Category: Podcast Transcripts

Season 1 Transcripts

Episode 6: Inventing The Inventor (Nancy Allbritton, UNC) [中文]

Dr. Allbritton shares her thoughts on what makes a trainee successful, how she has used gizmos and gadgets to create a model of the human intestine, and how one becomes a successful company founder.

Episode 5: Trust Your Gut (Michel Neunlist, Nantes) [中文]

Dr. Neunlist talks about how the nerves in our gut are linked with Parkinson’s Disease as well as the importance of integrity in scientific research.

Episode 4: Illuminating The Path (Nick Spencer, Flinders) [中文]

Dr. Spencer talks about the nervous system of the gut, and provides insight into how technology has changed science as well as the importance of perseverance in science.

Episode 3: Debugging Our Memories (Mauro Costa-Mattioli, BCM) [中文]

Dr. Costa-Mattioli gives us his thoughts on memories and microbes, and advice on how to push forward into new scientific fields.

Episode 2: Making The Jump (Ian Wickersham, MIT) [中文]

Dr. Wickersham discusses his work on rabies virus to probe connections in the brain and how he forms collaborations with other researchers.

Episode 1: Embrace The No (Cheryl Nickerson, ASU) [中文]

Dr. Nickerson shares her other-worldly ideas of sending bacteria to space, the challenges she faced, and what motivates her to do the work she does.

Dr. Allbritton [0:01] 

It’s got some interesting flavor notes in it that I can’t quite put my finger on. It tastes like a kind of peppermint flavored chip or some mint flavored chip of some sort.

Peter [0:14] 

Alright, you can take off the blindfold now. So what you have in your hand is actually a coconut chip. I thought it would be neat because one of the efforts in your lab is a gut on a chip, so it was pretty low hanging fruit. And the other thing that I thought was neat was if you look at a coconut cut in half, and kind of looks like a gut!

Peter [0:45]

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 and 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 learn how different scientists think and how they approach complex problems. So come join me as we explore our inner space on The Gastronauts Podcast!

Today, we have Dr. Nancy Allbritton, the Kenan Distinguished Professor of Chemistry at UNC, and the Chair of Biomedical Engineering at both UNC Chapel Hill and NC State University. A bit about Dr. Allbritton: she studied physics as an undergraduate at LSU, received her MD at Johns Hopkins and received her PhD in medical physics at MIT in the laboratory of Dr. Herman Eisen. She then went on to do a postdoc with Dr. Luber Stryer at Stanford, where she studied secondary messenger signaling. She’s been awarded numerous patents and is a scientific founder of four companies. I really want to pick your brain on the idea to go from research to establishing these companies. But I want to start by learning a little bit more about your work. From your web page, I found three major efforts: single cell enzymatic essays, a new method for analyzing and sorting cells through microrafts and these organ on a chip experiments- are these your lab’s current focuses and can you tell us a little bit more about each of these efforts in your lab?

Dr. Allbritton [2:43] 

Yeah, definitely. So those are the three major […] areas of the lab. And they seem like disconnected areas in many ways, but my lab builds gizmos and gadgets for a living, really small devices that are great for small scale sample handling, and for assays of single cells. So the first technology that we the lab started with, the idea was to measure enzymatic activity in single cells in parallel. You know, sequencing the genome has made a massive impact on science. And while all of these things are great, most of the time, what you really want to know is what’s the cells enzymatic activities are signaling behaviors, as opposed to just a list of the components. You know, you could have a list of your computer components, and maybe not know that it was a computer because a couple parts could be used to do something else. So the idea is that we could develop a technology that would have the potential to look at human samples from clinical samples, and measure signaling activity. So that’s about a third of the lab about another third of the lab, is our microarray-based sorting technology. And the idea for that technology came about when I was working with various biologists to come up with a better way for cell sorting. So we make this transparent array where the cells can just be plated down. It’s comprised of an array of little micro elements. And each element can be released on demand. So what you can essentially do is use any type of microscopy to screen the array, then have these computer algorithms or even some very simple things like for instance, rates of change, and go back and release those cells. So you can sort just 100 cells, or even 10 cells, instead of a million, which you would need, typically for flow cytometry.

Peter [4:37] 

Wow. And for those of us who are a little bit less familiar with flow cytometry, could you tell us a little bit about the technique and how it works?

Dr. Allbritton [4:44] 

Yeah, so it was an awesome technology and developed at Stanford quite some time ago by the Herzenbergs. And the idea is, you can take cells that have been detached from a surface, and then you can flow on through a very high-speed stream, and they’re interrogated with a laser-

Peter [5:00] 

Sounds intimidating.

Dr. Allbritton [5:03] 

It’s actually fun. And then as it goes by a computer makes a decision about […] a property, usually fluorescence, and we’re going to grab it and sort it or we’re going to let it go to waste. It’s a very high-speed sorting technology, but it has some, some real challenges. Typically, you need close to a million cells, there’s a lot of tubing and other regions of the device, and cells just get lost or disappear. So if you wanted to say, look for a one in a million cell or a one in a [100 million] cell, it’s difficult; it’s not one of its strong points. If you want a sort of very, very large number of cells quickly, though, it is quite excellent. And due to the fact that there’s high-speed flowing streams, there’s a lot of mechanical stresses that are applied to the cells. So a lot of delicate cells don’t survive the process, you get very, very high death rates-

Peter [5:59] 

Like a roller coaster ride, [you] go on, and you get torn apart from everyone else who was on that ride with you. And you’re certainly not going to be the same way when you come out afterwards.

Dr. Allbritton [6:08] 

Exactly, you get kind of all jumbled and mixed up. Again, a blockbuster technology that has some real strengths, but also some real weaknesses. So our technology is designed to have the exact opposite strengths and weaknesses: really, really great, almost no physical stresses or forces on the cells as they’re sorted. It’s never going to store it though millions and millions of cells, but it will sort very, very small numbers of cells very efficiently. And you can probably start up 100,000 or half a million cells reasonably well. And so each of these technologies was spun off into companies. And then our latest one, of course, is the organ on chip or the gut-on-a-chip system, both small and large intestine. And the whole idea there was to try and recapture the architecture and physiology of a living intestine all on a micro scale device. It’s not going to be as complex as a mouse, or a human, but it’s going to be a model system where you can tightly control all the variables. And in particular, what it will do is allow you to take human biopsy samples, and then rebuild a little miniaturized intestine. It’s very clear that our intestines […] have this extraordinary number of chemical and gas gradients, but understanding how these gradients impact the differentiated cells and control their behavior, and then the stem cells, especially in the human is pretty impossible right now. So our systems were designed to allow you to do that, to get different human disease models, see how they might behave differently from a normal person. You know, right now you use mice, but humans come in all different races, sexes, genotypes, and minorities, and that’s sort of wide open territory, but you can begin to […] look at how diverse populations respond by having bank tissues that you can then use to rebuild many different mini intestines on a micro device. The organoids for the intestines are actually essentially little mini-guts or mini-intestines. They have a lumen and a single layer of cells around the lumen. And they actually the cells, the differentiated cells as they die, go into the lumen. And over time, they’ll kind of open up and essentially poop out the dead cells, just like you would in a regular gut […] So it’s like the tube but it’s in a spherical shape. But they’re a little not quite right, the architecture isn’t quite right, the differentiated and the stem cells aren’t quite segregated, and the lumen of the gut or the interior is pretty inaccessible. So while it’s our breakthrough technology that […] I think will open the door to some amazing experiments by biologist and biomedical researchers, it still has some deficiencies. And our goal is to come in and build the next level, and create a tissue that actually has an accessible lumen just like the real gut does.

Peter [9:27] 

So, [that the organoid] will recapitulate everything exactly. And I think that was something that coming in as a younger scientist, I hadn’t realized the limitation of a lot of these systems that were done in a dish. I thought that we had the power to […] make the exact same things that was going on humans. And I realized that that is not the case. And this is a major progress forward in the sense that we are getting very close, we’re getting closer and closer to really mimicking what’s happening inside our body without having to go inside the body.

Dr. Allbritton [9:57] 

Right, exactly. And so now though, we can get human model systems and begin to do a lot of the screening on human systems. So you can now begin to use some of these systems to screen various human populations in people with different genetic backgrounds and make predictions. Okay, this group of people may do really well with this drug at this concentration. But in this group of people with this genotype, we’re going to need a tenfold lower concentration for the drug not to be toxic […] It’s now quite clear that our bacteria play a huge role in how we metabolize and uptake drugs, and they can turn drugs into toxic compounds, and for many drugs, [the bacteria] actually metabolize them into the active compound. So we can begin to think about understanding how we can manipulate the gut to make our drugs less toxic and more active.

Peter [10:54] 

You mentioned earlier that a lot of the projects or efforts in your lab have been spun out into companies. Could you tell us a little bit about your decision to found a company, the first company that you found was Protein Simple in 2000.

Dr. Allbritton [11:09]

Right, so I didn’t start out life thinking [I needed] to found companies, actually. I didn’t necessarily really feel that that was something I needed to do in academia. But what I discovered is, when you create a technology, if it’s a novel technology, it’s still viewed as high risk and immature. And so to go out and license that technology to a bigger company, it’s just too high risk. And it still needs a lot of investment in innovation to get from the prototype lab bench stage, to a marketable project. So what I discovered is, the only way my technologies would get out into the real world is if I started the companies that would build on them. So I had this technology, and my feeling was that if it was only limited to my lab, I wasn’t paying the taxpayer back. They had funded me to do all this innovative work, and it would just live and die in my lab. So the way to have real impact, at least if you’re a technology developer, is to have the technology go out into the real world and see other people using it. But much to my surprise, there was a huge gap. And companies just wouldn’t license your technology and start developing them. Right, I tried to license some of the first technologies and just hit brick walls. So I realized that, okay, if the technologies are going to get out into the real world and be useful to others, I need to do it, I need to found the company and I need to get it up and running. And actually, it was pretty exciting, because that’s a whole new skill set, right? And you can do great science that’s bad business. And you can have science, that’s okay. But it’s a great product. And so I actually came to enjoy it because you get to meet all sorts of different people with very different viewpoints. And the business world has a very different outlook and focus than academia. And I kind of like seeing that. But throughout all this time, I also realize that I’m not a business person, I should not pretend to be a business person. My job is to help found the company and be on the technology end. And so all of these companies have been partnerships with others. I think a characteristic of my career is always working in teams with other people. So the companies are always founded with a group of people, not just me as a founder. And we always try and pull in a business person pretty early, because there’s just a huge amount of work to go from technology feasibility to a functional company. And as an academic, I don’t have that skill set, but the business people do. And they can speak the lingo. And if we can work together as a productive team, we will do much more.

Peter [14:00] 

So it sounds like a really complementary skill set. You never felt the real push to ever leave science and go into venture capitalism or go into pharma, it was more so you realize you’re much more interested in passionate about being inventor than a salesperson, at the end of the day.

Dr. Allbritton [14:17] 

And I think that’s one of the coolest things. If you go to another lab, and you see your technology there, and they have no idea that’s your technology. And to me, that’s the ultimate mark of success for a tech lab is people using your technology. Recently for Cell Microsystems, I saw a Nature paper use the technology as a key piece of it. And it just said Cell Microsystems, and that’s pretty awesome.

Peter [14:44]

Do you have any advice for someone who is a young inventor, a new developer of a technology who is thinking about starting a company but not sure whether or not that is the right move for him or her; whether or not that is where he or she wants to see their lab perfect? Do you have any advice that you would give?

Dr. Allbritton [15:02] 

You know, it’s not for everybody, so does it get you excited? Are you willing to put in all that extra effort and time and get really excited about it. If you don’t, then it’s probably not your cup of tea, and you should spend your time doing something you get really excited about. The other thing I would say is, it’s really hard and a lot of work sometimes to start a company. So you just have to keep hammering away and staying motivated. You know, it’s like being a scientist: 95% of your experiments fail, and you have to learn to be motivated and just keep pounding away. And in the same way, starting a company is the same way. People will just often tell you what you need to do more of or why you can’t have any investment, blah, blah, blah. But you just keep hammering away and moving forward. So you have to believe in yourself. It’s hard work and believing in yourself. And being motivated, I think are the secrets. And I would say to anybody do something that gets you excited, because it’s easier to take the failures and the disappointment that are going to come no matter what you do in life. And if you’re still excited and you believe in it, you’re just going to be able to keep hammering away.

Peter [16:09]

Yeah, so it sounds like you really pushed yourself forward to not only be an investigator […] I was looking through a lot of your old work or your previous work where […] you won the Beckman Young Investigator Award on calcium signaling more recently in 2016. And 2017, you’ve been awarded on being an inventor. Has this kind of been transitioned in how you viewed yourself from an investigator on in your early stages to an inventor? Have you always thought of yourself as I am Dr. Nancy Allbritton and I am an inventor, or was there kind of a shift in that?

Dr. Allbritton [16:42] 

Yeah, […] when I was a kid, I used to work on my own car. And that was when you could actually work on your own cars and tune up the carburetors and all these other things. So I always like to build and design, you know, I used to build my own rabbit hutches, for example. So I always had that kind of bent where I like to tinker, and build and improve. So I’ve always been interested in building tools. And it’s always building a tool to solve a biological problem. And so that, I think, has been a hallmark. And even as I started my career as a professor, I was in a medical school. But even at that time, my lab was building technologies and tools to solve biological problems. And I like to think that I became smarter over time, because instead of me trying to figure out the right biology problems, over time, I began to focus more of my efforts on building the technologists and collaborating with others, rather than building the technologies and then also trying to solve the biology problems. Because I found that one, I can’t be an expert in everything. I can be really great at knowing all the engineering and analytical chemistry and physics, but trying to keep up with very fast-paced moving biology fields was going to be a struggle. And so I decided, I guess […] as I move forward [in my career] I realized what I was good at, and what I was less good at, and decided to focus more on the technology development, because I was quite clearly much better at that.

Peter [18:39] 

One of the questions that I was wondering how do you distinguish between the work you do in the laboratory and the work that is being done in these companies? Or is there kind of a distinction?

Dr. Allbritton [18:46] 

There’s actually a huge distinction. My lab is really good at coming up with new and novel ideas, and doing feasibility experiments and doing all the early stage work. But if you asked us to figure out how to make 1000 devices exactly the same, we would not be very good. Because we’re a small scale, we’re doing creative ideas and innovations. But our skill set isn’t such that we can figure out how to manufacture something that’s robust and reliable and the product is the same every time. And so if you think there’s a big gulf between demonstrating feasibility in the lab, and then getting a commercial product out. So my lab goes up to the demonstrating feasibility and utility. In my lab, we can fail. And we can fail a lot and keep going as long as we see succeed some of the time. But in a company, you need to succeed most of the time, and you need to serve the needs of a customer. And so I think the company does all of the innovation and creative thinking to get from our lab to what a customer needs, and make it reliable and robust and reproducible, and scalable. You can’t pay a massive sum per device, so how to make it manufactured at low costs. So there’s actually a very clean segregation between what the lab does and companies do. And it’s actually really good to have the companies because if people start to use our device, they’ll say, Nancy, can we have 100 of these little microarrays. And we’re like, oh, no, there’s no way graduate students in the lab can make 100 of these and send them out- one they’ll never graduate. And two, each one might be different from the next one that they make, because they’re being made by hand on a small scale. But for the company they’re easily able to serve those needs and purposes, as well as do some individual customization as long as they see a market. And then the company will also do a lot of automation innovation, which we may or may not do in the lab.

Peter [21:02] 

So the efforts in your lab are more broad horizon, seeing what’s out, developed techniques. And these companies, they’re really optimizing, refining. It’s nice to see that you are able to be involved in both: to see the entire process from start to finish, or from the inception of the idea to the customer.

Dr. Allbritton [21:21] 

Right, the company’s actually inform what we do in the lab. So you often see a lot of microdevices that while they’re great and elegant engineering, they’re never going to be a product, because they’re too complex and unreliable. And there’s too many moving parts. And biology is already complex enough. And so you can have a device with a lot of failure points. Simplicity is elegant simply is the way the best way to look at it. This, it’s really hard to design a simple device. But we try and head in that direction in the lab, because it means it’s going to be more usable by other people.

Peter [22:01]

So by working with these companies, you have simplicity in mind, you have an idea, if this isn’t usable-

Dr. Allbritton [22:07]

Then why am I doing it, and perhaps I’m wasting NIH’s money.

Peter [22:11] 

A lot of the skill set is […] the determination or dealing with failure between great science and being a […] founder of a company. But you also said there are great scientists who have failed products or great products that don’t have great science behind them. How would you optimize both of those?

Dr. Allbritton [22:27] 

Yeah, so you know, there’s all sorts of elegant technologies. And they’re used to answer fundamental questions, but they need a specialist in the lab that actually built the technology to use it. It’s so complex with so many moving parts, unless you have people in your lab that are spending all of their time keeping the equipment running or whatever; that technology is can be a breakthrough technology, but it’ll be a limited to a small scale effort. Whereas to have broader applicability. And to make it commercially viable, a lot of people have to want to buy it, there has to be profit, businesses are around to make profit. They’re not around necessarily solve science problems. And so there’s a real difference in the way you have to approach the two. And in science, […] in the lab, you want to solve a big problem. Even if it’s a technology that no one else will ever use. It’s in your lab, because it’s so complex. And that’s totally awesome. And then in the business world, the idea is to develop a technology that everyone can use that has no failure points, people can take off a shelf, figure out how to use it without becoming an expert. It’s like turning on your computer. If you have to learn how to program it, before you use it, it’ll be limited to computer scientists and that’s it. So for it to be a useful product and to be widespread, it’s got to be more turnkey and reliable, simple instructions, it’s got to fit into the workflow of people what people are already doing. So you know, when making a product, can you make it fit into the workflow of a biologist, make the form factor look simpler, make the process of using the technology have a look and feel similar to things they’re already doing. I’ll give you an example. Our first cell sorting technology, it used a laser, it was really quite an elegant technology. And we popped off these little devices, I thought it was an awesome technology. But it was very complex. And as we went around talking to business, people are like, you’ve got to lose that laser. Because it’s too complex, it’s going to be a very expensive tool and device. I don’t know how you’re going to manufacture that in a cheap form that’s going to be usable by a large number of people. And that was actually good advice. I was quite disappointed to hear that because I thought it was so awesome. But that kind of advice was really good. So my lab and I, we went back to the drawing board. We did complete design changes and then came up with a device. And you know, they’re […] somewhere around a penny apiece, you can break them. And it doesn’t cost any money. They’re easily replaceable. So it really just fit more into the look and flow.

Peter [25:28] 

That mentality of keeping it simple; Does it frame how you make your collaborations with others? How do you decide who to collaborate with?

Dr. Allbritton [25:35] 

Yeah, so we actually are collaborators in a way we look at them as our customers. So my lab is really great at building things and innovating and designing hardware micro-fabrication. But I wouldn’t say were the greatest biologists. And so the other thing we always want to do is make sure we’re building something that somebody wants. If you look at in the engineering world, they’re always lot of amazing devices that are looking for a problem to solve. And you talked to a biologist, and they’re like, so what, you know, elegant device with all sorts of bells and whistles, cool engineering, but why would anyone want to use that. So […] everything we do is a collaboration with potential end users. And we use their input and advice to drive what we do next. So they essentially tell us what’s needed. And then in some ways, we’re filling their order, if you will. If we listen to them carefully, we will understand what’s going to be useful to a broad community of people. And then we will design and tailor it. The other thing we like to do is we will make devices and we think they’re awesome. And then we give them to a biologist and they do things we did not realize they were going to do and we go. So yeah, they’ll come back and say, yeah, that worked. But this went wrong, that went wrong. And that informs us and then we’ll redesign, re-innovate, go through the whole design cycle, send it back to them. So we kind of work in this closed loop with all of our collaborators. And I think we end up with devices and tools that are much more usable and have immediate applications in end-users rather than us going out looking around and shopping for problems to try and find and use our devices far. So I tell the biologists and biomedical researchers, my job is to build a technology to enable you to do something you’ve never done before, and to make you famous. And if I make you famous, I fulfilled my goal, because I’ve created a really useful new technology that a lot of other people will want to use.

Peter [27:48] 

Yeah, one thing that just popped into my head was [on] how we present our information. A lot of times in research, we think about all the steps that could have gone wrong, and how we optimize these steps in order to get this system working. But if you think of it from kind of a company standpoint, it’s not so much, “oh, these are the things that could go wrong. These are all the things that you can do with it. This is why this is why it’s been optimized for you.” Right, having seen kind of both types of presentation styles are both ways of presenting the same product. Have you thought a lot about how researchers could be changing how they’re presenting their work? Or how they’re pitching their ideas?

Dr. Allbritton [28:26] 

Yeah, so that’s a good question. I think, you know, first of all, communication is everything in science. If you can’t communicate in a simple, clear and exciting way, your work is almost useless. Particularly, as time goes by, it’s very clear that we need to communicate to the public a lot better than what we’ve done. So making our science interpretable to a person’s everyday life. And so you can think of you know, the person on the street, how you show how your work is important into their life and can make their life better. But even as you go up in complexity, and you’re presenting your work to a scientist, how can you present your tools and technologies as not, gee, I got this great technology. But as you said, this is what you can do for you. And make it simple and clear and make the presentation style simple and clear. So I think that’s a skill set that we all need to work on in science, and to make sure we don’t disappear into jargon-land, which a lot of us tend to do, because it’s comfortable, we understand that. But it’s unfortunately, I think does science a disservice when one speaking to other scientists, but also speaking to the public.

Peter [29:41] 

Definitely, I value communication, I think it is important. One of the mantras that I follow is it’s important to be able to communicate effectively with everyone, right? Because if you’re speaking only in a way that you understand, no one else is really going to understand. So you’re not sharing the knowledge.

Dr. Allbritton [29:59] 

Exactly. And I think that you have to be able to recognize who you’re speaking to, and be adept at tailoring the content and level of your message for a different audience. So for example, you know, speaking to a gastroenterology group would be very different than speaking to a micro-fab group at a meeting. You know, I often go and give talks to high school students, which is a totally different style of presentation. Although the base concepts are the same, it has to be presented very differently and with a different style.

Peter [30:35] 

And an emphasis in your lab, I know you’ve mentioned is teamwork and mentorship, which kind of go hand in hand. And I was wondering, when you’re going from training the vast number of undergrads to grad students to postdocs, is there something that has encouraged you to maintain this role in education? And is there something that you’re looking for, in particular students when you’re accepting or deciding to mentor them?

Dr. Allbritton [30:57] 

In some ways, they need to have technical skills, I don’t care if they have the skill sets in my lab, I want them to be motivated. Often, it’s not the brightest people that succeed, it’s those that are willing to work hard, and those that are motivated, and those that are persistent. So I look for motivation, persistence, willing to work hard, ability to take constructive feedback, and not become defensive. If I look at the people that succeed the most, those are the qualities people have.

Peter [31:24] 

Is that regardless across the board, from someone who’s relatively new-

Dr. Allbritton [31:30] 

At all levels. Understanding that there’s no gimmicks or shortcuts to working hard, you know, working hard is what gets you there, you want students to understand that. And so my sense is that I like students that have those qualities. You want students that are a little adventurous, that will just try stuff and aren’t worried about failing. Because often I can’t approach a field with pre-conceptions. And I’ll tell my students, oh, that’s a really bad idea. I don’t think that’s going to work. Fortunately, they sometimes completely ignore me. And it’s like, “wow, what a brilliant idea. I’m so glad you didn’t listen to me.” So you also want people with a little bit of adventure, who like being ready to fall off that bicycle, you know, is a good thing, [people that are] just going out there and taking on new challenges and saying, I’m just going to try it and see what happens. And not saying well, I only do this, and this is what I do, because I do it well, but [people that are] willing to branch out and try different things.

Peter [32:33]

And on the flip side, these are skills that would be great for students, what are skills that you hope to nurture in students or trainees?

Dr. Allbriton [32:39]

Yeah, so I think communication verbal, I think written skills are extraordinarily important. I started my career probably without necessarily the best writing skills. So technical writing, having a clear, concise message in grant writing. I think most of us that are in science, at least engineers and chemists and physicists, we’re in those areas, because we don’t like to write. But realizing that still you’re going to have to learn to write and write and the better you write, the farther you will go in your career, even though it’s not your most necessarily favorite activity.

Peter [33:15] 

How do you go about improving your writing?

Dr. Allbritton [33:18] 

Yeah, for the students, you know, honestly, it’s hard work. There’s no gimmicks. The students in my lab, they have to write proposals for their research, I think I torture them to death, make them rewrite, and rewrite. And I think they think it’s pretty funny sometimes, because they get documents back from me, everything’s crossed out, but at the end, I think they develop sort of a camaraderie. Okay, we’re surviving Nancy’s editing. And so the idea is that through their career, we just iterate their papers, we edit their thesis, their edits, we edit their proposals to NIH. We edit and we just go round and round editing over and over. And you can begin to see them get better as they progress through the years. And people start out at different levels, some people are quite good when they start out. And so there’s not so much editing, but other people have a little bit more work to do. But the harder they work, they do better and going through this cycle. And then I think learning to work with others that aren’t like you- the lone wolf scientist, I think is pretty much a thing of the past. Teams of people work together, it’s quite clear will achieve far greater than someone working by themselves. If you look at all the breakthrough science these days, it’s teams of people from different nationalities, different backgrounds. So learning to be flexible, and work with others and tolerate others different working styles, I think is fundamentally critical for success in academia, government, industry, national labs, or even if you decide to be a teaching professional, the more you’re able to navigate and work as a team, the better off you’re going to be.

Peter [35:01] 

Yeah, oftentimes, it is challenging being that person who’s inserting themselves in a situation where everyone else has a groupthink mentality. Did you ever feel that as a woman entrepreneur in the biomedical sciences, that you had to face a lot of these challenges moving into kind of fields that have traditionally been dominated by men?

Dr. Allbritton [35:19] 

Definitely. And I’m old enough that there weren’t a lot of women, particularly in chemistry and physics. When I started my career, and things weren’t going right. I always think, how can I do better? You can say, well, it’s someone else’s fault. They didn’t treat me right, or they did this blah, blah, blah. But I tend to have a look at the world differently. And I think no matter who you are, you’re going to end up in situations where you’re not treated fairly, your age or sex or your race. And, to me at least through my career, it was always better to think how can I do better? Okay, if this is not a good line for me, for whatever reason, what direction can I take where, where I’ll see success, and try not to ruminate and get stuck in one area, but to say, “okay, let’s take a step back, and I’m going to go in a different direction. I’m going to try something else.” So I made some big changes in my career either, because I thought I want to do something, but I decided it was not a good idea, or ended up in a situation where it wasn’t quite right for something. And so the idea was that I always decided [to follow was] to take a step back and go in a different direction and push my goals. And I think that has served me well. So I kind of look at the world like that. And if you’re a little persistent, and you believe in yourself, and you’re highly motivated, you can just keep plugging along. And in the end, I come out ahead just from always thinking: okay, this is not working the way I’m doing it. And I just, I’ve got to figure it out myself and how to move forward and get advice from others, you know. When I started out my career, it was difficult to find anyone who looked like me in physics. And so it helped to be highly motivated and determined. But as my career went on, more and more people started to look like me. And that made life easier.

Peter [37:13] 

Yeah, so it sounds like, it’s not just tinkering with devices is tinkering with your mindset as well. Thinking about how we approach problems, not just from a device standpoint, but also from a fundamentally how do I think about this? And how is it affecting me? Because I was wondering, what’s next for Dr. Nancy? You have achieved so much, where do you see yourself going?

Dr. Allbritton [37:35] 

A lot of people have been asking me that. And I don’t have a great answer. Every 10 to 13 years, I’ve tried to reinvent myself. So I’m in a phase now where I’m working to reinvent myself. So I have a lot of directions, I’m kind of exploring and thinking about, and I don’t want to spill any secrets quite yet. But I also think, you know, to keep fresh and kind of on your toes, sometimes if you’re doing the same thing over and over, you begin to take things for granted. And that’s never good. So my sense is you kind of need to shake up your life every once in a while by just taking on a new adventure or taking on some new risks. And you know, different people have different time scales on which they do it. And my timescale has been like every 10 to 13 years. So I’m beginning to think about kind of what’s next. For Nancy Allbritton I’ve reached I’ve done a number of things, what are some of the big things I still haven’t done that I think that I could do? And you know, as you get older, you think, are there better ways I can contribute to the world other than just running a lab or starting a company? And what are the opportunities? And how can I have a bigger impact going forward? One thing that’s really good about getting older is your skill sets have expanded greatly and your ability to work with people and think about problems. At least I think now mine are considerably better. And I have more patience than I use to as a younger person. So you want to begin to think about how to use those skill sets, and just even begin to continue to broaden your impact. So I don’t have an answer for your yet but stay tuned.

Peter [39:12] 

That’s exciting. Thank you so much for agreeing to be on The Gastronauts Podcast.

Dr. Allbritton [39:16] 

Thank you for having me. It’s been fantastic to have a conversation.

Peter [39:32] 

Well, Dr. Nancy Allbritton really took us on an adventure, from a product idea to its execution and implementation. And along the way, we learned the importance of communication. Science is done in teams of varying expertise. And being able to tweak and tailor the way you convey information will help make your message that much more effective. So 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. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts, Dr. Diego Bohórquez and the Bohórquez laboratory.

Peter [0:00] 

You have it? All right, take a quick bite.

Dr. Neunlist [0:07] 

The food was clearly an apple. And the wine is red wine. I hope you gave me a French red wine.

Peter [0:17] There’s somewhat conflicting evidence on whether or not red wine is good or bad for Parkinson’s disease. We chose the apple for two reasons actually. First, because we saw that […] increasing fiber has been shown to help ameliorate Parkinson’s. But the other reason is that pesticides that are sometimes used in the growth of apples [are] actually a trigger environmental toxin that is associated with Parkinson’s. But I was wondering if you could use one word to describe how you were feeling when your eyes were closed. And when I was coming in with some food…

Dr. Neunlist [0:50]

I was anxious of what I would discover. But then I had the rewards of the sugar and the alcohol that’s contacted the anxiety

Peter [1:01] 

That’s good to hear.

Peter [1:13] 

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. And in particular, how our gut talks to our brain. We will be taking a deep dive into the mind and motivations of leading scientists and their work, and hope that by getting to know the individual behind the research, we can find out how scientists think and how we can build a better scientific community. So come join me as we explore our inner space on The Gastronauts Podcast.

Today, we are really fortunate to have Dr. Michel Neunlist speak with us. Dr. Neunlist did his PhD in cardiac electrophysiology, which is studies in the electrical activity on how the heart works, how it beats in Dr. Tung’s laboratory and Johns Hopkins and was awarded his PhD at the University of Louis Pasteur. He later went on to complete his postdoc in Dr. Sherman’s lab in Hanover, Germany, where he studied the entire nervous system, which is the system of nerves and supporting cells that controls our gut. Since completing his postdoc, he started his own lab and is currently the Director of Neurogastroenterology at the University of Nantes. So thank you for coming on the show. Dr. Neunlist, could you tell us a little bit more about the key functions of the enteric nervous system, and some of the efforts in your lab to study this?

Dr. Neunlist [3:03]

Thanks for your invitation to let me speak at this very interesting podcast session of Gastronauts. As you mentioned, the main focus of our laboratory is to study the enteric nervous system, what is commonly called as the second brain. And indeed, as you know, the gut is the second neurological organ, after the brain. And what we are studying is mainly how this nervous system that is integrated all along the gut wall, composed of about 200 million neurons, 1 billion glial cells in this nervous system is regulating major gut function, motility, barrier function. [We are interested in] how are so this nervous system is altered in various diseases, not only disease of the GI tract, but also diseases of the brain, neurological disorders, in particular, neurodegenerative disorders, such as Parkinson’s disease. And the last research axis that we’re developing is how to target this nervous system to restore organ function in disease condition.

Peter [4:25] 

That’s really interesting. It sounds like you have a lot of efforts that are going on in your lab. And I kind of want to break it down a little bit. The first thing […] that I want to ask about is, a lot of people may not be aware that the gut has- as many nerves you said 200 million neurons and then millions more glial cells; how does that compare to the number of neurons in the brain- is that more or less?

Dr. Neunlist [4:49] 

Of course, in terms of quantity, it’s much less. Quality is not always dependent on the number. But […] to give you an order of magnitude, it’s about 1000 times less nerve cells in the gut [compared to] the brain.

Peter [5:09] 

That’s really nice to have a visual representation of how many cells are part of this enteric nervous system. So it’s clear the enteric nervous system is essential for our day to day function for essentially life. You hinted a little bit earlier about some of the other efforts in neurodegenerative disorders that you are looking at. And I was wondering how the enteric nervous system plays a role in some of these neurodegenerative disorders like Parkinson’s or Alzheimer’s. And I was wondering what efforts you have done on that?

Dr. Neunlist [5:39] 

I think this is a very complicated question. And I think trying to prove the causal whole of the entire economic system in brain disorders is something that is still very speculative. But I think how we can integrate these two nervous system is that’s probably the affected by common mechanism. Because by definition, the two organs we consider the gut is a neurological organ.

Peter [6:06] 

So like the gut is a second brain?

Dr. Neunlist [6:08] 

Second brain in terms of quantity, but probably from an evolutionary point of view, it’s the first brain, the original brain […] because when you look at very primitive organs, like jellyfish, they have already neurons, they don’t have any brain on these animals, [and] they have already neurons within what is considered to gut. So to go back to the to the question, why is the nervous system affected in brain diseases in a large sense, not maybe only in genetic disease, but also maybe psychiatric diseases is probably because these disorders are in fact, associated with genetic defects, which all regulates neuronal function since they are co-expressed, both in the first brain and the second brain. They can induce GI comorbidity as well as a brain dysfunction. This is probably also the rationale why so often GI comorbidities observed in many neurological disorders, because they share common pathway, common origin.

Peter [7:19] 

Not many people are aware of the GI comorbidities or the GI issues that go along with the nervous issues. I think a lot of people when they think of Parkinson’s disease, they think of it as a movement disorder, kind of a little bit of the tremor, the unstable gait, but many patients with Parkinson’s often have constipation or diarrhea, is that correct?

Dr. Neunlist [7:40]  

Exactly […] What is also interesting to say is that these symptoms [or atleast] part of them can be considered as pre-symptomatic symptoms

Peter [7:49] 

That comes before the movement disorders.

Dr. Neunlist [7:51]

It comes before the movement disorders and there is this triad of pre-symptomatic symptoms, including sleep disorders, including anosmia or smell defects. […] and the third one is GI motility disorders such as constipation and dysphagia, which are the difficulties swallowing, and gastric emptying, slowing, which are considered as a frequent comorbidity that is pre-symptomatic.

Peter [8:30] 

These could be looked at kind of maybe warning signs of someone has two or three of the symptoms.

Dr. Neunlist [8:35] 

Exactly. So it’s not just one symptom, it’s not just because you’re constipated, that you are prone to develop Parkinson’s disease. But if you have sleep disorders, as well as constipation, then increased risk to develop Parkinson’s disease. So this has set the hypothesis that maybe if GI symptoms, presence prior developments of disease could originate within the gut. And probably, it’s still a very hot debate between pros and cons, because you could have GI symptoms and just because the systems is more sensitive to degenerative processes, and probably where the disease starts is very complex.

Peter [9:26] 

So you’re talking about kind of the GI or the gastrointestinal manifestations, whether they’re coming because the nervous system is more sensitive, or have these manifestations shown- is this chicken or egg, which one came first, right? The abnormalities within the GI nervous system versus the abnormalities in the central nervous system?

Dr. Neunlist [9:48] 

What is the driving hypothesis of not a pure brain origin, in Parkinson’s disease, but also more importantly, or degenerative diseases is that key molecules involved in the regulation of function for disease.

Peter [10:12] 

They all have misfolded proteins.

Dr. Neunlist [10:14]

Exactly. This mis-folding protein that can be used by probably a large spectrum of environmental factors. And effectively, this is one of the full diagnosis, the real diagnosis. And what is interesting is that access can only be done as a biopsy in post-mortem so the definitive diagnostic, Parkinson can only be done [after death].

Peter [10:37] 

And the reason it can only be done post mortem, is because we cannot grab that part of the brain and someone who is alive.

Dr. Neunlist [10:43] 

Exactly. So the idea is maybe you had to think about another organ, where we can do in a routine fashion. Biopsies result without being life threatening or with minimal risk.

Peter [10:57] 

You’re looking at a different organ where you can grab some tissue issues, where the person is still alive, is still alive and see if this is a diagnostic [tool].

Dr. Neunlist [11:06] 

Organs, which have neurons, we could use it as a [diagnostic tool] and what better than the gut that can fulfill this condition, meaning everybody […] has the opportunity or to undergo a biopsy, a colonoscopy. And the gut, as mentioned, has a nervous system. So this was a little bit the driving idea of looking at whether from a living patient, we could identify biopsies, identify the same normal v. pathological hallmark. So the idea supports that at least two organs are affected and whether treating the gut would improve treatment of brain function is something.

Peter [11:50] 

Is that something that you’re interested in? […] Is it known at this point? Or is it something that we need to continue to do research on?

Dr. Neunlist [11:57] 

Personally, I don’t really believe when patients have been diagnosed with Parkinson’s disease, you have a chance to free restore the disease, because you can slow the evolution of  […] disease progression, but there are some data suggesting that (and it’s an interesting, but still controversial study) showing that in patients that had appendectomy-

Peter [12:28] 

People who had their appendix taken out.

Dr. Neunlist [12:31] 

They have a significantly lower risk to develop [Parkinson’s] over the course of years. And what was even more interesting was that this observation lowered risk only was observed in patient living in the rural areas, but not impatient living in cities.

Peter [12:53] 

And there’s very different lifestyles and people who live in rural areas versus cities.

Dr. Neunlist [12:58] 

One of the hypothesis suggests that people (in cities) are more exposed to pesticides. For instance, farmers were exposed to pesticides develop higher risk of Parkinson disease. But again, this study is a controversial one… This is a study performed, of course, which could feed into good quality of medical studies, meaning you have […] 900,000 patients that were included over a long time, but you have other studies showing that there was no effects of appendectomy on the risk of Parkinson’s. And another one on showing that, in fact, it increases the risk.

Peter [13:44] 

The data is still a little muddy.

Dr. Neunlist [13:48] 

[…] And I’d probably point out to the fact that more research needed.

Peter [13:53] 

So it seems like Parkinson’s is kind of a combination of some genetic factors. And then certain environmental toxins or something that happens to affect the enteric nervous system.

Dr. Neunlist [14:03] 

And the brain and independently whether one is linked to the other is not known but affecting the two organs, of course, because of the function that will [be] responsible for, of course, for motor symptoms and GI dysfunction.

Peter [14:20] 

So understanding the interplay between the entire nervous system and the central nervous system, and how things can go wrong. And disease is somewhere where we have a lot of research to do.

Dr. Neunlist [14:31] 

And there is a lot of research to do especially to understand the mechanism of disease. And once we understand the mechanism of disease, we can propose an efficacious preventive treatment. This is mainly what is the goal is.

Peter [14:45] 

It’s challenging to do Parkinson’s research because we have to look at these environmental factors over time. And then there’s a certain time window where these environmental agents will have their most damaging effects. And getting the timing right now is just as important as understanding the entire progression. And I kind of wanted to take that to segway a little bit more so about your progression, as a scientist. I wanted to ask about your path. It’s being in the right place at the right time or having the right mentors at the right time. And I was wondering, could you tell us a little bit more about your training path. From the personal

Dr. Neunlist [15:20] 

From the personal point of view, I think you mentioned […] that encountering the right person at the right time is critical and crucial to develop your career. But overall, also you have to have and I think this is where a science of offers very much reward; you have to be passionate for science, and if you really want to do a career in science, you have to be curious. I mean, it’s like not easy, you have to keep your naivety, keep your motivation to discover to […] be really open minded. And you have also of course to be hard working. And I remember when I was doing my PhD in Hopkins, there was a flyer, where I saw a seagull, this is a builder that eats frogs. It had part of the frog in his mouth. And the frog was one of the arm was holding the neck of this bird in order to prevent it from swallowing it. And this is a little bit, the image of the scientist. As long as you don’t give up, you will always have hope and finding something. And if you give up, then you’ll be swallowed by the science. So it’s never give up. And this is the message of hope. I mean, this is a very critical because your hypotheses are not always [right] and your experiments don’t [always] work. But if you insist, insist there’s always a solution. I think it’s also message of optimism, you always have to be optimistic to go forward. And in science, there is one way is not the road is not the right one. And you have to go to another way in the end, the door will always open to success.

Peter [17:34] 

You mentioned briefly that maintaining an optimism maintaining a kind of a dedication to solving the science when something doesn’t go the right way, go another way. How do you know that this is not the right way to go? How do you know when to change directions?

Dr. Neunlist [17:49]  

This is the gut feeling, you know? That’s why we have nerves in the gut; that’s why we have the second brain.

Peter [17:57] 

As a graduate student, sometimes I’m thinking, I’ll do some experiments and they aren’t working out? Should I […] give up and move to a different project? Or should I continue to go on? Or and then how long should I continue on that process?

Dr. Neunlist [18:08] 

It depends […] I don’t like to give up. And you have to be confident in yourself that what you’re doing is the right thing. And if you don’t give up and you believe that what you’re doing is right. […] But often it’s your first ideas that are good ones. And again, the gut feeling. This is key: trust your gut and also trust, hear what your mentors are saying. I mean, that’s it.

Peter [18:36] 

You only have a few mentors in your life. And it’s important to develop those relationships with those mentors. You got your PhD from the University of the Louis Pasteur, but your scientific mentor at that time was Dr. Tung in Johns Hopkins. Is that correct? Could you tell me a little bit about that process about how you decided to go to Hopkins to do research?

Dr. Neunlist [18:56] 

This was not a gut feeling that drove me to Hopkins. But it was another type of feeling. meeting that I met someone. My girlfriend was American, so it was not a gut feeling. It was […] just life events. I mean, not everything is planned. So if you combine gut feeling with other type of heart feeling, then I chose Hopkins because of the reputation [of the] BME department in Hopkins, because I was a BME (biomedical engineer) […] and I tried. This is something you have to do, you have to try it. And then I wrote many letters. And then Dr. Tung [responded], and this is the huzzah; a good encounter at the right time. And when things are mature.

Peter [19:49]

How did you get interested in electrophysiology or in how electrical circuits regulate our body. I see that your passion, to my interpretation, is understanding how these circuits function.

Dr. Neunlist [20:02]

No, it’s understanding how biology works, how life is working, how organs are functioning, because this is basically also an engineering question. And what better and more complex machine for an engineer than understanding how the human body’s working, which is much more complex. So I think this is a little bit what drove me as an engineer to the world of biology. And as mentioned, then the opportunity was that I had to do this in the heart […] what’s kept me all along my career is looking at how electricity […] is involved in the […] biology of organs, the heart first and then the second, the gut because my definition as an neurological organ, bioelectricity places and recording functioning of the gut. And so this is a little bit [about my] path.

Peter [21:02] 

With your engineering background, and understanding the electricity and how circuits play a role in fundamental biology, was it kind of a natural segway from moving to the heart to studying the gut? Did you have any reservations? Were you thinking, Oh, you know, maybe the gut isn’t so similar to the heart?

Dr. Neunlist [21:19] 

No, because the link between the two was the methods. To measure electrical activity at that time, it was by microelectrodes. Then, of course, if you want to understand the activity of a neural circuit, it’s not just one neuron on at the time […], but it’s the global response of many neurons, that regulate. The advantage of optical sensing is that with optical measurements is that you can have a global measurement of electrical activity in the whole network. So it’s much closer to answer your question is how the network is altered in diseases […]So this is a little bit how the technology was used as a common path to ask a question to heart which was distinct from the question in the enteric nervous system and physiology.

Peter [22:12] 

So understanding the methods to understand the network is […] what you’ve used [to answer your questions]. You used it in the heart, and you saw there was applicability to the gut as well.

Dr. Neunlist [22:21]

Exactly. And then we’ll try to go further by integrating what was observed in terms of knowing the activity in terms of function, because the ultimate goal is to understand the function of the organ, whether motility or more a barrier function, which is more of interests to me.

Peter [22:43] 

What made it you have a seamless transition from studying cardiac tissue in the heart to gastro intestinal tissue in the gut, was the fact that you had this method, you had this technique that you could easily apply from one field to another. Being able to apply techniques to different fields is very powerful. But I also think it’s important to apply certain guidelines that you think are important for conducting science. Are there any of these principles that you instill in your mentees or people that you train? Are there any fundamental principles to approaching science that you like to share?

Dr. Neunlist [23:20] 

I mean, the most important aspect is to have a rigorous scientific approach in what you are doing. And [important for] science is also repeatability. I mean, you have to validate all the concepts; this is something that is crucial to study that I consider as a fundamental in any research in particular. It’s very basic principles I know. But this is the core structure of science, which is fundamental, especially in a world where science is declining very rapidly. It’s question very frequently [asked], and I think this is our only way to survive when we do our science. We also have to know it doesn’t mean that it’s right, because science is [going] to change, it [will] evolve. By the time you do science, it has to be running [appropriately].

Peter [24:28] 

So it’s essential to have good rigor or good dedication to your research. The reproducibility is something that you think is essential, something that you want to instill in others that you train; we want our science to be reproducible. I think there can be findings that are contrary to what we discover, but our experiments need to be reproduced. I think that’s really powerful. Because we live in a climate where news on certain scientific discoveries can be challenged very quickly. There has to be an understanding of the amount of effort, the amount of time that we put in each one of these discoveries, and to continue to instill that dedication in future scientists is something that we think is powerful.

Dr. Neunlist [25:10] 

I think this is fundamental, especially I think, where this credibility because science everywhere is also more and more driven by money. Especially in times of crisis where money is short, especially in this world. I think driven by money, it’s very important to keep your integrity.

Peter [25:29] 

Well, thank you so much Dr. Neunlist for being on our podcast.

Dr. Neunlist [25:31] 

Thank you very much was a pleasure for me to talk with you. Thanks.

Peter [25:45] 

Wow, I feel that’s a really important message to take home. At the beginning of your scientific journey, passion helps kickstart your research. But it is the integrity it is the rigor that helps your findings stay afloat and stand the test of time. I think it’s a lesson we’ve all heard before, but something definitely worth revisiting. How do we want our work and the work of our collaborators to be viewed years from now? Just think about it. Thank you so much for listening. And we’ll see you all 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.

Dr. Spencer [0:00]

It’s very sweet. It’s very pleasing. There’s a drive to put more in my mouth. So it’s a pleasant food. I’m pretty confident I got an idea what at least part of it is.

Peter [0:12]

All right. What [do] you think it is?

Dr. Spencer [0:19]

I think I’m guessing this chocolate on the outside and there’s something soft on the inside, like honeycomb or something not quite sure what’s in the middle.

Peter [0:25]

Alright, you can take off the blindfold. Really accurate description. It’s a Tim Tam. So are Tim Tam’s actually popular in Australia? I know that here in the States, we always talk about, “Oh, yeah. Tim Tam’s: the cookie of Australia.”

Dr. Spencer [0:40]

That’s really funny. And they are quite popular. Yeah. Okay. That’s sentimental.

Peter [0:48] 

Great, thank you.

Peter [1:03]

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. And 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 individual behind the research, we can learn how different scientists think and better understand the steps in the scientific process. So come join me as we explore our inner space on The Gastronauts Podcast.

This week, we have someone who has an exquisite understanding of the network of nerves that control our gut. Dr. Nick Spencer’s lab is working to specifically target these nerves to treat constipation and visceral or internal pain. He completed his PhD in neurophysiology at Monash University in Melbourne, Australia. He then traveled to the University of Nevada for his postdoc, where he studied the system of nerves that control the gut, and then continued this work after accepting a faculty position at Flinders University in Adelaide, Australia. Thanks for being on here with us today. Dr. Spencer,

Dr. Spencer [2:37] 

Thank you very much, Peter. It’s great to be here.

Peter [2:40] 

So one of the questions that I was wondering was, could you tell us a little bit about your current research and how you view it in the greater context of the neurobiology field and the gastroenterology field?

Dr. Spencer [2:52] 

Sure. Well, 20 years ago, when I finished my PhD, there was moderate interest in in the gut. People sort of perceived to be really an organ that absorbs nutrients, and expelled waste. But now as I’m sure you’ve seen, in the in the media, there’s a lot more attention and interest in the gut, not just for digestion, absorption, but bacteria in particular within the gut can have a major effect on our well-being and health. So many disciplines, for example, psychiatry and psychology, which would have never normally been interested in the gut are now paying tremendous interest in what we do. What we’re interested in is really how the nerves in the gut wall communicate with the brain and what are the mechanisms by which they’re activated.

Peter [3:42] 

Can you tell me a little bit about the techniques or the tools you use to study some of these nerves in the gut? Are they different from tools that people traditionally used to study they gut? Or could you tell us just in general, a little bit more about these tools?

Dr. Spencer [3:47] 

Sure. So technology is changing rapidly. Some of the things that we’re doing now were not, believe it or not, 20 years ago. Most of the techniques that we use were around, they include electrophysiology, where we can record the electrical signals from the nerves. That’s become refined, but no necessarily major breakthroughs in neurophysiology recordings [have occurred] per se. We use standard immunohistochemistry, where we can detect what chemicals are made within the nerve cells. That’s a relatively rudimentary technique. The new technologies that we use, one of which is called optogenetics, which is where we use light to stimulate cells. We can either excite cells like nerves, or we can inhibit them. And that’s a very, very exciting tool, which has only really been around in great strength, really the last sort of five to eight years.

So we use primarily immunohistochemistry, tracing techniques, optogenetics, electrophysiology, and the other major advance is been the development of transgenic animals, where we can manipulate the DNA in animals. For example, we can insert particular fluorescent markers into cells of interest, so we can see which cells in the in the animals light up and how they behave in the body.

Peter [5:21]

So it really sounds like you have a ton of really interesting technologies that are helping drive your research- from shining light into the gut to looking at specific proteins by labeling them with particular colors. Technology seems to be a huge motivating force in science in general. And I was wondering, if you were […] transported 30 or 40 years ago, how do you think your approach to science would be different?

Dr. Spencer [5:45]

Wow, that’s a good question, Peter. I’ve never been asked that and I haven’t really thought about the. I guess the caveat would probably have to say, before I answer that, is that 20, 30, 40 years ago, the questions would have been a lot different. Science, in general, is a lot harder now. It’s very, very exciting. We’re thrilled to be alive in this incredible era, where technology is developing at a phenomenal right. But questions are getting more difficult as things are getting out and more and more information is being uncovered. So I guess to answer your question, we would have had different questions back then. I mean, we were just talking at lunch […] DNA was only discovered at odd years ago, right? It’s extraordinary to think, you know, dinosaurs have been walking around for hundreds of millions of years. And we didn’t even know what DNA was in at this point.

Peter [6:37]

We’re hearing about CRISPR or other techniques to modify DNA.

Dr. Spencer [6:41]

That’s right. Absolutely, it’s phenomenal. Who would have ever thought we could take the DNA to make fluorescent markers in jellyfish and insert that foreign DNA into mice? And we wouldn’t have believed it, in answer to your question 20, 30, 40 years ago. So things have changed a lot; they’ve changed very rapidly, probably we’re back then we would have been restricted to relatively primitive techniques, like mechanical recordings and some basic electrophysiology.

Peter [7:10] 

So the questions, the type of questions that your lab would be asking would be completely different, is what you’re saying.

Dr. Spencer [7:15]

Yeah, pretty much. Very much.

Peter [7:17] 

Do you think that the questions would be simpler? I feel like when I think about scientific questions, oftentimes I think of them, and some of the simplest questions are still the hardest to answer. I think that the advent of […] these advancements in technology are helping us answer these simple questions, or do you think they’re moving us down the path of more specific targeted questions that are only a facet of a simple question?

Dr. Spencer [7:42] 

I think the answer would be both. I mean, as we uncover more information, we’re also unlocking more questions. So you’re right. I agree that sometimes the simplest questions are the ones we don’t know and haven’t yet- not necessarily haven’t yet addressed, but haven’t been able to get it answer to. Hardly because the technology might not have been there. One of the things we probably need to think about is that mammals like us adapt. So when we, for example, mutate a gene in a mouse, the animal changes its behavior acutely. But after time, it can often end up back the way it started. We use this word compensation. So if you if you deleted gene from birth, eventually, the animal may end up, may, not always, end up very similar to the way it started. So technology has got around that, for example, by being able to acutely, instantaneously delete a segment of DNA, and then see the effects in that same animal immediately after it. So you’ve got a good control reference. And that’s been very, very helpful to address some of the questions.

Peter  [8:53] 

I think that was interesting as a point of reference, in the sense that all these questions have been some related to time. And when we make […] a transgenic mouse, or when we modify it, we have to look at it immediately after because there is compensation that occurs in the long term. I touched a little bit upon CRISPR and gene editing. And we don’t really know enough about the technology to really implement that in humans at this time, because we don’t know what compensation will come about. And I think it’s, it’s interesting, and it’s powerful to know that these technologies that we have, they won’t fully be understood unless we take a look at them over a long period of time. And I wanted to touch a little bit on the optogenetics tool where you shine a light to turn on or open or close the channel, which will activate a particular cell or turn off a particular cell. How did you get to the idea of shining a light where they’re typically really isn’t light in the gut?

Dr. Spencer [9:52] 

That’s a good point. This certainly isn’t; there shouldn’t be. So the gut is part of what we call the peripheral nervous system. And the brain and spinal cord is part of what we call the central nervous system. As you know, and in general, probably more people are working on the central nervous system than the peripheral nervous system. So to cut a long story short, we’ve adopted technology from the greater mass of people that are studying the central nervous system and have successfully shown optogenetics works in the brain and spinal cord. And then we realized, look, there’s not much going on in the internal organs in the periphery. And the gut sets up beautifully for optogenetics, because it’s the only internal organ in the body with its own intrinsic nervous system. In other words, it’s got neurons, not just nerve endings, but actually the nerve cell bodies with the nucleus inside the gut. We call it the enteric nervous system. And what that means is that we can use optogenetics easily in the gut, to express the light sensitive channels which you were talking about and to manipulate the gut function.

Peter  [11:04]

And what kind of physiological or medical problems do you think this could solve by manipulating these nerves that are specific to the gut and aren’t really anywhere else in the periphery?

Dr. Spencer  [11:14] 

Yeah, that’s a good question. So there’s a number of potential avenues you could use the technology for. As you know, there’s a lot of diseases of the gut. Now, we don’t particularly work directly on disease, we’re usually trying to understand how the gut works on its own in a healthy state. The simplest answer to the question is that one of the big problems in the community is chronic or idiopathic constipation, where patients usually unfortunately, are restricted to laxatives. Now, there are some drugs on the market, which can stimulate the nervous system and the gut. But because receptors are usually expressed in multiple organs, when you take those same drugs that stimulate the nerves in the gut, it also stimulates nerves in other parts of the body. They’re not just specific to the gut nervous system. The beauty about optogenetics is that you can express the light sensitive protein, so make the channels the ion channels that respond to light, just in particular populations of neurons; just in the gut, which means that you can shine particular colors of light, in this case, blue light, which would excite the excitatory neurons, in our case, in the gut wall, right, causing the gut to contract and expel content without any drugs.

Peter [12:36] 

Do you think this is a potential application for humans? Are we able to shine a light in humans and eventually treat constipation?

Dr. Spencer [12:44] 

That’s a good question. So with the number of new techniques, there’s usually pros, and then there’s some cons. There’s some very, very clear advantages of using the genetics. And there’s some clear disadvantages. The big advantages that could stimulate just the gut to cause the muscle cells to contract to lead to an increase in the expulsion of content. In other words, improve transit. So the advantages are one is that the nerves in the gut would be activated instantaneously. You wouldn’t need to consume orally any drugs; it doesn’t have to get absorbed into the bloodstream, and wouldn’t be acting on all of the other organs non-specifically. And it’s a very potent way to just stimulate particular types of neurons, for example, the excitatory neurons in the gut, the negatives would be that you would need to incorporate the light sensitive DNA from the algae originally into the neurons. Now, that sounds a little bit like science fiction, but believe it or not, the notion of having a harmless virus in human has been approved and is on the market. But the question would then be is, well, what would happen if you shine the light onto the gut for long periods of time. There is some evidence that long periods of exposure might not be helpful. And you know, the other thing is that you would need to incorporate internally through the gut wall, the light source. Yeah, so usually, you would need to surgically implant miniature light emitting diodes onto the gut. Now, we’ve done that in mice, and it works. Conceptually, there’s no reason why that could not work in larger mammals. You would just need to make sure that you get enough neurons in the entire nervous system making the light sensitive channels.

Peter [14:42] 

Wow, that really does sound a little bit like science fiction. I think it’d be hard to convince someone right now, maybe whether or not to get a light emitting diode placed in their gut. But maybe if the constipation gets so bad, people are willing to try a lot of things. I’ve seen it in the clinic, [in] a lot of patients- it’s a really devastating problem. That’s one of their major concerns, right? They’ll come in with cancer, or inflammatory bowel disease, or any disease of the gut, and one of the major symptoms is that they have is abdominal pain due to constipation. I want to take a little bit of a step away from the science in particular and ask a little bit about your path. I wonder if you have any advice to graduate students? Or if you reflect a little bit about your time as a graduate student? How did you get the idea to go into this field to chase after a field that is rapidly evolving?

Dr. Spencer [15:19] 

Hmm, good question. I think the most important thing is that you pursue something that you’re interested in. Now, if you’ve come from an undergraduate background, and you have an interest in a field, my view is to pursue your interest. I’ve seen some people go into fields that they’re not really interested in just because there’s more money, or there’s, you know, some other side effects. And then, and then after a few years, they get quite unhappy. So I think the most important thing is follow a field that you’re interested in. And in terms of graduate school, I knew that I was interested in the nervous system and how these nerves were talking to each other, and how are they functioning, I couldn’t believe that you could remove a segment of gut from a mammal, and it would still work, even though it was no longer connected to the brain or spinal cord.

Peter [16:26] 

So the gut, by itself taken out of the mouse or whatever animal- how long does that last for?

Dr. Spencer [16:32] 

So we believe it or not we have taken the whole colon on out of humans with disease, and mice, rats, pigs, guinea pigs, and they will live for anywhere up to sort of 10 to 12 hours, you could keep something alive as long as it’s got some oxygen in the solution.

Peter [16:50] 

Wow, so that that’s super cool. And I’m assuming that drew you towards the gut.

Dr. Spencer  16:54 

It did, it was the if you can think of the gut a little bit like the heart, he took the heart handles still keep beating, there’s an intrinsic pacemaker. Well, there’s also pacemaker cells in the gut. And they’ve been on the recently last decade or so been identified. So the nerves within the gut wall can also behave in a rhythmic pacemaker top fashion. And I was really interested in how we could speed that frequency up or slow it down. It’s taken a while, but we’ve made some really pleasing progress. And it’s been extremely rewarding. So getting back to your other question, I think the reward and excitement for unlocking previously unknown questions is immensely powerful. And no salary can substitute the satisfaction for that.

Peter [17:44] 

Yeah. And I think that is a recurring theme that I see here- it’s the drive for answering a question that nobody else has the answer to, so thank you for sharing that with us. The other thing I wanted to ask was, we’ve talked a lot about the development of technology and how things have happened over time. And I think it’s important for us, as scientists, to recognize how the field has changed and some of the giants who came before us and the research that they did. I was wondering, is there a particular scientist, or is there a particular group, that you found truly inspirational or motivating your work or having a large influence on your work today?

Dr. Spencer [18:21] 

Yeah, that’s a good question. Yes, that definitely is there’s a number of people and groups, I think probably one of the most moving stories that I’ve the most influential for me was, ironically, an Australian guy. This person, Robin Warren, from Adelaide, is the only winner of the Nobel Prize for the gut. And what he discovered was that bacteria can actually live in the stomach. It wasn’t so much the discovery itself that fascinated me and inspired me it was the way the discovery was made. Because for at least two or maybe more decades, nobody believed him. In 2005, he got a phone call, that he had won the Nobel Prize. And I think the fact that he had an unwavering tenacity, and an incredible ability to persist, and not give up is extraordinarily inspiring.

Peter [19:43] 

Wow, that is a really inspirational story. I think we talk a lot about genius, right? We think that there’s genius, and there’s hard work. And we think, oh, you know, I can’t emulate that, because someone just has naturally more talent than me. But hard work is something that we think we can if we put more effort, and we can achieve this and we can persist. But being able to persist when everyone else is telling you. It’s not right is genius in and of itself.

Dr. Spencer [20:09] 

Absolutely.

Peter [20:11] 

And one other thing I wanted to ask was a little bit about your transition from making the decision to come to the United States to do a postdoc, and then making that decision to go back to Australia to being a PI, being an independent investigator, It’s certainly a risky decision to go back and forth and leave your country. Could you just tell me a little bit more about what was going through your head and any advice you would give to someone who is having kind of a similar decision-making process.

Dr. Spencer [20:37]

This is a really important question. So after nine years as a postdoc in a good institution with a good group of people University in Nevada, I had been moderately productive, and learned a number of new skills. And then I got some funding and it became a bit awkward, because the person that I went over there to work with was just down the corridor. And I found a very, very hard to break away, scientifically. And there was a little bit of tension about whose ideas were what and should I be working on this, or isn’t that your project or my project. I had an excellent offer to stay for good. And I had funding in North America, and I gave it all up to a much less prosperous offer. In South Australia, the offer was a permanent position. But I had almost no funding to move into, and I was leaving all the equipment and stuff behind. The reason why I left is because at some point in time, you have to really demonstrate you are fully independent. And whenever you submit an application, if you’re in a big group where you know, it doesn’t matter to the best group in the world, if you submit an application, immediately think that it’s the group or the senior investigator of that lab that’s dropping the project. And you’re, you know, really just working in there. You really just need to be able to break out and show that you can work on your own, and you’re actually driving the projects. You’re the senior author on the papers. And that’s a cycle everybody has to get into some point, if they want to become an independent PI. It’s very, very difficult to break out once you stay permanently in the same postdoc.

Peter [22:22] 

Did you ever feel like it was challenging to have your own ideas? Or maybe when you were going through the process, is there a point in time in your graduate career where you’re like, “ah, this is mostly my ideas?” […] I’m a relatively young graduate students. So a lot of the times you go into a lab, this is a lot of the PI’s ideas, and you’re learning a ton. But is there a point where you reach that transition where you’re like, these are majority of my ideas? And is there a way to kind of expedite that process? Or is that something that just happens over time?

Dr. Spencer [22:50] 

It’s a good question is something that happens. So when you first walk into a a laboratory, I don’t think anybody on the earth would know what they’re about to do or what they’re about to find. And that’s the whole point of doing independent scientific endeavor; it is to answer questions that have not been resolved. So you shouldn’t be discouraged from not knowing anything, anybody, when they go into a laboratory, you should think of the question. And if it’s of interest to you, and you’re really passionate, stay with it. Over time, as you do more experiments and you do more reading, and you go to more meetings, and you meet more people, certain things- your ears will pick up. And you’ll realize that, or you’ll hear just obvious, you know, things that have not been resolved. What are the major questions that we don’t know? And then you think: well, is there anything I could do that could answer that that others can’t? Now often, the answer is no. Other people are already doing it, or they’re doing it better. But it’ll come to a point where you often know more about your project than your supervisor. And you will be sometimes generating the data fully independent and thinking about the experiments. And by the end of the graduate degree, you really should know more about your project than your supervisor, because you’ve done it. And ideas will come up. And you’ll think well, you know, why don’t we try this or that. And a lot of it is trial and error- some things will fail and some things will work. And it’s a matter of knocking on as many doors as you can and finding the ones that will open that give you a path to breaking away from the field and showing that you can drive the projects on your own.

Peter [24:35] 

Thank you for that advice, Dr. Spencer, and I really want to thank you for taking the time to talk with us about the importance of technology and scientific discovery, and how you’re able to establish your own research niche, so thank you again for your time.

Dr. Spencer [24:48] 

It’s a pleasure. Thanks for having me.

Peter [24:59]  

Placing it LEDs in the gut as a clinical intervention to treat constipation may come off as quite the unusual idea. But listening to Dr. Spencer’s passion for his work, and his stories on the importance of persisting and believing in yourself makes me think, why not? Especially if we can limit the side effects. Perhaps in 20 years, this type of intervention will become the norm or perhaps it will even seem outdated. Regardless, in this rapidly changing and contentious field of science, it is important to not only be adaptable, but remain steadfast in your beliefs. Because if you do not, there’s no way to convince anyone else. With that, I want to thank you all so much for listening. And for more of our content, you can follow us on Twitter at gutbrains or visit our website at thinkgastronauts.com. The astronauts podcast would be impossible without the incredible team that we have here. Meredith Schmehl is our producer and theme 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.

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

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.

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.