In his 2010 book, Life Ascending: The Ten Great Inventions of Evolution, Nick Lane, a biochemist at University College London, explores with eloquence and clarity the big questions of life: how it began, why we age and die, and why we have sex. Lane been steadily constructing an alternative view of evolution to the one in which genes explain it all. He argues that some of the major events during evolutionary history, including the origin of life itself, are best understood by considering where the energy comes from and how it is used. Lane describes these ideas in his 2015 book, The Vital Question: Why Is Life the Way It Is?. Recently Bill Gates called it “an amazing inquiry into the origins of life,” adding, Lane “is one of those original thinkers who make you say: More people should know about this guy’s work.” Nautilus caught up with Lane in his laboratory in London and asked him about his ideas on aging, sex, and death.
The video interview plays at the top of the screen.
Nick Lane: So, I’m Nick Lane. I’m in the department of genetics, evolution, and environment at University College London and I work on really, energetics—how it is that life gets its energy and the consequences of that, which goes right back to the origin of life and all the way forward to why we age and die.
Philip Ball: That’s one of the things, Nick, that struck me most about your work, that it connects what seem to be quite disparate topics in the life sciences—evolution, origins of life, the beginnings of complexity—right through to things like sex and death; and it does so in a way that looks a bit different from the kind of standard Darwinian picture that we have of that—that’s gene based—even though it’s not incompatible with that.
I wondered if we could start with stuff that you know, we can all relate to—sex and death—because they’re a huge part of the culture of complex organisms like us. We expend so much energy on thinking about and doing things connected with both [of] those things. Now in your book, Power, Sex and Suicide you said something quite striking about the two. You said, “When did the drive for sex become punishable by death, and why?” Can you explain what you meant by that?
NL: Sex evolved with complex cells and so if we go back to bacteria and so on, they don’t do sex as we know it. They do something a little bit similar so they swap genes around and that’s essentially what sex is doing: It’s moving genes around and we’re combining them in different ways. But we—as what we call eukaryotic cells, and that includes us, but it [also] includes plants, things like mushrooms, fungi and so on—we all have sex, and that’s in itself quite remarkable.
We don’t really even know what the advantage of sex is. There are lots of ideas, lots of theories out there and some of them are certainly true in some circumstances, others true in other circumstances; but this is something that arose in evolution in this large group of complex cells and it seems to be necessary and it’s linked very tightly to death so in effect, selection is operating on our offspring, which we produce through sex, and the more we focus our resources on producing offspring, the more we kind of focus on sex—the better we will do in evolutionary terms. And so those two forces go together in a way [that] we simply don’t see in bacteria. If I focus all my resources on having sex, then effectively I take resources away from longevity. I take them away from surviving for longer and so I shorten my lifespan, almost deliberately, in evolutionary terms.
PB: At the same time you seem to suggest that what both of these things, sex and death, are about is a kind of hygiene, a way of coping with damage that accumulates in cells. You say in a way, sex, if you like, compensates for damage to genes by swapping them around; death compensates for damage to cells. Our cells are dying all the time because of that. So can you say something about that, what the relation of both of these things is, to the damage that accumulates through living?
NL: Yeah, okay, so death in that sense as an elimination of damaged cells is a very specific process [that] programs cell death and so it’s controlled by the genes and it costs energy and it’s very deliberate; it’s genetically controlled and it’s deliberate and it’s called apoptosis generally in our own cells and cells [that] have become damaged kill themselves and remove themselves and are often replaced with pristine new cells from the stem cell population.
Now sex is doing that at the level of individuals and it’s doing that by recombining genes so you’re bringing new combinations of genes together and what that’s really doing, in terms of natural selection, is it’s increasing the differences between individuals. It’s making you a visible combination of your genes. Technically, it’s increasing the variability in the population and what that does is it aids natural selection to see the differences between people. What natural selection is seeing as the differences between people is reproduction—it’s back to sex again. It’s how many offspring are you leaving, and certainly for men in particular, it’s very biased toward a relatively small proportion of men leaving far more children and you know a relatively large tail having very few if any children so that’s less pronounced in human societies. But if you look at birds or something then it’s really very pronounced, that there’s a big bias in reproductive success in males, and far less of a bias in females in that sense.
PB: Are you saying some males do very well …
PB: … and some do very poorly?
NL: Yes. What that is doing at the level of selection is it’s enabling the best, the best genes if you like, to leave more copies of themselves and what sex is doing is kind of increasing the variants in the population so that you have some very effective males, some fairly ineffective males and it’s giving the opportunity to the more effective males. It’s not a very pleasant way of seeing the world from a human point of view but that’s basically what evolution is doing.
PB: So you can make this explanation for sex in terms of genetics, in terms of why there are Darwinian advantages to it perhaps …
PB: … but one of the things that you’ve been keen to point out is that there’s more to it than that because as you say, you’ve got to consider the energetics of that process, the energetic cost that you invest in these different activities. That, you’ve traced that down to this part of the cell—part of our cells—called the mitochondria and I think we probably ought to spend a little bit of time talking about that. What are the mitochondria and where did they come from?
NL: Well they were bacteria once, pre-living bacteria that got into another cell. There’s still lots of argument about what that other cell actually looked like or was, but almost certainly quite a simple cell, and they became, in the end, the power packs of our cells so all the energy that we need just to live, they’re all coming from, it’s all coming from the mitochondria. And the way that this links into aging and death, is effectively we are, there is a cost to living, there’s a cost to doing everything; and that cost depends on the speed at which we’re living, to some degree at least. So if we are living our lives at a very fast rate, we tend to, in effect, wear out sooner, we don’t see that so much among humans but if you compare the lifespan of say mice or rats that have a very fast metabolic rate, it’s very familiar to people in terms of a fixed number of heartbeats—that’s not strictly true, but there is a very strong relationship between metabolic rate, the rate at which we’re taking in oxygen and burning up food, and lifespan.
Now the way that this relates to sex is, in effect, there’s a switch. So under good conditions we focus most of our resources on sexual maturation and so on—and again I’m speaking not so much about humans as animals in general, but this also goes beyond the animal kingdom. We focus resources on sexual maturation and leaving offspring, but if the conditions are very unfavorable, if we’re starving or something, then there’s a kind of a flip switch that switches from gearing up from sex—for protein synthesis, for bulking up, all those kind of sexual traits—to survival, so battening down the hatches and waiting out the bad times. So this is a genetic switch that really has been very much the focus of most work on aging over the last decade or so and it relates, not exactly to metabolic rate, but to flux to the way in which we are focusing our resources and we’re either focusing them on sex, or we’re focusing them on survival so calorie restriction for example and various genetic mutations which can double or treble the lifespan of very simple organisms, much harder with something as complex as us but they are flipping this switch and they are flipping it away from sexual maturation and towards longevity.
PB: That’s touching on something I wanted to ask you about, this idea of our best strategies that can increase the human lifespan. It seems, and you mention calorie restriction as one of them. It seems that there have been some studies on calorie restriction in mammals that suggest that actually this is a potential way to, in some cases, quite significantly increase lifespan. Is that going to work for humans? Do we know whether it does?
NL: I will say it’s pretty equivocal and even if we look at rhesus monkeys that have been quite long-term studies over decades done on rhesus monkeys, we’ve contradictory results. Some suggest it works quite well, I mean very well, extending lifespan by 30 or 40 percent or so even in rhesus monkeys; others have suggested that the food that they were feeding the control group ad libitum and they can eat what they want as much as they want actually is quite destructive to good health and so they live shorter lives than perhaps they should’ve done. And so there’s a lot of uncertainties in experimental design, and they take a long time, and most humans would not wish to restrict their diet by 40 percent or so their calorie intake. It’s difficult to do that. There are some people who do it and it’s not clear if it actually extends their life.
We’re not necessarily burning any fewer calories; it’s just that we’re burning them in a different way. We tend to, for example, break down proteins and fats and so on from our own body and that produces what’s called ketones and a lot of people go onto things like the ketogenic diet where you’re eating high fat and protein and very little carbohydrate and again it has potentially remarkable effects, not necessarily on lifespan but on the use of the use of nutrients and the flux through cell metabolism. It’s been known for a long time for example, that conditions like epilepsy can be controlled by a ketogenic diet because it restricts the number of excitotoxic attacks that you have in the brain that it has quite profound effects on human function. It does not slow down the metabolic rate, it just shifts it into a kind of different zone.
PB: Okay. We seem to have something like an extraordinary desire for this idea of extending lifespan. There are some researchers who think there are no potential limits to have longer lifespan. What do you think about the real possibilities for human longevity? What’s realistic in the next several decades?
NL: Well there seem to be, in an evolutionary sense, almost no limits. That’s what’s really striking. And it can change very quickly, so opossums for example, that are on an island without predators over the space of five or six generations double their lifespan. There are various supposed exceptions to the idea that metabolic rate correlates with aging so birds, for example, live far longer than they ought to if you just try and extrapolate from their metabolic rate alone. What it seems that they are actually doing is that they have—we’re back to the mitochondria again—they’ve effectively sealed off their mitochondria much better than ours so they don’t leak as many free radicals and this is a correlation. There is very uncertain causality about it but it’s interesting that they leak a lot fewer free radicals than our own mitochondria do. A pigeon for example, will live for about 30 years—up to 30 years—whereas rats, which have the same basal metabolic rate and the same body size, so you [would] predict a similar lifespan, actually only live for three or four years; so that’s a potentially tenfold increase in lifespan, so the possibilities are there. In our own case though, we are limited I would say by our brains.
But if we replace our neurons we’re also rewriting our own experience in the process and cease to be ourselves and I think that’s the real penalty for extending life beyond, if you like, the natural maximal lifespan of a neuron, which is 120 years or thereabouts. That’s where I see the real limit, is how do we prevent our brains from just effectively losing mass over time, losing your neuronal connections, losing synapses, which is where we’re storing memories and experiences and so on, in whatever way you do it.
This was a question that bugged me for a long time, is how is it that the mitochondria in neurons remain functional over so many decades where in virtually every other cell there’s a turnover and the stem cells have got essentially a pristine population of mitochondria in them. It seems that in the case of neurons there is even mitochondrial transfer from the glial cells, which are essentially stem cells surrounding them, into the neurons and those stem cells also are the cause of most brain cancers and so on, so there are issues with having stem cells in the brain just from that point of view as well. But there are all kinds of mechanisms relating to this interaction between the stem cells and glial cells and the neurons themselves that prolong the lifespan of neurons way beyond what we might guess if they were just kind of left to fend for themselves. How far those can be extended to prolong our lifespan further, I don’t know. I’m not sure that there are very many people who really would like to humans to live to 300 or 400 or something; I think what most researchers are trying to achieve is prolonging the health span so that the maximum lifespan remains at 120 years but we don’t spend the last three decades in a very poor state of health.
PB: I wonder if we could talk a little bit about the particular, the specific mechanisms, at the cell level of aging, because you mention free radicals. One hears a lot about free radicals particularly in relation to diet and how we should take things with antioxidants in them to, you know, supposedly mop up free radicals. I’ve been told that actually the mechanisms of aging at the cell level still aren’t very well understood. What do we know about where do these free radicals come from? What’s the problem with them and what can we do about that?
NL: Well there’s a lot to unpack there. The free radical theory of aging, as it was originally stated 50 or 60 years ago, said in effect that the mitochondria produce these reactive forms of oxygen, which are called free radicals. A certain proportion of the oxygen that we are breathing gets released as reactive free radicals that then can damage DNA, mutate DNA; they can damage proteins, they can damage the membranes themselves and over time, that damage builds up into what’s called an error catastrophe, where the cell’s no longer able to support itself.
Now what’s happened over the last couple of decades is that that theory, as originally stated, has been really I would say, comprehensively disproved; it’s not true. The idea then that we can prolong our lives or protect ourselves against age-related diseases, which includes cancer and dementias and so on, by taking large antioxidant supplements—that’s not true either and there have been a lot of large meta-analyses, putting together all the studies that have been done to see, is it true that antioxidants help, and actually the data show quite convincingly that if anything you’re more likely to die sooner if you take large antioxidant supplements. It’s not true for all of them, it’s not true all the time, but on balance this data shows it’s not beneficial, it’s detrimental. And so most gerontologists now I think would tend to discount the free radical theory of aging as being obsolete—possibly a contributor to the process of aging but probably one among many factors and not necessarily causal.
Free radicals signal essentially a stress state in the cell. There are all kinds of subtle distinctions but if something is going wrong, they are behaving a little bit like the smoke detector I suppose, or at least they are the smoke, and the cell is set up to detect the free radical smoke and to react accordingly. So the trouble with antioxidants is that they’re, in effect, disabling the smoke detector and that’s not a good thing to do, and so they will often make things worse.
What happens with the smoke detector is it sets off a stress response and that stress response changes the expression of all kinds of genes, which are protective for the cell, so very often more free radicals produces a stress response that is protective, which battens down those hatches and allows a cell to go on living for longer and the free radicals are very central to that whole mechanism so this is part of this flip switch, if you like, between sex as we were saying and longevity, the cellular stress state is controlled in part by free radicals and so messing around with that signal by throwing antioxidants at it, really doesn’t help.
PB: One of the things I was struck by in your book was you said, “to live longer and to rid ourselves of the diseases of old age, we will need more mitochondria.” Why do we need more?
NL: Well, I mentioned birds and their aerobic capacity. Effectively, what they have done is ramped up the number of mitochondria that they have and that in effect puts less pressure on each individual mitochondria and on and on—all individual cells—and so on; and it’s quite interesting. There’s almost a U-shaped curve, which I find really intriguing. If we think about lifespan and we look to reptiles—so tortoises, they live an awfully long time and the reason they live an awfully long time is that they’ve got an extremely low metabolic rate; they hardly move at all, and so they live a long time just because their cells are not really under any real stress. And at the other end of the spectrum, we see birds, which have a faster metabolic rate than we do. They have a higher body temperature, they consume more oxygen and yet they live longer than mammals because of their size and they seem to have done that by really selecting really high quality mitochondria, in effect, and having lots of them—so they’ve ramped up the function of the entire system. And we are somewhere in the middle, in between.
Our lifespan is relatively short compared to either birds or reptiles for our body mass because we have a fairly high metabolic but we don’t have the high quality mitochondria that birds have. And it’s partly the quality of the individual mitochondria and partly the number of them. So birds have far more, and we have far more as compared to tortoises or something. We’ve got 10 times as many mitochondria in our liver cells, for example, compared to a tortoise. So this seems to be, in my mind at least—and this is not proved so that’s why I say in my mind—selecting for high aerobic capacity seems to increase lifespan. This is over generations and this is one of the reasons why birds, but bats as well, also have very high power requirements to fly, live a long time. Now we also live much longer than gorillas or chimpanzees and again we seem to have been through a phase in early human evolution where we increased our aerobic capacity, our stamina. Whether this was related to chasing gazelles across the plains of Africa or what I don’t know; it’s disputed, but we certainly have a high stamina and capacity to keep on being active compared to other great apes.
PB: What you say makes it sound as though these energetic considerations are really central to how evolution played out and in particular, that the very existence of mitochondria—or the fact that, you know, our cells acquired mitochondria at some stage—seems to have been crucial in all sorts of ways to what followed subsequently. I know it’s been said sometimes that by acquiring mitochondria we didn’t just get these handy energy batteries; it was that process that seemed to make it possible for cells to become multicellular, to have the energy resources to do all kinds of things they couldn’t do before. Is that right? Can you say something about what seems to be that evolutionary moment when mitochondria appeared.
NL: Well, there’s been a very peculiar history of life on earth and we don’t have an agreed explanation for what exactly was going on but essentially, bacteria arose very early—4 billion years ago or thereabouts—and I sometimes show a slide where I have a bacterium in one corner and then I’ve got a kind of a time bar going across it for 4 billion years and at the bottom end we see an identical bacterium because they really have not changed. We see fossils of bacteria three and a half billion years ago and they look the same as modern bacteria and I have a feeling that life on other planets will get stuck in that same kind of rut; it’s probably relatively easy to come up with something like a bacterium and we will see bacteria almost everywhere is my hope and gut feeling; but complex life well that arose only once and it seems to have arisen, we’re fairly certain about this now, in some kind of a genomic … so one cell got inside another one. And that’s certain that that happened—or as certain as we can be in science; what’s very uncertain is what was the host cell that acquired this bacterium and also what was the bacterium that got acquired. We don’t really know what the basis of the relationship was or how likely it was, or what the consequences of it were.
Now I have a fairly strong view on how this might have happened, strong in the sense that I think it’s scientifically more pregnant with possibilities. If the host cell was, as a lot of evidence now points to it, a very simple bacteria-like cell called an archeon, it had nothing. It didn’t have a nucleus to store its DNA and it didn’t have sex; it didn’t go around engulfing other cells and it acquired, by what amounts to some kind of fluke accident, a bacterium that got inside and eventually became the mitochondria. So we have two very simple cells involved and one of them gets inside the other one. Now the reason I say that this is very good from a scientific point of view is it predicts specifically that all of these traits of eukaryotic cells—our own type of complex cell—arose in that context of interaction between the host cell and cells living inside it, which is a pretty unique arrangement. So all of this complexity, and that includes things like sex and it includes things like lifespan and aging and so on—that all arose in that context. And that means then that mitochondria, which are often dismissed essentially as a power pack, they have been really responsible for the evolution of all of this complexity and are still very much central to it all and I think if we’re looking at how can we extend human lifespan and so on, we’ve got to think about it, not from the point of view that here’s a power pack, which is just one of you know thousands of parts in a cell, but this was one of two key players that gave rise to all of that complexity and are still absolutely central to it; and so it’s not so much the metabolic rate as the flux through cells and the way in which mitochondria even control the checkpoint in the cell cycle. Whether a cell is going to make a copy of itself, divide, or die at that point, mitochondria are essential to all of that.
PB: You said that that moment was a fluke and I can’t help wondering because so much seems to stem from that event, whether—maybe this isn’t a question one can really answer at all with science yet but how, to what extent, do you think it really was a fluke? Do you think that this was an event waiting to happen or do you think that it’s if we find bacteria on other worlds that strong chances are they will have remained as bacteria for billions of years?
NL: I think it’s a fluke in the sense that it’s not something that is just going to happen so I think there’s a tendency to—especially among astrobiologists who would like to find intelligent life out there in the universe—there’s a tendency to think that as soon as you have bacteria then natural selection acting in large populations of bacteria will almost inevitably give rise to human intelligence. And so that’s why I’m calling it a fluke. It’s not really that I think that there aren’t environmental conditions that might lend itself to that happening, there probably are, but it’s not something that is going to happen spontaneously or easily. It’s something that is fundamentally rare and uncommon because we have small cells that are not really geared up to taking another cell onboard and they have a cell wall; they’re not geared up to engulfing other cells. What they really want is something that this cell is providing for them. I think again there’s no agreement about this among the people working in the field but it’s a reasonable possibility.
Let’s say, for the sake of argument, that this cell is producing something that this cell needs and so they snuggle up and the more close you are together, the more of this substrate you’re able to get from that cell. Now if you’re able to kind of grow around it, you’ll get more and more and so there are selection pressures and evolutionary reasons to see cells snuggling up together and actually we see that all the time now. It’s become very, very clear that bacteria for example, very often have a very strict stoichiometry and form little balls of cells with fixed numbers of cells in those balls and they’re providing services for each, but they don’t get inside each other. That’s fundamentally uncommon and for it to work, it requires almost certainly, gene transfer from one to the other and for that gene … that gene transfer goes on all the time anyway but it’s a pretty random process and it requires probably several hundred genes and the right several hundred genes to be transferred; so there are obstacles to it happening on a regular basis. So fluke, or freak, accident is probably actually too strong a term.
There was intriguingly, a few years ago a discovery down in a deep sea trench on a hydrothermal vent off the coast of Japan, a cell, which is not obviously a complex eukaryotic cell but neither is it a bacterium—it’s somewhere between the two—and it’s got bacteria living inside it so it looks as if this perhaps is recapitulating the evolution of complexity at an extremely low population density. These guys have been searching for 15 years and they found one cell in that time after tens of thousands of them that they’d looked for; but still, if there’s one there now there must have been thousands or millions of evolutionary time so it’s not necessarily trying to rule out complex life elsewhere—chances are it will happen for similar reasons but it’s certainly not an inevitable progression toward complex intelligent life.
PB: Right. Thinking about processes like this, like the development of complex life in energetic terms, clearly that gives us some new possibilities for thinking about the consequences of that, how it might have happened; but this focus on energetics is something you’ve taken even further back isn’t it? That you’ve looked at what the role of energy is in the origin of life. Can you say something about that issue, what role you see energetics playing in the origin of life?
NL: Well, it actually emerges very naturally from considerations of what mitochondria do for us and the very peculiar way in which they actually generate energy so what we are actually doing when we are respiring, is we’re stripping electrons from food and we’re passing them down a little wire inside a membrane to oxygen. So we’ve a current of electrons flowing from food to oxygen inside a membrane and that current of electrons is powering the extrusion of protons. So these are just the nucleus of hydrogen atoms, so the about the simplest kind of chemical particle that there is, and this is going on right across all of life.
So what we have is something very analogous to a hydroelectric power scheme. We’ve effectively got a lot of protons on one side of the membrane, very few on the other side of the membrane, so we’ve got this difference in, it’s partly charged because protons have a charge and it’s partly concentration—it’s called the proton motive force. You could think of it almost like the force in Star Wars or something. It’s a force field that surrounds cells and it drives absolutely everything and that’s what’s going on in our own mitochondria, in our own cells.
But what’s become very apparent over the last few decades is that it applies as well as how photosynthesis works in the same way or bacteria do exactly the same thing. This entire extra domain of life, the archaea that look a lot like bacteria but they’re very different in their genetics, but they also do this, it’s shockingly as universal across life as a genetic code itself. And that implies that it arose very early but we then have this paradox that the machinery is quite complex and if you talk about this machinery for generating these proton gradients and then … it seems to be very early and yet it seems too complex to be very early, so there’s a paradox there and I think like many scientists, any paradox is an interesting thing to sniff around and try and work out and it turns out that there is an environment, a particular type of hydrothermal vent, which has natural proton gradients across inorganic barriers and that’s the kind of setting that might be the origin of this energy flow in life and why it went that particular way rather than some other way.
So they become really almost philosophical astrobiological questions. Did life have to be that way? Could it be some other way? Is it really that way? And that comes down to experiment and that’s actually what this reactor is right behind us; we’re trying to do experiments to simulate the conditions in these vents to see, does the structure of having a different proton concentration across a barrier, drive the kind of organic chemistry that we see in life? And the answer seems to be working but not so well that we can get really excited yet.
PB: Finally, I just want to ask something that’s more a sociological question about all of this because I’ve been struck by how sometimes when I’ve looked back at nature in the 1920s—the science journal, Nature in the 1920s and 1930s—say, there’s quite a big focus on bioenergetics there. They seem to go away subsequently. I guess with the emergence of genetics as a molecular science, I just wondered whether you had any thoughts for why that happened; why bioenergetics seemed to have sort of fallen out of favor and also whether you think it’s coming back into favor?
NL: Well I think that as Peter Medawar said, science is the art of the soluble and I think in the 1930s, it seemed soluble. Energetics was something that … people were just realizing that ATP was more or less universal. The processes like glycolysis and fermentation, which is producing ATP that you find in yeast and you find in humans, but you can also find it in bacteria, and it was chemistry that could be understood. This process of proton gradients was completely separate from that and there was a period of acrimony in the 1960s and 1970s known as the oxphos wars—so oxphos for oxidative phosphorylation, which is the mechanism of respiration. During that time, Peter Mitchell, among others, worked out basically how respiration worked and since then, since we’ve basically all agreed that this is how it works, the principles of energetics seemed to be understood now. Their very early evolution is very hard to get at and so there hasn’t been very much interest in it; where the real interest has been is working out the structure of the proteins that are actually pumping protons across and that’s still going on and you still see Nature papers on that kind of subject but that structural biology it’s not really energetics; it’s about how the proteins actually function.
So it’s become a backwater, I would say, yes and that’s also because of DNA. It’s very easy to understand why that’s become so beguiling and now we have so many genome sequences that the amount of data that we have to study is just enormous. There’s an assumption I suppose, or a hope, that patterns will emerge from all of that data and explain why life evolved the way that it did. I personally think that that’s overlooking the whole energetic basis of how DNA is replicated in the first place. What’s the flow of energy which underpins living? It’s being neglected; not by everybody of course but relative to the number of people working on genes, it’s being seriously neglected and, yes I would hope that there will be some renaissance in thinking about things, life, from the point of view of energy flow.
PB: Well you’ve, I think given a very convincing case that allows you to think about a huge range of aspects of life, so we’ll have to see what happens. Nick, thanks very much indeed.
NL: Thank you, a pleasure.