Ep 1: Embrace the no

Transcript                                                                                                                                         

Peter [0:00]

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

Dr. Nickerson [0:04]

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

Peter [0:16]

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

Dr. Nickerson [0:23] 

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

Peter [0:29]

You can open up your eyes now.

Dr. Nickerson [0:32]

It’s a moon pie! Not too far off.

Peter [0:37]

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

Dr. Nickerson [0:38] 

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

Peter [0:54] 

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

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

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

Dr. Nickerson [2:24] 

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

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

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

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

Peter [5:49] 

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

Dr. Nickerson [6:48] 

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

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

Peter [8:33] 

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

Dr. Nickerson [9:08] 

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

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

Peter [11:17]

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

Dr. Nickerson [11:23] 

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

Peter [12:31] 

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

Dr. Nickerson [13:00]

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

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

Peter [15:50] 

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

Dr. Nickerson [16:06]

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

Peter [17:50] 

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

Dr. Nickerson [18:12]

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

Peter [19:22] 

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

Dr. Nickerson [19:29] 

It is my honor, thank you for the invitation.

Peter [19:43] 

Well, what a way to end our first episode, Dr. Nickerson gave us a lot of advice to digest. But what really stuck out to me is the importance of accepting uncertainty and embracing challenge. We never really know where we’re going to end up, or how the world will view our science. So find something that you’re passionate about and really fight for it. I want to thank you all so much for listening, and we’ll see you next time. For more of our content, you can follow us on Twitter @gutbrains, or visit our website at thinkgastronauts.com. The Gastronauts Podcast would be impossible without the incredible team that we have here. Meredith Schmehl is our producer and the music composer. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts: Dr. Diego Bohórquez on the Bohórquez laboratory.