Natural Prodcast Episode 16 – Marcy Balunas

Natural Prodcast presents our interview with Professor Marcy Balunas, currently at the University of Connecticut‘s Department of Pharmaceutical Sciences. This interview was conducted a few months ago, and since then Dr. Balunas announced that she will soon be moving to the University of Michigan‘s Department of Microbiology and Immunology, and we wish her and her family all the best during that transition. In this episode, we discuss her work in many areas of chemical exploration of natural products for bioactive compound discovery, understanding symbiosis, and a JGI project around ants and their fungus farms. Relevant links are linked throughout and at the end.

 

Transcript

DAN: Hey Marcy! 

ALISON: Hey Marcy? 

MARCY: Hello. How’s it going? 

DAN: Good. How are you? 

MARCY: Am fine. I live in a pandemic so I’m no different than anyone else. 

DAN: Yeah. I mean fine in pandemic adjusted terms right? 

MARCY: Yes– 

ALISON: Yeah. 

MARCY: Exactly. 

DAN: I’ve always mentally had you in firmly in the chemistry bucket. [LAUGHS] I don’t know that that’s ever necessarily like a good description of anyone because chemistry means a lot, especially when you’re working in natural products right. There’s many different avenues toward chemistry. But that’s kind of where I had you. How would you describe what your research is now then and all the cool things you’re doing now? 

MARCY: Sure. So my lab has really converged on the study of host-microbe chemistry. And the interactions– As much as we incorporate loads of different kinds of biology, one of the best things that we do is work with this really great group of biologists that know what they’re doing much better than I ever can at the level that we’re working. And so we do host-microbe chemistry. 

We’re interested in – like I can sort of see when I’m doing the work or thinking about something I can kind of see like the squid and the bacteria and how the chemistry is going back and forth between them is part of what fascinates me about what we do. And so yes, I think I’m firmly in the chemistry bucket. 

ALISON: All right. Hey Marcy. So I was wondering, how did you get interested in studying natural products? 

MARCY: That is a great question because my path has been what I would call circuitous. I didn’t follow the traditional sort of academic path or even just the scientific path of “I know exactly what I’m going to do and I’m going to do it as an undergraduate and a graduate student then a postdoc and then a job.” Instead I got interested pretty early on regarding cancer medicines and I didn’t really know what that meant. 

I was a chemistry major after being an optical engineering major after which was really laser physics, and then I switched to chemical engineering and realizing that wasn’t for me and eventually, I got to chemistry. And as I was doing my chemistry work I really became more and more interested in cancer drug discovery and pharmacology but I didn’t know how to get towards that. 

Organic chemistry doesn’t really help with getting to something other than the sort of really standard kinds of things and natural products definitely falls outside of that. And so, for me, I think the next step was thinking about what I wanted to do with cancer. And along the way I took so many biology classes, I ended up with a double major in biology and ended up actually studying ethnobotany in Brazil. 

And so I went to the Amazon rainforest and talked to people who as part of a program studying Amazon ecology, [in] Portuguese, and got to do an independent study on ethnobotany of some of the plants that people were using for medicines in this very remote village. And so it was done, like as soon as I did that, I was set like “This! I want to do this!” And so and of course this morphed along the way. 

And so I ended up actually taking a little bit of time off between my undergrad and my masters, but I ended up starting a master’s in plant ecology. And that masters helped me to figure out that I didn’t really want to study plant ecology– that there wasn’t enough application there. And so I moved from there to plant natural products, getting a PhD in pharmacognosy, which is one of– I think there’s only a couple of programs that actually call it that anymore. 

DAN: Yeah, I had to explain the word pharmacognosy to Alison the other day. [LAUGHS] 

MARCY: Yeah. How did you explain this? 

DAN: Pharma is “medicine” and cognosy is “knowledge”. So it’s knowledge of where medicines come from, essentially. So yeah. 

MARCY: Yeah. And so that was amazing but it didn’t have enough field work. And so I ended up as a postdoc Panama as part of the international cooperative biodiversity group (ICBG) based in Panama and was dual there and at Scripps where I first met Dan. I think you were almost finishing when I was getting there but– 

DAN: Yeah. I was uncertain of the timing because I know you were down in Panama for it at least a good long while. 

MARCY: Yes, that’s how I got to natural products. 

ALISON: So tell us about this squid-microbe relationship. Or is it a microbial community with microbial community relationship? 

MARCY: Yes. So I would say that the squid is one– is we work on a lot of host-microbe symbiosis at this point. But the squid is probably the most charismatic of those. And pretty it’s really quite intriguing. The squid – the Hawaiian bobtail squid has two organs that solely house– whose sole function is to house bacterial associates. And so the one that the Hawaiian bobtail squid is famous for is the light organ. 

And the light organ houses Vibrio fischeri, it’s one strain and there have been years and years and years about 35-ish years, I think, now, studying Vibrio fischeri and relationship to the Hawaiian bobtail squid. And so more recently one of my collaborators Spencer Nyholm has been working on the accessory nidamental gland or ANMG. And the ANMG is a second organ. 

And so this is what fascinates me because how does this– we don’t have organs for symbiotic bacteria so what’s – I guess that maybe you could say the gut is, kind of. But not the same way this is designed specifically to house symbiotic bacteria. And so that has a community. And so there are– I hesitate to make a guess but maybe 50 to 100 different strains and they are in individual tubules. 

And so these tubules are like tiny monocultures but the whole of the organ which is about the size of your pinky nail has maybe 50 to a hundreds of these. And so Spencer and his group have done the microbial profiling for what’s in there. It’s a fairly well conserved community but it does vary in terms of which strains and what not. And we’ve been working with him for several years now on the chemistry and biological activity. So the chemistry and function really of those microbes that live there. 

And in our work we’ve determined that the ANMG deposits those bacteria into the jelly coat of the eggs. And so these eggs are laid in a clutch. And I would say a clutch is probably the size of a golf ball and has 25 to 50 eggs. I’m guessing here. 

DAN: Sure, sure. 

MARCY: And that they’re laid – unlike octopus which tend to their eggs and so they don’t get biofilm. Squid just deposit and take off. And so they must be chemically protected in some way and lo and behold it’s this bacteria. And so the ANMG is depositing the bacteria into the jelly coat to protect the eggs as they’re developing over about a month. 

DAN: What are those bacteria making? 

MARCY: What are those– they make chemistry! And so they – secondary metabolites, specialized metabolites, however we want to call them obviously. And we’ve done some work with those and have a couple of publications out there on the chemistry. There’s so much work to be done. And more importantly, what we know is they’re quite selective in some way for antifungal activity. They are also, some of them, are antibacterial as well. 

DAN: OK. 

MARCY: And so what we think might be happening, we’re sort of converging on this model of this being called an egg defense model. And so maybe there are compounds in there that we know there are compounds in there that are antifungal and antibacterial. But maybe there are compounds in there from the bacteria that work against protistsproduce, algae and other types of settlers. 

DAN: Yeah you would think. Anything that could be swimming in the ocean right? 

ALISON: Follow up question: Does the organ float all of the bacteria in those different tubules because it’s like you have them all separated in the organ but do they all sort of get evenly distributed on each egg? 

MARCY: So you are definitely jumping into the realm of what we don’t know. And so my collaborator and I have this idea that they work like pastry bags almost and so they are essentially squeezed out into each of those eggs. And so as the jelly coat is wrapping around, the bacteria are also being deposited in there. And so whether or not it’s the whole community? We don’t know. 

And in fact, we are interested in how the community itself works together to elicit new metabolite production. And we are also interested in how the jelly coat, which is, kind of – it’s viscous. It’s like molasses, it’s viscous. And so how the jelly coat works to help concentrate the metabolites? 

These eggs are tiny. And so how does it– how is it possible that these bacteria which are not incredibly numerous are protecting their eggs with these compounds? And we think maybe the jelly coat is holding in some of the chemistry and helping to concentrate it. But that’s the next project. 

DAN: Thanks. 

ALISON: We had talked a little bit about your journey and how it took you to Brazil to Panama. But then Dan told me that you actually have done some work at the polls or is it the Arctic or Antarctic but you’ve gone to retrieve some bacteria that like it to be really cold. Can you tell us more about that. 

MARCY: Sure. In natural products one of the things that you have to do when you’re starting your group is to figure out what your niche is going to be. What are you going to work on that someone else isn’t working on? Or that you bring a unique perspective too? And so I was fascinated by – we spend a lot of time as natural products chemists and biologists, natural products folks, looking at the tropics because of this immense amount of biodiversity. 

What we don’t do is spend a lot of time at either of the poles. And so Bill Baker’s lab in Florida works in the Antarctic and does some really exciting work there. And I thought, well, why don’t we try to go to Alaska and see what we can find there. And so this was in part because the first time I went to Alaska and we were hiking on a glacier I was entranced. And I was like well, how do I get back here? And not just how do I get back here. But what is here? Is there anything here? 

DAN: Yeah. 

MARCY: So we did quite a bit. We went and did– we’ve only gone once but we collected tunicates from the – tides. The tides there are massive and so we were able to actually not dive to collect the marine tunicates, which was nice because it’s also cold. And so we waited until this really low tide and were able to just collect them off the dock pylons. 

And we also went back to the glaciers and had this custom drill made to drill about two feet of glacier core that we field sterilized and brought home. That was unique. And so we have done a little bit of work with that. As expected by everyone but me because I was still new in the field, these glacial bacteria grow slow and it’s not 100% clear that we know what their biological activities might be. So our hypotheses around this have been that maybe they are because they are so heavily exposed to the sun maybe they are able to produce chemistry that deals with reactive oxygen species and so potentially could go down that route. 

DAN: So the sun pierces down through the ice pretty well, is that right? 

MARCY: It refracts actually. 

DAN: Yeah OK. 

MARCY: Yeah. And so they are heavily exposed to sun. And the bacteria that we collected– so the guides that we took with us had this huge pick and one of them would take the pick and get us about two feet under the surface and then we would take our two foot core. And so that’s only four feet in. And there is quite a bit of sun and exposure to solar radiation with refraction through the ice. 

DAN: What’s your opinion then on bioprospecting in sparse nutrient environments versus the tropics? Because like you say there is definitely a long trend of people who go on collecting trips in the tropics. My [postdoc advisor] Brad Moore – who we talked to in, what, episode five – that’s one of his things was for a long time and I think a lot of people in natural products were there. 

I’ve always wondered if deserts or maybe glaciers are places where there are less nutrients there, so there would be more competition and so you would maybe expect more bioactive – at least antimicrobials – bacteria that need more defenses, that want to defend the niche or territory that they’ve grown into. So what’s your feeling about that? 

MARCY: So the squid is tropical, it’s Hawaiian. 

DAN: Sure. 

MARCY : It’s getting bacteria from there. We work on a fungus garden ant as well as the American honeybee. And so I have multiple opinions which I’m never short of but. In terms of thinking about these sparse nutrient environments I think that you’re right. I think that we haven’t explored them as much. There was an ICBG in Jordan to do just this– 

DAN: OK. 

MARCY: Several years back. And that’s really exciting to think about looking at desert organisms. There’s the group that looks at the Antarctic and we’ve done a little bit now in the not quite in the Arctic but in Alaska in these polar regions. And I think that there’s potential but I don’t think we know how to harness it yet. 

I don’t think – it’s actually one of the things that I think is a major challenge in natural products is that we don’t know what all the biosynthetic gene clusters look like. 

DAN: For sure. 

MARCY: We have so much information about what the Actinomycete biosynthetic gene clusters look like. And we’re just getting to where that’s getting expanded. But most of what we saw in Alaska is not Actinomycetes. And this actually holds true for the host-microbe work that we do now that’s really our main focus now, I think they’re not sparse nutrients environments at all. The human gut for example. This Hawaiian bobtail squid, it’s doing some sort of interaction with its microbes that it’s getting. 

But yet the organisms are almost never Actinomycetes. And so when we look at their genomes we don’t get the same kind of information that we would hope for but yet they produce chemistry. 

Dan: Yeah. Well we need more people like you finding the molecules so then we can tie them back to the gene clusters right? The more Info we have the more Info we have. 

MARCY:? Well so I have a question for you. I don’t know that this will go in. But do you think there are always clusters? Do you think that they always cluster or could the genes be separated on a genome? 

Dan: Oh yeah. It’s biology so anything is possible right? And I think in the kind of environments that we’ve looked at, like the nutrient rich tropical kinds of environments, where there are more bacteria there is more horizontal transfer. And so it’s beneficial then to have secondary metabolism in proximity within the genome so that things can transfer. 

Plants are a different kind of environment. You don’t have plants interacting with lots of other plants except in very, very local environments, and so they don’t transfer a lot of DNA back and forth, especially across species. And so then there isn’t horizontal transfer and so those pathways don’t have to be clustered so they end up probably over time dispersing across the chromosome. So I think that’s my feeling. 

And so it could very well be that in species that don’t do a lot of horizontal transfer you won’t see a lot of clustered secondary metabolism. It’s always been my feeling but I don’t really have any kind of statistical evidence for that. Yeah oh. You asked me a question, that’s cool! 

[LAUGHING] 

MARCY: That’s my job. [LAUGHING] 

ALISON: Marcy, is that something that your lab is exploring? 

MARCY: Mm-hmm, so this gets back to Dan’s comment about me being a chemist. The answer is we find that some of our bacteria produce chemistry that we know from – they’re proteobacteria typically – but not always. But often proteobacteria. We find chemistry that’s known, or sometimes novel, but often known, and yet the clusters don’t look the same. 

And so I think that there’s opportunity with the organisms we’re working on but we’re not exactly working on that. So it is beyond the realm of- I wouldn’t even know how to start if I must say. 

ALISON: Maybe Dan is that something that you think you could help with? Like in your vein of research using bioinformatics down the line maybe that’s something that your research will help inform? 

DAN: I mean yeah. That’s certainly the goal. I think with any kind of gene cluster identification, doing it with sequence alone you have to have some kind of a template to look for right? And so, like, a type I polyketide synthase is very easy to search for because there are patterns of domains, protein domains that you look for. And if you find those all together in the same place on the chromosome then you’ve definitely found a biosynthetic gene cluster. 

And so those are really easy to look for. And we’ve talked to Marnix about antiSMASH and that’s exactly what that does. But when you get more diverse, which, almost certainly, there’s a lot more stuff out there that we don’t know about exactly what Marcy is talking about. Then you have to first– there’s an interplay between the sequence and the chemistry where you have to have one or the other first in order to inform the other right? 

There’s always a dance back and forth. And so if you have a chemical compound that you’ve structurally characterized and you understand what that molecule is then you can start thinking about how that molecule is built and you should be able to find genes in the organism in its sequence that encode for that biosynthesis. But sometimes you have to know what those are in the first place. 

And so for a long time whenever you did a genome sequence, in about 40% of the genome the genes were completely unidentifiable. You had no idea what they were doing. Those numbers are a lot lower now but I think in secondary metabolism you know those numbers are still actually pretty high in terms of understanding from just sequence gazing alone what those are. 

And so like I said you do need that back and forth between chemistry and sequence to get anywhere. Like that’s why I say the more you know, the more you know because it really does build exponentially. When you find new things you can usually find those things somewhere else out and all the different genomes and also in the chemistry. 

MARCY: We isolated Lincomycin from one of our squid bacteria and we see the Lincomycin and genes in the genome but it’s not a closed genome. So this is part of the problem because it can be an assembly problem. But we don’t see them clustered. But why? Why not? We see the chemistry so what’s going on? So is it a genome sequence issue or is it a – like did we sequence it wrong? Or is it that it’s doing something different? Or working differently to make that same molecule? 

DAN: Yeah. There’s no inherent reason I think why a biosynthetic pathway needs to be clustered just because it’s the usual trend. I don’t know if that’s confirmation bias where you look for the things that you know how to find, right? And so you know clustered biosynthetic gene clusters are things we can usually find just like I say you find you have a pattern to search for and you find clusters of that pattern you got it right? 

But if they’re not clustered then maybe we’re not really identifying them very well. For sure. But plants certainly make all kinds of compounds and some of their stuff is clustered but often it isn’t or it’s separated by thousands of KB in terms of like strange chromosomal patterns. I’m not a plant guy so I don’t even understand all of the vagaries of plant biosynthesis. But I do know that it’s complicated which is why I don’t know anything about it. [GIGGLING] But you can carry that idea to bacteria for sure.

On your website and you’ve got some pubs on this. There is at least a paragraph or so on accessing silent chemistry and it does sound like you’re still interested in that for sure. So I wanted to talk to you a little bit about your approach to that and what you guys do when you’re exploring your systems. Because I think the JGI has a little bit of a different approach. We don’t really do culturing. 

And a lot of our trying to access silent chemistry is usually going to be through synthetic biology or genetic engineering. But I think from what I’ve read you’ve done a lot more with culture and culture permutations and what not. So is that a better approach? [LAUGHS] 

MARCY: Oh I don’t think it’s better, it’s what we can do. I don’t know that it’s– I think they’re in parallel right? And so if what you’re set up to do is to do synthetic biology that’s awesome. What we’re set up to do is to explore the elicitation of new metabolites using cultures. And one of the reasons we’re excited about it is because we can see new chemistry happening. 

And so one of the recently published papers was about doing this with human pathogens. And I had an undergrad in the lab who was just outstanding. And she decided to– she said to me, “So if we take these human pathogens that we usually use as an antibacterial assay, if we take one of those and co-culture them with say one of our Actinobacteria what will happen? Will it create chemistry that then is more bioactive against the human pathogen?” 

And Lo and behold that’s what we see or what we saw with that particular publication. And so that was– it was a lot of fun to do that paper and to have her in the lab obviously. But it was also really – how does it work? And so one of the things that we’ve come to there is that co-culture with MRSA, with methicillin resistant Staphylococcus aureus, worked better in elicitation of these molecules than co-culture with methicillin-sensitive Staph aureus. 

So just regular Staph aureus didn’t work as well. Why? There’s got to be some sort of protein or interaction or chemistry that the core-culture with MRSA is doing differently, even than this other strain that’s really closely related. And so we don’t know the answer because I can bet that that’s Alison’s next question. But it’s an exciting question in thinking about what it is between the chemistry of these different– the hosts? And I often think of the host having a protein-based chemistry but I think that’s not necessarily – There are small molecules that host make as well. And so hosts and microbes and just the interaction between them to produce different chemistry. And so we’ve been very excited about that. 

We have more recently been – and this should be on our website but of course is not. And so we’ve been working with metals and in particular rare earth elements or Rare Earth metals with our cultures. 

And we see some very interesting changes in the chemistry when we– so if you use too much of these rare Earth metals they’ll kill the bacteria. But if you use really a small amount of them the chemistry that you see changes quite a bit. And so what we don’t know is, is it oxidative stress? Is it just causing stress? But, metals that are known to cause oxidative stress don’t produce the same chemistry. The chemistry only happens with the rare earth metals. And so what’s happening? And so I get pretty excited in thinking about the biosynthetic implications of this. 

Is it interacting with, like, a binding pocket for one of the enzymes, so something that’s metal dependent? Is it– and we don’t know. And so it is sort of the next step. It’s both to harness the chemistry that the rare earth metals are causing as well as test to make sure that chemistry is actually more bioactive since we are interested in the biological activity. 

DAN: Right? 

MARCY: And then thinking about how they are interacting. Is it only with Actinobacteria or is it with our host microbe bacteria as well? And so the bacteria that we have been working on for this is a Streptomyces that we isolated from a tunicate, does it work with the proteobacteria that we’ve been talking about? And we don’t know. We’ve got lots of avenues here. 

ALISON: Two clarifying questions. One is, what is silent chemistry? And then two, what is co-culturing? 

MARCY: So the term silent chemistry or silent biosynthetic gene clusters can be controversial. People use cryptic, or silent, or hidden, obscured. But mostly it means that we– especially when we take a bacteria that lives in a community in an environment in a place that it has stress and/or interactions with other bacteria or other hosts or just different things. We take that we grow it on agar plates. And on that agar plate we often feed it lots of nutrients and in the process of giving it all these nutrients we make it happy. And it is a little bit of anthropomorphizing, but it doesn’t always produce the chemistry that you would see it produce if it were under the stressors and the environmental interactions that it has in the environment. And so in order to deal with the fact that our individual monocultures are not producing chemistry we can do what’s called co-culturing. 

And so co-culturing takes many forms. The ant project that we’re working on has one of the slowest growing bacteria that I’ve ever worked with. And so that is done on an agar plate with a strip of the bacteria down the middle waiting two weeks sometimes for it to grow and then putting some stressor bacteria on the plate as well. 

And so cross streak assays is what those would be. The work that we do at larger scale in order to look at the chemistry a little bit more easily is in liquid culture, and we have a co-culture in this case would be that we have a culture of the bacterium growing at fairly large scale, and we add a very small amount of something else to cause a little bit of stress, to cause those interactions to happen. 

And that in our experience and others experience is great for helping the chemistry to be upregulated or to produce chemistry. 

DAN: How would you try to tackle that? Would you do that through metabolomics or sequence or both or–? 

MARCY: So we do so much more metabolomics than I ever thought we would. 

DAN: Yeah that’s really where I wanted you to go with this. 

MARCY: Yes. And so we started out in the universe of natural product isolation. And in listening to some of the other podcasts I will say that my experience with mass spectrometry was nearly identical to most others where the mass spectrometer was somewhere else and we didn’t really have access to it. And now we have them in our labs and we are doing mass spectrometry on this massive scale. 

And of course, that brings about massive problems just as much as it brings about massive data into really interesting ways to look at our systems. And so we’ve done quite a bit of work figuring out how to filter out noise from the metabolomics data. We’ve done a lot of work learning about how to use statistical analysis to prioritize both to analyze our bigger system questions as well as to prioritize which strain to look at. 

And then figuring out how to show this data and to do it in a way that makes sense. And I always call this the needle in the Haystack. Because if we have 10,000 features which one do we look at because we are a small lab? How do we do this and how do we know it’s real? And so we spend a lot of time. Have been in the last several years figuring out how to adapt what we want to get out of the mass spectrometer to what we’re seeing. 

And all in all we haven’t spent much time yet talking about biological activity. 

But because that’s sort of the end goal for a lot of what we do, we would then test them. And so getting the assays on antimicrobial, antifungal, potentially anticancer or immune modulatory assays to see what role the compound might be playing in the system and then what role it might be we might be able to apply it for drug discovery. 

DAN: Tell me about that biological activity testing then because I know that I have been out of that game for a long time now at this point. And so I know that usually the plan was you would isolate a molecule and then you would throw it at say an NCI cancer panel and kind of see what happened right? Or if you’re doing antibiotics you would test it against a panel of bacteria and see what happens. Is that– what’s the modern way of doing that or is it still the same kind of thing? 

MARCY: I think the ideal is to use some sort of screening center that can do this at high throughput. And so there are several of these throughout the country. And there are folks that are lucky enough to have them at their University. We are not one of them. And so our throughput can be quite small. So we do a lot of work in the lab thinking about how to test our extracts, our simplified fractions, potentially even the organism itself. 

So doing sort of simplified super simple diffusion type assays and then using that to integrate with the metabolomics data. So we’ve got a control and a treatment for example and we get LCMS data for those and we also at the same time get bioassay data against a small panel. That’s what I would say from our lab. and see what’s happening. And so I think that this is one of the places function or activity depending on how you want to think about them. 

That is one of the really big frontiers for the next stage of natural product drug discovery I think. Or even chemical ecology figuring out what these molecules do in the human gut in the squid? And like how did they work? What do they work with? How do we figure out what they work on? 

DAN: Mmm. Yeah. That’s– 

MARCY: Still not solved. 

DAN: No. Not at all. Not even close. [LAUGHING] That’s a very difficult problem but that’s the Holy Grail right? 

ALISON: And then it’s not only like what one individual microbe might be doing and how that individual microbe is interacting with the host but then it’s the whole community. And so it just – it’s such a big problem to tackle. 

MARCY: Well right and so now you think about all the permutations that you could see here. So we’ve got 50 to 100 microbes in the accessory nidamental gland for the squid. And in the jelly coat they get the opportunity to interact, and they may interact in the squid itself, but I don’t know enough about that biology. 

And so now we’ve got this large number of microbes interacting and having a function. So we have to figure out their — it’s so much data. I cannot imagine. It’s, like, multifactorial all of the interactions of the bacteria and all of the biological activity possibilities. So– 

DAN: It’ll keep us all busy for a long time. 

MARCY: It will. Are you going to solve it at JGI? 

DAN: No. 

[LAUGHING] 

ALISON: Don’t shortchange JGI! 

DAN: JGI is great, but we’re not solving that problem. 

MARCY: I’m just– I’m not sure. There are people working in metabolomics, there are people working on culturing, elicitation, there are people working on function and biological activity. There are some that work together but yet I’m not sure that even in all of this I see the path to fully integrate all of them at a level that we could ask what the function is and feel confident that we know the answer. Holy grail for sure. 

DAN: Let me ask you about your JGI project. I know you are involved with a project that’s looked at ants and their symbiotic arrangement with a fungus and bacteria that protect the fungus. And we talked to Marc Chevrette in, I think, episode seven [Editor’s note: It was episode 6.] about this. And really his focus was on the evolution of these systems and I understand you’ve worked on some of the chemistry or metabolomics of it. Do you want to talk a little bit about that? 

MARCY: Sure. So I work on this project with Jonathan Klassen here at the University of Connecticut. And he has been looking at these fungus gardening ants for quite some time. And so he was the lead on our project with JGI in part to do some really exciting work on figuring out how to get genomic sequencing data for the fungus garden because it’s more challenging in many ways. 

They are symbiotic bacteria that live within that fungus garden, let alone the bacteria that lives on the propleural plate or the chest of the ant. And so we in this project, the interaction with JGI was really around sequencing for, I think, for the fungus garden and some of the bacterial symbionts. And so of course, the work that we’re doing is secondary metabolite related and we’re interested in multiple things here. 

A little bit in drug discovery. We have a molecule that is probably new but also related to some known chemistry. And so we are working on that aspect and it’s quite active against some fungi. But we’re also really interested in distribution. So we work on – the ant is called Trachymyrmex septentrionalis, and it is mostly in North America and so we can go and collect these things and we did. 

Jonathan’s lab does this all the time. We instead have only gone once or twice. And so, we’re interested in the chemistry. This is a multi partite system. And so what’s fascinating about this system is that there’s an ant and that ant has behaviors but it also has this bacterial symbiont Pseudonocardia that lives on its chest and protects the fungus garden. It gardens the fungus in order to make parts of it for food. 

And then some of our more recent work, what we’ve discovered is that it’s able to sense pathogen exposure in the garden. And we obviously, as a chemist, my first instinct is “this is chemistry.” This sense, whatever it’s sensing, is chemistry. And so we’ve done quite a bit of work now and are hoping to publish something soon on what that chemistry is. 

And the next steps in that project are really to figure out how does the ant sense it? Is it a signal from the pathogen to the ant? Or is it a signal from the pathogen to the fungi to the ant and how that works? 

DAN: Right. Yeah. I mean we’re probably out of time. Is there anything we didn’t ask you that you want to make sure – anything you want to get out there any papers you want to push or anything like that? 

MARCY: I didn’t talk about– like we talked and I’ve noticed that you stay focused on the science and I think that’s great. But I spend a lot of time nowadays thinking about women and gender and racial equity in natural products and in my school, in my University and, in different places. It’s interesting how much of our lives as scientists revolve around our science but then also about giving access to various different groups and overcoming challenges that we have along the way based on our backgrounds. 

ALISON: Marcy did you have anything concrete to say about– 

DAN: Yeah. I’m more than happy to give you any kind of a platform. 

MARCY: That’s interesting. Just making sure that natural products is as inclusive as it can be and that it’s an open and welcoming environment for scientists of all. Like one of the things that’s so great about natural products is it’s so many different kinds of science and because of that we get to pull in a whole bunch of different kinds of people. So– 

DAN: Yeah. I think like Marcy says our field definitely thrives on diversity. Certainly of scientific thought and there’s no reason for that diversity of thought to be all white males for sure. And I think natural products does a pretty good job of that. I mean we’re better than some fields for sure but things can definitely always be better. 

MARCY: And so I always think of us as being more inclusive in natural products. But it doesn’t always boil into like trickle up into the faculty ranks. So– 

ALISON: Yeah. Thank you. Thank you for mentioning it. I think it’s something that we all need to think more about and we all need to speak up about it and it makes that conversation easier and more present for everyone. Thank you Marcy. 

MARCY: Sure. 

DAN: It’s been great. Thanks a lot Marcy. 

MARCY: Thanks Dan, and thanks Alison, nice to meet you. It’s been very good to be here. 

DAN: So good seeing you again my old Connecticut buddy. And [LAUGHS] hope we can talk again soon. 

Relevant Links

• Some of the work we discussed about bobtail squid, and how their symbionts inhibit other bacteria using secondary metabolites
• Here’s a great recent example of some of her work on molluscs and their cyanobacterial feeding preferences
• A 10″ Simple Rules” article on increasing computational skills among biologists
• JGI CSP Proposal: Metagenomic mining of natural product diversity and understanding its contribution to ecosystem function in the cellulolytic fungus-growing ant symbiosis
• JGI Community Science Program