Natural Prodcast Episode 6: Marc Chevrette

DAN: You’re listening to the US. .Department of Energy Joint Genome Institute’s “Natural Prodcast,” a podcast about the science and scientists of secondary metabolism. 

DAN: Hi again, and welcome to Episode 6 of Natural Prodcast. What you’re going to get here is the very first episode we recorded. You’ll probably notice that the audio quality isn’t as good as what you’ll hear in other episodes, but it’s not terrible. I was able to clean it up quite a bit, and the conversation was so interesting that I wanted to include it. This is a conversation with Marc Chevrette. Marc is a postdoc in Jo Handelsman’s group at the University of Wisconsin, where, among lots of other things, he works on the Tiny Earth project, which you’ll hear him describe. [Go here to learn more about Tiny Earth and the JGI’s role in the project by watching Amanda Hurley’s presentation from the 2019 JGI Genomics of Energy & Environment Meeting.]

He’s also a really good friend of mine. I met him when we worked together at the late great Warp Drive Bio, a biotech startup where we did genome mining together. Marc was the Head of Experimental Genomics there, before he decided to leave for graduate school and pursue his PhD. Warp Drive was a really interesting place, in terms of secondary metabolism research, and I hope to be able to share a few more stories from there as we go forward. And Marc’s quickly built up a great body of work, with interesting perspectives on evolution of natural products biosynthesis.

I think it will be fun to be able to provide a semi-regular forum for postdocs and graduate students through Natural Prodcast, especially those who have unique backgrounds or interesting stories to tell. Academic research only exists through the energy and enthusiasm of young researchers, so it’s important to me to tell their stories too. If you have one of those stories, or want to suggest someone, reach out and let me know!

But for now, here’s our conversation with Marc Chevrette.

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DAN: Right, Alison, we’re recording. This is our, our first podcast. Right?

ALISON: Yeah, sure is. Are you ready, Dan? 

DAN: Am I What? 

ALISON: Are you ready? 

DAN: Am I ready? I don’t know. I don’t know. We’ll see. Let’s find out. 

DAN: All right, so the first person that I wanted to talk to today is a good friend of mine, Marc Chevrette. So Mark is here with us. I’ll give a little bit of background: Mark is a friend of mine from the company that we used to work at together called Warp Drive Bio, which was a genome mining company. So we’ll talk about those kinds of terms when we do our primer, podcast. Welcome, Mark.

MARC: Hi yeah. Great to be here. Thanks for having me.

DAN: We know each other pretty well. So I feel like it’s always fun to talk to you. I’m particularly interested… Well, first, in some of the science that you’ve been doing lately, which I think is really interesting. But also, I thought you were a good representative of maybe a different career trajectory than we sometimes see…

MARC: Yeah, I’m a little weird?

DAN: Yeah. So maybe we could start with that background – what got you into secondary metabolism, besides being forced to work with me? 

MARC: Forced? Yeah, that’s one way to put it. So, I was at the Broad Institute in Cambridge, Mass. for a couple years before joining Warp Drive. And what kind of pushed me towards the secondary metabolism side of things was looking at genomes and seeing where the really hard things to sequence were, and wondering what those … what those were and how they function. So I worked on a team at the Broad that was looking to develop new methods for DNA sequencing of microbes. And what kept breaking our methods was these damn secondary metabolite pathways. So that’s kind of how I fell down the rabbit hole. I was curious about what they were, what they were doing in these genomes and how they change over time. And yeah, I mean, that was let’s see, maybe 5,6,7 years ago, and I’ve – I haven’t looked back.

ALISON: So you were saying, Mark, how the DNA that was breaking the sequencing from really being functional was these secondary metabolite pathways. So why was that? What is it about secondary metabolite pathways that are so hard to sequence?

MARC: This isn’t true of all of them, but for certain types, they’re extremely repetitive. And what that means when you’re trying to sequence is, you have to have a sequencer that can read longer than the repeat, otherwise, you have no idea how to put it back together. So a lot of sequencing depends on Illumina technology, which is usually what we refer to as “short reads”. So that kind of resolution isn’t sufficient to put these pathways back together. When you’re trying to assemble them off of a sequencer, um, so that’s one thing. And another thing is the bugs that produce them – the microbes that make these secondary metabolites – are usually really strange in terms of genomic content. So, for example, the actinomycetes that people really like to look at, historically, for these pathways, they’ve got really high GC content, which means their base usage is skewed, and that can mess with some of the technology that creates the DNA sequence.

ALISON: Okay. And so maybe just to back up, because you started talking about the microbes that produce these secondary metabolites, like, like, tell me more about that world, you know, what is going on? In one of your favorite examples of a secondary metabolite producer, and why they produce those metabolites?

MARC: Well, I’m really biased and I like the bugs in the microbiome. So a lot of my work is as focused on insects As a host, and a little bit of my newer work is focused on plants, but in both cases, you know, these molecules are how microbes communicate with the world around them. Sometimes it means killing other microbes. Sometimes that means sending signals. But really unpacking that complicated network of chemistry and communication is what I’m really interested in. But it’s a tough question. And it’s very situational. And every microbe is a special snowflake. So…

ALISON: Yeah, I mean, would you say that all microbes can produce secondary metabolites? Give me a sense of this kind of functionality.

MARC: Some are more gifted than others. So a lot of the ones that have been historically studied and in academia and industry can make many dozens of them. Some are going to be involved in antibiotic activity, some are going to be involved in signaling. We’re not perfect at identifying what these pathways are yet. So there’s still a lot to be discovered. And even the ones that may look like they don’t have that much going on in terms of secondary metabolism, that’s just because we don’t know how to look for it yet.

ALISON: Um, okay, so it’s probable that all microbes are doing this. And we just don’t necessarily know how in all cases.

MARC: Yeah, and in some cases of really extremely small genomes, like symbionts that can’t live without their host. They have no extra genes hanging around, they still dedicate 20-30% of their genome to secondary metabolism. So it’s very important. That’s how they that’s how they communicate and oftentimes how they remain fit in their environments. 

ALISON: Okay, cool. Thank you for that picture. Certainly helpful.

DAN: Well, I wanted to I guess, start maybe reverse chronologically. So-

MARC: So today. 

DAN: Sure. What’d you do this afternoon? No. So you are doing a postdoc now, and you are involved in a project that collaborates with JGI called the Tiny Earth project. Would you want to tell us a little bit about that?

MARC: Sure. Yeah. So I’m in the lab of Jo Handelsman. For those that aren’t familiar with Jo, she’s really a champion of many different things in microbiology and biology in general. And her efforts first at Yale and now at University of Wisconsin and the Institute for Discovery here, are … surrounding Tiny Earth is to create a course and a network of people to crowd-source antibiotic discovery. So like I just mentioned, microbes that produce chemistry, some of that chemistry is going to be antibiotic. And traditionally where people have looked for antibiotics and the microbes that make them is in the soil. There’s … uh… there’s an issue there though, in that quite a few of the antibiotics that people were looking for in the soil kept getting found over and over again. So we call this the “rediscovery issue.”

And what Tiny Earth is trying to address is, is directly that in the face of growing antibiotic resistance, so we’re looking in soil that’s extremely diverse, and then it comes from all over the world. And we’re asking students and undergraduate and high school level classrooms to (A) become engaged with STEM and learn about microbiology but also bring their own perspective to this problem. So explore different media conditions, different growth conditions, really try and understand, without any biases or dogma from the fields, like how microbes might produce antibiotics.

So I mentioned it’s a course. So this is taught at over 270 places now worldwide with a rate of around 10,000 students a year. And that was those numbers were quoted a couple of months ago. We’re always growing. So those are probably out of date now. Yeah, so this is all over the United States in … I forget the number, but it’s over 42, 43 states, but we’re also in many countries, including Western Africa and Australia. So we’re – it’s really a worldwide presence.

ALISON: Wow, that’s bananas. I mean, it’s so big this program. Like how – is like Jo just the ambassador of microorganisms in soil and –

MARC: That is a perfect way to put it.

ALISON: She’s an international ambassador?

MARC: Yeah, I believe it was 2012 when she started this at Yale, and she only had six students sign up. She didn’t know if it was going to go anywhere. And, you know, it’s really a research-as-learning course. So they’re in the lab, they’re making discoveries, there is no like, you know, do your organic reaction and see if it smells like a pine tree. Like there’s no cookie cutter reactions here, we’re really trying to drive discovery. So from that six, it’s grown to the over 10,000 per year number. And very quickly, we’re getting really excited about January, we’re having our new crop of partner instructors come into Wisconsin so we can train them to take the course back to their home institutions.

ALISON: Oh, cool. So is that how it works, that people will come get trained and then teach it somewhere else?

MARC: Yeah, I mean, people that have a strong background in microbiology, they can take the course as is but for people that are maybe new to the field, we welcome them to come down to Wisconsin, we provide that kind of training.

DAN: So longer term. So the partnership with JGI comes in with genome sequencing. And so, like you described, JGI gets to do all the fun of trying to sequence some of these unusual things that might be sent our way, right?

MARC: Yeah, so I guess kind of where I left off is, is that the, the students are going out, getting soil, isolating microbes and seeing what kind of activity they might have against pathogens from the clinic. At that point, isolates get shipped to us in Wisconsin, and we try and use them to fuel a drug discovery pipeline. So that’s two prongs and one of those prongs is through a tight-knit collaboration with JGI to do genome sequencing, so to look for the genes that are involved in putting antibiotics together, getting them out of the cell letting them do their dirty work. So that’s one arm. And then and then another arm that we’re also pursuing here is metabolomics. So this is a way to get a snapshot of all of the chemistry that a microbe produces. And when the two of those “omics” are combined, you can really spot things you’ve seen before easily and also spot things you haven’t seen before easily. So trying to look for new antibiotics and assess whether something you have is linked to the killing you see against the pathogen is new or something you’ve seen before.

DAN: Yeah, yeah, fun stuff. 

MARC: And we call that whole thing, the “chemistry hub”, and that’s centered right now at Wisconsin, but we’re hoping to have many such hubs all over the world in the next couple of years.

DAN: What does it take to become a hub?

MARC: We’re still trying to figure that out. I mean, we’re still quite new. I joined as the lead on the genomic side about 6, 7, 8 months ago, and our metabolomics expert was around the same time as well. So we’re still trying to figure that out. I think what what’s going to be needed there is an expertise in those two fields and the ability to process samples at scale. So, lots of samples.

ALISON: Yeah, how many samples have already come through?

MARC: I’m the wrong person to ask on that. But, hopefully … I know the projections. The projections are that we would have, in about a year’s time, we’d be doing a rate of around 1000 genomes per year and an order of magnitude more than that of metabolomes. So 10,000. We have many more isolates right now than we’ve processed. So it’s an exercise of going back to the fridge and grabbing who’s next in line and deciding what’s exciting and what’s not exciting.

ALISON: Could you give a little bit of a picture into how you decide what’s exciting and what’s not?

MARC: Yeah, so one of the approaches that Tiny Earth is using to be different than screening in the past, is in the types of pathogens or challenges where we’re putting these bugs and assays against. So, one of those is Acinetibacter. This is a genus of bacteria that’s really popped up at funding agencies and the popular news recently because a lot of soldiers in the Iraq and Afghanistan area were coming back with these really bad infections. So the Army and the Department of Defense have invested a lot of money to try and understand this new emerging pathogen. What’s so crazy is, it picks up DNA very, very quickly. So it acquires resistance at rates other bugs don’t. This is kind of a new pathogen, so it wasn’t in big pharma screens of bacteria from 20-30 years ago. So it’s in our screen, and we’re seeing hits to that. So that makes us excited. But we’re also excited about antibiotics that might not be for human use. So things that we might be able to use against plant pathogens to use in agriculture and animal husbandry. So we’re looking for those kinds of activities as well.

ALISON: One concern that does come to mind when you talk about looking for antibiotics that could be used in animal husbandry, for example, is that microbiologists have shown that a lot of resistance has actually been due to antibiotic use in agriculture. Well, specifically raising animals and, so, like a prophylactic use, or used to make them grow bigger. What is kind of your lab’s mentality about how to address that issue and prevent that from happening, you know, with new antibiotics?

MARC: Yeah, and it’s a huge issue. I think a lot of that is going to lie in the policymakers and the people that are actually, like, in the administration phase of these antibiotics. It is something we think about quite a bit. But what we’re trying to do is more focused on the discovery side. So the usage is, you know, something that would happen many years after we would discover something new. And, likely, that would be outside of the lab setting as well. So it’s on our minds, but whether or not we’re the right movers and shakers that are going to make those policy changes happen is another question.

ALISON: Um, yeah, it could be that there could be a more of a collaboration and those discussions between scientists policy makers.

MARC: Yeah, and there’s a lot of movement on that both in the United Kingdom and in Canada. I just got back from a conference in Canada on antimicrobial resistance sponsored by the Garner foundation. And they’re really excited about the strides that they’re making in terms of stewardship. Now, that’s mostly talking about antibiotics in the clinics of for human use, but that spans all Canadian policy as well. So the US is moving in that way similarly, but it’s moving a little bit slower.

ALISON: Okay. Okay. Thank you for that insight.

DAN: So I suppose, coming up with large collections of new microbes and new activities, feeds into some of your other research interests, Mark, which is [something you’ve] published some great papers [on] recently – on evolution of biosynthetic gene clusters. And you and I have had some arguments over beers about some of the details on that. But um, you know, it’s great work. And I’d love if you want to tell us about that.

MARC: Yeah, I mean, I think you nailed it. Evolution is what I’m most interested in. And these pathways that put together antibiotics and other secondary metabolites, they’re really complicated. And that doesn’t just happen. They’ve evolved for many millions, sometimes billions, of years. And understanding how those changes that evolution brokers are happening. That’s really what my research focus has been. Maybe the last four or five years or so, this involves, you know, how biosynthetic gene clusters – those are those suites of genes involved in making antibiotics and secondary metabolites – how they come together in the first place, what kinds of changes they can tolerate, and how the chemistry of the molecules that get produced changes in response to different selective pressures. It’s really hard to assay because oftentimes we have no idea what natural products are doing in nature. And it’s a really difficult thing to unpack experimentally. But there’s a couple of different systems where people have made strides in that area.

Where I did my PhD, was also here in Wisconsin, in the lab of Cameron Currie. They work primarily within the “fungus growing ant” system where there is a symbiont, a microbe, that produces antibiotic chemistry to protect the crop that the ants grow. So it’s a cool tripartite situation where the ants are feeding a fungus, they eat the fungus, and that fungus is really susceptible to disease. So these symbionts come in and offer protection through chemistry. We’ve done really fine-scale sampling in my research and some of the research that’s been going on in Cameron’s lab since and before, to show that even on the scale of just a couple of kilometers, you see very obvious changes in chemistry that affect how these antibiotics are functioning against the pathogens that prey on the system. [Go here to learn more about Cameron Currie’s metagenomics research, enabled in part by JGI’s Community Science Program.]

So that’s one example where we know quite a bit, or at least quite a bit relatively compared to other systems. But something like soil, which I’m working on now, this is a complete black box, we’re talking many, many orders of magnitude more players in the game, they’re all talking to each other, most of them are angry with one another, and trying to unpack all of those interactions. You know, that’s what gets me excited. That’s going to change from day to day, year to year, and over millennia. So understanding how genes are changing and how chemistry is changing is, I think we’re the field – or at least my part of the field – where that’s heading, and I’m really excited about it. Because now we have the tools through genomics, and metabolomics, to ask these questions.

DAN: How far along do you feel like we are in terms of completing the fossil record? I mean, it’s always my perception of, yeah, there’s so much stuff out there, it’s really hard to get lucky and find things that actually connect to one another. Obviously, there are lots of evidence of evolution of BGCs, and you’ve reported on that, but what do you think about that? How much more sequencing do we need to do?

MARC: Well, we should never stop sequencing otherwise I’d be unemployed. 

DAN: Likewise.

MARC: But Gerry Wright just came out with a paper that I think kind of speaks to your question. So he basically put together the fossil record, if you will, of a certain class of antibiotic compounds called glycopeptides. And, you know, even though there were only, you know, a couple hundred examples, they were able to put dates on when major changes in the genes and chemistry happen, which I think is really exciting. So as far as I know, that’s the first paper that’s married a dated phylogeny to biosynthesis – to putting together these antibiotics. And it gets me really excited because, you know, the more we sequence, the more we see, the more we learn, the finer we’ll be able to tune those dates and understand how these things have changed over time. But it’s not prohibitive to start now. So I I’m very excited about that.

Alison: Yeah, I’m curious, where have your disagreements been? Do you want to talk about that? I don’t know…

MARC: Mostly beer choice.

DAN: Well, you know, I am largely of the opinion that on the geological timescale, that most bacterial natural product systems evolved, you know, a couple of billion years ago, and that on that timescale of the earth that geography doesn’t matter as much. But, you know, there’s clearly some, you know, equivalent to punctuated equilibrium of BGC evolution and, you know, Marc’s papers have steered me in that direction a little bit more. Toward mosaic theory.

MARC: So how quick, and how much geography matters, is going to be a function of what the molecules are actually doing. 

DAN: That’s right. 

MARC: So, you know that being such a hard question to ask. I don’t think a blanket statement can rule one or the other out. But if you’re smart about experimental design, you can start to get at that in certain systems. So again, I’ll talk about the ants and say that we did that in Cameron Currie’s lab – and plug for that, recently out in AEM so go check it out – but basically tied how the antibiotic producing bacteria on the ants related geography and antibiotic activity, and it fits pretty well a model that was developed for macro organisms like rabbits and foxes. So you’ve got this predator-prey dynamic. That’s, I think, quite fascinating because it plays out on a geographic scale that’s only a couple kilometers.

ALISON: You know, clearly you both have thought about the ecological theory and evolutionary theory that relates to the development of these systems and I think you’ve called them BGCs? Is that right, Dan?

DAN: Biosynthetic gene clusters.

ALISON: Okay, biosynthetic gene clusters. So yeah, so I’m you know, I’m a little bit familiar coming from a microbial ecology background myself, but not to this degree. So we did fine sampling which we would look at different particles in the ocean and look at the micro organisms on those particles, as well as like free-living you know, within the Vibrio genus. So, when I’m… I’m thinking about the evolution of these gene clusters, like it’s even finer scale, you’re looking into the genome, you’re looking at how these clusters are evolving in the context of their genomic hosts. But, you know, someone mentioned mosaic theory and like the timescales of, or the time and spatial scales that predator-prey/foxes and rabbits… So, can you kind of like link these pieces together for me a little bit more? Maybe it would involve like, a simpler example or story?

MARC: Yeah. So in the, in the example I alluded to before, I think the only reason that we’re able to speak about it is because it’s a quite a simple system. It’s a pretty reductionist system compared to something like soil. Again, there’s these ants, they grow fungus, eat the fungus and everyone’s happy until the pathogen comes along. So this pathogen preys on the food source for the ants. And the ants, they have a symbiont that produces antibiotics to protect against that pathogen. So the dynamics that I was talking about earlier with this predator-prey rabbit-fox analogy was that interaction between the protecting bacteria and the pathogen that would prey on the system. Now that’s – that’s a really simple interaction network. In the ant system, the ants eat a fungus and these are the really charismatic ants in the Neo tropics that go off into the forest and gather leaves, they carry them around on their heads and bring them back. They’re farming this fungus with the leaves, okay, so and then they end up getting the fungus, but it’s really similar to like human crops like corn. There’s low genetic diversity in the crop. So they’re susceptible to disease. One of the major pathogens is another fungus. It’s called Escovopsis. And that comes in and basically wipes out the system if it’s unchecked. And one of the ways the system has figured out a way to buffer this and deal with it is through these antibiotic- or antifungal-producing bacteria that live on the exoskeleton of the ants. And depending on the genius of the ants, you can spot them with your eyes. They – some of them look like they’ve been rolling around and powdered sugar and really coated with this stuff.

ALISON: That’s really cool.

MARC: Yeah, yeah, right. That’s why we’re able to talk about these predator prey dynamics because it’s relatively simple, and that there’s one protecting bacteria and one pathogen that’s coming into the system. Now, that’s probably not true across all of nature, but it’s a simplifying assumption that we wanted to test out in our paper, whether or not that conforms to mosaic theory. And in terms of how potent the antibiotic bouquet that these producers make, that does conform to the mosaic theory of coevolution. So it looks like there’s hot spots of really potent antibiotics. There’s cold spots where the pathogens are taking over and everything in between, as predicted by mosaic theory.

ALISON: So does mosaic theory, just to give you kind of a straw-man-like way of me explaining this… Does mosaic theory give you then a picture that, okay, it’s going to be a mosaic, you’re going to have hot spots and cold spots of the thing that you’re measuring. And that’s because the threat isn’t the same everywhere? It’s not uniform? Is that what it is?

MARC: I think that’s fair. So we looked at a couple of different types of this pathogen, and they’re all present across the Mosaic, but they’re there in different ratios. So that could have something to do with it. We saw hints of a rare advantage. So if you’re not the most popular pathogen, you can kind of sneak through the defenses. That being said, though, they’re all from the same genus of Escovopsis. So they’re – they’re related in in many ways, but they are different.

ALISON: What would be like a competing hypothesis? Like, if not mosaic theory, what were people thinking it might be?

MARC: Well, so the mosaic theory, basically, lets us say that there’s co-evolution happening within the system. And why that I think is important, from my point of view is that, you know, there’s a lot of different anecdotal studies out there that will say, you know, probably this one molecule is getting produced for this or probably antibiotics and protecting against XYZ. Here with entering the perspective of the pathogen as well, we’re able to say that these two things are co-evolving. So there is that link experimentally, which is more than a lot of people, you know, more trouble than a lot of people go to, but now we can look at how the genes involved in this antibiotic activity are changing in those different geographies. 

DAN: Also, what’s really fun about that is that you know this evolution is really an arms race right? This is a war of chemical evolution. And so you know, that’s where the secondary metabolism gets really interesting – when you can begin to see these guys building better weapons against one another. That gives us inspiration for medicine and for all kinds of things. 

MARC: Yeah, a lot of people like to invoke the Red Queen hypothesis there. And if you’re not familiar, it’s basically a throwback to “Alice In Wonderland” where the Red Queen just runs faster and faster to stay in the same place. So this race, if you want to call it that is basically reciprocal evolution on both sides to try and outwit and outpower the other. And yeah, how that changes can be really important to how we think about drug discovery. So where to look, but also how to tweak these molecules in the lab.

DAN: And so, taking one more step back chronologically, maybe? I’m pretty confident that I think you got your real good start in looking at these ideas when we worked together. 

MARC: Yeah, from you!

DAN: No. But we were obviously working at a company together that was kind of an unusual company. And I guess, what did you learn from industry and what inspired you to leave industry and go to academia.

MARC: Well, so we were at Warp Drive Bio. This was in Cambridge, Mass. Small… I guess we’d call it a small startup – while we were there at least.

DAN: Yeah, I don’t think it ever got that much bigger. 

MARC: Yeah. What was –

DAN: And now it’s gone.

MARC: – an exciting thing was – What’s that? Sorry? 

DAN: And now it’s gone.

MARC: Yeah. Yeah…

DAN: So some of our colleagues live on and are continuing the good fight, but – 

MARC: That’s a morbid way to put it. 

DAN: Maybe, maybe, you know.

MARC: I loved it there. I had a really good time at work. 

DAN: For sure. 

MARC: We were basically, Dan and I and one other computational biologist were tasked with looking at, you know, hundreds of thousands of Streptomyces and actinomycete genomes, and trying to find the needle in the haystack when it came to the molecules of interest for a company. Personally, that was my first taste of big data if you want, maybe it’s medium data now. But at the time, it was big data. And yeah, trying to understand, first of all, how to look for these things. How do you go looking for a specific chemistry in this big pile of genomes? That’s, you know, that’s really how I started to get interested in this, is approaching that question. Yeah, what I think drove me back to academia was seeing how much nature provides this within pathways. Why is this happening? How does it happen in other pathways? I think those were the things that motivated me to come back to academia. So I could focus on those without looming board deadlines.

ALISON: Yeah, it sounds like a good choice if the company didn’t make it.

DAN: What were you head of, I can’t remember.

MARC: Experimental Genomics. But if you have me define it, I have no idea what that – what that means. I think it means I was the computational guy that wasn’t scared of putting gloves on. But, yeah. 

DAN: Alright, so we’re approaching our time. So you’re in your postdoc now. What do you see as the future for Marc Chevrette? It’ll be fun periodically, if I do this for a while to kind of check in with you once in a while and see how your career goes.

MARC: Yeah, hold me to it and see how I’ve failed and not lived up to my projections? Yeah, so I think where the field is going, and specifically, the people that are pushing this forward are in my current lab. The Handelsman lab at the Institute for Discovery at Wisconsin is looking at secondary metabolism through the lens of a community. So almost all of natural products research to date it has been done in a petri dish with very few media perturbations. They grow happy. They make the molecule and you call it a day. But in nature, there’s many, many interactions that are happening, you know, on the second scale. So like, what does that mean when you’re in a community? How is the microbiome being shaped by different types of secondary metabolites? How does it respond to invasion? How are you resilient? And how does that change depending on what the community looks like itself? So I think marrying different fields is where I’m going.  So specifically to the fields of microbial ecology and community dynamics and understanding how secondary metabolites link different bugs together, whether it be you know, fighting with each other through antagonism or working synergistically or just tolerating each other within a niche. So those are big questions. I think that’s where my interests lie.

DAN: That’s also well aligned with JGI, I think, you know, we don’t do drug discovery. So, you know, second metabolism interests we have are largely around ecology and evolution. So, yeah, that sounds like we’ll have some intersection the future. Great.

ALISON: Oh, I guess I have a question about just JGI being a part of this project. Well, and maybe this is something for, for me and Dan to talk about offline, but just like the, you know, kind of antibiotics, I would think is more related to health and human health. And so JGI’s involvement kind of seems strange to me, but I’m new, so…

DAN: Well, you know, every bacterium that’s killing another bacterium is an ecological interaction, right? It just so happens that sometimes, you know, humans can harness those kinds of interactions for their own benefit. But, you know, there are lots of antibiotics out there that don’t really have any value when you inject them into a person or take it in a pill. And so, those are all still out there. And they’re important things that happen in the environment to create microbial community and shape it. Really important to agriculture –

MARC: The stuff we use in the clinic may not function as antibiotics when it’s in the soil. 

DAN: That’s right. 

MARC: So that whole spectrum there is – I think there’s a lot of ecology to unpack.

DAN: There’s so much science, too much science to do!

MARC: Fund me please.

DAN: That’s right. Give this man a grant.

MARC: I have no shame. I’ll plug for a grant.

DAN: I don’t know if – I don’t know if this is gonna help with that but uh maybe we’ll see if we can get like some sort of a Natural Prodcast grant funding bump. And yeah, we’ll totally go for that.

ALISON: It is definitely outreach. So you can you can put that on your NSF… qualifies. Well, I think I want to ask a little bit about where, where you’re headed next like, like, I know, we’ve kind of spoken in generalities about unpacking the ecology of these interactions and understanding their evolution. You’re just really, I think, drilling down on what’s happening at a micro scale. But could you talk a little bit more in terms of specifics where you see this going? In the next year, or two?

MARC: Yeah. So we’re trying to approach that through a reductionist model system. So Jo Handlesman, my boss, has developed a system. It’s relatively simple. So there’s three members, there’s a Bacillus, there’s a flavobacterium, and there’s a pseudomonad. And they all interact with each other in different ways, some of which are secondary metabolite media. So what we want to do in the short term is really understand how those interactions might change depending on different environmental perturbations. So if you introduce stress, if you introduce an exogenous antibiotic, if you introduce a substrate, like sand for them to grow on, things that they might encounter in their natural environments, and or things that human impact is going to play a role in, like antibiotic usage from clinical antibiotics. So yeah, even though it sounds relatively simple with three members, the interactions there are incredibly complex and some of them are synergistic, meaning that they’re more than you would expect by adding them pairwise together. And that’s really exciting to me, because how they talk to each other is chemistry. So understanding how that happens at a mechanistic level is where we want to go in the next couple years. And hopefully, some of the insights that we glean from that will be broadly applicable in things like soil. So the Bacillus, that’s a member of this system, has been used for a couple decades as a bio control agent. Basically, you put it in a squirt bottle and put it on plants, and if it takes up in the community, it’ll protect against oomycete pathogens. But we don’t really have a good handle on how it takes up in the community. It’s really variable. And, yeah, so hopefully this will start to get us down that road and maybe there will be broadly applicable insights there as well.

ALISON: Kind of what facilitates colonization of a new environment and like what are the other micro organisms that might be helpful in that process?  

MARC: Right. 

ALISON: Cool. Well, yeah, I feel like a lot of microbial ecology is thinking that way, you know more about the community less of the micro – the individual microbe. Oh, yeah, I think that I think that’s good. I mean, it’s closer to what actually happens in nature.

MARC: Yeah, and it’s – it’s manageable in the lab, which is why I like it. So you know, the whole spectrum from bulk soil being one of the most complex communities on earth, and the three-member community, and everything in between. I think that’s bold, but I think that’s where, where I’d like to see the field go in the next couple of years.

DAN: All right, Mark. Always good to talk to you. And hope we can find some way to get together soon. Thanks so much for joining us. Really interesting always to talk to you. Thanks again.

MARC: Yeah, awesome. Thanks so much.

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DAN: I’m Dan Udwary, and you’ve been listening to Natural Prodcast, a podcast produced by the US Department of Energy Joint Genome Institute, a DOE Office of Science User Facility located at Lawrence Berkeley National Lab. You can find links to transcripts, more information on this episode, and our other episodes at naturalprodcast.com

Special thanks, as always, to my co-host, Alison Takemura. <woohoo> If you like Alison, and want to hear more science from her, check out her podcast, Genome Insider. She talks to lots of great scientists outside of secondary metabolism, and if you like what we’re doing here, you’ll probably enjoy Genome Insider too. So, check it out.

My intro and outro music are by Jahzzar.

Please help spread the word by leaving a review of Natural Prodcast on Apple podcasts, Google, Spotify, or wherever you got the podcast. If you have a question, or want to give us feedback, tweet us @JGI, or to me @danudwary. If you want to record and send us a question that we might play on air, email us at [email protected] . And because we’re a User Facility, if you’re interested in partnering with us, we want to hear from you! We have projects in genome sequencing, DNA synthesis, transcriptomics, metabolomics, and natural products in plants, fungi, and microorganisms. If you want to collaborate, let us know! Find out more at jgi.doe.gov/user-programs.

Thanks, and see you next time!