Highlights from The Vital Question by Nick Lane, chenjin5.com
Highlights from this book
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We see some bacteria with folded internal membranes, others with no cell wall and a modestly dynamic cytoskeleton, yet others with straight chromosomes, or multiple copies of their genome, or giant cell size: all the beginnings of eukaryotic complexity. But bacteria always stop well short of the baroque complexity of eukaryotes, and rarely if ever combine multiple complex traits in the same cell. The easiest explanation for the deep differences between bacteria and eukaryotes is competition. Once the first true eukaryotes had evolved, the argument goes, they were so competitive that they dominated the niche of morphological complexity. Nothing else could compete. Any bacteria that ‘tried’ to invade this eukaryotic niche were given short shrift by the sophisticated cells that already lived there. To use the parlance, they were outcompeted to extinction. We are all familiar with the mass extinctions of dinosaurs and other large plants and animals, so this explanation seems perfectly reasonable. The small, furry ancestors of modern mammals were held in check by the dinosaurs for millions of years, only radiating into modern groups after the dinosaurs’ demise. Yet there are some good reasons to question this comfortable but deceptive idea. Microbes are not equivalent to large animals: their population sizes are enormously larger, and they pass around useful genes (such as those for antibiotic resistance) by lateral gene transfer, making them very much less vulnerable to extinction. There is no hint of any microbial extinction, even in the aftermath of the Great Oxidation Event.
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I mentioned earlier that there are a thousand or more different species of archezoa. These cells are bona fide eukaryotes, which adapted to this ‘intermediate’ niche by becoming simpler, not bacteria that became slightly more complex. Let me stress the point. The niche is viable. It has been invaded on numerous occasions by morphologically simple cells, which thrive there. These simple cells were not outcompeted to extinction by more sophisticated eukaryotes that already existed and filled the same niche. Quite the reverse: they flourished precisely because they became simpler.
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The crucial point is that these two domains, the bacteria and the archaea, are extremely different in their genetics and in their biochemistry, but almost indistinguishable in their morphology. Both types are small simple cells that lack a nucleus and all the other eukaryotic traits that define complex life. The fact that both groups failed to evolve complex morphology, despite their extraordinary genetic diversity and biochemical ingenuity, makes it look as if an intrinsic physical constraint precludes the evolution of complexity in prokaryotes, a constraint that was somehow released in the evolution of eukaryotes. In Chapter 5, I’ll argue that this constraint was released by a rare event – the singular endosymbiosis between two prokaryotes that we discussed in the Introduction. For now, though, let’s just note that some sort of structural constraint must have acted equally on both of the two great domains of prokaryotes, the bacteria and archaea, forcing both groups to remain simple in their morphology throughout an incomprehensible 4 billion years. Only eukaryotes explored the realm of complexity, and they did so via an explosive monophyletic radiation that implies a release from whatever these structural constraints might have been. That appears to have happened just once – all eukaryotes are related.
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Why do viruses, spores and tardigrades not fall to pieces, conforming to the universal decay dictated by the second law of thermodynamics? They might do in the end – if frazzled by the direct hit of a cosmic ray or a bus – but otherwise they are almost completely stable in their non-living state. That tells us something important about the difference between life and living. Spores are not technically living, even though most biologists would classify them as alive, because they retain the potential to revive. They can go back to living, so they’re not dead. I don’t see why we should view viruses in any different light: they too revert to copying themselves as soon as they are in the right environment. Likewise tardigrades. Life is about its structure (dictated in part by genes and evolution), but living – growing, proliferating – is as much about the environment, about how structure and environment interrelate.
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ATP works like a coin in a slot machine. It powers one turn on a machine that promptly shuts down again afterwards. In the case of ATP, the ‘machine’ is typically a protein. ATP powers a change from one stable state to another, like flipping a switch from up to down. In the case of the protein, the switch is from one stable conformation to another. To flip it back again requires another ATP, just as you have to insert another coin in the slot machine to have a second go. Picture the cell as a giant amusement arcade, filled with protein machinery, all powered by ATP coins in this way. A single cell consumes around 10 million molecules of ATP every second! The number is breathtaking. There are about 40 trillion cells in the human body, giving a total turnover of ATP of around 60–100 kilograms per day – roughly our own body weight. In fact, we contain only about 60 grams of ATP, so we know that every molecule of ATP is recharged once or twice a minute.
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The energy of respiration – the energy released from the reaction of food with oxygen – is used to make ATP from ADP and Pi. That’s it. The endless cycle is as simple as this: ADP + Pi + energy ATP We are nothing special. Bacteria such as E. coli can divide every 20 minutes. To fuel its growth E. coli consumes around 50 billion ATPs per cell division, some 50–100 times each cell’s mass. That’s about four times our own rate of ATP synthesis. Convert these numbers into power measured in watts and they are just as incredible. We use about 2 milliwatts of energy per gram – or some 130 watts for an average person weighing 65 kg, a bit more than a standard 100 watt light bulb. That may not sound like a lot, but per gram it is a factor of 10,000 more than the sun (only a tiny fraction of which, at any one moment, is undergoing nuclear fusion).
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Forms of growth that at first glance seem to have little in common, such as photosynthesis in plants, and respiration in animals, turn out to be basically the same in that they both involve the transfer of electrons down such ‘respiratory chains’. Why should this be? Life could have been driven by thermal or mechanical energy, or radioactivity, or electrical discharges, or UV radiation, the imagination is the limit; but no, all life is driven by redox chemistry, via remarkably similar respiratory chains.
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The Great Red Spot of Jupiter is a huge storm, an anti-cyclone several times the size of the earth, which has persisted for at least a few hundred years. Just as the convection cells in a kettle persist for as long as the electric current keeps the water boiling and steam evaporating, all these dissipative structures require a continuous flux of energy. In more general terms, they are the visible products of sustained far-from-equilibrium conditions, in which energy flux maintains a structure indefinitely, until at last (after billions of years in the case of stars) equilibrium is attained and the structure finally collapses. The main point is that sustained and predictable physical structures can be produced by energy flux. This has nothing to do with information, but we’ll see that it can create environments where the origin of biological information – replication and selection – is favoured.
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All living organisms are sustained by far-from-equilibrium conditions in their environment: we, too, are dissipative structures. The continuous reaction of respiration provides the free energy that cells need to fix carbon, to grow, to form reactive intermediates, to join these building blocks together into long-chain polymers such as carbohydrates, RNA, DNA and proteins, and to maintain their low-entropy state by increasing the entropy of the surroundings.
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Right across the entire living world, there are only six different ways of fixing carbon – of converting inorganic molecules such as carbon dioxide into organic molecules.
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The fit between the geochemistry of alkaline vents and the biochemistry of methanogens and acetogens is so close that the word analogous does not do it justice. Analogy implies similarity, which is potentially only superficial. In fact, the similarity here is so close that it might better be seen as true homology – one form physically gave rise to the other. So geochemistry gives rise to biochemistry in a seamless transition from the inorganic to the organic. As the chemist David Garner put it: ‘It is the inorganic elements that bring organic chemistry to life.’
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Four billion years ago, the oceans were probably mildly acidic (pH 5–7), while the hydrothermal fluids were equivalent to today, with a pH of about 9–11. Sharp pH gradients could therefore have been as much as 3–5 pH units in magnitude, which is to say that the difference in proton concentration could have been 1,000–100,000-fold.4 For the sake of argument, imagine that the proton concentration inside the cell is similar to that of the vent fluids. That gives a difference in proton concentration between the inside and the outside, so protons will flow inwards down the concentration gradient. Within a few seconds, though, the influx should grind to a halt, unless the protons that flow in can be removed again. There are two reasons for this. First, the concentration difference swiftly evens out. And second, there is an issue with electrical charge. Protons (H+) are positively charged, but in seawater their positive charge is counterbalanced by negatively charged atoms such as chloride ions (Cl–). The problem is that protons cross the membrane much faster than chloride ions, so there is an influx of positive charge that is not offset by an influx of negative charge. The inside of the cell therefore becomes positively charged relative to the outside, and that opposes the influx of any more H+. In short, unless there is a pump that can get rid of protons from inside the cell, natural proton gradients can’t drive anything. They equilibrate, and equilibrium is death.
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In the broadest of terms, prokaryotes explored the possibilities of metabolism, finding ingenious solutions to the most arcane chemical challenges, while eukaryotes turned their back on this chemical cleverness, and explored instead the untapped potential of larger size and greater structural complexity.
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But now think about a population of bacterial endosymbionts. The same general principles apply – this is just another population of bacteria, albeit a small population in a restricted space. Bacteria that lose unnecessary genes will replicate slightly faster and tend to dominate, just as before. The key difference is the stability of the environment. Unlike the great outdoors, where the conditions are always changing, the cytoplasm of cells is a very stable environment. It may not be easy to get there, or to survive there, but once established, a steady and invariable supply of nutrients can be relied upon. The endlessly circular dynamic of gene loss and gain in free-living bacteria is replaced with a trajectory towards gene loss and genetic streamlining. Genes that are not needed will never be needed again. They can be lost for good. Genomes shrink.
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Transfer the remaining mitochondrial genes to the nucleus, the argument goes, and the cell will die in time, no matter how carefully crafted the genes may be to their new home. The mitochondrial genes must be right there on site, next to the bioenergetic membranes they serve. I’m told the political term is ‘bronze control’.7 In a war, gold control is the central government, which shapes long-term strategy; silver control is the army command, who plan the distribution of manpower or weaponry used; but a war is won or lost on the ground, under the command of bronze control, the brave men or women who actually engage the enemy, who take the tactical decisions, who inspire their troops, and who are remembered in history as great soldiers. Mitochondrial genes are bronze control, decision-makers on the ground.
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How could an error catastrophe be averted? Simply by inserting a barrier in the way, according to Martin and Koonin. The nuclear membrane is a barrier separating transcription from translation – inside the nucleus, genes are transcribed into RNA codescripts; outside the nucleus, the RNAs are translated into proteins on the ribosomes. Crucially, the slow process of splicing takes place inside the nucleus, before the ribosomes can get anywhere near the RNA. That is the whole point of the nucleus: to keep ribosomes at bay. This explains why eukaryotes need a nucleus but prokaryotes don’t – prokaryotes don’t have an intron problem.
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Imagine 100 genes lined up on a chromosome that never recombines. Selection can only ever discriminate the fitness of the whole chromosome. Let’s say there are a few really critical genes on this chromosome – any mutations in them would almost always result in death. Critically, however, mutations on less critical genes become nearly invisible to selection. Slightly harmful mutations can accumulate in these genes, as their negative effects are offset by the big benefits of the few critical genes. As a result, the fitness of the chromosome, and the individual, is gradually undermined. This is roughly what happens to the Y chromosome in men – the lack of recombination means that most genes are in a state of slow degeneration; only the critical genes can be preserved by selection.
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The practical difficulties with hermaphrodites gives away part of the problem: neither partner wants to bear the cost of being the ‘female’. Hermaphroditic species such as flatworms go to bizarre lengths to avoid being inseminated, fighting pitched battles with their penises, their semen burning gaping holes in the vanquished. This is lively natural history, but it is circular as an argument, as it takes for granted that there are greater biological costs to being female. Why should there be? What actually is the difference between male and female? The split runs deep and has nothing to do with X and Y chromosomes, or even with egg cells and sperm. Two sexes, or at least mating types, are also found in single-celled eukaryotes, such as some algae and fungi. Their gametes are microscopic and the two sexes look indistinguishable but they’re still as discriminating as you and me.
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digested. What’s going on here? The
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There is no real competition between cells that are all genetically the same. That’s how our own cells are tamed, so that they cooperate together to form our bodies. All our cells are genetically identical; we are giant clones. But genetically different cells do compete, with some mutants (cells with genetic changes) producing cancer; and much the same happens if genetically different mitochondria mix in the same cell. Those cells or mitochondria that replicate the fastest will tend to prevail, even if that is detrimental to the host organism, producing a kind of mitochondrial cancer. That’s because cells are autonomous self-replicating entities in their own right, and they are always poised to grow and divide if they can. French Nobel laureate François Jacob once said that the dream of every cell is to become two cells. The surprise is not that they often do, but that they can be restrained for long enough to make a human being. For these reasons, mixing two populations of mitochondria in the same cell is just asking for trouble.
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One possible underlying basis is metabolic rate. Even the ancient Greeks appreciated that males are, literally, hotter than females – the ‘hot male’ hypothesis. In mammals such as humans and mice, the earliest distinction between the two sexes is the growth rate: male embryos grow slightly faster than females, a difference that can be measured within hours of conception, using a ruler (but definitely don’t try that at home).
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All this implies that growth rate is the real force behind sexual development, at least in mammals. The genes are just holding the reins, and can easily be replaced over evolution – one gene that sets the growth rate is replaced by a different gene that sets the same growth rate. The idea that males have a faster growth rate corresponds intriguingly to the fact that temperature determines which sex develops in amphibians and reptiles such as alligators.
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Imagine you can fly. Gram per gram, you have more than twice the power of a cheetah in full flight, a remarkable combination of strength, aerobic capacity, and lightness. You have no hope of getting airborne if your mitochondria are not practically perfect. Consider the competition for space in your flight muscles. You need myofibrils, of course, the sliding filaments that produce muscle contraction. The more of these you can pack in, the stronger you will be, as the strength of a muscle depends on its cross-sectional area, like a rope. Unlike a rope, however, muscle contraction has to be powered by ATP. To sustain exertion for much more than a minute requires ATP synthesis on the spot. That means you need mitochondria right there in your muscle. They take up space that could otherwise be occupied by more myofibrils. Mitochondria also need oxygen. That means capillaries, to deliver oxygen and remove waste. The optimal space distribution in aerobic muscle is around a third for myofibrils, a third for mitochondria, and a third for capillaries. That’s true for us, and cheetahs, and humming birds, which have by far the fastest metabolic rates of all vertebrates. The bottom line is we can’t get more power just by accumulating more mitochondria. All this means that the only way birds can generate enough power to remain airborne for long is to have ‘supercharged’ mitochondria, able to generate more ATP per second per unit of surface area than ‘normal’ mitochondria.
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The cost of high aerobic capacity is low fertility. More embryos that could have survived some lesser purpose must be sacrificed on the altar of perfection. We can even see the consequences in mitochondrial gene sequences. Their rate of change in birds is lower than in most mammals (except bats, which face the same problem as birds). Flightless birds, which don’t face the same constraints, have a faster rate of change. The reason that most birds have low rates of change is that they have already perfected their mitochondrial sequence for flight. Changes from this ideal sequence are not readily tolerated, so are typically eliminated by selection. If most change is eliminated, then what remains is relatively unchanging.
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A sluggish flux of electrons in respiration betokens a poor compatibility between the mitochondrial and nuclear genomes. The respiratory chains become highly reduced and leak free radicals. Cytochrome c is released and membrane potential falls. If I were a bird, this combination is the trigger for apoptosis. My offspring would die in embryo again and again. But I’m a rat and I don’t want that. What if, by some biochemical sleight of hand, I ‘ignore’ the free-radical signal that heralds the death of my offspring? I raise the death threshold, meaning I can tolerate more free-radical leak before triggering apoptosis. I gain an immeasurable benefit: most of my offspring survive embryonic development. I become more fertile. What price will I pay for my burgeoning fertility? Certainly I’m never going to fly. And more generally, my aerobic capacity will be limited. The chance of my offspring having an optimal match between mitochondrial and nuclear genes is remote.
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The evolution of two sexes, the germline–soma distinction, programmed cell death, mosaic mitochondria, and the trade-offs between aerobic fitness and fertility, adaptability and disease, ageing and death, all these traits emerge, predictably, from the starting point that is a cell within a cell. Would it all happen over again? I think that much of it would. Incorporating energy into evolution is long overdue, and begins to lay a more predictive basis to natural selection.
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I think we can reasonably conclude that complex life will be rare in the universe – there is no innate tendency in natural selection to give rise to humans or any other form of complex life. It is far more likely to get stuck at the bacterial level of complexity. I can’t put a statistical probability on that. The existence of Parakaryon myojinensis might be encouraging for some – multiple origins of complexity on earth means that complex life might be more common elsewhere in the universe. Maybe. What I would argue with more certainty is that, for energetic reasons, the evolution of complex life requires an endosymbiosis between two prokaryotes, and that is a rare random event, disturbingly close to a freak accident, made all the more difficult by the ensuing intimate conflict between cells. After that, we are back to standard natural selection. We’ve seen that many properties shared by eukaryotes, from the nucleus to sex, are predictable from first principles. We can go much further. The evolution of two sexes, the germline–soma distinction, programmed cell death, mosaic mitochondria, and the trade-offs between aerobic fitness and fertility, adaptability and disease, ageing and death, all these traits emerge, predictably, from the starting point that is a cell within a cell. Would it all happen over again? I think that much of it would
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But that tree has mitochondria too, which work in much the same way as its chloroplasts, endlessly transferring electrons down its trillions upon trillions of respiratory chains, pumping protons across membranes as they always did. As you always did. These same shuttling electrons and protons have sustained you from the womb: you pump 1021 protons per second, every second, without pause. Your mitochondria were passed on from your mother, in her egg cell, her most precious gift, the gift of living that goes back unbroken, unceasing, generation on generation, to the first stirrings of life in hydrothermal vents, 4 billion years ago. Tamper with this reaction at your peril. Cyanide will stem the flow of electrons and protons, and bring your life to an abrupt end. Ageing will do the same, but slowly, gently. Death is the ceasing of electron and proton flux, the settling of membrane potential, the end of that unbroken flame. If life is nothing but an electron looking for a place to rest, death is nothing but that electron come to rest. This energy flux is astonishing and unforgiving. Any change over seconds or minutes could bring the whole experiment to an end. Spores can pull it off, descending into metabolic dormancy from which they must feel lucky to emerge. But for the rest of us … we are sustained by the same processes that powered the first living cells. These processes have never changed in a fundamental way; how could they? Life is for the living. Living needs an unceasing flux of energy. It’s hardly surprising that energy flux puts major constraints on the path of evolution, defining what is possible. It’s not surprising that bacteria keep doing what bacteria do, unable to tinker in any serious way with the flame that keeps them growing, dividing, conquering. It’s not surprising that the one accident that did work out, that singular endosymbiosis between prokaryotes, did not tinker with the flame, but ignited it in many copies in each and every eukaryotic cell, finally giving rise to all complex life. It’s not surprising that keeping this flame alive is vital to our physiology and evolution, explaining many quirks of our past and our lives today. How lucky that our minds, the most improbable biological machines in the universe, are now a conduit for this restless flow of energy, that we can think about why life is the way it is. May the proton-motive force be with you!