Transcription
This is a kind of a dirty secret of bioenergetics, that what you actually measure is about 20 millivolts. And what the theory and the calculations say, and what the dyes are trying to tell us, is that actually it's more like 180 or 200 millivolts. There's a bit of a shocking difference.
[Music]
Thank you. Thank you very much for coming. I've been thinking about consciousness on and off, in a kind of non-engaged way, over about 20 years. But in the last few years, a chance encounter with someone brought it much more to the front of mind, and we've started doing some experiments on fruit flies, which might not sound like a very appealing start. But I'd like to tell you something about that. So, it may be a little bit more, I'm going to try and keep it as little scientific as I can, but it's basically, I want to try and put across an idea as to what consciousness really is. Consciousness in the sense of what are feelings? Because that's what has really plagued me as a biochemist. Because a feeling, it's, well, what is it in biophysical terms? It's just not clear. If a neuron depolarizes and some ions run into the neuron, and now we feel miserable, or hungry, or in love, or whatever it may be, what actually is that in terms of physics, or in terms of chemistry, or biochemistry? And I wrote a chapter on this in a book 10 years ago called "Life Ascending," and basically that chapter on consciousness was 10,000 years, in which I said, "Well, interesting question, but I have no clue." So, I maybe shouldn't say that either.
So, just to orientate at the beginning, this is a quote from Derek Denton, who, he died a year or two ago at the age of 97, and had thought a great deal about consciousness. And this was an example that he used to use. News about a fox that was caught in a trap and gnawed its own leg off to escape. And the point that he makes is, the animal aware that it's completely held, completely by its paw in the trap jaws? And it does it have an intention to get free? Gnawing through its own skin, muscle, and bone to set itself free is a purposive act, and very probably extremely painful. You bet. At least it seems a plausible viewpoint that the animal has enough body image sense to see that its paw is part of itself that is held, and intention is to get free. It is self-aware and has a plan. Now, I am sure that not everybody in this room would agree with that. I would like to think that most would. It seems kind of obvious to me. And most people who are familiar with animals would probably see at least that level of consciousness about them.
This is Stentor, and it's got all these little cilia which are beating continuously, and it works like an electric battery going around. And this is an amoeba, which is coming in, and it starts to engulf, very gently and very gradually, this Stentor. And its friend figures out what's going on, and off it goes. It kind of zooms away and comes back for a look later on. And this guy just gets engulfed and eaten by the amoeba. And you can see it's figured out at some point what's happening. And you feel quite sorry for it because it's just being, it's just being digested. But the top bit somehow wriggles itself free, and it's gone. It's basically, it's dead. You'd have said it was dead, but then these cilia start beating again, and they flicker to life, and they die, and they flicker to life, and finally comes back to life, pulls itself free, and off it goes.
So I just wanted to show you that because if the fox has a sense of self in escaping from a jaw trap, then did the Stentor have a sense of self? So it's very easy to kind of overstretch the imagination and just say, "Okay, well, obviously I'm reading human emotion into a cell which obviously has none of those things." But to any unbiased eye, it really looked like it's struggling to get free. It finally does get free, and off it goes over there. I don't think in any meaningful sense that it has an understanding that it exists, or that it has a self, or that it has an awareness, or anything. But it certainly struggles to stay alive, and it acts as an entity. And those are two things that I think are perhaps quite important.
I would have left it at that, except that a few years ago, this guy, Luca Turin, came to see me at UCL. Now, Luca Turin is quite notorious to some people, famous to others. He works on the sense of smell and has some quantum vibrational explanations for the sense of smell. And I have nothing to say about that. I just, I don't know. I thought that he wanted to come to see me about the sense of smell, but actually it was about anesthetics that he wanted to talk to me. And the reason he wanted to talk to me was because I work on mitochondria and energy flow in cells. And so he thought I would have something to say about it.
So what he said was that a very wide range of agents, and this is where he immediately gets my attention, ranging from the element Xenon to steroids and all kinds of other things, can act as general anesthetics on all animals, from protozoa. I love the way he calls protozoa animals. But from protozoa, protists, things like the amoeba and the Stentor that I was trying to show you, to man, suggesting that a basic cellular mechanism is involved and biological activity is unrelated to structure. Well, I love this kind of stuff. I mean, suddenly we're talking my language. We're talking about cells, and we're talking about unknown mechanisms of anesthetics. And you can literally make an amoeba go to sleep and stop moving around with the same anesthetic that we can put ourselves to sleep. It says that there's something more fundamental here.
And he went on to say that, well, two things about consciousness. Almost the only thing we know for sure about consciousness is that it is, so to speak, soluble in ether, chloroform, and other solvents. And while it's not known to what extent fruit flies are conscious, and he has a good point there, they are most definitely unconscious when exposed to chloroform or ether. So again, this is a kind of a way into a question that I never thought that I would have any way into this kind of question at all.
So he comments that, well, Xenon, this is the connection with his work on smell, it's an inert gas. It's not supposed to do anything. It's a sphere of electron density. It doesn't really have a shape in a meaningful sense. And pretty much all of pharmacology and biochemistry is about a protein and something binds to that protein, and it depends on the shape and the size, and you know, quite detailed molecular mechanisms. All of biom medicine is kind of built on that as a way of seeing it. And here we have an inert gas that can put you to sleep so that you don't know what happened all the time you were asleep. It's fantastic.
He points out that Xenon does have physics. It can facilitate electron transfer. And he points to examples like Xenon lights, where the light is from electrons crossing a vacuum with Xenon gas in that vacuum. I don't know much about that, so I'm not going to say much. But this is where it becomes quite spooky. I don't know if spooky is the word. He has shown that anesthetics, including Xenon, interfere with the transfer of electrons to oxygen in respiration. In other words, they somewhat inhibit us breathing at the level of cells.
Now, how on earth would they do that? Oxygen. This is liquid oxygen that you can, I hope you can see these things. So, if you pour liquid oxygen between the poles of a magnet, it's magnetic. It will hang there between those poles. The reason it is is that it's got two unpaired electrons. So in school, they'll teach you that there's a double bond in oxygen. Well, there isn't a double bond in oxygen. It's a single bond, and either side there's a single electron. And what that means is it can only accept electrons in the opposite spin state, and it needs to accept two electrons, both in that opposite spin state. And so if it gets them normally in a pair of electrons, it can't accept them. And so, you know, it effectively spits. That's why we exist, really. That's why we don't just go up in flames spontaneously. We don't react spontaneously with oxygen because it's not reactive because it only accepts electrons in a double up state or double down state, or which one it is.
So Xenon and these anesthetics apparently interfere with the spin state of electrons. This is quite new stuff, and I don't know if I really believe it, but it's so exciting that I think I'm going to kind of tentatively believe it for a while and see where it takes us. When electrons pass through a chiral medium, according to a guy called Ne, an Israeli scientist called Ne, they get polarized in the same spin state in the direction of travel. They're all polarized into the same state. Proteins are chiral. They've got chiral amino acids. And so electrons that are transferring through a protein should get polarized into the same spin state. And the anesthetic kind of unpolarizes them, depolarizes them, scatters them back into random states. And that is what slows down respiration.
So what is respiration? Respiration happens in your mitochondria. And the mitochondria, as you come on to it, they were bacteria once upon a time, but we have, you know, hundreds, maybe thousands, sometimes tens of thousands of these things in every cell. This is where respiration is happening inside cells. And they're often drawn like that, and I'm going to say how bad that is in a minute. But all I want you to take in, we're taking stripping electrons from food, and we're transferring them inside a membrane through these giant protein complexes. I'm doing no justice to any of this here. But we have a current of electrons going to oxygen from food. In effect, that current of electrons then is what the anesthetics should be scattering.
And I have a couple of people who've had a look at this in the lab, just out of curiosity, because we have a respirometer and we can measure it. So we've measured it in flies. And this was some of the results that we've got, and we're just really playing here. But this is all the same anesthetic. This is isoflurane. And this is a really high dose of isoflurane. That's, we're doing this just in the respirometer, so we don't really know what the right dose. And it'll take us a while to figure that out. This is a very high dose and will probably kill the flies. But this is 10-fold lower, 10-fold lower, 10-fold lower, 10-fold. These are each 10-fold steps. So it's almost independent of the concentration of the anesthetic, the effect that it's having, which is quite interesting already. So this is slowing down respiration by about 20 to 30% with that. And we found it with other anesthetics as well. And the electrical potential on the membrane, which is being driven by that, actually goes up slightly by 20% or so. That's not supposed to happen. I don't know why that happens. I can think of an idea or two that we'll test, but there is something happening definitely with respiration. So it's not just a quantum physicist who's come up with some crazy ideas that we can't just do a simple experiment in the lab and see that there's some truth in it.
What is it doing? This is the same that you just saw a moment ago with the current of electrons going to oxygen that is pumping protons into this space here. Now, protons, you know, a hydrogen atom is one electron and one proton. So what we're doing in respiration really is pulling the hydrogen out of food, splitting the electrons, we have the current of electrons to oxygen, and the protons are stuffed across the membrane. So now we have, because they've got a positive charge, we've now got a positive charge in this space. So that's why I talked about the electrical membrane potential. We have an increase in this membrane potential as a result of pumping fewer protons. That's why I say it doesn't make sense. But there's something about this which is badly wrong.
This is how mitochondria have been depicted in the textbooks over decades, and it's changing now, but it's something closer to this today. And so, which this is the what they call the cristae membranes, and they're kind of long and thin, and they're closed off at the bottom end. And we have down at the bottom of the cristae what are called dimers. They are beautiful structures of the ATP synthase. You may have heard of ATP, the universal energy currency of the cell. Just think of it as ATP, you stick it in a slot machine and it goes "ding." So these are dimers, and they bend that membrane. So there's a lot of structure to the way that the actual membranes work. And the protons then are being pumped into this space, not into this space necessarily.
So when we try to measure the membrane potential and we try to measure just how much of a charge is on there, we use dyes usually. And this is the kind of dye. It's, you might be able to make out these are all benzene rings joined together more or less. And it's very hydrophobic, but there's also a positive charge. So it's what's called a lipophilic cation. Lipophilic means it can cross the membrane, it likes lipid. So it will cross that membrane. And it's a cation, which means it's got a positive charge, which means it wants to accumulate in this space. We pump the positive charge into here, which means this becomes relatively negative. So it should accumulate. But I always wondered why, why would they cross to get into there, this positively charged space? Well, the fact is they don't. It's not continuous. This is again, just really discovered in the last few years, last year or two. This space is closed off most of the time. So it can cross relatively easily because there is no positive charge there. And these different cristae can sometimes have different electrical potentials associated with them. So there's a lot more going on here than we had realized until recently. And none of the, you know, this is not a change in molecular biology as such. It's still the same processes. It's just that the morphology, the structure of what we're dealing with has changed.
The other interesting thing is about this. These dyes go into this space and report back on the difference between here and here. They don't tell us anything about what the charge is inside there because no one's ever got a dye into there before. So they will come close to it and they will give some indication. Other people over decades have tried to measure directly this electrical potential using a microelectrode. You stick a microelectrode and it goes into this space, and there's not much of a potential there. This is a kind of a dirty secret of bioenergetics that what you actually measure is about 20 millivolts. And what the theory and the calculations say, and what the dyes are trying to tell us, is that actually it's more like 180 or 200 millivolts. There's a bit of a shocking difference. Why is that difference? Well, because the difference between here and here probably is 20 millivolts. The difference between here and here could be almost anything.
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