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00:00:00
(techno music) - Thank you. (audience applauding) Thank you very much. It's a real pleasure to be here. It's amazing to see so many people. You do know this is a talk about the Krebs cycle, don't you? (laughs) (audience laughing) It's hard to know, how do you try to make the Krebs cycle sexy for people?
00:00:29
And I've done my best to do a kind of Douglas Adams question here. His famous question to life, the universe and everything. And this is my question, what is it that brings the Earth to life and our own lives to an end? And perhaps might make us conscious too? So the answer, I'm sorry to tell you, is not 42. It's not 41 or 43, either.
00:00:55
It's that. And it is quite complicated, isn't it? The one thing I think we could probably all agree about that is that metabolism is scary. This is a metabolic map of our own metabolism. And all the little dots, the circles, are molecules, different types of molecules. And the lines that connect them up are enzyme-catalyzed reactions.
00:01:21
And so these are the metabolic pathways. And flux is passing through all of these things. This is what makes us alive. And it's enormously complicated. So how on Earth can we begin to kind of deconstruct it and make it simple so that I can understand it? This is why I write books. I try to understand these things myself, and if I can manage to make it plain to myself, then I think you can all understand it very easily as well.
00:01:45
So one thing to notice about this, which is what all biochemists immediately notice on these kind of charts is right in the middle of it there, you'll notice there's a blue circle that stands out and says, "I'm different." That is the Krebs cycle. And you have to say, what on earth is it doing that? Why is it like that? If you look really carefully, you'll see across to the right-hand side, in yellow, there's another cycle there,
00:02:10
which is almost concealed. That was actually discovered by Krebs as well. That's the urea cycle, but that's kind pf less central to all of metabolism. So biochemists as a rule, do not like asking why they perceive it as a speculation, rank speculation. Until relatively recently, you were not allowed to ask why you would never get a job,
00:02:36
you ask how. How does that work? Mechanistically, what's going on? And evolutionary biologist, they ask why, And I'm a biochemist who loves evolutionary biology and I look at that and I say, why, oh, why, oh, why? Why is it so complicated? How can we deconstruct it? Well, you start by looking at the bits, and this is the Krebs cycle as it's normally presented
00:03:01
in textbooks, and it really doesn't get any better, does it? I mean, you look at the molecules themselves, and these seem to be fiddling rearrangements of bits of carbon and hydrogen and oxygen. And then there's all these details of the different types of enzymes that do these different jobs and you look at it and you think, well, I'm not gonna become a biochemist. I'll go and do something else. Krebs himself is of course, famous.
00:03:24
This is a painting of Sir Hans Krebs, which was done for the Krebs Fest in Sheffield in 2015. So this would've been 80 years after he went to Sheffield. And he discovered the Krebs cycle in 1937 when he was in Sheffield. And his blackboard drawing of the cycle he discovered back then. It's very difficult to convey how little we knew
00:03:48
and how difficult it is to you look at a cell down a microscope and you can see squidy stuff, really. And now we can see proteins right down to atomic levels of structure. It's extraordinary what we can see now, but we still cannot see metabolism as it's happening. We still cannot see these molecules as they're going through a cell. They're really just too small to see in that way. And so we have to imagine it. And that's a really difficult thing again,
00:04:13
about biochemistry. You never really see anything. You have to try and reconstruct it. It's a little bit like detective work. So what do these look like, these molecules? Well, I've pinned a few out here. They look a bit like a beetle collection. And I think it was J. B. S. Haldane who was asked, what has all this study of biology taught him about God?
00:04:39
And he said, "Well, God had an inordinate love of beetles." I think that God had an even more inordinate love of carboxylic acids. These are everywhere in cells. This is basically, if you think that life is carbon-based, this phrase carbon-based, that, these are the carbon skeletons that life is made from, these are really central to it. I didn't bring my glasses.
00:05:04
And in any case, you probably don't really want to know. There are slight differences between these molecules. These are molecules in the Krebs cycle and it says plus or minus 2H, there's two hydrogen atoms have been pulled out or added in between those molecules. And you may think, why on earth or do you want to do that? Well, I'll come to that. This though is what most people come to the conclusion. Medical students, biochemistry students,
00:05:30
this is basically all they can remember about the Krebs cycle. All they want to know about the Krebs cycle. And so we tend to point poke gentle fun at it. And sometimes, at Professor Krebs himself, who did occasionally set himself up as a target. This is what it's all about. And I'm gonna spend a minute or two on this because we're gonna see this kind of thing
00:05:55
a few times in this talk. And this is my attempt to simplify it down. Everybody should know this. And it is taught in schools. What you're seeing here down at the bottom, it says glucose. It doesn't have to be glucose, it can be food of any description. And it's broken down into smaller bits. And I've just marked up one bit there, which is *** which is pyruvate. And pyruvates broken down a little bit more, and it goes into the Krebs cycle.
00:06:18
I'm not going to try and attempt to explain what's happening in the Krebs cycle step by step. I do do it in the book and I try to make it as engaging as I can. But essentially, you spin around the Krebs cycle and what's coming out? Carbon dioxide is coming out and hydrogen is coming out. It's not coming out as hydrogen gas, it's not bubbling out of there. I've written 2H. And that 2H is stuck to another molecule called NAD NADH, nicotinamide adenine dinucleotide.
00:06:50
This is another problem with biochemistry, there are all these difficult names, but actually, all it's doing is passing on two hydrogen atoms. Where's it passing them to? it's passing them into the membrane surrounding that. You can think of this as a mitochondria or as a bacterial cell or as not one of your cells because the mitochondria inside your cells. But that's 2H being split up.
00:07:13
I'll show you what happens in the moment, but they're eventually reacting with oxygen. And that's what's generating all our energy in the form of ATP. So that energy, this reaction between hydrogen and oxygen, you can think of it as rocket fuel, really. This is what's powering us. This is what's making us alive. In this slide is what makes us different to a corpse. There's no difference in information between a living person
00:07:42
or someone who died a moment ago. The information content is exactly the same. The difference is the flow of energy and the flow of matter continuously going through and this is the core of all of that. The Krebs cycle is spinning continuously in all ourselves. Notice there's a kind of a purple thing around the membrane itself. And I've got lots of little H plus signs there. These are the protons, these are the charged nucleus of hydrogen atoms.
00:08:09
And what's happening, the energy release from this reaction between hydrogen and oxygen is used to pump protons across a membrane. So don't worry if you're a little bit scared of terms like protons, but basically, you've got a charge now on that membrane. I noticed there was an email sent around by the RI yesterday and it started out about Frankenstein and said, "We all think life is about electricity."
00:08:34
And actually no, it's not. Nick Lane's gonna come and tell you it's all about chemistry. Well, no, it is about electricity. (audience laughing) Not quite like Frankenstein, but this cycle, the Krebs cycle is linked to powering up a membrane. So you have an electrical charge on the membrane. And that electrical charge on the membrane, it's tiny, it's 150 millivolts across the membrane, so it's not very much.
00:08:57
But if you were to shrink yourself down to the size of a molecule so that you were the size of, let's say a carbon dioxide molecule or something, the electrical force that you would feel there is about 30 million volts per meter. That's the field strength. So that's equivalent to a bolt of lightning, funnily enough, which is what brought Frankenstein to life. So we have this in front of Frankenstein's monster. We have this going on in all our mitochondria,
00:09:24
in all our cells all the time. Now, I've just drawn this circle to keep things simple. This is what mitochondria actually looked like. And you can see they've got these very thin membranes. These are called the cristae membranes. And this is where all this proton pumping is going on. So if you were to iron out all of these membranes from your own body, it would be about four football pitchers worth of membrane,
00:09:51
which is charged like a bolt of lightning. That's what makes us alive. And that charge will flicker and die if we're not keeping on turning the Krebs cycle. So that's why the Krebs cycle is so central to what's going on with life. Now, what I'm just showing down at the bottom, there is a kind of cartoon of this process. So the 2H, the two hydrogen atoms are split into the component parts into electrons and protons.
00:10:16
The electrons are passed in a kind of a wire inside the membrane. So we have a current of electricity inside the membrane flowing to oxygen. That current of electricity powers the extrusion of protons across the membrane so we have this electrical charge on the membrane. And then they flow back through a turbine in effect, the ATP synthase, which is at the right-hand side. So it's basically like a hydroelectric dam
00:10:42
where the membrane is equivalent to the dam. The proton reservoir, if you like, is equivalent to the reservoir. And the ATP synthase, well, it's a rotating motor. It's an extraordinary protein. This is another reason why biochemists don't like to ask why, how on earth does something with that majesty evolve? it's plainly a product of genes and natural selection and so on. But when I think about these questions,
00:11:11
I'm wondering about how did it arise in the first place? It's a strange fact, but basically, all life on earth works this way. This way of generating electricity is as universally conserved as the genetic code itself. This is how cells work. Bacteria work this way, archaea work this way, plants, animals, everything works this way. So there's something profoundly important
00:11:34
about how it works, and yet, it's very difficult to wrestle with in terms of how does it happen. These are two of the most important discoveries in my opinion, in the 20th century of science. One of them that the mitochondria themselves and the bacteria work in the same way are basically electrical fuel cells was discovered by Peter Mitchell. And I want to say, and Jennifer Moyle,
00:11:58
because Jennifer Moyle did all the experiments. Mitchell was a genius who thought things that nobody else had really ever thought before, but a lot of people thought he was a madman, insane and really would practically leave the room if he came in. He really infuriated people. It was Jennifer Moyle's experiments that made other people take Mitchell seriously. And it's the sorry state of the world that Mitchell himself
00:12:23
got the Nobel Prize in 1978. But Jennifer Moyle was overlooked, which I think would not happen today, let's put it that way. The other person on there is Lynn Margulis. She really nailed the idea that mitochondria were once bacteria. So mitochondria, the power packs in our own cells once were free living bacteria and were acquired 2 billion years ago,
00:12:50
probably in the course of the evolution of complex cells. And so these power packs that we have, were once free living bacteria. These are two of the most important discoveries that again, I think everybody should know. But it suddenly gets a bit more messy. And the Krebs cycle is not only about stripping hydrogen out of food and burning it in oxygen,
00:13:17
it's also used for making the precursors for everything else. It provides the carbon skeletons for growth. It provides the carbon skeletons to make amino acids and to make fatty acids and to make sugars. And from those, to make nucleotize, the building blocks of DNA and so on. So it's really central to biosynthesis as well as to energy,
00:13:42
which is always recognized in the textbooks, but it's a little bit messy and uncomfortable and it's put into a different chapter and we prefer not to talk too much about it. But there's a problem here because if you have a problem with respiration, it's not only affecting ATP synthesis, the energy currency, it affects the electrical charge on the membrane. If we can't have the flow of electrons going to oxygen,
00:14:08
then you don't have the electrical charge on the membrane, then the Krebs cycle can't spin and then you can't make anything either. So if you've got a problem with respiration, you've got a problem not only with energy, but with really everything with growth and development. Now luckily this doesn't really happen very much, and I'll come later in the talk as to why that is, but the clue to what's going on actually came from cancer.
00:14:32
From studies on cancer in the last 10 to 15 years or so. Now it turns out what you're seeing here is that you can. I'm going to point to this. This is showing one of the complexes, it's gone into reverse. And we're taking the two H instead of taking them from the mitochondria, we're taking them from over there, from the cytoplasm of the cell, from outside the mitochondria. We're feeding them into somewhere else.
00:14:56
And that allows us to keep this electrical charge. But notice what else is happening. The Krebs cycle is going backwards. It's flipped. And it's now taking carbon dioxide and hydrogen from around it and converting it into the precursors for biosynthesis. Cancer cells love this. Cancer cells wanna make copies of themselves. That's what they do. To grow and to divide, you need to have all of these,
00:15:24
you need to have more fatty acids for the membranes. You need more nuclear tides for the DNA. You need more amino acids for the protein. So cancer cells do this. and it's become increasingly clear that this happens quite a lot. So it becomes really very messy. This idea goes back to Warburg. Otto Warburg, a great German biochemist really in the 1920s.
00:15:48
He began talking about problems with mitochondria. He wasn't bang on. And actually this picture of him, he does look a little bit like Dr. Frankenstein, doesn't he? He was a very polarizing character, a brilliant biochemist, very extremely haughty. And he was in fact Krebs' mentor as as well. So these ideas that now very popular in cancer
00:16:13
known as the Warburg shift, the idea that mitochondria effectively become biosynthetic rather than producing energy go back 80 years, 90 years to Warburg and suddenly, they're in vogue again. And he wasn't quite right about everything, but he was right about a lot, and I'll come back to that. What I'm trying to say is it's not a cycle, it's more like a roundabout, a magic roundabout with things coming and going
00:16:41
from pretty much every junction. This is the magic roundabout in Swindon. I've noticed when you try and find pictures of the magic roundabout in Swindon, you always find the same picture and it's quite an old picture. Look at some of the cars on there and you see those are quite old cars. So we're still reusing the same picture of the magic roundabout, probably because it's the only one where everyone was driving correctly around it, I suspect. (audience laughing) I was there once and it is a terrifying place. It really is difficult to organize that kind of flow
00:17:09
so that it actually works. Why on Earth would life organize a system where you're using the same cycle to generate energy and to make all the precursors for growth? It seems a mad kind of thing to do. And if something goes wrong at any part of this because everything works in series, then the whole system goes wrong. This seems like a mad way of doing it. Now when things go wrong a little bit,
00:17:35
it changes the activity of the genes. There's an epigenetic switch. So literally, thousands of genes are switched on or switched off when things go wrong with the Krebs cycle. And this is something which has again been discovered over the last 10 years or so, that if the concentration of intermediates goes up or down, then it switches genes on or off. So it's far from just the power packs of cells.
00:18:00
This is really the beating heart of what's going on with life. So why then do we use the same cycle for creating and destroying? Not even a phoenix can do both at the same time. Well, this is not the answer. I put this slide in because today was the last day of a post-doc in my lab, Glar in one one, and he is going to take up a lectureship in Thailand. He is Thai, leaving this weekend.
00:18:28
And so this is in Thailand. I've got no idea where it actually is, but my God, it looks nice. I think this probably is the correct answer to pretty much every other question is this is close to 42 as we're going to get. But why do I say it is not the correct answer? Because plants have misled us. Because plants, the way that they do photosynthesis, they're basically making sugars that way.
00:18:55
And a lot of the chemistry, it took a long time to discover and it's kinda focused in the way that textbooks teach and the way that we are all taught biochemistry. I was helping my youngest son who's got his GCSEs coming up and it says in his textbooks that photosynthesis makes glucose. Well, no, not really. It actually took the people who were trying to work out the pathway, they couldn't understand why there was no glucose
00:19:23
being made whatsoever. It took them 10 years to figure out what was going on. Well, now we know. And we've got this idea that photosynthesis makes sugars and respiration burns, sugars and it all works as simply as that. This is the correct answer. And it's not quite as nice really, is it? It's definitely less than 42. This is in Yellowstone.
00:19:50
And these are green sulfur bacteria they're photosynthetic as well, but they grow in a completely different way. And they grow in a way which is far more ancient. This is probably at least one to 2 billion years before the origin of photosynthesis as we know it. And here's what they do. And this is the key to everything really. What you're see in there is the Krebs cycle again. It's a slightly extended version of the Krebs cycle
00:20:16
and what's happening? it's going backwards. As it happens in cancer cells and it's taking hydrogen, it's taking it in fact, from hydrogen sulfide in this case, and it's taking CO2 and it's joining them up to make organic molecules. So one spin of the cycle takes up four carbon dioxide molecules. This is about four times more effective than the more familiar Calvin-Benson cycle
00:20:39
which you see in most plants or all plants. It was discovered in in 1966. And the first author on that paper was Mike Evans. And there he is in 1964 with his car. And that car really dates it though. When I checked up, I realized that the car was actually already a vintage at the time. It's a 1950 model. So it kind of gives a slightly skewed version, but this is the reverse Krebs cycle.
00:21:06
First discovered in 1966 and it took literally 25 years before the field began to believe it. Krebs himself never referred to it. Krebs died in 1981. He wrote a paper in 1981 about the evolution of metabolic pathways and he didn't once mention the reverse Krebs cycle. I have no idea why not. But this really explains a great deal. Here was the original figure showing how it works
00:21:31
from that paper in 1966 at the left-hand side. And you'll see there it says reduced ferredoxin. Ferredoxin, it's the red protein. And you can see just at the top, these are X-ray crystal grafts showing the electron density. These are really beautiful, these figures. You don't see them done like this very much anymore. This is how they used to do them. This was a 1972 paper. And you can see the structure that they came to
00:21:57
from the electron density. Now can you just make out the some square a bits and you can see the little kind of cuboid lattices in there? Those are iron sulfur clusters. So there's four iron atoms or ions, and there are four sulfur ions in there. And it is a little cube structure, like a mineral in effect. And that is the bit in this molecule that does the work.
00:22:23
There's two places in the Krebs cycle where it's really difficult to make this chemistry happen and it's the ferredoxin which is driving it. And so the entire cycle can go backwards and it's not involved in energy really. It's involved in growth, in making things, in making all the precursors that you need for life. Now this also 1966 was another paper and this is perhaps one of the most important papers
00:22:52
that I've ever read. And probably Margaret Dayhoff. Can we have a show of hands? Who knows Margaret Dayhoff's name? Margaret Oakley Dayhoff. Anyone in here? John Allen does, but I know he does (laughs) But that's a real shame because she is really, she was described as the father and the mother of bioinformatics. And this was a paper.
00:23:17
She founded this entire field, which we now all comparing gene sequences letter by letter to say, well, this bacteria compares with this from that bacteria and so on, and we can reconstruct an entire tree of life. It all goes back to Margaret Dayhoff. And this is an absolutely gobsmacking paper. I don't know if you can quite read the abstract, but what she's saying there,
00:23:42
I can't read the abstract 'cause I forgot my glasses, but what she's saying there is that ferredoxin this molecule that makes the Krebs cycle go backwards, has a structure which is composed of smaller repeating units. In the end, it goes down to four amino acids, which are kind of repeated and repeated and repeated and it became more complex. And these are some of the most ancient amino acids. And she says in there, the bit that I've highlighted in red,
00:24:08
says that perhaps this goes back to a time at the origin of life before there was even a genetic code or before the genetic code was fully formed, which is one of the most thrilling lines that I've ever read in a scientific paper. And what she's done there, is a kind of piece of detective work of looking at the modern sequences, deconstructing what makes them up, realizing the whole context for it.
00:24:34
And pushing it right back to the very origin of life. It is a thrilling thing, is it? One of the great things about science, and that's a challenge then. How could that work at the origin of life? She had also pointed to some of the most ancient bacteria, clostridia and things like that which grow from carbon dioxide and hydrogen in pretty much the same way. They don't actually use the reverse Krebs cycle,
00:24:58
but they use something very similar. And so, the reverse Krebs cycle is using hydrogen and CO2, is using ferredoxin, this ion protein. And they also need to have the electrical charge on the membrane. They can't grow without this electrical charge. So it's really simple chemistry that they're doing. And this is a tree of life built by you might say,
00:25:23
bill would probably describe himself, Bill Martin here would probably describe himself as a disciple of Margaret Dayhoff. And he has a very similar view that he's bringing in real biochemistry and combining it with genetics. And this tree of life that he's got here goes right back. You can see down at the bottom, we have the bacteria in the archaea seeming to emerge independently from a hydrothermal vent down at the bottom there.
00:25:49
Now this was a radical, radical view when he put that forward in 1999. That's this paper. And remarkably, it's become, I won't say mainstream, but it's become far more accepted now probably, than it certainly was when he put it out. The bacteria in the archaea that are down there at the bottom are growing from carbon dioxide and hydrogen. And the vents were discovered the year after that paper,
00:26:19
the kind of vent that he was talking about by Deborah Kelley who was captain of the Alvin submersible. The Alvin submersible had discovered black smokers in 1978. So this was now moved forward in the year 2000 and she discovered a completely new type of vent system known as alkaline hydrothermal vents. And they're not like black smokers with smoke bellowing out of a chimney. These are in fact active vents,
00:26:44
but you don't see very much happening. They're more like a kind of gothic cathedral or something. They're really beautiful things and they're really rich in hydrogen gas. Hydrogen gas is bubbling out of these vents. And they were predicted to exist 10 years before their discovery by a guy called Mike Russell who's a geologist. And he had found something on land, a kind of a fossil version and worked out
00:27:10
what should be happening in the oceans and linked it to the origin of life. So amazingly lateral thinking. And the key to how Mike Russell was thinking about this is he was saying, these vents have a kind of mineralized sponge texture to them. It's a kind of a labyrinth of interconnected micropores. And the walls between them today in the ocean at Lost City,
00:27:34
discovered by Deb Kelley, today, it's calcium carbonate aragonite. But 4 billion years ago when there wasn't any oxygen in the atmosphere, they were probably made of other things. The ocean chemistry was very different and there were probably a lot of iron sulfur minerals in there with a structure which is very similar to the iron sulfur clusters that Margaret Oakley was talking about. And involved in the reverse Krebs cycle.
00:28:00
They bubble hydrogen out of the ground. The early oceans were rich in CO2, we've got these iron software cluster and because the alkaline vents going into an acidic early ocean, we also have pH gradients. So we have chargers effectively electrical charge on these barriers. So we have really, I think, the perfect set of circumstances, it's almost too perfect to be believable. And the scientists, we have to be skeptical and say,
00:28:25
well, am I seeing faces in clouds or something like that? This is what gets me excited about it. On the left you're seeing a pore, a kind of schematic of a pore in one of these vents. It's alkaline inside, it's acidic outside, there's a barrier around it. It's quite a thick barrier compared to a cell membrane and it's got these iron sulfur minerals in it. And on the right-hand side, we have a bacterial cell. It's acidic outside, it's alkaline inside,
00:28:51
we've got a membrane and it's got a protein in it, which is pumping protons out. So topologically, it's really very similar. And this is how I imagine it at least. So what I'm doing here is drawing it exactly as I've drawn the other things just to show you how the topology works. So on the left-hand side, you're seeing the pore with the iron sulfur barrier surrounding it. It's driving hydrogen to react with CO2 in something
00:29:18
amounting to the reverse Krebs cycle. It may not be a complete cycle, but it's basically driving this reaction. And coming from it are the amino acids and the fatty acids. Those are the easiest things to make. The fatty acids will form together to make a membrane. And on the right-hand side, you're seeing that this membrane has formed around and now, everything's enclosed, the concentrations are a bit higher, the driving forces are the same. And so we can go further through metabolism
00:29:43
and make more things. Make even perhaps nuclear types. That might seem like a bit of a far-fetched claim to make. It is far less of a far-fetched claim though than you might think. This is probably the most complex slide that I'm gonna show you this evening, and I'm not gonna go through it in detail, but all I really want you to take home from this is in, I can't see it properly, but in green, if I remember rightly, it says H2 and in brown, it says CO2.
00:30:10
Maybe it's CO2 in green. These are the steps starting with carbon dioxide and working through into metabolism as we know it into the Krebs cycle as we know it. And it's hydrogen, hydrogen, hydrogen, carbon dioxide, carbon dioxide. It is just one after another. It's exactly the same thing, repeating chemistry. And you think, well, why is it doing this chemistry? Again, I'm gonna skip lightly over this. It's doing this chemistry
00:30:38
because it can't really do anything else. When you think about what's happening with CO2 binding close to a surface, to a mineral surface or to a cell membrane perhaps, or to a metal cluster or something, electrons are being transferred from the hydrogen, where do they go? Well, I'm not gonna go through step by step, but what I would like you to take home from this is all I'm doing is transferring electrons
00:31:02
in the presence of protons and then going from carbon dioxide in each step through to, by the end of this slide, I've got as far as a methanol. So we're transferring, transferring an electrons onto it and then picks up a proton and we end up with one hydrogen. More electrons transferring on. This is the electron pair is moving onto the oxygen. Binds to a proton, binds to a proton,
00:31:26
we end up with methanol. And we can go on. It's the same chemistry. If you would like to know more, well, I explain it more in the book, but we've just taken it through here in a few simple steps, whoops, to pyruvate itself. Which I showed you at the beginning, is the lead into the Krebs cycle in our own Krebs cycle. But these are all the intermediates, this is the building blocks of life
00:31:50
and it's almost inevitable chemistry and it's now been done in the lab. Pretty much everything I've just shown you over the last five to seven years has now been done in the lab and it really works. So I've been talking about these ideas for a long time, for more than you know, 10 to 15 years or so now. And for a long time it's a bit embarrassing because I would say, "Well, in theory, all of this should happen, but is very difficult to make it work in the lab."
00:32:17
And now, not just in my lab but in other labs around the world as well, people are doing this chemistry. It really does work. It is fantastic. It's a very exciting time. So this is possible. It's not proved, but it's possible. And I'm gonna just say one more thing before I move on from the origin of life, which is that well,
00:32:41
to get beyond there, this is an entirely chemical system driven by the environment itself. To get beyond there, well, you need genes. You need to be a proper cell. This is not a proper cell. This is a kind of a protocell with a non-coded metabolism. Where do the genes come from? Well, there are known interactions, and I don't know quite how these work, and I've just drawn some things for fun here, really.
00:33:06
But there are known interactions between the bases, the nucleotides in RNA. So the letters, if you like, of RNA and amino acids. It's mostly about the hydrophobicity. So if the hydrophobic amino acid will interact with a hydrophobic base, so water-hating amino acids and water-hating bases. And the size matters as well. And what this means is that if we have these interactions, if we have a high enough concentration inside the protocells,
00:33:33
then we can ha we can introduce a random sequence of RNA, just any old letters you want. Meaningless, no information, content whatsoever. But if that will template in some way, a non-random sequence of amino acids to form a peptide, and it's non-random because the biophysical interaction say whenever you get this kind of hydrophobic base, you'll get this kind of hydrophobic amino acid.
00:33:57
Then you've produced a non-random peptide, which can have function because it can either make the protocell grow faster or grow slower. And effectively, it is coded by that sequence and that sequence when it's copied can be passed on. So I'm not gonna say any more about that. We can ask questions later on if you want, but in effect, there is no problem with the origin of information in biology if we think that metabolism comes first.
00:34:23
And that these kind of protocells come first. Everybody has to produce the building blocks. But if you have just a pure RNA world where RNA invents everything, it's really difficult to work out where does all this information come from? There's no problem in this setting. So let's skip forward. They've left these cells have got genes now and they've left. And it is interesting that they have retained, cells have retained a structure which is topologically similar to the planet itself.
00:34:51
So the inside of the planet, the core and the mantle, iron rich and iron is effectively saturated with electrons you might say, it wants to be rid of those electrons and become oxidized. And the outside is relatively oxidized, lots of carbon dioxide and water and so on. And the carbon dioxide will pick up the electrons from the iron. And these things that I'm showing in the membrane there,
00:35:17
there's a membrane, these are hydrothermal vents really, in the crust. These are the connection between the mantle and the oceans and the atmosphere. And the cells are basically exactly the same. Relatively negatively charged inside, relatively positively charged outside. And they're maintaining that difference. It's important because for these cells to grow,
00:35:40
they need to get their hydrogen, they always need hydrogen and they need to get it from hydrothermal systems. And they can't get it from anywhere else really, at this stage. They can get it as hydrogen gas or they can get it as hydrogen sulfide coming outta these systems or even Ferrous iron. So charged iron with two plus that can be oxidized to ferric iron, it can rust in effect,
00:36:05
and the electrons and protons can produce hydrogen. So it works in all kinds of interesting ways, but life is limited by the availability of the 2H that I've been talking about. Until photosynthesis. And what photosynthesis does, these are sign of bacteria. What photosynthesis does is take the 2H from water, it uses the power of the sun to strip out from H2O, it strips out the 2H and it puts them
00:36:30
into making organic molecules and oxygen is the waste product. And if you think about the earth as a battery, as a giant battery, then we're supercharging that battery. The outside the atmosphere and so on is now becoming even more oxidized, even more positively charged relative to the inside. It really wants to draw electrons out. And those electrons are now coming from water instead.
00:36:56
That led to a kind of catastrophic change in the history of the earth at the time of what's known as the Great Oxidation Event 2.2 billion years ago. And this is just a beautiful picture of a banded iron formation. I love these things. They're not actually diagnostic of the Great Oxidation Event, but they're beautiful to look at. Point is that oxygen appeared in the atmosphere around that time. Not very much.
00:37:19
I mean, limited amounts of it and a lot of the oceans remained really very low oxygen. It was probably zero oxygen for another billion years or so after that. But the thing is that when oxygen levels rise, we go, well, think about what the Krebs cycle is doing? For 2 billion years, all these bacteria are just growing by taking 2H out of the environment and so on and making the Krebs cycle go backwards, and that's how they grow. And then there's oxygen in the atmosphere
00:37:44
and everything goes backwards forwards, which way does it go? I mean, it flips direction and goes the other way. You kinda think, how can you avoid a crash when something like that is happening? Well, the answer seems to come from the first animals in part. So these are from around 560 million years ago, and these are the first trace fossils that have been found. So this is before the Cambrian explosion.
00:38:10
And these are little worm-like things that crawled through the mud. And the mud we know was full of sulfide, it was sewer gas really, conditions. And somehow, they needed oxygen to do this, but they managed to deal with these sewer gas type conditions. And it was a time when oxygen levels were rising and falling and quite unstable. And so how did they actually do that?
00:38:37
Well it seems that they didn't use a Krebs cycle as we know it necessarily. They actually have a two-pronged kind of Krebs cycle and a lot of bacteria do this as well. So rather than running it as a cycle in either direction, they kind of split it and they keep a balance there. So I won't go through the details of that, but it's basically a way of keeping, if you produce too much 2H, then then you become kind of saturated in it
00:39:03
and you can't work. And if you don't have enough, you're unable to burn anything. And so this is a way of keeping a balance so you have just the right amount. Now the interesting thing about these early animals is probably the way that they succeed in doing it, it took me a long time to see this. Blindingly obvious, really, but it took me a long time to see it. Bacteria, if you change the conditions, have to keep changing their state. Because if there's lots of sulfide around, you have to deal with the sulfide,
00:39:29
you switch these genes on and you switch those genes off, you run your Krebs cycle this way and you're okay. And now it changes, now there's some oxygen. So you've switched those genes off, you switched these genes on, you switched the Krebs cycle and you do that. What animals can do with different tissues is have this tissue doing one job, that tissue doing a different job, this tissue supporting that one and so on. So we have different patterns of flux going different ways of making the Krebs cycle operate.
00:39:53
I think this was probably one of the things that really made the Cambrian explosion possible, this differentiation of tissues. We think about them as doing different jobs, but all of those jobs are supported by the way that the Krebs cycle is working. So this is a picture I've always liked showing the Ediacaran fauna at the left-hand side. So we don't really know what they were. Their sessile filter feeders
00:40:17
stuck to the bottom of the ocean. Often 200 meters down, so too deep for them to be photosynthetic. They look a lot like plants, but they're too deep. It's pitch black 200 meters down, so they're not plants. And they all died out. The reason we don't know much about them is that they fell extinct right before the Cambrian explosion. And they probably fell extinct because we know that there was a time where the sulfide levels rose
00:40:42
around then and they probably just suffocated. And those first animals that I showed you crawling through the mud dealing with sulfide, were effectively pre adapted to those conditions. They got different tissues that were doing different jobs and they were able to survive those changing conditions. And oxygen levels rose around the time of the Cambrian explosion. And so suddenly, what we're seeing there
00:41:05
is predators and prey. We're seeing armor-plated animals and they're scuttling around and eating each other. And you can't do that without oxygen. And the simple reason for that is you can't really have multiple trophic levels in the absence of oxygen because of the efficiency. So aerobic respiration is about 40% efficient.
00:41:29
And what that means is that you extract about 40% of the energy from the lunch that you eat and the rest is waste. And then another trophic level will extract 40% of the energy from that. So an aerobic ecosystem can support five or six trophic levels, whereas an anaerobic one where it's more driven by fermentation is about 10% efficient in comparison. So you can only have two at most three, trophic levels,
00:41:54
and that means predation really just doesn't pay. You never have large enough population sizes. So the Cambrian explosion, we know from geological evidence and we know from the types of behavior that these Cambrian animals were predators and would've had a Krebs cycle just like our own and would've had the same problems that we have with it. You can be fairly certain that they would've shown signs of aging and things like that.
00:42:20
So I'm showing you here again, the full Krebs cycle that I showed you before this, the full system where we have. We're eating food, glucose, whatever it is, we're spinning the cycle in an oxygenated atmosphere where charging the membrane, we have an electrical charge on the membrane. The trouble is you can't do that forever. You are going to end up with damage. Just the turnover, the pace of life. You will get damaged protein,
00:42:45
you can replace the damaged proteins, fine. You can fix everything if you want to. But this is the obsession of evolutionary biologists. You'll never see an evolutionary biologist who is not obsessed with sex. So how much effort do we want to put in to sex? And what you can see behind is pacific salmon. They put all their effort into sex and then undergo what's known as catastrophic and essence. They drop dead right afterwards in piles.
00:43:12
They put everything into it for the sake of their offspring in effect. Now we all do the same thing to some extent, not catastrophically, but we have to make some kind of evolutionary decision. How much repair do we want to do? Because the more repair we do, then the fewer offspring we're going to have because we've devoted more resources to that rather than this. You have to take the pick to some extent. And so different animals make that decision
00:43:37
in different ways. Some put much more resources into extending their lifespan and others put much more resources into sex immediately, if you like. The problem is, this is, again, you've seen this before, this is just showing if we're accumulating damage, if we've made a decision, well, we're gonna put most of our effort into sex and some into surviving a little bit longer,
00:44:02
you're going to get damage. And that damage, some of it's going to be in respiration. And when you get the damage in respiration, then you're gonna have a problem with the entire system because it's all linked in series. And I showed you this before as well with Warburg. Now it turns out that this is not just specific to cancer cells, this is more or less what's happening in a lot of our cells as we get older. And the reason is the damage. So again, you can see, am I painting it?
00:44:28
I should have painted that one blue. But anyway, if we have damage here and we have some flux of protons back, we're putting the Krebs cycle into reverse again. I'd like to call this a wiring diagram for being old because what you're seeing here is less energy because we're cutting out the first. So instead of pumping 10 protons, we're pumping six protons. So for every 2H that we have, we get less ATP out.
00:44:55
So we're losing energy in comparison. And we're spinning the Krebs cycle backwards. So we are beginning to put on weight. We're fixing CO2 as if we were plants or something. We're putting on weight and getting slower. And that is the essence of aging. Now also, it makes us more vulnerable to cancer and the diseases of old age. So rather than having a forwards operating Krebs cycle,
00:45:21
we are getting something much more sluggish like that. It's not necessarily pumping it out that way. It's much more subtle than that, and this can last for decades, this kind of state. So there are though some cells which can't do that. So these are pancreatic beta cells. And this is amazing to me. They detect glucose and when glucose levels rise in the bloodstream,
00:45:49
they put out insulin and that lowers the glucose levels again. How do they detect glucose? Well, they detect glucose by effectively having a flux capacitor system. So they allow glucose to flow in freely and they allow the Krebs cycle to spin freely. And that generates a membrane potential. So it charges up the electrical membrane. And if you have a highly charged membrane,
00:46:14
that's the signal to put out insulin. Now, if you have damage to respiration and you cannot highly charge your membrane, there's glucose signal coming in and you can't be spinning the Krebs cycle in that way. So you can't do it. So you don't put out the insulin. So you end up with hypoglycemia and you end up with diabetes. Now it's not just those cells, it's also neurons.
00:46:39
Neurons love glucose. They can get by on ketones and things as well, but they're really reluctant to burn amino acids or fatty acids or other things like that. Why? Well, regardless of what the reason why is. I've come to that in a moment, they have the same problem as they get older, then you're going to be losing power if you're not careful. Now if you face that situation,
00:47:03
if you stick with glucose and you can't burn the glucose because you don't have a full Krebs cycle, well, you won't be able to think. So what are you gonna do? Well, this is an idea coming from Eric Schon and Estela Area-Gomez, which is a very neat idea. It's not a very popular idea in the field, I have to say, but I think they're onto something. What they're saying is that you ramp up the calcium because the calcium, you can ramp up
00:47:32
the rates of respiration and the charge on the membrane. So pump some more calcium. If you don't have enough glucose, pump some more calcium, meaning you can charge up your membrane a little bit more. And it works except that calcium can be damaging and it's especially damaging to the place where the calcium source is, which are the membranes right next to the mitochondria called the MAMs, the mitochondria associated membranes. Now this is part of another membrane system called the endoplasmic reticulum.
00:47:57
And this is making proteins and processing proteins and a lot of the proteins that you'll be familiar with in Alzheimer's disease. So you'll see plaques and tangles in the brains of people with Alzheimer's disease. The plaques are made from amyloid protein and the amyloid protein is a small part from a processed precursor protein, the amyloid precursor protein. All of that chopping up proteins
00:48:21
and sorting them out is happening in the MAMs, in these membranes right next to the mitochondria and are damaged by the calcium because the mitochondria themselves are not working correctly. Is he right? Is she right? I don't know, but it makes a lot of sense to me. But the other reason I like this, and this is the last few minutes now. The other reason I like this is it says it's really important to have a high membrane potential
00:48:45
when glucose floods into a brain area. So you can see on PET scans and things, the parts of the brain lighting up when glucose comes in. So it's gated. The capillaries open the flow, glucose comes in, this part of the brain lights up, we're getting a big electrical charge on the mitochondrial membranes. And we seem to really need that charge. Is it connected with things perhaps even more important
00:49:10
than just thinking or just the mechanics of thinking? Is it connected with consciousness itself? He is a really beautiful idea from Luca Turin. Now, Luca Turin is a biophysicist and he's had all kinds of interesting ideas. I'm not gonna talk about most of them, but he came and visited me at UCL a few years ago now. I wanted to talk about general anesthetics and I knew nothing about general anesthetics,
00:49:34
but what he told me is that, well, nobody knows anything about general anesthetics. We don't know how they work. They all have different shapes and they all have different charges and none of them interact in a meaningful way with the kind of the hand and glove type receptor mechanism. And that was what interested him. Even xenon, he said, an inert gas, which is basically
00:49:57
a sphere of electron density, it doesn't really have a shape, it doesn't really have any chemistry, but it does have physics, he said. And this physics involves somehow, I don't really know how he does it. He's able to transfer electrons and what he had shown using EPR and techniques like that. So electron paramagnetic resonance is that oxygen is involved. The transfer of electrons to oxygen, xenon speeds it up.
00:50:24
And that is associated with why it can put you under general anesthesia. It's short circuits respiration. It can only do it in a very mild way because if it did it in a big way, it would kill you straight away. So it must be a very subtle effect. But if you get an overdose of a general anesthetic, it will kill you. So there's some subtlety probably these things are actually quite bad at doing it and therefore, are less likely to kill you
00:50:47
but they do it somewhat anyway. Now we don't know either. Many things were really profoundly ignorant about, we don't know what the electroencephalogram is. We can interpret it really well, but we don't know which structures in the brain are producing the electrical fields that are giving the EEG. We know it's neurons and we know it's not just single neurons, it's networks of neurons because the signals
00:51:12
are sufficiently high that they must come from networks. But the assumption in the field is that it's coming from the axonal membranes, from the plasma membranes themselves, which are depolarizing as a neuron is firing. But inside the neurons or mitochondria and there's a lot more mitochondria and the charges at least double the charge on the plasma membrane. And we have these beautiful, I showed you earlier on, these beautiful cristae membranes.
00:51:37
They're often parallel to each other and we have an oscillating current in them. They do generate electromagnetic fields. It's really difficult to measure them. I am trying to think of ways of doing it. Other people are trying to think of ways of doing it, but it is quite likely, it seems to me that the electromagnetic field is generated, where we're detecting with the EEG are generated by the mitochondria inside cells
00:52:03
rather than the membranes themselves and that they're interacting with the fields on the plasma membrane, and this is going on. So why mitochondria? And why electromagnetic fields? And this is the final slide that I'm going to leave you with. And this is the first slide that I showed you pretty much as well. This system, now think of it as a bacterium and it's got the Krebs cycle. It's generating the amino acids and everything.
00:52:26
It needs all the precursors and it's burning things in oxygen and it's taking up glucose or whatever from the environment and it's charging up the membrane. And this system is working in series. So everything is connected in time. And as time goes by, as oxygen levels fall, then respiration will slow, the membrane potential will fall. And so moment by moment in the life of a bacterial cell, and I'm showing you a bacterial cell here,
00:52:53
the stream of consciousness is in effect. A real time report on the status of the cell in relation to its environment. I'm not saying anything about the human consciousness, I'm just saying what, from the point of view of biophysics, is a feeling? If we feel in love or if we feel pain or if we feel hungry or whatever it may be, what is a feeling?
00:53:21
We don't know. There is no answer to that. And there are really two types of explanation for it. One of them is it's some kind of concoction, it's an emergent property of a sufficiently complex central nervous system. But it still doesn't say what it is. And actually what that says is there's some deceit going on. That it is not real. It is just a concoction to triggers into thinking that we're conscious. I don't find that very appealing as an idea.
00:53:45
The alternative idea is that, well, it's a property of matter. There's an unknown law of physics and the sun is conscious in some way or another and so is everything else. And I don't find that really very believable either. Consciousness strikes me to be widespread across at least the animal kingdom. It seems to me anybody who has a pet will recognize that it has feelings. And where do we stop then?
00:54:11
What is natural selection acting on to embellish consciousness going from simpler animals to, in the end, the majesty of the human consciousness? What is the simplest possible form of consciousness that we can imagine? What is, if you like, a quantum of solace, what is the simplest possible form? I think is the electrical charges on the membranes generated
00:54:36
by the spinning of the Krebs cycle in relation to the environment as a real-time report on the status of cells in relation to their environment. I'm gonna stop there. I have to say thank you to my group because they are doing amazing work. I haven't presented any data this evening. I normally give kind of quite data-heavy talks, I have to say these days. They are brave.
00:55:01
They're working on some of the most amazing questions in science, but they're not easy questions and it can take a long time to make much progress. And that can kill a career. And that's why I say you have to be brave. If you do a PhD and you don know papers and every result you get over three or four years is negative, well, that's not great. You may be forced to leave science. So it requires some bravery to do that. And I'm really grateful to them
00:55:25
for coming for this adventure and making this adventure for me so much more thrilling because we are making progress and I think we're beginning to understand things. And I'm gonna leave just with the painting of the reverse Krebs cycle by Odra Noel as an Oraboros. I hope I've done that in time. Yes, eight o'clock. Fantastic. (audience applauding)
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