The future of lipids in evolution

0:00This is Stanford Engineering's The Future of Everything, and I'm your host Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world. and it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody.

0:37In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here and that you'll share it with your friends, family, neighbors, co-workers as well. So this planet has been in existence for 4 billion years and you have to imagine that the first 3 billion years of the planet and life evolved very much soon after the planet formed, those first three billion years is all microbial. So we really don't start to see more complex organisms until the later part. And, you know, humans haven't been around on this planet that long compared to microbes.

1:10And so for geochemists that are really interested in thinking about what the earth was way in the past and how it interacted with life, they need to understand microbial life.

1:26this is stanford engineering's the future of everything and i'm your host russ allman if you're enjoying the show or if it's helped you in any way please consider rating and reviewing it on whatever podcast app you use we'd love to get a 5.0 if we deserve it plus your comments your input is extremely valuable to help others discover the future of everything today paula Wielander will tell us that the lipid molecules or fat molecules that make up the membranes that surround cells are incredibly complex and they can last for millions of years long after an organism dies. That allows us to study the evolution of chemistry on earth and the evolution of life on earth.

2:06It's the future of lipids on earth. Today we are continuing our new feature that we're calling the future in a minute. At the end of the interview, I'll ask Paula a few rapid fire questions and she'll give me some quick answers.

2:25Lipids are fat molecules that have many functions in the cell, but the most important is to create the membrane or the barrier that surrounds a cell. That's what keeps the inside of the cell separate from the outside. Now, not all cell membranes are the same. And across organisms, we see different membranes with different physical properties because of the different environments that the cells live in. The cells in our liver and the cells in our brain have different environments, but especially single-celled bacteria that are living in a hot springs in Yellowstone Park or in a very acid bath part of the ocean, they need very special membranes.

3:04And in fact, there is a huge diversity of the lipids that make up the membranes of these organisms. Not only that, but it turns out that the lipids can last almost like fossils for a long time. Millions of years, you can take a sample and you can identify the lipids. And using your knowledge of what kind of lipids go with what kind of organism, you can kind of create a tree of life over millions of years to see what organisms were living where and why. That also helps you understand the effects of these organisms on Earth itself as they helped model the planet over the 4 billion years that it has existed.

3:42Well, Paula Wielander is a professor of Earth science and an expert on lipid biochemistry. She's looking at how lipids differ across different bacteria, especially, and a new branch of life called archaea. and she's also looking at how those differences might lead to differences in how earth has evolved and also what are the effects on humans paula to start out why do you study the lipids or fats used by bacteria and other organisms on earth so lipids are kind of i think i would say the unappreciated macromolecules of life that we have i think we think they're kind of boring they kind of just form, you learn from high school biology, kind of the membrane of a cell.

4:26But, you know, if we think about all the other macromolecules, there's DNA, there's protein, there's RNA, but lipids can also be dynamic. They can have, particularly when you look in the microbial world, you start to see these differences that are very unique and interesting. And lipids are one of the few molecules that can actually be preserved in the rock record billions of years in the past. so if you think about like dna and protein that can be preserved i think now we're saying dna is like hundred thousands of years which is amazing that you can get dna that far back but lipids can go even further back and so for many years they've been used as what we call molecular fossils or biomarkers by geochemists who are interested in understanding life in the past so aside from all the functions that we can study from them biologically they have this connection to the ancient world.

5:15And so I think that's kind of why they were exciting to study. Yes, that does sound. So let's go back to some basics. You reviewed a little bit of high school biology, but since we don't want to lose anybody. So the general idea is that these, when you, when you draw a picture of a cell, you draw a big circle and that circle is actually the, you know, the barrier between the outside world and the inside of the cell. And tell me if I'm getting this wrong, but that barrier is made out of these things called lipids. And I think what you just said is the lipids are um different across different species is that true yeah so they can be different so the overall structure of a lipid this idea that if you remember like from high school biology you have like a hydrophobic inner core and a hydrophilic outer core and they form this bilayer that is kind of a basic principle of life right you need an encapsulation and um but microbes are especially their their membranes are especially important because it's their barrier from their inside to the outside environment because they're single celled organisms now our cells are encased in our body and we have cells all kinds of different cells there's a barrier many layers right there's like layers of protection but for bacteria and archaea these microbes like they're in a in a in a lake and they're that's the environment they have and they have to protect themselves from the environment so many microbes inhabit environments that we consider extreme, like hot springs, acidic environments, alkaline environments, and they have to kind of modify their membranes so that they're able to resist a lot of the stresses they have out there.

6:46So if you look at the, like I said, the basic principle is the same, but if you start to look at the chemistry, that's where you start to see some diversity and some interesting kind of features that they have. So our cells have pretty boring membranes. They don't really change them that much. but microbes really and what that leads to is not just this idea that different structures can be preserved differently and so you can see different microbes in the past based on their lipids but also the biochemistry we can discover and uncover from how they form these lipids is unique okay great so now i want to go back so this idea i mean i i get very excited whenever somebody says billions of years ago.

7:22And I think you said that. And so, so, so you, so you're, you're a professor of earth science. So that it was, it was very surprising, or somebody could be very surprised to see, you know, she's a professor of earth science, but she's studying bacteria. And now she's using the words billions of years ago. So paint a picture for like, what was happening billions of years ago, I guess the earth is about 4 billion years old, if I'm, if I'm not mistaken. so four billion years ago obviously there was no humans there was not even any dinosaurs probably there was just these single cell organisms and they probably had to have these membranes that you're talking about these these lipids so can we actually learn about the earth billions of years ago by this kind of study and and how does it work like how do you how do you learn stuff yeah so absolutely so unfortunately we can't go all the way back we don't have rocker four billion years back but that is the estimate of when life first emerged and yes the first forms of life were microbial.

8:18So this planet has been in existence for 4 billion years. And you have to imagine that the first 3 billion years of the planet, and life evolved very much soon after the planet formed, those first 3 billion years is all microbial. So we really don't start to see more complex organisms until the later parts. And, you know, humans haven't been around on this planet that long compared to microbes. And so for geochemists that are really interested in thinking about what the earth was way in the past and how it interacted with life, they need to understand microbial life, right? They need to understand how do you connect, you know, modern day microbial life to the past.

8:57That's what geologists do. They're really great at going back to the rock record, which is our really our only historical record of our earth's history, as well as life's history. So if you're interested in microbes, you know, 2 billion years ago, interested in the planet two billion years ago what kind of fossils do you look for now microbes don't are not dinosaurs they don't have bones right so they don't leave right this was the surprising thing is i thought that there would be no way we would see what bacteria were hanging out because they would be too squishy and just degrade that's absolutely true the majority of an organism like a single-celled organism in an environment that's over two billion years would be degraded because you know that process of like you know the sediments turning into rocks is really really rough.

9:42It's hard. It's pretty rough. And so the fact that they can find lipids is one of the most amazing discoveries that was made. And then the challenge is connecting it to what it means, right? So you find this molecule and you're left with this, well, what is this molecule telling me? This chemical fossil. And how do we know that a dinosaur bone that's found in the geological rock record is like a leg bone? It's because studying anatomy of animals today, you understand that. So what we do is we study microbes today and how they make these lipids to help the geochemists understand what the connection is to the past, right?

10:20And so a lot of times they just want to know who makes this. A lot of what we call these molecular fossils can be orphaned. They find the fossil, they find an organism. And so we are able to kind of harness genomic approaches to kind of identify organisms that might have these lipids. And then once we find that, we can do a lot of studies in the lab to understand, you know, is this just a membrane lipid or does it go beyond that? Are there certain conditions in which the organism will make this lipid? For example, when it gets really hot, you know, okay, well then is that saying this environment, this geocabins found the lipid is a hot spring or is it a connection like that to the environment?

10:55So this goes back to what you were saying about they have to adapt, especially the single cell organisms, because they could be in a very hot spring. They could be an acid. And so that's going to manifest as different choices that they make, choice, so to speak, about how to build up their outer membrane. And is it the case that some molecules that you find indicate that this was probably an acid living bacteria and other molecules tell you something else about its lifestyle, so to speak? Yeah, exactly. Some of the lipids that we don't study these lipids, but some of the most interesting ones are the pigments that are found in photosynthetic bacteria.

11:30So it can tell you like, you know, different pigments absorb light at different depths. So it can tell you about kind of how, say, an ancient ocean was stratified and how deep the light would go if you can see these different kinds of lipids at different layers. So it can give you that kind of granular information. And so you might ask, so who cares? Who cares if there were microbes in the past? Why do I want to know? Well, microbes have impacted our planet's chemistry for billions of years. Earth did not look like it did today from a physical standpoint, like it did four billion years ago. It's completely different.

12:03There was no oxygen. As a matter of fact, it was bacteria that invented oxygenic photosynthesis that oxygenated the planet and allowed all of us to evolve, animals to emerge. So this is why we want to understand that kind of connection, that inner play between how life evolved, particularly microbial life, and how the chemistry and the geology of the Earth evolved and how those two things pulled on each other. right because as the earth is changing microbial life changes and as microbial life changes then the earth changes and that's this kind of co-evolution of life and earth that we're really interested in and it is amazing to think that the amount of bacteria on earth was and is big enough so that it could actually change things like what the atmosphere looks like and and and of course i'm sure it was breaking down the rocks in some way okay well i want to so you you mentioned these we've talked about billions of years and we've made a little bit of a nod towards kind of evolutionary changes.

12:58And I know that there's a branch of life that you're especially interested in. And is one of the topics that a lot of your recent papers have focused on. So tell me about how you look at the tree of life on earth. And what is this special branch that kind of is underappreciated? Yeah. So when we think about life, for a long time, life was divided into like roughly two kinds of organisms. We call them prokaryotes and eukaryotes. And the only difference between these organisms was that eukaryotes like you and me have nucleuses in our cells and bacteria prokaryotes do not so within the bacteria though like there are single-celled organisms that we thought were bacteria when we looked at their genes turned out to be a completely different group of organism evolutionarily right so if you look at them in the microscope they look like a bacterium but when you actually like do the what we call molecular phylogenetic analysis to look at their genes and see how they're related evolutionary.

13:50It was this group that's no more closely related to any bacterium than it is to us. Like they're kind of like their own little entity. These are the archaea. These were discovered like in the 1970s. And since we've been studying the archaea, we have found them that they are present all over the planet. And we usually find them by sequence. We actually, they're hard to culture sometimes. And they have interesting molecular biology. And one of the things I'm excited about is their lipid membranes completely different. And so they're very old. They're as old as the bacteria. So you have to imagine like the first cell emerges, the origins of life, and then very quickly split into these two groups, the bacteria and the archaea.

14:28And this is way before the eukaryotes, way before the nucleus is. So this is like about 3.8 million years ago, we're estimating. Wow, 3.8. So Earth is only a couple of hundred million years and already we're seeing signs of life. Yeah, absolutely. Absolutely. And then, so you have these two, and when you look at the membranes, like the chemistry of the archaea, they have a completely different like hydrocarbon chain and the way they fuse their membranes together to make the hydrophobic and the hydrophobic is different. For many years, the majority of archaea that we were able to culture were from very extreme environments.

15:02Like they grow at like 100 degrees Celsius. I don't know what that is Fahrenheit. Boiling, right? Acidic environment. It's very close to boiling, if I'm not mistaken. environments and they've modified the chemistry converted like ester bonds to ethyl bonds which are more resistant and you can't break them so that's part of that signature that you said we would see of strengthening based on the niche that they're living exactly and so as we've come to appreciate the archaea we've noticed these differences and so for me loving lipids that's what i i wanted to study and although we knew how bacteria now our lipids are just like the bacterial ones right and so the big kind of like um oh really so we are closer to bacteria in our lipids than we are to these archaea oh that's in lipids but it's funny because in recent years is our genomic sequencing has gotten better and better and i like our evolutionary analysis of genes across all domains of life so across the bacteria the archaea and everything else that eukaryotes turns out that our ancestor were probably descended from an archaea uh so now you have you know and there's a lot of features of the archaea in terms of like cell division and how they transcribe their dna that is more more reminiscent of what we see from a molecular standpoint in eukaryotes so they're kind of like this so now we're getting serious because these are our not just our relatives but they're our ancestors we think they're our ancestors and so in my in my lipid world there's this thing called the lipid divide because you think bacteria and archaea split, right?

16:37And then from the archaea come us, but our membranes look like the bacteria. And so how did we switch our membranes completely to resemble something else? And then why? Is it because we don't live in a hot spring? I don't know. But how that happened is such a black box. We know it happens because the data right now really does say that we descended from a group of archaea. It really does say that that's what we're coming from. There's still some controversy on that. Some people don't totally buy it. But if that's true, then there's a real difference in terms of our membrane structure, the chemistry.

17:12So it seems to me, it seems to me that we split from the bacteria. And at that time, when we and archaea were basically the same, either the archaea changed from away from bacteria, but we stayed, or we were more like archaea and for some reason we went back to being more like bacteria i'm sure that that's what you're trying to figure out right yeah and and you know how do you figure that out it's kind of it's really hard question to answer i don't a lot of evolutionary questions we're going to be able to yeah but one of the things you need to do is you just need to understand the basics you know of the chemistry right and so in the archaea world there just hasn't been a lot of work done on the basics of what their lipids look now the in particular the the archaea that we are thought to be descendant of those have been really hard to bring into the lab we know they exist from genomic sequencing because sequencing has gotten so robust you can just sequence dirt and so these didn't die out these are still hanging around on probably our descendants died out but but yeah but descendants of these uh something that's close to what might have been the ancestor there and their environment and um about i think in 2020 the first one was isolated in culture um and it took 10 years to culture it and you can't culture it on its own it has to have a partner another bacterium in there um and so there's a lot of like uh nuances about bringing these into the lab because that's what we like to do as microbiologists we want to see it but two more have been cultured this summer i went to a conference where they were actually doing cell biology on them so they looked at them under the microscope and they're they're pretty weird looking they're like around and have these appendages um and so what i want to know and i don't think anyone has done that robustly what do the lipids look like?

18:53Because if this is our closest descendant, do they have a membrane like the other archaea or is it different? Does it look more bacterial? That's what we don't know. And so I think kind of understanding that will help us understand the steps to how things change because you pointed out two different scenarios we could have for how our membranes have changed over time. Now, going back to the molecular fossils, that when you find these lipids, do they retain enough of their kind of original chemistry so that you can recognize unusual molecules or have they broken down so much that it's very iffy what they actually look like it depends on the lipid but the ones that are the most what we call robust biomarkers have retained a lot of their information and the reason the ones from the archaea are really interesting is because they they are made to kind of resist kind of tough environments that they do preserve a little bit better and the changes in them the modifications that they make are preserved as well and so you can see these changes under over time and you can make like kind of connections to the environmental conditions but it does depend on the lipid there are some lipids that don't preserve at all this is the future of everything with russ altman we'll have more with paula wielander next

20:19Welcome back to the Future of Everything. I'm Russ Altman. I'm talking with Paula Wielander from Stanford University. In the first segment, Paula told us about lipids, membranes. She told us about the bacteria and how they have different types of membranes based on their niche that they're living in, and that these can be used for archaeology because the lipids can last for millions of years. It's an amazing story. And in this segment, I asked Paula about sterols, cholesterol, one of our favorite lipids as humans, not really, and what role it has, if any, in bacteria and archaea. I'm also going to ask her about archaea in our gut.

20:55Are they there? And what do they do? Well, I want to start out asking you about sterols, which include cholesterol, because I know they're an important component of human membranes. And I was just wondering, do they play a role in any of this kind of lipid archaeology that you're doing yeah so cholesterol and other sterols and that have that kind of similar structure can actually are some of the most well-preserved lipids they go back about so they do well in the in the rock they do and they do because they're like a bunch of rings they're like four rings and those rings are really um hard to break um and so for many years they were used as biomarkers for um um eukaryotic organisms like algae you know single celled organisms but eukaryotic right and they've been used to trace kind of how our oceans shifted from being predominantly like bacterially dominated um to being shifted to being algal dominated which are our oceans are dominated now and by following the staring marker over time you can make those connections it's also you can use them to kind of trace when sponges which are the first animals that have ever evolved when those kind of potentially evolved because they also make cholesterol like molecules and so that's where i came at it because i was looking at different biomarkers that needed to be studied.

22:08And one of the big questions for me as a microbiologist who loves bacteria and archaea was like, well, do bacteria make cholesterol? Do they make sterile? Right. And the answer was no. It was this is something that's very restricted to eukaryotes. And that's why it makes it a good biomarker, right? Because it's restricted. But I found this paper from like 1971 that said there was a couple of organisms that did not produce cholesterol because cholesterol, you need like 11 biochemical steps to get to that final molecule. But it produce kind of a precursor to cholesterol. So it is a sterile. And so then I thought, well, the geologists have known since the seventies that this makes sterile.

22:41Why do they say it's only eukaryotic? So it turns out that only like five strains of bacteria in the world made sterile. The sterile they made were not cholesterol. They were what we call simple sterile. And so geochemists ruled them out as a source. Right. But I was like, I don't know. I just wanted, and I want to understand why particularly like this subset of bacteria would produce this lipid so you know aside from right because bacteria just don't do things randomly no no they have a reason right and if they evolved it or if they acquired it from somewhere if they you know stole it it had some function it something it was something that was useful for the bacteria in its niche and at the time when i started to go into this is when we started to explode in genomic sequencing right and we knew the genes required to make sterols and so i just looked in genomes i mean at the now we have like 150 ,000 bacterial genomes.

23:32At the time when I did this, it was like a thousand. It was like, oh, that's so many. But yeah, I found other bacteria that had these genes. And so the quest became to be like, do these organisms make sterols? They do. And then I had one student who was very interested in this weird microbes known as mixobacteria that are found mostly in soil. And they kind of, they grow, like they form these like structures. They kind of look kind of weird in the microscope. But I was like, these are really weird. She's like, I think they make really complex sterols and she found cholesterol being produced by one of these oh oh that's a big one that's not just a sterol no it's not just a sterol it's a sterol that's associated with vertebrates right it's our sterol right we make cholesterol and so we make this joke about do these bacteria get heart disease right right exactly do we need to give them statins yeah so sterols and i think you know cholesterol does have a bad rap like it causes but it's an essential molecule for us, for any organism that makes it.

24:26They utilize it for complex multicellular organisms. It's important in development. If we don't move our cholesterol around in our cells, if we don't move it out of like our organelles into like the membrane, that trafficking can cause diseases. There are diseases associated beyond like high cholesterol heart disease that can occur if you're not utilizing cholesterol as it should be used, right if it's misused so my question was then like okay so what about what is the role of it in bacteria is it just to rigidify the membrane which is the main function you see with cholesterol so when even even in even in humans it's making our membranes a little bit less bending yeah it's one of our responses so if we have a stress response if our membranes get a little too hot or something they will put the cholesterol in there to help rigidify it right um and it helps to reduce permeability.

25:18So it's just a way to modify the membrane to produce this lipid that they're already using for other states. But the main function we always think is kind of rigidifying the membrane, but we know from lots of studies that there's other functions. So my question was, in bacteria, are there other functions? And so we started at a very basic level, like in that organisms that make cholesterol, my student realized that it doesn't have the full cholesterol pathway to every protein that's required that you see in humans, right? And she found that like in the middle, there's like these unique bacterial proteins that are doing some interesting biochemistry.

25:49So not only the bacteria acquire cholesterol, but then they evolve their own proteins to be able to make the molecule. So you have the same molecule made by different pathways. And you know, that's, you know, that's really interesting why they do that. And back to your point, they do it for a reason, right? Why are they going to evolve these proteins to do that? And so that's where we've gotten with this organism. Where my future work is going now is I'm really interested in understanding beyond just like how they make it is why they make it, right? And studying what other pathways it interacts with.

26:24I, you know, my suspicion is they could be helping in signaling and helping the cell develop in some way because these cells are a little more complex than most bacteria. Yeah, I'm struck by this because you're studying this bacteria, but you're going to learn about things that cholesterol does that we may not even know. And it may actually reflect back on human biology in unexpected ways. There's no promise that that will happen. But by doing a deep dive into what's going on in the bacteria, you may say, oh, my goodness, this could explain such and such in human systems. Well, in the last few minutes, I wanted to get to the one other issue, which is your gut.

26:59Are we having archaea in our gut? We all know that there's a ton of bacteria living in our intestine. It's good. It's good. This is not bad bacteria. They help us live. They they're like commensal organisms that do something to help us. what about archaea when you look in the gut do you see them you do see archaea um and you see a very limited number archaea this is actually a new area of research in archaeobiology kind of thinking about um how we interact with you how are you with humans so archaea do not cause any disease so this is probably another reason they haven't been studied as much but we do have surprise surprise methanogens in our gut and methanogens are archaea and methanogens are known for making methane gas methane gas and we all are familiar with that phenomenon yeah so I think the number is about 10 % of the population have some kind of methanogen in their gut.

27:46And they're trying, people that study this, they study archaea in the gut, are trying to make some connections with health factors. You know, if we look in a population that has a high level of these methanogens, are there certain factors that they are more prone to or less prone to? Are they healthier? Are they less healthier? So that's the area where it's going to right now. that's really interesting because of course we also hear about methane in the context of uh its effect on on global warming through the huge amounts of like cattle farming and other things like that and i'm presuming that the cattle methanogens are also archaea so this could have a huge uh implication for our understanding of like these big cycles of gas absolutely and engineering ways you know through like therapeutics for guts for the guts of the cows to be able to lower the amount of methane that they are producing by affecting their archaeal microbiome is actually a big area of research so so you said that the archaea don't cause disease as far as we know but that raised the one issue question kind of a random question is do bacteria that we take kill archaea?

28:53Do we take kill archaea? No, I don't think so. So like if I prescribe an antibiotic, I'm a doctor. If I prescribe an antibiotic, do we know if that antibiotic will kill archaea? Because since they're a little bit removed from bacteria, they may evade. I just don't know if this is even known. They don't. So one of the big things that antibiotics target are the cell wall of bacteria and the cell wall of archaea are different. So those antibiotics. And this is what makes them hard to study because a lot of the molecular work we do requires our bacteria to be sensitive to antibiotics so we can manipulate them in the lab.

29:26In archaea, we don't have antibiotics because they're not bacterial. And a lot of the mechanisms that they do for protein modifications and translation are different. And so those types of antibiotics don't target them. So we're very lucky archaea haven't figured out how to infect us because we have no way of actually being able kill them like we have an abode. Exactly. That's the downside is if they do become troublesome, we're going to be in big trouble. Okay. Well, that was a great, thank you so much for that introduction to these amazing, the amazing lipid molecules, the membranes, and then this really, one of our ancestors, the archaea.

30:02I want to move on now before we finish up to our final segment called the future in a minute. Just to review, I'm going to ask you a few rapid fire questions, and then you'll give me some rapid fire answers and we'll see how it goes. Does that sound okay? Okay. What is one thing that gives you the most hope about the future? That would have to be my kids and the students that I teach. So my kids are in college. They're the same age as the students that I teach. And I am just, they are wonderful. They're full of joy. They can hustle. They love life. But at the same time, they're very laid back.