Natural Prodcast Episode 1: The Primer, Part 1

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: Hey there, and welcome to the first episode of Natural Prodcast. First, maybe, a little bit of background. My name is Dan Udwary. I – as well as my co-host, Alison Takemura, whose voice you’ll hear in a minute – we work for the US Department of Energy Joint Genome Institute, or JGI. JGI is a DOE Office of Science User Facility located at Lawrence Berkeley National Laboratory. Being a User Facility means that scientists from all over the world bring us big problems related to energy and the environment – problems that might need special technology for DNA sequencing, genomics, metabolomics, and synthetic biology, that maybe they don’t have available in their labs, and we use our resources to help them solve those problems. It’s a fantastic place to work, and this is the best job I’ve ever had.

So, ok, that’s fine and all, but what the heck is a Natural Prodcast? Well, obviously, it’s a play on words – a podcast about natural products. And natural products is an older term for the special, natural chemical compounds that you find in plants, fungi and bacteria, basically all living things. When your crazy Aunt is posting on Facebook about cinnamon or turmeric curing every disease and helping you sleep at night (I’m not sure if that’s a real example), she’s talking about natural products, even though the science in that Facebook post is probably more than a little fuzzy. The natural products – or secondary metabolism – field, though, is real, and it’s a field with very real and truly amazing science with a long history, and that’s what we’re going to be talking about here.

JGI, as an institution has recognized how important natural products are to understanding the natural environment, and so our Director, Nigel Mouncey, started and leads the JGI’s Secondary Metabolites Science Program, which I was hired into, and my job is to do cool research, and also to talk to the wider natural products community about what they need to advance their science, and what JGI can do to help that.

So here we are. This is the first episode, and at the same time I’m going to release 5 other episodes so you can get a good feeling for what this podcast is. The first three episodes are what we’re calling a Primer. We wanted to try and give a general audience some of the basics of natural products science, and, of course, the word Primer is a molecular biology term. We recorded the Primer as a much longer conversation, which I cut into more digestable pieces. If you’re an expert in the field, you can probably skip straight on to Episodes 4 5 and 6, for some fun interviews, unless you want to fact check us. I like fact-checking, so go nuts.

But here, in this first episode you’ll meet me, and my co-host, Alison. We’ll tell you some stories about natural products, so you can get a feel for why I think they’re so important, and we’ll start to explain some of the terms and the basics so that you, the audience, who might not be familiar, can start to understand what this is all about. In the second episode, we’ll talk some more about the differences between primary metabolism and secondary metabolism, and we talk about the early history of the field. Then, in the third episode, we’ll discuss the modern history of  natural products and where we are today.

After that, we have lots of great conversations that we’ve already recorded with some excellent scientists, and that’s probably how we’ll continue for a while. To be fair, it’s probably going to help you some to have some basic knowledge of modern biology. We’re trying to keep this as general as possible, but scientists love technical jargon. If you don’t have that background, well, everybody starts somewhere right? Most of what you need to know is a Google search away!

If you like these primer episodes, let me know by emailing us to [email protected], or on twitter @JGI or @danudwary. We’ll probably do a few more of these in between blocks of interviews, as we go on, so if you hear a topic you’d want us to dive deeper on, let me know!

All right, so here we go. This is episode one of the Natural Prodcast Primer! 

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DAN: Hey, Alison. 

ALISON: Hey, Dan. 

DAN: So we are doing this podcast on secondary metabolism. And I thought it’d be a good idea to have the opportunity to talk more about some of the background and sort of the reasons why we want to do this. And also to provide a little more information and context for people who might possibly be interested in listening to a podcast about secondary metabolism. There are probably not that many people who want to do this, but I think even 

ALISON: Passionate few

DAN: Yeah, maybe and I think one of the one of the fun things that I hope that I can express today is why secondary metabolism is interesting and why it is that we need more people to do work in this field, and why people who are not in this field could be doing work in this field. So yeah, I thought we’d go through some of some of the background of the science and a little bit of the history of the field and lead into the current state of things so that when we talk to other scientists, we have a better idea of what’s going on and what the context for their work is. 

ALISON: Cool. That sounds great. I’m so glad that you invited me to have this conversation today. And I wonder if we should start off with who we are. 

DAN: Okay. Sure. Do you want to go first? 

ALISON: Sure. So my name is Alison Takemura and I work here with you, Dan, at the Joint Genome Institute. And do you want to hear a little bit about my background? 

DAN: Yeah!

ALISON: Okay. All right. So I did a PhD in microbiology at MIT, and I studied microbial ecology. I studied Vibrio species in the ocean, so heterotrophic bacteria. Now, we didn’t get into secondary metabolites really in my studies. So this is, is an area that was adjacent to what I worked on, but my experience of how microbes are interacting in the environment like, like my journey into exploring that world, I did feel like there are there is a big importance on the kind of molecules that they’re sharing and expressing, and that it seemed like we didn’t know very much about that world yet. So I am very interested to hear more about it. And I’m excited to talk with you who is an expert. Dan is an expert in this– 

DAN: Let’s not get crazy.

ALISON: Someone who works in this field. And just to say that again, I’m excited to talk with you, Dan, because you are working in this field.

DAN: Well, it’s nice to have someone who can be a sounding board and keep me on track. And it’s always been good talking to you. So I think it’ll be fun to have the conversation.

So I am Dan Udwary. I’m a researcher in the Secondary Metabolites Science Program here at JGI. It’s a new group formed under the director who has also got a long background in secondary metabolism. I have been in – working in secondary metabolism for almost 20 years now. Which when I did the math, that was a surprise to me, too. I started working in second metabolism in graduate school. I joined the lab of Professor Craig Townsend at Johns Hopkins University. He does biosynthesis of natural product molecules and sort of the intersection between biochemistry and synthetic chemistry. And I did postdoctoral work with Brad Moore who we’re going to talk to you in a couple of weeks at Scripps Institution of Oceanography. He got me into genomics of microbes, specifically of some that lived in the ocean and made some cool natural products that we’ll talk to him about. 

ALISON: Cool! Ocean microbes! 

DAN: Yeah, absolutely. And then after that I was a professor at the University of Rhode Island for a couple of years before I left that to join a biotech startup. And after that came to work with the JGI. And so now here at the JGI, I work with all of the sequencing data that the JGI produces to try to find and identify natural product biosynthetic gene clusters and to do research to get a better understanding of that data.

ALISON: Awesome. So tell me why should I even care about secondary metabolites? I mean, I kind of I kind of feel like I should, but tell me more and maybe… 

DAN: Sure. So you asked me to tell you a story. And so I came up with three short stories that I think might illustrate some of that. So first, put a picture in your head. It’s a warm summer day, it’s been dry for a while maybe it hasn’t rained in a while. Picture that, you know you’re outside, maybe in a field. And suddenly, it starts to rain. Just a little bit of drizzle at first a few big drops. Now, think about that picture – that smell of that. You picture that? That smell is a chemical compound called geosmin that’s produced by soil bacteria that live all over the place. So that smell of rain is just these terpene molecules that these bacteria produce and secrete out into their environment to make their environment a little more hospitable to themselves and when it gets when it gets dry then it suddenly gets wet –  that kind of volatilizes and it gets up into the air and you can smell it. That fresh dirt smell: that is bacteria making natural products 

ALISON: Hmm. It kind of – it’s kind of like I’m smelling bacterial perfume. I mean – but it’s purposeful so it’s some kind of – Is it a compound that helps them from drying out? Or… What is it?

DAN:  Yeah I don’t know! When I was thinking about this story I tried to go look that up and I couldn’t find the answer, so it’s not known as far as I could tell. 

ALISON: It could be bacterial blankets, or coats, or water bottles, in a metaphor….

DAN: Or because they’re bacteria it could be could be phone calls. This is how they communicate – with chemicals. 

ALISON: We could be smelling bacterial phone calls. When it rains.

DAN: All right. Okay, second story. You have probably heard of the Salem Witch Trials back in the what? 15th, 16th century. 

ALISON: Yeah, I lived in Massachusetts for a while.

DAN: There you go. So you’ve heard about that. And so what many people think happened – one of the, I mean, there are a lot of reasons why people might start, you know, burning their neighbors at the stake. But one of the one of the main triggers of that, that most people, I think, believe now is that the communities where this happened have a tendency to be susceptible to a fungal infection of rye grain – a specific fungus, Claviceps purpurea, can infect grain. And when it does, it produces compounds called ergot alkaloids. And these ergot alkaloids, which are – actually some of them are pretty closely related to LSD. They can cause hallucinations and make people see things that maybe aren’t real, and so it’s thought that based on historical records and weather recordings of the time that they’re pretty sure that it was Calviceps purpurea secreting natural products into the grain that people are eating in hard times, and becoming ill, and then hallucinating, and deciding to burn witches at the stake. 

ALISON: Oh my gosh. It was in the bread. Oh, no. 

DAN: So where the natural products giveth they taketh away.

ALISON: Oh those poor pilgrims. Wait, are they pilgrims if they’re up there? I don’t know. 

DAN: Maybe early colonists? Yeah.

ALISON: Wow, that’s nuts. I had not heard that. Actually. I feel like there needs to be more talk about that. 

DAN: Yeah, you know it took several hundred years for us to even understand that it was maybe natural products that would cause some, you know, major historical events and craziness in human history. 

ALISON: Yeah, that natural products could be so mind bending and that we might just kind of happen across them in our food. That’s crazy! 

DAN: Yeah, just like the geosmin – they’re everywhere and you don’t always necessarily know what they are. 

ALISON: Yeah, okay, well, I’m definitely seeing why this is such an important area to study. Okay, what’s your third story? 

DAN: The third story is, I wanted to just briefly talk about taxol. So taxol is a natural product, a cancer drug. It was the largest selling drug back in the early 2000s for cancer. You know, a billion dollar drug. But where taxol comes from is, from the bark of the yew tree, is where it was originally discovered. And so that sounds great. There’s a natural source, right? It turns out, it takes the bark from three yew trees in order to make enough or to isolate enough taxol to give one dose to one person.

ALISON: Oh no. And I bet that’s not a renewable resource.

DAN: …A yew tree takes about 200 years to mature, so that is not a practical thing. So the natural products are there and we can find them, but can we always produce them? That’s a little bit more of a problem. And so there was a major effort to try to figure out ways to get around this. Often when you can’t isolate enough of a compound, then you turn to synthetic chemists, but Taxol is actually a very large molecule. Very complicated to synthesize. And so synthesis wasn’t really possible. Eventually, they worked out that you could get a precursor of it from the needles and then do a “semi-synthesis”. So, you take a natural precursor, and make a few modifications to it with synthetic chemistry and produce more. And then eventually they figured out that they could culture the plant cells and produce enough that way in really large like 7500 Liter bioreactors. 

ALISON: Cool. 

DAN: And then a few years later, a few years ago actually, they discovered that Taxol is also produced by a fungus that happens to grow near this tree and so there was probably some historical evolutionary event where the DNA transferred from the fungus into the tree and became incorporated. And because it had some advantage to the tree – it almost certainly, you know, prevents some animals from eating the bark or something that makes them ill when they do. And so the natural products are everywhere, they’re moving around, even from fungus to trees and doing things that are useful to us or harmful to us and understanding all of that I think is what really drives me to understand what’s going on with natural products and secondary metabolism.

ALISON: I love the stories thanks so much Dan. I mean where do we go from here?

DAN: Podcast done!

ALISON: I just want to see some – I want to go experience some natural products now but maybe that’ll be a different episode. I mean, I’m sure we are experiencing some right now and I don’t I’m not even aware of it. But that was amazing. 

DAN: Well, you’ve got a cup full of natural products sitting right in front of you. Coffee. You’ve got a natural product extract. Even then you’re just grinding them up and extracting compounds which is exactly what you do sometimes when you start doing a “find and grind” chemistry, which we’ll talk about. 

ALISON: So you’ve been telling me these stories, but what exactly is a secondary metabolite? You know, slash natural product. And, can you just use that interchangeably?

DAN: Sure. I mean, maybe — First, we can say, if you’re going to talk about what a secondary metabolite is, that implies that there’s a primary metabolite and you know, there are. So, primary metabolites are the thing we have on the screen right now. Maybe you want to describe that. 

ALISON: Okay. We’re looking at a schematic of different pathways in a microbial cell, it looks like. It could be a eukaryotic cell, but you know, it’s like a big rectangle that has colorful pathways of pink and teal, and Dan pointed out the Krebs cycle to me earlier – I kind of see it.

DAN: So what we’ve got here is, I just grabbed a photo of a “biochemical pathways” chart. So if you spend any time hanging around biochemists or a biochemistry lab then there’s a pretty good chance that somebody’s got one of these posters hanging on a wall somewhere because we do use them. And what this shows are all of the common biochemical pathways shared by almost all living organisms.

So almost all of these reactions are going on in your body. Almost all of these reactions are going on in the coffee beans that you – at least before they were ground up into coffee – bacteria, fungi, you know everything. These are shared pathways for making amino acids and nucleic acids for DNA and breaking down food so that you produce energy, all of the common things that every organism needs in order to live and reproduce and grow. And so secondary metabolism is everything other than this. Basically, it’s all of the other stuff.

So you asked about terms and so I will probably end up interchangeably using the term secondary metabolite and specialized metabolite and natural products. Yeah, some people have – in the field – and we may talk to some of them -will have different ideas about this, this term for what secondary metabolism should be called. Some people don’t like the term “secondary metabolism”, because it implies sort of, it’s not as important, or it’s secondary, and they prefer the term “specialized metabolite”. Natural Products is sort of the old, older fashioned term for it. And it’s still around. But if you Google “natural products”, you’re going to find, you know, people selling strange lotions and things. 

ALISON: Oh, yeah, so that’s not the kind of natural products we’re talking about.

DAN: Yeah. So at JGI, we call this area secondary metabolites or secondary metabolism.

ALISON: Right sort of outside of the core that’s central for living organisms.

DAN: Right, all of the other stuff. So caffeine is a natural product. It’s not something that is found in all organisms. And it’s all of the chemical things in a cell or a living creature that make it specialized or adapted to its environment. Chemical- chemistry-wise. So it’s very important for bacteria that they have specific chemicals that they, you know, put into their environment or produce themselves. It’s the pigments in flowers. It’s communication molecules that some organisms use to say, grow near each other, or fight each other with antibiotics. It’s all of that other stuff that things use to adapt. So secondary metabolism is, itself, evolution.

ALISON: Hmm, yeah, I guess this relates to when I was studying heterotrophic bacteria: the core genome and the flexible genome. So that’s kind of the mentality that I’m looking at it with, you know, it’s within a species or microbial population, you have some set of shared traits that everyone has but there’s still variability. Although this secondary metabolism, you take it to a different level. It just makes me think about how funny, you know, the human endeavor of understanding nature is: we want to categorize things into these arbitrary bins. And you know, for an organism the ability to communicate might be as critical or it might be as big a part of its life as metabolizing sugars, but it’s something that we decide is not so important or essential to life. 

DAN: Well, maybe you, but this is my field. So I think it’s very important!

ALISON: It’s true. That’s true. Yeah. 

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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 archive.jgi.doe.gov/user-programs.

Thanks, and see you next time!