Natural Prodcast Episode 13: Francisco Barona Goméz

DAN UDWARY: You’re listening to the Department of Energy Joint Genome Institute’s Natural Prodcast– a podcast about natural products and the science and scientists of secondary metabolism. Hey everybody, this is Dan with episode 13 of National Prodcast. This continues our little section on international genome miners, and today we have Francisco Barona-Goméz, or Paco, as he prefers to be known among friends in natural products. He’s from Langebio in Irapuato, Mexico, and an incredibly bright guy who’s been thinking for a long time about the evolution and natural products systems.

This conversation came about because he challenged me on my use of the term “secondary metabolism.” And so we talk a lot here about the terminology we use and where it falls short, and maybe what we should be saying to be more clear about what we mean. So if you want to learn about the differences between primary metabolism and centralized metabolism, or what a secondary metabolite is versus what a specialized metabolite is, then this is the podcast for you. A lot of this is based on a really great paper that came out in 2020 where this is all explained in detail, so if you’d like a link, just check out the show notes above or at naturalprodcast.com.

I should also mention that I’m a bit embarrassed that we recorded this conversation about 10 months ago. I was pretty green at the time and had some really tedious technical problems with editing the recording. But I recently changed the audio editing suite I use which had some nice magic that clean things up.

So I didn’t get to talk to him about more recent work like ActDES, which is a curated database of actinobacteria for evolutionary studies, and hopefully we can catch him again some time to chat about it. This was a great conversation which has really shaped some of my views and language, and I hope you’ll enjoy it too. So here we go– episode 13 with Paco Barona-Goméz.

DAN UDWARY: Hey Alison.

ALISON TAKEMURA: Hey, Dan.

DAN UDWARY: So we recorded the Primer episode a little while ago. And the primer episode, for anybody who hasn’t listened to the primer episode, it’s sort of an introduction to secondary metabolism. And when we were talking about definitions around words I made a possibly false statement. I said that I thought that the terms secondary metabolism and specialized metabolism, and natural products, or metabolites, were basically interchangeable terms in terms of common usage.

And I was recently challenged on that on Twitter by Francisco Barona-Gomez. And so he is here to, at least, talk to us, first about my definitions of things and why I am wrong, and also talk about some of the great science that he does. So welcome to the show Paco Barona-Gomez from the Laboratorio Nacional de Genómica para la Biodiversidad. That is Langebio in Mexico. So, welcome Paco.

FRANCISCO BARONA-GOMEZ: Thanks to Dan, and nice to meet you Alison. Thanks for the invitation too. Let’s talk a little bit about secondary metabolism.

DAN UDWARY: Yeah, great. We’re really happy to have you here. Tell me what you think the terms we should be using for what we do are, and why there and why it’s important to make those distinctions.

FRANCISCO BARONA-GOMEZ: I think that the very first thing that got us into this is that we should, in any case, use definitions that are useful. So if you use a term that is not useful, then I think it needs to be revisited. And I think that a secondary metabolism as a field, or subdisciplines, started to grow and have different perspectives– from the chemists on one side, microbiologists, and evolutionary biologists more recently– we and my co-authors thought that it was time to put a little bit of order in terms of the definitions, such that everybody could have a understanding of what we’re talking about.

And while thinking on that, which was a very complicated and challenging issue, we realized that the only really intrinsic feature of secondary metabolism, which will not change over time– for example, because of technologies or uses or applications– are the evolutionary nature of these compounds. At the end of the day, all the content produced by microbes the result of millions of years of evolution. And if we could actually link terms to those emerging features that are natural to this complex, then we might have a better understanding of what is what.

This is not new. It actually was first proposed by two authors called Firn and Jones. I’m sure that people excited in natural product biosynthesis overall have had read some of their papers and one seminal book, which talks about this idea of linking natural products to the evolutionary forces that drive them to appear. So based on that, is that we start thinking on how we could call things such that the terms will be useful. The community– we should say that. I mean, we just proposed something, and if people find it useful then we have a set of rules that we can stick to.

DAN UDWARY: All right, well let’s talk about that. Oh, sorry go ahead Alison.

ALISON TAKEMURA: Yeah, well I was wondering if you could give an example.

FRANCISCO BARONA-GOMEZ: Yeah, so any metabolite, produced by bacterial or fungal metabolism by microbes, will have a functional role. We started from that. Evolution doesn’t invent stuff to see what happens and keep it alive for a while. It does it because it’s been selected for. So if you think about the possible functions that each one metabolite could have, then you could figure out that there are metabolites that will rely their activity in the physical, chemical features of the compound. For example, lipids– doesn’t matter if it has one extra carbon or two or one less, at the end of the day, it’s because it is a hydrophobic molecule, flexible, that will confer one particular feature to a membrane.

So, similarly, you have siderophores which are metabolites that will actually chelate any divalent metal. So it could be iron, could be silver, it could be copper, but unless you don’t mess about with the three pairs of electrons that you need to do these coordination bonds, then many structures will be able to work.

So, for example, in that respect, what Firn and Jones is talking about is that you could, therefore, expect a lot of chemical diversity. So many compounds will fulfill the same function. So that is called support metabolism. Many of this stuff will actually do a job, so, therefore, evolutionary forces will be very flexible. They will allow promiscuity and the enzymes are driving the production of these compounds, which, in turn, translate into a high chemical diversity.

So that’s just the type of relationship between the natural forces, the chemical structure that is derived from those natural, evolutionary forces, and then how these compounds really should be seen with a different term. I mean, if you talk to most people in the field, they will say that a siderophore is a secondary metabolite. In a way, that doesn’t tell you nothing. It’s not very useful to say that a siderophore is a secondary metabolite. It’s better to know that it’s a result of an evolutionary process that has led into large chemical diversity because the function relates to the physical, chemical features of the compound.

So that’s just one of the examples. There are many others, of course, there’s ones related to antibiotics that’s obviously a big question, and how you can start defining that type of metabolism.

DAN UDWARY: So does primary metabolism have meaning?

FRANCISCO BARONA-GOMEZ: So the case of primary metabolism is a very interesting one, because if you think about it, the only way a primary metabolite or a primary metabolic pathway is good for anything, it is if the final product is obtained.

So let’s think about synthesis of an amino acid, like tryptophan. You are not allowing any chemical diversification throughout this seven-enzyme pathway, because the only thing that is important on the pathway is the final product. In that respect, evolution is acting very strongly. There is very strong purifying selection, and what matters is a final product. So it doesn’t matter what happens at the beginning of the pathway, you need to end up with tryptophan, which will be the amino acid that is relevant for the synthesis of proteins, and will more often end up in the active site of an enzyme.

So there is no promiscuity, generally speaking, in primary metabolism. Nevertheless, these pathways and these compounds are also part of metabolism. They are also natural products. And under certain circumstances, for example, if you are a tryptophan-producing organism but you are grown on medium without tryptophan, probably you will shut down the pathway just like E. coli, and therefore it is a secondary metabolite, because he’s not mutated under those circumstances. Whereas the nature of the evolutionary force, the selection there is shaping the pathway itself on the products that are produced will never change irrespective of the conditions, unless it happens on the long term, millions of years.

So interesting case. It could well be that some of the secondary metabolites that we see today used to be primary metabolites, or vice versa. I mean, if you think about it, the evolutionary forces are shaping each part of the metabolic network in each specific organism. Really, what matters is the forces that are acting upon them.

DAN UDWARY: Yeah, so when I described it, I thought of primary metabolism as being the standard set of shared reactions that most living organisms share – have together. Obviously that is flawed, because it’s biology and there’s always an exception to everything, but I always thought the conceptual framework was useful, at least. Certainly, I can see many, many flaws with thinking that way. So is that not a good conception of what’s going on in biology?

FRANCISCO BARONA-GOMEZ: One concept that you have right is that central metabolism– or it’s also called integrated metabolism, by Firn and Jones, because it’s highly tightly integrated in order to lead to the final product. It’s that stuff that is always shared between different microbes. And I think the important thing to remember is that, thanks to genomics, we now know that it is very hard to find stuff that is universally conserved.

No matter what you look at, we will always find a new way on how to do the Krebs cycle. There are microbes that will actually redefine that. There are microbes that will actually redefine how you synthesize nucleotides. Stuff that are at the core of what we call the central dogma.

So what we would like to see about it is that we talk about conserve between or within a particular genomic lineage. So there is no doubt that if you look into all the Streptomyces of a particular part of the Streptomyces phylogenomic tree, then you will be in a position to say, this group of Streptomyces share this. And it will be very surprising to you, Dan, to realize that some of that shared stuff are typically defined as secondary metabolism. So that’s the other side of the coin. You stick to this idea of sharing something, you often end up realizing that what is defined by the KEGG [database], for example, is not enough even there. So it’s highly variable. So the conservation depends on the genomic lineage you are looking at.

So that’s why the term “central,” or “primary,” doesn’t tell you anything, whereas “integrated,” for example, if you have a shared group of reactions, they have to be integrated. And they, more often, produce something that is relevant only once you have the final product that make the network feasible.

DAN UDWARY: OK, so tell me then how is it that you are defining secondary metabolism?

FRANCISCO BARONA-GOMEZ: OK, so all these ideas of “central” against “integrated,” or “supportive” against “peripheral,” or siderophores or lipids are more or less quite straightforward, at least in my mind, that you can really connect what type of evolutionary pressure is simplest. High purifying selection will lead to a highly purified pathway without promiscuity, without chemical diversity, whereas the supportive siderophore/lipids kind of things, you end up having chemical diversity, because what matters is not a particular structure but the ability of the structure to do something, typically physical, chemical terms. So that is kind of nice and neat.

But when you get into what we call secondary or specialized metabolism, what we are often coming across is very complicated pathways with many, many enzymes, but even if people do not report back this these observations, most, if not all, of the pathways that people have been cloning and analyzing are producing not only one metabolite.

They produce a large array of different molecular species related– chemically related– but nevertheless we did enough differences between them, for example, in terms of the stereochemistry, such that single changes can lead to a particular high activity towards a particular target. That’s why an antibiotic has to be a particular structure– because we are targeting a very – specificity – a particular target and only one structure will do the job.

So the question is why is it that microbes bother to produce these highly complex pathways that lead to many compounds from the beginning to the end. It’s not only the final product that is highly diverse, but also many of the intermediaries. And, in a way, I find it counterintuitive, because we are taught that microbes produce highly specialized, highly potent and specific compounds to defend themselves. And the reality– the actual observation of the work of anybody who has been doing research in this field– is that that’s true for one compound with relation to one target, but will always ignore all the other compounds that are produced, and we don’t know what potentially other targets, if there are actually other targets.

So Firn and Jones called this metabolism a speculative metabolism, which is basically, they don’t define a mechanism of how this could be taking place in terms of the evolutionary forces, it’s kind of a speculation through the evolutionary process. But what we’ve been thinking about is that the only way we could understand this is that the actual chemical diversity is selected for. Because, otherwise, it will be purified just like a central metabolic pathway. If we are only interested in that final product, which is completely potent and specific to the target we’re thinking about, then it doesn’t make sense to keep alive all the chemical diversity. So that’s one interesting consideration to take into account once we talk about the definition.

And the other thing is that in certain niches, ecological niches, probably Marc Chevrette‘s contribution to talk about this, he’s very interested in very highly coevolved systems where a microbe becomes a symbiont, for example, of an ant. So these are very stable interactions that have been evolving for 300 million years, that could be a reasonable number if you are talking about a plant and a microbe interacting very stably. So it makes sense that you end up having a very unique on one compound.

So cahuitamycin is an antifungal that will actually protect the fungal farms from other fungus that want to take advantage of that resource. So in those type of situations, what we would like to call is a specialized metabolism. So it’s something that has evolved to provide a very specific, highly specialized function to a particular producing organism in the context of a clearly defined ecological interaction. So it’s not central because it’s not just supports energy and yeast-type function, it’s very specialized function, which more likely is the result of a very tightly coevolving unit, so the holobiont kind of thing.

In fact, if you take a look at the recent reviews where they discuss whether an antibiotic is really an antibiotic in nature, what is the general belief is that that is the case when there is a strong connections between the producing organism and strong interactions and the host or even in tripartite systems. So, in those cases, it’s been, in the last five years, obvious that these are specialized metabolites. They are produced to fulfill a very specific function.

But what about all the others? I mean, we know that any of these organisms, even if they’ve been coevolving for millions of years in these particular niches, produce probably 20 or 30 more metabolites, which have this particular feature of many metabolites being produced throughout the whole pathway.

And that is what we call secondary metabolism. It is truly a secondary product of evolution that, yet, does not fulfill in a specialized role or even an integrated metabolic role– I’ll come back with an example of that one later– or some sort of siderophore kind of role. It is just something that nature has been selecting throughout many years. And that’s a big question mark– why is it that we have these microorganisms that have truly secondary metabolism. The other three are easy to explain– they can function.

But what about all that chemical diversity. So there are two ways of approaching it. One is there is a school of thought that simply believe that we are just not good enough to identify all the functions that this particular microbe with 30 pathways of secondary metabolism are producing. It’s a very fair argument.

But if you think about it in the context of tightly coevolved units, it is hard to imagine any scenario, given the fact that these niches are highly stable, they don’t tend to be exposed to many dramatic changes, environmentally speaking. It’s hard to imagine that there will be one function to every single one of these metabolites.

So that take us back to the idea that chemical diversity selected for. But why? I mean, why is it that our organization is spending so much resources on energy and keeping alive a very complex chemical matrix. And that’s the term we use in this paper. We talk about secondary metabolism from the perspective of a chemical matrix, which is very important, because then you can see it as a fitness landscape, which is very common in evolutionary biology but, for some reason, chemical microbiologists have ignored this idea of fitness landscapes.

So, in one hand, you could imagine that there is a lot of chemical diversity, on the other hand, you can imagine there are a lot of targets which are just one function for each one of these molecules. And, at the end of the day, that will be selected for only if you contribute into fitness. That is what a fitness landscape is. You have to correlate two or more factors that will actually have an impact to bring positive or negative into fitness.

So while we were trying to draw these ideas conceptually, we didn’t realize something that I think is the main take-home message of this long review –that is more like a, not only  the literature that we are citing, but it’s more of an intellectual effort to better understand secondary metabolism — is that everybody ignores negative selection in the field of natural product biosynthesis.

To our surprise, we couldn’t find a single suggestion in the literature where somebody would say, hey, this could be a highly toxic compound. The conditions have changed. Let’s get rid of it, because otherwise it will be targeting a target that is not beneficial anymore, and instead of being a nice antibiotic to protect me, it is now like a very toxic compound that will actually go everywhere and cause a lot of trouble.

DAN UDWARY: Oh, yeah. That’s an interesting thought, because I think probably most of the time, we tend to think of these things as the organisms would turn the regulation off, rather than negatively get rid of the genes from their genome.

FRANCISCO BARONA-GOMEZ: Exactly right. It, we feel, is new to the field, and we are looking forward to seeing how people receive this idea of negative selection. Which would, in a way, solve the problem of chemical diversity because you are basically just moving around, from one point to another, until it’s clearly the time for positive selection through a very long period of time, because you are already on a stable niche that you want to colonize and become the main player, and that’s when and only when positive selection could take place.

Whereas just the secondary metabolism which could– I mean, we all know, from experience, that when you have a culture, you grow it in one medium, exactly what you think is the same medium from the previous experiment, and you get non reproducible results, or chemical diversity. I mean, depends how you want to see it.

So we had the feeling that we have overlooked the real nature of secondary metabolism as a truly wonderful and unique complex trait that has to be evolving under an array of different forces, not only one, and more often natural product biosynthesis is very directional. That’s wrong.

DAN UDWARY: So how do you test for that? How do you find evidence of negative selection?

FRANCISCO BARONA-GOMEZ: That’s the big question, right? I mean, you have to test for that. So, first of all, we were approaching it on the basis of the available data that is out there. So let’s think about the metabolomic data that, very nicely, with new approaches like that one push forward by Pieter Dorrestein – the molecular networking, you can have a global view on the chemical diversity of metabolism.

We haven’t done it thoroughly, but the sense, the feeling, we have is that if you have in these molecular networks, nodes that are not so highly diversified, for example, we have some data from desferrioxamines in the environment. You see like hundreds of molecules. That is probably something that is not an antibiotic. So if you start looking into cephalosporin producers, we also have data from these type of organisms.

Then you do realize that cephalosporin is only one molecule. There are no networks. So that could be already something that has been purified, because the connection from which we actually isolate these microbes, unfortunately, in many cases we are lacking a lot of mycological information. It could be a very unstable interaction, mediated by this antibiotic. So you can start looking into these type of profiles or patterns from the molecular networking. So that’s one thing.

Another way to approach it is more related to what JGI does, which is sequence genomes. And we just published last year in the Nature Chemical Biology— or early this year– this new tool that we call CORASON, which is basically an acronym to look into core syntenic units that are actually are constructing a BGC, a Biosynthetic Gene Cluster.

So we do have enough data, and if you follow them, different core biosynthetic journeys throughout the evolutionary process. Then there are examples, as the one that is reported in the paper, where you could see how the biosynthetic gene cluster starts to merge and expand and accept new genes coming in and out. So, if you start making the chemistry of those organisms, then you could start seeing there is a correlation between the, what you expect on evolutionary natural history with a chemical history.

So it is not an easy one, obviously, to design an experiment rather than just going for evidence on the data that is out there. It’s a real challenge and the real goal, for our group at least. But this is still something that we’re working on it and it’s not an easy one.

DAN UDWARY: And how does this relate to EvoMining?

FRANCISCO BARONA-GOMEZ: OK so the EvoMining idea starts– it’s another algorithm that we have developed in the lab inspired by evolutionary ideas. So CORASON is obviously a phylogenomic algorithm, whereas EvoMining is, as well, a phylogenomic algorithm, but is based on the natural history of a specific enzymes of which we don’t know anything about them. So the idea is to go outside the known knowns, and to move a little bit away from that to try to unmask chemical dark matter.

And the idea behind this is that, if we acknowledge that a pathway is a result of evolutionary forces, irrespective of what is the raw material– for example, in the cases of polyketide synthases, the fatty acid synthases should actually be the raw material, then trying to track down that history, or natural stories like this one, should tell us where a microbe is evolving a new pathway, irrespective of any knowledge that we may have beforehand.

So that idea is that we identify evolutionary signals that if they are properly processed with the right algorithm, in this case EvoMining, we might be able to find any new genomes, new areas or regions or loci, that encode for new, truly chemical dark matter BGCs. That’s the idea. If you understand that evolution is driving these, why don’t we exploit it as a hint to flag a potential group of genes are directing the synthesis of completely unknown compounds. And so far, so good. It’s been working. It’s high risk, high gain. That’s the problem with this approach.

DAN UDWARY: It’s really great. The other approaches of using homology, you’re only going to find the things that you know what to look for. Right? And so I think your approach is really cool because you can find things that you wouldn’t know to spot.

FRANCISCO BARONA-GOMEZ: Exactly. There is a problem of finding a PhD student that wants to work on something that is completely, you know, very difficult.

DAN UDWARY: Is that a problem? Oh boy, got to find the clueless ones.

ALISON TAKEMURA: Is there just identifying these gene clusters that gets you to– I guess, then, because of the structure of the gene cluster, you know it produces a natural product?

FRANCISCO BARONA-GOMEZ: It is a very good question because it’s not easy to find. I mean, any genome will have many metabolic enzymes. So how do you know which ones are more or less related to metabolism first and then to natural product biosynthesis. So one of the key ideas behind EvoMining is that we exploited the actual knowledge that is already deposited on the MIB– the main repository we use for BGCs.

DAN UDWARY: It’s sort of a database of known experimentally validated natural product clusters.

FRANCISCO BARONA-GOMEZ: But the nice thing about it is that more often, let’s say that Dan submitted something there that he’s been working on for 20 years. But out of the 30 genes that make these BGCs, he’s been working with two genes. But we all know that the entire BGCs is part of that particular pathway. So all these BGCs encode between 80-90% of all known genes. Or genes that you can put a name into it, some sort of annotation, but they are not really well characterized. But, nevertheless, you can assume with high confidence that they belong to the universe of natural product biosynthesis.

So by merging the outputs of the different actions, then we can say, OK, there is an expansion, you have two copies. And then you ask the question of whether that second copy exists, or there is some evidence that might start toying with the idea of becoming a natural product biosynthetic pathway. And that’s what the algorithm does. So it’s kind of recapitulating the direct evolutionary process, but with a few tricks to dissect the information such that you can really put a confidence value into your prediction.

Otherwise it would have been like a very broad phylogenomic tool. You’ll see two copies of one gene, whatever that means. It’s too much of an output, and you cannot make sense of that. So there are a few things that were part of the algorithm to make it work. And one has to do with this idea that we have a large amount of genes that we can confidently predict that there are suggestive of natural product biosynthesis, irrespective of their function.

ALISON TAKEMURA: And what does the duplication part have to do with it?

FRANCISCO BARONA-GOMEZ: So the duplication part– which we don’t call it duplication, because in bacteria, I will say it, but I don’t think duplications take part. Is more often what we call “expansion.” So it could be many different sources. A duplication is highly related to diploids and sexual differentiation. So we feel that the best way to define these processes– “expansion.”

So the raw material for natural product biosynthesis should be metabolism itself. I mean, there is no other source, unless you believe in something else. Then the only source that you have, as a microbe, to evolve something, is your own metabolism. So we came up with this idea of exploiting expansion as an evolutionary signature, telling us, this is something that is evolving in one direction.

Then, of course, the next question is, which is this direction? What is the fate? It could be catabolism, for degradation of xenobiotics. If you find a way to measure that, it could be natural product biosynthesis as we did, exploiting this large universe already encoded in this database. And so on and so forth. So it’s just exploiting this as a raw material telling us, hey something is happening along this particular route. There is expansions. You should look here.

ALISON TAKEMURA: And I’m trying to get a little bit more intuition about how you go from the expansion to comparing to the database. Is it like, let’s say I’m drawing a face, and an expansion is like I add an eyebrow, but then when you get back to the database, you have complete faces, and these are your biosynthetic clusters. And so, is it like giving you a clue to the trajectory that could make these clusters? And then you can begin– it sounds like homology. Because I’m getting confused with the idea of–

FRANCISCO BARONA-GOMEZ: OK, that’s a very important question. As we started with the definitions, we have a database that we sorted out on a phylogenomic tree, such that we can really say what Dan was saying: “central” or “primary” metabolism is what is conserved.

So we had a series of criteria to say this is a bunch of genetic material that exists in one copy, and it is homologous to an expansion, but it is going to be different. So, in the example, you gave of the two faces– you don’t have two faces, you have one face and something else, because there is a direction. So they are homologous, but there are very different.

And the driving force behind this process is enzyme promiscuity. So enzymes we believe– and, I think, not only us but many people– are typically very inefficient, not specific mechanical molecular motors or whatever you want to call them. I have read so many definitions in the textbook– I’m not surprised how people come up with intelligent design after reading these definitions. So it’s not. In fact, in evolution, what matters is that you have to be sufficiently enough, not that you are the best.

DAN UDWARY: All right, so let me see if I can recap terminology. So we’re going to say that central metabolism is the metabolism shared by a group of species.

FRANCISCO BARONA-GOMEZ: Yeah, and that it’s under strong purifying selection.

DAN UDWARY: And under strong selection, sure. Because it needs to be conserved, because it’s necessary for life in most cases.

FRANCISCO BARONA-GOMEZ: In that particular lifestyle.

DAN UDWARY: In that particular lifestyle. So primary metabolism, then, would not be a universal thing. We’re going to have central metabolism. Then, secondary metabolites are going to be the group of metabolites that are evolving and possibly under some selection, but are the sphere of other things that are being produced by a given organism or organisms. And then the specialized metabolites are a subset of those that are being heavily selected for, because they serve some important purpose that may not be important for central metabolism, but is important in some way to its lifestyle.

FRANCISCO BARONA-GOMEZ: Yeah, you got it right and I have beat that a lot. Because it tells you something. Now when we talk about secondary metabolism, then we know, as a microbiologist, that we have a culture that will have a lot of different chemical compounds up and down that probably we’ll need to play around with the conditions, that once we clone a group of genes, might not express any more. It translates into something useful. If you talk about specialized metabolites, you know that there was going to be a very tight correlation with the target. Hopefully we’ll have more examples where people really find these definitions useful and we can really start testing and organizing things beyond artificial names.

ALISON TAKEMURA: Just because I think I don’t quite understand: is – are those– what I would think of as a consumer, is antibiotics, like the rapamycin. You think that people might consider them specialized, but they might not be because of maintaining of a chemical diversity that the organism may be doing?

FRANCISCO BARONA-GOMEZ: So that’s an interesting question, because what you are leaning into, the question is the anthropocentric view. We typically talk about secondary metabolism because they are useful for humankind. We forget that the real champions of the story are the producing organisms.

So I would imagine– this is speculation– that any of the very successful antibiotics that we have discovered to date is because they have, at least, analogous role in nature. In other words, there’s already a specialized metabolite. Because they are more stable, the specificity is very high, nobody can question that the mechanism of action of rapamycin, with one side of the molecule hitting the TOR system and the other part hitting another set of proteins. It’s hard to imagine that it was an accident in nature. This is very hard.

But, unfortunately, all of these compounds that people are using in the clinics were kind of kidnapped from nature without paying attention to the evolutionary biological relationships from which they were taken away. Now things are changing, we natural product biosynthetic people are more and more concerned about the biology behind these stories, because what we want to learn are lessons that can be translated into applications, not the application itself. We start from another perspective.

So I would imagine, Alison, that to answer your question, is that if there is something very strong, actively speaking, I would imagine that it comes from a very tight coevolving evolutionary unit. Therefore, it is a specialized metabolite. But not because it kills a bunch of bacteria in our body is it a specialized metabolite. You see the difference.

ALISON TAKEMURA: You’re talking about an effect versus a cause. Like it’s specialized because it’s been undergoing purifying selection vs.interaction.

FRANCISCO BARONA-GOMEZ: Exactly. And I have just written a small piece where we discuss the future of merging evolutionary thinking with synthetic biology. And I have the feeling that once we have the synthetic biology tools, we finally are in a position to exploit secondary metabolism. So far, what we have been exploiting is a specialized metabolism, because secondary metabolism is tricky. It’s hard to– most people will not go and purify the small peak on a HPLC, because that’s a hard one. They will probably go and work with the one that is highly expressed and stable and so on. So I have the feeling that we are just at the stage in which synthetic biology could be making secondary metabolism more useful than before. With these definitions, of course, that’s important.

DAN UDWARY: Sure, and that’ll be a really important step towards you being able to engineer these systems and do the kinds of things that we’ve always talked about being able to do.

FRANCISCO BARONA-GOMEZ: Yeah, truly engineering and going beyond what nature has evolved, which could be useful for our own applications. Nowadays, we talk about antibiotic resistance, and I was talking to my daughters– what did they think would be important in 100 years. Would natural products be important for antibiotic resistance, or for something else? So it’s important that secondary metabolism is also seen as a resource that we should exploit sustainably, because we don’t know what is going to be the needs in the future.

DAN UDWARY: All right, so if I had to sum up the last half hour or so, I think it sounds like what, maybe, I was stuck in is that we’ve been discussing natural products from a human-centric point of view. And it sounds like what you’re advocating is that we think– in terms of the evolution and everything else that’s going on– we have to think about it in terms of the bacteria-centric terms and think about things that way, in terms of how these systems have actually evolved and come about, and that will help us understand them better.

FRANCISCO BARONA-GOMEZ: You said it better. Yeah, you said it better than me.

ALISON TAKEMURA: Thank you so much Paco.

FRANCISCO BARONA-GOMEZ: Thanks, Alison.

DAN UDWARY: Yeah, really great conversation. Good talking to you.

FRANCISCO BARONA-GOMEZ: Thanks, Dan, for listening and inviting me. Thanks, Alison.

DAN UDWARY: Absolutely.

ALISON TAKEMURA: Thank you too, Paco. All right, thank you everyone. Bye.

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DAN UDWARY: I’m Dan Udwary, and you’ve been listening to Natural Prodcast, the 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. If you like Alison, you 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 Jazzar. 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. That’s D-A-N U-D-W-A-R-Y.

If you want to record and send us a question that we might play on air, email us at JGI-comms. That’s JGI dash C-O-M-M-S @lbl.gov. 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.