Buzz Baum (3:41)

Yes. So archaea are a kind of cell and of course every living thing on Earth is actually made of cells. So everything's cellular. But the things that we're used to, which are made of cells, are big things like plants and animals, and archaea are small cells and the cell is the organism and the organism is the cell. So the single celled organisms, and they are wonderful in a way because there are things that they share, as you sort of pointed out with us, and there are also things in which they share with bacteria. And there are other ways. They're completely otherworldly. And so it's as if one had sort of come across an organism from another planet here on Earth in many aspects of their biology.

Misha Glennie (4:24)

So until that point they weren't recognized. People thought that they were bacteria. Is that right?

Buzz Baum (4:29)

Yeah. So down a microscope, especially a light microscope, where the resolution is not very good, archaea can seem to look very similar to the other very small organisms that we know about, which are bacteria. And so everybody had conflated the two and treated them the same. And then Carl Woese, one of the things he enabled us to do is to look at them through a different lens, through the lens of molecular biology. And suddenly by teaching us that there are these separate organisms, we could then look to see which of these things we thought were bacteria were archaea. And suddenly the sort of scales fell away and, and looking at life after Woese, it looks different. And there are archaea everywhere, which are extraordinary.

Misha Glennie (5:09)

We'll come to Woese's research a little bit later. But before we do, some of these archaea are called extremophiles. So what sort of extreme environments do they live in?

Buzz Baum (5:21)

I mean, of course we call them extremophiles and they think we're extremophiles because each organism is accustomed to living someplace where it's happy. But it is amazing that archaea really can live. You know, what lives in the Dead Sea? Archaea in abundance in salt crystals. What lives at the bottom of wells, Oil wells at the bottom of the sea, in volcanic springs? The cells we have in the lab are from Yellowstone National park. They grow at 75 degrees centigrade. We have other ones from the bottom of deep sea vents that grow at 90 degrees on hydrogen gas.

Misha Glennie (5:55)

And.

Buzz Baum (5:56)

And they're the ones that Krista Schlepper and myself work on, which grow without oxygen and live quietly. So they live in these extraordinary different environments. But, of course, they've been on planet Earth for a long, long time. And so they've also evolved to live in all kinds of niches and probably all niches. As the Earth changed, they've been changing with the Earth, and they really live everywhere.

Misha Glennie (6:18)

Okay, in order to understand the difference between us bacteria and archaea, there are some basic terms we're going to have to. So, Torsten, Alice, can you explain to us what prokaryotes and eukaryotes are? Can you define those for us?

Thorsten Allers (6:36)

Yes, with pleasure. Let's start with eukaryotes. That's us. So we humans, we're all eukaryotes. And eukaryotes comprise animals, plants, fungi, and some larger microscopic organisms like amoebae. And all of our cells are, on average, large, about a tenth of a millimeter across. And they have all of these complicated internal structures, which include the nucleus, that's where our DNA resides, and then mitochondria, which we use to generate energy, using oxygen to power our metabolism. And if you're a plant, you have chloroplasts. And the chloroplasts use the energy of the sun to make sugars and energy for the plant to grow on, but generate oxygen as a byproduct. Prokaryotes, on the other hand, they comprise archaea and bacteria. They have no complicated internal structures. And much as it's unsatisfactory to do so, they are defined in negative terms. It's what they lack that defines them. But you have to remember that the terms eukaryote and prokaryote were never meant to have any evolutionary significance. They were meant to describe just the morphology of the cell. They were an organizational concept. And that's because appearances, even at a cellular level, can be deceptive. So, for example, hippos, rhinos, and elephants, they all look similar. They're big grey animals, and they grow in Africa, but they all Descended separately from small furry ancestors.

Misha Glennie (8:12)

Different furry ancestors.

Thorsten Allers (8:13)

Different furry ancestors. Absolutely.

Misha Glennie (8:16)

Okay, so in the context of prokaryotes and eukaryotes, the complex cells, how did we understand that life had evolved before Woese made his discovery?

Thorsten Allers (8:30)

So Buzz has already mentioned the limitations of a light microscope and even going back to a Dutch draper named Anthony van Leeuwenhoek. He was the first person to invent the microscope because he was looking for threads and the quality of the cloth had been sold, and he scraped some gunk off his teeth and observed bacteria for the first time. And then we get the kind of light microscopes you'll be familiar with from school, but they're really not much good at doing anything other than seeing this cell is small and this one big, and this might have a nucleus in it. When we then get onto the electron microscope now, we can tell apart some of these internal structures. And one of the first things we notice is these mitochondria and chloroplasts actually look a lot like bacteria. And that then leads. And maybe we'll come back to this later about the theory that Lynn Margulis put forward about how the first eukaryotic cells evolved by engulfing bacteria and domesticating them. But coming back to that ancestor that engulfed those bacteria, even if it was still around, even the electron microscope would have a problem tearing it apart from other prokaryotes, because at a microscopic level, all prokaryotes look like elephants, hippos, and rhinos.

Misha Glennie (9:42)

I see. So up until Rose's discovery, we just couldn't tell the difference between bacteria and. And archaea.

Thorsten Allers (9:52)

Under the microscope, they look identical.

Misha Glennie (9:54)

So, Christa Schlaper. Oh, you're looking a little skeptical there about that last statement. Maybe you can explain. So what was it that Carl Woese did to change all that, to change our fundamental understanding?

Christa Schlepper (10:09)

So this is an interesting story. Kyle Woese was really a pioneer. It was in the 1970s, and he was a professor in West Urbana in Illinois, and he was a specialist for the ribosome. And the ribosome is a big machinery that every living cell has, and it is there for making the proteins in our cells. And Carl Vos decided that the genetic material of ribosomes could be used to find a natural history of the life forms, like what they are really related to, as Thorsten pointed out, the elephants and the other animals. And he decided that the genetic material of ribosomes would be perf because it's so conserved in all organisms, so that he could trace back evolutionary roots really, really far back. And he wanted to make a natural system of evolutionary relationships, stepping away from the morphological, you know, the shapes and all that that was used to classify organisms. And he did this very early, long before DNA sequencing actually came into place in the late 1970s.

Misha Glennie (11:17)

Yes. So how did he do it if we didn't have DNA sequencing?

Christa Schlepper (11:20)

It was hard work. He had to grow the organisms with radioactive material, and then he had to isolate the ribosomes and to find out about the rna. And then he chopped the RNA with different enzymes, and then he got black spots on an X ray film. And only from comparing these black spot patterns that he got, he could tell that he has found a third form of life, a fundamental third form of life, because there were certain odd bacteria, considered bacteria before coming from odd places that showed a completely different pattern, as very different to eukaryotes, but as different also to bacteria. So it was clear it was a third life form.

Misha Glennie (12:01)

For listeners who as troubled as me by this subject, we'll explain about the difference between DNA and RNA a little later. But I want to carry on with what the implications of Woese's discovery was. So what does this imply for the origin of eukaryotes? Complex cells like the ones in our bodies?

Christa Schlepper (12:25)

So, Calvus, he commented on this early on, actually, that having three fundamental lineages of life forms, this will help us to understand at the end the evolution of eukaryotes. And so it cannot have been so easy. Maybe that was also his idea. And so he relatively early on talked about the early split of bacteria and archaea in the evolution of life, so about 4 billion years ago, and that there were separate evolutionary lineages. But for him, it seemed more like a soup of events where you would have a lot of exchange of genetic material, and eventually he would think that there's a lineage a little bit more related to archaea, which would have been the ancestor of an organism that later engulfed, what Thorsten already mentioned, engulfed bacteria. Bacteria to form mitochondria and then later plastids.

Misha Glennie (13:21)

So, Buzz, following on from that, how do you picture this happening? I'm talking now about how archaea and bacteria started, how can I put it? Hanging out with each other.

Buzz Baum (13:34)

I mean, this is one of the big mysteries in the history of life on Earth. In a way, it's one of the big problems in all of biology up there with the seed of consciousness and the origins of life, because it was a step change. So as we heard, for 2 billion years on Earth, there were simple cells, bacteria and archaea, living Together, often in communities, but nothing more, nothing bigger than something that you could see with a magnifying glass, something small like that. And then suddenly, we think it was suddenly, as oxygen rose in the atmosphere, these new creatures arose. And now we see them everywhere in a walk, in the woods, trees, mushrooms, birds. So all this stuff, as you count, and as Torsten explained, the cells are profoundly different. So how do you do the jump? And so this has always been an area where, because there's nothing in between, there's simple, and then suddenly you have this jump to complex. How do you bridge the gap? And so there are lots of models out there and people look at the thing through different lenses. But my journey into it was my cousin, David Baum. He answered a question when he was a student in university where he disagreed with the textbook model, and he came up with this idea that maybe archaea grew into eukaryotes from the inside out. So the idea is you have two partners, two cells living together in this sort of complicated. So one bacteria, one bacteria, one archaea.

Misha Glennie (14:53)

Right?

Buzz Baum (14:54)

And then, because archaea don't have a cell wall, they actually can have a flexible shape. So his idea was, which we then grew together, was that the protrusions can come out and enable two cells living together in a particular ecological niche to share resources and become more and more intimate with each other. And through growing intimacy, they kind of merged together over time to give rise to this common thing, which is the eucalyptic cell. But it would have been a long journey in the imagining, and there are lots of unknowns. And so Dave and I put forward this idea in 2014, but it was really just fantasy speculation, and lots of other people had other models. But in a way, our timing was good.

Misha Glennie (15:36)

Well, were you proved right or don't we yet know?

Buzz Baum (15:40)

Well, the truth is, a model is only a model. We'll never. We don't know, and we're not sure whether we ever really will know, because These events happened 2 billion years ago. But since that model, a group led by Thais Etimer, Anya Spang, which Crystal was involved in, really discovered this new creature that really looks like a stepping stone between simple archaea.

Misha Glennie (16:00)

We're going to come to that new creature a little later on. But before we do, the thesis that you and your cousin put forward was posited against the idea that archaea had eaten bacteria. Is that correct?

Buzz Baum (16:14)

So I think the simple idea that one is that it's like a predation, where a big cell ate a small cell and then couldn't digest it. That sort of abrupt and it's sort of it's dominance. So I think this idea is more like biofilms, which are everywhere on Earth, where microbes live together, fighting and sharing. And these environments are everywhere and they're everywhere now on Earth. And so it sort of frames it in that more ecological context where organisms start to share, become more intimate, and then do this amazing transition where suddenly two become one more complex, higher level individual, which is an amazing thing which happened only once on life on Earth, but it changed everything.

Misha Glennie (16:57)

Wow. And in order to forward that, I think you quote the theories of Prince Peter Klepotkin, who I know from reading about anarchism and its relationship to the state, but he had a whole different area of interest as well. What was Kropotkin saying about how life evolved?

Buzz Baum (17:19)

So there's always been these two threads in biology. There's the kind of selfish survivor of the fittest idea which sort of came from Darwin. And there's always been this other idea which Prince Kopotkin came up with, which is about the idea that when he went to Siberia, he realized organisms can only live together in some environments. So it's not just survival of the fittest. Organisms have to live together. And in fact, Lynn Margulis, who's the one who Torsten mentioned, who showed the bacteria live inside of complex cells, she, you know, grew up in the 60s where again, there was an idea that we sort of lived together in communes that she looked at the cell and saw a commune where people were to love in together. And, and, and the, and yet there's the selfish gene idea, which is sort of in opposition. So in a way, this transition of eukaryotic genesis challenges it because we have two selfish cells fighting it out in a biofilm, coming together to give rise to a higher level consortium, which is this usually harmonious, not always collaborative venture, which is the complex cell which our body is made of and plants and all other moles.

Misha Glennie (18:21)

Okay, Torsten, back to DNA transcription and translation and the role of RNA. Why are DNA's functions and RNA relevant to our story here?

Thorsten Allers (18:35)

Perhaps the best way of illustrating this is imagine you're working in a robotic car factory. The blueprints are stored on a computer. That's the DNA. They are then copied into a set of instructions at a cellular level. That's done by an enzyme called RNA polymerase. RNA polymerase makes an RNA copy of the DNA and that then becomes the set of instructions which in our robotic car factory tells the robots what to do at A cellular level. It tells the ribosomes which proteins to make. Now, imagine that you're not actually looking at a robotic car factory. The factory's making other robots, and those robots go on to make other factories. And that's what the cell does. It wants to make more of itself. So going right back to the beginning, there's our DNA, the blueprint. It has to be copied every time we make a new factory. And that's done by another class of enzyme called DNA polymerase. It makes DNA copies of DNA. Now, when we look in the archaea, as opposed to bacteria, the enzymes that carry out these processes, so that's the DNA polymerase that copies DNA, RNA polymerase that makes an RNA copy, and the ribosome that then turns that RNA into protein. They are uncannily similar to the enzymes we find in us in eukaryotes, and they are very different to the ones we find in bacteria.

Misha Glennie (19:57)

So this is the key thing about archaea, is that they actually in some respects, look like our cells. Is that right?

Thorsten Allers (20:05)

Yes, they do.

Misha Glennie (20:07)

Buzz, you wanted to come in there?

Buzz Baum (20:09)

Yeah, yeah. And so just following up on what Thorsen said, I mean, one of the wonderful things, in a way, the genius of woese was he saw that because this machine, this ribosome which contains rna, is so well conserved across his life, it's the perfect system to test where do organisms come in the tree of life. And as you know, sort of mentioned, he saw that this machine, this really ancient machine, the one that we have, is more related to the one in archaea. So this is really the evidence that all the information processing that happens in our cells has its origins in archaea. And that was really the clue that when you have a eukaryotic cell where the bacteria becomes a mitochondria, this energy production center, the rest of the cell, the information processing, really smells like it's archaeal

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Misha Glennie (23:27)

So, Krista, you made a really important discovery when you were working on Arcare called Asgard Archaea. This was around 2015, I understand. How did the Asgard archaea. Well, first of all, what are they? Where do they come from? And how did they change our understanding of the relationship between archaea and eukaryotic structures?

Christa Schlepper (23:51)

Yeah, everything changed, it feels like in 2015. But before I come to the Asgard archaea, I would like to point out what we already have known about archaea before 2015, and that was that several people actually in Europe mostly, who worked on the information processing system that Torsten elaborated so well on how it works in a cell, that the information processing in archaea has a lot of similarities to that in all eukaryotes and all complex living beings. So this had been in place and then in 2015, there was made like almost another step because we found organisms that have even more than those similarities. So a PhD student in my lab, I was professor in Norway back then, took samples from sediments near Loki's Castle, which is the northernmost hot vent that has been discovered, and was named after

Misha Glennie (24:44)

a Norwegian God, Loki, the God of mischief, I believe.

Christa Schlepper (24:49)

Yes, yes. And these sediments were very interesting because they had very specific layers. They were very stratified, we say. And in certain distinct layers, we found a large amount of DNA of genetic material of archaea that we had never seen before in this amount and in this abundance. And so that was enough material to do genetic analysis. And this was actually done by Thais Etema, Leonel Guy and other colleagues who looked into this genetic material from our student and found that the genomes can be assembled quite far and that these archaea have even more features that they share with the complex organisms than any other archaeon ever had before. In fact, hundreds of genes were found that we had not seen in any prokaryote before. That was a big prediction. On top of that, the phylogenetic analysis. So the phylogenetic trees they built to find out the relationships showed that these, what are now called Asgard archaea actually are the closest lineage to eukaryotic organisms. So actually that as if complex life came like from this archaeal branch directly from there.

Misha Glennie (26:06)

So let me get this straight. This is as good close as we've got to finding out the origin of complex eukaryotic cells?

Christa Schlepper (26:16)

Yes, that's what we think now. And they actually look a little bit different in the microscope. That was the next step we have to come to that. That's why I had this little comment before, because they look slightly different already. So there is a lot of transition going on in that lineage. Indeed. But first I would like to tell that they are also very diverse. From 2015 on, there were a lot of more lineages found that are all related to these. Loki, Achaea and that are now called Ingun and Heimdall and Thor, all these Norwegian gods. Also one Chinese God, Vukong, but mostly Nordic gods. And that's why they are collectively called the Asgards, because in the mythology that is the home of the Nordic gods.

Buzz Baum (26:57)

Right.

Misha Glennie (26:58)

Well, that's the sort of Divine relationship. But there's also a tendency to anthropomorphize archaea. What do they look like? How do they move? What do they do?

Buzz Baum (27:09)

Well, maybe just building on what Krista said, I mean, one of the. So there really was a revolution in 2015 when these genomes were put together. You know, it was a revolution that had all these things that make them look like, have genes that sort of resemble things that we have. The question is, what do they look like, the cells like, and how do they behave? And we had to wait and wait and wait. And I wanted to know, to test our model, but lots of people wanted to know. And in 2020, we got our first glimpse from a study by Imachi inobu, who'd spent 12 years cultivating creatures from the bottom of the sea off the coast of Japan in anaerobic conditions without oxygen. It was incredibly hard work. And in their images they saw these extraordinary cells with long protrusions which only live with other organisms in partnership. In a way, this really did look like something that completely new way of seeing our care. They look completely different to any our care. And they lived in communities. And then there was this amazing thing that Christa's team then followed up with beautiful studies using electron microscopy, where they cultivated their own one from Slovenia, the bottom of a lake. I mean, Krista should speak about this more than me, but the images were gorgeous. With electron microscopy, we could see that not only did these cells have like information processing machinery like us, but they have the kind of underlying cellular structure that resembles, for example, a migrating dendritic cell in your body that's hunting down bacteria like one of our cells. And recently Christa's team has really shown that they do stuff in culture which looks a bit like one of our cells. So suddenly this huge gulf between complex and simple life has been bridged by these mischievous low key Ascot Archaea.

Christa Schlepper (28:55)

One could call them the Archaeopteryx lineage, because it is like a transition, right? Like the flying dinosaurs, you know, that have died out, but that are the transition from dinosaurs to birds. This is here you could do that like a missing link, one could call it, between the prokaryotes and the eukaryotes, kind of.

Misha Glennie (29:13)

This is extraordinary. Torsten, tell me about how archaea managed to survive in these extreme conditions where we can't. Ludicrous temperatures like 90 degrees centigrade, as buzz mentioned, and very salty environments. How do they do that?

Thorsten Allers (29:32)

Well, actually in excess of 95 degrees at the bottom of the ocean at some of these hydrothermal vents, because you have so much pressure of all that water above you, you can get organisms growing at 110 degrees because the water won't boil down there. How do they manage it? It's surprising when you look at the proteins in these archaea that grow in these conditions. They're called thermophiles because they love heat. They look remarkably like us. And this is surprising because if you take an egg and put it in 105 degrees centigrade water, all the proteins in the egg white, they unravel and coagulate, and it makes a really nice breakfast for us, but it's not much good at making a new chicken. So you would think that that would be a problem for archaea, but they solve this by having the same structure of our proteins, but they have lots of internal bridges and buttressing that makes them much stronger on the inside and much less likely to unravel at high temperatures. But there is a downside to this. If you now take one of these archaeal proteins and you bring it down to our temperature, they become too rigid, they can't do stuff anymore. Now, you would have exactly that same problem. If, let's say, you're still driving an internal combustion engine car and you now want to take it to the Sahara, your mechanic is going to tell you you need a thicker grade of oil because your oil is going to be too runny in the Sahara and your engine's going to wear out. If you take that same car now to the Antarctic, it will seize up because the oil is too viscous. And it's the same thing at a microscopic level with the proteins in the thermophiles.

Misha Glennie (31:12)

This may sound like a tangential question, but why are flamingos pink?

Thorsten Allers (31:18)

So this goes to a subject very dear to my heart, which are halophiles. These are organisms, archaea, that thrive in very high salt conditions. So high salt is. Imagine you've put too much soy sauce on your Chinese meal. That's how salty and worse. So the Dead Sea, as Buzz already mentioned, this is where we find them, Salt works. And if you've ever been to a salt works, or to any of these seas in Australia, they have some great examples of salt lakes there that are bright pink, the bright pink coloration that's in the membranes of these halophilic archaea. And they form food for some microscopic eukaryotic organisms, brine shrimp, which feed on them. And in turn, the brine shrimp are food for flamingos, where we find them. So if we didn't have the red coloration in the halophilic archaea, we wouldn't have pink flamingos.

Buzz Baum (32:14)

And it's also why, if you buy Himalayan salt, it's pink, because. Partly because of the archaea.

Misha Glennie (32:21)

So we're eating archaea when we eat Himalayan salt. Krista, where do we see the impact of archaea in the ecology, in the environment, in the ground, in the atmosphere, in water?

Christa Schlepper (32:33)

Yeah, so this is also important to mention because archaea are very interesting for their adaptations and evolutionary aspect, but there's also a big aspect of ecological effects on Earth. And the one group is the methanogenic archaea. These were the ones that Carlos first investigated, by the way, when he found out about the relationships. And methanogenic archaea are almost everywhere, but they don't like oxygen. So they are in all anoxic environments, in the marine sediments, in a lake, down in a lake bottom. They also in our gut system. Right. Where there's no oxygen in some places. And these methanogens are important for ecosystems because they are at the end of the food chain. They use the very last products from bacteria, bacterial and fungal degradation, and convert it into methane, which is again, a food for other bacteria. When it bubbles up, it's a gas, and then it comes up and it's the food again for bacteria to degrade it further on. So it is an important part in the, we say, global biogeochemical carbon cycle, but it is also problematic because with global warming, methanogens in the Arctic soils where the permafrost is thawing, or methanogens in wetlands around the equatorial area, they are producing more methane now they become more active. And methane is a very strong greenhouse gas. And it is responsible for. There are debates, but 25 to 30% of global warming effects because it's a very strong greenhouse gas, 30 times stronger than CO2. So that is one group that is important to look at. They also have a lot of good sides. You can also make biogas from them, which is also the same methane. But yeah, one has to keep an eye on them, one could say. And the other group is ammonia oxidizing archaea that occur or that are found in many soils and in the ocean and virtually everywhere where you also have oxygen. So they also occur. They also live on our skin. Actually, we have just isolated an organism from our skin. But they are good. They are good for our skin, we think. We have not proven that, but these organisms are involved in the global nitrogen cycle, which has to do with fertilization, how we produce food you know, and fertilizer is escaping into the surface waters. And part of this problem can be traced back to archaea that feed on these nitrogen compounds or to also certain bacterial groups.

Misha Glennie (35:00)

And can any of you chip in on cattle methane and archaea?

Thorsten Allers (35:05)

I can. This is so Krista already mentioned, where methanogens. These are archaea that produce methane. They live in our gut. They don't just live in our gut, though. They also live in the guts of cattle. And we have a much bigger consequence when we look at cattle metabolism. So what are they doing in there in the first place? So Chris already mentioned that they feed off the end products of bacterial fermentation, of products that we cannot digest. So it's principally dietary fiber that we cannot digest directly that bacteria then ferment. The end products of their fermentation, hydrogen and carbon dioxide, are turned by these methanogenic archaea into methane. And we emit about 350 millilitres of methane every day. But that pales into insignificance compared to cows, which put out about 200 liters of methane a day. And given that methane is 20 times more potent than carbon dioxide, we now have a big problem on our hands.

Misha Glennie (36:02)

Talking about the food cycles. What's the favorite food of some of the archaea you study?

Thorsten Allers (36:09)

I think we all have to chip in here. Let me start then with halophiles that we grow in my laboratory. These have a very simple diet in microbiological terms, because if you're a microbiologist and you don't know what to feed something, you feed it powdered marmite, yeast extract. Nearly everything grows on this, nearly everything. They then have some additional requirements on top of that.

Buzz Baum (36:36)

Well, the thing. But the thing in a way, though, is that because these microbes live in communities, and as we heard from ascods, they'll live with, they have to live with other cells to actually survive. You know, you could have two cells living together where one likes the Marmite, the other doesn't, but that one can use the Marmite and release its waste products with the other one can then use in turn. So this is the sort of principle of symbiosis which archaea and all microbes in fact, engage in all the time. So our idea about individual organisms living by themselves fighting each other is wrong in that sense that food can be shared by different organisms.

Misha Glennie (37:09)

I've got to say, I can't help notice the tremendous enthusiasm that researchers working with archaea, the enthusiasm they express. But these things are very hard to study. I mean, if you've got something living at 95 degrees or more. How do you get them back into the lab and look at them?

Buzz Baum (37:29)

It's incredibly hard. And in order to work on them properly, my lab had to ditch everything else. We're working on flies and human cells and to work on our care, because each one requires devotion. You have to really love them to get them to grow, to grow some more than others. But the thing is, it's so rewarding because they haven't been studied, we don't know how to grow. It means that when you discover things with them, they're completely new. But my lab, for example, in the last few years, spent five years trying to build a microscope that will work at 75 degrees centigrade, which if you touch it, you burn your hand, which is ambient for these organisms from Yellowstone national park that grow in these sort of sulfurous volcanic springs. And then we had to evolve proteins we can put inside that emit light so we can see how proteins move in these things. So these things for a bacterial cell, a human cell, were done decades ago. But for archaea, if you want to do anything at all, you have to invest huge amounts of time learning to nurture them, love them, and then find ways to engineer solutions so you can actually study them.

Misha Glennie (38:33)

Did you succeed Inventing the 75 degrees?

Buzz Baum (38:36)

Yes. And the trick is to heat the lid.

Misha Glennie (38:41)

Congratulations, Krista. Buzz has told us about how you look at them in the. How do you go and get them in the first place? If they're in Lockie's castle down at the bottom of the sea, how on earth do you find them?

Christa Schlepper (38:54)

Good point, good point. So to get them from Loki's castle is of course with a submarine, you know, with an rov, they have been taken. But those are also difficult to work with. And we have not succeeded yet to culture them from Loki's castle. But we are using marine, shallow marine sediments. And there also we take care that we keep them without oxygen. So we bring them in a little tube, we bring them home to the lab right there at the site where we take them and then we inoculate, we put them into new flasks and try to grow them right away and try to avoid oxygen right away, that's one thing. But then there's also other archaea. For example, I have also, many years ago, isolated one of the most acidophiles, which means an acid lover. So if you isolate an acid loving archaeon, you need to be very careful how to bring it home, because it will be killed. Because it needs its own activity and metabolism to be able to cope with the acid. And so you have to shift a little bit away. You have to dilute out the acid a little bit, but not kill it, because it needs acid also. So you need to find compromises. And there's an interesting story from the 1980s, when the first archaea were discovered as such from Calvos. Then people went out like. People like Wolfram Zillig, who were strong proponents of Kaivos's idea because of their findings, and they went out to get novel organisms from hot springs and they brought a thermo bottle, you know, at the beginning, because they thought, you have to keep them warm, you have to keep them like they are in the warm water. But that was not true. They actually happy to get cooled down because then they become more inactive. Then they are like we would be frozen kind of. So it depends.

Thorsten Allers (40:36)

So I have to say, though, not all archaea are that difficult to work on. So traditionally, if you have wanted to work with the organism in the laboratory and do some more complicated genetic experiments and not spend all of your time and energy like Kristen Schlepper and Buzz here, trying to keep them alive, you work with halophiles. What do you need besides marmite? You just need a lot of salt. Pour in salt until it becomes almost saturated. And actually, conversely, if you want to decontaminate something, if you accidentally spill some of these halophilic archaea on the bench, wipe it down with water, it kills them.

Christa Schlepper (41:13)

Yeah. But you have other problems with your halophiles because it's very hard to do biochemistry, for example.

Thorsten Allers (41:19)

Well, it.

Buzz Baum (41:20)

And electron microscopy is very hard.

Thorsten Allers (41:22)

Okay, so there's no perfect species.

Buzz Baum (41:25)

Yeah.

Thorsten Allers (41:26)

So it turns out that what Krista is referring to is that the way that halophiles cope with high salt is they have salt inside the cells as well as outside. And it means that all of their enzymes have to be able to function in very high salt concentrations, which brings with it its own challenges, including for us, if we want to study those proteins in the laboratory using biochemistry. So I. I avoid doing biochemistry.

Misha Glennie (41:51)

You mentioned a little earlier on about the fact that they live in our gut in an anaerobic environment. Now, this is. I'm going to confess my huge ignorance here. I didn't realize things could live without oxygen. But most of these archaea apparently seem to thrive outside of an oxygenated environment. Why is that?

Thorsten Allers (42:12)

The answer to that is partly because the enzymes they use to make methane are poisoned by oxygen. So they have to grow without oxygen. You only Find them in environments like our gut, like landfill sites, like swamps, where, in fact, the first person to ever discover methanogens was Alessandro Volta back in the 18th century, from whom we also have the term Volt. And he was poking around some. Some swamps in northern Italy and noticed some bubbles of methane coming up. And arguably, he's the first person to have discovered methanogens.

Buzz Baum (42:47)

Because they caught fire, right?

Thorsten Allers (42:48)

They caught fire, yes. Yeah. You can light fire to methane.

Misha Glennie (42:52)

Buzz, you were going to come in there.

Buzz Baum (42:54)

Yeah. I mean, also, we have to remember that, you know, we call archaea extremophiles, but of course they think we're extremophiles. And one reason, for example, to make that distinction is for most of Earth's history, there was no oxygen in the atmosphere. And so for 2 billion years, archaea and bacteria were living on a planet with no oxygen. And in fact, the increase in oxygen about 2.5 billion years ago, made by cyanobacteria doing photosynthesis, changed everything, led to a catastrophe in a way that lots of things that couldn't live with oxygen suddenly died. And archaea had to hide away in these places, which are still anoxic, like in our guts and in sediment. But this also meant that at the margins, you could have new evolution of new things, like complex cells, which was beautiful.

Misha Glennie (43:38)

So, Krista, did complex cells come because oxygen suddenly appeared?

Christa Schlepper (43:44)

Yes, this is probably the case. Yeah, this is probably the case. So the idea at the moment, there's a little bit of a debate what the Asgard archaea, the exact Asgard archaea that maybe we are looking for, that were existent 2 billion years ago, we cannot find them nowadays, of course, but something similar, if they were, how much they were already adapted to the first oxygen, and how much they actually then profited from engulfing a bacterium that was already coping with oxygen. And because why did life expand so much with oxygen? Also, the new forms of life that could cope with this is because you can gain a lot of energy when you have oxygen involved. Right. When you can breathe oxygen and not other chemicals.

Buzz Baum (44:29)

Which is why we burn hydrocarbons in oxygen to drive planes and cars, for that reason, generates a lot of energy.

Misha Glennie (44:37)

Let's have a final question. Bacteria. We have good bacteria and we have some very bad bacteria. Do we have good archaea and bad in terms of their relationship with us, pathogens that cause disease?

Thorsten Allers (44:51)

So we have archaea that grow inside us in our gut, as we've already mentioned, and it's a big mystery in the field why none of these become pathogenic, cause us any disease, because we have bacteria that grow in our gut which, if they can then overtake the good bacteria, cause us all kinds of gut problems. This doesn't seem to be the case with archaea. Now, why might that be? One thing that we've not touched on so far is that archaea have on the outside of the cell a fundamentally different membrane structure to the one that we have, and that bacteria do. And that different membrane structure both gives them extra thermostability, allows them to colonize high temperature environments, but it might also make them a really good target for our immune system.

Misha Glennie (45:39)

Buzz?

Buzz Baum (45:40)

Yeah, I mean, I think, as Torsten said, also, I'm not sure we know the consequences of our care for our health. We know we've been living them for a long time because when they looked at the DNA on the teeth of Neanderthal skeletons, they found the same our care that we have on our teeth. So our ancestors are not just making babies together, also kissing and sharing food maybe, but it means they've been living with us a long time. They're in our gut. When we take antibiotics, it kills the bacteria, not the archaea. But when you take statins, actually it kills the archaea and there are no studies, like we don't know yet. I think the consequences. So it's true that archaea, there are no diseases we know about and they do grow slowly as well, and they might be seen by the immune system. But I think, watch this space. Who knows how important they might be for our health. And.

Thorsten Allers (46:23)

But actually on that point, just very briefly, Buzz, you can take statins to cure constipation due to excess mythanogenic archaea.

Misha Glennie (46:31)

Well, well, well. My huge thanks to Christa Schlepper, Buzz Baum and Thorsten Allers. Next week, it's Dadaism, the nonsensical chaos that emerged in the Zurich art world during the first World War. Thanks for listening.

Christa Schlepper (46:45)

And the In Our Time podcast gets some extra time now with a few minutes of bonus material from Misha and his guests.

Misha Glennie (46:54)

Well, and now we can go over to the podcast thing. And I have to tell you, I. I'm going to be honest here. I had no idea. I didn't even know archaea existed. And as I was doing the research for the program, my jaw just dropped further and further down. It's absolutely fascinating.

Thorsten Allers (47:18)

But you're not alone. Most scientists don't know they exist either.

Buzz Baum (47:21)

And they can't pronounce archaea either. Most of my colleagues.

Christa Schlepper (47:25)

Maybe the problem is actually the name that is that they are not so famous. I don't know.

Misha Glennie (47:31)

Yes and no. I don't know. Okay, so what else have we, we missed out? I mean, I think the, the key thing for me and what I was trying to understand is that relationship between our cell structure and their cell structures, or at least what we, what we share in common with them. Do we have a similar relationship to bacteria? Well, help me, please.

Thorsten Allers (47:58)

So it depends on your perspective.

Buzz Baum (48:02)

That's true.

Misha Glennie (48:03)

Right.

Buzz Baum (48:03)

So from my point, I have a strong perspective.

Misha Glennie (48:05)

Okay, you start.

Thorsten Allers (48:08)

My perspective here is that I work on DNA replication. So how we turn one molecule of DNA into two molecules of DNA. Why do we even have this two step process of turning DNA into RNA and then RNA into proteins? Because DNA is more stable. But if you wind back the clock, we all now think RNA was the original genetic material. So it must have been an RNA polymerase that made new copies of rna.

Misha Glennie (48:34)

So it preceded DNA.

Thorsten Allers (48:36)

It did, because rna as well as being able to code for itself, can do catalysis, something that DNA can't do. It's just down to a single oxygen atom. This is where we have deoxy.

Misha Glennie (48:49)

Just explain catalysis for us.

Thorsten Allers (48:52)

So catalysis is you can have non enzymatic catalysis. That's chemical catalysis.

Buzz Baum (48:58)

It means speeding up a reaction.

Misha Glennie (48:59)

So something that won't go as in catalyst.

Buzz Baum (49:01)

So for example, a big piece of wood won't burn.

Thorsten Allers (49:03)

Yeah.

Buzz Baum (49:04)

Because it just sits there. But if you add a catalyst like you. Yeah. Like you heat it up, suddenly you get a flame. Yeah. So it. Yeah, yeah.

Thorsten Allers (49:10)

So for example, the platinum in your car's catalytic converter, that's a chemical catalyst. But you can also have an enzymatic catalyst. So it'll speed up a biochemical reaction. RNA can do that because it's got an oxygen atom on its backbone that's very reactive. DNA is lacking this, so it can't do catalysis. But that on the other hand makes it much more stable. And that's where we have this now split of things. But when it comes to archaea and the enzymes that make new copies of DNA and new copies of rna, there's a really fascinating discovery that came out about six, seven years ago. The DNA polymerase that makes new copies of DNA. There's a version of this enzyme that we find in archaea, and only in archaea. And at its core, the bit that does all the work looks like a dead ringer for RNA polymerase. So if we trace the clock back to the Beginning of life, RNA was there first being copied by RNA polymerase. When we now make that leap to DNA polymerase, perhaps this is still the DNA polymerase that did that first bit of DNA copying. And we only find it in archaea. We find bits and pieces of this DNA polymerase now in us, in eukaryotes, but it's since been supplanted by other more efficient enzymes.

Christa Schlepper (50:36)

But when it comes to quantity of genes or enzymes that we share with eukaryotes or with archaea, that us eukaryotes share share with archaea, then it is not so many. It is because you think Thorsten and I agree that information processing these events are maybe the most important in a cell. But if you argue from a metabolic point of view how we gain energy or things like this, then actually there is a lot from the bacteria in us.

Misha Glennie (51:04)

So mitochondria, for example, can we explain about mitochondria because it was introduced as a concept.

Buzz Baum (51:11)

I mean, not everyone. Yeah. So the complex cells, eukaryotic cells, have these two, we think, at least contributing organisms, an archaeol cell and a bacterial cell. And the bacterial cell is the one that then does acts a bit like a bacterial cell in living in oxygen. It will burn hydrocarbons and oxygen to generate energy, which then it gives to the whole and the rest of the cell. A lot of the machinery, as we said, comes from the archaeal side. Now you can look at the two and sort of look at it like an equal partnership. But the truth is, when you look at a eukaryotic cell, one of our cells down the microscope, there is a bacterial like mitochondrial sitting there, which is why Lynn Margulis said there's a bacterial cell living inside. And other people had seen that before for chloroplasts. It really looks like a bacterial cell. The rest of the cell looks completely alien like this, you know, where did it come from? Woes didn't think it came from, you know, thought it had this sort of a separate lineage. But now we know that there are archaea, which, as Krista sort of said, have many of the things that we thought had never been seen before in any prokaryote. So for example, my lab, we would argue we've now seen even compartments within side archaea. They have long protrusions, they move. Christa's lab has shown they can move. But also the information that they contain is encased sort of in a hub at the middle and they have these long protrusions which are a bit like the edge. So Very much like our cells. We think they have spatial separation between information storage and execution. So what archaea do is they change the way you look at cells because before the discovery of askel archaea, you couldn't really see the origin. But now we're learning to look afresh at these archaeal cells and see in them maybe a protonucleus, maybe a protocytoplasm, maybe, you know, cell motility, maybe compartments that resemble the compartments we have in our cells. So suddenly these asca really are like a stepping stone from simple to complex that give us clues about how it works. But of course, the eucalic cell really requires the mitochondria. So you might have a very complex archaea ancestor, but until the mitochondria came on board, it wasn't this amazing thing that can make a bird of paradise and a mushroom.

Christa Schlepper (53:22)

And we should maybe also refer to the other studies that, that argue maybe there were more partners because there's more bacterial type genes in our cells that might have come earlier. There's a way of doing that, just transferring one gene by the other, not by such a big merger, but by individual processes. And this has also been hypothesized.

Misha Glennie (53:43)

Right.

Thorsten Allers (53:43)

So the archaea, sorry, are very much like a blended family. And we inherit not just genetic components by genetic vertical lineage, the way that we like to think of a family tree, but also we acquire them laterally by genes which have been traded between cells and sometimes hitchhiking on viruses, so they speed up evolution.

Buzz Baum (54:06)

I mean, this in a way was one of woes is again, one of his brilliant insights is that if you look at actually all organisms on earth, bacteria in our care, actually genes move all the time. And that's why people in hospitals get these, you know, antibiotic resistance, because these, these bits of DNA jump. But Woes realized that the one thing that doesn't jump is this core information stuff, and that is inherited, as cells grow and divide in two and their daughters grow and divide in two. So in a way, although there's been all this mixing of genes, there's a one cell lineage on Earth. There was once a cell and we are all its progeny. And it gave rise to two branches, archaea, bacteria. And each of those cells grew and divided itself. Single lineage, which then fused to give rise to eukaryotes 2 billion years later. Two billion years later, it goes like this.

Misha Glennie (54:49)

Good God. So, Christa, so we have three branches, also known as three kingdoms. You mentioned a researcher who you worked with, Wolfram Tsillig. Why was he so distressed about the three kingdoms.

Christa Schlepper (55:09)

Yeah. This was at the time when not just him. Not just him. Maybe that was at a time when these kingdoms were also called Reiche, the Reich or the Ur Reich even, you

Misha Glennie (55:22)

know, so the Reich, meaning empire in German, of course.

Christa Schlepper (55:25)

Yeah, also. Exactly. And then when he heard about that, there was this researcher in Illinois who had found a third Reich of organisms. He was not pleased. It was in the 1970s, 80s and

Misha Glennie (55:40)

he was a committed anti Hitlerite.

Christa Schlepper (55:43)

Yes, he was very committed.

Misha Glennie (55:45)

So that's a rather unfortunate name, the Third Reich, particularly as it's describing something that is just so dramatically wonderful.

Van Tulleken Twins (55:52)

Yeah.

Christa Schlepper (55:52)

But now we talk about domains. So that has.

Misha Glennie (55:54)

So we're back. Domains, the third domain. That's good. It's almost time for. Almost time for a cup of tea. But I, you know, I mean, I've. In a short space of time, I have learned so much about which I knew nothing. This has been a fantastic discussion and thank you very much for everything. Buzz, do come in there.

Buzz Baum (56:19)

I just want to say one thing, I just wanted to say maybe that I think is so exciting about RKL research is because it almost changes the way so everything you learn in a textbook, when you start working on care, it all falls away. But it also means that you start to realize, like, it's not survival of the fittest. Things can live together. They can also, they affect ecology. So you have to look at cells in light of evolution, ecology within the world. So for me it is like also our CARE researchers are the ones who are studying life in the environment in an evolutionary context, which is, as woes would say, I think, proper biology.

Misha Glennie (56:52)

Simon, who'd like tea and who'd like coffee? Tea, please. Tea, please. Four T's.

Buzz Baum (56:58)

Thank you very much indeed.

Christa Schlepper (57:00)

Thank you very much.

Thorsten Allers (57:01)

Thank you.

Christa Schlepper (57:03)

In our Time with Misha Glennie is produced by Simon Tillotson and it's a BBC Studios production.

Van Tulleken Twins (57:09)

Hi, we're the Van Tulleken, the identical twin Dr. Van Tullekens. Chris and Zand in what's Up Docs. We're diving into the messy, complicated world

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No, we won't.

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