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。

Episode 11: Jumpstart Your Career (Transcript)

Peter 0:12
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.

Today, we have a double-header, we have two young scientists who are rising stars in their field. First up, we have Dr. Natale Sciolino, who is a postdoctoral fellow at the developmental neurobiology group at the National Institutes of Environmental Health Sciences in Dr. Patricia Jensen’s lab. She completed her PhD in Dr. Phillip Holmes lab at the University of Georgia, where she studied the effects of voluntary exercise in preventing cocaine relapse. She is currently studying the role of norepinephrine neurons in the locus coeruleus. These neurons are traditionally thought to be involved in that fight-or-flight response and related to these stress or panic like situations. But Dr. Sciolino has uncovered some interesting results that they may also play a role in feeding behavior. So could you tell us a little bit more about this project and how you stumbled into this field from going into a research field to begin with?

Dr. Sciolino 1:58
Yeah. So the thing that’s always fascinated me is how does the brain form emotions and then take those complex internal states and integrate them with essential needs like hunger to then drive motivated behavior of an animal. Because all the things that we do are not happening in isolation. All of these internal states work together in concert, and the brain must decide what gets priority. So to me that orchestration is the most interesting. And it turns out, as you said, the neurons that orchestrate the fight-or-flight response, actually do much more in that coordination. They also tap into other internal needs, like relaying information about hunger or feeding. So what I’m talking about is the locus coeruleus. So the locus coeruleus is the largest grouping of norepinephrine containing neurons in the brain. These neurons actively synthesize the neurotransmitter norepinephrine. But they have diverse projections all throughout the brain. And that’s how come the neurons are able to modulate a variety of processes in the brain. So they’re implicated in emotion regulation, stress responses, cognition, arousal, sleep wake, the list goes on and on and on. And we’ve uncovered they also play a role in modulating feeding. So how does this transmitter system do all of these things? And it turns out, it does so many things through circuit-specific projections throughout the brain. And really, what we think the system is doing is turning up the gain and neural networks to say, “okay, this is the priority right now based on my internal state or the environment […] well, I’m full, there’s no predator around. I can work on cognition; I can focus my efforts towards that. So I want to turn up the gain if I’m norepinephrine in cognitive circuits.” Whereas say there was a predator around and you have to run for your life, I want to turn up the gain and my stress responsive centers to get away from that predator. If you were to think of it as a radio dial, right? But you have that radio dial not on one particular channel, but you have this Master Control Center, where you have radio dials on a bunch of stations, and you’re turning up those radio dials to see what kind of signals you want to listen to, on these different channels.

Peter 4:47
So how does the stress feed into this circuit? To my understanding what you’ve described so far is, once you’ve had this stressful state, you can affect the game based off of norepinephrine, but how does the stress get into the circuit to begin with?

Dr. Sciolino 5:00
Yeah, so good question. So I think a lot of it has to do with what the level of activity is in locus coeruleus neurons. So we know stress classically, can cause this robust activation of locus coeruleus neurons. Whereas other things, let’s say appetitive things that are rewarding, unpleasant, like feeding, cause the opposite change, a decrease in locus coeruleus activity. And that magnitude of effect of just endogenous eating is small when you talk about every bite by bite effects. So we have all of these, all of these ways that our behaviors can change locus coeruleus activity.

Peter 5:44
That’s really neat. And do we have an idea of kind of where the locus coeruleus projects to, to control feeding or to control these different responses?

Dr. Sciolino 5:53
Yeah, so we’ve identified a circuit in the brain; probably, there’s many more But there’s a projection from locus release to lateral hypothalamus that suppresses feeding. And it also induces a negative emotional state, so characteristic of an anxiety-like response, if you will. And it’s aversive. So this is just one circuit that we’ve identified, but there may be others.

Peter 6:21
Do you think there’s a way to uncouple the anxiety effect with the feeding behavior? Do you think those two go hand in hand?

Dr. Sciolino 6:27
I think it’s probably projection specific, or if not projection-specific, cell type specific at the target. I think that there probably is a way to uncouple the anxiety and feeding. And the reason why is because a lot of beauty in science comes from just observing. And so one really cool observation that we found is when we just looked at natural endogenous activity of locus coeruleus neurons. When animals are eating, we found that there’s this dynamic change in activity during feeding and local coeruleus activity. So here’s the dynamicness, when you approach food, you have this sharp rise in locus coeruleus activity. And when you consume food, you have a smaller decrease in activity. So you have two different processes that are happening. And both of those processes are modulated by how hungry you are. So if you’re less hungry, both responses are attenuated. And so they’re looking at endogenous activity. And this is just speculation, but if I were to guess, I don’t think that they’re having moment-to-moment instant changes in anxiety. I think probably what’s going on, there are the subtle changes in arousal or salience. And so perhaps, if that’s true, the circuits that are mediating those food related changes in locus coeruleus activity and changes in arousal or salience those may not be anxiety dependent.

Peter 8:01
So that’s how you think about kind of teasing apart the two effects? Really interesting. And then your previous work was on the effects of exercise and preventing relapse from cocaine. How do you see that work related to the work that you’re doing? Now, I know you mentioned you’re very interested in these physiologic states and [during your] postdoctoral training was there something in particular a field in particular or type of environment that you’re looking for in particular, to move you towards this direction?

Dr. Sciolino 8:30
Yeah. So it all falls within the umbrella of what is motivated behavior. So motivated behavior, simply put, is the ability to seek pleasure or to avoid harm. And we have adaptive processes set in place in the brain to allow us to fulfill those two motivated behaviors, right? So to seek pleasure, you know, we seek out food, but there can be maladaptation in those processes, leading to, let’s say, drug addiction. So it’s just I guess, a dysfunction versus an adaptive behavior, but it’s all looking at the same, probably tapping into similar circuitry and mechanisms.

Peter 9:15
Was the locus coeruleus involved at all in the exercise?

Dr. Sciolino 9:18
Yeah, it turns out if you run a lot, you see this up-regulation of a growth factor or a trophic factor called galanin. And it’s only in one brain region. The locus coeruleus is, you don’t see it and other galanin-expressing neurons in the brain. Exercise selectively dramatically up-regulates this trophic factor glanin. The work I did as a PhD student and Phil Holmes lab was really trying to understand what galanin was doing in the locus coeruleus, in terms of how it would affect the function of locos coeruleus in terms of its chemical functions, structural changes, as well as its behavioral effects. And we found out that galanin is necessary and sufficient for promoting resilience to stress. Because when you exercise, you’re very resilient to stress. And those changes are mediated by gallon.

Peter 10:21
And do you feel like galanin will also have any influences on kind of the norepinephrine gating of appetitive behavior?

Dr. Sciolino 10:29
Yeah, that’s a really cool question. I don’t see why not. Yeah, but we haven’t looked at that. Yeah, that’s a really cool question.

Peter 10:38
Well, I’m excited to see what comes out of that. You were recently awarded a K99 from the NIH, and congratulations on that. For those who are not familiar with the term of the K99, it’s a grant that will allow you to transition to starting your own laboratory. Now that you’ve gone through the process, I was wondering if you have any advice for others, looking to apply For this award or something that you felt was really helpful for your application.

Dr. Sciolino 11:06
I’m trying to decide if I want to give the true answer or the polished answer. I’ll first give the polished answer. The polished answer is: submit. Even if you think you’re not ready, because I think that oftentimes we are our own gatekeepers, and we can be the hardest on ourselves. So get over that if that’s something that you’re struggling with. And then number two, have it be as polished as it can be, have multiple people look at your application materials and critique it. I think I spent probably, like literally months on just my specific aims page. And then soon as I figured out what the aims would be, then the rest kind of followed suit, but leave a lot of time to work and edit. My first time, I was reviewed on the first submission and I received an OK score, not fundable. And then the second time I received a perfect score. And I think that has a lot to do with the fact that I revised a lot, and had the opportunity to bounce my ideas off of multiple people. So I think that’s really important. And I tried that, and it’s well, I got I was funded by an institute that only awards 1 K99 a year. So the odds were stacked against me. So maybe for me, it was more important to really have a polished application whereas other institutes that say fund 50%, maybe that’s less important. So inherent in that processes, know your institute and your odds.

Peter 12:44
Was that your polished answer your real answer-

Dr. Sciolino 12:48
The real answer is polish the turd. And that is like: a lot of things in science don’t work out. So how to spin your experience and you know, your failed experiments, and all of these things together as one uniform logical flow. And I think that the answer always is polish the turd.

Peter 13:18
So what was the turd that you’re polishing? I know briefly we have talked about your view of these locus coeruleus neurons, or these norepinephrine neurons within the locus are really just tuning [the gain]. How you go about testing this?

Dr. Sciolino 13:30
Yeah, so for me, it was more, it was a really big challenge to get up fiber photometry in the locus coeruleus. And I thought photometry is so it’s a way to measure endogenous activity of neuronal cell types. And I study a really hard area to target and study in the brain the hindbrain: the locus coeruleus. And so for me, my thing that I had to polish was really gaining access to that cell type in a reliable way so that we could trust the data. And so that took me a really long time to do. And so you know, that first submission, what I had was proof of principle that I could record from that cell type. And you know, that’s good enough. Like it wasn’t the inherent answer to the question. But I overcame that hurdle. And that was what I presented as a strong point. And by the time I had the second revision, I actually had real data to support the underlying hypothesis of my research.

Peter 14:34
Yeah, that’s neat. So then you were able to measure the changes. You mentioned that when these mice moved closer, or when they started approaching food, you saw a spike in these norepinephrine neurons, but then as they started consuming it, they had a decrease in activity and that was measured through this fiber photometry. What do you see this technique being used for expanding upon that research?

Dr. Sciolino 14:59
Basically, fiber photometry is really great for recording from deep brain structures. However, what it is not good at is defining cellular resolution. So what you’re recording is actually a population of neurons. So if, let’s say, the neural signatures that we just described, and the locus coeruleus neurons are only mediated by, I don’t know, a third of the cells, then the response, let’s say, when you record in the population might look entirely different than if you were to record from that third of the population. So I would say that the next steps are getting at subpopulations and really identifying the neural source. And then once we do identify the causality, are they causally linked to the changes in behavior?

Peter 15:52
Do you have aspirations in your lab to potentially silence these specific norepinephrine neurons and look at whether or not you can modulate their stress levels and their consumption?

Dr. Sciolino 16:03
Right, and in a very temporally specific manner.

Peter 16:07
That’s really cool. I can’t wait to see what you find out. I wanted to take kind of a step backwards, even before you started doing this type of research. When you were transitioning from a grad student to a postdoc position, how did you decide to pick the NIH versus any other academic institution?

Dr. Sciolino 16:25
What I really like about being in the intramural program at the NIH, is that we have all kinds of incredible resources. And that resource comes in the flavor of money to buy reagents or equipment, but also people and that’s probably where it shines the most. So we have phenomenal cores and staff scientists and postdocs and post backs, and all are very skilled. And because the PI’s don’t have to write grants, they’re more in the lab and to me I saw that as a huge strength to be a postdoc in that kind of environment. Because you can work one on one with the expert in in whichever be that a PI or the head of a core of an imaging core say, for example, or are really phenomenal neuro-behavioral core

Peter 17:19
And then one last question I wanted to ask was mostly focused on where you see the field moving forward with regards to the involvement of norepinephrine in feeding, or is there even a field for this? Are you pioneering this field to begin with?

Dr. Sciolino 17:35
Yeah, I think what this argues is it supports the work of many people in the field. Basically, newer work is showing that there’s a lot of diversity and the noradrenergic system. Previously, the idea was that the noradrenergic system is just, you know, this pretty homogenous neuromodulatory system that is acting at multiple places all at once. And it’s basically just turning up the gain of function of multiple neural networks. But I think what we’re learning is that there’s a lot of diversity in terms of projection specific functions, or molecular diversity or genetic or developmental diversity in the system. And once we uncover that diversity, we can really link it to complex behaviors. So I think that my research fits within that framework. And that locus coeruleus neurons are doing diverse functions, one of which includes feeding and modulation.

Peter 18:39
Do you feel like […] the fact that current complex behaviors haven’t been modulated specifically by targeting this homogenous population that we haven’t appreciated the diversity for- so ultimately, do you feel that by getting to the crux of the diversity within kind of norepinephrine cells or cells that we’ve classified as a particular subtype we’ll be able to really treat or modulate complex behaviors.

Dr. Sciolino 19:05
Yeah, I think that that’s, that’s one way to get out. And and that’s where the latest advances and tools currently allow us to get out.

Peter 19:15
Yeah, I think like a lot of the technology that we’ve seen has been, at least with the development of technology, we’ve seen more finer and finer kind of granulation of cell types of tissue of anything in general. And do you think there will reach a point where we continue to look at each of these individual cells and then continue to, break them down into smaller and smaller parts- do you think there will be a point where we’re going too deep, and that we won’t be able to see a large behavioral response by targeting kind of a sub population of a sub population of cells?

Dr. Sciolino 19:49
Yeah, I don’t know. I guess it’s all worth studying. And I think I use behavior as that readout of whether something is functionally important, right? So that’s that’s how I see behavior as a way to ground, whatever you’re studying. And its basic relevance, not to say that things that don’t change behavior are not relevant. But of all the things to study and there are so many, that’s just the way that I make my decisions.

Peter 20:19
It’s a very important readout, right? If we see a change in a protein, we don’t know what this affects in the animal or in the human in the long term. Yeah. Well, thank you so much for sharing some of your thoughts and ideas with us.

Dr. Sciolino 20:31
Yeah, thank you for having me. This was fun.

Peter 20:52
We also have Dr. Sophia Axelrod here with us today. She is a postdoctoral researcher at Rockefeller University in Dr. Michael Young’s lab. Her current research focuses on how circadian rhythms work and what physiologic or homeostatic processes are regulated by our circadian rhythms. We were just talking a little bit beforehand and I wanted to ask her a little bit about her career development or career path coming to this postdoctoral position, and trying to find out where she was doing her PhD, but had some difficulty researching this. So I just wanted her to share some of her story.

Dr. Axelrod 21:28
Happy to be here. Thank you. And yeah, I think when I was, you know, an undergrad, I had two main areas of research interests and those were immunology and the nervous system. And I did the immunology part first, but then I wanted to switch to neuroscience and from my PhD, I joined a lab at Rockefeller with Ulrike Gaul and she studied developmental neurogenetics, so how are genes affecting development of the nervous system. And specifically, we were interested in glia. So it was actually glial phagocytosis apoptotic cells that means, how do glia remove dying neurons during development?

Peter 22:15
Because our brain produces an excess of neurons.

Dr. Axelrod 22:18
That’s right. And that was also the connection to the immunology thing I did before, because in my undergrad, I studied how macrophages eat tuberculosis bacteria. So I came from infection biology, where I studied phagocytosis of bacteria. And then I switched to neurodevelopment where I studied how glia eat dying neurons. And then for my postdoctoral work, I wanted to do adult behavior. I had seen a couple of talks where people study behavior in flies, and I thought that was preposterous that you would even you know, consider doing that but you can figure out so many things about it in flies that I thought, “yeah, why not stick with the, with the fly.” Ultimately, all behaviors are, you know, we all have to achieve the same stuff.” Whether we are fruit fly or a person, we have to find the food, we have to avoid dangerous stuff and we have to find a mate. And we don’t know how it works in any organism. So we might as well study it in something simple.

Peter 23:20
So the transition from development to adult behavior, was that kind of an organic process for you? Did you have to tell yourself, oh, I’m not going to be a developmental neuroscientist anymore? Or is that something that you’re still thinking is part of where you want your career moving forward?

Dr. Axelrod 23:37
So there is actually a development aspect in my story here. You know, in my postdoctoral work, it’s just, you know, that there is something like developmental contributions to adult behavior, obviously. And I’m not excluding it for the future. The transition was pretty smooth, because, you know, we’re all such specialists anyway, and the focus really in my lab, like it in Ulrike’s lab is a genetics. And so if you if you think from a genetic perspective, it doesn’t matter what the actual assay is, whether it’s like, looking at macrophages in the embryo or looking at sleep in the adult, you know, you’re knocking out genes in certain cells, and you look at the contribution of these cells to whatever your phenotype is. So it’s not you, of course, you need to understand a lot of new stuff, but it’s not that different to me whether it would be a different topic in developmental biology versus just switching to adult behavior.

Peter 24:30
So just understanding how the genes interplay [and] the programming of the biology in the cell types as opposed to what the readout is. Yeah. Okay. Really interesting. And now your current work really focuses on circadian rhythms. And you mentioned you’re interested in an array of physiological behaviors. Can you tell me what roles the circadian rhythms play in governing different types of behavior?

Dr. Axelrod 24:54
Yes, um, it’s kind of shocking actually. Pretty much anything you can think of is circadianly regulated not just when we sleep, that’s the most obvious thing, right? Like, the timing of sleep is regulated by circadian rhythms, but also things like your body temperature, your bowel movements, but also your mood, alertness. Any hormone you can think of, any physiological parameter that has been tested, almost any logic parameter is circadian regulated. It’s like a bead of strings that exists to optimize processes in our body. And we’re not even aware of it.

Peter 25:33
And other particular behaviors or actions that you’re looking to read out from the circadian rhythms. And let me take a step back- a circadian rhythm is an internal clock within yourself that correct kind of something that has a certain sense of timing throughout the day.

Dr. Axelrod 25:47
Right. So the definition of a circadian rhythm means that it’s a physiological parameter or a behavior that takes about a day- circadia means about a day. And there’s another actually aspect to the definition and that is that it has to be entrainable, entrainable to a so called zeitgeber, a time cue, the most famous zeitgebber is light. But the big focus of the field is right now uncovering other time cues. Like for example, food, food is another zeitgeiber. But all kinds of things can be zeitgebers. In fact, you can think of it as anything you do or don’t do at a certain time of day might be a zeitgeber.

Peter 26:23
So we have these intrinsic clocks that can also be governed by kind of environmental cues such as light or food or whatnot. And if the cues are discordant, say like, you go on a flight, right, and you have jet lag, and your cues are discordant is the one that wins out if your environmental cues are very different than your kind of molecular clocks. How does your body resolve this?

Dr. Axelrod 26:45
Yeah, that’s a good question. So when you go on a trip, and the light input starts conflicting with your inner clock, what happens is that the amplitude of your circadian rhythm just breaks and there is a phase reset going on. And that takes a few days and then you were back on track with the new timezone. If you create a conflict between, for example, different zeitgebers. So you eat out of sync with your food, that’s actually fine. And you will have split rhythms in your body, like your brain can be on one timezone. And your liver can be on another one.

Peter 27:22
What effects will that have if your brain and your liver functioning on different time scales?

Dr. Axelrod 27:27
So that’s actually not a big problem probably as long as it’s regular. So I feel like there’s a big thing in the field right now. It’s called time-restricted eating, or feeding, where you don’t eat at certain times of the day, and then your liver clock is probably going to be entrained to a phase shift to your light input. If you don’t eat, for example, for the first six hours or so of your wake time, but as long as you do this every single day, there are no negative effect. And in fact, we know that time-restricted feeding has a lot of health benefits. So like everything with rhythms, it’s important to repeat it all the time.

Peter 28:02
certainly. And these rhythms govern pretty much all of our biology, and I was wondering, are you focusing on any particular biology in particular? Or do you care about all of these different physiological behaviors that are regulated by the circadian rhythm?

Dr. Axelrod 28:16
So what I wanted to actually work on was sleep when I came to the lab, because sleep independently of rhythms is kind of an enigma. We don’t really understand the function of it still; some people think it’s one of the big frontiers in science. So a lot of basic research is focused in you know, in the field is trying to understand why we sleep, what happens to the cells in our body when we sleep, and why is it so bad if we don’t sleep? And do other animals sleep the same way that humans sleep? No, in fact, our sleep is pretty unusual, and that is so consolidated, most animals nap, including fruit flies. So sleep and most animals have a circadian rhythmicity but it’s still much more fragmented than in humans. Almost no animal sleeps in one block. And also the amount of sleep is vastly different across the animal kingdom. And there are theories about what that means, and how we can use that information to understand what sleep is. But basically what I wanted to know when I came to the lab is how glia affect circadian rhythms and sleep. And what I found was that there is this thing called the blood brain barrier that is basically like a protective membrane or protective layer around the brain to ensure that in the brain, you have very specific, a very specific micro environment, so that neurons can function. And I found out that this barrier is actually not always closed and that that barrier opens and closes and that has something to do asleep. So that’s what I work on. So no, I don’t work at all on all aspects of circadian biology. I try to say it’s a huge, huge field.

Peter 29:55
Interesting. Could you tell us a little bit more about this blood brain barrier membrane changing with regards to sleep. Are you saying that if you sleep more, is there a a stronger membrane or a stronger barrier? Is it the fact that the barrier changes its integrity? Or is it the fact that the barrier kind of moves?

Dr. Axelrod 30:14
So yeah, that’s exactly what I found. I found that if you don’t sleep, the BBB, the blood brain barrier, it kind of breaks down and it’s, it’s the tight junctions, it’s the the proteins that are between the cells that form the barrier. It’s like a diffusion barrier. It doesn’t let anything through. It’s like it looks on the electron-microscopy looks like a ladder. And this ladder protects the brain because stuff just can’t get through. But when you don’t sleep, the ladder breaks a little bit. And when you then catch up on sleep, it closes again. That’s what it found. And that’s kind of unusual. I mean, it’s kind of unexpected, because we thought the BBB is static. We thought it just has to be made and it has to stay in place. And that’s that and I don’t think that’s the case. And that has all kinds of interesting implications.

Peter 31:02
Yeah, that’s really neat. I was wondering, why do you think the blood brain barrier changes with regards to lack of sleep? Do you think it’s perhaps because you’re not getting enough sleep? Your brain thinks that, oh, maybe I need to grab something else from the bloodstream?

Dr. Axelrod 31:15
Yeah, that’s the million dollar question, at least in my mind: what is actually going through? And what is the body trying to achieve? I do think that it is trying to do something, I think this isn’t some kind of adaptive response. I don’t think it’s actually breaking because I know that it closes really quickly again. So I think it’s trying to accomplish something, either letting something get out or letting something get in. And I don’t know what that is. But of course, I thought about what it could be. And there is, of course, a number of things that are asymmetrically distributed across the blood brain barrier. That is why we have it in the first place, right? And one of the most basic things that is that has a differential is our ions, the ion concentration, for example, potassium is very different in the blood than from the brain and you could actually say that opening the BBB just a little bit would allow ions to flow according to their concentration gradient. And then you could imagine how that could affect globally neuronal excitability in the brain. In fact, that has been shown in, in […] lab a few years ago there across the wake states, you see changes in ionic concentrations outside of neurons, but they don’t know where that comes from. So I still don’t know where it comes from. But it could be the BBB that allows those changes. And then that could be a mechanism to quickly switch from asleep into an awake brain. Because that’s what we experience right when we fall asleep, our arousal threshold is higher, clearly something changes in a pretty profound level about the way you know how arousal the whole brain is. So you know, this could be how-

Peter 32:49
Sorry I must have missed something. Did you say that when you’re going from a sleep state to waking up your blood brain barrier changes as well or is that only over time, in a sleep deprived state.

Dr. Axelrod 33:02
So I’ve done both experiments. I’ve just, I’ve just looked at the blood brain barrier in its natural state. And what I’ve done over over 24 hours, and I see that there is a change in the permeability of the blood brain barrier. And that change is very subtle. It took me years to figure out that it actually happens. But when you then sleep deprived an animal, then there is a big change, and it really breaks down.

Peter 33:26
That’s really interesting. What comes to my mind is whether or not there’s a circadian factor or some. So we talk about these light entrainment cues, whether or not there’s a cue within the bloodstream that helps to regulate your circadian rhythms.

Dr. Axelrod 33:38
Yeah, that’s an interesting question, because I actually have a second project that is about this time restricted feeding that I mentioned before, and there you definitely are taking up stuff, right, taking up food at different times a day or not. And what we tried to understand is whether this helps the animal’s health. So we know already that time restricted feeding is really beneficial, but we wanted to know the ultimate question: does it help you live longer and it is it actually dependent on a functioning circadian clock. So if you are arhythmic and you don’t know what time of day it is because you have you know, mutations in and clock genes, then it’s not beneficial which suggests that it acts like a like a time cue at certain times of day that really helps you have a really good rhythm and at other times of the day you don’t eat your body maybe can do other stuff. For example, repair itself versus if you eat all the time. You’re just in this constant state of digestion, which is not good. And here what I also saw that the BBB is actually normally degrades over time and is actually not degrading as much when you have this time restricted feeding that helps you with your longevity.

Peter 34:41
So how long over the course of time does your blood brain barrier degrade? Is it over the course of months, years?

Dr. Axelrod 34:50
So for flies, they live only about three months which is why we can do this these longevity experiments directly. In there, you can see that in old flies, the BBB gets leakier, so it means about like halfway through their lifespan. In humans, it’s different and actually blood brain barrier degeneration is a hallmark of almost all neurodegenerative disorders. But nobody really understands what that means is that cause or effect. And I should mention that many of these [individuals] also have sleep problems. So there are these three areas: age, neurodegeneration, blood brain barrier and sleep problems. And if my findings from flies are true in humans, then they might not just be correlated, but actually causally linked to each other.

Peter 35:35
Yeah, that’s really neat. When you’re talking about extending the lifespan width time restricted feeding, one of the other studies that I know that has been done to really understand kind of dietary interventions to extend lifespan is caloric restriction. Do you think there’s any interplay between the time restricted feeding and the caloric restriction feeding?

Dr. Axelrod 35:54
So that was a major question. Of course we had, are we […] just doing caloric restriction? So we did assays where we watch how much they eat, and they actually eat more in those 12 hours than the animals that eat for 24 hours. So it’s not that, which is good, because it means it’s a distinct mechanism from caloric restriction.

Peter 36:15
So if you could calorically restrict and time restrict, would that extend lifespan even further?

Dr. Axelrod 36:20
So we did that too. And it seems like there’s an additive effect, which also speaks to the fact that those effects are different. And, yeah, it’s pretty, it’s pretty strong effects, actually, in those flies. And they were actually so strong that I started doing it myself, time restricted feeding.

Peter 36:40
It’s very popular, very popular, and-

Dr. Axelrod 36:41
it’s really easy for me, I always skip breakfast. So it’s just like, yeah, I’m gonna live longer.

Peter 36:46
It’s really interesting, right? Because people always say, you know, breakfast is the most important meal of the night. True.

Dr. Axelrod 36:52
Yeah, yeah. There’s this concept of like grazing, having like five meals a day. That’s not what we think. We think you really want to partition these activities, so that your body is not constantly burning fuel.

Peter 37:06
I think from an evolutionary perspective, right, because of the abundance of food now, it’s very easy. But if you thought about like when we were kind of a hunter/gatherer society and we had to go hunt for food, I don’t think we would eat or have these grazing properties. And I wonder whether or not our circadian rhythms are more in tune back then than they are now.

Dr. Axelrod 37:24
Yeah, there is also just the light. You know, people used to spend a lot of time outside and we don’t know we have lighting inside, but the light outside is way, way stronger. And we just don’t sense it. And because we don’t sense it, we don’t think it’s important. But our circadian system senses it very well. You know, the cells in the back of our eyes that react to the blue light, which resets our circadian clock. They respond to light exactly in the in the intensity that it is presented to our eyes. And so by being indoors a lot, our circadian rhythm is dampened a lot. There are studies that show that just a weekend Camping really boosts your melatonin rhythm, which helps you sleep.

Peter 38:06
Yeah, that’s really interesting, because we talked about all this time restricted feeding on extending lifespan. But what about kind of governing the light that you get every day and whether or not that has an impact on your overall lifespan? So making sure that[we] don’t get too much artificial light, is that been shown as to have an effect on lifespan as well?

Dr. Axelrod 38:26
Yeah. So there’s this cool question about why have circadian rhythms at all. And some of the experiments that have been done are, for example, constantly shifting your light/dark schedule, or having you in constant conditions and constant light conditions, which fruit flies, for example, and that definitely shortens your lifespan.

Peter 38:46
So there’s like an ideal amount of light and an ideal time to eat and there’s all of this will help to kind of cue our body to the best physiological state. Yeah, it’s really interesting. I want to transition a little bit to kind of the fact that you have (or) are in the process of publishing a book?

Dr. Axelrod 39:02
Yeah, it’s actually available for pre ordering. And it comes out in bookstores in May.

Peter 39:07
Amazing. And the book is on how babies sleep. And I was wondering, a why publish a book and then, what was kind of the motivation behind that, as we typically want to publish articles? What made you decide to go ahead and publish a book for general public?

Dr. Axelrod 39:24
Yeah, it’s a good question because I was actually always someone who really did not was not interested in translational things at all. I was always someone who almost prided myself in thinking I want to understand like basic principles of biology, I don’t care if there’s any applications to human health. But I just landed in the lab where, you know, it’s kind of unusual for a field like circadian biology is that it goes from you know, molecular genetics and fruit flies to human health, literally in one step. That’s that’s very unusual. And so when when you don’t want your mice to To wake up you have these special red filters in the in the door and you have this red light if you have to open the incubator at night. We have the same thing for our fruit flies. We have these dark incubators and if we have to handle the flies, we have red torches. So when my first baby was born, I was like, why I remember not using red light bulbs at night because you know when I have to go and feed her or when I have to change her diaper. I know that any light but red light will affect her melatonin, her sleep, everything.

Peter 40:30
We do that for our experiments.

Dr. Axelrod 40:31
Why not do it for our babies? So I exchanged all the lightbulbs to red bulbs. So of course it works, it’s known that this is our biology. And then there’s other things. What else do I know to help my baby sleep? I use to be a bad sleeper, so for me the biggest biggest fear was that when I have kids, I’ll never get sleep again. So I used everything that I had to help them sleep at night and then it all kind of works, which is in a way it’s not that surprising. And I need to write it down, so I remember just for myself, so I remember what I did exactly if I have another kid, I know what worked. And then it just became more and more and eventually became a book and I thought, it’ll be a book that I’ll self-publish or whatever, and I talked to a couple people and there was a lot of interest and here we are.

Peter 41:25
That’s really cool. Something that I realized was that I’m very early in my graduate career, but the things that we do in science definitely have an impact on our daily life. I’m currently doing research on how amino acids are sensed in the gut and I’m definitely thinking about how many amino acids that I’m taking in and what is the food composition. It’s really nice to see that you’ve taken the information you’ve felt you’ve gotten from your day to day research and shared that with other people and I think that’s really neat. I think that should be more in science. I’m sure there are people who are making discoveries and implementing them, maybe not to the degree that you are with circadian rhythms, but at least impacting how they make life decisions on a day-to-day basis.

Dr. Axelrod 42:02
Yeah, you should write a book.

Peter 42:04
I don’t know if I’m there yet, but definitely something to consider. I was wondering now that you have this really good understanding of circadian rhythms and how they can be applied to modifying our sleep and extending our lifespan. Where do you see your research moving forward from this as you plan to potentially start your own lab?

Dr. Axelrod 42:29
I’ve thought about this a lot this year as I was writing research statements and I tried to think where I want to take all of this. I’m lucky because this whole blood brain barrier can go in many different directions as well as time restricted feeding and there’s also intersections between these projects. But one thing I was interested in, apart from the very hard question of how it actually works or what is exchanged? We touched on each of these things as a graduate student working on their post-doc. But something I was also interested in is, is this true in mice and mammmals? If it’s true, maybe our blood brain barrier also not static? I started collaborating with mouse researchers and there seems to be indications that this is true as well. So something that I’m trying to decide is if I want to, in the future, do I want a lab that also does mouse work, because it’d be fun to bridge those two model systems.

Peter 43:26
I think that’d be really exciting and I can’t wait to see what you come up with.

Dr. Axelrod 43:30
Thank you.

Peter 43:31
I want to thank you so much for your time.

Peter 43:42
Dr. Sciolino and Dr. Axelrod shared with us two different paths to being a successful researcher. What I really want to emphasize is the importance of taking that first step. Don’t take too much time deliberating your ideas. Go ahead and write it down, pitch it to others, and polish it. If there’s something you don’t quite understand something about your daily routine, think about why. Don’t brush the thought aside and see if you can integrate this thought into a research question. The first step is often very daunting, but constantly pushing ourselves to put our foot down is the quickest way to progress forward in science. 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.

Episode 10: Food For Thought (Transcript)

Peter  0:00 

What are you feeling right now?

Dr. Schwartz  0:02 

Well, I’m really bad at identifying the flavors. I mean, it tastes like some kind of sandwich, some onion flavor. And maybe something like avocado. Maybe have some chicken in it. Some kind of like chicken fajita-y kind of taste.

Peter  0:21 

Sure you can open up your eyes and take a look. So this is an arepa, it is from a Venezuelan restaurant called Guasaca. I realized you probably don’t have time to go grab food before your flight.

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.

Today, we have Dr. Gary Schwartz, a Professor in The Departments of Medicine, Neuroscience, and Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine. Dr. Schwartz completed his Ph.D. in physiological psychology from the University of Pennsylvania, his post-doctoral fellowship in neurophysiology at the Monell Chemical Senses Center. He received his first faculty appointment at Johns Hopkins and since 2004 has been at Albert Einstein. His research focuses on communication between the gut and brain and how this circuitry and in particular the vagus nerve regulates food intake and energy balance. So I want to start with the fact that you now serve on the International Advisory Council at Monell Center, which must be a nice coming full circle for you allowing you to advise for the institution which you trained at. Could you tell me some more about this?

Dr. Schwartz  2:17 

Sure. Monell is a very unique institution in the United States that has had a history of both academic and commercial support, sponsorship and interaction. And it’s a basic research institute that is focused on identifying things that were very important to me in my career, and that is the neurobiological basis and the chemical basis for chemical senses smell and taste. So it has collaborations with investigators around the world, and in particular University of Pennsylvania. And as a postdoctoral trainee there I was interested in moving from the study of eating behavior and how taste and taste nerves affected eating behavior to actually try to identify how the brain encoded the sense of taste that was important to control eating. So, my PhD had been in really the very fine grain analysis of actual eating, behavior, licking, chewing, etc. and the roles of the nerves that supply the tongue. So I would interact by transacting those nerves and seeing the effects on actual eating and licking behavior. And while that was very intriguing, it got me to thinking about what types of signals were actually available in those nerves that I was interrupting or what types of signals actually arose from the tongue when we eat, and where and how were they transmitted to the brain and how did the brain respond to those. And so I really wanted to move on to what I thought was at the time, harder science, which was actual neurophysiology or how nerve cells respond. And at the time, Eva Kosar was studying the neurophysiological responses of taste stimulated cells in the brain in particularly in cortex. And she had really pioneered the identification of a region of the brain that received input directly from the tongue. And so when we think about how the body is represented in the brain, we think of a map of the body surface along the brain. And what Eva Kosar had done was to map how taste is identified in the brain, not just the tongue, but taste in particular. And so my postdoctoral experience there was perfect for me because I learned how to identify the regions in the brain that were sensitive to tastes on the tongue. And I already knew how those tastes would affect eating behavior. So I felt that I was getting insight into how we actually processed taste and how taste could reach the level of the brain where we could be conscious of it, we could learn from it and we could act on it so I thought I was getting at the wet biology of taste.

Peter  5:01 

Really interesting. So from taste and our understanding of taste in the brain were you looking at particularly the circuitry that links these taste buds to regions in our brain? Or were you looking at particular signaling molecules? How exactly is that information conveyed?

Dr. Schwartz  5:16 

The types of studies that we were doing were to try to, we’re based on again, the behavior- […] my perspective was formed from my behavioral studies that showed that the different basic qualities of tastes that we now consider to be not only solved sour, bitter and sweet but also umami, or the amino acid or protein taste. It […] was early in those times, but people were beginning to study the molecules that were in the taste cells on the tongue that were responsible for the generation of signals at the tongue, but we didn’t know how those types those five basic types could represented in the brain, whether they were in a mixture of cells that were all mixed together, or whether like the visual system, perhaps there were particular columns of cells that mapped particular taste qualities, or there was another mapping possible that had to do food, how I interpreted my behavioral studies. And that was, the oral cavity, in general, has multiple taste nerves, one for the front of the tongue, one for the back of the tongue and one for the palate. And so another possible organizing strategy, or organizing framework could be that each nerve projected to a particular region of the brain so that there’d be a map of the different taste nerves and thereby a map of the front of the tongue versus the back of the tongue versus the palate. And as we started to place so it was a circuit perspective, but it was also sort of a mapping perspective or a mapping outlook that is based on the map of the tongue and its sensitivity. How was that map repeated or represented in the brain that we see a remapping of the tongue in the brain, according to the nerves, or according to the tastes. So the experiments were really designed to try a variety of tastes in a very systematic order in the front of the tongue, in the back of the tongue, and on the palate, with or without the nerve […] so that we could distinguish between those two possibilities. And what we found is that, in fact, there’s both kinds of maps […] And so different tastes stimulate different populations of neurons in the taste cortex, and as well as the different nerves corresponded to slightly different regions of the map. So the segregation of the information arising from a particular place on the tongue, and a particular chemical on the tongue was preserved. So there was sort of a high fidelity mapping of the oral expression variance at the highest level of the taste brain in the cortex.

Peter  8:04

Cool. That’s really interesting. Yeah, I had not known specifically about that. I think I hear colloquially a lot about tastes and like, Oh, I really like this because of how it tastes, but not really understanding how that reaches certain circuits within our brain.

Dr. Schwartz  8:18 

And in in the brain as it reaches it. This region of the cortex is the earliest processing in the cortex. There are other regions of the brain that tastes reach that are important for choice and are important for effects that are important for our emotional responses to taste for animal models of understanding taste behavior, you know, We can’t use verbal communication, so we have to use tests of animals willingness to continue to eat or to reject. And those responses happen. Typically they happen very quickly. Sometimes they happen by reflexes that happen in the brainstem. So very early on in the brainstem. The first place […] where taste information comes in. And that information has access to motor neuron neurons or motor nerve cells that actually control our jaws, and our tongue and our swallowing muscles. It’s important for species especially like rodents who don’t have emesis, they’re not able to expel or vomit. So[…] the oral decision to continue to ingest or to spit out can be life determining, right, because they only have one chance- if they ingest a toxin then they have to face the consequences of that toxin. So it’s very important to have some very hard-wired early detection mechanisms for the sensation of something that’s potentially good versus potentially bad. So that[…] the organism has the ability to either ingest or reject, so that it doesn’t have to survive bad consequences. And so that mapping is also present at the level of brainstem, but then for higher species with more cortex and other, more developed central nervous systems that have more capability for learning, that have more capability for choice and that have different kinds of effect, it’s important to have that information represented at other higher levels of the central nervous system such as the cortex. So it has both a sort of a cognitive mapping, if you will, a sensory mapping as well as a hedonic affective map.

Peter  10:24 

Cool. So then from there, you moved further down the alimentary tract, and then you started studying the gut. What was going through your head when you were thinking, at least from your graduate work, studying tastes to moving kind of to post-ingestive sensing. Why did you make this switch?

Dr. Schwartz  10:39 

I think that’s a really interesting question. To answer it, I want to take a step back as an undergraduate at Hopkins, I had the opportunity to be in work study and I knew I wanted to work in a laboratory, and I was interested in behavior in general and the laboratory that I found was with Elliott Blass. And in fact, Tina Williams, and they were involved in understanding how we develop the control of eating. Eating in mammals [and] especially in humans, there’s a critical phase because human infants are altricial. You know, they rely on the mom. And so rodent models are appropriate to study the beginnings of feeding, the development of feeding and what controls it. And I was really fascinated by the idea that, you know, smell became very important for these young rodents who were born hairless and blind and couldn’t thermoregulate well. Smell was an important sensory control. And then, other studies were underway where the oral cavity was stimulated with nutrients and that could control eating as well. So those early undergraduate experiences really made me interested in how food can drive sensation per se. And so in my undergrad and my graduate school work I then studied specifically in the oral cavity. But it became clear that the oral cavity is really only the beginning of our interaction between the external environment and our inside-most intimate selves, the internal mileu. And what became clear was that, sure, the acceptance or rejection of food is important, but then what becomes very important are the consequences of that food for nutrition for our basic biology. So it made sense to start to look at conservation of mechanism, the oral cavity is important to accept or reject, and the post oral area of the elementary tract is important to absorb and digest, then there must also be some important chemosensation there. And we also know from a variety of studies that have been done well before that, you know, that there are certain sensations that we Have from the gastrointestinal tract that help determine our feeding. So it was a natural segue for me. And for me, it was sort of it was my move to something more novel at that time, because people really weren’t working on those types of signals in that way from the perspective of how chemosensation drives feeding and how, when, what the neural circuits that mediate that controller. Yeah, now it’s really hot area.

Peter  13:26 

Understanding gut sensing is very popular. Do we have a good understanding of if something is palatable or tastes good, but in our gut, we have some sense of the fact that this is a non-nutritive material or something that is non-rewarding with regards to gut sensation. How are those two lines of information conveyed? Or is there a way to compute both of those?

Dr. Schwartz  13:49 

[…] I think the short answer is we don’t know. There’s several lines of evidence. First of all, this is a very hot area of investigation. For a couple of obvious reasons. Our body’s able to discriminate between things that are nutritionally good for us and nutritionally not good for us. And yet we eat them anyway and and our food sources designed to […] bypass our normal biological controls and precipitate overeating for example. And so, you know, one can imagine from a health perspective with overeating and obesity or serious epidemic problems, especially in childhood. Now, it becomes really important to appreciate how our guts are or are not sensitive to either naturally occurring nutritional sources or unnatural non-nutritional sources. So, we know first of all that there are tastes like cells not only in the oral cavity, but also in the gastrointestinal tract. And in fact that when nutrients or even these non-nutrient artificial sweetener-like molecules are placed directly into the intestines, they can actually affect food in similar ways, suggesting that they we can fool our natural detectors by synthetic compounds. And some of the consequences of that could be to overeat […] It also turns out that some of the artificial sweeteners and some of the sensors that we have in our gut may be enough- the artificial sweeteners may be enough to drive the secretion of factors that can precipitate diabetes, for example, so that […] the artificial sweeteners might act on Beta cells to drive insulin release. And you don’t want that unless you really have nutrition available for the insulin to have its effects on glucose absorption, so that could drive insulin insensitivity. So it becomes from a practical day-to-day health perspective, very important to understand the degree to which our gut actually does sense nutrients and how well it discriminates among those nutrients and how it can or can’t be fooled by artificial sweeteners. And if so, what are the molecules that are responsible for transmitting that signal from the sweetener, the artificial or real to the brain?

Peter 16:09

So some of these signaling molecules or the way that our gut senses different macronutrients have some overlap, right? In the sense that some enteroendocrine cells or some of the cells in our gut that sense nutrients or any stimuli within the gut are able to convey this information to our brain through different signaling molecules. I was wondering, we think traditionally of this is a satiating food, or this is a food that decreases the amount of my appetite. But do you think there is finer resolution of information? How is that more detailed information encoded to the brain?

Dr. Schwartz  16:45 

The answer to that is I’m really not sure. What we do know from studies of the sensors of the gut is two classes of information: one, the actual sensors that are responsible for detecting lipids or detecting carbohydrates or detecting amino acids in generating a neural response in the gut sensory nerves are not well known. Some taste cell elements are present, and those are for sweeteners. Some sodium-like elements are present, but sodium chloride is not really an important constituent in terms of nutrient absorption. So, the actual sensors, the molecular characterization of those sensors is really still in its infancy and we can’t make a mapping or a one to one correspondence of which transducers are for which nutrients. Also, it’s important to remember that when we eat food, it’s not just the nutrient that’s in that food, that food has physical and chemical properties in addition to the nutrient itself. And because there are endocrine cells in the gut the nutrients also have the ability to drive secretions of hormonal or paracrine hemical factors that themselves can activate nerves. So we can think about it maximally as the simple something as simple as a nutrient in the gut really has a mechanical properties that occupies space, it can stretch etc. It can have pH properties that are relevant. It could as osmotic or viscosity properties that are relevant, even if it’s diluted, it has the nutrient and it has the ability to secrete factors that can act on the nerves so […] even when it gets passed from the stomach to the duodenum, it’s a very complex stimulus, and the nerves have the capability to respond to multiple dimensions of those. Having said that, I think that it is very unlikely and one can make the analogy of sort of two point discrimination. You know, we know from a skin sensitivity perspective that our fingertips are very sensitive to the distance between two sharp points, but if we put those two points on our back, we can’t tell There are two we feel it as one object. And I think that certain types of feedback from the gut about food are like that, that we just really need to know we certainly need to know something about caloric density and that we do know that because gastric emptying and the delivery of nutrients is directly proportional to how many calories per per unit volume of food we have. So calories are sensed somehow. But other than that, we really have a sense of food, and that food can either be more or less satiating, depending on a variety of things. How calorically dense it is, how many endocrine factors are releases over what timeframe and how fast or slow it tends to empty which correlates with the calories again. And people’s ability importantly for the real gist of your question, behaviorally people’s ability to discriminate how they feel in their guts is notoriously poor. We’re not really tuned into exactly how our guts feel. And in fact, one could make the argument that with the plethora of sensory stimulation that we get from the outside world, every day, we become even less sensitive, you know, we become more inured. And you know, there’s many reasons to eat and to continue eating. So we have 24-7 access to food, if not food, then pictures of food on television. We go to the refrigerator, we go to the convenience store, etc. So the head factors, our head senses, the sight, the sound, the smell, the touch of food, are always being driven, and our behaviors or habits about eating and the consistent availability of food, if anything, promote the acquisition of food, and really, I think can help make us less sensitive to the gut signals. And in fact, along those lines, there’s evidence to suggest that the ability of the gastrointestinal tract and neurons in the gastrointestinal tract to dictate certain features of foods actually gets dampened during obesity. So carrying around excess adipose tissue or having too much energy stored on board in the form of fat causes the release of factors that contribute to a dampening of the neural signals both in the central nervous system and even in the gut in terms of gut sensing. So it’s really sort of a triple whammy, we have an accentuation of the head factors, the sight, the smell, the constant availability of food and the ease of acquisition of food, our habits of eating that food, the fact that having eaten it, we become less sensitive to the filling effects of food. So those three things really conspire to make us even less sensitive to this kind of rich environment.

I want to mention briefly though, let’s look at the flip side. You know, now in this country, unfortunately, it’s more rare to have normally scheduled meals: morning, afternoon night. Even with the social aspect, everyone’s busy: kids are busy, families busy, so we don’t all sit together at time. And so we lose both the social context and the temporal context that determines nutrient availability. So our stomachs are full all the time, irrespective of the social interaction and irrespective of the time of day. Well, that just wreaks havoc with any kind of biological rhythm of waxing and waning of energy-use, exercise, how tired you are, how awake you are. The reason I bring that up is that when one can establish a social rhythm of eating that is in-sync with the circadian rhythm, those types of social constructs have very beneficial biological consequences, and those been beneficial. So those, we can modify our behavior to have those traditional experiences and that by itself, I think will go a long way to improving the ability of our gut senses to do what they’re supposed to do rather than to act in ignorance of them?

Peter  23:04 

Yeah, there’s so many complex factors, even the surrounding factors, not even the food itself, which is already a very complex particle or a stimulus that we have to ingest or comprehend. Right? And I think a lot of approaches to understanding this is really simplifying it down, right, taking a particular macronutrient or taking a particular composition of the food to study how it is signal to the brain. What is I guess the significance of breaking it down into individual macronutrients? If that is not typically what we ingest or consume?

Dr. Schwartz  23:36 

So that’s, that’s a really great question. And I think part of the answer that question, quite frankly, is that at least Western science tends to approach biological problems in a very reductionistic way, where we use the knowledge that we do have about how the physical and chemical world is organized and apply that directly to biology as if it would be appropriate. However, because even throughout evolution, there are […] animals with very specific appetites […] for different kinds of insects or different kinds of prey, etc. But in general, almost everything that everyone eats is typically has a mixture, or we make mixtures of a variety of macronutrients. And I think part of the rationale for studying individual macronutrients or individual stimuli is that we sort of have to start somewhere and I think that is guided by and it could be you know, insufficient, but is guided by our rudimentary understanding of how biochemistry works between receptors and ligands […] we know that this is how biology is organized to some degree, it is an important organizing principle. And so for the periphery, it makes sense to try to parse that. It does sidestep the question of well, in real life, you’ve got everything happening at once. So, what does it matter? And so now I want to bring in another aspect and that is related to the idea that foods are complex stimuli. And that is that in biology even though we apply the individual tools, we also know that there’s multiple sensitivities. And so we know that in biology for any system that it is very important, like eating, there needs to be redundant mechanisms to get a signal across. So I think that the analytical approach provides the opportunity to see the contribution of each individual and it also provides the opportunity to say, well, does the sum provide a greater signal than the individual parts? And if not, fine, and if so, how did does that work? So I think there is some sort of conceptual benefit to this analytical approach, remembering that it allows recombination and then assessing how the real world phenomenon works when you have the whole food available.

Peter  26:15 

So kind of breaking a complex problem into smaller parts and then seeing whether or not these two these parts together-

Dr. Schwartz  26:21 

Together account for the whole. And if not, that becomes very [nice] and even if so either way, it becomes very interesting.

Peter  26:27 

Certainly, and I think this is a nice segue to asking a bit about one of the grants that you’re funded for. I saw on the NIH reporter that you’re funded for a P30 Grant on animal physiology and animal phenotyping. Could you tell us a little bit more about what this entails?

Dr. Schwartz  26:42 

Sure. So the P30: that’s a code that the National Institutes of Health use for what’s called a center grant. And this in particular, there are two center grants that I’m involved in the New York Obesity Research Center, which is headquartered at Columbia University. And the Albert Einstein-Mount Sinai Diabetes Research Center, which was originally based at Einstein, for the last 30 some years and over the last five years, we’ve joined forces with investigators at Mount Sinai. And these center grants are funded through the National Institutes of Health and particularly the National Institute of Digestive and Kidney Diseases, to bring together investigators with expertise in a variety of approaches both human & animal, not only live animal but also tissue based approaches and molecular and computational approaches. So that one can attack a problem from multiple perspectives. And so that when there are a critical mass of investigators in one of these center granted institutions, then the different investigators bring their own separate research questions and their own research expertise to the forefront. The function of the animal physiology cores that I run is to help investigators understand the whole landscape of energy balance in the animal models or in the human conditions under investigation. So let’s say someone finds a new mouse genetic strain that exhibits overeating and obesity in development. And they want to understand how that happens. So the function of the grant, the part of the core that I serve as director of is to help them break that down. It’s like, well, what part of their phenotype is due to overeating? And do they overeat only certain nutrients? What is their local motor response like and what is their basal energy expenditure, their basal metabolic rate like and are they very susceptible to exercise? What is their hormonal profile like? So in order to really understand the multiple causes of obesity or diabetes, one needs to have a systematic way of examining contribution of behavior and metabolic physiology and organ physiology and molecular biology. That’s what this core does in sort of multi-level, multi-disciplinary, taking apart the energy balance equation, energy intake and energy expenditure, energy availability and energy expenditure and how it happens. And then we work with the investigator to understand what is it about the phenotype of that animal? What is it about the gene expression of that animal that can lead to these different behavioral and metabolic changes? So we try to take either natural experiments that result in obesity or diabetes, or targeted experiments where genetic susceptibility to obesity or diabetes has been identified in humans and to try to develop animal models, which will then allow us to probe how will this genetic change manifest itself in either the behavior of theology and that’s what we do.

Peter  29:58 

At what stage in your career did you think that this was, oh gee, I think I would love to be a director of an animal core?

Dr. Schwartz  30:04 

So this was something that I fell into. I mean, I was recruited because I have my own R01s: regular grants from a principal investigator that where I study gut-brain communication and nutrient detection, etc. And I was recruited to the Diabetes Center because they were interested in the way that the brain communicated with the peripheral organs to control metabolism, which 15 years ago was a newer idea in the field. We knew about gut-brain for feeding, but people hadn’t been looking at the role of the brain as much in terms of the control of metabolism. And so for me, it provided an opportunity to learn about metabolism. And as a result, it became clear that there were certain capabilities that I used in my own research that were amenable to the Diabetes Research Center group at large. And so it was at a realization on your end or other people or sort of both. So because I sometimes get bored easily or I’m very interested in learning other things, I became interested in moving outside of feeding behavior and into neural control of metabolism. And at the same time, the field was moving in a direction of neuro-control metabolism. So other investigators at Einstein & Sinai had been becoming very interested in this, and I was the one who had actually developed sort of the range of tests that could directly be applied to those so it became sort of a natural fit.

Peter  31:32 

This is something that I have not thought much about. As early in my career, how to become more involved in overseeing larger projects or larger opportunities. Is there some way that you would recommend a younger trainee or someone earlier in their graduate career going out and interacting with other professionals? Is there a way that you approach this?

Dr. Schwartz  31:52 

It’s interesting, because this core directorship business, you know, it’s not something that you want to necessarily pursue as you become a senior investigator. Because you have your own projects that you’re really running and your other grants and other interests, but it is a great career development tool for young investigators these days in the field. So in the feeding and metabolism, there are so many good meetings. And so many approaches that are being used that the younger investigator can really take advantage of expertise from people with very specialized interests and specialized approaches. And by going to meetings, they can start to really identify the outlines of their interests and what things fit into their interests. And as they do so, they will gain […] expertise in the techniques that are required to really address their problem. I guess the point I’m getting at is, as a junior investigator, you have a problem that you think you’re interested but you don’t really necessarily yet understand the full ramifications of that problem or how many ways into that problem. There are how many experimental ways into that problem. And as you mature and as you encounter other research programs, hopefully you maintain your interest in your core problem that you began with, then you’ll naturally start to find yourself interested in other ways that people have of tapping into that problem. And that may express itself in Oh, well, I really need to incorporate this kind of measurement into the way I’m doing experiments and into the way I’m thinking about the problem, because the problem is maybe a little bigger than I thought it was. Or there’s other ways and those ways require some technical and conceptual advance. And so your stick-to-itiveness about your initial problem as a junior investigator, and your curiosity will help feed your growing knowledge base of finding out who’s doing similar work, and are they approaching it the same way and if not, oh, well, that might open a new perspective for you that you can incorporate into your own. I think one of the guiding features of successful career development is how, as people mature intellectually, they gain a greater perspective by appreciating what other people’s work can bring to their own. Both technically and conceptually. And that’s how you grow intellectually. And that’s how you become authoritative. And that compels you to become more thoughtful. And the more thoughtful you are, the more you read and the more you meet and incorporate other people’s ideas. The core answer to your question about, you know, well, how would you advise a, you know, a junior investigator to consider, you know, directing a core or being involved in these multiple kinds of projects? Part of the core of the answer is that I think I was trained this way. I feel fortunate to have been trained this way that science is, in essence, a very human endeavor, a social human endeavor. We do hear of people working away in a basement lab by themselves coming up with some amazing discovery, but those days are mostly gone. And in fact, you know, a lot of high profile work, it’s no exaggeration to stand that, to say that, you know, people stand on the shoulders of giants that they really do represent collaborations in real time but also collaboration of historical growth from concepts and incorporating concepts and techniques that others have developed. And junior investigators, I think successful junior investigators learn how to effectively communicate and draw from other people bounce challenge their own ideas with other people or against other people and take from that, how they can really synthesize and incorporate and advance their problem. So I think that the key to the successful trajectory is identifying what you think you’re interested in, testing the strength of your interest by challenging it with other people. And as a result of that incorporating their sense of the problem. And finding out however you can, how to approach it by any means necessary and making it part of yourself. That’s really what I think.

Peter  36:28

Wow, that’s really powerful. Knowing that you’ve served on several study sections and you’ve reviewed many grants, do you think this is actually a weakness of a lot of young investigators coming in who are approaching it with more of, I guess, a siloed approach from writing a proposal? Does the fact that this kind of lack of desire to challenge their approaches with other faculty or leaning on more experienced members, and limit kind of their ability to see alternative approaches, potential pitfalls. Are these things that you see as common weakness in early grants?

Dr. Schwartz  37:02 

I think a couple of things. One, while the electronic data age and you know, PubMed are great, amazing tools. I think that many junior investigators, through no fault of their own have developed their mentality about science or their mentality about their specialty area of interest from reading abstracts on PubMed. I don’t think that’s really an over-exaggeration. You know, papers have become larger and larger, more complex, but there’s large bodies of literature, older literature where the papers are smaller and simpler, but junior investigators typically have not had as part of their graduate education, the discipline to really read through the actual corpus of how science progressed to the point where there and I don’t mean going back 100 years, although sometimes it might take that, but I do mean the actual discipline of going to the trouble to find out the sources and really read them so that you have the ability puzzle over them. And I think that comes across in grant writing in grantsmanship. Because your ability to conceptualize a problem and justify what you think is important about it typically is too shallow, because there are typically many other findings that one could reference that actually have the thread of the thought that provide a very strong rationale. And in the culture where the background and significance or rationale sections are just done by pegging citations from a few paragraphs, it’s short sells the significance of a grant, so that the significance sections and the rationales are either very self contained. Look, I did all these experiments, I have 48 preliminary figures, in complete ignorance of the fact that a field had developed of this several times with, you know, large findings, or at least a lot of the major concepts already laid out. So it’s not that the person’s rationale or experiments aren’t interesting or potentially important. It’s that they could be even more so had they taken into account a consideration of the idea of body hosting that had occurred before. I think that’s a major issue. The other side of that from a study section perspective, is that so you know, people get older, they get more senior they rotate off study section, and the NIH has guidelines dictate that people who do have R01 you know, the primary Principal Investigator Grants are the ones who are now reviewing others. And if they themselves have this rather formulaic, superficial approach to okay, well, here’s how I took in my grantsmanship course: I have to have a background significance. I have to have certain preliminary data and this should sell and they use those criteria to evaluate a proposal, then that perpetuates this cycle. In addition, those younger reviewers because they don’t have the background in this way, they’ve been themselves siloed. They don’t really appreciate that, or it’s more difficult to appreciate that study sections function through advocacy, both for and against. And advocacy requires the ability to compellingly convince people about how important the research perspective and how important the research rationale is. Okay? So not only is the pursuit of the scientific experiment a human endeavor, but the evaluation of a scientific research program for the purposes of funding is a very social endeavor and requires advocacy either for or against that where the reviewers actually are able to instill in the other panel members an understanding of the perspective of where that grant is coming from. And if those younger PI’s themselves have never really developed what it means to have that kind of perspective, then they’re not going to be as effective advocates. So both from the applicant and the reviewer perspective, I view the superficiality and the ease of you know, making bullet points and making citations and sort of more confined turf protection, if you will, you know, defending your own turf or your own specialized research area has really significant complications and impediments to the review process for science.

Peter 41:21

If you aren’t an expert in the field of the proposal that you are reviewing, how do you read deeply into that?

Dr . Schwartz 41:28

It depends on who you are, but you learn. You learn how to become a reviewer. It’s on-the-job training and you learn how to learn. Part of going to college and going to graduate school is not to do a project particularly, but it is actually how to learn how to learn, so that when you find out what you’re interested in, you have the intellectual tool kit to do it. The same is true for evaluation of science, you need to learn. Hopefully you’ve learned how to learn and that skill can be applied to disciplines outside of your own. Again, junior investigators have not typically been pushed that way, because it’s very labor intensive to start over. Where do I start? How do I read? Learning how to read. You get better at it with age. You get better at sorting wheat from chaff in terms of the findings and what the significance of the findings and your ability to peg facts if they are hypothetically deductive or if there are logical flaws. You get much better at your critical acumen of whether or not someone has put the pieces of the story together logically, scientifically according to the scientific method or not. You also get better because you do expand your knowledge base just with age if you’re reading at all. There’s an inundating amount of reading to be done, but you do get better with that and as a result, your knowledge base broadens and your knowledge base of other people and their expertise broadens too and so your ability to tap into and at least begin with an intuition of what the problem is helps target your reading. There are people who have come to study section who read every single grant and try to develop the expertise, but that’s not sustainable in any stretch. But more senior people and junior people too, as they read and interact, and as they make doing science their identity for intellectual function, it comes more naturally. But make no mistake, it’s real work and it requires that you immerse yourself in someone else’s intellectual effort. Put yourself in someone else’s head. And that’s a very unique, a little bit scary position to be in and one of great responsibility and so I think that the reviewers have a really great responsibility to the field.

Peter 43:55

Well, I want to thank you for your time Dr. Schwartz.

Peter 44:09

Dr. Schwartz showed us how little we actually understand about a process that we conduct multiple times a day: eating. How unique properties of food are relayed and interpreted in the context of behaviorally complex individuals is a question that has only begun to be answered. In order to get to the crux of some of these challenging, but essential research questions, Dr. Schwartz has taught us to truly put ourselves in the shoes of others. Dig deep into the existing literature, appreciate what other’s research can bring to your own, and continuously teach yourself to learn. In doing so, we can begin to ask more thoughtful and compelling questions that will advance our research. Thank you all so much for listening and we’ll see you on the next episode. For more of our content, you can follow us on twitter @gutbrains or visit our website @thinkgastronauts.com. The Gastronauts podcast would be impossible without our incredible team. Meredith Schmehl is our producer and theme music composer. And special thanks to the founders of Gastraonuts: Dr. Diego Bohórquez and the Bohorquez laboratory.

第一期: 拥抱不可能

张旭朏/译

Peter [0:00]

您感觉如何,谢丽尔? 您觉得是什么呢?

Dr. Nickerson [0:04]

它可能是一种甜点,似乎里面有某种奶油,但总体上比较干燥。 我会说中等甜度,不是很甜,但有点甜味。

Peter [0:16]

如果非要让您用一个词来形容它放到您嘴里时的感觉呢。

Dr. Nickerson [0:23]

我想用一个连字符词汇:半-甜-干[…] 哦,这是个两连字符词汇。半-甜-干。

Peter [0:29]

现在您可以睁开眼睛了。

Dr. Nickerson [0:32]

是月饼! (看来猜的)还不算太离谱。

Peter [0:37]

太空,月亮,饼,我们试图将它们融合在一起。

Dr. Nickerson [0:38] 

很棒,很棒。 我没想到这一层。 太赞啦!

Peter [0:54] 

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,我们希望更深入地研究优秀科学家们及其工作背后的灵感和动机。让我们一起来到Gastronauts播客:探索科学家们的肠道情怀。

在首期播客中,我们非常高兴邀请到亚利桑那州立大学生物设计学院的Cheryl Nickerson博士。 Cheryl的研究重点在于太空、微重力和物理作用力对细菌和细菌病原体的影响。她曾与NASA(美国国家航空航天局)合作,在航天飞机执行任务时携带了细菌,并且研究了这些细菌在外太空条件下的改变。 Cheryl,欢迎您。

相信您从您的研究中获得了很多成果,我想问您的第一个问题是,什么吸引您进入太空领域的呢? 您如何决定将太空环境用于细菌研究?

Dr. Nickerson [2:24] 

这是个很好的问题,我以前也同样问过自己。 对了,顺便说一句,谢谢你们邀请我参加本期播客。 这是一个你永远不知道自己的生活会走向何方的故事。当时我在研究生院攻读微生物学博士学位,当我读到最后一年的时候,有个新学生加入这个项目,他那时已经获得了德克萨斯大学的工程学学位,而他却来攻读微生物学的博士。 我们很快成为了好朋友,我也立刻被他如何将微生物更多地看作是回路(这种思维方式)而着迷。 他总是像工程师那样进行分析(思考)。 而我对微生物却有完全不同的看法,因为我有传统的生命科学背景,并且(都是)信号转导机制。 这都非常复杂。 并没有100%的黑与白,而是一个灰色地带。而他非常注重数学。

直到今天,我们一直是很好的朋友。 我们一直在合作; 一直共同发表文章; 我们也一起拿到了项目资金。长话短说的话,在博士后期间,我开始在细菌病原学领域任职,主要研究食源性病原体沙门氏菌,研究它如何与人体肠道细胞相互作用以及它如何与肠道样动物模型小鼠相互作用,引发疾病。 而他去了美国宇航局约翰逊航天中心,开始在他们的微生物学小组工作。从而他参与了国际空间站航天飞机中空气和水系统中微生物的采样。 他是一位出色的微生物生理学家。

随着时间推移,他现在成为了约翰逊航天中心微生物学的负责人。而我在博士后阶段之后,掌握了细菌,尤其是肠道细菌病原菌的发病机理,并且知道如何培养肠道细胞、感染小鼠从而研究肠道与病原体的相互作用。在我启动了第一个实验室一个月后的一个晚上,也就是我在新奥尔良的杜兰大学医学院任职的第一个职位,而他在美国宇航局约翰逊航天中心(NASA JSC),他在电话中对我说:宇航员在太空中(开始)免疫力下降。由于我现在的专业专长是传染病,我说,稍等片刻,因为这只是感染后是否会患疾病的一半方程式。仅仅因为你被感染并不意味着你会罹患疾病,不是吗?它取决于病原体的毒力,病原体的剂量以及你(身体)的免疫反应。因此,你要知道太空飞行对该方程另一半的影响,即免疫反应。您知道些什么吗?(或者)是否有人知道航天微重力环境对病原体毒力能力的影响吗?

其实,没人知道这一点,所以这就是合作的开始。 我们进行了基于地面的实验,这些实验有力地表明了太空飞行(中的)培养可能会影响病原体的毒力、应激反应及其基因表达。从而(我们)进一步进行了多次太空飞行实验,这些实验进一步表明并证明了微重力环境太空飞行确实增强了病原体的毒力。这种病原体的确改变了它的基因表达,并且改变了它的应激反应。 我们将这些发现用于许多不同方式的机理研究中:我们发现,在航天中,其他细菌病原体可以使用与沙门氏菌类似的信号传导机制,我们也找到了在飞行中关闭毒力增强的方法。这也引导我们在相同种类的物理作用力下进行了三维细胞培养。

Peter [5:49] 

在我看来,这些(灵感)很多都是您与完全不同领域的科研工作者一起工作而产生的。曾经研究过工程学背景的人正在从更数学的角度思考系统的功能,而您的加入,带来了您在微生物学和毒力方面的专业知识。这似乎是一场完美的(头脑)风暴:他在NASA任职;他研究了宇航员的免疫反应,然后您对细菌有所了解,并且知道如何使免疫系统与细菌相互作用,这对于我们了解人类健康的未来发展至关重要。我想和太空开个玩笑。您是如何决定“啊哈”(关键)时刻的呢?就像,这就是我要走的路?您有什么顾虑吗?您是否因为微生物不在太空中频繁研究而对微生物发病机理方面有所顾虑呢?(例如)我没想到能将这些微小的微粒(微生物)送到太空呢?您是如何坚定这种信念,决定研究空间(生物学)的呢?

Dr. Nickerson [6:48] 

首先,我要感谢美国宇航局为这些研究所提供的经费资金。 因为我一开始是向NIH(美国国立卫生院)提出了这些研究(项目),我想,当时这项目已经超出他们想要资助的范围。 所以我要谢谢他们,因为这促使(我们)进行了一系列卓有成效的实验,这些实验已转变为现实,不仅对飞行中的宇航员有益,减轻他们的传染病风险,也与地球上的(生命)健康直接相关。 一个完全符合逻辑的问题是:为什么-我和我的同事们都知道-为什么在世界上,谢丽尔(Cheryl),你会认为你将通过在微重力下进行微生物学来学习某些新知识,或促进传染病的某些方面呢? 我的意思是,(这种情况下)生命没有进化的吗? 对于地球恒定的一种力量就是重力。

这是使你思维受到限制的逻辑方法,而我的大脑则受到了不同的影响。 因此,我对自己说,当大大减弱自行星诞生以来一直存在于地球上的一种力量时,你为什么不去学习有关生物系统、微生物、人类细胞的新知识呢? 生命在单位引力的作用下进化,而我们对其他的一无所知。 为什么我们不思考一下,当大大减弱这种力量时,这些与健康或疾病相关的新兴表型特性是否可能会出现呢? 我们了解到,当我们研究极端环境下细胞和生物系统的反应时,我们会得到更多信息,也会得到更多有关细胞如何进化、适应和反应的机制。 对我来说,太空飞行只是下一个极端环境,其潜力才刚刚被挖掘出来。

Peter [8:33] 

这我十分感兴趣,尤其是作为一名正在发展的科学事业的年轻人:在不了解将要发生的事情的情况下开拓未知领域时,我想在进行研究时肯定会遇到很多困难。 当尝试纠正一切错误之后,你的结果对你来说还是变得毫无意义,这很容易使你陷入困境,并且有时会失去(前进的)动力。 我想知道,在这些困境中时,您是如何继续激励自己的呢?在这种情况下,您又是如何激励您的学生和学弟学妹们的呢?

Dr. Nickerson [9:08] 

首先,你必须要有一点点反抗(精神)。而且,当每个人都告诉你(停止)时,你必须要有反抗。每当你开拓创新,进行范式性变更研究,发现别人未曾见过的事物时,你都会听到很多人说“不可能”。没关系,(要学会)拥抱不可能。事实上,我是一个喜欢听“不” 的人,一开始并不喜欢听,你写的项目书“不行”,您发表文章的手稿不行。没关系。 如果你不能听“不”,也就无法在这个领域中解决“不”,那么这个领域就不适合你。“不”激励了我,因为我知道我们正在做的工作是极好的,因为我了解这些团队-我了解我的团队,我也了解我的实验室,我知道我们与之匹配的团队都是优秀的科学家。这并不意味着我们的每个假设都是正确的,这些假设可能是对也可能是错的。我们知道我们的科学(问题)是好的,并且我们相信自己所做的事情。我们相信我们的科学;我们相信彼此。而且我们知道我们(走)在正确的轨道上。

我保存了每份手稿、每份项目资助书中的每份拒绝意见,而从早期开始我就有两份。我不会告诉你他们来自什么资助机构。有人说,我们有单层,我们不需要3D组织模型。你对3D组织模型的细菌发病机理一无所知。好的,我们可以将其从清单中剔除,因为这只是激发您的动力,不是吗?所以在我们帮助诞生了这个领域的20年后,现在这成了一个非常热门的领域。这很棒!但是科学需要时间。这就是所发生的。我们提交的第一个项目经费申请书是研究:细菌在摇瓶中以350 RPM的速度生长和与在实验室静态生长(这是大多数人培养细菌的方式)的相对比时,生理流体剪切力如何将细菌完全重新编码的。我也收到了第一封拒绝信。它说这项(研究)是不合理的。没关系。现在,传染病的力学生物学已成为一项很酷的研究,这是一件令人兴奋的事情,而且这很好,[接受]拒绝信是关键。如果您保持专注、下定决心并坚持不懈,您最终将会成功。您必须有胆量去进行那场战斗与大火相抵抗的战斗。然后你付诸行动。

Peter [11:17]

真的受教了。 (要学会)接受“不可能”。

Dr. Nickerson [11:23] 

其实您不必一定要喜欢它,这只是来激励你。 最终益处的是,你可以让所有这些兴致勃勃的年轻科学家们产生新颖且有创意的想法。 我从我所敬仰的一位科学导师那里学到了非常重要的一课。我总是会告诉我的学生,她所说的一句话。 她说:“不要自大。 因为当你以为自己什么都知道而其实不然时,狂妄就杀死了你的好奇心。”我认为这是一个美丽的陈述。 每个科学学科都有很多东西要学习。 有许多新现象需要被发现。 一个实验室,一个课题组,一个团队不可能全部拥有它们。 每个人也都有自己的空间。 那么,要接受这点,不要认为你已经学到了一切。 因为这是不可能的。

Peter [12:31] 

到目前为止,您告诉我的所有内容都很有意义。 科学是在有趣的情况下完成的。 我认为,始终要根据前后因果来实现-我们想看看我们可以创建什么样的环境来给(所研究的)系统施压,然后看看会发生什么。但是我很想指出的一点是,当有人打电话给您并说太空可能很有趣以及它如何影响细菌时,您的第一反应是什么呢? [是刚好]恰逢时刻出现在您的脑海的呢?或者,(您想)这(刚好是)我可以融合在一起的东西的呢。

Dr. Nickerson [13:00]

使用微重力平台来研究/鉴定新的生物学特性、现象、细胞反应、分子/遗传表型的整个概念对我来说似乎并没有不合理或惊讶-使用微重力平台来做研究似乎非常令人兴奋。但是你要知道,这可能是错的。 我们可能发现不了任何差异。 当我第一次获得用于资助这项研究的项目基金时,对我来说这并不是关键时刻的到来。 而当我们拿到结果并分析数据陷入僵局时,关键的时刻才真正到来,因为那才是真正令人激动的时刻。

我们能够模仿某些在微重力条件下发现的现象,并采用一些特殊的方式在类似于某些地面微重力的条件下培养细胞。他们虽无法模仿一切,但可以模仿我们在飞行中的一些关键发现。所以我们知道这不仅仅是一些现象-我们首先非常兴奋,因为我认为,哇,我们将帮助宇航员保持健康了,对吧?我们对此感到非常高兴,谁又不会呢?但是,当我意识到细菌随着引力变化而更新或进化并不合理时,这对我来说就没有意义了。我是说,这(种现象)对我来说并不合理,这种力的变化必须类似于他们在地球自然生命周期某个地方遇到的另一个物理环境。因为他们演变成这样是不合理的。事实证明,我们的证据表明它们并没有对重力减小做出直接反应,而是直接对减小流体剪切力做出反应,其程度与它们在组织中遇到的程度非常相似。当它们影响我们时,对我来说,就是一个关键时刻。然后,我们意识到,哦,天哪,我们在微重力平台上所发现的可以转换回此处,以帮助你我(的研究),也因此我们不必去太空(进行研究)了。然而我们基本上是在揭示病原体感染我们身体时可以做出的反应,我们并没有发现其他方式。因此,现在,我们已经开发出包含人体组织结构的三维肠道培养物。它们具有在肠上皮细胞中发现的多种细胞类型。他们有丰富的(肠)黏液。它们有顶部和底部。他们被很好的两极分化。当我们将免疫细胞放入其中时,它们可以显示出更多体内对感染所作出的反应。因此,我们的目标是使这些肠道模型越来越像体内的物质。我们既从研究细菌病原体如何响应生理流体剪切力的角度出发,又利用这些相同的力在体外开发出更多的有缺陷的患者人体组织模型,以研究宿主病原体的相互作用。这可能会致使但我并不保证一定致使研制出疫苗或其他新型疗法来帮助人们。

Peter [15:50] 

这是一个非常有趣的观点。 我想我将需要些时间来消化一下。 我想知道,您认为未来十年太空科学领域和微生物学领域的发展方向是什么呢? 从现在开始十年后您想看到实验室发展到什么程度呢?

Dr. Nickerson [16:06]

这又是个很好的问题。而我敢肯定,不同的人给你的回答是不同的。最终,我认为最重要的任务之一就是摆脱动物测试。我们必须在实验室中这样做,因为我们始终无法感染人类而且没办法(直接在)人体中测试一切。我们必须有更好的更具预测性的替代模型。而我认为我们可以实现这一点。顺便说一句,许多课题组正在取得长足的进步,做着我们未曾谈论过的事情,利用细胞来发展人体外部的人体组织和器官,这些细胞将具有功能性并100%预测你对病原体的反应方式。尚无人能100%预测,但是我们在实验室中做到了。其他正在做此研究的实验室也为人类提供了越来越多的预测模型。对我来说,这是我们必须解决的主要问题之一,这些领域也正在朝着这个方向发展。但是,这需要生命科学家、工程师和物理学家的跨学科团队合作,而这就是现代科学的运作方式,这很棒。我们的团队,您的团队正在执行此操作,因为没有人可以成为懂得一切的专家。当你采取这些多学科的方法来解决此类问题时,我们看到的是-我们看到了以新的方法来更好地解决或帮助理解病原体感染人类时的作用。他们在必须感染的整个微生物组的背景下做什么?他们是如何用物理作用力做到这一点的?他们又是如何在健康和疾病中做到这一点?我们又将如何建立更好的人体模型、人体外部组织和器官模型来概括我们体内的每个生物、化学和物理因素呢?

Peter [17:50] 

我从您刚才提到的内容中概括出的一件事是发现如此关联密切的事物,并将其与人类健康联系在一起是不可思议的。 我对您在讲话中表现出的热情,您在对话中的热情感到敬畏。那么,我想知道,这种热情真的会激励您吗? 您觉得它是自然而然的吗? 还是,您必须真正等到关键时刻才有呢?

Dr. Nickerson [18:12]

我一直说,(要)绝对自然。如果我不是绝对喜欢自己所做的事,我会心跳加速。我对自己对科学学科和领域的承诺充满激情。它驱动了我所做的几乎所有事情。我很高兴在实验室工作的团队成员的内心深处也是这样的。那么,是的,我们住在实验室外,但我们喜欢睡觉和呼吸,因为我们喜欢它。你的思维中必须有那股热情。当你找到对的事物时,它会激励你早晨起床,你迫不及待地要想出下一步的方法。这一直是一个难题,需要解决。激情就在那里;我们以它为食,我们互相激励;我们以发现为生,因为归根结底,离开这个世界要比你在这里时好一些。如果有我们的发现,我们的任何工作、任何研究,都意味着可以得出更好或新颖的方法来对抗、治疗和预防传染性疾病。这就是我们正在学习的方法。

Peter [19:22] 

谢丽尔,我们的谈话有了非常振奋人心的结尾。 非常感谢您成为Gastronauts 播客的第一位客人。

Dr. Nickerson [19:29] 

我很荣幸,谢谢你们的邀请。

Peter [19:43] 

Nickerson博士给我们提出了很多建议来(让我们慢慢)消化,这是第一期的结束方式。 但真正让我领悟到的是接受不确定性与接受挑战的重要性。 我们永远不知道最终将要到哪里,或者世界如何看待我们的科学。 因此,找到您感兴趣的东西并为之奋斗。 非常感谢您的收听,我们下期再见。 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。

Episode 9: Beyond the Hypothesis (Transcript)

Peter  0:00 

What are your thoughts? What are you feeling right now?

Dr. Clevers  0:02 

I’m on a tropical island. Sweet, sweet fruits. Very relaxed. Enjoying the sun doing nothing.

Peter  0:12 

So what it was, was a gummy worm. The reason why I picked the gummy worm and I like your interpretation of it. The reason why I picked the gummy worm is because it kind of looks like an intestine with its ridges and I thought that was really interesting that they put the effort into making these ridges into gummy worms. Why not just make a smooth surface …

Dr. Clevers  0:30 

Can I have another one?

Peter  0:44 

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.

Today, we have Dr. Hans Clevers, the director of research at the Princess Máxima Center for pediatric oncology and a professor of molecular genetics at Utrecht University. For those of you who study the gut or use organoids in your research, he needs no introduction. Dr. Clevers was the first to discover stem cells in the intestine and that the disruption of a downstream effector of the Wnt pathway, TCF4 abolishes stem cell crypts. He also showed that activating Wnt mutations underlie the development of colon cancer. He developed the first organoids through culturing living stem cells in the intestinal tract and has been awarded the Louis-Jeantet Prize for Medicine, the Breakthrough Prize in Life Sciences, the Heineken Prize from the Royal Netherlands Academy of the Arts and Sciences to name a few and has authored over 600 publications with over 100,000 citations. We really appreciate you taking the time to be on our podcast, Dr. Clevers.

I want to start by discussing your scientific journey. In hindsight, it is always easier to explain a career decision as planned; however, you have been very open about your initial thoughts on pursuing a career in both medicine and science. Can you take us through a few different big-decision moments in your career and what went through your head and what helped you make those decisions?

Dr. Clevers  2:48 

Yeah, so I’m actually 62 so I’m not the youngest anymore. When I was a young kid, I already knew that I was going to be a scientist. I was interested in biology. I read all the discovery stories of Africa and the bulls. And so when I was 18, in Holland, you go to university at 18. I picked up biology and was actually quite disappointed because it was still […] 19th century science, very descriptive, lots of Latin names, taxonomy, very little [instruments or] tools that you could do much with. Because this was [1975], this was just before molecular biology, DNA technology was just being developed and spread around the world. So I then also went to medical school. I completed two studies in the course of my master’s in biology. I spent some time at NIH; I spent a year in Nairobi, and that’s when I started learning about monoclonal antibodies that had just been developed, and about the first gene cloning experiments and I realized biology is probably going through a revolution now, but I also liked socially the medical environment, […] the clinical environment much more than the lab environment In labs, you’re locked up with a few people that you have selected. It’s much more social- you see the entire population of your city combined, all the young, poor, rich- you have nurses, you have the doctors, you have the students, you have the patients. In a lab, it’s 10 – 15 people, always the same. But so I then got a training position, pediatrics in Utrecht. They asked me, well, because of your double background, why don’t you start some research and you can do a PhD, which we don’t leave University with a PhD, we leave with a masters. So I started some research. And in that year, I realized although socially, it’s not always the simplest environment, really I’m a scientist. I’m not a doctor. And I then gave up that training position, wrote four papers on a project that I designed myself entirely, and didn’t end up in the biggest journals. Also, I was an immunologist. Essentially, I wrote two pairs of papers: on T cells and I repeated the exact same thing on B cells. And that already I think people started looking at me, “how can you be interested in T cells and be interested in B cells- you have to choose.” And that [is] something I I’ve learned that you don’t have to confine yourself to, to a discipline. But then I also realized I had to learn molecular biology from scratch. And I got a postdoc position in Boston in a lab of a Dutch PI, Terhorst. And I learned to clone TCL genes, and I was still a molecular biologist. And that is when I although was a tough time: 4 years. In the end, it worked out well and that’s when I realized this was the right decision for me. I’m a scientist. I find hospitals fantastic places, […] also the patients are better off if I’m in the lab and not with the patients.

Peter  5:47 

Yeah, so you mentioned- I know this is a while back at this point, but you mentioned that other people in the clinic and mentioned maybe you should go into research. Was there any hesitation or reservation thinking that, “oh, if I leave medicine now, I won’t ever come back to it at that time.” I think now you certainly have established yourself as a scientist, but at the time, did you have any concerns?

Dr. Clevers  6:06 

It was a real decision point for many reasons, but one thing is that the medical profession is a hard profession; it’s not easy. You have to be able to work hard. You have to be social. You have to be smart. But what I could see is that most doctors that would bring this with them, have a nice life, they have a good career. They work hard, but everybody understands what they do. There’s not this hierarchy, you have a few top doctors and then all sorts of other levels of doctors. There’s not this constant competition that you have in science. On the other hand, I knew that I am a scientist that says. Im not really sure I’m going to be a successful scientist, but that’s where my passion is. So I actually sat with my father for quite some time and asked him for advice. He said, it’s your decision. That’s if you if that’s where your heart is, go there. But it’s extremely risky because a career in science is very unpredictable […] As a doctor, you know, by the end of your day, you know, whether you have the skills to be a good doctor. As a scientist, even after a PhD or a postdoc, you don’t know whether you have the skills and the luck and persistence to be a PI and everything with it for many, many years because it’s just very hard work.

Peter  7:17

So when do you know that you have the stuff to be a scientist?

Dr. Clevers  7:20

Well when we first started discovering things [that were really just] small but were important. I was probably eight years into being a PI when I realized that we’re now doing things that […] people find interesting. And it was luck. So we’ve apparently made a few choices of where to go with the with the science, but it might also have not happened. And there’s also if you’re too long without a significant new insight, that is the end of your career, even if you’re as good as somebody else who did get an insight and got this boost to the career.

Peter  7:57 

But you mentioned earlier that people were telling you can either be a T cell scientist or a B cell scientist and you saw this not true- you can always pivot your research in the direction that you want it to go. Could you elaborate or unpack a little bit more about that?

Dr. Clevers  8:08 

Yeah, I can maybe describe the trajectory of my lab, which is very abstract. It’s because almost everything we did failed, and I forgot about it, but my [early] people actually know all this, because they went through that. So we started as a lab that wanted to find transcription factors in T cells. And knowing that these genes, although the genome was known in the late 80s, at all was still a decade away. But we knew that transcription factors are very important for cell decisions. And so we cloned a few amongst them, [and one] was a gene called TCF1. And then it took about five to six years until we realized that this was a crucial transcription factor, but not so much for T cells, but for early development in any kind of animal. It’s part of the Wnt pathway. So then I basically changed my lab from a molecular immunology lab. We had fruit flies, we had frogs, all these in collaborations. We have zebrafish, we did lots of mouse genetics. And then we finally hit on this link with the gut. And then I again converted my lab from a developmental model organism lab to a gut lab and we had to get to know somebody who knew histology and paraffin sectioning.

Peter  9:19 

Do you have any hesitation with making that switch?

Dr. Clevers  9:21 

No, it’s part of the personality of me, but also you sense that the lab around you starts to, I don’t know how that works, but has the same personality as yourself. I don’t know whether the lab programs me or I program the lab, so as long as the technologies around it doesn’t really matter if you need DNA sequencing. It doesn’t matter if it’s a zebrafish, or yeast or human cancer, sequencing is sequencing. So we’ve always been going in areas where we at least knew that we have mastered the technology and then the biological questions in the end [everything that] we’ve discovered is always simple. So there’s a few things if I can, if I look back, because I’ve been doing this now for 30 years, that have been very well for us. One is no fear [and] an enormous amount of trust. And that’s what I learned from my PhD advisor. So you can trust other scientists, you can share unpublished information you can, and you always get more bang [for your buck], because if people trust you, they are easy collaborators, they will help you when you need them. And it’s more fun. So there’s a lot of paranoia in science, which I think is sort of self-fulfilling. Because if you’re paranoid about your neighbor, bad things will happen. And if you’re open to your neighbor, that’s one thing. So trust, and courage so you can make a difference in somebody else’s discipline. If you bring in the right technologies and a good way of thinking, you can actually make a discovery. You have to have good collaborators to protect you from stupid mistakes, but also introduce you into that community. We’ve done that a lot. So we’ve written on fruit fly genetics on zebrafish genetics on the highest level journals, but always with a collaborator in that field that had helped us. And then one thing that I’ve often said is, I strongly discouraged my lab to formulate hypotheses. Now this is not how science is supposed to work. So my strong sense is if you enter a field where little there’s known and where you don’t really know the questions, you can ask. So don’t ask strong questions that are looking for strong answers where you already know the answer, because that’s your hypothesis. Just be open-minded, go into experiments, build a robust experimental system, and just watch. Watch and watch and watch. And then the human brain always immediately comes up with solutions, which other hypotheses, but you can sit down with a number of smart people and come up with 1000 solutions to your problems that could all be true. And evolution has picked one randomly. So why would your brain- I think it’s very arrogant to sit down and formulate a hypothesis in a field where you know nothing. And the human brain also works in that way that once you have your hypothesis, you will publish the hypothesis. You’ll find the evidence that it’s true. And that’s I think, where many non-fraudulent but papers are produced that turned out to be wrong, because in that process, you lose your open-mindedness. That’s not how our brains are comfortable to work with. So that’s something that I see a lot in my lab and somebody says, experiment fails, I say, “why? Did you drop it on the ground?” No, no, no, because you know, this is the result I got, and I should have gotten this. This is because you have your hypothesis. Get rid of your hypothesis and look at the results with an open mind […] So I think for discovery science, this is really the way to go. You cannot write grants, you cannot write papers [in which] you refuse to work with hypotheses, but it’s for me at least has been the most productive way of doing this. I guess a more applied science like in clinical science where you have to have a strong question and you have to have a hypothesis and there’s only a few answers: a drug will or will not work. So there it works. But for this open end where, you have no clue what you’re looking at and what the processes are, the hypotheses will blind you rather than help you.

Peter  13:21 

Yeah, one thing that you just said that really resonated with me was the fact that our context really biases our hypotheses. Where we are situated in a particular lab, or where we are in the world biases or informs our decision on how we approach science. And this is why it’s important to have collaborations with people who have different viewpoints than your own. In an era where communication internationally is just a few clicks on your computer away, what do you see the value in, in these large […] scientific organizations or societies that bring people together for an international conference? And if you were in charge of one of these conferences, how would you run it so that you would have effective communication?

Dr. Clevers  13:58 

That is a very good question. So for me, personally, these meetings [where] I’m a speaker, I have good access to the other speakers. So that’s where I get my information from. That’s where I build my, my networks, my collaborators. And that’s where I hear about the newest technologies about who to trust, who not to trust, what works, what doesn’t work. I rarely read papers. So I don’t read- I read Nature and Science but not the second or only the first part about the political things. So because we review a lot of papers so there’s a source of information so […] I would advise anybody you know, [when] you get asked to review, review. Because it gives you connections with journals; you learn a lot you learned before it’s appears half a year later in print. And so that’s for me, and I guess for many people, the face to face is still very important and Skype works well once you know people and you collaborate, so it’s a very good way of collaborating long distance. I guess for young people, it’s these larger meetings really, for me when I was young, you get a very good sense of who’s who in the field, you know what’s happening? What’s the general thinking, you know, what is the argumentation in this field? Or do people like or don’t like? Where are the open questions? On whose toes will I step if I say this? […] so I’m not really sure what I would do if we would organize meetings- I spend lots of time in meetings. I would organize them very differently. I would have more young people into podium. Shorter talks to basically get them exposed to, to communicate to audiences. Yeah, I think they get-togethers like large poster sessions with free beer work fantastically well. But the face to face at least for me, I’m not from the millennial generation, is very important. And many of the papers that that that we’ve written often result from talking to someone, get a good idea together, work it out together and you create a lot of friendships along the way as well.

Peter  16:15 

You talked about […] not stepping on other people’s toes, but the value of a lot of these conferences is to know who’s in the field. I saw recently that you tweeted some classic images from Lieberkühn’s thesis regarding the structure of the gut, and then some of Joseph Paneth’s pictures of the Paneth cells. I was wondering what drew you to these pictures in particular and what about these scientists encourage you to tweet about them?

Dr. Clevers  16:36 

Yeah. Well, so of course, these two have written extensively about guts and Lieberkuhn, who lived in the 1700s was German but worked in Holland did a PhD, which my students were very happy to read that it was only 32 pages. But then I could point out this actually written in Latin, so… well as a as a medical student, I had a very good memory, which isn’t so good anymore. But there’s many structures and diseases and phenomena that have a person’s name attached to it […] and nobody ever knows, you know, [for example], who was Merkel? And so I’ve made it a bit of a hobby to try to figure out, you know, who was this person? Why, and often they’re not the first discoverers, but for some reason they were the most visible person. Actually between Europe and the US, there are differences; like Kahler for us is multiple myeloma. Now I don’t think the US uses Kahler’s disease for this, but it was discovered by a German called Kahler. So I’d like to dig up these […]  just a hobby, and to find something that’s 300 years old, and it would be sitting in a museum and nobody knew what it was. So I found this thesis and then I realized this is really good.

Peter  17:50 

Do you encourage your graduate students to go through and the history of science as well?

Dr. Clevers  17:54 

Not really. So what I do a lot with my graduate students is discuss the process of science, and all the different decisions you take and what information is true, everything published, and doubt what was published. And so that I do a lot. I try to create a culture of interrogation and also try to explain that when you argue with somebody or you criticize or you have remarks about the work of somebody, you’re not criticizing the person, you’re criticizing something that the person says because it feels very personal. When you the paper gets reviewed, you see the review report, it hurts when it’s negative. But the process intended not to hurt you, but actually  say something about the same bit of work that you have. So that’s something is that I do a lot with my students.

Peter  18:45 

If you could travel back in time and have a conversation with any scientist, who would it be in what would you talk about?

Dr. Clevers  18:51 

Yeah, there’s a guy, Leblond, who is my personal hero, who is I think, originally French [and] migrated, because his wife is Jewish, migrated to Montreal in Canada, French Canada, and was still an active scientist at a very high age when he was 94-95, actively engaged, and many of his original discoveries [were] when he worked in the Curie University in Paris where radioactivity was discovered. So he learned how to use radio labels and he started applying them in biological systems. He saw the first label DNA, the first to label protein, the first to label sugars. Essentially, I think, he discovered stem cell hierarchies by showing how labels travel through the skin. For instance, he was the first to show that all cells make protein- quite a quite a spectacular finding because people believed that the liver makes all protein and the rest just take it up from serum. He was the first to show the ER Golgi secretory pathway. So he could have earned three, four Nobel prizes. Those papers are published in journals and were repeated later and several people got Nobel Prizes [for this work]. He’s always a bit a bit neglected. I don’t know why. But also everything we published about the gut stem cells. After the fact I found out that he had published sort of theoretical papers that predicted everything. So this is like a string of maybe 10 Nature, Cell, Science papers, we can now safely say after they have published that they were not original, because actually Leblond, CP Leblond had already published the hypotheses.

Peter  20:27

What would you like to ask him?

Dr. Clevers  20:28

What would have liked to ask him? I think, how his findings relate to disease, the various diseases of the gut. He doesn’t say much about [his views] in his papers. But it’s clear that he was a pathologist. He must have been looking at all of these structures from a pathological point of view.

Peter  20:47 

I think that’s fascinating. And personally, I like to get to know the scientists behind the science and I know a lot of times for people who are key figures in the field, they publish books, and we really like to know what their frame of mind is or what their reference and viewpoints are, but oftentimes when we’re judging the science currently in when we’re reviewing […] some article during a journal club, we […] dissociate the scientists from the science and I was wondering, at what point do you think we should look at the context that the scientist is working in when we’re evaluating their work?

Dr. Clevers  21:20 

I think always. So my thought when I started science was this is this is an extremely rational activity that you know, you sit, you’re smart, you design, you test, that’s how you define hypothesis, you design experiments that would contradict what you’re thinking and you would re-formulate your hypotheses. Over the years, I’ve learned that in experimental biological sciences that’s not how it works. I think 80-90% of what happens leading up to a discovery is random events between people. It’s characters of individuals, and eventually when that turns into a potential discovery, then we go into this mode that people think scientists always do. You become very rational you do your experiments you do your controls and this and that and then you write your paper as if you would always be looking for that particular phenomenon which you basically stumbled across it and you interpreted it well. So I think that first 80% that’s the biggest difference between people who constantly make discoveries and people who are extremely smart and know everything but don’t make discoveries that […] actually in this process of searching, stepping into dark [and] changing opinions, talking to people, hooking up with people, that that is where the discoveries really arise and then once use you see the light then you switch to this mode and that is the second part is you can learn. For a doctor there’s much more of the second part; so if you’re a clinician a lot of what you do once you know, it is this disease then you do this and these are the tests I do this how I follow up. For us is much less so, in basic exploratory science. So the context of a person that contacts you know why this person all of a sudden switch from this model system or that model system? What happened in his life that he meets somebody? Did he do that? That is that is crucial if you want to really, it would be good if you could make the discovery process more efficient, because we waste most experiments, as everybody knows, end up on the floor. And if you could make that process more efficient, that would be fantastic. So I’ve been talking a lot to colleagues knows more senior scientists who have made discoveries and they also don’t know exactly how this works. And it would be great […] but a lot of it is in the social interactions in the unexpected ideas that pop up because somebody says something, you make a link with something you’re thinking and all of a sudden there is an answer.

Peter  23:49 

I think that’s a nice way to paint it because a lot of people who aren’t in the scientific field think it’s a very isolated process. You’re working on a project you’re kind of hitting your head against the wall, kind of racking your brains but you need to reach out to other people and communicate with them to see if they have some other framework for you to think about.

Dr. Clevers. 24:04

Exactly.

Peter  24:06 

I also noticed on the other aspect of your Twitter, you posted a couple of animations or videos. Could you tell me a little bit about what got you into using videos or animations to explain science?

Dr. Clevers  24:18 

Yeah, so I’ve always I used to draw a lot as a kid. I collect art paintings. And so I’ve always been drawn by the visual. So stepping back I learned how to write papers over the years and what I used to do for a long time, so I spend endless amounts of time on the title and the summary. And if the title and the summary don’t draw attention, build up some tension and resolve. The storyline of a scientific paper is extremely important. And if you cannot write up your story in 125 words, which some of these journals [require], then there’s something wrong with the stories. There’s two stories or there’s only three quarters of a story or the order is wrong. If you cannot produce a 100 character title that has the message and draws attention has all the keywords, there’s something wrong with what you’re trying to communicate. So that I knew that for a long time. Then I got into contact with this guy who was, I think a physics PhD student, and he never graduated. He had this extreme talent- I think he uses the Pixar software. And the way we started working together is whenever I thought, we have a really nice discovery, I will do my title, my summary and we then try to write a script, they have a one minute audio, video animation video. And he would look at it, we talk he said, Well, this doesn’t work, and then he would turn it into so he gave a lot of images. Now what does this look like ? And he asked how many cells are there? How fast the move? So really, a lot of this is really correct modeling in these as many 40 or 50 animations now. Then he makes a cartoon of how we think the animation should go. And then we’ll go back and forth. And then I’ll say, well, that’s not what I said. Then read your text. This is what you say. I said, well, I meant something else. Yeah, so text is very ambiguous. And it’s clear that to listen to people talk or to read, particularly to two people talk, you get tired and lecture can last 45 minutes, but then it’s done. So and part of it, I think, because it takes a lot of brainpower to interpret what the person is trying to communicate. So once we figured out, okay, this is what I mean and okay, now I understand it, then he would make this movie and then it will be back and forth. And then when the movie is there, all of a sudden, everybody who watches the movie is effortless. They just look at when I give talks- I have many but often what I used to do is I would first show the experiments and summarize in the video, but I didn’t realize what works much better is if I first showed a video, people know the story and you see it and it’s the moment that it moves, people sit up, and they watch and it’s effortless to enjoy. And it’s artistically well done. And then I just showed the slides that show the evidence for what I just said. So you can say show, much more in 45 minutes you could ever do if you’re just talking and showing static slides. I also see when it’s playing- I speak a lot for lay audience like politicians or an artist [or] journalists, and the moment it moves, everybody pays attention. So the more I have movement on the screen, the easier people find it to just stay with me and I can communicate much, much more information through these visuals and they could ever do. Probably the people who are in in animations probably know this, I just discovered this. And the way they are made […] originally, they were made for scientific audiences. But it turns out that it works [for] any lay person with some education, know what the stomach looks like. You zoom in, they know what they’re looking at. They know more or less what a cell looks like […] so they understand immediately. The enjoy the aesthetics, they would not enjoy the aesthetics of a table. So in papers, I have very few tables or blocks […] You want different kinds of variables in the paper, and definitely colorful ones. You don’t want just numbers or lines.

Peter  28:20 

Do you feel like working on these animations has influenced how you write your papers? And is there kind of now a different type of structure or some principles that you follow when you’re writing?

Dr. Clevers  28:29 

Yeah, so this is writing this script, but it’s a bit like writing a summary but at the same time, you have to it’s not only the summary where you have you know, 10 sentences or so of a paper but you also have all the support that you would have that you use the entire paper for. So animation essentially captures everything that’s in the paper in one minute. And so I must say that I now find myself thinking, is this story ready to be submitted? Is a complete? Is it exciting? Will people like this? What is the real message here? When I think through the eyes of the animator, I get a much better sense of you know, what we need [is] a single message, we don’t need three message. We don’t need […] to prove five times what we know is true. We just show it once. And then we have all the backup evidence if needed. So to make a sort of an abstracted, clean, aesthetically pleasant representation of the work that I think in these animations works best.

Peter  29:27 

Really neat. How do you feel like how you frame a picture has influenced how you think about questions in science, when you’re doing this animation, you need to have this kind of viewpoint or this needs to be zoomed in here. Does that affect how you think about when you’re conversing with other people about their science? Like, oh, should we focus more on this part of the scientific process?

Dr. Clevers  29:47 

Yeah, sort of? Well, there are what you’re asking. There are several questions that have arisen in the process of making these animations because, like where cells come from where do they go and why? Why does this go there. So when you visualize the process you’re looking at you actually, you note the holes in your knowledge? Well, we’re not looking at this at all, but it’s a big issue because we don’t know where the cell will go next, or why it dies here and not there. So I guess it’s formalizes, in a way, a process of asking questions or seeing where the openings still are, or where the research can go, because literally you can see in these animations, we know this, we know this, but we don’t know this. So we just keep it out of the current animation [and it’s where] we should really be moving the [of] in the lab.

Peter  30:41 

I want to ask one quick question about your lab work. I know you have pioneered the field of organoids. And people are using organoids. And they’re using kind of spheroids, tumoroids. They’re developing a lot of different in vitro systems to model […] high throughput personalized screening of therapeutics. Where do you see the field going? And what do you think the current limitations of organoids are.

Dr. Clevers  31:03 

There are two types of organoids. The type that we developed is based on the stem cells or stem cell activities that are present in adults, in born bodies. And so every organ will have its own stem cell function. And then there’s the embryonic stem cell-based organoids that [built] brain that we cannot do or built our kidney or heart. So we basically use stem cells that maintain or repair tissues, [which is a] very different, very different approach. So for our approach, and I won’t speak for the other field, but for our approach, it is, like the best lab models, extremely reductionist, so it is an abstraction of reality. The original mini guts grown from one stem cell was aesthetically very nice because you start from one cell, it builds a gut. It’s very surprising that’s possible at all, and we still don’t understand much of that process. But is a complete gut, it has no immune cells, it has no muscle. It has no nerves, no blood vessels. So I think the big challenge is now is to, and this looks extremely promising, add additional layers. My approach would always be start as reductionist, as simple as you can. Add one variable, figure out how it works, add another variable and slowly build up the system. There’s a strong tendency with many scientists to say well there’s not a real life this is not how it works; it’s much more complex. And then they add everything together, and reviewers will tell us, you have to add this and that, but then I no longer know what I’m looking at. It’s too noisy. But that’s the style of research. So I thought I see now people are adding the microbiome by injecting and scientists many guts people adding organs, nerve cells, muscle cells, co-culturing […] You can you can have a piece of gut and a piece of brain and see how they communicate so that I think the developments that are currently happening in any place is just adding more complexity and getting closer to what a real organ looks like. Having said that, I must say there have been a large number of discoveries made by many labs in these extremely simplified systems that could then be checked in mice or in humans and patients, and confirmed to be true. So I think the power of modern science has been reductionism to a large extent and these organoids are an ideal model for that approach.

Peter  33:25 

Well, thank you so much for your time, Dr. Clevers.

Dr. Clevers  33:27 

Okay, thank you.

Peter  33:39 

Dr. Clevers shared a few of the things that went through his mind over his extensive research career. And one of the things that really stood out to me was the importance in trying to interpret your results without any preconceived notions. Natural processes are incredible, and it is important for scientists to really appreciate all the facets of the process. When you think you have a handle of these biological phenomena try and portray it as a movie. Use your imagination to piece together your observations and direct your future scientific questions by filling in the missing parts. I want to thank you all so much for listening, and we’ll see you on the next episode. For more of our content, you can follow us on Twitter @gutbrains or visit our website 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.