Clandestine Rulers of the World
A mitochondrion—one of many tiny power-houses within cells that control our lives in surprising ways
Mitochondria are tiny organelles inside cells that generate almost all our energy in the form of ATP. On average there are 300-400 in every cell, giving ten million billion in the human body. Essentially all complex cells contain mitochondria. They look like bacteria, and appearances are not deceptive: they were once free-living bacteria, which adapted to life inside larger cells some two billion years ago. They retain a fragment of a genome as a badge of former independence. Their tortuous relations with their host cells have shaped the whole fabric of life, from energy, sex, and fertility, to cell suicide, ageing, and death.
A mitochondrion—one of many tiny power-houses within cells that control our lives in surprising ways
Mitochondria are a badly kept secret. Many people have heard of them for one reason or another. In newspapers and some textbooks, they are summarily described as the 'powerhouses' of life—tiny power generators inside living cells that produce virtually all the energy we need to live. There are usually hundreds or thousands of them in a single cell, where they use oxygen to burn up food. They are so small that one billion of them would fit comfortably in a grain of sand. The evolution of mitochondria fitted life with a turbo-charged engine, revved up and ready for use at any time. All animals, the most slothful included, contain at least some mitochondria. Even sessile plants and algae use them to augment the quiet hum of solar energy in photosynthesis.
Some people are more familiar with the expression 'Mitochondrial Eve'—she was supposedly the most recent ancestor common to all the peoples living today, if we trace our genetic inheritance back up the maternal line, from child to mother, to maternal grandmother, and so on, back into the deep mists of time. Mitochondrial Eve, the mother of all mothers, is thought to have lived in Africa, perhaps 170000 years ago, and is also known as 'African Eve'. We can trace our genetic ancestry in this way because all mitochondria have retained a small quota of their own genes, which are usually passed on to the next generation only in the egg cell, not in the sperm. This means that mitochondrial genes act like a female surname, which enables us to trace our ancestry down the female line in the same way that some families try to trace their descent down the male line from William the Conqueror, or Noah, or Mohammed. Recently, some of these tenets have been challenged, but by and large the theory stands. Of course, the technique not only gives an idea of our ancestry, but it also helps clarify who were not our ancestors. According to mitochondrial gene analysis, Neanderthal man didn't interbreed with modern Homo sapiens, but was driven to extinction at the margins of Europe.
Mitochondria have also made the headlines for their use in forensics, to establish the true identity of people or corpses, including several celebrated cases. Again, the technique draws on their small quota of genes. The identity of the last Russian Tzar, Nicholas II, was verified by comparing his mitochondrial genes with those of relatives. A 17-year-old girl rescued from a river in Berlin at the end of the First World War claimed to be the Tzar's lost daughter Anastasia, and was committed to a mental institution. After 70 years of dispute, her claim was finally disproved by mitochondrial analysis following her death in 1984.
More recently, the unrecognizable remains of many victims of the World Trade Center carnage were identified by means of their mitochondrial genes. Distinguishing the 'real' Saddam Hussein from one of his many doubles was achieved by the same technique. The reason that the mitochondrial genes are so useful relates partly to their abundance. Every mitochondrion contains
5 to 10 copies of its genes. Because there are usually hundreds of mitochondria in every cell, there are many thousands of copies of the same genes in each cell, whereas there are only two copies of the genes in the nucleus (the control centre of the cell). Accordingly, it is rare not to be able to extract any mitochondrial genes at all. Once extracted, the fact that all of us share the same mitochondrial genes with our mothers and maternal relatives means that it is usually possible to confirm or disprove postulated relationships.
Then there is the 'mitochondrial theory of ageing', which contends that ageing and many of the diseases that go with it are caused by reactive molecules called free radicals leaking from mitochondria during normal cellular respiration. The mitochondria are not completely 'spark-proof'. As they burn up food using oxygen, the free-radical sparks escape to damage adjacent structures, including the mitochondrial genes themselves, and more distant genes in the cell nucleus. The genes in our cells are attacked by free radicals as often as 10 000 to 100 000 times a day, practically an abuse every second. Much of the damage is put right without more ado, but occasional attacks cause irreversible mutations—enduring alterations in gene sequence—and these can build up over a lifetime. The more seriously compromised cells die, and the steady wastage underpins both ageing and degenerative diseases. Many cruel inherited conditions, too, are linked with mutations caused by free radicals attacking mitochondrial genes. These diseases often have bizarre inheritance patterns, and fluctuate in severity from generation to generation, but in general they all progress inexorably with age. Mitochondrial diseases typically affect metabolically active tissues such as the muscle and brain, producing seizures, some movement disorders, blindness, deafness, and muscular degeneration.
Mitochondria are familiar to others as a controversial fertility treatment, in which the mitochondria are taken from an egg cell (oocyte) of a healthy female donor, and transferred into the egg cell of an infertile woman—a technique known as 'ooplasmic transfer'. When it first hit the news, one British newspaper ran the story under the colourful heading 'Babies born with two mothers and one father'. This characteristically vivid product of the press is not totally wrong—while all the genes in the nucleus came from the 'real' mother, some of the mitochondrial genes came from the 'donor' mother, so the babies did indeed receive some genes from two different mothers. Despite the birth of more than 30 apparently healthy babies by this technique, both ethical and practical concerns later had it outlawed in Britain and the US.
Mitochondria even made it into a Star Wars movie, to the anger of some aficionados, as a spuriously scientific explanation of the famous force that may be with you. This was conceived as spiritual, if not religious, in the first films, but was explained as a product of 'midichlorians' in a later film. Midichlorians, said a helpful Jedi Knight, are 'microscopic life forms that reside in all living cells. We are symbionts with them, living together for mutual advantage. Without midichlorians, life could not exist and we would have no knowledge of the force.' The resemblance to mitochondria in both name and deed was unmis-takeable, and intentional. Mitochondria, too, have a bacterial ancestry and live within our cells as symbionts (organisms that share a mutually beneficial association with other organisms). Like midichlorians, mitochondria have many mysterious properties, and can even form into branching networks, communicating among themselves. Lynn Margulis made this once-controversial thesis famous in the 1970s, and the bacterial ancestry of mitochondria is today accepted as fact by biologists.
All these aspects of mitochondria are familiar to many people through newspapers and popular culture. Other sides of mitochondria have become well known among scientists over the last decade or two, but are perhaps more esoteric for the wider public. One of the most important is apoptosis, or programmed cell death, in which individual cells commit suicide for the greater good—the body as a whole. From around the mid 1990s, researchers discovered that apoptosis is not governed by the genes in the nucleus, as had previously been assumed, but by the mitochondria. The implications are important in medical research, for the failure to commit apoptosis when called upon to do so is a root cause of cancer. Rather than targeting the genes in the nucleus, many researchers are now attempting to manipulate the mitochondria in some way. But the implications run deeper. In cancer, individual cells bid for freedom, casting off the shackles of responsibility to the organism as a whole. In terms of their early evolution, such shackles must have been hard to impose: why would potentially free-living cells accept a death penalty for the privilege of living in a larger community of cells, when they still retained the alternative of going off and living alone? Without programmed cell death, the bonds that bind cells in complex multicellular organisms might never have evolved. And because programmed cell death depends on mitochondria, it may be that multicellular organisms could not exist without mitochondria. Lest this sound fanciful, it is certainly true that all multicellular plants and animals do contain mitochondria.
Another field in which mitochondria figure very prominently today is the origin of the eukaryotic cell—those complex cells that have a nucleus, from which all plants, animals, algae, and fungi are constructed. The word eukaryotic derives from the Greek for 'true nucleus', which refers to the seat of the genes in the cell. But the name is frankly deficient. In fact, eukaryotic cells contain many other bits and pieces besides the nucleus, including, notably, the mitochondria. How these first complex cells evolved is a hot topic. Received wisdom says that they evolved step by step until one day a primitive eukaryotic cell engulfed a bacterium, which, after generations of being enslaved, finally became totally dependent and evolved into the mitochondria. The theory predicted that some of the obscure single-celled eukaryotes that don't possess mitochondria would turn out to be the ancestors of us all—they are relics from the days before the mitochondria had been 'captured' and put to use. But now, after a decade of careful genetic analysis, it looks as if all known eukaryotic cells either have or once had (and then lost) mitochondria. The implication is that the origin of complex cells is inseparable from the origin of the mitochondria: the two events were one and the same. If this is true, then not only did the evolution of multicellular organisms require mitochondria, but so too did the origin of their component eukaryotic cells. And if that's true, then life on earth would not have evolved beyond bacteria had it not been for the mitochondria.
Another more secretive aspect of mitochondria relates to the differences between the two sexes, indeed the requirement for two sexes at all. Sex is a well-known conundrum: reproduction by way of sex requires two parents to produce a single child, whereas clonal or parthenogenic reproduction requires just a mother; the father figure is not only redundant but a waste of space and resources. Worse, having two sexes means that we must seek our mate from just half the population, at least if we see sex as a means of procreation. Whether for procreation or not, it would be better if everybody was the same sex, or if there were an almost infinite number of sexes: two is the worst of all possible worlds. One answer to the riddle, put forward in the late 1970s and now broadly accepted by scientists, if relatively little known among the wider public, relates to the mitochondria. We need to have two sexes because one sex must specialize to pass on mitochondria in the egg cell, while the other must specialize not to pass on its mitochondria in the sperm. We'll see why in Chapter 6.
All these avenues of research place mitochondria back in a position they haven't enjoyed since their heyday in the 1950s, when it was first established that mitochondria are the seat of power in cells, generating almost all our energy. The top journal Science acknowledged as much in 1999, when it devoted its cover and a sizeable section of the journal to mitochondria under the heading 'Mitochondria Make A Comeback'. There had been two principal reasons for the neglect. One was that bioenergetics—the study of energy production in the mitochondria—was considered to be a difficult and obscure field, nicely summed up in the reassuring phrase once whispered around lecture theatres, 'Don't worry, nobody understands the mitochondriacs.' The second reason related to the ascendancy of molecular genetics in the second half of the twentieth century. As one noted mitochondriac, Immo Schaeffler, noted: 'Molecular biologists may have ignored mitochondria because they did not immediately recognize the far-reaching implications and applications of the discovery of the mitochondrial genes. It took time to accumulate a database of sufficient scope and content to address many challenging questions related to anthropology, biogenesis, disease, evolution, and more.'
I said that mitochondria are a badly kept secret. Despite their newfound celebrity, they remain an enigma. Many deep evolutionary questions are barely even posed, let alone discussed regularly in the journals; and the different fields that have grown up around mitochondria tend to be pragmatically isolated in their own expertise. For example, the mechanism by which mitochondria generate energy, by pumping protons across a membrane (chemiosmosis), is found in all forms of life, including the most primitive bacteria. It's a bizarre way of going about things. In the words of one commentator, 'Not since Darwin has biology come up with an idea as counterintuitive as those of, say, Einstein, Heisenberg or Schrodinger.' This idea, however, turned out to be true, and won Peter Mitchell a Nobel Prize in 1978. Yet the question is rarely posed: Why did such a peculiar means of generating energy become so central to so many different forms of life? The answer, we shall see, throws light on the origin of life itself.
Another fascinating question, rarely addressed, is the continued existence of mitochondrial genes. Learned articles trace our ancestry back to Mitochondrial Eve, and even use mitochondrial genes to piece together the relationships between different species, but seldom ask why they exist at all. They are just assumed to be a relic of bacterial ancestry. Perhaps. The trouble is that the mitochondrial genes can easily be transferred en bloc to the nucleus. Different species have transferred different genes to the nucleus, but all species with mitochondria have also retained exactly the same core contingent of mitochondrial genes. What's so special about these genes? The best answer, we'll see, helps explain why bacteria never attained the complexity of the eukaryotes. It explains why life will probably get stuck in a bacterial rut elsewhere in the universe: why we might not be alone, but will almost certainly be lonely.
There are many other such questions, posed by perceptive thinkers in the specialist literature, but rarely troubling a wider audience. On the face of it, these questions seem almost laughably erudite—surely they would hardly exercise even the most pointy-headed boffins. Yet when posed together as a group, the answers impart a seamless account of the whole trajectory of evolution, from the origin of life itself, through the genesis of complex cells and multi-cellular organisms, to the attainment of larger size, sexes, warm-bloodedness, and into the decline of old age and death. The sweeping picture that emerges gives striking new insights into why we are here at all, whether we are alone in the universe, why we have our sense of individuality, why we should make love, where we trace our ancestral roots, why we must age and die—in short, into the meaning of life. The eloquent historian Felipe Fernandez-Armesto wrote: 'Stories help explain themselves; if you know how something happened, you begin to see why it happened.' So too, the 'how' and the 'why' are intimately embraced when we reconstruct the story of life.
I have tried to write this book for a wide audience with little background in science or biology, but inevitably, in discussing the implications of very recent research, I have had to introduce a few technical terms, and assume a familiarity with basic cell biology. Even equipped with this vocabulary, some sections may still seem challenging. I believe it's worth the effort, for the fascination of science, and the thrill of dawning comprehension, comes from wrestling with the questions whose answers are unclear, yet touch upon the meaning of life. When dealing with events that happened in the remote past, perhaps billions of years ago, it is rarely possible to find definitive answers. Nonetheless, it is possible to use what we know, or think we know, to narrow down the list of possibilities. There are clues scattered throughout life, sometimes in the most unexpected places, and it is these clues that demand familiarity with modern molecular biology, hence the necessary intricacy of a few sections. The clues allow us to eliminate some possibilities, and focus on others, after the method of Sherlock Holmes. As Holmes put it: 'When you have eliminated the impossible, whatever remains, however improbable, must be the truth.' While it is dangerous to brandish terms like impossible at evolution, there is sleuthful satisfaction in reconstructing the most likely paths that life might have taken. I hope that something of my own excitement will transmit to you.
For quick reference I have given brief definitions of most technical terms in a glossary, but before continuing, it's perhaps valuable to give a flavour of cell biology for those who have no background in biology. The living cell is a minute universe, the simplest form of life capable of independent existence, and as such it is the basic unit of biology. Some organisms, like amoeba, or indeed bacteria, are simply single cells, or unicellular organisms. Other organisms are composed of numerous cells, in our own case millions of millions of them: we are multicellular organisms. The study of cells is known as cytology, from the Greek cyto, meaning cell (originally, hollow receptacle). Many terms incorporate the root cyto-, such as cytochromes (coloured proteins in the cell) and cytoplasm (the living matter of the cell, excluding the nucleus), or cyte, as in erythrocyte (red blood cell).
Not all cells are equal, and some are a lot more equal than others. The least equal are bacteria, the simplest of cells. Even when viewed down an electron microscope, bacteria yield few clues to their structure. They are tiny, rarely more than a few thousandths of a millimetre (microns) in diameter, and typically either spherical or rod-like in shape. They are sealed off from their external environment by a tough but permeable cell wall, and inside that, almost touching upon it, by a flimsy but relatively impermeable cell membrane, a few millionths of a millimetre (nanometres) thick. This membrane, so vanishingly thin, looms large in this book, for bacteria use it for generating their energy.
The inside of a bacterial cell, indeed any cell, is the cytoplasm, which is of gel-like consistency, and contains all kinds of biological molecules in solution or suspension. Some of these molecules can be made out, faintly, at the highest power magnification we can achieve, an amplification of a million-fold, giving the cytoplasm a coarse look, like a mole-infested field when viewed from the air. First among these molecules is the long, coiled wire of DNA, the stuff of genes, which tracks like the contorted earthworks of a delinquent mole. Its molecular structure, the famous double helix, was revealed by Watson and Crick more than half a century ago. Other ruggosities are large proteins, barely visible even at this magnification, and yet composed of millions of atoms, organized in such precise arrays that their exact molecular structure can be deciphered by the diffraction of X-rays. And that's it: there is little else to see, even though biochemical analysis shows that bacteria, the simplest of cells, are in fact so complex that we still have almost everything to learn about their invisible organization.
We ourselves are composed of a different type of cell, the most equal in our cellular farmyard. For a start they are much bigger, often a hundred thousand times the volume of a bacterium. You can see much more inside. There are great stacks of convoluted membranes, bristling with ruggosities; there are all kinds of vesicles, large and small, sealed off from the rest of the cytoplasm like freezer bags; and there is a dense, branching network of fibres that give structural support and elasticity to the cell, the cytoskeleton. Then there are the organelles—discrete organs within the cell that are dedicated to particular tasks, in the same way that a kidney is dedicated to filtration. But most of all, there is the nucleus, the brooding planet that dominates the little cellular universe. The planet of the nucleus is nearly as pockmarked with holes (in fact, tiny pores) as the moon. The possessors of such nuclei, the eukaryotes, are the most important cells in the world. Without them, our world would not exist, for all plants and animals, all algae and fungi, indeed essentially everything we can see with the naked eye, is composed of eukaryotic cells, each one harbouring its own nucleus.
The nucleus contains the DNA, forming the genes. This DNA is exactly the same in detailed molecular structure as that of bacteria, but it is very different in its large-scale organization. In bacteria, the DNA forms into a long and twisted loop. The contorted tracks of the delinquent mole finally close upon themselves to form a single circular chromosome. In eukaryotic cells, there are usually a number of different chromosomes, in humans 23, and these are linear, not circular. That is not to say that the chromosomes are stretched out in a straight line, but rather that each has two separate ends. Under normal working conditions, none of this can be made out down the microscope, but during cell division the chromosomes change their structure and condense into recognizable tubular shapes. Most eukaryotic cells keep two copies of each of their chromosomes—they are said to be diploid, giving humans a total of 46 chromosomes—and these pair up during cell division, remaining joined at the waist. This gives the chromosomes the simple star shapes that can be seen down the microscope. They are not composed only of DNA, but are coated in specialized proteins, the most important of which are called histones. This is an important difference with bacteria, for no bacteria coat their DNA with histones: their DNA is naked. The histones not only protect eukaryotic DNA from chemical attack, but also guard access to the genes.
When he discovered the structure of DNA, Francis Crick immediately understood how genetic inheritance works, announcing in the pub that evening that he understood the secret of life. DNA is a template, both for itself and for proteins. The two entwined strands of the double helix each act as a template for the other, so that when they are prized apart, during cell division, each strand provides the information necessary for reconstituting the full double helix, giving two identical copies. The information encoded in DNA spells out the molecular structure of proteins. This, said Crick, is the 'central dogma' of all biology: genes code for proteins. The long ticker tape of DNA is a seemingly endless sequence of just four molecular 'letters', just as all our words, all our books, are a sequence of only 26 letters. In DNA, the sequence of letters stipulates the structure of proteins. The genome is the full library of genes possessed by an organism, and may run to billions of letters. A gene is essentially the code for a single protein, which usually takes thousands of letters. Each protein is a string of subunits called amino acids, and the precise order of these dictates the functional properties of the protein. The sequence of letters in a gene specifies the sequence of amino acids in a protein. If the sequence of letters is changed —a 'mutation'—this may change the structure of the protein (but not always, as there is some redundancy, or technically degeneracy, in the code—several different combinations of letters can code for the same amino acid).
Proteins are the crowning glory of life. Their forms, and their functions, are almost endless, and the rich variety of life is almost entirely attributable to the rich variety of proteins. Proteins make possible all the physical attainments of life, from metabolism to movement, from flight to sight, from immunity to signalling. They fall into several broad groups, according to their function. Perhaps the most important group are the enzymes, which are biological catalysts that speed up the rate of biochemical reactions by many orders of magnitude, with an astonishing degree of selectivity for their raw materials.
Some enzymes can even distinguish between different forms of the same atom (isotopes). Other important groups of proteins include hormones and their receptors, immune proteins like antibodies, DNA-binding proteins like his-tones, and structural proteins, such as the fibres of the cytoskeleton.
The DNA code is inert, a vast repository of information housed out of the way in the nucleus, in the same way that valuable encyclopaedias are stored safely in libraries, rather than being consulted in factories. For daily use the cell relies on disposable photocopies. These are made of RNA, a molecule composed of similar building blocks to DNA, but spun-out in a single strand rather than the two strands of the double helix. There are several types of RNA, which fulfil distinct tasks. The first of these is messenger RNA, which equates in length, more or less, to a single gene. Like DNA, it, too, forms a string of letters, and their sequence is an exact replica of the gene sequence in the DNA. The gene sequence is transcribed into the slightly different calligraphy of messenger RNA, converted from one font into another without losing any meaning. This RNA is a winged messenger, and passes physically from the DNA in the nucleus, through the pores that pockmark its surface like the moon, and out into the cytoplasm. There it docks onto one of the many thousands of protein-building factories in the cytoplasm, the ribosomes. As molecular structures these are enormous; as visible entities they are miniscule. They can be seen studding some of the cell's internal membranes, giving them a rough impression on the electron microscope, and dotting through the cytoplasm. They are composed of a mixture of other types of RNA, and protein, and their job is to translate the message encoded in messenger RNA into the different language of proteins— the sequence of amino acids. The whole process of transcription and translation is controlled and regulated by numerous specialized proteins, the most important of which are called transcription factors. These regulate the expression of genes. When a gene is expressed, it is converted from the somnolent code into an active protein, with business about the cell or elsewhere.
Armed with this basic cell biology, let's now return to the mitochondria. They are organelles in the cell—one of the tiny organs dedicated to a specific task, in this case energy production. I mentioned that mitochondria were once bacteria, and in appearance they still look a bit like bacteria (Figure 1). Typically depicted as sausages or worms, they're able to take many twisted and contorted shapes, including corkscrews. They're usually of bacterial size, a few thousandths of a millimetre in length (1 to 4 microns), and perhaps half a micron in diameter. The cells that make up our bodies typically contain numerous mitochondria, the exact number depending on the metabolic demand of that particular cell. Metabolically active cells, such as those of the liver, kidneys, muscles, and brain, have hundreds or thousands of mitochondria, making up some 40 per cent of the cytoplasm. The egg cell, or oocyte, is exceptional: it
passes on around 100000 mitochondria to the next generation. In contrast, blood cells and skin cells have very few, or none at all; sperm usually have fewer than 100. All in all, there are said to be 10 million billion mitochondria in an adult human, which together constitute about 10 per cent of our body weight.
Mitochondria are separated from the rest of the cell by two membranes, the outer being smooth and continuous, and the inner convoluted into extravagant folds or tubules, called cristae. Mitochondria don't lie still, but frequently move around the cell to the places they are needed, often quite vigorously. They divide in two like bacteria, with apparent independence, and even fuse together into great branching networks. Mitochondria were first detected using light microscopy, as granules, rods, and filaments in the cell, but their provenance was debated from the beginning. Among the first to recognize their importance was the German Richard Altmann, who argued that the tiny granules were in truth the fundamental particles of life, and accordingly named them bioblasts in 1886. For Altmann, the bioblasts were the only living components of the cell, which he held to be little more than a fortified community of bioblasts living together for mutual protection, like the people of an iron-age fortification. Other structures, such as the cell membrane and the nucleus, were constructed by the community of bioblasts for their own ends, while the cytosol (the watery part of cytoplasm), was just that: a reservoir of nutrients enclosed in the microscopic fortress.
Altmann's ideas never caught on, and he was ridiculed by some. Others claimed that bioblasts were a figment of his imagination—merely artefacts of his elaborate microscopic preparation. These disputes were aggravated by the fact that cytologists had become entranced by the stately dance of the chromosomes during cell division. To visualize this dance, the transparent components of the cell had to be coloured using a stain. As it happened, the stains that were best able to colour the chromosomes were acidic. Unfortunately, these stains tended to dissolve the mitochondria; their obsession with the nucleus meant that cytologists were simply dissolving the evidence. Other stains were ambivalent, colouring mitochondria only transiently, for the mitochondria themselves rendered the stain colourless. Their rather ghostly appearance and disappearance was scarcely conducive to firm belief. Finally Carl Benda demonstrated, in 1897, that mitochondria do have a corporeal existence in cells. He defined them as 'granules, rods, or filaments in the cytoplasm of nearly all cells . . . which are destroyed by acids or fat solvents.' His term, mitochondria (pronounced 'my-toe-con-dree-uh'), was derived from the Greek mitos, meaning thread, and chondrin, meaning small grain. Although his name alone stood the test of time, it was then but one among many. Mitochondria have revelled in more than thirty magnificently obscure names, including chondriosomes, chromidia, chondriokonts, eclectosomes, histomeres, microsomes, plastosomes, polioplasma, and vibrioden.
While the real existence of mitochondria was at last ceded, their function remained unknown. Few ascribed to them the elementary life-building properties claimed by Altmann; a more circumscribed role was sought. Some considered mitochondria to be the centre of protein or fat synthesis; others thought they were the residence of genes. In fact, the ghostly disappearance of mitochondrial stains finally gave the game away: the stains were rendered colourless because they had been oxidized by the mitochondria—a process analogous to the oxidation of food in cell respiration. Accordingly, in 1912, B. F. Kingbury proposed that mitochondria might be the respiratory centres of the cell. His suggestion was demonstrated to be correct only in 1949, when Eugene Kennedy and Albert Lehninger showed that the respiratory enzymes were indeed located in the mitochondria.
Though Altmann's ideas about bioblasts fell into disrepute, a number of other researchers also argued that mitochondria were independent entities related to bacteria, symbionts that lived in the cell for mutual advantage. A sym-biont is a partner in a symbiosis, a relationship in which both partners benefit in some way from the presence of the other. The classic example is the Egyptian plover, which picks the teeth of Nile crocodiles, providing dental hygiene for the crocodile while gaining an easy lunch for itself. Similar mutual relationships can exist among cells such as bacteria, which sometimes live inside larger cells as endosymbionts. In the first decades of the twentieth century, virtually all parts of the cell were considered as possible endosymbionts, perhaps modified by their mutual coexistence, including the nucleus, the mitochondria, the chloroplasts (responsible for photosynthesis in plants), and the centrioles (the cell bodies that organize the cytoskeleton). All these theories were based on appearance and behaviour, like movement and apparently autonomous division, and so could never be more than suggestive. What's more, their protagonists were all too often divided by struggles over priority, by war and language, and rarely agreed among themselves. As the science historian Jan Sapp put it, in his fine book Evolution by Association: 'Thus unfolds an ironic tale of the fierce individualism of many personalities who pointed to the creative power of associations in evolutionary change.'
Matters came to a head after 1918, when the French scientist Paul Portier published his rhetorical masterpiece Les Symbiotes. He was nothing if not bold, claiming that: 'All living beings, all animals from Amoeba to Man, all plants from Cryptogams to Dicotyledons are constituted by an association, the emboîtement of two different beings. Each living cell contains in its protoplasm formations, which histologists designate by the name of mitochondria. These organelles are, for me, nothing other than symbiotic bacteria, which I call symbiotes.'
Portier's work attracted high praise and harsh criticism in France, though it was largely ignored in the English-speaking world. For the first time, however, the case did not stand on the morphological similarities between mitochondria and bacteria, but turned on attempts to cultivate mitochondria as a cell culture. Portier claimed to have done so, at least with 'proto-mitochondria', which he argued had not yet become fully adapted to their life inside cells. His findings were publicly contested by a panel of bacteriologists at the Pasteur Institute, who were unable to replicate them. And sadly, once he had secured his chair at the Sorbonne, Portier abandoned the field, and his work was quietly forgotten.
A few years later, in 1925, the American Ivan Wallin independently put forward his own ideas on the bacterial nature of mitochondria, claiming that such intimate symbioses were the driving force behind the origin of new species. His arguments again turned on culturing mitochondria, and he, too, believed that he had succeeded. But for a second time interest waned with the failure to replicate his work. This time symbiosis was not ruled out with quite the same venom, but the American cell biologist E. B. Wilson summed up the prevailing attitude in his famous remark: 'To many, no doubt, such speculations may appear too fantastic for present mention in polite biological society; nevertheless it is within the range of possibility that they may some day call for some serious consideration.'
That day turned out to be half a century later: aptly enough for the tale of an intimate symbiotic union, in the summer of love. In June 1967, Lynn Margulis submitted her famous paper to the Journal ofTheoretical Biology, in which she resurrected the 'entertaining fantasies' of previous generations and cloaked them in newly scientific apparel. By then the case was much stronger: the existence of DNA and RNA in mitochondria had been proved, and examples of 'cytoplasmic heredity' catalogued (in which inherited traits were shown to be independent of the nuclear genes). Margulis was then married to the cos-mologist Carl Sagan, and she took a similarly cosmic view of the evolution of life, considering not just the biology, but also the geological evidence of atmospheric evolution, and fossils of bacteria and early eukaryotes. She brought to the task a consummate discernment of microbial anatomy and chemistry, and applied systematic criteria to determine the likelihood of symbiosis. Even so, her work was rejected. Her seminal paper was turned down by 15 different journals before James Danielli, the far-seeing editor of the Journal of Theoretical Biology, finally accepted it. Once published, there were an unprecedented 800 reprint requests for the paper within a year. Her book, The Origin ofEukaryotic Cells, was rejected by Academic Press, despite having been written to contract, and was eventually published by Yale University Press in 1970. It was to become one of the most influential biological texts of the century. Margulis marshalled the evidence so convincingly that biologists now accept her once-heterodox view as fact, at least when applied to mitochondria and chloroplasts.
Bitter arguments persisted for well over a decade, and were arcane but vital. Without them, the final agreement would have been less secure. Everyone accepted that there are indeed parallels between mitochondria and bacteria, but not everyone agreed about what these really meant. Certainly the mito-chondrial genes are bacterial in nature: they sit on a single circular chromosome (unlike the linear chromosomes of the nucleus) and are 'naked'—they're not wrapped up in histone proteins. Likewise, the transcription and translation of DNA into proteins is similar in bacteria and mitochondria. The physical assembly of proteins is also managed along similar lines, and differs in many details from standard eukaryotic practice. Mitochondria even have their own ribosomes, the protein-building factories, which are bacterial in appearance. Various antibiotics work by blocking protein assembly in bacteria, and also block protein synthesis in the mitochondria, but not from the nuclear genes in eukaryotes.
Taken together, these parallels might sound compelling, but in fact there are possible alternative interpretations, and it was these that underpinned the long dispute. In essence, the bacterial properties of mitochondria could be explained if the speed of evolution was slower in the mitochondria than in the nucleus. If so, then the mitochondria would have more in common with bacteria simply because they had not evolved as fast, and so as far. They would retain more atavistic traits. Because the mitochondrial genes are not recom-bined by sex, this position was sustainable, if somewhat unsatisfying. It could only be refuted when the actual rate of evolution was known, which in turn required the direct sequencing of mitochondrial genes, and the comparison of sequences. Only after Fred Sanger's group in Cambridge had sequenced the human mitochondrial genome in 1981 did it transpire that the evolution rate of mitochondrial genes was faster than that of the nuclear genes. Their atavistic properties could only be explained by a direct relationship; and this relationship was ultimately shown to be with a very specific group of bacteria, the a-proteobacteria.
Even the visionary Margulis was not correct about everything, luckily for the rest of us. Aligning herself with the earlier advocates of symbiosis, Margulis had argued that it would one day prove possible to grow mitochondria in culture— it was only a matter of finding the right growth factors. Today, we know that this is not possible. The reason was also made clear by the detailed sequence of the mitochondrial genome: the mitochondrial genes only encode a handful of proteins (13 to be exact), along with all the genetic machinery needed to make them. The great majority of mitochondrial proteins (some 800) are encoded by the genes in the nucleus, of which there are 30 000 to 40 000 in total. The apparent independence of mitochondria is therefore truly apparent, and not genuine. Their reliance on two genomes, the mitochondrial and the nuclear, is evident even at the level of a few proteins that are composed of multiple subunits, some of which are encoded by the mitochondrial genes, and others by the nuclear genes. Because they rely on both genomes, mitochondria can only be cultured within their host cells, and are correctly designated 'organelles', rather than sym-bionts. Nonetheless, the word 'organelle' gives no hint of their extraordinary past, and affords no insight into their profound influence on evolution.
There is another sense in which many biologists today still disagree with Lynn Margulis, and that relates to the evolutionary power of symbiosis in general. For Margulis, the eukaryotic cell is the product of multiple symbiotic mergers, in which the component cells have been subsumed into the greater whole to varying degrees. Her theory has been dubbed the 'serial endosym-biosis theory', meaning that eukaryotic cells were formed by a succession of such mergers between cells, giving rise to a community of cells living within one another. Besides chloroplasts and mitochondria, Margulis cites the cell skeleton with its organizing centre, the centriole, as the contribution of another type of bacteria, the Spirochaetes. In fact, according to Margulis the whole organic world is an elaboration of collaborative bacteria—the microcosm. The idea goes back to Darwin himself, who wrote in a celebrated passage: 'Each living being is a microcosm—a little universe formed of self-propagating organisms inconceivably minute and numerous as the stars in the heavens.'
The idea of a microcosm is beautiful and inspiring, but raises a number of difficulties. Cooperation is not an alternative to competition. A collaboration between different bacteria to form new cells and organisms merely raises the bar for competition, which is now between the more complex organisms rather than their collaborative subunits—many of which, including the mitochondria, turn out to have retained plenty of selfish interests of their own. But the biggest difficulty with an all-embracing view of symbiosis is the mitochondria themselves, which wag a cautionary finger at the power of microscopic collaboration. It seems that all eukaryotic cells either have, or once had (and then lost), mitochondria. In other words, possession of mitochondria is a sine qua non of the eukaryotic condition.
Why on earth should this be? If collaboration between bacteria were so commonplace, we might expect to find all sorts of distinct 'eukaryotic' cells, each composed of a different set of collaborative microorganisms. Of course, we do—there is a great range of eukaryotic collaboration, especially in the more obscure microscopic communities living in inaccessible places, such as the mud of the sea floor. But the astonishing finding is that all these far-flung eukaryotes share the same ancestry—and they all either have or once had mitochondria. This is not true of any other collaboration between microorganisms in eukaryotes. In other words, the collaborations that attained fulfilment in eukaryotic organisms are contingent on the existence of mitochondria. If the original merger had not taken place, then neither would any of the others. We can say this with near certainty, because the bacteria have been collaborating and competing among themselves for nearly four billion years, and yet only came up with the eukaryotic cell once. The acquisition of mitochondria was the pivotal moment in the history of life.
We are discovering new habitats and relationships all the time. They are a fabulously rich testing ground of ideas. To give just a single example, one of the more surprising discoveries at the turn of the millennium was the abundance of tiny, so-called pico-eukaryotes, which live among the micro-plankton in extreme environments, such as the bottom of the Antarctic oceans, and in acidic, iron-rich rivers, like the Rio Tinto in southern Spain (known by the ancient Phoenicians as the 'river of fire' because of its deep red colour). In general, such environments were considered to be the domain of hardy, 'extrem-ophile' bacteria, and the last place one might expect to find fragile eukaryotes. The pico-eukaryotes are about the same size as bacteria and favour similar environments, and so generated a lot of interest as possible intermediates between bacteria and eukaryotes. Yet despite their small size and unusual predilection for extreme conditions, all turned out to fit into known groups of eukaryotes: genetic analysis showed they don't challenge the existing classification system at all. Astonishingly, this new bubbling fountain of variations on a eukaryotic theme adds up to no more than subgroups to existing groups, all of which we have known about for many years.
In these unsuspected environments, the very places we would expect to find a tapestry of unique collaborations, we do not. Instead, we find more of the same. Take the smallest known eukaryotic cell, for example, Ostreococcus tauri. It is less than a thousandth of a millimetre (1 micron) in diameter, rather smaller than most bacteria, yet it is a perfectly formed eukaryote. It has a nucleus with 14 linear chromosomes, one chloroplast—and, most remarkably of all, several tiny mitochondria. It is not alone. The unexpected fountain of eukaryotic variation in extreme conditions has thrown up perhaps 20 or 30 new subgroups of eukaryotes. It seems that all of them have, or once had, mitochondria, despite their small size, unusual lifestyles, and hostile surroundings.
What does all this mean? It means that mitochondria are not just another collaborative player: they hold the key to the evolution of complexity. This book is about what the mitochondria did for us. I ignore many of the technical aspects that are discussed in textbooks—incidental details like porphyrin synthesis and even the Krebs cycle, which could in principle take place anywhere else in the cell, and merely found a convenient location in the mitochondria. Instead, we'll see why mitochondria made such a difference to life, and to our own lives. We'll see why mitochondria are the clandestine rulers of our world, masters of power, sex, and suicide.
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