Episode 3: Debugging Our Memories (Transcript)


Dr. Costa-Mattioli  [0:00]

I’m sitting on an almond tree, [I’ve] been sitting in the countryside in South America under a big tree.

Peter [0:12]

And what do you think the microbes in your gut are thinking right now?

Dr. Costa-Mattioli  [0:16] 

They cannot think because they have no brain!

Peter [0:19] 

So you can open up your eyes now or take the blindfold off. The almond was correct, there are a couple of nuts in there. And the reason why I chose that kind of mixture was because a lot of people think there are certain foods that we can eat to improve our memory. People feel like walnuts are good for memory, blueberries with their antioxidants and dark chocolate have some capacity to improve our memory. But I was wondering how you feel about food being a treatment option moving forward to alter our microbiome or to improve our memory.

Dr. Costa-Mattioli  [0:47] 

I think this is a great option. For centuries, we’ve been discussing the idea of using food to treat a variety of disorders. Now, we are in a position in which perhaps we can use different foods to treat essentially different disorders. So I think this is clearly a great avenue. We know very little, but it’s very interesting. And you know, one of my last point of my website is to perhaps consider the idea to develop […] food therapies that we could use to modulate specific microbial communities in a way to affect the brain or other centers, which are not just specifically brain related, but could improve the quality of life of people as well.

Peter [1:35]   

Really cool. We are what we eat.

Peter [1:52]

Hi, my name is Peter, and I’ll be your host for The Gastronauts Podcast. Here at Gastronauts, we are committed to understanding communication in the body. In particular, how our gut talks to our brain. We will be taking a deep dive into the mind and motivations behind leading scientists and their work, and hope that by getting to know the individuals behind the research, we can understand how different scientists think and why they’re so passionate about their work. So come join me as we explore inner space on The Gastronauts Podcast.

This week, we have a memory expert, who has not only uncovered a pathway that cells use to encode memory, but also discovered specific bacteria in our gut that are capable of regulating social behavior. Dr. Mauro Costa Mattioli’s career path is quite the fascinating one. He studied microbiology as an undergrad at the University of Republic in Montevideo, Uruguay, later traveling to France, where he studied at Pierre and Marie Curie University, and the University of Nantes for his PhD, where he worked on understanding strategies that viruses used to escape immune attack. After completing his PhD, he traveled to McGill University in Montreal to work in Dr. Sonenberg’s lab, where he first got curious about memories, and in particular, the role of protein synthesis in memory formation. So Dr. Costa-Mattioli, thank you so much for being on today.

Dr. Costa-Mattioli [3:43] 

Thank you for having me.

Peter [3:44] 

The first question I wanted to ask has to do with memories- memories are such an integral part of our life; they’re very powerful; they’re the core of our existence and define our experience. Seeing as you’re an expert in this field, could you tell us a little bit about how you and your lab views memory? Is it something that simply stored and retrieved? Or is there a little bit more to it?

Dr. Costa-Mattioli [4:04] 

So […] I am a molecular biologist, and I was interested in the mechanisms which are required to form a memory. And as you pointed out, you know, memories are, you know, essential for survival in animal species, but, you know, it makes the […] core of our identity. So we were interested in trying to identify what are the key components, which essentially make an animal memorize a particular event, which is meaningful. When I joined lab of Nahum Sonenberg at McGill University, we tried to work [out] those mechanisms, which are now they have become sort of the gold standard or key for memory formation.

Peter [4:45] 

Could you tell me a little about these mechanisms?

Dr. Costa-Mattioli [4:47] 

So the major question that we were interested is how a short term memory is converted into a long term memory. And we know that protein synthesis is required for this process. Indeed, this is the molecular process that baptizes a long-term memory. If you were to baptize, what a long term memory has to have molecularly to be long term is a requirement for protein synthesis. But we didn’t know the mechanisms underlying this. And when I joined the lab of Nahum, Sonenberg at McGill University, I thought I was in the ideal place to try to answer that question. And, I decided to switch fields and go from […] virology and microbiology to neuroscience. And we have discovered what appears to be sort of like a switch for memory formation, the mechanisms by which the synthesis of proteins takes place. And if you were to turn it on, now the animals has any has memory, and if you were to turn it off, now the memories actually impaired. In the last 10 years or so, there are many investigators around the world that they have built upon these [findings] and actually reproduce and greatly […] enhance those findings, which they go from, you know, rodents, rats, mice, to even chicks, and hopefully they will make it to humans.

Peter [6:00] 

That’s really interesting. I want to touch up a little bit on the differentiation between long term and short-term memory. How do you explain the difference between the two- is it encoded differently? You did mention that protein expression is important for long term memory formation; how about for short term memory? Is it so much so that […] a buildup of protein formation takes time, and that’s why this is long-term specific?

Dr. Costa-Mattioli [6:20] 

So what we know is that the machinery that gets engaged, you know, have the ability to synthesize a protein, seems not to be activated when a short term memory process takes place. So you could think about in a very naïve way, that in the case of a long term memory, you have these proteins, which are synthesized that will be […] building blocks that will allow now the connections between brain cells to last for a longer time. Whereas in the case of a short-term memory, those connections, you don’t require them to be you know, stable, because eventually […] they will wind down as the time goes by. So the machinery get engaged for a short term memory is different than the one that gets engaged for a long term one.

Peter [7:05] 

So short term memories don’t turn into long term memories, how they’re encoded within the brain are two separate process.

Dr. Costa-Mattioli [7:11] 

Well, short-term memories could be converted into a long-term memory and the […] activation of these protein synthesis mechanisms could take place. So for instance, in some of the experiments that we have done, we have given these animals […] a short term memory training protocol. And because protein synthesis is taking place in those animals to start with, now, this short-term memory can be converted into a long term memory, and vice versa, we can essentially convert a long term memory into a short term memory, if we turn the switch off.

Peter [7:48] 

That’s really cool. [A] couple more questions on […] memory in general, I have a lot of […] experience trying to remember things, and I have difficulty remembering some things that I feel like I should remember. Other times when I’m not trying to remember something, you know, it pops up in my head. But I do feel like I’m better able to remember information when I am an active participant rather than someone who’s passively listening. For example, when I try and explain something that I’ve learned with someone else, like talking through the process helps me remember the information better. Is this simply a matter of […] reinforcement or repetition? Or do you think that there’s an effect of social behavior and its impact on memory? Or do we even have a good understanding of this?

Dr. Costa-Mattioli [8:34] 

We might have, but I don’t have it perhaps. So I’m not sure whether we’ll be able to answer that question. But we know that, of course, when you are more engaged and you are more focused, you are not distracted. So if you were to have a distraction, you know, let’s say the TV on or someone is talking to you on the phone, and you are trying to read a book, the way that information is going to be storing your brain is going to be much less because you know, you have that behavioral interference, and so on. The other thing is that we have memories, which gets stored in the brain very, very effectively, in some cases, even without repetition. [This is] when there’s a very strong emotional component. If you have a very strong emotional component, you know, when we learn we need repetition. It’s practice that makes perfect, right? And that practice, I think it needs to be space, you know, it’s not like you need to wait until the last day to study for your exam and spend all night reading. If you were to take several days in advance, and you read it, you know, several times in a repeated fashion you give it space, you go for a drink and so on… the possibility that information will be stored, we can store it way more efficiently. But for those memories, [where there] is a very strong emotional component, you receive information only once and that the information gets stored, we don’t know very well, how this is taking place.

Peter [9:48] 

Is emotion encoded at the cellular level? Or is it kind of a brain region level? I totally agree that […] more emotional experiences have been more memorable? And do you think that is working on a cell to cell level? Or do you think […] certain brain regions are potentiating signals?

Dr. Costa-Mattioli [10:05] 

Well, we have specific regions, you know, let’s say that instance reward that ultimately […] will essentially have connections with another brain regions that control memory formation. But you know, the circuitry or the cell level, I think there’s much to do on this. We need to try to figure it out whether it’s specific circuits, that essentially, they are connecting, you know, those brain areas to the memory areas. So yeah, I think there is a circuit specificity that determine these specific circuit that gets activated. But to be honest with you, I don’t think that we don’t we don’t know much about.

Peter [10:39] 

Yeah, so tagging off of that. What do you think are some really important questions with regards to memory that the field still needs to answer?

Dr. Costa-Mattioli [10:46] 

So I mean, I think there are many. Some of them, you know, from the more fundamental standpoint is, I mentioned to you that it’s been probably 50-60 years that we know the new protein synthesis is required for memory formation. We don’t know, what are the subset of proteins which are required for this process. We don’t know whether this synthesis proteins needs to take place in neurons or different types of neurons (excitatory or inhibitory neurons). We don’t know what makes memories to become fractured. […] Our focus has been trying to enhance memory. But erased memories are very important aspect as well. And those memories that you retrieve became fractured, and you can essentially erase them. Can we generate mechanisms to target specifically those bad memories, like those associated with PTSD, and get rid of them? So there are these two […] situations, you know, enhancing memory and erasing memory. And [if] we were able to essentially find mechanisms associated with retrieval […] we could […] could help people with cognitive problems as well.

Peter [11:55]

So understanding […] the retrieval aspect of memory, in addition to the repression of memory, fundamental biology that underlies those. Thank you for sharing that knowledge with us. I want to kind of move on to the second aspect of some of the work in your lab: understanding how these gut microbes or the microbiome can influence the brain function. And I think this is kind of like a nice, coming full circle for you. I know that you did microbiology as an undergraduate. And then you’re now studying the microbiome and microbiology again, and how that impacts the brain. I was wondering what prompted you to kind of go into the microbiome field from being very heavily focused on memory […]

Dr. Costa-Mattioli [12:34] 

I will say serendipity. We were not originally looking to look into the microbiome, so the project that we started, actually aimed at looking at how diet could affect behavior. And specifically, the positive that was driving this project was interested in in microglia. So a particular result that led us to think about the microbiome was that animals that […] have social deficit, [with] moms that were given a high fat diet, were put together with normal animals. And when we do that experiment, and we measure the behavior later on, the behavior of the social animals completely disappears. In other words, the animals become normal. At the moment is when, you know, we start to think about how diet affects the microbiome. So just by looking at that hypothesis, and testing that hypothesis, we end up with that surprise that yes, there’s a particular bacteria that it gets eliminated by the diet in the mom. And ultimately, that bacteria is required for social behavior. Because if you were to put it back in the animals, which are social, the behavior is completely normal. So in my wildest dream, I could have conceived the idea that a particular microbe in the gut were to be required to reverse or to affect our behavior, which is […] brain driven? And today, we know that a maternal high fat diet, essentially can change the offspring microbiome, even in humans.

Peter [14:01] 

That’s really neat, so these autism-like phenotypes are seen in the children of obese mothers. And why do you think the case is that the babies will have this kind of predilection, as opposed to the mothers?

Dr. Costa-Mattioli [14:12] 

It’s like everything in life should you know. You have a particular critical period where the brain or the gut, or the gut-brain connection becomes vulnerable. So if you do the high fat diet manipulations, if you can think about it, you know, the babies are in the womb, this is the time when an animal is way more vulnerable. And if you were to do the same insult, when the animal is adult, you know, the synaptic connections are already formed. So the possibility that you will have an impact in the mom is actually lower […]

Peter [14:45] 

So the networks are a little bit more hardwired at that point; there’s less room for change or impact. So I think this microbiome field is really picked up steam lately, how it can affect anything from depression to obesity to how we process a lot of the drugs that we take, what do you think some of the biggest things that the public gets wrong about the microbiome [are]? And what do you wish some people knew more about this field and the effect of microbiome on our health?

Dr. Costa-Mattioli [15:13] 

This is an emerging field. This is a field that, as the audience is learning, we are scientists that we are doing the science we are learning. This is a field, if you were to think about it was sort of inconceivable, you know, if 10 years ago, 15 years ago, a microbe in the gut, which could affect our behavior […] couldn’t be conceived, right? Today, you know, we are even thinking about ideas of using some of those single bacterial species with the possibility to perhaps, in humans, have an impact. So because the field is emerging, and we are starting, of course, we understand the other side, which is the audience of those, specifically, parents of kids that have autism, that they go under rush to the supermarket, and they buy any kind of […] probiotic with the hope that this is going to work. From our own work, we know that we have a specific species, and a specific strain to be specific, which actually are active, whereas others, they are not. And if you ask me why it is so I don’t know yet. Scientists, which are being working in the brain, as a main driver of those pathologies, they have benefit of 20-30 years of research. And I think we need a little bit more of time to essentially see whether any of what we are doing here could be translated or could be applied into humans. For the time being. Everything that we do in my lab is with animal models, and we have great fun. Whether this is going to be translated into human therapies remains to be seen.

Peter [16:52] 

So all the yogurts and the probiotics that are being advertised in the supermarket right now, not really something I should jump on the shelf for if I’m trying to improve my microbiome, or it’s just not proven at this point?

Dr. Costa-Mattioli [17:03] 

Well, so first, I don’t know I mean, but it is a function of the yogurts that you buy, and so on, and you can perhaps you can improve your microbiome. They say you can digest much better, or you don’t have as much constipation. But whether this is going to affect the brain, I have absolutely no idea whether this will be the case. So there are, you know, some probiotics, which perhaps they can help you, especially some of those probiotics, help constipation in young kids, that apparently they are apparently alleviate stomach discomfort, and so on. But for the brain, I don’t think that we have any indication yet. And it remains to us to see whether these could be used for humans. We are tackling the problem from a completely different angle. We are not doing what some other people are doing. This is a different way of thinking perhaps how to treat the disorder, and whether we will be this is going to be effective or not, I can answer that.

Peter [18:04] 

How important do you think different perspectives or tackling problems from a different viewpoint are in science? And how would you recommend someone who is a young new scientist with an idea that they think is somewhat radical, very different from what is going on currently- how do they go about pursuing an idea like that?

Dr. Costa-Mattioli [18:20] 

So it’s not about [being] radical, or have a completely different view. The answer is to have the right answer. But the problem is that we don’t know what the right answer is, right? So what […] fascinates me is ideas that not many people will conceive, rght? And which could be right [or] could be wrong. But if they are right, these open a completely different avenue on which you can, in this particular case, tackle the brain. Perhaps some behaviors could be ameliorated by using microbial based treatments, and others they would have to go with a more conventional route that will essentially affect directly the brain.

Peter [19:06] 

Thank you for those perspectives. I wanted to transition a little bit to some more personal questions. I know you have received numerous awards: the Alkek Award for Pilot Projects and Experimental Therapeutics; you are awarded the Eppendorf Science Prize for Neurobiology for your essay on switching memories on and off; and you’ve been named-dropped on Jeopardy for one of the questions. I was wondering what is the accomplishment that you’re most proud of? And what continues to motivate the research that you do?

Dr. Costa-Mattioli [19:34] 

That’s a great question that I asked myself every day and frankly speaking, I don’t believe I have discovered anything so far. I believe that she has been playing around with a few things and some of them they have become have been important and some others they don’t, I believe that the times are headed the best to come. This is what essentially makes me wake up very early in the morning and makes me go to bed very late at night, some of those ideas and concepts. So I’m not by any means [settled]. And frankly speaking, I was speaking with someone just a few days ago, and I was telling the person that I really felt that there was not much that I have done, because there are these people that they have [had such] great accomplishments. So I think, I hope, the better is still to come.

Peter [20:28] 

That’s very humbling to hear. You have done so many things that have been so successful, and you have such a great experience and I was wondering if you could think about what a common mistake graduate students do, or someone who’s just entering the scientific field, what is something that they frequently make a mistake of. And how would you go about trying to help them fix this?

Dr. Costa-Mattioli [20:47] 

So there are a few rules that you know that I set in into my mind, right? So the first one is trust no one. So as a grad student comes to a lab and start to work on a project and the believe that the project supposed to work in a similar way that the Cell or the Nature paper that was published by another graduate student, [but] you have to see it with your own eyes. So this is a clear thing that student has to go and see when your own eyes and if the experiment doesn’t work one, two, three or four times, this is the moment where you need to go and be vocal and, and tell people that perhaps you’re not doing things the right way and get all the help to see whether you can build your story and continue with this. The other important thing is you need to be curious and curiosity might not just be driven by your PI. [You should be driven by a] specific aspect of the biology that you are doing that your PI is not thinking [of]. You need to go to the office and say, guys, what I’m interested in this, because this is a way more important question than doing what you’re telling me to do, right? So I think those are, a few [pieces of] advice that I will give to entering grad students. Never get discouraged. Never get discouraged. […] This is a marathon, this is not a sprint, for some people could be a sprint, but for the majority of us it’s a marathon. This is something that takes time. Your PhD takes time […] Now that I’m thinking [about it], I will tell you what I think is the more important factor. The more important factor is learning to fail. And if you learn to fail, because in science you fail every single day, every single day is a failure. The majority of the experiments that you do, they don’t work. If you learn to fail, or how to fail, or how to cope with that failure, things become much easier because you don’t go back depressed, because you know! You know at the onset that  things are not going to work. And when they work it’s sort of a gift.

Peter [22:56] 

So it all comes down to- the first thing you said was, trust no one, but trust your own experiments. And that invariably is going to lead to a lot of failure. It is not easy to repeat what other people have done, maybe they did something slightly differently, maybe they thought about something that they didn’t write down in the protocol. But going through that process, learning a little bit about it, is what you think is kind of essential to the growth of someone as a scientist and something that they should take with them moving forward.

Dr. Costa-Mattioli [23:21] 

I take it seriously because you go and you do an experiment, you find a paper that was published, you go you do it in two minutes, the experiment didn’t work. This is the easy thing. Of course, it’s not going to work because you didn’t optimize it. For every single of the experiments that we do, we need to essentially optimize the protocol, find that particular window, where the experiment essentially [can live]. Give the experiment a chance to be successful. Right, so from the moment that you have a story, which is strong, and you believe in it, this is where your PhD starts.

Peter [24:12] 

I’ve seen in some of your other interviews that you reference Eric Kandel influencing your decision to delve into the neuroscience field. What advice do you have for someone who is trying to delve into a field that is slightly different? I know previously, you’ve done a lot of work in virology and microbiology. And then having heard this talk from him, you felt like your lab was really well positioned to move into understanding the mechanisms that are driving memory. So how do you go from someone who is a microbiologist, a protein lab to someone who studies memory or what advice do you have for someone who is trying to make a career job.

Dr. Costa-Mattioli [24:47] 

As I said, I mean, in retrospect, you work it out. But the shift was risky. So I was reading a book by Francis Crick the other day, which he was just saying that before, of course, the discovery of the DNA structure, he just knew physics. He had absolutely no idea about biology, but he had an ability to turn into things and turn these things to work. So there’s a lot of determination in going and a lot of cojones, as well, because you need to move from area in which you are comfortable with. For most of the scientists, I will say when they reach the age of 30-35, they are established already. The possibility to change their career to a new direction is very low. In my case, I am interested in biology. And if you come to my lab, and you […] show me something that gets me excited, I don’t care where this is going to bring me because I’m interested. That’s my thrill. Now, in that process, you’re required to get to know the field and there’s a lot of learning. The way that I have done it is consulted and learn from experts in the field, the best that I could find in electrophysiology, the best that I could find in behavior, and just go and reach out to them.

As a postdoc, I went into their office, and I told them, this is my idea, they told me you’re crazy. It doesn’t matter, because it helps me and they didn’t listen to me and ultimately it paid off. And in the case of that very late switch, you know, from say, memory to microbiome-brain, as you pointed out, to me, it was like a natural transition, because, you know, I knew about evolution. I knew about microbiology and, and during my PhD, I was looking at how particular selective pressure will affect a viral population and how the virus could escape. So I would say that the transition has been smooth. But I have so much to learn, I have colleagues like Jeff Gordon, [sic], and others, which are experts in the microbiome, that every single time I have a chance to read their papers or meet them in conference, I learn so much from them. And I think this is what keeps me going: learning every single day so I feel like a student again. Learning new things. Going to different directions. Some of them are crazy. Some of them are more conservative. But I think this is what science is about. And this is how we do science in my lab.

Peter [27:29] 

Yeah, it’s really nice to see how you’ve kind of kept that curiosity, kept that passion with you, and it hasn’t really subsided. Or maybe it has, but you have kept it with you and its continued with you from your days as a graduate student to a postdoc to now. I was wondering, just one last piece of advice from you that you could give to someone who is going into that new field, starting a new lab, being a PI for the first time, what advice would you give to them to develop their ideas or how you think some of the problems that they may run through.

Dr. Costa-Mattioli [28:01] 

So times have changed from when some of my mentors became PIs to the moment that I became a PI. We have a tremendous pressure for funding, what I see repeated time and time, again, is that people who start the labs, and the first thing that they do is they start to write grants. Of course [this is the case], because they want to have money to run their operation. When you start your lab, if you end up in a great institution like Duke, for instance, they will give you enough money to do science for a few years. And this is the time that I feel that is remarkable, because all you have to do is do your science and show your science. Forget for the first year or two years about grants. Do your science. Do [the] more interesting experiments that you want to do. If your experiments are good, if you’re sinking correctly, that science is going to bring money. And that money should support more science. And if the science is good, is going to bring more money. And this is the cycle that all of us we get into. From the moment that you are in, the cycle is non-stop. But during those first two or three years, you are not in the cycle, don’t get into the cycle until you need to.

Peter [29:22] 

I feel like it’s hard to feel like you’re not part of the cycle.

Dr. Costa-Mattioli [29:25] 

It’s fine, it’s fine. You will be an amazing outsider. Don’t worry about money doing your science. And I think you know, for some of the people that I discussed [earlier], they just told me, oh my God, I didn’t have those first two years in which I was enjoying doing the experiments myself and teaching my post-docs or students. They are so committed. I understand the pressure. The pressure is massive. The funding is actually low. We have great science and unfortunately part of the great science doesn’t get funded. So I really hope that these agencies like NIH, the government, the DOD and so on increase the payment and support those great projects […] because we have other countries like you know, like China or South Korea, which are putting tremendous amount of money in science. And I think you know, the innovation that we have in the US is still top, but we need to keep it away.

Peter [30:26] 

We have to continue to foster [our science]. Well, thank you so much for your time, Dr. Costa-Mattioli.

Dr. Costa-Mattioli [30:30]

My pleasure.

Peter [30:40]

From memories to microbes, we have got the chance to see how Dr. Costa-Mattioli has not let himself be defined by one particular field. It was the refusal to let go of an interesting finding that sparked his curiosity that has made it easy for him to push forward into new fields. I feel like we should take this mentality and try and invest a little bit of time every month to reflect on what excites us about what we do. Perhaps even write it down or share it with someone. If nothing comes to mind, maybe it’s time to rethink our approach to our work. Just some food for thought until next time. And thank you so much for listening. 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 the music composer. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts Dr. Diego Bohórquez and the Bohórquez laboratory

Episode 2: Making The Jump (Transcript)

Dr. Wickersham [0:00] 

I’m trusting you Peter.

Peter [0:03] 

If you could use one word to describe it.

Dr. Wickersham [0:06] 

Bread-y, I’m feeling like that’s a hot dog. I only got the bun, I think

Peter [0:15] 

That is fine. You can open up your eyes now. It was a hot dog on gluten free bread (we made sure). I think the reason we ended up choosing a hot dog was we think that dogs are associated with rabies, so what’s the closest food we could go for and we thought of hot dog.

Dr. Wickersham [0:31] 

Yeah. Nice.

Peter [0:41] 

Hi, my name is Peter and I will be your host for the Gastronauts podcast. Here at Gastronauts, we are committed to understanding communication in the body, and in particular how our gut talks to our brain. In this podcast, we take a deeper dive into the mind and motivations of leading science and their work. We hope that by getting to know the scientists behind the science, we will be able to bridge the gap between different scientific spheres, and between the scientific community and mainstream culture. So let’s dive right in, The Gastronauts Podcast: Between Two Spheres.

We’re really thrilled to have Dr. Ian Wickersham here today. Ian studied physics as an undergrad here at Duke University and then went on to do his PhD at UCSD in neurobiology. He later did his postdoc at MIT, and now serves as head of the genetic neuro-engineering group at MIT. He focuses on developing powerful and precise techniques to study the structure of the brain. He’s taken advantage of really unique features of viruses and modified them so that they can infect particular cells and light up so we can visualize brain networks. One of these viruses that he’s worked with is rabies virus. And I’ll be honest, when I first heard of using rabies virus as a tool, I got a picture of […] a rabid salivating dog with somewhat of a crazed look. And I was wondering, […] how did you get drawn to rabies? Did it take some convincing to get you to work with a virus that has somewhat of a scary reputation?

Dr. Wickersham [2:40] 

Well, no. And of course, I actively wanted to work with it, so I had to convince others more than the other way around. But the thing about rabies virus is that while it is terrible pathogen that does kill many people worldwide every year, it is a tremendously useful, naturally occurring tool for neuroscientists, because the way that it spreads is between synaptically-connected neurons. It spreads between neurons in a way that doesn’t kill the neurons outright for quite some time. So when I started my PhD, we were looking for ways of identifying connected neurons in the brain. Because neurons in the brain are of very many different cell types and they’re all mixed in together and they have these long processes, axons and dendrites that overlap. And it’s impossible to tell just by looking at them, even if you are lighting up different types of them or staining them. It’s impossible to tell which are connected to each other. And the exquisitely precise connectivity between neurons is basically maybe the most unique aspect of the brain as opposed to other organs. So it’s very important for understanding how the brain works, or how one little aspect of the brain works, to understand how the neurons that are involved in that behavior that you’re interested in, are connected to each other. So we needed a tool that would allow us to identify cells that are connected to a targeted group of other cells and rabies virus was beckoning as the most promising way of doing that.

Peter [4:29] 

That’s really interesting. You mentioned rabies, more so as a tool, than kind of a pathogen. And your lab really focuses on developing tools and prototypes and modifying these viruses so that we can use them to understand different circuits and different connections. And I was wondering, when we go through developing these tools, we go through an iterative process where you go through prototype one or generation one, generation two, generation three. How do you know when generation one is ready? How do you know when you’ve made a construct that you think this is kind of a tool that we can sell to other people or let other people know about?

Dr. Wickersham [5:06] 

Well, as far as the first-generation version went, there was nothing else out there. And so as soon as we had a basic sort of demonstration that we could do this, and I should say that the system that we were trying to invent was a way of specifically labeling neurons that are directly connected to a targeted group of neurons. So basically, we would be able to selectively infect whatever type of neuron one wanted in the brain with a modified form of rabies virus and allow the rabies virus to spread not throughout the entire brain, like wild type rabies virus does, but only to the cells, which are directly synaptically connected to the starting neuron population.

Peter [5:55]

So you control kind of the specificity of how its spread.

Dr. Wickersham [5:58]

We control two things, actually, one was the specificity of which cells it would infect to start with, and we also controlled the number of synaptic steps that it would travel, basically. So naturally occurring rabies virus will infect essentially any neurons it encounters if you were inject in the brain. And it would, once it infected those cells, it would spread in a retrograde direction, that is from the starting cells to the cells, which are pre-synaptic to them.

Peter [6:29] 

And pre-synaptic means that it forms the connection upstream of it.

Dr. Wickersham [6:33] 

That’s right, to cells, which release neural transmitter on to the cells that you’re starting with. And wild-type rabies virus will simply replicate within those cells, and keep spreading to the cells, which are pre-synaptic to them, and so on, and spread throughout the entire brain. And we wanted a system that would allow us to label only the directly pre-synaptic cells, so that we could very precisely identify sort of a connection matrix between cell types in the brain.

Peter [7:01] 

So kind of like a controlled rabies infection.

Dr. Wickersham [7:05] 

Yeah, that is the first-generation system being able to do that. And of course, we publish it as soon as we had any kind [of data], like one does basically in neuroscience. Once you have something which is novel, no one has ever shown before, even if it’s not perfect, you want to get it out there. So without waiting for perfection, one simply publishes each new, major advance.

Peter [7:30] 

But at the same time, you want to make sure that the toxicity or the lethality of the rabies is controlled as well.

Dr. Wickersham [7:36] 

Exactly, and the toxicity of rabies viruses is maybe its biggest downside. It’s certainly less toxic than many other viruses. And the reason, if you will, that it’s less toxic is the rabies virus wants to keep the cells of the of the nervous system intact, so that the host, the infected animal, will be able to go on and transmit the virus. Basically, the viral life cycle depends on not trashing the nervous system as it spreads through it so that the animal is in a position to implement that behavior, which causes the spread the virus. So basically, the virus is already fairly non-toxic. But within neuroscience, there are many, many experiments that one would like to do that involve manipulations or study over a long period of time, not just a few days or a couple of weeks. But in mice, for example, that are learning a task, that are developing over time, and one would want to see how the synaptic connected networks of neurons evolve their responses over time as the mouse learns a task, for example, something like that. And that basically has not really been possible with the rabies virus systems that have been out there, or mainly the system that has been out there, because it does kill the neurons. And so a huge effort in my lab has been in recent years to develop non-toxic versions of the so called model synaptic tracing system, the rabies virus tracing system.

Peter [9:13] 

And the mono-synaptic tracing system is kind of just having a jump one synapse, right and not continuing to spread, and that’s how you control a little bit of the toxicity?

Dr. Wickersham [9:17] 

Well, that’s how we control the spread of the virus, but that doesn’t directly do anything about the toxicity per se, of the virus to the infected cells. So in the second, and now, third generation versions that we have underway, the rabies virus appears to be completely non-toxic. And so that means that we can label pre-synaptic cells, and then leave them alive indefinitely so that they can be studied and manipulate for long-term behavioral experiments.

Peter [9:52] 

Okay, so what I’m getting is kind of your generation one is […] you have this vision set forth, you want to be able to label a pathway and […] you found a way to do it. It is modestly toxic, relatively low toxicity. And then when you went to generation two, you’re really trying to focus on how can we reduce this toxicity  almost zero? And then how can we get this labeling to persist?

Dr. Wickersham [10:16] 

Yeah, exactly. I mean, the very first pass was, if I may say so is a huge step forward, because basically, it is, and remains the only way of identifying cells which are directly connected to some population of the brain that you’re interested in, without already having a hypothesis that you can then test. So for example, let’s say you’re interested in dopaminergic cells of the membrane. These are cells which project to the cortex and depending on the cells, the striatum, and other places in the brain, and they’re tremendously important for motivation, and reward and movement control. And being able to identify what the inputs are to the those tremendously important, dopaminergic neurons in the membrane will allow neuroscientists to map out the entire circuit manipulates various inputs and see something basic about how the organization of this key system of the brain or the systems probably more properly, is put together. Now, the first order question that one has is what are those cells and where are they? And so the first generation rabies virus system was just to answer that […] anatomical question: what and where are the cells which are present? Wherever they are in the brain, it will label them. And so just to be able to do that anatomical mapping before going on, and then maybe manipulating pre-synaptic cells with other means.

Peter [11:48] 

So what really makes this rabies still powerful is kind of the resolution that you get, is that correct? Because my previous understanding of neurobiology is we have these brain regions, and we know they’re, to anthropomorphize, talking to one another. But we don’t know specifically, what neuron is talking within this brain region to this other neuron, right? And the rabies virus gives you the ability to look at this direct connection between two cells.

Dr. Wickersham [12:12] 

That’s correct. That’s exactly right. So what one can do without rabies virus or with a variety of other tracers, and what people had done before this came along was see where in the brain there are cells that project to a brain region. But with any of those techniques, there’s no way of seeing which cells in the targeted region, those upstream neurons project to. So you basically can get, with high resolution, mapping of cells everywhere in the brain, that project to a place. But before the rabies virus system came along, there was no way of identifying which cells in that target location, were post-synaptic to, all these pre-synaptic neurons. So what we can do with the rabies virus is select the cells that you’re interested in, mapping the inputs to, and then map the inputs specifically to them. And they’re different, essentially, everywhere in the brain, there are many different cell types and they differ in their conductivity by and large. And so essentially, you may have differences just in degree of the numbers of neurons in a particular brain region that project to one type of cell in, let’s say the cortex, or another. Or you may have completely non overlapping types of cells, which are pre-synaptic to the two, for example. And this allows you a much higher resolution ability to map conductivity.

Peter [14:00] 

Yeah, so that really shows like even neurons that are close in space that are localized may not be part of this network that we’re looking at. To pick your brain a little bit. Where do you see the future of this going? I think structure belies function. And I think understanding this network is important for us to really know how the brain works. And I was wondering […] where do we see this going forward? How do you think, our understanding of these networks? Or how do you think we can better understand these networks with new techniques within the next 10 years or so?

Dr. Wickersham [14:32] 

Yeah, well, for one thing, be able to see more about those specifically pre-synaptic cells than just where they are and what they look like, and what they express and so on, would be good. So if you can, with a non-toxic version of all of this, do patterned stimulation of pre-synaptic neurons to be able to perturb the activity of these pre-synaptic cells, and see how that affects the activity of these targeted post -synaptic cells. And one can with the rabies virus, do mapping of inputs to not just a group of neurons, but a single neuron. And this allows beautiful anatomical mapping for a start of inputs to individual cortical neurons, but so you can express calcium indicators in those pre-synaptic cells, and be able to image, for example, visual response properties of all of those pre-synaptic cells, as well as of the single targeted synaptic cell and then see, for example, whether a neuron in the visual cortex, for example, that responds in a certain way to visual stimuli, gets input from primarily other neurons that respond in that same way, or whether it’s doing something maybe a bit more interesting. So in other words, answering the question, which I think is one of the most fundamental questions of neuroscience, how does a single neuron take the input that it’s getting and process that information to produce its own output?

Peter [16:02]

So what I’m hearing is moving forward, you think kind of understanding these on a single cell level, how we integrate information, more how these neurons integrate information in a single cell level and how they can take that information and integrate and send that message over that synapse to another cell, is where you see the future of these techniques moving forward.

Dr. Wickersham [16:23]

Yeah, well, so I think that’s, that’s a really great goal and a motivating goal. In terms of the futures of the techniques themselves, we should soon have a highly efficient, completely non-toxic mono-synaptic tracing system that would allow those sorts of experiments. I mean, at that point, neuroscientists of all stripes can use the technique and do whatever exciting science they want with it. We as the tool developers are going on and developing other tools that will allow other exciting science.

Peter [16:55] 

Now that’s really exciting moving forward, I can’t wait to see what your group does in the future. I’m going to go transition a little bit more now towards you as a scientist in your own career development. Moving from physics to neuroscience is kind of a big jump. And I think that I’d be interested in hearing how you made the jump from being a student in one field into a researcher in another?

Dr. Wickersham [17:23] 

So I mean, in my case, I was always interested in in the brain, not necessarily neuroscience, per se. But from the perspective of wanting to understand how it worked. I was always interested in physics, too. I enjoyed it. So that was my major in college. But I also became interested in the brain, and minored in neuroscience here at Duke. And was thinking about, though, from the perspective of neural networks [and] that was my, that was my motivation. So I was thinking, Okay, how can how can we build a brain? So now, I think the majority of people probably go into neuroscience, the goal of understanding the brain in its entirety, and so on, you know, figuring out how consciousness works, or building robots that think and that sort of thing. And then you sort of get to neuroscience, and it’s like, “okay, well, what you can actually do is this…” [What] might be a more direct path to take for actually building architectures that are more like thinking in a sense than, than we’ve had before. But going into neuroscience, my motivation was just to understand as much as I could about the organization of the brain.

Peter [18:28] 

What about the brain in particular? Is it just the fact that it is such a poorly understood network? Is it because we don’t know much about it? What drew you towards the brain?

Dr. Wickersham [18:37] 

Oh, I just think intelligence is cool. And, you know, it seems like okay, well, we should be able to build a machine that does that. So that really was the motivation. And I better start by understanding what we do know about the brain. So I ended up joining a PhD program- but, it just turns out that we don’t understand all that much is the truth of it and that’s sort of the glass half empty, or 99% empty, kind of a view of it. But in fact, in fact, we know an enormous amount, it must be said, but that basically, that was my trajectory, I was coming at it from a from a neural network sort of point of view, and interest and in construction, doing programs and architectures that […] were intelligent, and so on. But [when I] got to actual neuroscience, and realized that what I wanted to know- that information was not out there. From my perspective, what I wanted to know, for starters, was okay, what are the connections between all these different types of […] cells? What are the connections between them? What are they doing? And the tools for knowing all that didn’t exist.

Peter [19:45] 

And you decided to make them yourself!

Dr. Wickersham [19:46] 

Yeah. So […] it just seemed like the bigger bang for the buck, as it were, in terms of the impact that I could have, rather than using existing tools to study laboriously some circuit in the brain and get, you know, sort of incomplete answers about that circuit would be to develop tools that would allow people working in any aspect of the brain to just have much more powerful and precise experiments.

Peter [20:19] 

Yeah, something that just came to my mind was, your research is really focused on the synaptic labeling, or, first off, this mono-synaptic labeling how you jump from one cell to another. I was thinking, […] this kind of reminds me about how people make the jump from being a trainee to being a mentor. So how did you make that transition from kind of being a scientist, learning about neurobiology, learning about these neural circuits to being someone who was a pioneer in the field. Were there some tools or mindsets that you could […] share with people who are trying to make that transition from trainee to mentor.

Dr. Wickersham [21:00] 

So I guess my focus has always throughout been pretty much the same in just trying to develop tools that would just basically allow a huge increase in the abilities of experimental neuroscientists to study circuitry. So I mean, that was kind of like the driving characteristic in the PhD and throughout, it’s still the same thing. It’s just that now I can do a lot more, because I don’t have to do it all myself. And so that is, it is a different role, for sure. But analogously, if you can just make tools that will allow other people to find out things about the brain, then more will be found out than if you were trying to just do it yourself with the existing tool. Similarly, if you have ideas, and can delegate them to your co-workers, a lot can get done.

Peter [21:55] 

So it certainly sounds to me that when you were a trainee, kind of, the fascination with the tools to understand the network is what kind of drew you in, when you were first getting interested in research. But then, as you were trying to study these networks, you realized that you needed to build your own network of, you know, collaborators that would help develop this.

Dr. Wickersham [22:15] 

Throughout I was learning from mentors, postdocs in the same lab-

Peter [22:20] 

And how do you go about looking for this help, do kind of just see who’s in the area reach out to them,?

Dr. Wickersham [22:25] 

That’s a really good way to do it. The truth is, they’re there are great people all over the place, wherever you are. And so you want to find them. It’s just certainly at a place like the Salk, or MIT or Duke, it’s easy to find world class people who are happy to teach you. The degree of collegiality, I think, differs between places, but I’ve had certainly good luck with people being happy to help.

Peter [22:51] 

That’s really nice to hear, kind of, how collegial it is for science, because I remembering […] going back [to our earlier conversation], you’re thinking, Oh, you know, when I discover something, I really need to push it out. There’s a sense of competition, and having people that are available to you having, you know, a group of people within your institute or between institutes that are really driven and motivated to kind of help you succeed is important to taking that next step.

Dr. Wickersham [23:18] 

That’s right. That’s right. And it’s almost always win-win. And that’s the only really effective way of collaborating. Generally, it’s an academic collaboration and if there’s a significant amount of help, they’ll get some of the credit for the work and in many cases, be able to use the technology or whatever that’s being developed in their own work. People have a stake in the outcome like that, then they’ll be more motivated to help.

Peter [23:42] 

Right? So when forming collaborations, you want to make sure that it is a win-win for both parties, right? So we’re both people can advance their own work to advance the field and develop.

Dr. Wickersham [23:51] 

And generally people share authorship on the paper. And if the project is exciting enough that it’s going to be a high impact publication, just to put it in that sort of crass form, then […] that’s in their interests to participate in the development of that.

Peter [24:10] 

That’s really great. Well, I really want to thank you for taking the time to be on this podcast. Dr. Wickersham. Oh, I think we learned a lot about forming connections in the brain in our science, then yeah, thank you so much for your time.

Dr. Wickersham [24:23] 

My pleasure. Thank you very much.

Peter [24:34] 

Well, there you have it. Forming a collaborative network is easy when you take the time to get to know your colleagues. We challenge you to reach out. Share your ideas with the people down the hall, or the person sitting next to you at your next lunch or seminar. 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 the music composer. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts: Dr. Diego Bohórquez and the Bohórquez laboratory.

Episode 1: Embrace The No (Transcript)

Peter [0:00]

So what are you feeling, Cheryl? What are you thinking?

Dr. Nickerson [0:04]

It might be a type of dessert, it seems like it has maybe some kind of a cream in it, but it’s overall a drier consistency. I would say semi-sweet, not very sweet, but a little sweet.

Peter [0:16]

If you had to use one word to describe how you felt when that went in your mouth.

Dr. Nickerson [0:23] 

I’m doing a hyphen: semi-sweet-dry […] That’s two hyphens. Semi-sweet-dry.

Peter [0:29]

You can open up your eyes now.

Dr. Nickerson [0:32]

It’s a moon pie! Not too far off.

Peter [0:37]

Space, moon, pie and we tried to get it all together.

Dr. Nickerson [0:38] 

Very nice. Very nice. I’m slower to catch up on that one. Very nice.

Peter [0:54] 

Hi, my name is Peter, and I’ll be your host for The Gastronauts Podcast. Here at Gastronauts, we are going committed to understanding communication in the body, and in particular, how our gut talks to our brain. In this podcast, we aim to take a deeper dive into the mind and motivations of leading scientists and their work. So let’s dive right in- The Gastronauts Podcast: where scientists talk about their gut feelings.

In our inaugural episode, we are really excited to have Dr. Cheryl Nickerson from the Biodesign Institute at Arizona State University. Cheryl’s research focuses on the effects of space, microgravity and physical forces on bacteria and bacterial pathogens. She has collaborated with NASA to actually send bacteria on space shuttle missions, and has studied how these bacteria can change to the conditions of outer space. So welcome, Cheryl.

And the first question I had for you, which I’m sure you get this a lot, is what drew you to space? And how did you decide to bring space into bacterial research?

Dr. Nickerson [2:24] 

That’s a great question, and I have gotten that question before. And by the way, thank you for inviting me to be a part of this podcast. It’s a story of you never know what direction your life is going to take. So I was in graduate school, getting my PhD in microbiology, and I was in my last year of the program, when a new student came into the program, who already had his engineering degree from the University of Texas and he came to get a PhD in microbiology. We immediately struck up a friendship and I was instantly intrigued with how he viewed microorganisms more as circuits. He was very analytically driven as an engineer. And so I had a completely different perspective of microorganisms because I came from a hardcore life sciences background and you know, there’s signal transduction mechanisms. This is all very complex. There’s no on and off switch that is 100%. Right? It’s shades of gray, and he was very mathematically oriented.

And so we struck up a friendship, which lasts to this day. We collaborate all the time; we publish all the time; we get grants together all the time. And long story short, for my postdoc, I went and took a position in bacterial pathogenesis and focused a lot on the foodborne pathogen- Salmonella, and studying how it interacted with human intestinal cells and how it interacted with animal model intestinal tract-like mice to cause disease. And he went to the NASA Johnson Space Center and started working in their microbiology group. So he was involved in sampling microbes from the air and water systems in the space shuttle on the International Space Station. And he’s an excellent microbial physiologist.

So as time went on, he now heads up microbiology at the Johnson Space Center. But after my postdoc, I had learned the mechanisms of bacterial pathogenesis, especially in enteric bacterial pathogens, and I knew how to culture intestinal cells and infect mice and study the intestinal interaction with pathogens. On the phone one night, a month after I got my first lab, my first tenure track position at Tulane University Medical School in New Orleans and he had been at NASA JSC, he commented to me on the phone in passing that the astronauts were immunocompromised in space. So now my expertise is in infectious disease, so I said, now hold on a minute, because that’s kind of half of the equation of whether you’re going to get disease after you get infection. Just because you get infection doesn’t mean you get the disease, right? It depends on the virulence of the pathogen, the dosage of pathogen and on your immune response. So you know something about the effect of spaceflight on half of that equation, the immune response; what do you know, does anyone know about the ability of the microgravity environment of spaceflight to impact the virulence of a pathogen?

Well, nobody knew about that, so that’s how this collaboration started. We did ground-based experiments that gave a strong indication that spaceflight culture might impact the virulence of the pathogen and its stress responses and its gene expression and that led into multiple spaceflight experiments that further showed and proved that the microgravity environment spaceflight did increase the virulence of this pathogen and it did change its gene expression and it did change it stress responses. We have leveraged those findings into mechanistic studies of a lot of different ways: we found that other bacterial pathogens can use similar signaling mechanisms to Salmonella in spaceflight, we have identified ways to turn off that increased virulence in flight. That also led us into doing three-dimensional cell culture under the same kinds of physical forces.

Peter [5:49] 

It sounds like to me a lot of this was bred from you working with someone who is in a field completely different from your own. Someone, who studied engineering background, was thinking about how systems function from more mathematical perspective, and you’re coming in, bringing your expertise in microbiology and virulence. And it kind of seemed to be a perfect storm: him at NASA; him studying the immune response and astronauts and you looking a little bit at bacteria, and how can we get the immune system to interplay with bacteria, which is essential for us to understand how human health is going to progress. And I was interested in teasing a little bit more into space. How did you decide- Was it an aha moment? Like, this is the way I want to go? Did you have any doubts? Were you thinking about other things with regards to microbial pathogenesis, because bacteria are not frequently studied in space? It’s not something that I think of, you know, these microscopic particles sending them all the way in outer space? How did you make that leap of faith take that jump to decide to study space?

Dr. Nickerson [6:48] 

Well, first, I have to thank NASA for funding those studies. Because had I proposed those studies to NIH in the beginning, that would have been, I believe, outside their realm of what they would have been willing to fund at that point. So I thank them because that led to a very productive series of experiments that have transitioned to actually being beneficial for not only astronauts in flight to mitigate their infectious disease risk, but directly relevant to our health down here on Earth. And a question that is just a completely logical question is: why- and I get this with my colleagues- why in the world, Cheryl, would you think that you would learn anything new, or advance any aspect of infectious disease by doing microbiology in microgravity? I mean, life didn’t evolve there, right? The one force that’s been constant in the face of the earth has been gravity.

That’s a logical way to have your mind wired, and my brain is wired differently. So I thought to myself, why would you not learn something new about biological systems, microbes, human cells, whatever, when you greatly reduce the one force that’s been constant on this planet since it began? Life has evolved under unit gravity; we haven’t known anything else. Why would we not think when […] you greatly reduce that force that these emergent phenotypic properties that could be relevant to health or disease could emerge? We’ve learned that when we study cellular and biological systems in response to extreme environments, we learn more information, we learn more mechanistic insight about how cells evolve and adapt and respond. And so to me, space flight was just the next extreme environment whose potential is just beginning to be untapped.

Peter [8:33] 

This is of interest to me, especially young in my career as a developing scientist: when trailblazing into the unknown without really knowing what is going on, I think there are certainly hills and pitfalls to fall into when you’re doing research. And it’s easy to get bogged down into the weeds, and a little bit, demotivated sometimes when your results don’t quite make sense to you after […] trying to control for everything that goes wrong. I was wondering, how do you continue to motivate yourself in these pitfalls? And how do you motivate your trainees and your mentees in these situations?

Dr. Nickerson [9:08] 

So first of all, you have to be a little feisty. And you have to be just a little bit defiant, when everybody tells you, anytime you’re trailblazing, and you’re doing paradigm changing research, and you’re finding things that others haven’t seen, you’re going to hear a lot of no. Embrace the no- it’s okay. As a matter of fact, I’m someone who likes to hear no, not at first, you’ll hear no on your grants, you’ll hear no on your manuscripts. That’s okay. If you can’t hear no, and you can’t tackle no in this field [then] this is not the field for you. No motivates me, because I know the work we’re doing is good because I know the teams- I know my team, and I know my lab and I know the teams that we’re pairing with are excellent scientists. That doesn’t mean we’re right on every hypothesis, but hypothesis can be right or wrong. We know our science is good, and we believe in what we’re doing. We believe in our science; we believe in each other. And we know we’re on the right trajectory […]

I save every rejection letter from every grant from every manuscript, and I have two of them from the early stages. I won’t tell you what funding agencies they’re from. One said, we have monolayers, we don’t need 3D tissue models. You learn nothing new about bacterial pathogenesis with 3D tissue models. Okay, we can check that off the list because that just motivates you, right? So after we helped birth that field 20 years later, now it’s a really hot field. That’s great! Okay, but science takes time; this is what happens. The first grant we submitted on saying, look how physiological fluid shear forces […] just completely reprogram bacteria to do different things than [what] we do when we grow them in a shake flask at 350 RPM where we grow them statically in the lab, which is how most people grow them. I got the first rejection letter from that. This is pretty much heresy is what it says; that’s fine. Now, mechanobiology of infectious disease is a cool thing and it’s an exciting thing and it’s good, [accepting] the rejection letters is key. You will ultimately prevail, if you stay focused and determined and persevere. You have to have that fight and that feistiness and the fire in the gut. And you just do it.

Peter [11:17]

I will certainly take that with me. Accept the no.

Dr. Nickerson [11:23] 

You don’t have to like it, but just let it motivate you. And then the good thing in the end is you get all these exciting, new scientists coming in with new creative ideas. And I learned a very important lesson from one of my scientific [mentors] who I view as heroes. She always has a statement and I tell my students this all the time. She says, “Don’t be arrogant. Because just when you think you know everything- you don’t, arrogance kills curiosity.” I think that’s a beautiful statement. Every scientific discipline has so much to learn. There’s so many new discoveries to be made. One lab, one group, one team couldn’t possibly own them all. There’s room for everybody. So be accepting and don’t think you’ve learned it all. Because it’s not possible.

Peter [12:31] 

Everything you’ve told me so far really makes sense, right? Science is done in interesting circumstances. It’s always done, I think, contextually- we want to see what environment can we [create] to really stress the system and see what happens. But I really want to get to the point that when someone calls you and says space could be interesting and how it affects bacteria. What was your gut reaction? [Did it] come to your head at any point where you were like, ah, this is something that I could blend together.

Dr. Nickerson [13:00]

The whole concept of being able to identify a new biological property, phenomenon, cellular responses, molecular/genetic phenotype, did not seem at all unreasonable or surprising to me to use the microgravity platform to do- it seemed to be very exciting to use the microgravity platform to do it. But you know, it could have been wrong; we might not have seen any differences there. The aha moment to me didn’t come when we first got our grants that we wrote to fund that. The aha moment came when we got our results back and we analyzed our data and [it] just boggled our mind […] because that’s when the real excitement set in.

We were able to, to mimic some of those findings that we saw in microgravity with some special ways that we have to culture cells under conditions that kind of mimic certain aspects of microgravity on the ground. They can’t mimic everything, but they could mimic some of our key findings in flight. So we knew this isn’t just something- we were super excited first, because I thought, wow, we’re going to get to help astronauts stay healthy, right? We were super delighted with that, who wouldn’t be? But then when I realized, it doesn’t make sense to me, that bacteria would have invented or evolved the way to respond to a change in gravity. It just didn’t make sense to me, I said, this change in force must be similar to another physical environment that they encounter somewhere in their natural life cycles on Earth. Because that just didn’t make sense- they evolved into this. And it turns out, our evidence suggests they’re not responding directly to reduce force of gravity, they’re responding directly to reduce force of fluid shear, and at levels that are very similar to what they encounter in our tissues. When they affect us. That, to me, was the aha moment. Then we realized, oh my gosh, these discoveries we’re making in the microgravity platform can translate […] back down here to help you and I, so we don’t have to go to space. But we are basically unveiling responses that pathogens can make when they infect our bodies, that we can’t see other ways. So now, we have developed three-dimensional intestinal cultures that contain human tissue like structures. They have multiple cell types that are found intestinal epithelium. They have beautiful mucus. They have a top and a bottom; they’re beautifully polarized. They are showing more in vivo like responses to infection. […] We put immune cells in them. So our goal is to make those intestinal models more and more like what’s in your body. We’ve kind of taken that line of reasoning both from studying how bacterial pathogens respond to physiological fluid shear forces, and also using those same forces to develop more patient defective human tissue models outside the body to study host pathogen interactions. And that could lead could lead to, I’m not promising, could lead to a vaccine or other new types of therapeutics to help people.

Peter [15:50] 

Yeah that is a really interesting perspective. And I’ll think about that for a long time. And I was wondering, you know, where do you see the space science field, the microbiology field going in the next 10 years? And where do you see your lab moving 10 years from now?

Dr. Nickerson [16:06]

Well, that’s a great question. And I’m sure you will get different responses from different people. Ultimately, I think one of the top priorities is to move away from doing animal testing. We have to do that in my lab, because ultimately we can’t infect humans and test everything in humans. But we have to have better more predictive surrogate models. So, I think we can get there. By the way, a lot of groups are making huge strides and doing something we didn’t talk as much about, but developing human tissues and organs outside of the body with your cells that will function and be 100% predictive to how you respond to a pathogen. Nobody has one that’s 100% predictive yet, but we do this in our lab. Other labs that are doing it getting more and more predictive models for humans. That, to me is one of the major things that we must address, the fields are moving towards that direction. But that demands a multi-disciplinary approach of life scientists and engineers and physicists working together in large teams, and that’s the way science works now, which is great. Our team, your team are doing this, because no one person can be an expert and everything. And when you bring these multi-disciplinary efforts to solve these kinds of problems, we’re seeing that- we’re seeing this unveiling of new approaches to solve or help understand better, what pathogens do when they infect us. What do they do in the context of the whole microbiome that’s there that they have to get through to infect us? How did they do this with physical forces? How did they do this in health and disease? How do we make better models of humans, tissues and organs outside the body that will recapitulate every single biological, chemical, and physical factor in our bodies?

Peter [17:50] 

One thing that I really took away from what you’ve just mentioned is […] seeing something that is so disparately related, and tying it to human health is incredible. I think I am in awe of your enthusiasm that you gave at your talk, your enthusiasm in this conversation, and I was wondering, does that passion really drive you in the morning? Do you feel like it comes naturally? Or do you have to really wait for an aha moment?

Dr. Nickerson [18:12]

It’s absolutely natural. I’ve always said, If I do not absolutely love what I do, I will change in a heartbeat. I am beyond passionate about my commitment to my scientific discipline and field. It drives almost everything that I do. And my team members that I have the pleasure to work with in my laboratory have that same fire in the gut. So yes, we have lives outside the lab, but we kind of eat sleep and breathe this, because we love it. You have to have that fire in your gut. When you find what is right, […] it just drives you to do you get up in the morning, and you can’t wait to figure out what’s next. It’s constantly a puzzle to solve. So the passion is there; we feed off of it; we feed off of each other; we feed off of the discoveries, because at the end of the day, it’s all about leaving this world a little bit better than when you were here. And if any of our findings, any of our work, any our studies translate to coming up with better or novel approaches to combat and treat and prevent infectious disease. That’s what we’re learning to do.

Peter [19:22] 

That was a very motivating end to our conversation, Cheryl; and I want to thank you so much for being the first guest on The Gastronauts Podcast.

Dr. Nickerson [19:29] 

It is my honor, thank you for the invitation.

Peter [19:43] 

Well, what a way to end our first episode, Dr. Nickerson gave us a lot of advice to digest. But what really stuck out to me is the importance of accepting uncertainty and embracing challenge. We never really know where we’re going to end up, or how the world will view our science. So find something that you’re passionate about and really fight for it. 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 the music composer. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts: Dr. Diego Bohórquez on the Bohórquez laboratory.