Ronda [14:32]
So the fundamental questions that we’re still trying to address in the field is the mechanism of how deep microbial communities can affect human physiology. At the mechanistic level, we are still lacking a lot of knowledge. If we wanted to really understand and unravel the complexity of the community that inhabits us, we want to try to modify them and understand how they interact with the host. If you conceptualize the microbiome as a complex network of different nodes and different points where each node is a species or micro-consortia, then you try to simplify a problem, which is if you want to understand that network, what you’re going to do, you’re going to try to twitch and manipulate and take away or introduce new nodes. So you can see how the network reacts to the specific changes and by looking at how the [system] reshapes after you change these nodes, and understand the role of those nodes. So the method the genome engineering, it’s the tool of genome engineering of this allows us to manipulate specific bacteria that will allow us to take out or put in a new node in this network. This allows us to really deconvolute the complexity of this network, because-

Peter [16:20]
The microbial community and even host physiology communities are so complex, that we have to break it down, we have to take it kind of one piece at a time and then look at everything that changes from this one manipulation because if we try and change many things at the same time, you don’t know what is causing the whole change in the network. So will [there] come a time where we have all the tools to understand each of the nodes within the network? Do you think that is kind of within the near future far away with regards to understanding kind of these subpopulations of bacteria and how each one of these subpopulations affects the entire network?

Dr. Ronda [16:53]
I think there are multiple efforts to actually do that to try to understand what is the contribution of each species within the community, at the community level? And also how do individual species affect the physiology of the host? I think they all try to really understand and map out these interactions and these roles. I can give a definite answer. Maybe at one point they will know everything because it’s like asking if we’ll know everything about biology at one point. It is so difficult to say […] and so much to unravel, that I don’t see it as I complete work within a timeframe that I can picture […] It’s a very exciting, flourishing field. And people are tackling the problem from different angles. That’s what I find […] very fascinating.

Peter [18:03]
That’s really great. Well, thank you so much for sharing your excitement with us, Dr. Ronda, and thank you for being on our podcast.

Dr. Ronda [18:08]
Thanks a lot for having me here. It’s been great.

Peter [18:27]
We also have Dr. Martina Sgritta here with us today. She is a postdoctoral researcher at Baylor College of Medicine in Dr. Mauro Costa-Mattioli’s laboratory. She completed her PhD at the University of Pavia on spike-timing dependent plasticity in the laboratory of Dr. D’Angelo. Her current research is quite different and focuses on understanding mechanisms that underlie social behavioral deficits in autism spectrum disorder. A recent publication in the journal Neuron showed how transplantation of a specific bacterial strain in the gut is able to enhance social behavior within mice. Can you tell us a little bit more about this project and additional projects that you’re working on?

Dr. Sgritta [19:10]
Of course. Hi, everybody. So my project was kind of a follow up from previous work published in our lab. So a former colleague, Shelly Buffington found how a specific bacterial strain was reduced the gut microbiota [in an] environmental model of Mouse Mouse model for ASD, autism spectrum disorder, and this was a maternal high fat diet model. So she found that mice that were born from mother fed with a high fat diet were socially impaired and these specific microbial strains were reduced in the gut, and essentially found that reconstituting these […] lactobacillus strain in their gut could correct these social deficits. So a lot of questions were open, remain open. And that’s how my work started. My projects are [aimed at] understanding whether this same treatment could also correct this social behavior using another mouse model, not just the one coming from the environmental factors, but also [a] mouse model related to genetic factors or a combination of genetic and environmental factors. And so we started considering another model and treating the mice with the same bacteria. And we found that the same single bacterial strain was able to correct social deficits in the other mouse model. And this was very nice because the regardless the cause of the ASD regarding this the first insult, these bacteria were still able to correct social deficits.

Peter [20:51]
Do you think that these bacterial strains could be more generalized and not even just mice that had social deficits, perhaps even extending beyond the autism spectrum disorders [and] taking this to just in general enhancing sociability or does it change sociability?

Dr. Sgritta [21:07]
Well, we hope that. We also are trying to understand whether it is the bacteria strain is also correcting other behavior. And because as you know, autism spectrum disorder is heterogeneous and is a spectrum. So, there are a lot of other co-morbidities and phenotype like repetitive behavior language impairment. So it would be nice if it’s just one single treatment that could cure all the co-morbidities, but it is not very realistic. I guess I think the most amazing thing would be to understand, [what] is the function of different bacteria and maybe to combine different bacterial strains to have a collection of different phenotypes.

Peter [21:45]
This is really interesting. You’re getting into the bacterial sphere, but your previous work in your PhD was more electrophysiology […] Did you need any convincing to kind of study bacteria or did Mauro say that you’re going to work on bacteria now or how did this come about?

Dr. Sgritta [22:00]
Not at all. Well, I started working basic science very basic like on cerebellar circuitry and synaptic plasticity in the cerebellum […] I have always been attracted by something that was more preclinical and I tried to be involved in projects that were more clinical during my PhD, but it was very difficult because I was in a very electrophysiology-based lab. So we were really just studying basic neural circuitry. And so, I decided I wanted to move and I wanted to try to do research in the US because there is a lot of money here, and so I think, that you have to do right when you do research to try to travel and to have an experience other countries. So I looked for a lab that I could have been interested in. I actually I heard about Mauro during a talk at FENS in Europe. And I got attracted by the research he was doing in his lab. So I asked him for an interview. And when I got in the lab, they just started this Gut-Brain Axis Project. And actually I didn’t need to be convinced because I’ve been always fascinated about this aspect of science.

Peter [23:20]
Really cool. Yeah. I wanted to unpack a little bit more about your [comments] about needing to travel places. You were previously doing your PhD in Italy, and you decided to come to the US because you wanted to expand your opportunities. And here, I’m from the US doing my PhD here. I don’t really think about going to other countries, and I haven’t thought about it until right now. I was wondering, what made you decide to focus on this in the United States, or was it a lab specific thing? Just walk us through a little bit of your thoughts?

Dr. Sgritta [23:52]
Yeah, well, it was United States because, you know, Italy is an amazing country, but we don’t have a lot of funding for search. For scientific research and we always look at the US as you know the dream place where you can do all the research you want because there is so much funding there. You know everything is accessible, you get to learn a specific technique and your boss can send you in another you know lab and for like one week to learn a technique or you need specific antibodies just order it. In Italy, we were really desperate we were exchanging: I give you an antibody and you give me a solution. Yeah, it was crazy. And so you know, and I always want you to think that

Peter [24:35]
Do you think that made you more careful with your reagents?

Dr. Sgritta [24:39]
Absolutely. When I started in the US, I was putting so much attention to the prices. Eventually, [my PI said] Martina, don’t worry about it. I mean, we can buy this antibody.

Peter [24:51]
Yeah. But it’s still crazy, right? Because the amount of money that we spend in the US on research, people feel is too much. But other researchers, we show you We need more research-

Dr. Sgritta [25:01]
Exactly. And like such as anything in our life, we should just be more careful to not spend too much. And yeah, so I wanted to go to the US, for this reason, because of the more accessible life of scientists. Everything was more accessible. And in particular Mauro’s lab just because I was attracted by the the work that has been done in his lab.

Peter [25:23]
Are there any challenges for applying to the United States as a foreigner and joining their lab? I know, I’ve talked to some other people who are graduate students, and they tell me that the process to getting into a graduate program in the United States is much more challenging. Is a similar process that you face going for a postdoc?

Dr. Sgritta [25:39]
Yeah, well, initially, the PhD process, I think it’s easier from one point of view and less from the other side. So let me explain this. So basically, we have usually a strict three year PhD program, so it’s shorter [than the US]. And this could be a good thing from one side. From the other side, doing a PhD in the US is much longer as you probably know, but at least you can have the opportunity to go out from the lab with much more experience. Stronger maybe to start, your postdoc can have more publications, especially because it’s not that easy to publish a paper in three years. If something goes wrong, you’re like, you know. And so this is one part. And the other part of it is that you basically have these admission problems [of getting into the US] that [take] much longer. So it’s probably get, you know, is expanding even more the time you have to spend trying to get into program while in Italy.

Peter [26:43]
Yeah. And I want to jump back to your research a little bit more. We talked about looking at how this particular strain of bacteria (L. Reuteri) is able to modify social behavior in the autism spectrum disorder in the mouse and I was wondering, where do you see your next projects going? Are they even related, are you going on a different front?

Dr. Sgritta [27:01]
They are related just because I got so passionate about this that I don’t want to leave it. So this the thing. There are so many other things to understand about these and I feel like I’m not done with this. I want to understand how […] the mechanism underlying how these bacteria can correct social behaviors depend on the vagus nerve and [how] they [act] on the oxytocin and dopamine system. But we don’t know how exactly. We don’t know how the vagus nerve is activated by the bacteria. [We don’t know] what is activating the vehicles or something released by the bacteria or something released by the particular cells in the gut that are activated by the bacteria. And so, there is so much work to do.

Peter [27:44]
So, looking [specifically], are you moving on to studying particular components of the bacteria? Are you looking at specific subsets of these oxytocin cells?

Dr. Sgritta [27:55]
Well, we need to dig deeper in any of these steps. So we want to understand what is released by the bacteria? So, what is the molecule responsible. Also what is the gene in the bacteria there is responsible to give this capability of L. Reuteri to correct social behavior and genetically modify other bacteria. So exactly there’s so many things that can be done. And then also at the [systems] level, the vagus nerve is activated. So is the activity changing upon the perfusion of the bacteria and how the stasis increased. So is the activation of these paraventricular nuclei of the hypothalamus, which is the oxytocin is produced that is, through the activation of the vagus nerve that is increasing oxytocin production. So there are you know, many things to understand in any of the steps bring into the change in behavior from the bacteria to the behaviors.

Peter [28:48]
Certainly. And if you’re thinking this oxytocin production is involved in having more social behavior than in an ASD model, why not just give oxytocin? Why go through this pathway?

Dr. Sgritta [28:57]
Well, this is a good question because oxytocin has been shown to increase social skill to improve social behavior. And yet we’re still seeing the problem with oxytocin is that it’s temporary. So there are two hours of the effect. And there’s also the reason why we administrate intranasal access into the mice, 30 minutes before behavior. And the problem is that it’s so temporary the fact that the children with that use oxytocin to improve the quality of life, they have to spray oxytocin, you know, every day every couple of hours. It’s you know, it’s a pretty invasive treatment and not very long lasting. So L. Reuteri can increase endogenously oxytocin it will be a less invasive treatment that children can, you know, be treated all over life.

Peter [29:48]
So ideally, you’re looking for a mechanism kind of to treat the brain without having to have such an invasive procedure and whether or not L. Reuteri is the answer to that we still have to do the research to figure out [the] specific pathways.

Dr. Sgritta [30:00]
Exactly, exactly. I think we have an amazing opportunity now that we have understand that specific microbes can modulate brain function, we have this amazing opportunity to [develop] a non-invasive treatment that can be combined, or by itself, to improve some of the behavior. Of course, we cannot, you know, we cannot say that we can improve all the symptoms, but at least some of them.

Peter [30:29]
Yeah. So, as you start to kind of get to the end of your postdoc, I know, most people start thinking about how they’re going to start up their own lab afterwards. And how do you see yourself moving into this microbiome, social behavior field while differentiating yourself from the work that you’ve done previously?

Dr. Sgritta [30:45]
So well, actually, I’m very, very much in attracted by the translation of research to the clinic, so I don’t […] see myself in the academia system forever, but I still want to be in science, because I’m passionate about science. So I think I want to keep on being a scientist and work on these fields, but maybe not in the not in academia.

Peter [31:11]
Yeah, that’s really nice to hear. Because I know as we go through the graduate school track, most people most of the advice that we get is to pursue the academia field. And there are other ways to be a scientist outside of academia. And I think it’s important to get that realization. I also noticed when I went to your LinkedIn and saw that you had gone to the Rice Jones Business School for learning about entrepreneurship. What do you think what is the value of kind of studying entrepreneurship is for a scientist?

Dr. Sgritta [31:40]
I think it’s amazing. And I suggest these courses to anybody who’s interested in expanding their knowledge. It is very important also, for a scientist who wants to stay in academia because we have to deal with industry and companies all the time also in academia for collaboration. Very important collaborations sometimes are born between these two different words. So yeah, it was super interesting and I think anybody working in academia should also expand their knowledge on the startup company system.

Peter [32:15]
Are there any other fields that we think are helpful for scientists? Should we go into like studying law school?

Dr. Sgritta [32:22]
Well, if you’re interested in patents, you know, it could also be helpful because you have to, you know, carry out some patents sometimes where we are in academia. But I think the most important thing is to also be able to share scientific knowledge in the right way. So to be able to communicate with people that are not scientists. It is a very important thing because you know, anytime you publish a paper and then there is this mini coverage that keeps bringing your information to the public, […] many different voices from people […]

Peter [32:58]
Yeah, certainly, I think communication is important in science. And we talk about, you know, we always have teams of varying degrees of expertise. We have some neurobiologists, and they work with microbiologists, and they are both studying the microbiome together. So I think it’s important to differentiate your expertise, have a group that has a bunch of different skill sets and bring them together. And I was wondering what advice you have for someone who’s more younger, in the research field, someone who’s kind of just getting into the field of a PhD? What advice would you have for them to kind of figure out what projects they want to pursue?

Dr. Sgritta [33:31]
Explore a lot. Be surrounded by people who are older than you, more experienced than you and ask a lot of questions. Just be driven by curiosity. And don’t be afraid to ask any of the more simple questions because you know, this is what actually then drives you. Especially if you a scientist, you have to keep your passion alive otherwise, it was a difficult war.

Peter [34:00]
Yeah, but if you have a little bit of that social anxiety and you’re not sure, could I take L. Reuteri? Maybe to help with that or no? So I was wondering, in addition to where you see your lab moving forward […] what kind of aspects are important for the career development of younger postdocs or people who are moving into postdoctoral positions. You mentioned you were looking mainly at Mauro’s research in this opportunity to really go into a new field that was different than your own and PhD, but what else do you think is important for the career development of a young postdoc?

Dr. Sgritta [34:34]
I think one of the most important thing is to learn also how to deal with people and collaborate with people in the most productive way. Not just in the lab, but also outside the lab. And this allows you not only to learn new techniques, and to increase you know, to dig deeper in expand your knowledge and other field but you know, networking is very important. It is part of our job. And most of the times scientists are very much concentrated on themselves like so you know, these idea of the scientist closing the lab without a social life. But he’s you know, a very important aspect that will come back and help ourselves in many other ways in the future when you are a post-doc when you are a PI, so you know, networking is also very important.

Peter [35:27]
And then I was wondering what questions do you think the field needs to answer with regards to kind of social behavior or even, our understanding of autism spectrum disorder is so kind of superficial, it’s on a very surface level, what questions do you think are the next big ones that we really need to hit on regarding social behavior or microbiome modification, since those are the two kind of fields that you’re working in right now?

Dr. Sgritta [35:53]
Okay, well, I think understanding the mechanism by which the bacteria modulate brain function will be very important so that we can understand whether there are other alternative therapies because we don’t know whether we can use these therapeutical approach for the future. So understanding mechanisms so if we know that the bacteria is acting on the vagus, there may be this nerve stimulation could be important for ASD. So understanding mechanisms that will bring us a lot of other inputs and would expand our knowledge to be able to understand whether other therapies can be used. And yeah, I think this is one of the most important thing to understand

Peter [36:34]
You want to understand these specific mechanisms. And you think that with these mechanisms understood, we’ll be able to develop therapeutics that are specific enough?

Dr. Sgritta [36:44]
Maybe not for all of the symptoms, but for some of these symptoms, yes. And of course, we have to remember that this is basic science done in animals. So before being able to say that this can be translated to human we have to reproduce this data in and other, more translational animal models and do clinical trials. So you know, there is a long, long road.

Peter [37:09]
Yeah. Cool. Well, I can’t wait to see what you’re gonna come up with next. Well, thank you so much for being on the podcast.

Dr. Sgritta [37:17]
Thank you so much for having me.

Peter [37:30]
Dr. Ronda and Dr. Sgritta has shared with us two different ways of studying the microbiome and gave us a look into what they have done to position themselves to be successful. To study a system as complex as the microbiome, it is important to really break it down and not be afraid to ask what you feel are the fundamental questions.

I want to thank you all so much for listening, and we’ll see you next time. 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 the incredible team that we have here. Meredith Schmehl is our producer and theme music composer. And special thanks to the founders of Gastronauts, Dr. Diego Bohórquez, and the Bohórquez laboratory.



Dr. Allbritton [0:01] 

其中有一些有趣的味道使我无从考究。 它的味道像胡椒薄荷味的薯片或某种薄荷味的薯片。

Peter [0:14] 

好了,您现在可以摘下眼罩了。您手中的其实是椰子片。 我想这(个表达)会比较直接,因为您实验室中的一项工作是在芯片上做一个肠道,所以用薯片来形容。 我想表达的另一层含义是,如果您看着这切成两半的椰子,是不是很肠道呢!

Peter [0:45]

嗨,大家好!我是本期The Gastronauts 播客的主持人Peter。 在Gastronauts,我们将致力于理解人体的(内在)联系,尤其是肠道与大脑的对话方式。我们希望更深入的研究优秀科学家们及其工作背后的灵感和动机,并希望通过了解科学背后的科学家们来了解不同科学家的想法以及如何解决复杂的问题。 那么,请跟我一同走进本期播客,探索我们的内部空间。

今天,我们有幸邀请到北卡罗来纳州立大学(UNC)凯南化学特聘教授Nancy Allbritton博士,现任UNC教堂山生物医学工程系主任。关于Allbritton博士的一些背景是:她曾在路易斯安那州立大学(LSU)学习物理学,(之后)获得约翰·霍普金斯大学医学博士学位,并在MIT的Herman Eisen博士实验室获得医学物理学博士学位。此后,她在斯坦福大学的Luber Stryer博士实验室进行了博士后研究,在那里她研究了辅助信使信号(通路)。她获得了多项专利,并且是四家公司的科学创始人。我真的很想了解您从研究到建立这些公司的想法。但我(还是)想先从您的研究工作问起。从您的网页上,我发现了三项主要工作:单细胞酶测定,通过微筏分析和分选细胞的新方法以及这些在芯片上进行的器官实验-这些是您实验室当前的重点,您能否告诉我们更多有关您实验室中的工作呢?

Dr. Allbritton [2:43] 


Peter [4:37] 


Dr. Allbritton [4:44] 

可以。这是一项很棒的技术,它是斯坦伯格(Hanzenbergs)在很久以前开发的。 其想法是,取出已经从表面分离的细胞,再通过高速流继续流动,然后用激光对它们进行处理。

Peter [5:00] 


Dr. Allbritton [5:03] 

其实是很有趣的。 随后由计算机决定一种属性,通常是荧光,然后我们将其抓取并分类,或者丢弃掉。 这是一项非常高速的分选技术,但确实存在一些实际性的挑战。 这通常需要将近一百万个细胞,设备上还有很多管道和其他区域(可能会导致)细胞的丢失或消失。 因此,如果要发现一百万个细胞或一亿个细胞中的一个,那很难。 这不是它的优点。 但是,如果想要快速地处理非常大量的细胞,这是个非常好的选择。 由于存在高速流,细胞上会承受许多机械应力。 因此,许多脆弱的细胞无法生存,从而导致很高的(细胞)死亡率。

Peter [5:59] 

就像坐过山车一样,继续(快速)前进,您和同行的其他人都(要)被撕裂了。 而后出来时(的状态)肯定不会是一样的。

Dr. Allbritton [6:08] 

确实,你会觉得这是错杂和混乱的。一项轰动一时的技术既有它的优势,也有它的劣势。那么,我们的技术设计具有恰好相反的优点和缺点:确实非常好,分选时几乎没有物理压力或作用在细胞上的力。它永远不会存储成千上万个细胞,但是它将非常有效地分选非常少的(特定)细胞。你可以很好地从100,000或50万个细胞开始测起。而这之中的每项技术(我们)都分别组建了公司。 我们最后一项工作/技术是小肠和大肠的芯片上器官或芯片上肠道系统。整个想法是尝试在微型设备上重新捕获活肠的结构和生理(特性)。它不会像小鼠或人类(器官)那样复杂,而是一个模型系统,你可以在其中严格控制所有变量。尤其是,它允许你采集人体活检样本,然后重建一个小型的小肠。很明显,我们的肠道具有相当数量的化学和气体梯度,但是目前几乎还不可能了解这些梯度如何影响分化的细胞并控制其行为,进而影响干细胞,尤其是人类的干细胞。因此,我们的系统旨在做到这一点,以获取不同的人类疾病模型,并观察它们与正常人的行为有何不同。现在使用的多数是老鼠(模型),而人类来自各个种族、性别、基因型和少数族裔,这是一个广阔的领域。但是你可以开始研究具有种群组织的不同人群的反应,然后可以在微型设备上重建许多不同的微型肠道。肠的类器官实际上是很小型的肠道。它们具有管腔和管腔周围的单层细胞。它们实际上是细胞,即死亡时分化的细胞进入内腔。随着时间的流逝,它们会打开并从本质上排出死细胞,就像在常规肠道/管道中一样,但它却是球形的。这(似乎)仍有不正确的地方,架构也不正确,分化后的细胞和干细胞还没有完全隔离,并且肠腔或内部腔几乎无法接近。虽然这是我们的突破性技术,它将为生物学家和生物医学研究人员进行一些令人惊叹的实验敞开大门,但它仍然存在很多不足。我们的目标是进入并建立一个新的层次,并创建一个像真正肠道一样可进入的具有内腔的组织。

Peter [9:27] 

因此,[类器官]将准确地涵盖所有内容。 我想这是作为年轻科学家发明的东西,而我还未曾意识到在培养皿中完成许多此类操作的局限性。 我觉得我们有能力做出与人类完全相同的器官,而事实并非如此。 从我们越来越接近于模仿体内发生的情况而不必进入体内的意义上来说,这是一个重大的进步。

Dr. Allbritton [9:57] 

是的,完全正确。现在,我们可以获得人体模型系统,并开始对人体系统进行大量筛选。 所以,你现在可以开始使用其中一些系统来筛选具有不同遗传背景的人群中的各种人并做出预测。这群人在此种浓度下使用这种药物可能确实有很好效果。 但是在具有某种基因型的人群中,我们需要将其浓度降低10倍才能使药物无毒。现在很明显,我们的细菌在我们代谢和摄取药物的过程中起着巨大的作用,并且它们可以将药物转变为有毒的化合物。 对于许多药物而言,[细菌]实际上将它们代谢为活性化合物。 因此,我们可以考虑来揭秘如何操纵肠道以降低药物的毒性和提高活性。

Peter [10:54] 

您之前提到过,实验室中的许多项目或工作都已经分解成公司。 您能否告诉我们一些有关您决定成立公司的事情呢?您成立的第一家公司是2000年的Protein Simple(公司名),对吗?

Dr. Allbritton [11:09]

是的。实际上我一开始并没有考虑要建立公司。我实在不觉得这是我在学术界需要做的事情。但是我发现,当你创建了一项技术时,如果它是一种新颖的技术,它仍然被视为高风险且不成熟,(这时)要将该技术许可给更大的公司就太冒险了。从实验室的试验台阶段到推向市场,它仍然需要大量的创新投资。那么,我发现,要将我的技术投入实践的唯一途径是我来创办以此为基础的公司。 我已经开发了这项技术,如果仅将其限于自己的实验室,那我就不能偿还纳税人的钱了。他们资助我完成了所有这些创新工作,而这些工作只会在我的实验室中生死存亡。至少在你是技术开发人员的情况下,产生具有实际影响的方法是将技术推广到市场,并让其他人使用它。令我惊讶的是,两者之间仍然存在巨大差距。公司并不会只是许可你的技术并进行开发。没错,我尝试获得了一些第一批技术的许可时就撞墙了。我才意识到,如果这些技术要进入市场并且对其他人有用,那么我要做到的一点是去找到一家公司,使其开始运营(此技术)。实际上,这非常令人兴奋,因为这是一种全新的技能,不是吗?而且,你能做好科研但不一定适合从商。 没关系,你仍然可以继续科研工作。 但这是个很棒的产品。我之所以真正享受它,是因为遇到了各种各样不同观点的人。商业界与学术界有着截然不同的前景和重点。我有点喜欢这一点。但是在这整个过程中,我还意识到自己不是商人,也不应该假装自己是商人。我的工作是帮助公司成立并致力于技术发展。所有这些公司都与其他公司建立了合作伙伴关系。我认为我职业生涯的一个特点就是总是与其他人一起工作。因此,公司总是由一群人创立,而不仅仅是我作为创始人。而且,由于从技术可行性到功能性公司的工作量很大,我们总是尽早聘请业务人员。作为一名学者,我没有那种技能,但是商人却有。他们会说方言。而且,如果我们可以作为一个高效的团队一起工作,我们将做更多的事情。

Peter [14:00] 

这听起来像是一种真正的补充技能。 您从来没有感觉到离开科学,进入风险资本行业或进入制药业的真正推动力,更使您意识到您对成为发明家的热情比对销售人员的兴趣更大。

Dr. Allbritton [14:17] 

我认为这是最酷的事情之一。 如果你去另一个实验室(的时候),看到了你的技术,而他们却不知道这是你的技术。 对我而言,技术实验室成功的最终标志是人们使用你的技术。 最近,有关Cell Microsystems,我看到一篇发表在Nature杂志的论文将这项技术用作其中的关键部分。 它只是说了Cell Microsystems,这真是很棒。

Peter [14:44]

您对年轻的发明家,新技术的开发人员,正在考虑创办公司但不确定是否适合他或她的人有什么建议吗? (这)是否正是他或她希望看到他们的实验室完美的地方呢? (对此)您有什么建议吗?

Dr. Allbritton [15:02] 


Peter [16:09]

是的,如此看来,您确实敦促自己不仅仅局限在研究者之列。我在浏览您以前的许多工作时(发现)您最近在2016年和2017年获得了贝克曼年轻钙质信号研究者奖,您被授予发明家奖。 从早期的开发者到发明家,您是否已经转变了这种看法呢? 您是否一直觉得我只是Nancy Allbritton博士,我是发明家,还是会有这种转变呢?

Dr. Allbritton [16:42] 


Peter [18:39] 

我想知道的问题之一是,您如何区分实验室的工作和这些公司的工作呢? 还是(这两者)是有区别的呢?

Dr. Allbritton [18:46] 


Peter [21:02] 


Dr. Allbritton [21:21] 


Peter [22:01]


Dr. Allbritton [22:07]


Peter [22:11] 


Dr. Allbritton [22:27] 


Peter [25:28] 

保持简单的心态; 这是否是您与他人合作的方式呢? 您又是如何决定与谁合作的呢?

Dr. Allbritton [25:35] 


Peter [27:48] 

是的,我想到的一件事是我们如何展示自己。在研究中,很多时候,我们都会考虑可能出错的步骤,以及如何优化这些步骤才能使该系统正常运作。 但是,如果从公司的角度来考虑,这就不算什么,“哦,这些都是可能出错的地方。 这些就是您可以使用的所有功能。 是的,这就是为什么它会被您所优化。 您是否对研究人员如何改变其展示工作的方式进行了很多思考呢? 或者他们是如何提出自己想法的呢?

Dr. Allbritton [28:26] 


Peter [29:41] 


Dr. Allbritton [29:59] 


Peter [30:35] 


Dr. Allbritton [30:57] 

从某些方面来讲,他们需要具备技术能力,我不在乎他们是否具备我实验室中的技能,我希望他们有动力。 通常,成功的不是最聪明的人,而是愿意努力工作、有动力和坚持不懈的人。 因此,我寻求的是有动力,坚持不懈,愿意努力工作,能够接受建设性反馈并且不会抵触的人。 如果让我来评价最成功的人的话,这些就是他们所具备的特质。

Peter [31:24] 


Dr. Allbritton [31:30] 


Peter [32:33]


Dr. Allbriton [32:39]

是的,我认为口头交流,书面写作技巧非常重要。 我可能在还没有达到最好的写作技能时就开始了我的职业生涯。 而技术性写作,在项目书写作中要能表达出清晰、简洁的信息。 我想我们大多数科学领域的人,至少工程师、化学家和物理学家,我们都在这些科学领域中,因为我们并不喜欢写作。 但值得注意的时,尽管这并不是你最喜欢的事情,但你仍然必须学会写,而且写得越好,你的职业生涯就可以走的越远。

Peter [33:15] 


Dr. Allbritton [33:18] 


Peter [35:01] 


Dr. Allbritton [35:19] 


Peter [37:13] 

是的,这听起来像是,不仅是对设备进行修改,而且也在对您的思维方式进行修改。 不仅从设备角度考虑问题,而且从根本上考虑我们如何解决问题, 对我有什么影响,对吗? 因为我在想,南希博士接下来要做什么呢? 您已经取得了很多成就,您认为自己会走向何方呢?

Dr. Allbritton [37:35] 

很多人一直在问我同样的问题。而我还没有很好的答案。每隔10到13年,我都会尝试重塑自我。因此,我现在正处于重塑自我的阶段。我有很多方向,我正在探索和思考,但我还不想透露任何秘密。而且我也认为,要保持新鲜感。有时候,如果你一遍又一遍地做同样的事情,你就会开始认为事情是理所当然的。这永远都不是好事。所以我的感觉是,你需要偶尔通过一次新的冒险或承担一些新的风险来改变自己的生活。要知道,不同的人在执行此操作时有不同的时间范围。而且我的时间范围大约是每10到13年。所以,我正在考虑下一步的发展。对于Nancy Allbritton,我已经完成了许多工作,还有哪些我还没有做过的大事情我认为可以做?随着年龄的增长,除了经营实验室或创办公司之外,还有其他更好的方法可以为世界做贡献吗?还有什么机会呢?未来我将如何产生更大的影响呢?变老的真正好处是,你的技能有了很大的提高,并且你与人合作和思考问题的能力也得到提高。至少我认为现在的我好了很多。而且我比年轻时更有耐心。因此,你要考虑如何使用这些技能,甚至要开始继续扩大影响力。所以,我还没有答案,敬请期待吧。

Peter [39:12] 


Dr. Allbritton [39:16] 


Peter [39:32] 

Nancy Allbritton博士带领我们进行了一次“冒险之旅”,从产品构想到其执行和实施。在此过程中,我们了解到了沟通的重要性。科学(研究)是由具有不同专业知识的团队完成的。能够调整传达信息的方式将有助于使您的信息(传递)更加有效。非常感谢大家的收听,我们下期再会。有关我们的更多内容,您可以在Twitter @gutbrains上关注我们,或访问我们的网站thinkgastronauts com。没有我们在这里的优秀团队,就没有Gastronauts 播客。 Meredith Schmehl是我们的制作人和音乐作曲家。 Laura Rupprecht博士是我们的社交媒体经理。特别感谢Gastronauts Diego Bohórquez博士和Bohórquez实验室的创始人。