by Nick Lane
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 unmistakeable, 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 Schrödinger.’ 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, b
ut 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 multicellular 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 Fernández-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 l
ife. 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).