Ep 4: Illuminating the path

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.