Natural Prodcast Episode 8: Eric Schmidt

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 back for Episode 8 of Natural Prodcast. This week, we have our conversation with Professor Eric Schmidt, from the University of Utah. I’ve known Eric for a long time – we worked together on Aflatoxin biosynthesis while he was a postdoc in Craig Townsend’s lab at Johns Hopkins, where I was a graduate student. Aflatoxin, of course, is a fungal natural product which is a liver toxin when humans accidentally eat it, but it has a really fun and interesting biosynthetic pathway, and I’ll have to do a whole show on it one of these days. If you listen to the Nancy Keller interview, I think you’ll have heard how a lot of us who work in fungal natural products, especially in the old days, saw how hard it was – it felt kind of like training for a marathon by running at a high altitude! And a lot of us moved on to work in simpler systems, like bacteria, where we figure we can make more progress faster, which is sometimes true. Other people, like Eric Schmidt, love a challenge, and love the idea of working on harder organisms, with the kinds of challenges that usually lead to surprises and really great discoveries! And Eric’s done an awesome job, in that respect.

One of the natural product families we talk a lot about in this interview are the RiPPs, which stands for “Ribosomally synthesized and Post-translationally modified Peptides.” You’ll have to use your imagination a little bit to really make that make sense as an acronym, but there you go. A tiny bit of background on this: Most of the machinery in any living organism are proteins, which are made up of chains of amino acids. “Peptide” is just another word for a small protein. And it turns out that a lot of natural products are built up from amino acids, so they’re secondary metabolite peptides. And there are two ways that nature does this. The more well-known secondary metabolism systems are the “Non-Ribosomal Peptide Synthetases” or NRPSs. These are enzyme systems that grab amino acids and stick them together to make small peptides. Those are fun, because the host organism can use whatever amino acids it has access to, which can be really weird and different, and makes for lots of variety in chemistry.

The other way – the RiPP way, is to make a protein using the normal cellular way of making proteins, with a ribosome. Then, some other enzymes chop the protein into smaller pieces, and other enzymes might make other kids of chemical modifications to it. Eric has done a lot of work on this RiPP process, and it turns out it’s pretty engineerable – you can change the protein to some extent, and end up with a different peptide, which might lead you to changes in bioactivity, and new uses for these peptides in medicine or materials science or really anything you can use peptides for! That’s what his collaboration with JGI is all about, and we talk about it a bit here. I have like a million more questions for him, but we were a little pressed for time on this interview, so I’m hoping we can follow up with him again as the project progresses!

If you’re interested in RiPPs, I’ll put some more info in the show notes, which you can find, along with a transcript at naturalproducts.com. We also talked about Eric’s mentor, the late great John Faulkner, and Eric told us a story about how John made Eric cut his hair because it was too long. Well, when we went looking for a photo of John, we found one from the 70s in the Scripps library, and in it he’s got shoulder-length hippie hair. So, I’ll put a link to that in the show notes, as well.

All right. So, here is our conversation with Eric Schmidt. Enjoy!

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DAN: Alison, we’re at SIMB, still, so we’re talking to more awesome people. And you made the comment yesterday that some of the speakers we have spoken to, I had a very personal connection to. And we have one more speaker today who I have a very personal connection to. So our “target” today is Eric Schmidt, who’s a professor at the University of Utah. And Eric , I first met in the Townsend lab, where I did my PhD. Eric was a postdoc, and Eric and I worked on the aflatoxin project together, which – we’ve already talked a little bit about aflatoxin in some other talks. But yeah, Eric taught me an awful lot about chemistry. And he has been a good friend in my life. And so I’m very happy to be here and have Eric sitting in the chair and talking to us today. How’s it going, Eric? 

ERIC:  Good. It’s an honor to be targeted by you, Dan.

DAN: I’m not quite sure where to start with you. Because I know we’ve known each other a long time. And I tend to like to ask people, how did they get started? How did you get started, Eric, in natural products? What brought you to the Townsend lab?

ERIC:  Well, I’d like to think that everything is really rationally planned. But as usual, there’s a lot of chance in life. And so, if I go back, and I look at my seventh grade list of goals in life: on that list are being a marine biologist and being a chemist, and it’s actually quite hard to put those two things together. And natural products is one of those fields that you can do it. So, it seems like a rational story that I’ve planned this for a long time. But in reality, by chance, I happen to stumble as an undergraduate on the amazing John Faulkner’s work, who passed away about 17 years ago now. It looked really interesting. He was interested to know how animals in the ocean use chemistry to interact and it went from there. 

ALISON:  I want to hear more about that story. Just a little bit!

ERIC:  So Which part do you want to know about?

ALISON:  What animals?

ERIC:  So he was really a specialist on sponges. And he’s worked on lots of different creatures. And you can find sponges everywhere in the ocean, and most people think of them as being bath sponges or something. But they’re sitting there undefended, and, so, many of them are loaded with chemicals that they make that are very potent in preventing predators from eating them. And so there’s a long history. There’s, I think, 60 years of history now of people looking at sponge chemistry and looking for active compounds and pharmaceuticals.

ALISON:  Okay, and he was looking at how the sponges talk to each other?

ERIC:   He was looking at interactions between sponges and other organisms. So one of my favorite things that he worked on was he worked on how very beautiful sea slugs that eat sponges concentrate those toxic compounds and then are defended further from being eaten by fish. And so that’s one of the things that he looked at – that it’s easy to fall in love with because the creatures are very charismatic, and they’re very beautiful. It’s something that I’d noticed as a kid just being out in the ocean, you can see these beautiful nudibranchs, these sea slugs, and finding out that there’s a chemical story and natural products – a secondary metabolism story – was really interesting. So lots of reasons that I was attracted to work in that environment. Yeah, so that was here in San Diego. So yeah, so I did feel very lucky. John, was a bit of a caustic person, which was – I loved – and one of the things I liked about him. One of the things he made me do is, I had long hair as an undergraduate student, and he told me if I wanted to get into his group that I would have to cut it, and so I came in the next day with it shaved off. Dedication. So..

DAN:  Yeah, I think anybody who’s been around Scripps [Institution of Oceanography] has heard some John Faulkner stories.

ERIC:  Yeah, he was a character. He was known for being very tough, which he was, but you know, it was always – in my experience, anyway – it was always aimed in the interest of science. So it was overall it was good.

DAN:  Yeah, I think you brought some of that culture too, to the Townsend lab, too, when you got there, eh?

ERIC:  I don’t think so. I think that Townsend lab culture had a lot of its own toughness to it in various different ways. So, the director of the lab, Craig Townsend, was very tough. And a number of people who went on to do amazing things – like, I don’t want to name names because there are too many – but, they could also be quite strong characters. So I think that it was a strong environment overall.

DAN:  Yeah, tough but good science. 

ERIC:  Mm hmm. Yeah. So there was nothing unfair or cruel about it. Just a tough environment, I would say.

DAN:  Yeah. What do you see as the overall “theme” of your research? I know you’ve generally worked in various marine organisms. Except during the time that we worked in fungi. But what do you see as the overall theme of your research aims?

ERIC:  My theme changes, but currently, my research theme really focuses on animals. I think animal biochemistry is something that’s really rich and underappreciated. And we’ve worked both with the microbiome. So, with symbiotic bacteria that live in animals and with animal metabolism itself, and it’s really amazing what diversity there is in animals. I think, even despite the long history of research, they’re pretty understudied in comparison to organisms such as bacteria, which chemists love to work with.

ALISON:  And when you’re talking about animals, you know, I picture – because I went to the zoo recently – I picture like zebras and lions and tigers, but I feel like you’re probably not limited to those.

ERIC:  Right. So the zebras and the tigers and the charismatic big animals… They actually do have interesting chemistry, but it’s not an area that we work on. We’ve worked almost exclusively with animals that live in the ocean. And of those, we’ve worked with the invertebrates, which are the animals that are lacking backbones, and so that’s our specialty. That’s where most diversity of life on earth is located.

ALISON:  Have you been continuing the research in sponges and nudibranchs?

ERIC:  In my lab, I decided to focus on tunicates, which not a lot of people know who are not specialists, but they’re also called (unfairly) sea squirts, because if you kill them and squeeze them, then you can use them to squirt your friends. But they’re actually beautiful. Sorry about that! They’re actually beautiful and diverse organisms. And they also have a rich chemistry. And so we’ve worked on those for a long time, we’ve worked with a lot of mollusks. And more recently, we’ve come back to some of the old nudibranch problems. So, in addition to the tunicates, we’ve been working with a lot of mollusks, and sea slugs – most of them are mollusks – and so we’ve had a chance in the last couple of years to go back to the sea slugs. And we do have a few projects on sponges. It’s an area – there’s some good groups around the world that focus on sponges. And so I feel like for the most part, that area is taken care of. 

DAN:  We haven’t had anybody talk too much about sponges, but sponges have been a big part of natural products for a while. To somebody who doesn’t really know about sponges, can you maybe explain what’s going on with their biology and why they’re so important to natural products?

ERIC:  Sure. So sponges are one of the most common animals in the ocean. They’re really species-diverse. I lost track actually of the number. But, say, the last time I checked, it was on the order of 10,000 species. And whenever you’re talking about a new species with natural products in different species, you’re talking about new chemistry. So there’s really a lot of different chemistry in the sponges. Sponges basically are kind of uninteresting, from the layman’s perspective, I would say. They sit there on the reef, or in whatever habitat they’re in. They’re not doing anything. They don’t move. But if you really look closely, and focus on what they’re doing there, they’re responsible for filtering out a lot of the bacteria in their environment and eating them. They’re filter feeders that have a really important role on the reef and other environments. And you can find them everywhere. They’re at the base of the animal kingdom, in terms of evolution. Because they’re sitting there, they tend to have a lot of chemistry in them. And so far people looking at that chemistry have focused on how their microbiome – how bacteria living with the sponges – contributes to chemistry. But there are also many other stories, waiting for good scientists to uncover.

DAN:  So you’ve also done a lot of work on cone snails. I’ve seen you give a few talks on that. Can you tell us why cone snails are so cool?

ERIC:  So cone snails are basically shelled mollusks that kill and eat fish. Which is kind of amazing to think about. Something that can – a little shell that will stab and consume a whole moving fish. And they don’t eat just fish. They eat a variety of things, all of which they have to hunt down. And to do that they harpoon them, and they inject a toxic cocktail into their prey. Most of those toxins are kind of like venoms – like, thinking about peptide venoms, like what a rattlesnake might inject, or what a bee might inject. And those have been looked at extensively. One of them is a drug that’s used to treat pain. It’s one of the only new, really new, pain drugs to come out in the last couple of decades. And mechanistically new, I should say. And there’s a lot of other stuff that’s in there.

So what we focused on is, are there other things beyond these peptide venoms, that might be interesting? And what we found is there are a lot of small molecules that are active, that are also found in the venoms. And so we’ve been working on that. But why small molecules matter is because this pain drug, this peptide that’s used, it’s very effective. But in order to use it, it’s got to be surgically placed into your spine into your – intrathecally – and then you tune up the dose and so it’s not something, if you’re hurting, you can just take a pill, right? But with a small molecule potentially, you can do that. And so we were really lucky. In our university, we have Todo Olivera, who’s a renowned neuroscientist and an expert on cone snails. And so he was my introduction, and I’ve been working with him for the last 10 years in this area.

ALISON:  Just a clarifying question, like small molecule versus peptide. It’s the small molecule you’re thinking of is not a peptide?

ERIC:  So what we’ve been looking at is non-peptides, so very small molecules that have a chance of turning into a pill that could be absorbed orally through that mechanism, instead of having to be injected, which most of the peptide drugs do have to be injected still.

ALISON:  I see because peptides get digested?

ERIC:  They get digested and they have all kinds of unfavorable properties, although saying that is a little bit unfair, because there’s probably thousands of groups working on solving that problem in one way or another, currently. But as of now, it’s still a hard problem that’s not solved. So we’re focusing on the other avenue.

DAN:  So, speaking of peptides, you are not the first, but you are the first person that I personally knew who got really interested in “ribosomally processed peptides”. And, you know, we don’t need to get too deep into the chemistry but let’s talk about that compound class a little bit and why, why they’re so fun.

ERIC:  Yeah. All right. So the ribosomal peptide natural products, as they’re called now, this is a class that is absolutely found everywhere in all forms of life. And they take these peptides that I just talked about, as far as not being available, having to be injected, and they make lots of chemical modifications that change their properties. And so a lot of groups are working on this area on the ribosomal peptides.

Types of things you can do: By changing these properties, you can make compounds that are better antibiotics, for example, that are more stable to absorption, for example, and distribution and so on. So there’s a lot of reason to look at those ribosomal peptides.

So when I started doing this, they weren’t really known to be a class. There were really good chemists and biochemists and biologists already working on various sub-classes, but they weren’t grouped together. And so the literature was very hard to piece together. It was in pieces. And so one of the things that’s really advanced us over the last few years is, everyone in the field has come together in an unusually friendly and cohesive way, and defined, the pieces that go together – have related all of these different types of ribosomal pathways to each other. And so, that kind of group dynamic has changed this from a field where everyone’s working in their own space to a common framework where we hold the problems in common.

DAN:  Yeah, that’s a, that’s an interesting perspective. What do you think it was about that? What factors led to the community – not necessarily competing, but – sort of, diving into this in a collaborative way, rather than a competitive way?

ERIC:  Well, so obviously, we’re all competing to one degree or another. I think it’s friendly. I think there are a couple of factors that made that happen. One of which was, there’s really a need to define a field. We were working in pieces that couldn’t be related to each other, even though they had common elements. And so we really needed to get together. You know, I’d like to say, what I was doing and what a couple of other groups were doing played a big role because we started finding common elements,

DAN:  But back up and talk about a little more of the details on how you got into this. Uh huh.

ERIC:  So I was interested in this because one of the compounds that I thought was really cool – found in marine animals – was a peptide. And we had no idea how it would be made. It could be made in any number of ways. And what was interesting about this class of peptides is that it’s just everywhere. And it’s structurally really varied. And so we thought by understanding that we could learn how to make peptides, rationally. We’d find these tools, we’d understand them, and we’d apply them. And so, I spent a number of years trying various methods, back in the old days, to figure out how they’re made from whole animals. It’s a hard problem because it’s not known. It’s the “unknown unknowns” as Rumsfeld famously said. We don’t know how they’re made. We don’t know exactly what type of biochemistry might be involved. We don’t know who makes them. Is it the animal or part of the microbiome that’s making these compounds? So in the end, we took an approach that was kind of a simplified metagenome sequencing approach to pick this system apart. 

DAN:  And the system was?

ERIC:  So we were working with tunicates, and tunicates living with cyanobacteria, and various other types of bacteria. So I got interested in this problem because, in the field of marine natural products, natural products coming from animals in the ocean, more or less, there was a question, Who makes those compounds? Are they made by animals? Are they made by the bacteria living with the animals? I would say all of the evidence was very indirect at that time.

And why does that matter? It matters because there are a lot of potential drugs from marine animals, and you really can’t develop them. If you have to go and harvest animals on a coral reef, for example, you really need to know how they’re made. You need to bring the genes into the lab, and you need to manipulate them in the lab. So who’s making them? It was a big question. And the whole question of the microbiome at the time was really interesting too. How do bacteria participate in the chemistry of animals or humans and so on?

And so the project that I picked was one where there was a kind of a good well defined symbiosis. The compounds found in those animals were really interesting. And these included a tunicate, living with lots of bacteria, but especially with these cyanobacteria that were photosynthetic. So we wanted to know if the cyanobacteria were involved in making compounds, and how that happened. And we thought if we could crack this case, then that would open up our field to other study. And so it was kind of an early example, to try to open that microbiome field.

In the end, it was really challenging, because we didn’t know who was making the compound, and we didn’t know what types of enzymes might be involved. And so what we ended up doing was pursuing with Jacques Ravel, at TIGR, metagenome sequencing, which was very early days for that technology. And we found the pathway. That way, it turned out that this symbiosis was important – that the cyanobacteria did make this compound of interest.

You know, unbeknownst to us beforehand, it was made via this ribosomal peptide type of pathway. So that brought me into that field. And when I found this, it had features of other ribosomal peptides, but really mixed up compared to what was known, really unknown by a chemical space. That was pretty exciting. And so it got me thinking about how those peptides were related to what other people were working on in these diverse areas of ribosomal peptide chemistry. And I think that plus amazing leadership in our field by people like Wilfred van der Donk at University of Illinois, and many others who are very collaborative in nature, I think, led to kind of the definition of our field – of the ribosomal peptide field.

ALISON:  I thought I knew what ribosomal peptide meant, but I’m not sure after hearing you describe the project. Could you just give a short primer for someone who is familiar with biology, but not necessarily sure.

ERIC:  Ribosomal peptides are pretty easy to understand for biologists, because everyone knows about post-translational modifications of proteins in biology. And every protein – not every protein, but most proteins – probably have one, or a few, modifications that are put on. And with the ribosomal peptide natural products, the idea is similar. They’re small peptides made on the ribosome, and then there are post-translational modifications that take place to make them very different from what you think of as a normal protein. The difference with the ribosomal peptide kind of natural product world is that those peptide products are much smaller than proteins. And the modifications provide the phenotype that is produced. So the modification turns a peptide, for example, from a disordered sequence into an antibiotic that kills bacteria through a specific mechanism. Or whatever that peptide might be doing. So, you take a peptide, a short sequence, decorated with all kinds of diverse post translational modifications, and it becomes this active agent that’s used in biology.

ALISON:  Okay.

ERIC:  Closer? 

ALISON:  Definitely. And are they evolved from any ribosomal proteins? Or are they just called ribosomal peptides because they’re coming off the ribosome?

ERIC:  Because they’re coming off the ribosomal. Exactly. So it’s an artifact of chemistry nomenclature, because many of the most important natural products that are peptides are like the penicillins of the world, and vancomycins. They’re made via a “non-ribosomal” mechanism. So we decided to name the other ones ribosomal peptide natural products, the “RiPPs”. 

ALISON:  Okay, got it. All caught up now!

ERIC:  So it’s kind of now I think, if not for that weird history, they would not have that name. 

DAN:  I think that was a great explanation. Where do you see your lab going in the future? What’s your future avenues of research? What do you see? 

ERIC:  I have, kind of, two areas that I’m really interested in right now. And beyond that, it’s hard to see, because technology is moving so fast that who knows? But one of those areas is I’m really interested in what natural products from the ocean are doing. And specifically, they’re aimed outwards at the behavior of other animals. And so they are likely to and do affect neurons, many of them, and so we’re interested in that. And we have a project working on pain drug discovery from those animals.

A second area that I’m really interested in is how to use design principles to make new compounds. And that’s related to what my project is with the JGI. Where, it’s again, with ribosomal peptides, we’re looking at some design rules so we can more predictably make compounds. And so that relates to nature very directly because natural evolution tells you what some of those design rules might be and constrains hypotheses that you can test about how to put things together.

So I think those are two areas I’m really interested in for the foreseeable future. And the way we’re going about it is we’re looking extensively at the natural biodiversity of animals and their symbiotic in the ocean.

DAN:  Yeah. Do you want to talk a little more about your JGI project? 

ERIC:  Sure. So with that project, we’re looking at how different ribosomal peptide scaffolds can be manipulated to design products, rather than to just use the products made by nature. And there’s kind of two basic questions about how those pathways work. Number one is timing. So, when the peptides are made in living systems, they make the substrate which is a short peptide and all of these enzymes that do reactions on that peptide. Often, the reactions that take place take place on the same amino acid residue, for example. So how those reactions are timed are really going to tell us how to control some aspects of chemistry with the enzymes and so we’re interested in that. And working with the JGI is really helpful because you’ve got experts in designing promoters and so on that we can consult in designing pieces of DNA that we can use to test these issues.

The second area that’s really crucial and very unknown has to do with how proteins interact with each other. There’s a lot of leading data from excellent groups about specific interaction motifs. But there’s still many more questions than answers about how these pieces fit together. And if we can design those interactions, I think we’ll be a lot better at rationally making compounds. 

DAN:  Alright, that sounds really cool. 

ERIC:  It is really cool. So thanks to the JGI for their support.

DAN:  I look forward to working with you, Eric, on all of this stuff. And thanks so much for being here today. I think we’ll wrap up there. Yeah, it’s great talking to you, as always.

ERIC:  Alright, thanks. Thank you very much!

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.

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