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 16: Tracking Our Behavior

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Hilary 25:56
Cool. Thankyou.

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

Episode 15: Shaping Our Appetite

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

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

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

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

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

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

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

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

reem hasnah 4:52
Me too.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

reem hasnah 16:33
Yeah,

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

Dr. Lisa Beutler 16:38
right

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Anthony Sclafani 25:28
I agree.

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

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

Peter Weng 26:03
Thank you all.

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

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

The Gastronauts Podcast Season 3

Season 3 Transcripts

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

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

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

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

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

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

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

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

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

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

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.

第六期:创造发明家

张旭朏/译

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] 

当然可以。这些是实验室的三个主要领域。从许多方面来看,它们似乎都是不连通的区域,但是我的实验室为(研究)生物的小物件和小工具构建了设备,这些设备非常小,非常适合小规模样品处理和单细胞测定。那么,我们实验室开始使用的第一种技术是,可以并行测量单个细胞中的酶活性。你要知道,基因组测序对科学产生了巨大影响。尽管所有这些事情都很棒,但在大多数时候,你真正想知道的是细胞中的酶促活动在信号(通路中)的作用,而不仅仅是一串成分列表。你可能知道了计算机组件的列表,也许并不知道这是一台计算机,因为使用几个零件也可以来做其他事情。所以,我们的想法是,可以开发一种从临床样本中查看人类样本并测量信号传导活性的潜在技术。这大约是实验室工作的三分之一,而实验室另外三分之一的工作是基于微阵列的分选技术。当我与各个领域的生物学家合作时提出了一种更好的细胞分选方法,进而产生了该技术的想法。因此,我们制作了一个透明的阵列,可以在其中放置细胞。它由一系列微小的元素组成。每个元素都可以按需发布。你实际上可以做的是使用任何类型的显微镜来检查阵列,然后使用这些计算机算法或一些非常简单的方法,例如变化率,再返回并释放这些细胞。因此,你只能分选100个细胞,甚至10个细胞,而不是通常用于流式细胞术所需的一百万个细胞。

Peter [4:37] 

哇!对于我们当中不太熟悉流式细胞术的人,您能告诉我们一些有关该技术及其工作原理吗?

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] 

听起来有些不可思议。

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] 

你要知道,这不一定适合每个人,这会让你兴奋吗?你是否愿意付出所有额外的努力和时间,并对此感到非常兴致勃勃呢?如果不这样做,那可能就不是你想做的,那么你就应该花时间做一些自己真正感兴趣的事情。我想说的另一件事是,成立一家公司确实很辛苦,有时需要做很多工作。你只需要继续努力并保持动力即可。这就像是一名科学家:95%的实验都失败了,您必须有前进的动力并不断努力。同样,创办公司也是如此。人们只会经常告诉你,你需要做更多的事情,或者为什么你无法进行任何投资,等等。而你只是不断努力前进,并且必须相信自己并受到激励。我认为这些是(其中的)秘密。我想对那些正在做自己喜欢的事情的人说,无论你做什么工作,都会遭受失败和失望,(但)如果你保持这种兴致并充满信心,那么你便能不断进步。

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] 

是的,当我还是个孩子的时候,我曾经用自己的汽车进行改造性工作。那个时候,你可以自己改造汽车,调整化油器和所有其他东西。我一直喜欢建造和设计,例如,我曾经自己建造了兔子厨具。而且我总是喜欢修改、创造并改进。所以,我一直对构建工具兴趣颇深。而且一直在构建解决生物学问题的工具。我想这是一个标志。甚至当我开始做教授时,我还在医学院。但是即使在那个时候,我的实验室也在建立解决生物学问题的技术和工具。而且我一直感觉随着时间的推移自己会变得越来越聪明。因为随着时间的推移,相对于试图找出正确的生物学问题,我开始将更多的精力集中在建立技术人员和与他人合作而不是(单纯)构建技术上,然后尝试解决(这些)生物学问题。因为我找到了那个人,我不可能在所有事情上都是专家。我很擅长于了解所有的工程、分析化学和物理学,但是要跟上快速发展的生物学领域的步伐仍是一项艰巨的任务。因此,我决定在[职业生涯]前进的过程中,认识自己擅长的领域以及不太擅长的领域,更加专注于技术开发,是因为我对此更擅长。

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] 

实际上有很大的区别。我的实验室非常擅长提出新颖的想法,并进行可行性实验和所有早期阶段的工作。但是,如果要求我们弄清楚如何使1000台设备完全相同,那不是我们所在行的。由于规模较小,我们可以进行创意和创新。但是我们的技能并不足以使我们弄清楚如何制造出坚固而可靠的产品,并且(确保)每次产品都是一样的。在演示实验室的可行性与推出商业产品之间(往往)存在很大差距。我的实验室可以展示其可行性和实用性。在实验室中,我们可能会失败。而且,我们可能会多次失败。但只要我们偶尔会成功就可以继续前进。但是在公司中,大多数时候需要成功,并且需要满足客户的需求。公司要进行所有创新和创造性的思考,以便从我们的实验室获得客户所需的信息,并使其可靠,强大,可再现且可扩展。你无法为每台设备支付巨额费用,因此如何以较低的成本制造设备呢。实验室和公司之间实际上存在非常清晰的区别。拥有公司真的很不错,因为如果人们开始使用我们的设备,他们会说,Nancy,我们可以买100个这样的小芯片吗?而我们想,哦,不,实验室中的研究生不可能造出100个这样的芯片,这样的话,他们永远都不会毕业了。还有就是,每个芯片都可能与下一个不同,因为芯片是手工制作的。但是对于公司而言,只要他们看到了市场,他们就可以轻松满足这些需求和目的,并且可以进行一些个性化定制。然后,该公司还将进行很多自动化创新,而这些可能会或可能不会在实验室中完成的。

Peter [21:02] 

因此,您实验室的工作范围更广,根据结果来开发出先进的技术。而这些公司实际上是在优化和完善(这些技术)。很高兴看到您能够参与到这两个过程中:从头到尾或从​​构思到面向客户的整个过程。

Dr. Allbritton [21:21] 

是的,公司实际上是在告知我们(要)在实验室做什么。你经常会看到许多微型设备,尽管它们是出色而优雅的工程,但它们永远不会成为产品,因为它们过于复杂且不可靠。而且活动部件太多。生物学已经足够复杂。你可以拥有一个不那么完美的设备。而简单就是优雅,简直就是看待它的最佳方式。这确实很难设计一个简单的设备。但是我们尝试在实验室中朝这个方向发展,因为这意味着它会对他人更有用。

Peter [22:01]

所以,通过与这些公司合作,您会想到简单的想法,如果无法使用,则会有个(新)想法。

Dr. Allbritton [22:07]

那我为什么要这么做,也许我是在浪费美国国立研究员(NIH)的钱。

Peter [22:11] 

许多技术是决定着伟大科学与成为公司创始人的成败。但是您也说过,伟大的科学家也曾有过失败,或者伟大的产品背后并没有足够的科学依据。您将如何优化两者呢?

Dr. Allbritton [22:27] 

是的,(这之中)有各种各样的优雅技术。它们被用来回答基本问题,但是他们需要实验室中的专家来实际构建这些技术来得以使用。如此之多的活动部件是如此复杂,除非你的实验室中有人花其所有的时间来保持设备运转之类的。该技术可能是一项突破性技术,但仅限于小规模工作。而要具有更广泛的适用性,使它在商业上可行,很多人都想要购买它,必须有利润,企业才可以赚钱。(但)这不一定会解决科学问题。因此,你对待这两种方式的方式确实有所不同。在科学(或)在实验室中,你想解决一个大问题。即使这项技术是其他任何人都不会使用的(都没关系)。它可以在实验室中(完成),即使它是如此复杂。这都很棒。然后在商业界中,其想法是开发一种每个人都可以使用的,没有故障点的技术。人们可以放下架子,在不成为专家的情况下弄清楚如何使用它。就像打开计算机一样。如果必须学习如何编程,那么在使用它之前,仅限于计算机科学家,仅此而已。因此,要使其成为有用的产品并广泛传播,就必须提供更全面、更可靠且更简单的说明,并使其适合人们已知的工作流程。在制造产品时,是否可以使其适合生物学家的工作流程,使外观看起来更简单,使使用该技术的过程和感觉与他们已经在做的事情相似。我举一个例子。我们的第一个细胞分选技术是使用激光,这确实是一种非常好的技术。我们推出了这些小设备,我认为这是一种了不起的技术。但这非常复杂。当我们四处与商界人士交流时,他们会说,你必须去除那束激光,因为它太复杂了,这将成为非常昂贵的工具和设备;我不知道你将如何以便宜的形式制造这种产品,以供大众使用。这实际上是一个很好的建议。听到这个消息我感到非常失望,因为我认为那(技术是)很棒的。但是这些建议也真的很好。所以我和我的课题组(成员)回到了绘图板上。我们做了完整的设计更改,然后制造了这个设备。而且,大约一个便士,可以将它们破坏。而且很便宜。也很容易更换。因此,它确实更适合外观和流程。

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] 

是的,我们实际上是在将合作伙伴视为我们的客户的方式下开展合作的。我的实验室非常擅长于构建事物以及创新和设计硬件微制造。我并不想说(我们是)最伟大的生物学家。我们一直想做的另一件事是确保我们可以构建他人所需的东西。如果你是在工程界,那么他们总是有很多令人惊奇的设备来解决问题。然后你与一位生物学家进行了交谈,他们正是(需要设备的人),所以呢,(仅管)你带有各种酷炫装置的好设备,很酷的工程技术,但是为什么他们要使用你的设备呢?其实我们所做的一切都是与潜在的最终用户进行协作。我们利用他们的意见和建议来推动下一步工作。他们告诉我们(他们)需要什么。然后,如果(他们)愿意,我们可以通过某些方式来填写他们的订单。如果我们认真听取他们的意见,我们就能了解对广大人群有用的东西。然后,我们对其进行设计和定制。我们想做的另一件事是制造设备,我们感觉这很棒。然后,我们可以把(设备)交给生物学家,他们会做一些我们没有预想到的事情,而我们已经离开了。是的,他们会回来告诉我们这出了错,那出了错。这会提醒我们,随后我们会重新设计,重新创新,经历整个设计周期,然后将其发回给他们。我们与所有合作者都在这种循环中进行工作。而且,我认为我们最终会开发出更实用的设备和工具,并且可以最终让用户想要使用这些工具,而不是我们出去四处游说,寻找问题以尝试并找到(解决方法)来(让客户)广泛使用我们的设备。因此,我告诉生物学家和生物医学研究人员,我的工作是建立一种技术,使您能够做以前从未做过的事情,并使自己成名。如果我让您成名,我就实现了我的目标,因为我创造了一种非常有用的新技术,很多其他人(也)都想使用。

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] 

是的,这是一个好问题。我认为,首先,沟通是科研的一切。如果你无法通过简单、清晰和令人兴奋的方式进行交流,则你的工作几乎毫无用处。特别是,随着时间的流逝,显然我们更好地与公众沟通比我们做了些什么更重要。以使我们的科学来解释一个人的日常生活。这样一来,你就可以想到街上的人,如何展示你的工作对他们的生活至关重要,如何使他们的生活变得更好。但是,即使在复杂的情况中,如果(你)正在向科学家展示你的工作,你怎么能不展示你的工具和技术呢,(因为我的工作中)运用了这项很赞的技术。但是正如你所说,这就是你所可以做的,使其简洁明了,并使展示方式简单明了。因此,我认为这是我们所有人都需要在科学研究中习得的技能,并确保我们不会消失在行业领域中。我们很多人都倾向于这样做的,因为我们知道这很舒适。不幸的是,我认为与其他科学家交谈,也与公众交谈时,科学确实对社会有害。

Peter [29:41] 

很赞同。我重视交流,我认为这很重要。我遵循的口头禅之一是,与所有人进行有效沟通很重要,对吧?因为如果您只是以一种自己能理解的方式讲话,那么没有其他人会真正理解。您也不能分享知识。

Dr. Allbritton [29:59] 

是的。而且,我认为你必须能够识别与你交谈的对象,并擅长为其他人量身定制相关内容。例如,与胃肠病学课题组的谈话和在会议上与微型工厂组的谈话完全不同。我经常去对高中生进行演讲,这是一种完全不同的演示方式。尽管基本概念相同,但必须以不同的方式呈现不同的形式。

Peter [30:35] 

我要强调的一点是,您实验室中的重点是团队合作和指导,这是紧密结合的。我想知道,当您从培养大量的本科生到研究生,再到到博士后时,是什么激励着您在教育中保持这种状态呢?您是否正在寻找某些东西,特别是当您接受或决定指导他们的时候?

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] 

那他们是不是全部都是来自相对较新的人呢?

Dr. Allbritton [31:30] 

是所有人。知道工作没有偷懒或捷径,要努力才可以到达目的地,你希望学生能明白这一点。所以我的感觉是,我喜欢具有这些素质的学生。你希望冒险的学生会尝试一些东西,而不担心失败。因为通常我无法凭空想象(结果)。我会告诉我的学生,哦,那真是个坏主意。我认为这行不通。幸运的是,他们有时会完全忽略我。就像,“哇,好主意。我很高兴您不听我的话。”所以你还希望那些具有冒险精神而且已经准备好失败的人。这是一件好事,[只是]走出去,面对新的挑战,然后说,我想尝试一下,看看会怎样。并不好说(结果会怎样),我只能这样做,这是我想做的,因为我做得很好,但是想尝试尝试不同的东西。

Peter [32:33]

另一方面,这些是对学生非常有用的技能,您希望培养学生或实习生的哪些技能呢?

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] 

那您是如何提高写作的呢?

Dr. Allbritton [33:18] 

是的,老实讲,对学生来说,这很辛苦,没有尽头。在我实验室的学生,他们必须为研究写计划,我想我将他们折磨的够呛,让他们重写、重写再重写。而且我觉得他们有时感觉这很有趣,因为他们从我那儿拿回了稿件,一切都给划掉了,但到最后,他们发展出了一种友情。是的,我们在南希所做的修改中幸存了下来。所以,我们的想法是,在他们的整个职业生涯中,我们只需要迭代他们的论文,修改他们的论文及他们的文稿,并修改他们在NIH的项目书。我们进行修改后,再进行一遍又一遍的修改。随着他们不断进步,您可以开始看到他们写的越来越好。人们开始时的水平不同,有些人刚开始时就很出色。因此,修改工作并不多,但是其他人还有更多工作要做。但是他们越努力,他们就会越做越好,并度过这个周期。然后,我认为学会和与你不同的人一起工作-我认为所谓孤独的狼科学家已经成为过去。很显然,团队成员共同努力所取得的成就远胜于自己工作的人。如果你看一下当今所有的突破性科学,那就是来自不同国籍,不同背景的团队。因此,学会灵活应变,与他人合作并容忍他人不同的工作方式,我认为对于学术界,政府,行业,国家实验室的成功至关重要。即使你决定成为教学专业人士,能够与团队一起航行和工作,你将做的更好。

Peter [35:01] 

是的。通常,在其他所有人都有集体思维的情况下插入自己的人是具有挑战性的。您是否曾经感到过,作为生物医学科学领域的女企业家,您不得不面对许多挑战,而这些挑战来自于传统上由男性主导的领域呢?

Dr. Allbritton [35:19] 

绝对是。而且我年纪大了,特别是在化学和物理领域没有很多女性。当我开始我的职业生涯时,事情并没有进展的很顺利。我一直在想我该如何做得更好?你可以说,这是别人的错。他们没有正确地对待我,或者他们这样做了,等等,等等。但是我倾向于以不同的方式看待世界。而且我认为,无论你是谁,你都将面临年龄、性别或种族受到不公平待遇的情况。至少在我的职业生涯中,思考如何做得更好总是更好的选择?如果这对我来说不是一条好的路,无论出于何种原因,我可以朝哪个方向,哪里可以看到成功,并尽量避免反省并陷入一个领域,而是说:“好吧,让我们退后一步,我将朝另一个方向前进。而我在职业生涯中也做了一些重大改变,因为我想做点什么,但我又觉得这不是一个好主意,或者最终遇到了某些不太适合的情况。所以,我的想法是,我始终决定[遵循]后退一步,朝另一个方向前进,以实现自己目标的方法。我想这对我很有帮助。我有点像这样看待世界。如果你有一定的执着精神,并相信自己,且积极性很高,那么你可以继续努力。最后,我只是从一直思考中脱颖而出:好的,这没有按照我的方式进行。我只是想弄清楚自己,以及如何前进并从他人那里获取建议。当我开始我的职业生涯时,很难找到在物理学上跟我一样的人。这有助于激发人们的积极性和决心。但是随着我事业的发展,越来越多的人开始向我学习。这使生活变得更加轻松了。

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] 

真的很振奋人心。非常感谢您做客本期Gastronauts播客。

Dr. Allbritton [39:16] 

谢谢你们的邀请我。今天的对话真的很棒。

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。

第五期:相信你的肠道

张旭朏/译

Peter [0:00] 

您拿到它了吗? 好的,那您咬一口吧。

Dr. Neunlist [0:07] 

这显然是一个苹果。 这酒是红酒。 我希望你给我的是法国红酒。

Peter [0:17] 

关于红酒对帕金森氏病的好坏存在一些争议。 我们选择苹果实际上有两个原因。 首先,因为我们已经知道纤维的增加有助于改善帕金森氏症。 但是另一个原因是,有时在苹果生长过程中使用的农药实际上是与帕金森氏病有关的触发性环境毒素。但是我想知道您是否可以用一个词来描述闭上眼睛时的感觉。当我(拿着)一些食物进来的时候…

Dr. Neunlist [0:50]

我很担心自己发现的是什么。 但后来在这种焦虑的情绪下,我得到了糖和酒作为回报。

Peter [1:01] 

听起来很不错。

Peter [1:13] 

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建立一个更好的科学共同体。 那么,请跟我一同走进本期播客,探索我们的内部空间。

今天,我们很荣幸邀请Michel Neunlist博士。 Neunlist博士在Tung博士实验室和Johns Hopkins获得了心脏电生理学博士学位,旨在电活动中研究心脏如何运作,如何跳动的,并获得了路易斯巴斯德大学的博士学位。 之后,他在德国汉诺威的谢尔曼(Sherman)博士的实验室继续完成博士后研究,旨在研究整个神经系统,即控制我们肠道的神经系统和支持细胞。 自完成博士后工作以来,他开始了自己的实验室,目前是南特大学神经胃肠病学主任。 那么,感谢您的到来。 Neunlist博士,您能否告诉我们更多有关肠神经系统关键功能的信息,以及您实验室中对此进行的一些努力呢?

Dr. Neunlist [3:03]

感谢你们的邀请,让我在这个非常有趣的Gastronauts播客里发言。 正如你所提到的,我们实验室的主要重点是研究肠神经系统,通常称为第二大脑。 确实,正如您所知,肠道是仅次于大脑的第二神经器官。 我们正在研究的主要是整个肠道壁上整合的神经系统(由大约2亿个神经元和10亿个神经胶质细胞组成)如何调节主要的肠道功能、运动性及屏障功能。 [我们感兴趣的是]神经系统如何在各种疾病中发生变化,不仅是胃肠道疾病,而且也包括脑部疾病、神经系统疾病,特别是神经退行性疾病,例如帕金森氏病。 我们正在进行的最后一项研究是在疾病状态下,如何针对神经系统的器官功能恢复。

Peter [4:25] 

这真的很有趣。听起来您的实验室正在付出很多的努力。 我(有点)想将其分解开来。 我想问的第一个问题是很多人可能不知道肠道有-如您所说的那样多的神经2亿个神经元,而且还有数百万个神经胶质细胞。 与大脑神经元的数量相比,这又是多少呢?

Dr. Neunlist [4:49] 

当然,就数量而言,它要少得多。 质量并不总是取决于数量。 但是给你一个数量级(的话),与[大脑]相比,肠道中的神经细胞少了约1000倍。

Peter [5:09] 

能够直观表示肠神经系统中有多少个细胞,实在是太好了。 那么很明显,肠神经系统对于我们的日常生活至关重要。您之前提到了您正在研究的神经退行性疾病的一些工作。 我想知道肠神经系统在帕金森氏症或阿尔茨海默氏症等某些神经退行性疾病中如何发挥作用的呢?您在这方面做了哪些研究工作呢?

Dr. Neunlist [5:39] 

我认为这是一个非常复杂的问题。 并且我认为,试图证明脑疾病中整个识别系统的因果关系仍然是一种推测。 但是我想我们如何整合这两个神经系统可能受到了通用机制的影响。 因为根据定义,我们认为肠道是一个神经器官。

Peter [6:06] 

就像肠道是第二大脑这样吗?

Dr. Neunlist [6:08] 

就数量而言,它是第二个大脑,但从进化的角度来看,它(可能)是第一个大脑,即原始大脑,因为当您观察非常原始的器官(如水母)时,它们已经有神经元,但这些动物并没有大脑。[并且]它们已经具有所谓的肠道神经元。 因此,回到问题上来,为什么神经系统在很大程度上受到脑部疾病的影响,不仅在遗传疾病中,而且在精神疾病中。可能是因为这些疾病实际上与遗传缺陷有关, 由于它们在第一脑和第二脑中共表达,因此它们都调节神经元的功能。 它们可以诱发胃肠道合并症以及脑功能障碍。 这也可能是为什么在许多神经系统疾病中经常观察到胃肠道合并症的原因,因为它们具有共同的途径和共同的起源。

Peter [7:19] 

很少有人意识到胃肠道合并症或与神经问题相关的胃肠道问题。 我想很多人在提到帕金森氏病时,都将其视为运动障碍,有点震颤,步态不稳,但是许多帕金森氏症患者经常会出现便秘或腹泻,是这样吗?

Dr. Neunlist [7:40]  

确实如此还有意思的是,这些症状[或至少部分症状]可被视为症状前症状。

Peter [7:49] 

那是在运动障碍之前。

Dr. Neunlist [7:51]

它发生在运动障碍之前,并且有三联征的症状前症状,包括睡眠障碍,包括失眠或嗅觉缺陷。 第三个是胃肠动力障碍,例如便秘和吞咽困难,(具体来说)是吞咽困难、胃排空困难或减慢,这被认为是症状前的常见合并症。

Peter [8:30] 

(我们)可以将这些看成是某人有两个或三个症状的警告信号。

Dr. Neunlist [8:35] 

确实。这不仅仅是一种症状,也不只是因为便秘,就认为你更容易患帕金森氏病。 但是,如果您有睡眠障碍和便秘,那么患帕金森氏病的风险就会增加。 因此,这就有了一个假设,即如果胃肠道症状,存在于疾病的先前发展可能起源于肠道。 也许,这在利与弊之间仍然是一个非常热门的争论,因为您可能会出现胃肠道症状,且仅仅是因为身体对退化过程更加敏感。而在此处疾病的发生可能相当复杂。

Peter [9:26] 

所以,您是在谈论某种胃肠道或胃肠道表现,无论是因为神经系统更敏感而来,还是表现出的这些表现- 胃肠道神经系统的异常与中枢神经系统的异常,就像是先有鸡还是先有鸡蛋,对吗?

Dr. Neunlist [9:48] 

在帕金森氏病中,这并不是纯粹源于大脑,更重要的是退化性疾病的驱动假设,参与疾病功能调节的关键分子。

Peter [10:12] 

它们都有错误折叠的蛋白质。

Dr. Neunlist [10:14]

是的。 这种错误折叠的蛋白质可能被多种环境因素所利用。 有效地来说,这是全面诊断之一。(对于)真正的诊断,有趣的是,只能在验尸后利用活检进行检查,因此帕金森病只能在[死后](才能)进行明确的诊断。

Peter [10:37] 

之所以只能在验尸后完成,是因为我们无法掌握那部分还活着的人的大脑吗?

Dr. Neunlist [10:43] 

是的。 因此,这个构想可能是你不得不考虑另一个器官,可以按常规方式来操作的器官。 (而)活检结果不会威胁生命或风险最小。

Peter [10:57] 

您正在寻找您可以掌握一些组织问题的另一器官,(保证)人还活着,而且(也)看看这是否能诊断。

Dr. Neunlist [11:06] 

具有神经元的器官,我们可以将其用作[诊断工具],有什么比能满足这种条件的肠道更好的了呢,这意味着每个人都有机会或进行活检,结肠镜检查。 如上所述,肠道有神经系统。 因此,这是我们是否可以从活着的患者那里识别活检,鉴别正常与病理标志的驱动思想。该想法支持至少两个器官受到影响,而且治疗肠道是否会改善脑功能的治疗(也)是一个问题。

Peter [11:50] 

这是您所感兴趣的,对吗?目前(有人)了解吗? 还是说,这是我们需要继续进行研究的内容呢?

Dr. Neunlist [11:57] 

就我个人而言,我真的不相信当患者被诊断出患有帕金森氏病时,你有机会恢复该病,虽然你可能(有机会)减慢疾病发展的进程,但还是有一些数据(一项有趣但仍具争议的研究)表明,这会发生在进行了阑尾切除术的患者中。

Peter [12:28] 

取出阑尾的人。

Dr. Neunlist [12:31] 

在过去的几年中,患帕金森氏症的风险大大降低。 更有趣的是,这种降低患病风险的结果仅出现农村地区的患者中,而非城市中的患者。

Peter [12:53] 

而且居住在农村地区与城市的人生活方式截然不同。

Dr. Neunlist [12:58] 

假设之一表明(城市中的)人们更容易接触农药。 例如,农民接触农药会产生更高的帕金森氏病风险。 但是,这项研究再一次受到争议……当然,这是一项可以提高医学研究质量的研究,这意味着很长一段时间内你有(相关的)900,000名患者,但其他研究表明阑尾切除术对帕金森氏症的风险没有影响。 而另一个研究表明,这实际上增加了(患帕金森病)风险。

Peter [13:44] 

数据仍然有些混乱。

Dr. Neunlist [13:48] 

我可能会指出一个事实,那就是需要更多的研究

Peter [13:53] 

如此看来帕金森氏症是某种遗传因素的结合。 而后是某些环境毒素或某种会影响肠神经系统的物质(所导致的)。

Dr. Neunlist [14:03] 

由于大脑的功能会影响运动症状和胃肠道功能障碍,但是不知道大脑是否独立存在,或者是否与另一个器官相关联,从而影响这两个器官。

Peter [14:20] 

因此,了解整个神经系统和中枢神经系统之间的相互作用,以及如何出错(的机理)。 疾病仍是我们需要攻克的难关。

Dr. Neunlist [14:31] 

尤其是了解疾病的机理(方面)还需要很多的研究工作。一旦我们了解了疾病的机理,就可以提出有效的预防方法。这是主要目标。

Peter [14:45] 

(我觉得)进行帕金森研究非常具有挑战性,因为我们必须随着时间的推移考虑这些环境因素。 然后在一定的时间范围内,这些环境因素将发挥最大的破坏作用。 而立即把握时机与了解整个进度同样重要。 作为科学家,我有点想借此来进一步了解您的成果。 我想问一下您的研究之路。 是在正确的时间和正确的地点,或在正确的时间有正确的导师(领导)呢? (就个人而言)您能否告诉我们更多有关您的成长之路的内容呢?

Dr. Neunlist [15:20] 

从个人的角度来看,我认为你提到在正确的时间遇到​​合适的人对于发展你的职业至关重要。但是总的来说,您也必须这样做,我认为这是一门科学可以提供很多回报的地方。你必须对科学充满热情,如果你真的想从事科学事业,就必须(具有)好奇心。我的意思是,这并不容易,你必须保持幼稚,保持发现并开诚布公。当然,你也必须努力工作。我记得在霍普金斯大学攻读博士学位时,有一个传单,在上面我看到一只海鸥,这是一个吃青蛙的建筑工人。它的嘴里有青蛙的一部分。青蛙则是一只手臂握住了这只鸟的脖子,以防它被吞下。这就是科学家的形象。只要你不放弃,你总会充满希望并有所收获。如果你放弃了,那你就会被科学所吞噬。所以永远不要放弃。这就是希望的讯息。我的意思是,这非常关键,因为你的假设并不总是[正确],而您的实验也不[总是]有效。但是,如果你坚持你所要坚持的,那就总有解决方案。我认为这也是乐观的讯息,你必须始终保持乐观的态度。而在科学中,有一种方法是不正确的路。但是你必须走另一条路直到最后,成功之门将永远打开。

Peter [17:34] 

您曾简短地提到过,保持乐观的态度是一种在解决问题的道路上不遗余力的奉献精神。 您是怎么知道这不是正确的方法呢? 您(又)如何知道何时要更改方向呢?

Dr. Neunlist [17:49]  

这是直觉。 这就是为什么我们的肠子会紧张。 这就是为什么我们有第二个大脑。

Peter [17:57] 

作为一名研究生,有时我会在想,我会做一些实验,但却没有结果。 我应该放弃并转到其他项目吗? 还是我应该继续下去? 或者我应该继续坚持多久呢?

Dr. Neunlist [18:08] 

这取决于我不愿意放弃。 你必须对自己充满信心,认为自己所做的是正确的事情。 而且,你不放弃,并且相信自己做的事是对的。但通常来说好主意(总)是你的第一想法。 再次,(就是)直觉。 这很关键:相信自己的直觉,也要相信(或)听听导师的建议。 我觉得是这样的。

Peter [18:36] 

您一生中只有几个导师。与这些导师建立这种关系很重要。 您从路易斯·巴斯德大学获得博士学位,但您当时的科学导师是约翰·霍普金斯大学的董博士。对吗? 您能告诉我一些有关您决定去霍普金斯大学进行研究的情况吗?

Dr. Neunlist [18:56] 

这并不是我进入霍普金斯的直觉。 但这是另一种感觉。我遇到了某人。 我的女友是美国人,所以这不是一种直觉。 这只是生活事件。 我的意思是,并非所有事情都已计划好。 因此,如果你将直觉与其他类型的心脏感觉相结合,那么我之所以选择霍普金斯是因为霍普金斯的BME(生物医学工程师)部门享有盛誉,因为我是一位生物医学工程师,并尝试过(申请)。 这是你必须要做的事情,你必须尝试一下。 然后我写了很多封信。 然后董医生[回复了],这就是“好哇”。 当事情成熟时,在合适时间的相遇。

Peter [19:49]

您是如何对电生理学或电回路如何调节我们的身体感兴趣的呢? 我的理解是,您的热情是了解这些回路的功能,是吗?

Dr. Neunlist [20:02]

并不是。(为了)了解生物学如何运作,生命如何运作,器官如何运作,因为这基本上也是一个工程问题。 对于工程师来说,还有什么比了解人体的工作方式更好、更复杂的呢?人体要复杂得多。我想这也促使我成为了生物学界的工程师。 如前所述,机会是我必须在心脏内这样做,在我整个职业生涯中一直伴随着我的是,研究电(信号)如何参与器官的生物学,首先是心脏,然后才是肠道。因为我的定义是神经器官,生物电部位和记录肠道的功能。 因此,这是关于我的研究之路。

Peter [21:02] 

您具有的工程背景,并且了解电以及电回路如何在基础生物学中发挥作用,这是从心脏移植到研究肠胃的自然转变吗? 您有所保留吗? 您是否在想,哦,也许肠道与心脏不太相似呢?

Dr. Neunlist [21:19] 

是的,因为两者之间的联系是研究方法。 为了测量当时的电活动,它是通过微电极进行的。 当然,如果你想了解神经回路的活动,不仅是当时的一个神经元,而是还调节着许多神经元的整体反应。 光学传感的优势在于,通过光学测量,你可以对整个网络中的电活动进行全局测量。 因此,最能回答你的问题的答案是(电)网络如何改变疾病。此技术如何用于解决心脏问题的常见方法,这与肠道神经系统和生理学中的问题截然不同。

Peter [22:12] 

因此,了解网络的方法就是您来[回答问题]的方法。 您在心脏中使用了它,并且发现肠道也具有适用性。

Dr. Neunlist [22:21]

是的。 之后,我们将尝试通过整合观察到的功能来进一步了解已知的活动,因为最终目的是了解器官的功能,无论是运动功能还是更多的屏障功能,这对我来说会更有趣。

Peter [22:43] 

您能够从研究的心脏组织无缝转换到肠胃组织,是因为您拥有了这种方法,并且拥有了可以轻松地从一个领域应用于另一个领域的技术。 能够将技术应用于不同领域是非常强大的。 但我也认为,重要的是要应用(那些)您认为对科学研究至关重要的某些准则。 您是否向您的学生或受训人员灌输了这些准则呢? 您能分享些科学方法的基本原理吗?

Dr. Neunlist [23:20] 

我的意思是,最重要的方面是对你的操作采取严格的科学方法。 科学的[重要性]也是可重复性。 我的意思是,你必须验证所有概念; 对于我而言,这是至关重要的研究,我想这(也)是任何研究的基础。 我知道这是非常基本的原则。 但这是科学的核心结构,这是基础,尤其是在科学(研究)正在迅速下降的当今社会, 这个问题经常(会)被问到。我认为这是我们做科研时生存的唯一途径。 我们还必须知道,这并不意味着它是对的,因为科学正在[不断变化],它[将会]发展。 在你从事科学工作时,它必须已经[适当地]运行。

Peter [24:28] 

所以,对您的研究有严格的要求或奉献精神至关重要。 可重现性是您认为必不可少的东西,您想(将其)灌输给您培训的其他人。 我们希望我们的科学具有可复制性。 我想可能会有与我们发现的发现相反的发现,但我们的实验需要重现。 我认为这真的很厉害。 因为我们生活在一种大环境当中,某些科学发现的新闻可能会很快受到挑战。 我们必须了解这些发现中每个工作所付出的努力,所花费的时间,并继续灌输对未来科学家们的奉献精神,这是我们认为的强有力的东西。

Dr. Neunlist [25:10] 

我认为这是基础吧,尤其是在具有这种信誉的地方,因为各地的科学也越来越多地由金钱驱动。 尤其是在资金短缺的危机时期,尤其是在当今社会上。 我认为在金钱的驱使下,保持正直非常重要。

Peter [25:29] 

非常感谢Neunlist博士参加我们本期播客。

Dr. Neunlist [25:31] 

非常感谢你们,很高兴与你交谈。 谢谢。

Peter [25:45] 

哇,我觉得这是一个值得珍藏的非常重要的信息。 科学旅程伊始,热情有助于开启研究。 但完整性才是严格的标准,它可以有助于永存您的发现并经受时间的考验。 我认为这是我们所有人都曾经听过的一课,但是绝对值得回顾。 从现在开始,(请您)思考一下,我们如何使我们的工作和合作者的工作得到重视呢? 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。

第四期:照亮前路

张旭朏/译

Dr. Spencer [0:00]

它很甜,非常好吃。(让我)有种想要吃更多的冲动。 所以这是个令人愉快的食物。 我非常有信心至少知道其中的一部分。

Peter [0:12]

嗯嗯!那您认为是什么呢?

Dr. Spencer [0:19]

我猜有巧克力包裹在外面,里面有一些柔软的东西,像蜂窝状或(我)不太确定中间是什么。

Peter [0:25]

好啦,您可以摘下眼罩了。 真正准确的描述。 是Tim Tam,(Tim Tam)在澳大利亚真的很受欢迎吗? 我知道在美国这边,我们总是谈论:“哦,是的。Tim Tam :澳大利亚的小甜饼。”

Dr. Spencer [0:40]

蛮有趣的。它们很受欢迎。是的。人们对它很痴迷。

Peter [0:48] 

太好啦!谢谢您。

Peter [1:03]

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,并更好地理解科学过程中的步骤。 那么,请跟我一同走进本期播客,探索我们的内部空间。

本周,我们邀请到一位对控制肠道的神经网络非常在行的专家。 尼克·斯宾塞(Nick Spencer)博士的实验室专门对这些神经进行研究,以治疗便秘和内脏或体内的疼痛。 他在澳大利亚墨尔本莫纳什大学完成了神经生理学博士学位。 随后,他前往内华达大学进行了博士后工作,在那里他研究了控制肠道的神经系统。在澳大利亚阿德莱德的弗林德斯大学(Flinders University)任教后,继续了这项研究工作。斯宾塞博士,感谢您今天的到来。

Dr. Spencer [2:37] 

非常感谢你,彼得。 很高兴来到这里。

Peter [2:40] 

那么,我想了解的问题之一是,您能否向我们介绍一下您当前的研究工作,以及您如何看待神经生物学和胃肠病学这两个学科的背景呢?

Dr. Spencer [2:52] 

当然可以。20年前,当我完成博士学位时,人们对肠道的兴趣一般。 大家认为它确实是一个吸收营养并排出废物的器官。 但如今,正如你已经了解到的那样,在媒体上,人们对肠道的关注和兴趣越来越多。(它)不仅是为了消化,吸收,尤其是肠道内的细菌会对我们的幸福和健康产生重大影响。 如此多的学科,例如精神病学和心理学,以前对肠道毫无兴趣,现在对我们的工作极为感兴趣。 (而)我们真正感兴趣的是肠壁神经与大脑的通讯方式以及相应激活机制。

Peter [3:42] 

(那么)您能告诉我一些研究肠道神经的相关技术或工具吗? 它们是否不同于人们传统(意义)上用来研究肠道的工具呢? 或者,您可以大致告诉我们一些有关这些工具的信息吗?

Dr. Spencer [3:47] 

当然。 技术发展日新月异。 信不信由你,现在我们正在做的某些事情已于20年前(大为不同)。 我们现在使用的大多数技术,包括电生理学,(已经)可以在其中记录神经传导的电信号。 这种情况已经完善,但本质上并没有在神经生理学记录上取得重大突破。 我们使用的标准免疫组织化学,可以检测神经细胞内产生的化学物质。 这是一种相对基本的技术。 我们使用的新技术之一是光遗传学,使用光来刺激细胞。 我们可以(通过这种技术)激发或抑制神经等细胞。这是一个非常非常令人兴奋的工具,一种很强大的工具,实际上发展(到现在)也就只有五到八年的时间。

因此,我们主要使用免疫组织化学,追踪技术,光遗传学,电生理学,另一个主要进展是转基因动物的开发,我们可以在其中操纵动物的DNA。 例如,我们可以在目标细胞中插入特定的荧光标记,这样我们就可以看到动物体内的哪些细胞发光,以及它们在体内的行为。

Peter [5:21]

所以,听起来好像您拥有大量真正有趣的技术,这些技术正推动着您的研究-从光线照进肠道到特定颜色标记蛋白质来查看特定蛋白质。 一般来说,技术似乎是科学的巨大动力。 我想知道,如果让您回到30或40年前,您对科学的态度会有何不同?

Dr. Spencer [5:45]

哇,彼得,这是一个很好的问题。 从来没有人问过我,我也没有真正考虑过。在我回答之前,可能不得不说是20、30、40年前,这些问题会大不相同。 一般来说,现在的科学(研究)要困难得多。 这非常非常令人兴奋。 我们很高兴能在这个令人难以置信的时代生存下来,在这个时代,技术正以惊人的速度发展。 但是随着科技的发展和越来越多的信息被发现,问题变得越来越困难。 因此,我想回答你的问题(答案是),那时候我们会有不同的问题。 我的意思是,我们只是在午餐时谈论[…] DNA仅在几年前才发现,对吧? (人们)认为恐龙已经存活了好几亿年,这非同寻常。而我们那时甚至都不知道DNA是什么。

Peter [6:37]

我们听说CRISPR(基因编辑技术)或其他修饰DNA的技术。

Dr. Spencer [6:41]

那就对了。 绝对是惊人的。 谁曾想到我们可以将DNA用作水母中的荧光标记物并将该外源DNA插入小鼠体内呢? 如果在20、30、40年前回答你的问题,我们并不会相信。 所以科技发生了很大的变化,而且变化非常快。也许我们回到了那时,我们只能局限于相对原始的技术,例如机械记录和一些基本的电生理学。

Peter [7:10] 

所以,您要说的问题,实验室所提出的问题类型将完全不同。

Dr. Spencer [7:15]

是的,差不多。非常(接近)。

Peter [7:17] 

您认为问题会更简单些吗? 我觉得当我想到科学问题时,常常会想到这些,而一些最简单的问题(往往却)是最难回答的问题。这些技术的进步正在帮助我们回答这些简单的问题,还是您认为它们使我们朝着更具体的针对性问题前进,而这些问题只是简单问题的一个方面?

Dr. Spencer [7:42] 

我想答案是两者兼有。我的意思是,随着我们发现更多的信息,我们还将解决更多的问题,所以你是对的。我同意,有时最简单的问题是我们不知道且尚未解决的问题-不一定尚未解决,而是无法获得答案。几乎并不是因为这项技术可能还没有出现。我们可能需要考虑的事情之一就是像我们这样的哺乳动物(如何来)适应。例如,当我们在小鼠中突变基因时,动物的行为会急剧改变。但是通常一段时间之后,它又可以回到开始时的状态。我们使用“抵消”这个词(来形容)。因此,如果从出生时(就)删除了一段基因,该动物可能会最终,也并不一定总是最终恢复到这种与起始行为非常相似的状态。 那么,技术(层面)已经解决了这一问题。例如,(现在)能够迅速、瞬时地删除一段DNA,然后立即观察到对动物的影响。因此,你有很好的对照参考。这对于解决某些问题非常非常有用。

Peter [8:53

我认为这很有趣,因为所有这些问题都与时间有关。当我们制造转基因小鼠或对其进行修饰时,我们必须立即对其进行研究,因为长期(的情况下)存在(行为)抵消。我对CRISPR和基因编辑有些感触。而且我们对这项技术真正的实现尚未了解,因为我们不知道会发生什么(形式的)抵消。而且我认为这即很有趣,也很强大,就我们现有的这些技术(而言),除非我们长期研究,否则它们不会被完全理解。我想谈一谈光遗传学工具,在此(技术中)您会(利用)发出(的)光线以打开或关闭通道,这将激活或关闭特定的细胞。您是如何想到在光线不足的肠道中直射光线的方法的呢?

Dr. Spencer [9:52] 

这是个很好的点。当然不是,(或者说)应该没有。肠道是我们所谓的周围神经系统的一部分。大脑和脊髓是我们所谓的中枢神经系统的一部分。一般来说,在中枢神经系统上的研究人员可能要多于周围神经系统。总而言之,我们利用大量研究中枢神经系统的科研人员所采用的技术,成功地证明了光遗传学在大脑和脊髓中的作用。然后我们意识到,周围的内部器官并没有发生太多变化。肠道是光遗传学的绝佳选择,因为它是体内唯一具有自身内在神经系统的内部器官。换句话说,它有神经元,不仅是神经末梢,还有神经细胞体及肠内核。我们称其为肠道神经系统。这意味着我们可以轻松地在肠道中使用光遗传学,以表达你所谈论的光敏通道来操纵肠道功能。

Peter [11:04]

您认为通过操纵这些特定于肠道的神经而不是周围其他任何地方的神经,可以解决什么生理或医学问题吗?

Dr. Spencer [11:14] 

是的,这是一个好问题。你可以使用该技术的多种潜在途径。如你所知,肠道疾病很多。现在,我们不是特别致力于疾病的研究,我们试图了解肠道在健康状态下如何独立运作。(这个问题的最简单答案是)其中的主要问题之一是慢性或特发性便秘,不幸的是,患者通常只能使用泻药(来缓解)。现在,市场上有一些药物可以刺激神经系统和肠道。但是由于受体通常在多个器官中表达,因此当您服用刺激肠神经药物的同时,也会刺激身体其他部位的神经。它们不仅仅针对肠道神经系统。光遗传学的优点在于,你可以表达对光敏感的蛋白质,因此使通道成为对光做出响应的离子通道,尤其是在特定的神经元群体中。在肠道内,这意味着它可以发出特定颜色的蓝光,这会激发在肠壁中的兴奋性神经元。在我们的研究中,它刺激在肠壁上,导致肠道在没有任何药物的情况下收缩并排出便便。

Peter [12:36] 

您是否认为这对人类是潜在的应用呢? 这是否可以用于人类并最终治疗便秘呢?

Dr. Spencer [12:44] 

这是个好问题。随着大量新技术的出现,通常都有优点,然后伴随一些缺点。使用遗传学有一些非常非常明显的优势。也有明显的缺点。优势在于,仅刺激肠道就可导致肌肉细胞收缩并使排泄物增加,换句话说就是改善运输。因此,优点之一是可以立即激活肠内神经。你不需要口服任何药物;它不必被血液吸收,也不会非特异性地作用于所有其他器官。这是一种仅刺激特定类型的神经元(例如,肠道中的兴奋性神经元)的有效方法。其不利之处在于,你需要将最初来自藻类的光敏DNA掺入神经元中。现在,这听起来有点像科幻小说,但是不管你相信与否,关于在人类中拥有无害病毒的概念已经得到认可并投放市场。但是问题是,如果长时间将光照射到肠道上会发生什么。有证据表明,长时间接触可能无济于事。而另一件事是你需要通过肠壁(光源)在内部合并。通常,您需要通过外科手术将微型发光二极管植入肠道。现在,我们已经在老鼠身上做到了,并且可以正常工作。从概念上讲,没有理由不对大型哺乳动物起作用。你只需要确保在整个神经系统中获得足够的神经元,从而形成光敏感通道即可。

Peter [14:42] 

哇,听起来确实有点像科幻小说。 我想现在很难说服某个人,是否在他们的肠道中放置发光二极管。 但是,如果便秘变得如此严重,人们是愿意尝试很多事情的。 我在诊所中看到在很多(便秘的)患者-这确实是一个灾难性的问题。 这是他们的主要担忧之一,对吗? 他们(可能将)会患有癌症,炎性肠病或任何肠道疾病,其中一个主要症状是便秘引起的腹痛。 我想更进一步走近科学方面,并询问您的发展道路。 我想知道您对研究生有什么建议吗? 或者,如果您对自己读研究生期间有何感想? 您是如何想到(研究)这个领域来追赶快速发展的领域的呢?

Dr. Spencer [15:19] 

嗯,好问题。 我认为最重要的是,你要追求自己感兴趣的事物。现在,如果您来自大学背景,并且对某个领域感兴趣,那么我的观点就是追求自己的兴趣。 我见过有些人进入他们并不真正感兴趣的领域,只是因为有更多的钱,或者还有其他一些附带作用。几年后,他们变得非常不高兴。 因此,我认为最重要的是关注您感兴趣的领域。就研究生期间而言,我知道我对神经系统感兴趣,这些神经如何相互交流,以及它们如何发挥作用,我简直不敢相信可以从哺乳动物身上切除一部分肠,即使它不再与大脑或脊髓相连,它仍然可以工作。

Peter [16:26] 

那么,从老鼠或任何动物身上抽出来的肠子能持续多久呢?

Dr. Spencer [16:32] 

无论我们是否相信,我们已将患者的整个结肠移除,而小鼠,大鼠,猪,豚鼠(移除结肠后),(肠道)可以存活长达10到12个小时之久。只要溶液中有氧气,您可以保持它们的存活。

Peter [16:50] 

哇,太酷了。 我想(是)这把您吸引到肠道的研究中的。

Dr. Spencer [16:54]  

确实如此,你会觉得肠道有点儿像心脏,你握住心脏,它仍在跳动,这是一个内在的心脏起搏器。肠道里也有起搏器细胞。 而且他们在最近十年已经被证实。 因此,肠壁内的神经也可以以有节奏的起搏器方式表现。 我真的对如何提高或降低(它的)频率很感兴趣。 这花了一段时间,但我们取得了一些令人兴奋的进步。 这是非常有益的。 那么,回到你另一个问题,我认为解开以前未知的问题所带来的奖励和兴奋是非常强大的。没有薪水可以代替这种满足感。

Peter [17:44] 

是啊。 我想这(也)是我经常看到的主题,它是回答其他人没有答案的问题的动力,感谢您与我们分享。 我想问的另一件事是,我们讨论了很多有关技术的发展以及事物如何随着时间而发展。 我想,作为科学家,对于我们来说重要的是要认识到这一领域是如何变化的,以及我们之前出现的一些巨人和他们所做的研究。 我想知道,是否有特定的科学家或特定的小组真正启发或激发了您的工作,或对您的工作产生了重大影响呢?

Dr. Spencer [18:21] 

是的,这是一个好问题。 是的,肯定有很多人和团体。我想可能对我影响最大,最动人的故事之一是位澳大利亚人。 来自阿德莱德的罗宾·沃伦(Robin Warren),他是唯一一位获得诺贝尔奖的(澳大利亚人)。 他发现细菌实际上可以在胃中生活。 吸引我的并不只是发现本身,激发我灵感的是他的发现方式。 因为至少有二十年甚至更多的十年,没人相信他。 2005年,他接到一个电话,说他获得了诺贝尔奖。 而且我认为他坚韧不拔,永不放弃的毅力鼓舞人心。

Peter [19:43] 

哇,那真是一个鼓舞人心的故事。 我想我们谈论过很多关于天才的事,对吧? 我们认为既有天赋,又有努力。 而且我们认为,我无法模仿,因为某人天赋比我多的多。 但是我们又认为,如果我们付出更多的努力,我们同样可以做到,并且可以坚持下去。 但是当其他所有人都告诉你时,你就能够坚持下去。 天才(这个观念)本身就是不对的。

Dr. Spencer [20:09] 

是这样的。

Peter [20:11] 

我想问的另一件事是关于您从决定来美国做博士后,然后再决定回到澳大利亚成为一名PI,成为一名独立研究员,来回离开您的国家无疑是一个冒险的决定。 您能否告诉我更多一些有关您所经历的事情以及您对正在经历类似决策过程的人的建议呢?

Dr. Spencer [20:37]

这是一个非常重要的问题。在内华达州大学和一群优秀的人,在一个好的机构里做了9年的博士后,我的产出率中等,并且学习了许多新技能。然后我得到了一些资金,这变得有点尴尬,因为与之共事的人就在隔壁(并产生了分歧)。从科学上讲,我发现很难脱离。关于谁的想法是什么以及我应该在这个问题上进行什么工作,或者是你的项目还是我的项目,(这些情况变得)有些紧张。(此时)我获得了一个很好的机会。而我在北美有资金,但我全部放弃了,放弃了这个不是很好的机会。(而)在南澳大利亚,这是个永久性职位。但是我几乎没有资金可以投入,我将所有设备和东西都留在了(原来的课题组)。我离开的原因是,在某个时间点上,你必须真正证明自己是完全独立的。每当你提交申请时,如果你所在的课题组很大,对于世界上最好的课题组来说都没关系。如果你提交申请,请立即认为是该课题组或课题组的高级研究员放弃了该项目。而你实际上只是参与其中的工作。你实际上只需要突如其来,证明自己可以独立工作,就可以真正推动项目。你是这些论文的资深作者。如果要成为独立的PI,每个人都必须进入一个循环。而永久留在同一博士后(工作)中,很难突破。

Peter [22:22] 

您是否曾经想过拥有自己的想法是具有挑战性的呢? 或者,也许您在经历此过程时,您的研究生生涯中是否有一个时间点,例如:“嗯,这主要是我的想法?”(而)我(只)是一个相对年轻的研究生。很多时候您在实验室,都是PI的许多想法,而您在学习大量知识。 但是,是否在某个时间点,您遇到了可以实现自己想要的转折点的机会,而这些主要是我的想法呢? 有没有一种方法可以加快该过程呢? 还是(这是个)随着时间的流逝而(自然)发生的事情呢?

Dr. Spencer [22:50] 

一个好的问题是:发生了什么。当您第一次走进实验室时,我想没有人会知道他们将要做什么或将要发现些什么。这就是进行独立科研的重点;它是回答尚未解决的问题。因此,不应让你因一无所知而灰心丧气。当进入实验室时,任何人都应该考虑这个问题。而且,如果你对它感兴趣,并且你充满热情,请坚持下去。随着时间的流逝,随着你进行更多的实验并进行更多的阅读,参加更多的会议,遇到更多的人,您会(从中)发现某些事情。你会意识到,或者你会听到显而易见的事情,这些事情尚未解决。我们不知道的主要问题是什么?然后你会想:我能做些什么来回答别人无法解决的问题呢?现在答案是否定的。其他人已经在做,或者他们做得更好。但是到了某个时候,你常常比导师更了解项目。有时你可以完全独立地测出数据并分析实验。而且,在完成研究生学位课程之前,你确实应该比导师更了解您的项目,因为是你做的项目。(这时)想法就会出现。而且你会思考的很好。我们为什么不尝试这种方式。很多都是反复试验和出错-有些事情会失败,有些事情会起作用。这是一个尽可能多敲开门的问题,找到打开的门的问题。这为你提供了一条打破现状并证明你可以自己推动项目的途径。

Peter [24:35] 

Spencer博士,谢谢您的建议,我真的很感谢您抽出宝贵的时间与我们讨论技术和科学发现的重要性,以及您如何建立自己的研究领域。再次感谢您。

Dr. Spencer [24:48] 

这是我的荣幸。谢谢你们的邀请。

Peter [24:59]  

将LED放置在肠道中作为临床治疗便秘的方法可能并不常见。但是,听了Spencer博士对他工作的热情,以及他关于坚持和相信自己的重要性的故事,我想,为什么不(能实现)呢?特别是如果我们可以限制副作用。也许在20年后,这种干预将成为常态,或者甚至看起来已经过时。无论如何,在这个瞬息万变的科学领域中,重要的是不仅要适应能力强,而且要坚定不移地坚持自己的信念。因为如果您不这样做,也就无法说服其他任何人。非常感谢大家的收听。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。

第三期:记忆调试法

张旭朏/译

Dr. Costa-Mattioli  [0:00]

(感觉)我正坐在一棵杏树上,[我]一直坐在南美洲的一棵大树下。

Peter [0:12]

那您认为您肠道中的微生物现在在想些什么呢?

Dr. Costa-Mattioli [0:16] 

他们没有办法思考,因为他们没有大脑!

Peter [0:19] 

那么您现在可以睁开眼睛或者摘下眼罩了。(您猜的)杏仁是正确的,那儿还有几颗坚果。 我选择“混搭”的原因是因为很多人认为我们可以通过吃某些食物来增强我们的记忆。 人们觉得核桃对记忆有益,蓝莓含有抗氧化剂,而黑巧克力则能够改善我们的记忆力。 但我想知道您如何看待用食物作为一种治疗方法来改变我们的微生物或者来增强记忆力呢?

Dr. Costa-Mattioli [0:47] 

我认为这是一个很好的选择。几个世纪以来,我们一直在讨论(如何)利用食物来治疗各种疾病的理念。 现在,我们有可能用不同的食物来治疗不同的疾病。 所以我认为这确实是个很好的途径。(然而)我们(对此)知之甚少,但它却又如此有趣。 你要知道,我的网站最后一个观点就是:可能考虑开发食物疗法,我们可以利用这种方法来调节特定的微生物群落,从而影响大脑或其他(调控)中心,这不仅仅与大脑相关,也可以提高人们的生活质量。

Peter [1:35]   

真的很酷。 人如其食嘛!

Peter [1:52]

大家好,我是Peter,本期The Gastronauts 播客的主持人。在Gastronauts,我们致力于理解人体的(内在)联系。 尤其是肠道与大脑的对话方式我们将深入研究优秀的科学家们及其工作背后的思想和动机,并希望通过了解科研背后的个人,来了解不同领域的科学家是如何思考以及为什么他们对自己的工作如此充满热情。 因此,请同我一起探索The Gastronauts 播客的内在秘密。

本周,我们邀请到一位记忆专家,他不仅揭秘了细胞用来编码记忆的通路,还发现了我们肠道中能够调节社会行为的特定细菌。 Mauro Costa Mattioli博士有着相当精彩的职业生涯。 他曾在乌拉圭蒙得维的亚的共和国大学学习微生物学,之后前往法国,在皮埃尔和玛丽居里大学(今索邦大学)学习,在南特大学攻读博士学位,在那里他主要研究了病毒免疫逃逸机制。 在完成博士学位后,他前往蒙特利尔的麦吉尔大学,在Sonenberg博士的实验室工作。在那里,他首次对记忆产生了好奇,特别是蛋白质合成在记忆形成中的作用。 那么,Costa-Mattioli博士,非常感谢您今天的到来。

Dr. Costa-Mattioli [3:43] 

谢谢你们的邀请。

Peter [3:44] 

我想问的第一个问题与记忆有关 – 记忆是我们生活中不可或缺的一部分; 它们非常强大; 它们是我们存在的核心,并且定义了我们的经验。 知道您是这个领域的专家,您能告诉我们,您和您的实验室(同事)是如何看待记忆的呢?它只是简单存储和检索用的吗? 还是有其他更多的作用呢?

Dr. Costa-Mattioli [4:04] 

我是一名分子生物学家,并且对形成记忆所需的机制很感兴趣。 正如你所指出的,记忆对于动物物种的生存至关重要。但同时它又是我们身份的核心。 因此,我们尝试着来鉴定那些关键组件,这些组件可使动物记住一个特定事件,这很有价值。 当我加入麦吉尔大学的Nahum Sonenberg实验室时,我们尝试着揭秘这些机理,现在它们已经成为了记忆形成的黄金标准或关键因素。

Peter [4:45] 

那您能给我介绍一些相关机理吗?

Dr. Costa-Mattioli [4:47] 

其实我们感兴趣的主要问题是如何将短期记忆转变为长期记忆。我们知道这个过程需要蛋白质的合成。实际上,这是为长期记忆“洗礼”的分子学过程。如果你要进行“洗礼”,那么长期记忆的蛋白质合成需一个必要条件就是具有分子长期性。但我们并不知道这背后的机理。当我加入麦吉尔大学的Nahum Sonenberg实验室时,我认为我来到了理想的地方可以尝试着解决这个问题。而且我决定改变领域,从病毒学和微生物学转向神经生物学。随后,我们发现了一种似乎有点像记忆形成的开关,即蛋白质合成的发生机理。如果你打开它,这时动物就会形成任何记忆,如果你把它关闭,此时记忆实际上已经受损了。在过去10年左右的时间里,世界上许多研究人员的研究工作建立在这些[研究结果]的基础上,并得以重现,而且进一步在啮齿动物,大鼠,小鼠,甚至小鸡中验证了这些研究结果,希望将来这些能为人体(研究)所用。

Peter [6:00] 

这真的很有趣。 我想稍微谈谈长期和短期记忆之间的区别。 您如何解释这两者之间的区别呢?是编码方式不同吗? 您提到了蛋白质表达对于长期记忆形成的重要性; 那对短期记忆又是怎样的呢? 是不是因为蛋白质形成的积累需要时间,故而具有长期特异性呢?

Dr. Costa-Mattioli [6:20] 

那么,我们所知道的是与此相关的“机械部分”具有合成蛋白质的能力,在短期记忆过程发生时它似乎不会被激活。 因此,你可以以一种非常简单的方式来思考(它),在长期记忆的情况下,你拥有这些蛋白质,而这些蛋白质的合成将为脑细胞之间更长时间的连接建立基础。然而,在短期记忆的情况下,你并不要求那些连接是稳定的,因为随着时间的推移,这些连接最终会逐渐减弱。 因此,(这也就是)短期记忆与长期记忆的不同机理。

Peter [7:05] 

也就是说,短期记忆不会变成长期记忆,它们在大脑中的编码方式是两个独立的过程。

Dr. Costa-Mattioli [7:11] 

其实,短期记忆是可以转化为长期记忆的,并且这些蛋白质的合成机制也是可以被激活的。 例如,在我们所做的一些实验中,我们为这些动物提供了短期记忆的训练方案。 而由于训练开始时蛋白质合成就在这些动物中启动,这个时候,短期记忆就可以转化为长期记忆。反之亦然,如果我们关闭(蛋白合成的)开关,我们也能够将长期记忆转化为短期记忆。

Peter [7:48] 

这真是太棒了。关于记忆,还有一些大众性的问题,我有很多尝试记住事情的经验,而且我很难记住一些我觉得应该记住的事情。另外一些时候,当我并不想记住某些东西时,它却突然出现在我脑海中。我觉得当我是一个积极的参与者而非被动倾听者时,我能够更好地记住信息。 例如,当我尝试解释我跟其他人学到的东西时,通过解释的这个过程就可以帮助我更好地记住这些信息。 这只是加强或重复的问题吗? 还是您认为这是社会行为的作用及其对记忆的影响呢? 还是我们对这种现象有更好的解释呢?

Dr. Costa-Mattioli [8:34]

我们可能有,但我也许还没有(答案)。所以我不确定我们是否能够回答这个问题。但是我们知道,当你更加投入并且更专注时,你确实不会分心。如果你会分心,比如,电视打开或有人在电话里和你说话,而你正试图去读一本书,信息存储到你大脑的路径就要少得多,因为你有行为学干扰,等等。另一种是我们有些记忆在某些情况下甚至不需要重复就可以非常有效地存储在大脑中。 这种情况要有一个非常强烈的情感因素(存在)。你要知道,如果你有一个非常强烈的情感因素,那么我们(潜意识里)知道我们需要重复。正所谓熟能生巧,不是吗?而且我认为这种训练(方式)是需要间隙的。并不是说你需要等到最后一天去复习考试并且彻夜未眠。 如果你选择提前几天开始,阅读它,多次重复,间隔(休息)一下,小酌一杯等等方式,这些信息被存储的可能性会大大提高。但对于那些有非常强烈情感因素的记忆,你只接收到一次信息,而信息就被存储了起来。(目前)我们还不太清楚这是怎么发生的。

Peter [9:48]

那么,情绪是在细胞水平上编码呢? 还是在大脑区域水平呢? 我完全同意(您所说的)更多的情感体验更令人难忘。 那您认为这是细胞与细胞之间的作用吗? 还是您认为某些大脑区域正在增强(这些)信号呢?

Dr. Costa-Mattioli [10:05]

我们有特定的区域,或者说这实际上最终会与另一个控制记忆形成的大脑区域有联系。 但是我认为这主要发生在通路或细胞级别。 我们需要弄清楚它是否是特定的通路,而最终将那些大脑区域与记忆区域连接起来。 所以,是的,我认为是通路的特异性决定了这些被激活的特定通路。 但老实说,我们对此还不是很了解。

Peter [10:39]

是的,所以具体来说的话。 您认为该领域仍然需要回答的关于记忆的一些非常重要的问题是什么呢?

Dr. Costa-Mattioli [10:46]

我想还有很多。其中一些是站在更加基础(研究)的立场,我想告诉你的是,我们知道新的蛋白质合成是记忆形成的必要因素已有五、六十年之久。我们不知道的是,这个过程所需的蛋白质子集是什么。我们也不知道这种合成蛋白质是否需要在神经元或不同类型的神经元(兴奋性或抑制性神经元)中发生。我们更不知道是什么让记忆变得破碎。 […]我们的重点一直是在努力增强记忆力。但删除的记忆也是非常重要的方面。而你找回的那些记忆变得破碎后,你基本上可以将它们删除了。我们能否发现某种机制来针对那些例如与PTSD(创伤后应激障碍)有关的不良记忆,并删除它们呢?因此,这就有这两种情况,增强记忆和擦除记忆。而[如果]我们能够从本质上发现与检索相关的机制,我们就可以帮助那些有认知困难的人。

Peter [11:55]

所以理解记忆的检索方面,除了记忆的抑制,基础生物学才是这些的基础。 感谢您与我们分享这些知识。 我想(继续)谈谈您实验室工作的第二个方面:了解这些肠道微生物或微生物组是如何影响大脑功能的。 而且我觉得这对您来说就像一个不错的回归。 我知道您本科学习的是微生物学。 然后,您现在再次对微生物组和微生物学进行研究,以及它们如何对大脑产生影响。 我想知道是什么促使您进军与记忆十分相关的微生物领域的呢?

Dr. Costa-Mattioli [12:34]

我会说这是个意外发现。我们原本不打算研究微生物组,我们项目开始时实际上旨在研究饮食如何影响行为。具体而言,推动该项目的积极因素是(我们)对小胶质细胞的兴趣。因此,让我们思考微生物组的一个特殊结果是,把那些有社会行为不足的动物(与接受高脂肪饮食的动物妈妈)与正常的动物放在了一起。当我们做那个实验时,我们进行了行为学测量,(发现)社交动物的行为(不足)完全消失了。换句话说,动物变得正常。在那个时候,我们开始思考饮食如何对微生物组产生影响。因此,仅仅通过观察这个假设,并检验这个假设,我们就会得到这样的惊喜:是的,有一种特殊的细菌可以通过妈妈的饮食来消除。最终,这种细菌是社会行为所必需的。因为如果你把这种菌放回到社交(缺陷)的动物身上,行为又完全正常了。因此,在我最疯狂的梦想中,我设想了这样的想法:我们的行为需要肠道中的特定微生物来逆转或影响,这是由大脑驱动的吗?现在,我们知道孕妇的高脂饮食,基本上可以改变后代的微生物组,即使在人类中也是如此。

Peter [14:01]

这真的很厉害,所以这些自闭症表型常见于肥胖母亲的孩子。 为什么您认为这个自闭症表型常常出现在婴儿身上,而不是母亲呢?

Dr. Costa-Mattioli [14:12]

这就像你应该知道的生活中的一切一样。你有一个特定的关键时期,大脑或者肠道,或者肠脑连接变得脆弱。如果你做高脂饮食操作的时候能想到这些,婴儿在子宫里,是它更脆弱的时期 (婴儿更容易受到影响)。如果你对成年动物做同样的处理,而这时突触连接已经形成(影响就变得很微弱)。 所以你对妈妈产生影响的可能性实际上更低。

Peter [14:45]

因此,神经网络在这一点上连线的更加紧密; 改变或受影响的空间更小。所以我想微生物组领域最近有了很大的进展,微生物组如何影响从抑郁症到肥胖症的一切,再到我们如何处理所服用的大量药物。您认为公众对微生物组有哪些最大的错误认知呢? 还有,您希望人们更了解这个领域以及微生物组对我们健康影响的那些方面呢?

Dr. Costa-Mattioli [15:13]

这是一个新兴领域,也是一个众人正在学习的领域。我们作为科学家,我们正在研究我们所学习的科学领域。这个领域,如果你认为它有点不可思议,如果在10年前或15年前,肠道中的微生物可能会影响我们的行为[…]这是无法设想的,不是嘛?而今天,你要知道,我们甚至有使用这些单一细菌菌种的想法,并且(研究它)可能在人类中产生的影响。因为这个领域正在兴起,我们开始了(研究),当然,我们了解到另一方面是那些患有自闭症孩子的父母,他们迫切的冲进超市,去购买任何一种益生菌,希望这些益生菌对自闭症有治疗效果。从我们自己的工作中,我们确实发现了一种特定的菌株,一个具体的特定效果的特殊菌株,实际上它是具有活性的,而其他的菌株不具有。如果你问我为什么会这样,我也还不知道。正在大脑学科工作的科学家们作为这些病症的主要驱动因素,他们受益于20-30年的研究。而且我认为我们需要更多的时间从本质上解决我们在这里所做的任何事情是否可以被转化或者可以应用于人类。到目前为止,我们在实验室里做的一切都是动物模型,我们研究的很开心。这是否会被转化为人类疗法还有待观察。

Peter [16:52]

所以说,如果我想改善我的微生物,现在所有在超市里做广告的酸奶和益生菌,并不值得我冲进货架?还是说现在还未得以证明呢?

Dr. Costa-Mattioli [17:03]

嗯,首先,我不知道,我的意思是,你购买的酸奶是有功能的,你或许可以改善你的微生物组。 他们说你可以更好地消化,或者你能减少便秘。 但是,这种情况下是否会影响大脑,我就完全不知道了。 所以,有些益生菌,也许它们可以帮助你,尤其是那些可以帮助孩子改善便秘的益生菌,它们显然可以缓解胃部不适,等等。 但对于大脑,我想我们还没有发现任何迹象。 我们仍然有待于观察这些益生菌是否可以作用于人类。 我们正在从一个完全不同的角度解决这个问题。 我们没有像其他人那样做。 这是一种不同的思考方式,也许如何治疗这种疾病,以及我们这样做是否有效或无效,我还不能回答。

Peter [18:04]

从不同的角度看待不同观点或解决问题在科学中有多重要呢?(如果)一位年轻的科学家觉得他们的想法很有激情,与目前的(研究)情况截然不同,您会给他怎样的建议呢? – 他们该如何实现这样的想法?

Dr. Costa-Mattioli [18:20]

这无关于[激情],或者是完全不同的观点。 答案是得到正确的答案。 但问题是我们不知道正确答案是什么,对吧? 那么让我着迷的是那些没有多少人会想到的想法,对吗? 哪个可能是对的[或]可能是错的。 但如果他们是正确的,这就开辟了一条完全不同的途径,在这种特殊情况下,你就可以解决脑科学的问题。 也许一些行为可以通过使用基于微生物的治疗来改善,而另一些行为则必须采用更传统的方法,该方法实际上将直接影响大脑。

Peter [19:06]

谢谢您的这些观点。 我想稍微转换到一些个人问题。 我知道您获得了许多奖项:Alkek试点项目和实验治疗奖(奖项名称); 您以打开和关闭记忆的文章获得了Eppendorf (生命科学公司名称)科学神经生物学奖; 并且您已经在Jeopardy(美国电视智力竞赛节目)上被提名了一个问题。 我想知道您最引以为傲的成就是什么?又是什么继续激励着您的研究?

Dr. Costa-Mattioli [19:34]

这是一个很好的问题,我每天也在问自己,坦率地说,到目前为止我不觉得我发现了什么。 我相信现在只是发现了一些东西,其中一些已经变得很重要,而另一些则没有,我相信这个时刻已经来临。 这些想法和概念激励我很早就醒来,让我很晚才睡下。 所以我绝不是[已经解决]了。 坦率地说,几天前我和某人聊天,我告诉那个人我真的觉得我做的不多,因为有些已经有很多大成就的人。 所以我想,我希望,会越来越好。

Peter [20:28]

很惊讶听到这一点。您做了那么多非常成功的事情,您有这么好的经历,我想知道您是否能想到研究生常犯的错误,或刚进入科学领域的人,什么是他们常犯的错误呢? 你会如何帮助他们解决这个问题呢?

Dr. Costa-Mattioli [20:47]

你知道有一些规则要牢记在心,不是吗?所以第一个是不要相信任何人。因此,当一名研究生来到实验室并开始研究一个项目,并相信该项目应该与另一名发表Cell或Nature(科学杂志名称)论文的研究生类似的方式工作,[但]你必须亲自验证并看到它。所以这是一个明确的事情,学生必须用你自己的眼睛看,如果实验一,二,三或四次不成功,这时你需要去倾诉,并告诉其他人或许自己的方式不正确,并得到所有的帮助,看看你是否可以建立自己的故事并继续这样做。另一个重要的事情是你要充满好奇,好奇心可能不仅仅是由你的导师所驱动。 [你应该被你正在做的生物学的一个特定方面所驱动,这却是你的导师没有想到的]。你需要去到办公室,然后说,伙计,我对这个感兴趣,因为这是一个比你告诉我要做的更重要的问题,对吗?所以这些是我对刚刚开始博士生的一些建议。永远不要气馁,永远不要气馁。这是一场马拉松,这不是冲刺,因为有些人可能是冲刺,但对于我们大多数人来说这是一场马拉松比赛。这需要时间。你的博士需要时间现在我正在思考这个问题,我会告诉你我认为更重要的因素。学习失败是更重要的因素。如果你学会失败,因为在科学中你每一天都会失败,每一天都是失败的。你做的大部分实验都不起作用。如果你学会失败,或者如何失败,或者如何应对失败,事情会变得容易,因为你不会沮丧,因为你知道!你知道一开始事情是行不通的。当实验成功时,它就是一份礼物。

Peter [22:56]

所以这一切都归结为 – 您说的第一件事是,不相信任何人,但相信自己的实验。 这总会导致很多失败。 重复其他人所做的事情并不容易,也许他们做的事情略有不同,也许他们想到的是他们没有在实验流程中写下的东西。 但是,通过这个过程,一点点学习。您认为对于科学家的成长以及他们在前进中应采取的一些行动,什么是必不可少的呢?

Dr. Costa-Mattioli [23:21]

认真对待它,因为你去做一个实验,你找到了一篇发表的论文,你一会儿就完成了,但实验没有用。 这是很容易的事情。 当然,它不会起作用,因为你没有优化它。 对于我们所做的每一个实验,我们都需要从根本上优化实验流程,找到特定的突破口,实验才[可以成功],让实验有机会获得成功。 是的,所以从你有一个强大的故事,你相信它的那一刻起,这就是你博士的起点。

Peter [24:12]

我在您的其他一些采访中看到你引用埃里克坎德尔影响到您深入研究神经科学领域的决定。 对于那些试图钻研略有不同的领域的人,您有什么建议? 我以前知道,您在病毒学和微生物学方面做了很多工作。 然而听了他的一席话,您觉得您的实验室真的很适合去了解驱动记忆的机制。 那么您如何从一个微生物学家,一个蛋白质实验室的人成为一个研究记忆的人呢?或者您对那些想要从事职业生涯的人有什么建议呢?

Dr. Costa-Mattioli [24:47]

正如我所说,我的意思是,回想起来,你要解决这个问题。但这种转变是有风险的。所以前几天我正在读弗朗西斯克里克的一本书,他在书里刚说到,在发现DNA(脱氧核糖核酸)结构之前,他只知道物理学。他完全不了解生物学,但他有能力转化为事物并将这些事物变为现实。因此,有许多决定要去做,也有许多窘境(corners),但你还是需要离开自己的舒适区。对于大多数科学家来说,当他们到了30-35岁时,他们已经成熟起来。将职业生涯转变为新方向的可能性非常低。就我而言,我对生物学很感兴趣。如果你来我的实验室,你向我展示让我兴奋的东西,我不在乎这会给我带来什么因为我感兴趣。那是我的快感。现在,在这个过程中,你需要了解这个领域并且学习很多。我这样做的方式是咨询并向该领域的专家学习,这是我在电生理学中可以找到的最好的,我能在行为中找到的最好的,并且与他们联系。

作为博士后,我走进他们的办公室,我告诉他们,这是我的想法,他们告诉我你疯了。没关系,因为它能帮助到我,他们没有听我的话,最终还是得到了回报。对于那种非常晚的转换,正如你所指出的,从记忆到微生物 – 大脑,对我而言,这就像是一种自然过渡,因为,我了解进化。我了解微生物学,并且在我的博士期间,我正在研究特定的选择性压力将如何影响病毒群体以及病毒如何逃逸。所以我觉得过渡是顺利的。但是我也有很多需要学习的东西,我有像杰夫戈登这样的同事,也有其他人,他们都是微生物组的专家,每次我有机会阅读他们的论文或在会议上见到他们,我都从他们那里学到很多。而且我认为这就是让我继续前进的原因:每天都在学习,所以我觉得我又像个学生。学习新事物。走向不同的方向。他们中的一些人很疯狂。其中一些更保守。但我认为这就是科学的意义所在。这就是我们在实验室里做科研的方式。

Peter [27:29]

很高兴看到您如何保持这种好奇心,保持这种激情,而且它并没有真正消退。 或者也许它已经存在,但是您已经把它和您一起留在了您从研究生到博士后到现在的日子里。 我想知道,只是最后一条建议,您可以给那些进入新领域的人,开始一个新实验室,第一次成为首席研究员,您会给他们什么建议来开拓他们的想法或者您如何看待他们可能遇到的一些问题呢?

Dr. Costa-Mattioli [28:01]

从我的一些导师成为导师,到我成为导师的那一刻,时代已经发生了变化。我们面临着巨大的资金压力,我一次又一次的看到,那些启动实验室的人,他们做的第一件事就是开始写项目书。当然[就是这种情况],因为他们想要有钱来开展他们的科研。当你开始实验室的时候,如果你最终进入像杜克这样的大机构,他们会给你足够的钱来做几年科研。这是我觉得很关键的时刻,因为你所要做的就是做你的科研并展示你的科学成果。第一年或第二年不用考虑项目资金。做你的科研。做你想做的更有趣的实验。如果你的实验很好,如果你如愿以偿,那么科研结果就会带来资金。这笔资金应该支持更多科研项目。如果科研做的好,那就会带来更多的资金。这就是我们所有人都进入的良性循环。从你进入的那一刻起,这个循环就不停了。但是在前两三年,你不在循环中,在你确定需要之前不要进入这个循环。

Peter [29:22]

我觉得很难不觉得自己不是这个循环当中。

Dr. Costa-Mattioli [29:25]

没关系,没关系。 你将是一个了不起的局外人。 不要担心钱而做你的科研。 而且我想你要知道,对于我之前讨论的一些人,他们只是告诉我,天哪,在前两年那会儿,我没有享受过自己做实验、指导我的博士后或学生的乐趣。 他们如此投入。 我理解这种压力。 压力很大。 资金实际上很少。 我们有很好的科学想法,不幸的是,一部分好的科学项目并没有得到资助。 所以我真的希望像美国国立卫生研究院,政府,国防部等这些机构增加支出来支持那些很好的项目,因为我们还有其他国家,比如中国或韩国,它们在科研中投入了大量的资金。我想我们在美国的创新仍然是最重要的,但我们需要将其保留下来。

Peter [30:26]

我们仍需继续努力。非常感谢您的宝贵时间,Costa-Mattioli博士。

Dr. Costa-Mattioli [30:30]

这是我的荣幸。

Peter [30:40]

从记忆到微生物,我们有机会看到Costa-Mattioli博士如何不让自己被一个特定的领域所定义。这是一个没有放弃的有趣发现,引发了他的好奇心,使他很容易进入新的领域。我觉得我们应该采取这种心态,并尝试每个月投入一点时间来反思我们所做的事情来让我们感到兴奋。甚至有可能的情况下,将其写下来或与某人分享。如果没有想到任何事情,也许是时候重新思考我们的工作方法了。只是想一想,下期再见。非常感谢您的收听。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。

第二期:跨越无极限

张旭朏/译

Dr. Wickersham [0:00] 

我相信你Peter。

Peter [0:03] 

如果让您用一个词来形容它。

Dr. Wickersham [0:06] 

面包似的,我觉得像是根热狗。 但觉得我只吃到了面包。

Peter [0:15] 

好吧。 您现在可以睁开眼睛了。 这是无麸质面包热狗(我们确定)。 我想我们最终选择热狗的原因是,我们觉得狗与狂犬病有关,所以我们能找到与此最接近的食物,于是想到了热狗。

Dr. Wickersham [0:31] 

太赞啦!

Peter [0:41] 

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。 在本期内容中,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。 我们希望,通过了解科学背后的科学家们,我们将能够跨越不同科学领域之间以及科学界与主流文化之间的鸿沟。 那么,让我们一同进入本期播客:两个领域之间。

我们非常高兴今天邀请到Ian Wickersham博士。 伊恩(Ian)曾在杜克大学(Duke University)攻读物理专业,然后在加州大学圣地亚哥分校(UCSD)取得了神经生物学博士学位。 之后他在麻省理工学院做博士后,现在是麻省理工学院遗传神经工程小组的负责人。 他致力于开发强大而精确的技术来研究大脑的结构。 他利用病毒的独特功能,对它们进行了修饰,使这些病毒可以感染特定的细胞并发光,从而使我们的大脑网络可视化。 他修饰过的其中一种病毒便是狂犬病病毒。 老实说,当我第一次听说使用狂犬病病毒作为工具时,我想到了一张[…]看似有些疯狂的狂犬病狗狗的画面。 我想知道,[…]您是如何被狂犬病所吸引的呢? 是不是需要一些说服力才能让您对这种令人恐惧的病毒进行研究呢?

Dr. Wickersham [2:40] 

其实不然。其实我是很积极地想对它开展研究,因此我不得不说服其他人,而不是相反的情况。但是关于狂犬病病毒,尽管这种可怕病原体每年都会杀死许多人,但它对于神经科学家来说是一种非常有用且自然存在的工具。因为它的扩散发生在突触连接的神经元之间。它在神经元之间的传播方式在相当长的一段时间内不会完全杀死神经元。当我开始攻读博士学位时,我们正在寻找识别大脑中连接神经元的方法。因为大脑中的神经元具有许多不同的细胞类型,而且它们都混合在一起,它们经历了这些漫长的过程,所以轴突和树突会发生重叠。即使你让不同类型发光或对它们进行染色处理,也无法仅仅通过观察来分辨它们。更无法确定哪些是彼此相连的。与其他器官相反,神经元之间的精确连接基本上可以说是大脑最独特的方面。那么,了解大脑如何运作或大脑的一个小部分如何运作,了解与你感兴趣的行为有关的神经元之间如何相互连接(显得)尤为关键。因此,我们需要一种工具,这种工具可以帮助我们识别与目标细胞相连的其他细胞,而狂犬病病毒则是最有希望(实现这些)的工具。

Peter [4:29] 

这相当有趣。 您提到的狂犬病(毒),更像是一种工具,而不是病原体。 您的实验室实际上专注于开发(这些)工具和原型,并修改这些病毒,以便我们可以应用它们来研究不同的回路和不同的连接。 我想知道,当我们开发这些工具时,会经历一个迭代的过程,在此过程中,您会经历原型一或第一代,第二代,第三代。 您怎么知道这个就是第一代了呢? 当您构建完结构后,您又怎么知道这就是一种我们可以提供给其他人或让其他人知晓的工具呢?

Dr. Wickersham [5:06] 

那么,到第一代发现为止,没有其他的(发现)了。一旦有了基本的证明,我们就可以做到这一点,我应该说,我们试图发明是一种专门标记直接连接到某个目标神经元组的系统。 因此,基本上,我们利用改良形式的狂犬病病毒选择性地感染大脑中任何类型的神经元,并使狂犬病病毒不会像野生型病毒那样扩散到整个大脑,而是只传播到与起始神经元群体直接进行突触连接的细胞。

Peter [5:55]

因此,您可以控制其传播方式的特异性。

Dr. Wickersham [5:58]

实际上,我们控制着两个方面,一方面是(控制)首先要感染的细胞的特异性,另一方面是控制它要经过突触的数量。如果注射到大脑中,自然条件下的狂犬病病毒基本上会感染它所能接触到的任何神经元。 而且,一旦感染了这些细胞,它将沿逆行方向扩散,即从起始细胞到突触前细胞。

Peter [6:29] 

突触前意味着它在上游形成连接。

Dr. Wickersham [6:33] 

是的,对细胞而言,这会将神经递质释放到起始细胞上。 野生型狂犬病病毒将在这些细胞中简单复制,并继续向突触前细胞扩散,周而复始,遍及整个大脑。 而我们想要一个仅允许直接标记突触前细胞的系统,以便我们可以非常精确地识别大脑中细胞类型之间的连接矩阵。

Peter [7:01] 

所以有点像一种被控制了的狂犬病感染。

Dr. Wickersham [7:05] 

是的,这是能够做到这一点的第一代系统。 当然,只要有任何类型的数据,我们就可将其发表,就像在神经科学领域一样。 一旦有了新颖的成果,并且从未有人展示过,即使它并不完美,你也想展示给大家。 所以,无需等待完美时刻,只需发布每个重要的新进展即可。

Peter [7:30] 

但同时,您也要确保狂犬病的毒性或致死性得到控制。

Dr. Wickersham [7:36] 

确实,狂犬病毒的毒性可能是其最大的缺点。它的毒性确实比许多其他病毒低。而其毒性较低的原因是狂犬病毒希望保持神经系统细胞的完整性,以便宿主(即被感染的动物)能够继续传播该病毒。基本上而言,病毒的生命周期取决于在传播过程中不被破坏的神经系统,以便动物有能力实施这种行为,从而导致病毒传播。所以,这种病毒已经相当于无毒。但是在神经科学领域,有很多人想做的实验涉及很长一段时间的操纵或研究,而不仅仅是几天或几周。例如,在学习一项任务的老鼠中,(老鼠的行为)会随着时间而发展,并且人们希望了解随着老鼠学习这项任务时,神经元的突触连接网络是如何随着时间的推移而反应的。对于狂犬病病毒已经存在的地方,或者是已经存在的狂犬病病毒系统,这基本上是不可能实现的,因为它确实杀死了神经元。所以,近年来,我的实验室付出了巨大的努力来开发所谓的模型突触追踪系统(狂犬病病毒追踪系统)的无毒版本。

Peter [9:13] 

单突触追踪系统有点儿像是只跨越了一个突触,是吗?而且不会持续扩散,这就是您如何控制毒性的方法吗?

Dr. Wickersham [9:17] 

嗯,这就是我们控制病毒传播的方式,但这并没有直接影响病毒本身对被感染细胞的毒性。 因此,在我们正在进行的第二代以及现在的第三代版本中,狂犬病病毒似乎是完全无毒的。这意味着我们可以标记突触前细胞,然后让它们无限期地存活,以便可以进行长期行为实验的研究和操作。

Peter [9:52] 

所以我了解到的您的第一代(病毒系统)的情况是[…]您已经提出了这一愿景,您希望能够标记(神经)通路,而且您找到了实现这些的方法。 它毒性适中,毒性相对较低。 然后当您进入第二代时,您实际上是在专注于我们如何才能将这种毒性降低到几乎为零? 然后我们如何才能使该标记保持不变?对吗?

Dr. Wickersham [10:16] 

是的,完全正确。我的意思是,第一步是(如果可以这样说的话)向前迈出的一大步,因为从根本上讲,这仍然是识别与你所感兴趣的某些大脑种群直接相连的细胞的唯一方法,而没有一个可以进行测试的假设。举例来说,假设你对膜的多巴胺能细胞感兴趣。这些是投射到(大脑)皮层的细胞,取决于细胞,纹状体和大脑中的其他位置,对于机动、反馈和运动控制而言,它们非常重要。(它们)能够识别出膜中那些非常重要的多巴胺能神经元的输入,可以使神经科学家绘制出整个电路来操纵各种输入,并了解有关如何将大脑关键系统或可能更适当的系统整合在一起的一些基本知识。现在,所遇到的第一个问题是这些细胞是什么,它们在哪里?因此,第一代狂犬病病毒系统只是为了回答这个。解剖学方面的问题是:这些细胞是什么,存在于哪里?无论它们在大脑中的何处,都可以对其进行标记。因此,在继续进行解剖学定位之前,也许可以用其他方法操纵突触前细胞。

Peter [11:48] 

那么,真正使这种狂犬病(病毒)强大的是您所能达到的那种(成像)分辨率,对吗? 因为我以前对神经生物学的理解是我们拥有这些大脑区域,所以我们知道它们是拟人化的,可以互相交谈。 但具体来说我们不知道在这个大脑区域中,哪个神经元正在与另一个神经元对话,对吗? 而狂犬病病毒使您能够查看两个细胞之间的这种直接联系。

Dr. Wickersham [12:12] 

没错,很正确。如果没有狂犬病毒或其他多种示踪剂,人们可以做什么,而人们在此之前所做的就是看到大脑中有哪些细胞投射到大脑区域。但是,采用这些技术中的任何一种,都无法查看这些上游神经元投射到了目标区域中的哪些细胞。因此,你基本上可以以高分辨率来追踪映射到大脑某处各个地方的细胞。但是在狂犬病毒系统出现之前,还没有办法确定该靶位中哪些细胞与所有这些突触前神经元发生接触。因此,我们可以使用狂犬病病毒来选择你所感兴趣的细胞,将输入(信号)针对性地传输给这些细胞。而且它们本质上是不同的,在大脑的每个地方,都有许多不同的细胞类型,并且它们的电导率也大不相同。因此,从本质上讲,你可能在特定大脑区域中投射到一种或多种皮层细胞的神经元数量上存在差异。或者,你可能具有完全非重叠的细胞类型,例如,这两种细胞都为突触前细胞。这使你能够以更高的分辨率绘制电导率图。

Peter [14:00] 

是的。就像是,即使在空间上相近的神经元,也可能不是我们正在研究的这个(神经)网络的一部分。(稍微动一下脑子)。 您如何看待这项技术的未来前景呢? 我觉得结构掩盖了功能,而且了解这个网络对于我们真正了解大脑的工作方式非常重要。 我想知道我们(对此)能了解到什么地步? 您如何看待我们对这些网络的认知? 或者,您认为我们如何在未来10年左右的时间内通过新技术更好地揭秘这些网络?

Dr. Wickersham [14:32] 

是的。一方面来讲,(这)能够更好地了解那些突触前细胞,而不仅仅是它们的位置,外观、表达等等。因此,如果可以使用所有这些方法的无毒版本,对突触前神经元进行模式化刺激,以使其能够干扰这些突触前细胞的活性,并观察其如何影响这些靶向突触后细胞的活动。狂犬病毒不仅可以利用输入(的信息)追踪到一组神经元,也可以追踪到是单个神经元。这可以为开始输入(信息)到单个皮层神经元提供漂亮的解剖图,但是你可以在这些突触前细胞中表达钙指示剂,并将其进行成像。例如,所有这些突触前细胞的视觉反应特性以及单个目标突触细胞,然后查看(例如)视觉皮层中的神经元是否以某种方式对视觉刺激做出反应,是否主要从其他以相同方式做出反应的神经元获得输入(信息),或者它是否正在做某种可能更有趣的事情。换句话说,要回答这个我认为是神经科学最基本的问题之一的问题,(需要弄清楚)单个神经元如何获取正在获取的输入并处理该信息以产生自己的输出?

Peter [16:02]

那么,我所了解到的是(这些研究都)正在向前发展,您认为应该在单细胞水平上理解这些信息,我们要如何整合信息,更多地了解这些神经元如何在单细胞水平上整合信息,以及他们如何获取信息,整合并发送信息的呢? 通过突触传递到另一个单元格的消息,这是您所预见到的这些技术的未来发展方向吗?

Dr. Wickersham [16:23]

是的,我想这是一个非常伟大的目标,也是一个激励人心的目标。 就技术本身的未来发展而言,我们应该很快就能开发出一个高效、完全无毒的单突触追踪系统,并利用此系统来进行这类实验。 我的意思是,到那时,各行各业的神经科学家都可以使用该技术,并应用到他们想要进行任何令人兴奋的科学研究。作为工具开发人员,我们正在继续开发其他工具,这些工具将有望来支持其他令人兴奋的科学研究。

Peter [16:55] 

现在,这确实是令人兴奋的进展,我迫不及待地想看到您课题组未来的工作进展。 现在我想微微倾向于您个人作为职业发展中的科学家来提问。从物理学转向神经生物学是一个巨大的跨越。 那么,我很想听听您是如何从一个领域的学生转变为另一个领域的研究人员的呢?

Dr. Wickersham [17:23] 

我的意思是,就我个人而言,我一直对大脑很感兴趣,而不一定对神经生物学感兴趣。但更多的是从想了解它是如何工作的角度来看的。我也一直对物理学感兴趣,我很喜欢它,那也是我大学的专业。但是我也对大脑感兴趣,并在杜克大学学习了神经生物学。不过,我是从神经网络的角度来思考的,这就是我的动力。所以我在想,我们怎么才能建立大脑呢?所以现在,我想大多数人可能都进入了神经科学领域,以了解整个大脑为目标,来揭秘意识是如何产生的,或者制造了可思考的机器人,诸如此类的事情。然后你便进入了神经科学领域,就像,“好吧,好吧,你实际上可以做的是……” [什么]可能是一条更直接的路径,可用于我们以前思想概念的架构的实际构建。但是进入神经科学领域,我的动机只是想尽可能多地了解大脑的组织架构。

Peter [18:28] 

大脑又是如何的呢? 仅仅是这样一个知之甚少的神经网络吗? 还是因为我们对此不太了解呢? 又是什么吸引了您走向大脑的呢?

Dr. Wickersham [18:37] 

哦!我只是觉得智慧很神奇。而且,你要知道,这看起来还可以,我们应该能够制造出能够执行此类操作的仪器。所以,这确实是动机。我最好还是先从我们对大脑的认知开始(讲起)。那么,我最终加入了一个博士计划,但是事实证明,我们并不太了解它实际是什么,有点像是半杯水,或者是99%的空水杯。但是实际上,我们必须懂得很多,但这基本上就是我的轨迹,我是从神经网络的角度,兴趣和构造,智能程序和体系结构等等来进行研究的。但是[当我]进入实际的神经科学领域时,我才意识到我想了解的-这些信息并不存在。从我的角度来看,对于初学者来说,我想知道的是,所有这些不同类型的[…]细胞之间的联系是什么?它们之间有什么联系?他们在做什么?还有了解所有为止的工具是什么?

Peter [19:45] 

然后,您决定自己制作!

Dr. Wickersham [19:46] 

是啊。就我可能产生的影响而言,[…]这似乎是很大的一笔经费,这并不是使用现有的工具费力地研究大脑中的某些回路并获得某种关于该回路的不完整答案,而是要开发工具,这种工具将允许在大脑任何方面工作的研究者们进行更强大、更精确的实验。

Peter [20:19] 

是的,我刚想到的是,您的研究确实集中在突触标记上,或者首先,这种单突触标记是如何从一个细胞跳到另一个细胞。 我当时在想,[…]这种方式使我想起人们是如何从实习生成为导师的。 因此,您是如何从成为科学家,学习神经生物学,学习这些神经回路,到成为该领域的开拓者这一转变的呢? 您是否可以[…]跟(正)从见习生过渡到导师的科研工作者们分享一些经验或心态呢?

Dr. Wickersham [21:00] 

那么,我想我在尝试开发这些用来大大提高那些基础神经科学家对(神经)回路进行研究的工具时,始终将重点放在了与他们相同的位置。 所以我的意思是,这有点像博士学位中的驱动特性,并且贯穿始终,这都是一回事。 只是现在我可以做更多的事情,因为我不必自己做所有事情。 那么,可以肯定的是,它是一个不同的角色。 但是类似地,如果你能制造允许其他人揭秘大脑事物的工具,那么与你仅仅使用现有工具自己进行研究相比,将会发现更多的信息。 同样,如果你有想法,并且可以将其委托给你的同事,则可以完成很多工作。

Peter [21:55] 

那么,从我的理解来看,当您刚开始对研究感兴趣时,当您还是一名学生时,对探索网络的工具的迷恋就是您的动力。 但是,随后,当您尝试研究这些(神经)网络时,您意识到需要建立自己的合作网络,以协助开发此网络。

Dr. Wickersham [22:15] 

在整个过程中,我一直在同一个实验室中向导师,博士后学习。

Peter [22:20] 

而您是如何寻求这种帮助的呢?您是否只是看看该领域有谁,然后与他们联系呢?

Dr. Wickersham [22:25] 

这是一种非常好的方法。 事实是,无论你身在何处,他们都遍布各地。 您想找到他们。 可以肯定,在Salk(研究所),MIT或Duke之类的地方,很容易找到乐于教您的世界一流人才。 我认为大学之间的合作程度不同,但是我很幸运,人们乐于为你提供帮助。

Peter [22:51] 

真的很高兴听到这样的信息,科学是如此博大,因为我记得[…]回到[我们之前的对话],您在想,哦,当我发现某些东西时,我真的需要发表出来。 这是一种竞争意识,在您的研究所内或研究所之间拥有一群真正愿意为您提供成功的动力并有动力为您提供帮助的人,这对您而言至关重要。

Dr. Wickersham [23:18] 

对的。 对的。 而且几乎总是双赢的。 这是唯一真正有效的合作方式。 通常,这是一次学术合作,如果有大量帮助,他们将在这项工作中获得一些荣誉,在许多情况下,他们可以使用该技术或应用到自己的研究工作当中。 人们在这样的结果中担当重任,然后他们会更有动力提供帮助。

Peter [23:42] 

是的。 因此,在建立合作时,您要确保对双方都是双赢的,对吗? 也就是说,我们双方都可以推进自己的工作,以推动该领域的发展。

Dr. Wickersham [23:51] 

通常,人们在发表的文章上享有著作权。 而且,如果该项目令人兴奋,则足以成为具有高影响力的研究文章,只是以这种通俗的形式,那么[…]参与该项目的开发也符合他们的利益。

Peter [24:10] 

真的很棒。我真的很感谢您抽出宝贵时间参加本期播客。 威克瑟姆博士。 哦,我认为我们从科学中了解了如何在大脑中建立联系的知识,并再次非常感谢您的宝贵时间。

Dr. Wickersham [24:23] 

这是我的荣幸。 也非常感谢你。

Peter [24:34] 

好的,就到这里吧。 当您花时间了解了您的同事时,形成合作网络就(变得)很容易。 我们向您提出一项挑战。 (那就是)在下一个午餐或研讨会上与大厅里的人或坐在您旁边的人分享您的想法。 非常感谢您的收听,我们将在下一期与您相见。 有关我们更多的内容,您可以关注我们的Twitter @gutbrains,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。 梅勒迪斯·施梅尔(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。 特别要感谢Gastronauts的创始人:Bohórquez实验室的Diego Bohórquez博士。