NEB Podcast #80 -
Transcript
Interviewers: Lydia Morrison, Marketing Communications Manager & Podcast Host, New England Biolabs, Inc.
Interviewee: John Burns, Ph.D., Senior Research Scientist, Bigelow Laboratory for Ocean Sciences
Lydia Morrison:
Welcome to the Lessons From Lab & Life Podcast, brought to you by New England Biolabs. I'm your host, Lydia Morrison, and I hope this episode brings you some new perspective. Today I'm joined by John Burns, a senior research scientist at Bigelow Laboratory for Ocean Sciences. John works at the interface of bioinformatics and molecular biology, studying symbiotic reactions and exploring marine lineages.
John, thanks so much for being here with us today. Could you tell our listeners about the type of research that you do?
John Burns:
Yeah. So the research that I do, the definition of it has changed a lot over time. I mean, long time ago I was studying geoscience, but in my real professional career, I started out doing molecular and cell biology, which changed over to more evolutionary biology. But now I'm part of this new kind of emerging field that's called evolutionary cell biology, which means taking a look at how cells are formed, what they're made of, but always looking at that through the lens of evolution. So we're looking at those classic molecules that make up cells like proteins, lipids, and nucleic acids, but taking them through the lens of diversity and evolution so we see how they change and how different branches of life use them in different ways. So I think it's really exciting.
Lydia Morrison:
Yeah, really interesting. And a lot of your work focuses on marine systems, right?
John Burns:
It does, yeah.
Lydia Morrison:
Why is that?
John Burns:
It wasn't always that way. I did my PhD in cancer biology, so I was doing something very, very different. There's not a lot of cancer research in marine systems, it was more human work. And it was really on the foundations of how does DNA change and how do cells resist those changes? But when I finished the PhD, I really started to think more about my history in geoscience and my interests that were in art and in exploration. And my mind went to these little critters called radiolarians and they're a type of single-celled organism. They're only found in the oceans and they make skeletons or little shells... Or they're really actually internal, so they're skeletons and they're out of a glass, like pure glass like the kind you drink out of. And they make them in these really beautiful different types of shapes and forms.
And I was really interested in that kind of cell biology, like how can a single cell that doesn't have the advantage of piecing things together from lots of different parts, it has to construct everything from within itself, make this glass structure, which is hard and dilute in oceans, and make it in with really fine resolutions? So it makes these structures that are microns or submicrons across or even less than that out of glass, which just blows your mind. And they work in really different ways than most of any other kind of cell you could imagine. So that really brought me to wanting to do marine science and it took me a long time to really get there. I worked first from the PhD in this kind of more human-focused world, I moved to more evolutionary biology at the Museum of Natural History in New York City, which is wonderful place to work, and it was until after that that I was able to steer myself more towards these marine systems where I am now.
Lydia Morrison:
Yeah, interesting. It sounds like it was just one really cool organism that really drove the shift for you, which I love. It's like you find one thing that you're really into that you've got to understand, right? Changes the whole path of your career. So I know you just got back from an expedition where you were collecting samples of DNA material from deep in the ocean. Could you tell us about that trip? I'm sure that some of... Obviously those results are unpublished and you literally just got back, but whatever you can share, we'd be interested in hearing about your latest research expedition.
John Burns:
Yeah, thank you. I mean, it was a really exciting trip. And what drove that trip is we got this funding from an award called The Ocean Shot, which is kind of a take on the moonshots and things like where you're really trying to do groundbreaking research to open up new fields to exploration and discovery. And that ocean shot comes from a Japanese foundation called the Sasakawa Peace Foundation. And along with that Ocean Shot funding, we also got awarded ship time on the Schmidt Ocean Institute's new research vessel called the Falkor (too). So we were boarding the Falkor (too) with this project from the Ocean Shot and our goals were actually really simple of innovation, exploration and discovery really. There were two teams out there. One of them was led by museum scientists, so they're interested in species discovery and there are all these experts in taxonomy, but you need those people to help you understand what you're looking at.
And my team was mostly engineers and we're developing the tools that allow us to look at animals in this crazy space, which is not at the top of the ocean or the bottom, but in the middle, and that's like the largest ecosystem on Earth. So you can imagine the oceans over 70% of the globe, it's just water, and we know very little about it in general, but we know most about the top and the bottom because we like to think about things in plains. But there's on average 4,000 meters of water in the oceans, over 70% of the Earth, and that's two and a half miles deep. And we don't spend a lot of time just wondering about what's floating around in the middle if it's not about our food, like fish and stuff, but there's mostly little microscopic organisms and big weird jellyfish floating around there.
We were kind of focused on tools that can help us find, describe and measure those kinds of animals in their natural habitat, and that's what that cruise was about. So we ended up going 350 miles east of Brazil out into international waters, sending this ROV equipped with all this new technology down and just using it to explore the water. It was really like if you go for a walk in the forest and you don't know what you're going to find and we're just driving it around and encountering weird new life.
Lydia Morrison:
What an amazing experience.
John Burns:
Thank you.
Lydia Morrison:
It sounds kind of otherworldly to me to think about being at that depth of the ocean and just driving around and seeing who you cross paths with. So really interested to hear more about those findings when you've had some time to dive into the materials that you were able to bring back. And I know that that was sort of the most recent project and you've been working on that a lot, but I wanted to back up a little bit and talk about some of your previous work. I know you've studied the salamander algae symbiosis system for years, specifically the biotrophic lifestyle of these symbionts, and I was wondering if you could tell us about that and how those organisms managed to live inside another cell without triggering a massive immune response and eviction notice.
John Burns:
Yeah, thank you. That's a great question. And it is a system I've been working on for even before I left the cancer biology, I started working with these salamanders mostly because I had a specific type of expertise that the people that recognized the endosymbiosis, the cell living inside another cell part of this interaction we're looking for, and that was called cell sorting. So the salamanders is a multicellular animal. It's a vertebrate. It's kind of like related to us. They're amphibians.
Lydia Morrison:
Very cute, yeah.
John Burns:
And they're super cute, yeah. And they have lots of cells and this endosymbiosis happens in only a subset of them. And to study it, we really wanted to be able to get at those specific cells where the algae were living inside. And so the folks, Ryan Kearney and Eunsoo Kim, came were the two people that really set off this discovery in the first place. So actually to back up a little, we've known about this symbiosis between salamanders and algae and their eggs for a very long time, since... The first description was in the 1880s.
Lydia Morrison:
Wow.
John Burns:
Yeah, and it was like a naturalist. His name is Henry Orr and he was a guy that walked around in the forest and saw these green egg masses and really just wondered about them. So it all started with this observation. And from that time period on, people studied it to understand why are these algae and these eggs... And it wasn't until 2011 with Ryan and Eunsoo who recognized that the algae also invaded the salamander's tissues and then they recruited me for this flow cytometry. And the funny thing is we never got that part to work. The embryonic cells are really fragile and they didn't do very well in the flow cytometer and that sorter. So what I ended up doing was using skills coming back to radiolaria. So I had taken a couple little trips to learn about how to see and isolate radiolaria and these single-cell marine things, I applied those skills and it was manual isolation of single cells. I could see the symbiotic cells, I could pick them out and we could use that to learn about how they interact together.
Yeah, and to get to your question about the immune response, so that's kind of a little bit of the history of it, but the immune part is actually a really, really interesting part of the story that these salamanders are vertebrates like us, I said it already, but that means they have adaptive immunity, which means that they can make antibodies. So you could vaccinate a salamander against anything you wanted. And there's this thought in the symbiosis world that actually very few vertebrates or really no vertebrates have endosymbiotes, have cells that live within their cells. We have symbiotes that live in us. We have the stuff that lives in our guts. We've heard of our microbiome, but most animals are the inside is actually still kind of part of our outside.
We're like a tube. So the bacteria, our microbiome that lives in our gut is still on the outside of us. It's kind of inside our body but outside of our cells. In this salamander, the algae are actually getting all the way into the cells and doing this biotrophic lifestyle thing. So how do they evade immunity? It's actually a funny coincidence of development that they're evading immunity simply because the salamanders haven't developed their immune system yet. And this is a thought that's not perfectly original to me. It actually came from a symbiosis researcher named Dr. Angela Douglas and she's a real giant thinker in the field. And after I gave a presentation, she came running over to me one time to my poster and she was like, "These salamanders are the exception that proved the rule," and I don't know exactly what she meant right away, but after a couple minutes, I started to understand that most vertebrates don't have endosymbiotes potentially because of this adaptive immunity.
These salamanders do, they're vertebrates, but actually when they're in their eggs, their adaptive immune system hasn't turned on yet. So they're actually a lot more like invertebrates and there are lots of examples of invertebrates that have endosymbiotes. So the algae are not triggering an immune response because there isn't one there yet. So they're able... Just like in other invertebrates, they're able to find a way around innate immunity, which is the kind of immune system that all organisms have or all animals have, but they don't have to contend at least at that period with adaptive immunity with antibodies.
Lydia Morrison:
That absolutely makes sense, and I think it's really interesting, but it's a great demonstration of the amount of time that it takes to develop those complicated systems even in a more simplistic multicellular organism like a salamander. I think it's a great example.
John Burns:
Yeah.
Lydia Morrison:
I know your comparative genomics work has revealed some pretty striking patterns around functional conservation and divergence within marine microbial lineages. Looking back, what do you think was the biggest insight that's emerged or something that changed how you think about microbial evolution?
John Burns:
Yeah. So that work maybe you're thinking about was this... I was working on something called mixotrophic green algae, so it's... Green algae are related to plants, and as we know, plants don't eat other things for the most part. I mean, there's like the Venus fly... They're really specialized ones, but they are also kind of external digesters. But this was a green algae, it was related to plants and it was able to feed on bacteria by taking them inside itself. So this is a capability that's common to amoebas and things, but isn't typically found in the plant lineage. So this was a very unique system. And one of my first projects when I worked at the museum was the genome of this algae, trying to understand it. And one of those aspects was how can it be eating? What's so different about it than plants and other green algae that allows it to eat?
And by investigating its genome, I wasn't actually able to answer that question very well. I got some hints at what could be going on, but it wasn't until I was able to release myself from this specific thing that I was studying that I was able to get at this broader question of how can you use this comparative, the information in cells to say something a lot more broadly and then use it to predict something complicated, like eating. So eating, it doesn't happen from one or two genes that you can identify. It's like this mix of hundreds of genes that you can use in all different ways and through that comparative genomic... So it was like a flash. I actually remember very specifically with, I was standing with my wife and we were in a subway platform in New York City and I was standing here, I was like, "I think I know how to do this," and I was like, "I think I have this small thing that can solve this problem about how to make predictions using genomes."
And the inside was more like, instead of thinking about genes as individual units, think about them as building up into these functional cores and instead of trying to predict on genes, which can vary a lot from one species to the next, those functional cores can kind of collapse a lot of the noise into themselves and you can make the predictions on those that allows you to see how a more complex system can emerge from a genome. So that was the insight. I mean, it sounds a little bit out there, I think, but it really allowed me to go from this one thing that I was studying very, very intensely to broaden myself out to say, "Well, what does everything have in common, and then what can they have indifferent, but not at the level of one gene, but at the layoff of how those genes are interacting?" And that's what really changed the way I think about comparative genomics, genomes, all of this kind of information that drives biology. I don't know if that answers the question all the way.
Lydia Morrison:
It does. It does. I think it's a really interesting take on it. It's kind of like applying a level of organization to the genes within the genome themselves and sort of trying to categorize them into functional similarity and being able to translate that into actual cellular processes. Does that make sense?
John Burns:
It does. And actually to follow up one more point is that there were a bunch of studies that I leaned on where people characterized this cellular eating specifically. A cell makes compartments. Our cells make these little packets of sub-cells that have a set of proteins associated with them and they measured what all those proteins were. And so I looked at those proteins. I was like, "Oh, these are the ones I need to predict whether or not you can eat because these are the ones that they use to eat," and it turns out those ones were useless for predicting. Even collapsed into functions, every single type of life had those same proteins and functions, they just didn't all use them for feeding. So that's the other insight is that a lot of the processes that we have aren't specific to one function, they can be used in many, many different ways.
And that part I still don't fully understand, but what came out of the comparative predictions is that there's a lot of accessory things happening around the outside of that core function and those became predictive. So it was things that regulate it... Or one of my favorite examples is something called the WASH complex. So it's this protein complex that allows you to recycle pieces of membrane and protein. So imagine you're feeding. So you're taking a piece of yourself from the outside and pulling it in and along with that comes all this other stuff, and you don't want to digest all that stuff because that'll be a waste of energy. So if there's stuff that you want back out on the outside of your cell, the WASH complex bundles it up and puts it back out there so you don't have to make it again. So it turns out that that WASH complex is actually pretty important for being able to feed because it saves you the energy of having to remake all that stuff by recycling. And that's not something that was obvious at all to me. So there's one of those very particular insights.
Lydia Morrison:
Yeah. I mean, it sounds like you were able to make some really incredible observations around the functionality of those systems. Super cool. You've also done some work on the origins of animal development, looking at a protist. For that work, you led the bioinformatic analysis, I believe, and uncovered some developmental-like programs. From a data perspective, I'm curious, what was the most surprising signal that emerged? How did computational analysis allow you to see something that would've been missed experimentally?
John Burns:
Yeah, that's a great question. So that work was led by a researcher named Dr. Omaya Dudin, who's now in Switzerland, and he is a real pioneer in imaging cells, even really small cells, but he's very interested in this question of how do cells developed, but where did development even come from? And so the foundation of that work was a lot of this observation and imaging to see how this weird little protist, and it's a protist in a group called holozoa and holozoa actually includes us animals. So holozoa is animals and its closest single-cellular relatives. Outside of holozoa, the next closest group to us is actually fungi. So fungi are our cousins, then there's us plus our protist relatives and then we can break animals up into many different groups. So this little holozoa, it's called an ichthyosporea and it's teeny tiny thing and it goes through this process where it starts as one tiny cell and it starts growing into this big ball and then it starts dividing.
And when it divides, it looks just like an embryo dividing. And so that was the observation that kicked off all of this analysis. And what Omaya did was he took very specific time points during that, what he recognized as a developmental process and pulled RNA, which is like the functional content of what the cell is doing at the time, and then I analyzed that. And what was really beautiful about it is that there's this cascade of gene expression. So there's this cascade of things that happen reproducibly at different time points as this little protist is developing that tells you about what that cell or bunch of cells, what's happening to it as it develops. And we were able to map that to developmental processes in animals and metazoans, like real animals. We also go from one cell to many cells and then we continue to develop into people, but other animals into whatever they are.
These little protists, they go from one cell to many cells and then they break back up into small cells again. But the key thing that we saw actually both microscopically and in the data, in the informatic data was that it goes through this process called differentiation. So from that one cell, while it's still in that little ball of many cells, it turns into at least three different types of cell and that's pretty remarkable. And that's a key aspect of development, that you're actually not just going from one cell and making more of yourself, you're actually changing into different parts. So that was one of the cool things that came out of it. Other things were that some of the real important genes for our own development from one cell to many, not all the way to people, but from those first steps are the same genes that this protist is using.
We don't know for sure right now whether or not... And they're being used in the same pattern. So they go from off to on or on to off in sort of the same timeframe. But we don't know for sure if it's coincidental or if there's this core developmental program that these protists had access to that our ancestors, we had single-cellular ancestors long time ago too, also had access to, and they just kind of ended up using it in different ways. So there's these two competing hypotheses that we're trying to move forward with now, but it gives us a really nice and interesting window into evolution.
Lydia Morrison:
Yeah, kind of mind-blowing actually that a single cell could sort of be that fluid in differentiation and that potentially that programming could still be there in our cells or in at least first multicellular organisms.
John Burns:
Yeah, that was the coolest part from the information perspective.
Lydia Morrison:
Yeah. Yeah. So I know we talked about it at the beginning of the podcast that you just got back from an expedition, but I know you've given a lot of thought to how marine samples are collected and how that can affect the findings, if you're taking a sample from an animal, what kind of stressed state they might be in at that time when the sample is being taken, that sort of thing. You've done some work involving soft robotic fingers and proven that sampling marine life can be done without stressing them out entirely at a genetic level. So as we look forward to 2030 and beyond, do you see a future where sort of invasive biology is replaced by these more gentle technologies?
John Burns:
Well, that's such a loaded question. Yeah, so I just came back from this research cruise and I operate in this space. I think about it a lot, like you said.
Lydia Morrison:
Yeah, you're invested.
John Burns:
But I also used to work at a museum and at the museum, I really learned the value of collections, like proper collections where you take the whole animal. And on this cruise, I was paired to these two projects, one technology looking for ways to do this gentle sampling, and the other real taxonomists and museum folks that are wonderful experts at identification and learning how animals are distributed, how they behave and all these different aspects of how they work and also preserving that for the future. So we both have these same kind of concepts in mind. We're approaching it in different ways. I think there's a real value to collections for a couple reasons and I'll finish the thought about the gentle collections as well, but just to say that from working at a museum, I know that the museum is full of things that people collected hundreds of years ago, animals, all different kinds of life. And when they collected it...
Imagine this, right? Any collection from before 1951, people didn't even know that DNA was the genetic material of cells or the molecule that carries information. So everything from before then, nobody did genetic analysis. We didn't even know what the genetic material was. And now today we can go back to those specimens and ask new kinds of questions that you wouldn't be able to do if you didn't collect them. So there's so much about... And then there's other... Even though we're developing these great tools, we're never going to catch all the information of the animal. So I think there's a value.
Now all that said, I think pushing forward is also really, really important, and what we're trying to do with our technology side of the project is to be gentle, is to say the animals that we're encountering, especially in this strange and unexplored environment of the ocean, the mid-water ocean are valuable in themselves and the first time we see something, we don't necessarily want to take it out of its water because what if it's the only one there? We would never know. It's the first time we've ever seen it. So another way to approach this is to actually try to get all the information we can while it's underwater, so at least if we see it again, we can identify it and we'll know what it was, and then if you like, "Oh, no. We really need to get more information about it," might be important to collect it.
In the meantime, the team that I work with... So I do the genetics and genomics, the team of engineers, the people that make the soft robots and the laser scanners and stuff are just brilliant and amazing, they are at MBARI, the team (Rob Wood, Brennan Phillips, Dhugal Lindsay, David Gruber) for the Bioinspiration Lab led by Kakani Katija is they're building these underwater cameras that do basically optical scans of the animals. So it's basically like a lot of these animals are transparent or semi-transparent and you can scan all the way through them so you get their internal and external structure while you're observing them underwater that you can build back up into a 3D model that might be sufficient for identification. So those expert taxonomists can go back to that model and say, "Okay, here's the parts that I need to know about and this is how I can identify this animal in the future, and it's this species or maybe it's this new species."
And then this aspect of interacting with it gently is that one of the things we want to know, like I did with that study on development is what genes are these animals using now while they're in their kind of normal state? We don't want to know as much about when they're stressed out. We want to say like, okay, this is how it swims or this is how it senses its environment, and that kind of information you can get if you can either catch it really fast where it doesn't have time to change or you've just got to interact with it very gently and just get enough material from it and preserve it in place so it's not sitting in a jar for hours so that that information is locked in place so that we can then get the genetic information from these animals and that's part of its description.
So imagine we're trying to make a digital specimen. So part of it is this underwater scanning and imaging and another part is getting its genetic information that all fits together into this digital specimen and part of it can be the gene expression, which is I think what's the most important part about that gentle sampling as well as being able to catch and release these things that we want to value. I mean, some of the animals... So on the expedition I was just on, some of the animals we saw we estimated were a hundred years old or older. We don't necessarily want to collect something like that. We just let it live its life, but we still want to get some of the information from it. That's why we're trying to envision these tools that allow us to sample remotely or sample gently and let that animal go.
Lydia Morrison:
Yeah, I can see the real value in that, especially considering how much we don't know about the ocean and how many new species there are yet to be identified and how little we know about the populations of those species. So it seems like a really important way to be able to catalog and categorize these organisms that you're finding. I'm curious, just your thoughts on the future of marine exploration, where do you see the future of marine exploration headed?
John Burns:
Do you mean on Earth or specifically, or can it be out in ocean worlds and space? I mean, we do think about that too sometimes.
Lydia Morrison:
Yeah. I mean, I think it could be either. I love that you're already thinking about space ocean.
John Burns:
Yeah, we think about it. I mean, it's way out there. First, we need to solve the problem on Earth. But I think the biggest problem that we're facing right now, even given this expeditions that we're on and there are several of them every year that many really brilliant scientists are out there searching the oceans is a problem of scale. And it's really obvious when you're out there on this boat... And the boats are huge. They're ships. I'm a molecular biologist. I don't have all the right ocean terms all the time. I get corrected a lot. They call them ships. They're really big, but they're really insignificant in the context of the ocean. And I see us dropping this little net down in the water taking a sample and saying, "That's the ocean. I just took this one meter net sample and that's the ocean," which really doesn't cover very much of it.
The same thing with our ROVs and the studies that we're doing. I mean, it's wonderful experience and it's a great exploration. This thing is going down there... Marine snow is the debris from all the activity that's happening on the surface coagulating and then raining down to the deeper ocean. And so the ROV, it's like a submarine, it's a remote submarine, remotely-operated vehicle, is basically flying through that marine snow. And if you've ever seen Star Wars, it looks like you're flying through space. It looks like stars zipping by because it makes little lines. It really looks like you're flying through space. But if you imagine how much ground you're covering with that ROV, it's really, really little.
So I think that's one of the biggest problems is a problem of scale. And I think that's where the technology part comes into play. We only do so much collections and we really don't want to scoop the whole ocean up with a net and peek through it. But with technology that can be automated, can create things like that digital specimens, we might be able to scale that by shrinking it and sending it out on its own autonomously. So this is another open area.
Lydia Morrison:
That's what I was just thinking. What if we put tiny little ROVs all over the ocean? Is that good or bad? I'm not sure.
John Burns:
It's a thought. I mean, it's one of the places we're thinking of and how we might be able to scale this, and in addition, it's like learning how to identify these animals more remotely so that the computers on board can identify them for you and chase them around or come back with all this information. So that's the way I'm thinking we're going to have to scale the problem if we really want to understand how the ocean works. I mean, everything we're doing is helping that. All of these expeditions that people go on with all of their different expertise in geoscience, mapping and chemistry, all of that is really doing wonders for our understanding, but it's still only looking at one little piece at a time in a very small timeframe over the course of something that's changing over thousands of years.
So yeah, we need to scale it, and the tools that we're developing... This is my own advertisement. The tools that my team's developing and other people that I've heard of and actually we went and talked about some of these other Ocean Shot Awards, this award that we have, they award other technology-advancing tools that are going to help us scale that problem and understand ocean a lot better.
Lydia Morrison:
Yeah. It sounds like there's lots still to be understood and lots of studies still to do, but I wanted to thank you so much, John, for taking time out of your schedule today to talk to us about the little things. I'm so glad that you're interested in the tiny single-cell organisms that seem to have a lot more to offer in terms of insights into multicellular organisms and humans and microbiomes and the interaction between algae and cellular organisms. It's been really incredibly interesting talking to you today and learning more about your work. So thanks so much for your time.
John Burns:
Yeah, you're welcome. Thank you so much for having me. I love to talk about it, so that part is easy for me.
Lydia Morrison:
Thank you for joining us for this episode of the Lessons From Lab & Life Podcast. We invite you to check out the episode's transcript on neb.com for helpful links from today's discussion. And we hope you'll join us next time when I'm joined by Carika Weldon, founder and CEO of CariGenetics, which focuses on bringing genetic research expertise and equipment to the Caribbean.
