Oxygen

by Nick Lane

  Allen’s fundamental idea is as follows: if mitochondria damage their own DNA by respiring oxygen, and cannot systematically cleanse their genome of error by either sex or binary fission, then the only way to prevent mitochondria from passing on damaged DNA to the next generation is to stop them from respiring at all. In other words, the only way of maintaining mitochondrial integrity is to switch them off. This proposition leads to a number of predictions, many of which are undoubtedly true,

  The Rate of Living and the Need for Sexes • 279

  and all of which are testable. If these predictions each turn out to be true, then we can use the detailed process of sexual reproduction to confirm the validity of the mitochondrial theory of ageing.

  To follow Allen’s ideas through, we need to go back to one of the fundamental problems facing sexual reproduction — how to find an appropriate partner. The problem affects single cells as well as lonely-hearts, and the solution is somewhat similar. To have two people searching for one another is no more effective than having one person stay put and the other doing the searching: this is the idea behind dating agencies.

  For sex cells, one cell must move around in its quest for a suitable partner, but the probability of meeting the cell of choice is no greater if both cells move around. One cell can stay put, as long as it signals its presence or availability. In our case, and in many other animals, the sperm are motile, while the eggs are immobile. Indeed, the word ‘male’ is conventionally defined as the sex which produces a large number of small, mobile gametes, while ‘female’ is defined as the sex that produces a small number of large, immobile gametes.

  Motility, of course, requires active mitochondrial respiration, and this damages mitochondrial DNA. Since the objective is not to pass on damaged mitochondria, we can predict that sperm will not pass on their mitochondria to the next generation. If the reason that they do not is indeed because of damage, then we can also predict that the sperm’s mitochondria should be damaged and as a result destroyed. There is some evidence that this is the case. Peter Sutovsky and his team at Oregon Health Sciences University, Oregon, published a paper in Nature in 1999

  showing that in cattle the male mitochondria become tagged with the protein ubiquitin. This tag is normally used as a marker of damaged proteins, consigning them to breakdown and turnover. The implication is that the sperm’s mitochondria are spotted as defective and destroyed in the early stages of embryonic development. Sutovsky’s more recent work confirms this mechanism, in cattle at least. Thus, discrimination between male and female mitochondria seems to be achieved on the basis of damage, as predicted by Allen’s theory.9

  9 This may also explain how some species can receive mitochondria from both sexes. We might predict that either: only undamaged mitochondria survive, that is, only those not tagged with ubiquitin; or that there are subpopulations of mitochondria within both sex cells that are switched off, as discussed above. We might also guess that the motility of sex cells would be limited in both cases. Pollen, for example, requires little output of energy to fertilize a flower.

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  A second prediction relates to the timing of sex-cell production.

  Because the recombination of chromosomes during sex cleanses the nuclear gene-line, and the new combinations are subjected to selection for viability, then it should not matter exactly when the new sex cells are produced. There is no obvious reason why both types of sex cell should not be produced continuously throughout life. So why is it, then, that sperm are produced through life, but eggs are only produced early in development and then last half a lifetime? Well, think about the mitochondria. Sperm mitochondria are not passed on to the next generation.

  It does not matter if these mitochondria are damaged, provided that they are still functional enough to get the sperm to the egg. In our bodies, this is the average state of mitochondria for most of our lives: damaged but functional. Thus, there is no reason why sperm should not be produced continuously throughout our lives. The only proviso is that the nuclear DNA must be shielded against escaping mitochondrial free radicals by antioxidant defences. This is indeed the case. The midpiece of sperm, containing the mitochondria, is encapsulated in selenium-containing proteins. Sperm contain a higher concentration of selenium than any other cell type in the body. Dietary selenium deficiency is a common cause of infertility in some parts of the world. One of the selenium proteins is a form of glutathione peroxidase, which disposes of hydrogen peroxide.

  Glutathione peroxidase would probably not protect the mitochondria from damage, but would prevent hydrogen peroxide from diffusing into the nucleus, where it could react with iron to produce hydroxyl radicals.

  What about the egg? In this case the mitochondria are passed on to the next generation. If the eggs are formed throughout life, then their mitochondria will become progressively more damaged as time goes by.

  Nuclear DNA can be rejuvenated by sex but mitochondrial DNA cannot.

  One solution is to cordon off undamaged mitochondria very early in life, switch them off, enclose them in an egg, and then maintain the egg in a dormant state until it is needed. This is very close to what does happen, and brings us to our third prediction: that the mitochondria in the egg should be switched off.

  The easiest way of switching off mitochondria is to halt the production of respiratory proteins. Imagine a room full of dominoes standing in line: the simplest way of preventing the whole line from toppling is to remove a domino or two, so that a falling domino cannot touch the next in line. So it is with the chain of respiratory proteins in the mitochondria: if a few strategic proteins are omitted from the chain, then respiration

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  cannot take place. The strategic proteins omitted are those encoded by the mitochondrial genes, certainly in mice and the African clawed frog, Xenopus laevis. In the mouse, the mitochondrial genome is largely inactive in the egg and the early embryo. In Xenopus, DNA-binding proteins are known to inhibit mitochondrial gene transcription. Thus, in a few known cases at least, the mitochondria are indeed ‘switched off’ in the egg.

  If this sort of mitochondrial inhibition turns out to be generally the case, as we would predict, then the egg cells would be unable to provide all their own energy by respiration. This leads to a final predication from Allen: that the follicle cells surrounding the developing egg should provide the egg with energy in the form of ATP. Whether or not this is true is unknown, but the morphological structure of the follicles suggests that it may well be.

  Overall, then, the facts fit the theory. Passing mitochondria from one generation to the next is a liability that requires extraordinary measures to make it possible at all. These measures probably contributed to the evolution of two specialized types of sex cell, or anisogamy. Anisogamy, in turn, is equated with the origins of sexes: once the two types of sex cell have become mutually dependent, there is no way back, so the only path is towards the increasing specialization of sexual traits. Breathing oxygen is thus intimately linked with both ageing and the origins of gender.

  Considering the situation from the other extreme of life, I feel that the elaborate precautions required to reset the mitochondrial clock to zero in a new generation confirm the main tenets of the mitochondrial theory of ageing. If so, then we have reached a watershed conclusion: there is indeed a process of ageing that is independent of age-related disease. Ageing is not simply the accumulation of late-acting mutations, as argued by the theory of antagonistic pleiotropy (see Chapter 12, page 239). Even without succumbing to genetic disease, we will eventually die of mitochondrial wear and tear. It is quite plausible that the time required for mitochondrial burn-out in long-lived cells, such as neurons, heart and skeletal muscle cells, is close to the maximum human lifespan of 115 to 120 years.

  Few people live out their maximum lifespan: even in the Western world, most people die of some disease, usually with a genetic basis, in

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  their seventies or eighties. It is no use working out how to prolong our maximum potential lifespan if only a handful of people live that long.

  The question for the next chapter, then, is how do age-related diseases, such as cancer and heart disease, fit in with the mitochondria story? Are they completely unrelated, or might it be possible to postpone the onset of such diseases by delaying the underlying process of ageing?

  If it is possible to postpone the onset of particular diseases through a general mechanism, then the present emphasis of medical research, on pinpointing the genetic causes of disease, is wrong. With the excitement surrounding the human genome project, and our focus as a society on individual rights, pharmaceutical research is heading towards the individ-ualization of treatment. Great weight is placed on tiny genetic differences between individuals, such as single-nucleotide polymorphisms — differences of just one letter in a given stretch of DNA. I suspect we may be losing our way in the detail. If slowing the process of ageing can postpone the onset of age-related disease in species as diverse as nematode worms, Drosophila, rats, monkeys, and perhaps ourselves, then we should be looking for commonalities, not particulars. In the next chapter, we shall see that there are good grounds for thinking that the whole thrust of gene-searching for drug treatment is misdirected.

  C H A P T E R F O U R T E E N

  Beyond Genes and Destiny

  The Double-Agent Theory of Ageing and Disease

  Oedipus kills his father and sleeps with his mother. He does all this in ignorance: he had been left for dead at birth and raised in another land. He returns unknowingly to his homeland and becomes a good and noble king, only to be cut down by the machina-tions of fate. His terrible future is revealed by the old sage Tiresias: “Blind from having sight and beggared from high fortune, with a staff in stranger lands he shall feel forth his way; Shown living with the children of his loins, their brother and their sire, and to the womb that bare him, husband-son, and, to his father, parricide and co-rival.”

  When I first read Sophocles’ great tragedy, I was amazed at how un-Freudian the story was. When he discovers the true nature of his actions, Oedipus tears out his eyes and condemns himself to a wandering exile, thus fulfilling the prophecy; hardly the action of one who desires his own mother. Curiously, his wife-mother, Jocasta, is more ambiguous. She is the first to grasp what has happened, and she tries to prevent the truth from emerging. Only when she sees that Oedipus is set on the truth does she damn him and hang herself. One wonders if she would have continued as before, had the truth not been revealed; but if Sophocles intended a subplot here, he paid little attention to it. The most striking element of King Oedipus, and indeed so much of Greek tragedy, is the implacable role of fate. The characters, for all their eloquence, are just puppets. Motive

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  scarcely matters. Jocasta’s attempt to turn a blind eye to the workings of fate merely illustrates the impossibility of her task, and the penalty for anyone who tries.

  Today, millions of people enjoy reading astrology columns in daily newspapers, and some no doubt believe them, but the sense of ineluctable fate went out with Christianity. When Adam and Eve ate of the apple of knowledge, humanity was freed to suffer or prosper of their own free will. The concept of sin is a foundation of Christianity, yet must have been alien to the ancient Greeks — how can Oedipus be said to have sinned, he who was condemned by an oracle before his own birth? For Christians, sin is a choice, and we are judged on the choices we make. The difference is clear in tragedy. The Greek sense of tragedy is quite unlike Shakespeare’s. Hamlet is faced with choices throughout the play, notably the ultimate question, “To be or not to be?” The terrible final scene is the outcome of a series of contingencies. The tragedy of Hamlet lies in the fact that it could all have been averted. One can imagine a satirical reworking, in which a peace-broker brings the two sides together to mediate a solution. The mediator would have failed with Oedipus. Indeed, there was a mediator, Jocasta, and she did fail. What a tragic breed we are! The tragedy of Oedipus lies in its inevitability, the tragedy of Hamlet in its evitability. After two millennia of Christian choices, it is the inevitability of Greek tragedy that shocks us today.

  For the first time since the ancients, a sense of implacable fate is returning. The certainties of Greek theatre have been superseded by the certainties of modern genetics, which at times seem just as disturbing. We read about genes ‘for’ heart disease, cancer or Alzheimer’s disease. Few people, even the scientists working on them, have a clear idea of exactly what these genes do, but we eye them with mistrust. We resist the intru-sion of insurance companies who wish to pry into our genetic makeup —

  to read our oracles — yet our resistance owes more to a sense of personal infringement than a questioning of the veracity of genetics. We seem to accept that if we have the gene ‘for’ multiple sclerosis, then we will go on to develop the disease. We accept the inevitability of genetics in the same way that the Greeks accepted the inevitability of fate. The analogy is sharpened by our powerlessness to alter the course of many diseases.

  Many people prefer not to know what they cannot change. Tiresias put it well 2500 years ago: “Ah! How terrible is knowledge to the man whom knowledge profits not.”

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  Many writers have riled against the idea of genes ‘for’ diseases. No gene is

  ‘for’ a disease any more than an aeroplane is ‘for’ crashing. Genes, however, like aeroplanes, do go wrong. Historically, the attitude of medicine has been that this is a mischance, a part of the human lot. The human body is tremendously complex, so there are many ways in which it can go wrong. Genes are one of these ways. A gene goes ‘wrong’ and the result is havoc. Cancer is the classic example. A handful of chance mutations lead to that most terrible of human fates. These mutations only need to happen in one cell out of 15 million million. There is no ‘reason’, beyond such unsatisfying explanations as mischance, environmental toxicity or genetic susceptibility.

  The spirit guiding the human genome project is the apotheosis of this view: genes go wrong and cause disease. Therefore, to cure the disease, find the gene and put it right. Today this might not be possible, but in the future we will no doubt perfect gene therapy. All we need to do is excise the faulty gene and replace it with a nice new one: replace the carburettor and the engine will work again. Many single-gene disorders, such as haemophilia or muscular dystrophy, are in principle amenable to this approach. In the case of haemophilia, the gene that codes for a blood-clotting protein, factor VIII, is mutated, so the protein is absent. The protein can be replaced by transfusion, or ultimately the gene can be fixed by gene therapy. There are many practical obstacles to overcome, but in conceptual terms the only subtlety is to ensure that the right amount of factor VIII is present at the right time.

  The trouble is that single-gene disorders are rare. For the vast majority of diseases, especially the diseases of old age, a whole assortment of genes increase our susceptibility to disease. There is typically no genetic

  ‘defect’ as such. The word is too black and white — there are as many shades of grey between a working gene and a broken gene as there are between good and evil. Consider: a gene codes for a protein. If the sequence of the gene changes in the course of evolution, the structure of the protein changes. Sometimes the new protein may not work at all — in which case, if it is important, it will be eliminated by natural selection along with its bearer. Sometimes the change will have no effect on the function of the protein: it will simply be slightly different.1 Then there 1 The sequence of the same gene in different species may vary in almost every letter, without affecting function. The differences are due to ‘evolutionary drift’, in which mutations that do not affect the function of the protein are passed on and species drift apart over time (see Chapter 8). The evolutionary relationship is often betrayed by conservation of purpose,

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  may be several other versions that work to some degree or other. Given a particular set of environmental conditions, one of these may work best —

  but that is not to say that the others are ‘broken’. Change the conditions and a different form may well work better. In the same way, a tractor is not really cut out for the city, but comes into its own in the countryside. If you move with your tractor from the countryside to the city, and cannot afford to buy a car, you may not be as well adapted as before, but you are still better off than if you had to walk. The tractor is not broken.

  The different working versions of a gene are known as polymorphic alleles. It is hard to overstate their importance: they are the molecular units of variation and adaptation, the very essence of the individual. The genetic differences between people do not lie in different genes but in ever-so-slightly different versions of the same genes. On average, our DNA has between one and ten variant letters in every thousand, which are known as single-nucleotide polymorphisms, or SNPs (pronounced ‘snips’).

  These are being catalogued exhaustively, although we have a long way to go: there are expected to be a million SNPs in the human genome. When they are shuffled and recombined in sex, these SNPs account for our endless genetic variety. For exactly the same reasons, they also influence our susceptibility to both diseases and treatments.

  Some polymorphic genes — particular SNP configurations — may come to predominate within a population as a result of evolutionary selective pressures. Selective pressures can blur the distinction between a pathological process and an evolutionary trade-off. Our genes must make the best of a bad job. In previous chapters we have noted several examples of diseases that are not really pathological. Insulin-resistance in diabetes, for instance, is a genetic response to hard times, selected for over many generations. It is only pathological if a high-energy Western diet is superimposed over a ‘thrifty’ genotype. Similarly, sickle-cell anaemia and the thalassaemias protect against malaria through small changes in the structure of haemoglobin. These anaemias are maintained at a high frequency in areas where malaria is endemic because the carriers do not suffer from anaemia, but are protected against malaria. How many other human diseases are maintained in the gene pool because they offer a hidden benefit is anybody’s guess.