Life force

After the depredations of Douglas Adams and Monty Python, it is a surprise that anyone can write about the meaning of life with a straight face these days. Life is not, after all, the sort of thing that has a meaning, any more than gravity or time does. Words have meanings, stories have meanings, and as humans are creatures of narrative our individual lives, too, can have meanings gleaned from or thrust upon them. It is hard, though, for any non-religious person to see life in general as a thing that should have a meaning, any more than it is easily seen as something that might have a colour or a scent. Meaning must surely rest upon an intention to communicate, and uncreated life lacks such intentions.

That said, there are meanings in life. When the structure of DNA was discovered, it was clear that the sequence of bases that tied the long molecules into double helices could have a meaning: it could define the sequence of amino acids in a protein. Ever since, life as revealed by molecular biology has been seen largely in terms of information—its storage, replication and translation into physical forms. And this has also tended to mask the fact that life, as well as being concerned with information, is also—and just as fundamentally—concerned with energy, its acquisition and its conversion into useful forms.

In part, this is because it is easier and more appealing to talk about the meanings of genes than the importance of energy transduction systems. Genes sound like graspable things—peas on an abacus of heredity—and come with a convenient infinite-staircase icon. And their nature and disposition matter to us. A gene is, in the phrase with which Gregory Bateson once defined the concept of information, a difference that makes a difference. As a result, it has been relatively easy for a popular science culture to arise in which all that is ever said about the wonders of modern biology is couched in the language of genes. Genes, depositories of meaning within life, become mistaken for the great meaning that isn't there.



Nick Lane's magnificent new book Power, Sex, Suicide: Mitochondria and the Meaning of Life acts, in part, as an antidote to the gene-centric view of life in which much biology and a great deal of its transmission to the public is entangled. Cells convert the energy they take in from the environment into a form that can be used to drive chemical reactions by a fundamental mechanism, which, Lane shows us, has a central relevance to questions that range from the astrobiological—how common is complex life in the universe?—to the fundamental—how did life begin?—to the world-historical—how realistically can we imagine lengthening human life expectancy by a century or two? And he draws these disparate questions into a single narrative in which the way cells use energy becomes, if not the meaning of life, a sadly neglected aspect of it.

The modern story of life's use of energy dates back to a discovery made in the early 1960s by Peter Mitchell, a British biochemist who cultivated a resemblance to Beethoven and spent most of his career at a research foundation he set up for himself in Cornwall. Thanks to the hegemony enjoyed by the information-based view of life, Mitchell is a far less well-known figure than Jim Watson, Rosalind Franklin or his Cambridge contemporary Francis Crick. But his discovery was a considerably greater intellectual feat than theirs. Leslie Orgel, a friend and colleague of Crick's, has described Mitchell's discovery as the first biological breakthrough since Darwin's—"as counterintuitive as those of, say, Einstein, Heisenberg and Schrödinger," and it is hard to disagree.

To understand Mitchell's achievement, we need a to know a bit of molecular biology. The molecular machinery on which animal and plant cells depend is centred on a molecule called adenosine triphosphate (ATP). Proteins that need energy to get their jobs done snap off a phosphate group from an ATP molecule which releases the energy required. The rate at which this goes on is quite remarkable; every day your body uses more than its own weight in ATP. So every day your body also has to make the same amount of the stuff, using adenosine diphosphate, phosphate ions, and the energy released by reacting foodstuffs with oxygen by means of respiration. This energy is released as electrons that have been pulled off food molecules which are passed down a chain of proteins called cytochromes. (They end up stuck to an oxygen atom, which is turned into a water molecule in the process.)

Peter Mitchell set out to discover how the energy that was given up when electrons were passed from cytochrome to cytochrome in the respiratory electron-transfer chain was used to make ATP. The assumption when he started was that the energy was at all times associated with molecules and chemical bonds; that the cytochromes stored the energy of the electrons passing through in the chemical bonds of some unknown "high-energy intermediate" molecule from which it was later released in reactions that formed ATP. Mitchell's genius was in rising above the molecular level and seeing the possibility of something much stranger and grander.

The cytochromes which make up the cell's electron transfer chains are proteins embedded in a membrane within the cell like rivets down the seams of heavy-duty denim. Mitchell decided that the key to the problem lay in the way things moved back and forth across that membrane. The cytochromes, he argued, used the electrons' energy to pump hydrogen ions (protons) from the inside of the membrane to the outside. This pumping increased the concentration of protons outside, and also build up an electric potential across the membrane itself. Both these factors would make the protons on the outside eager to get back in. As they did so, they drove reactions that created ATP, reactions catalysed by another protein stuck in the membrane, ATPase, which acted as a channel for the protons' return.

As an analogy, consider systems like those at Dinorwig in Wales and Ben Cruachan in Scotland that store energy by pumping water uphill into reservoirs before letting it rush back down through turbines, thus generating electricity. In Mitchell's system the protons are the water, the cytochromes are the pumps, the difference in charge and concentration across the membrane is the height of the reservoir and the ATPase is the turbine. Like the hydroelectric reservoir systems, Mitchell's biological system doesn't create energy, it stores it. But it also bridges the gap between two different forms of energy, the local energy of the flowing electrons and the storable, transportable energy in ATP.

Mitchell's system is not unique to the reactions involved in respiration. Photosynthesis, which is in global terms more or less the antithesis of respiration, pushes protons across membranes in just the same way. The difference is that the photosynthetic electron-transfer chain is fuelled by sunlight instead of food. And though ATP production is the purpose of respiration in plants and animals, in bacteria proton gradients across membranes are sometimes used directly, driving the systems that import food into the cell and powering the flagellae that drive the cells from place to place. The use of electron transfer chains to produce proton gradients is a basic feature of all earthly organisms; Mitchell's insight is as fundamental to understanding life as the knowledge that genes are stored in DNA. It's just that, because it involves a variety of different proteins, a flow of electrons, a membrane, an electric potential, the topology of the cell and differences in the concentration of protons, it is rather harder to get your head around than the idea of a sequence of letters. And it can't answer everyday questions, such as the identity of George Grundy's father.

It does, however, illuminate some profound questions about why life on earth is as it is. Mike Russell of Glasgow University has argued that the early stages of life, before the development of organic cells, must have been powered by similar energy-transducing reactions taking place in an inorganic setting, such as the tiny bubbles of iron sulphide produced in some hydrothermal systems, and Lane makes this view of the origin of life quite compelling. But perhaps his most impressive arguments bear on a question almost as puzzling as life's origins but less frequently raised: its capacity for complexity. More specifically, why are all bacteria simple, while lots of other stuff isn't?

On the earth, cells come in two forms. There are prokaryotic cells—the bacteria and a family of morphologically similar, if biochemically distinct, creatures called archaea—and eukaryotic cells, from which animals, plants, fungi and algae are made. The difference between these two types is normally explained in terms of the nucleus: eukaryotic cells have a nucleus in which to carry their large and impressive genomes, while prokaryotic cells leave their smaller genomes lying around higgledy-piggledy. Eukaryotes have impressively shelved genomic libraries; prokaryotes a few books on the coffee table.

Another difference, though, is in energy transduction. Prokaryotes mostly keep their electron-transfer chains in membranes wrapped around the outside of the cell; they pump protons out into a space between the cell proper and its encompassing wall. Eukaryotes do their respiration inside a structure called a mitochondrion. A mitochondrion is a bag within a bag; its electron-transfer chains pump hydrogen ions out over the membrane separating the inner from the outer bag, and its ATPase molecules let them back into the inner sanctum. Both mitochondria and chloroplasts (which house the photosynthetic electron-transfer chains in plants and algae) are descended from once free-living bacteria that eukaryotic cells incorporated into their internal economies.

In traditional accounts of the eukaryotic cell, mitochondria are seen as important—in most cells they provide the vast bulk of the ATP—but peripheral. Lane's account, in a bracingly and convincingly revisionist way, puts the mitochondrion at the centre of what it is to be eukaryotic. The amount of energy a creature needs in order to reproduce will be roughly proportional to its volume, since it is the volume that has to be doubled in reproduction. But the amount of energy a membrane system like that in bacteria can produce will depend on the creature's surface area. When things get bigger, their volume increases quicker than their surface area, so bigger bacteria will take longer to produce enough energy to reproduce themselves than smaller ones will. Evolution is not kind to bacteria that reproduce more slowly than their neighbours. So unless bacteria can develop a way to have more and more of Mitchell's membranes the bigger they get, evolution will keep them small and simple—as it has done for four billion years.

For cells to get big and ambitious, they need a way of increasing their energy capacity along with their volume. The mitochondria are a solution to this problem. If a cell doubles its volume, it can increase its energy in line with its needs by simply doubling its complement of mitochondria. The mitochondria are the infrastructure that make big cells possible, and thus permit the other superstructural appurtenances of the eukaryotes, such as nuclei and big genomes, which take a lot of energy to copy.

But this solution raises a problem in its turn. The flow of electrons along an electron-transfer chain is a sensitive matter; it can easily stall or run dry. To keep it balanced you need to be able to produce the relevant new cytochrome and ATPase components precisely when and where they are needed. A single nuclear genome could never hope to keep tabs on all the glitches and thrown gaskets in all its mitochondria, never mind despatching new proteins to each individual mitochondrion as and when they were needed. To get around this problem, each mitochondrion has a genome of its own—one just big enough to keep incipient kinks out of the electron-transfer chain which is the core of the mitochondrion's being.

Mitochondria have their own genomes because the bacteria from which they are descended had their own genomes. After the initial fusion that created the first eukaryote, this bacterial genome was whittled away, some of it discarded, other parts sequestered into the nucleus, until just the genes needed to regulate the crucial electron flow were left. In humans there are more than 20,000 genes in the nucleus, and just 37 in the mitochondria. This is normally seen as an interesting quirk of history with some pleasing practical upshots (the DNA in mitochondria is well suited to studies of ancestry). Lane makes a strong case that this whittling is, in fact, the only way to create a system in which subsidiary genomes can control local processes in the cell. Evolution, a blind process, is much more likely to hit on the answer by chipping away at an existing genome, and being punished when it chips too far, than by creating random subsidiary genomes from the bottom up.

Lane speculates that this may be a crucial constraint on complex life throughout the universe. It is often tacitly assumed that though complex cells on the earth happened to come about through fusion, they might in principle have evolved more straightforwardly from smaller ancestors; indeed, it is often assumed that eukaryotic cells got big before they co-opted their mitochondria. Examining the question in terms of the need for local control over a distributed energy system, though, makes that seem unlikely. The likelihood of complex cells arising from simple ones depends on two of them fusing in body and genome in just the right way. That this doesn't happen every day can be seen from the fact that on earth complex cells seem not to have arisen until simple cells had been around for perhaps 2bn years. If the earth was precocious in this respect, then on many planets the necessary union may simply never take place, with life remaining simple and bacterial.

Lane goes on to argue that the presence of mitochondria may have spurred the development of sexual reproduction. Here his argument is less compelling, but the subsequent argument that the presence of mitochondria accounts for the fact that procreative sex takes place between different genders is well established. If the gametes that meet to form a zygote both brought their own mitochondria to the party, the two complements of mitochondria would interfere with each other, competing for the right to get into the next gamete somewhere down the line. To avoid this, natural selection developed systems in which only one gamete—the egg—gets to keep its mitochondria. This is the root of the difference between sperm and egg, which in turn drives much of the rest of the difference between males and females. This was enough for Lane to choose to follow "power" with "sex" in his attention-grabbing title.

The title's "suicide" refers to the suicide of cells—the orderly process of "programmed cell death," or apoptosis, by which cells lay down their lives for the good of the organism as a whole. (Lane, in an uncharacteristic piece of pedantry, asks us to keep the second p in apoptosis silent out of respect for the word's Greek roots. If he convinces me he is happy talking of helico'ters, I may consider it.) The system of self-slaughter is vital to the development and maintenance of large complex organisms and it makes considerable use of the mitochondria, which provide the triggers for the process.

Apoptosis leads on to the question of old age. When the respiratory electron-transfer chain stalls it becomes a source of free radicals, highly reactive compounds that damage any other chemical in the neighbourhood. The mitochondria bear the brunt of this, and tend to get clapped out as life goes on; mitochondrial genes get damaged far faster than nuclear genes do. This can lead, among other things, to more apoptosis than one would wish, and less leaky mitochondria may allow people to live longer. In Japan, people who have a gene that makes one of their cytochromes less likely to leak electrons are half as likely as the population at large to end up in hospital in the second half of their life; two thirds of Japan's centenarians benefit from this robust cytochrome.

The damage done by free radicals is a much more complex issue than it might appear, not least because the radicals are used as a signal by the systems that regulate electron-transfer; without leaks, the system is harder to monitor and control. But there is evidence that the sensing system might be improved: birds live far longer than mammals of the same weight, and their unleaky mitochondria have a lot to do with that. And if we can understand why all this is, we are in a position to redesign mitochondria in ways natural selection would never dream of. Maybe a way could be found to store a reference template for the mitochondrial genome safely in the nucleus, sending out fresh imprints of it to the mitochondria as their old copies got dog-eared and tattered. That would require the genetic alteration of unborn humans, to which there is understandable opposition. But it might also double or triple life expectancy, for which there may be a countervailing enthusiasm, especially if world population starts to decline.

Lane's book is a fascinating synthesis of ideas—including, but not limited to, those of Bill Martin, John Allen and Mike Russell—at and around the forefront of science, pulled together into a broadly convincing narrative that provides a fresh angle on a wide range of biological topics. In this it is reminiscent of Richard Dawkins's The Selfish Gene; it is carried off with less metaphoric verve, but it has the same freshness to it, the bliss-it-was-in-that-dawn. If someone does start work on redesigning the mitochondrion, this book should be either inspiration or primer. It is not perfect. For example, there seemed to me to be too much about power laws and metabolic rates, an area where rather too much of the flux in the field gets through to the reader. But in general it is a most excellent book, one I suspect it will be worth rereading for some time to come.

The most significant obstacle in its way is that the vast ranks of readers with no previous grounding in molecular biology may find it hard going; but this, frankly, is their fault, not Lane's. Molecular biology has allowed us to see into the workings of life with an unmatched acuity; and what's more, at the sort of level needed to read a book like this, it's really not that hard. One would have to be fairly extreme to think that the drama, music and novels of the late 20th century rank with the finest history has had to offer; but its biological science, I think, could be justified in such a boast. At best, to ignore such wonders is to give in to the sort of self-doubt that unreasonably excludes many of us from exciting realms of intellect and imagination: at worst it is blinkered philistinism. Books like Lane's cannot give life a meaning, but they can explain its workings, fabric and inner logic with a previously unapproachable coherence. That is more than enough to make them worth any effort involved in the reading.