"Oxygen"

[fiefoe]

Nick Lane's comprehensive account of the long entwined history between oxygen and living creatures on earth was often heavy going, but he did manage to beat some key points into my head in the end.

• If pressed for an unemotional reason for not cutting down the rain forests or polluting the oceans, we may argue that these great resources are the ‘lungs’ of the world, ventilating the Earth with life-giving oxygen. This is not true, as we shall see, but illustrates the reverence in which we hold oxygen.
• Lavoisier who bequeathed the name oxygen, and he who finally proved that oxygen was the reactive constituent of air.1 Combustion, said Lavoisier, was the reaction of oxygen with carbon or other substances.
• Nitre (potassium nitrate, KNO3)：  When added to drinks, nitre cools them down as effectively as ice, yet when taken as a medicine produces a strong warming effect. The acid of nitre ( aqua regia, or ‘queen of waters’) could dissolve gold
• fellow alchemist Cornelius Drebbel, a lost hero of Renaissance science： After constructing a solar-powered perpetual-motion machine and a variety of refrigerators and automata for King James I of England, Drebbel built the world’s first submarine.
• Strikingly, Priestley’s words contain the first suggestion (to my knowledge) that oxygen might accelerate ageing.
• Another reason for caution was spelled out by Haldane early in the twentieth century — the possibility of oxygen toxicity. Haldane himself had written that: The probable risks of prolonged administration of pure oxygen must be borne in mind and if necessary balanced against the risks of allowing the oxygen-want to continue... The realization that oxygen is toxic came from the experiences of the earliest scuba divers,
• Such adaptations illustrate the importance of unchanging oxygen levels in the body. They also mean that we cannot gain any long-term benefit from either high or low levels of oxygen, except when we are sick and pathologically oxygen-deprived.
• The secret to all the chemistry of oxygen, whether we think of it as ‘good’ or ‘bad’, is the formation of free radicals.
• It is probable that photosynthesis (which generates oxygen as a waste product) could only have evolved because life had already adapted to provide itself with defences against the oxygen free radicals produced by ultraviolet radiation in the environment. This may explain why life took off on Earth but never did on Mars... The first multicellular organisms probably evolved from clumps of cells which clustered together to deal collectively with the rising tide of atmospheric oxygen produced by photosynthesis.
• anaerobic: For their ancestors, who ruled the ancient world, pollution with oxygen must have been calamitous. From dominating the world they shrank back to a reclusive existence at the margins.
• Oxidation is named after oxygen, which is good at stripping electrons from molecules; to help you remember, think of oxygen as being caustic or destructive, like a paint-stripper.
• So firmly entrenched was this story in my own mind that I was exasperated to hear a claim on television that oxygen levels once reached 35 per cent — during the Carboniferous period, around 300 million years ago. Nonsense, I thought! Everything would burn!
• Neon is the seventh most abundant element in the Universe... If any of the Earth’s original atmosphere had survived the meteorite bombardment, it should have contained about the same amount of neon as nitrogen. In fact, the ratio of neon to nitrogen is 1 to 60 000... Where, then, did our modern atmosphere come from? The answer seems to be volcanoes.
• The oxygen released by the photosynthesizers is almost completely (99.99 per cent) used up by the animals, fungi and bacteria which feed on the remains of the producers, or on each other. The apparently trivial 0.01 per cent discrepancy, however, is in fact responsible for all life as we know it. It represents the organic matter that is not burnt, but is instead buried under sediments... Almost all our precious oxygen is derived from a 3-billion-year mismatch between the amount of oxygen generated by the primary producers and the amount used up by consumers. The vast amount of dead organic matter buried in the rocks dwarfs the total carbon content of the living world.
• Solar energy, especially the ultraviolet rays, can split water to form hydrogen and oxygen without the aid of a biological catalyst.. Oxygen, a much heavier gas, is retained in the atmosphere by gravity. On the early Earth, most of the oxygen formed in this way reacted with iron in the rocks and oceans, locking it permanently into crust... our existence today is attributable to the early invention of photosynthesis on Earth, and the rapid injection of oxygen into the atmosphere through the action of a biological catalyst.
• photosynthetic cells using carbon dioxide from the air or sea to make organic matter prefer to use carbon-12. This is because the lighter carbon-12 atoms have a slightly greater vibrational energy, which means that a smaller input of energy (activational energy) is needed for a reaction to take place... organic matter becomes enriched in carbon-12 relative to carbon-13... As more carbon-12 is buried as part of organic matter, more carbon-13 is left behind in the oceans, and so the carbonate rocks have a relatively high content of carbon-13.
• Throughout the Precambrian period, most cyanobacteria lived in communal structures called stromatolites: great domes of living rock, which grew to heights of metres.
• The current state of the Black Sea seems to have developed about 7500 years ago, several thousand years after the end of the last ice age, in an event that has been linked to Noah’s Flood...  Whether as the consequence of an earthquake, or stormy weather, or the pressure of the rising Mediterranean, the land bridge spanning the Bosphorus finally collapsed with a roar that must have sounded like the wrath of God. This, say Ryan and Pitman, was the reality of Noah’s flood.
• The seasonal fluctuations in iron deposition would have been set against a steady precipitation of silica... in the days when bacteria ruled the waves, silica was not used in this way, and so must have continuously exceeded its solubility limit of about 14–20 parts per million.
• Then, around 2.2 billion years ago, there was an abrupt rise in the sulphur-32 content of iron pyrites, suggesting that the amount of sulphate in the oceans must have risen to the point where they could support a much larger population of sulphate-reducing bacteria. This, in turn, indicates that much more oxygen must have been available to produce the sulphate.
• The natural reactors in Gabon had apparently been sustained for millions of years by a steady flow of water from the streams that fed into the ancient uranium lakes. Water slows the speed of neutrons, reflecting them back into the core of the reactor, so instead of quelling the inner fires, water actually promotes nuclear fission. The streams did more than this, however — they also acted as safety valves against nuclear explosion... Whenever the chain reactions approached danger levels, water boiled off, allowing neutrons to escape. This scuttled the chain reactions and shut down the reactors until flow was re-established... a testament to the potential long-term safety of burying nuclear waste.
• The fact that it finally dominated, to the extent that virtually all eukaryotes have mitochondria, means that it must ultimately have been beneficial. The advantage is obvious in today’s world: mitochondria use oxygen to generate energy, by far the most efficient means of biological energy generation known... Both the symbiotic bacteria and their hosts would have produced ATP independently, by fermentation in the case of the eukaryotes, and by burning carbohydrate ‘fuel’ using oxygen in the case of the bacteria.
• while the host cell may have gained no energetic benefit, it might instead have been protected from within by its oxygen-guzzling guests. By converting oxygen to water, the symbiotic bacteria would have protected their hosts from potentially toxic oxygen. This acquired immunity to oxygen poisoning would have enabled the early eukaryotes to inhabit the shallow waters where oxygen levels were highest, and so exploit the benefits of light
• the Cambridge team reconstructed the anatomy of numerous strange bilaterally symmetrical creatures, placing one ‘weird wonder’ after another into taxonomic groups of their own. Their names spoke for themselves: Hallucigenia, Anomalocaris, Odontogriphus
• Worm: To burrow through mud requires muscles, and in order to contract, these must be opposed by some form of ‘skeleton’ — in a worm’s case a body cavity filled with fluid. Muscular contraction demands oxygen, and as this cannot diffuse through more than a millimetre or so of tissue, the early worm-like animals must also have had a circulatory system and a mechanism for pumping oxygenated fluid,
• the Hox genes. They are remarkable in two ways. First, there are relatively few of them: just a handful of genes control many of the steps in the early development of all animal embryos — from flies to mice and men. Second, the Hox genes of different species have very similar coding sequences.
• the Cambrian explosion was above all a diversification of segmented bilateral animals similar to modern-day crustaceans... was probably driven by a rewiring of the regulatory loops between the master Hox genes and the genes under their control... Goldfish, rather surprisingly, have 48 Hox genes in seven clusters; biology never stoops to a perfect correlation... In essence, though, duplication of Hox genes allows the replication and subsequent evolutionary modification of repetitive body parts. Having extra, dispensable, body parts makes specialization and complexity easier to achieve... One reason why the segmented bilateral body plan is so pregnant with genetic potential is that small changes in Hox genes, shifting their zone of responsibility, can lead to sudden and dramatic changes in morphology
• So in today’s world, where there are large land masses at or around the poles, any spread of the polar glaciers towards the Equator is offset by a greenhouse effect that gets stronger whenever the glaciers advance, and weaker whenever they retreat... Now consider what happens if polar ice forms over the oceans instead of the continents. This is what may have taken place to form the late Precambrian snowball Earth. Because the continents were clustered together in the tropics, glaciers at the poles formed over sea only. These polar glaciers could not affect the rate of rock weathering on the continents. The rocks kept on drawing down carbon dioxide from the air.
• I find the central assertion convincing — there was a rise in free oxygen in the immediate aftermath of the snowball Earth. This rise corresponded in time with the evolution of the first large animals — the Vendobionts.
• The solubility of many elements differs according to the level of oxygen. We have already seen that iron becomes less soluble in the presence of oxygen, whereas uranium becomes more soluble. If we see a shift in the relative concentrations of different elements in the rocks (some becoming more abundant, some less so) we get an indication of the degree of oxygenation of the oceans at the time of their formation... Uniquely in the history of our planet, all these factors — the carbon isotopes, sulphur isotopes, strontium isotopes and rare-earth elements — simultaneously point to a rise in free oxygen. Indeed, the wild swings in environmental conditions during the 160-million-year snowball Earth period may have pushed atmospheric oxygen up to nearly modern levels.
• Graham Logan and his colleagues... contradicted Nietzsche, arguing, in effect, that we owe our most god-like qualities, indeed our very existence, to the primal need for defecation. Faecal pellets from the first large animals, they say, cleansed the oceans, paving the way for the Cambrian explosion... Logan argues that the status quo was finally broken for ever by the evolution of animals with guts — a leap that could only be achieved in shallow waters with the aid of oxygen (only oxygen-requiring respiration is efficient enough to support the evolution of multicellular animals with guts). The relatively heavy faecal pellets of these animals must have sunk rapidly to the ocean bed, cutting swathes through the heaving population of oxygen-hating sulphate-reducing bacteria. Peppering the bottom sediments with nutrients, the faecal pellets were buried in turn under more sediments, so depriving the sulphate-reducing bacteria of their organic nutrients and, through their burial, contributing to the oxygenation of overlying waters.
• Large size requires structural support. The two most important structural components of plants and animals, lignin and collagen, require oxygen for their synthesis. Lignin is best known as the cement that binds cellulose into a strong but flexible matrix in the wood of trees... As animals get older, more collagen cross-links form, which is why meat from older animals is tougher than that from younger animals.
• The giant was dubbed the Bolsover dragonfly, but although one of the oldest and most beautifully preserved of fossil insects, it was far from unique.
• The unparallelled rate of coal formation in the Carboniferous and early Permian is explained, then, by an exceptionally high rate of lignin production, an exceptionally low rate of lignin breakdown, and nearly perfect conditions for preserving organic matter on an unprecedented scale. We know of no negative feedback mechanism that could have constrained atmospheric oxygen under these conditions,
• Tiny bubbles trapped in amber might conceivably contain ancient air, which had once dissolved in the resin of trees and later formed pressured bubbles, as the resin hardened to form amber. As luck would have it, Landis had the right equipment for the job: a quadrupole mass spectrometer, ... Might it be the case, Berner and Landis wondered, that, like the dragonflies, the dinosaurs needed high oxygen levels to achieve their giant size, and could not survive in our thin modern atmospheres?
• If we then misguidedly applied the law of fixed proportion, we would have an exaggerated impression of the total amount of carbon that had actually been buried. Any mechanism that makes plants use more carbon-12 than normal could have this effect.
• Plants at high risk of fire may also accumulate high levels of fire retardants, such as silica. Some straws, for example, have an unusually high content of silica, which can make it hard to burn agricultural waste. Housewives apparently discovered this trick long ago: silicate paints were commonly applied to curtains during the Second World War... (Jennifer Robinson) argued that if oxygen levels were high during the Carboniferous, we should expect to find adaptations to fire in fossil plants.
• flying insects achieve the highest metabolic rates in the whole of the animal kingdom. Almost without exception, insect flight is totally aerobic, which means that their energy production is dependent entirely on oxygen... Sprinters cannot breathe in enough oxygen to power their efforts and their muscle cells must instead resort to the less efficient process of energy production by anaerobic glucose breakdown, or glycolysis, which produces a mild poison, lactic acid, as a by-product... If you ever thought that a housefly never grows tired of buzzing, you were probably right: unfortunately for us, it does not poison itself with lactic acid.
• Then Chapelle and Peck had a clever idea and applied it to their amphipod data. What if the true correlation was not with water temperature at all, but with the dissolved oxygen concentration? Oxygen dissolves better in colder water and is nearly twice as soluble in polar seas than in tropical waters. The salt content also affects the solubility of oxygen, which dissolves 25 per cent better in fresh water than in saline. <> The highest oxygen saturation is therefore in large freshwater lakes verg-ing on the Arctic tundra, such as Lake Baikal — and this is where the largest crustaceans are to be found.
• The answer is that radiation exerts its biological effects through a mechanism that is very similar to the effects of oxygen poisoning. The mechanism hinges on an invisible thread of reactions, linking oxygen to water. The lethal effects of radiation and oxygen poisoning are both mediated by exactly the same fleeting intermediates along this pathway... Respiration can therefore be seen as a very slow form of oxygen poisoning... The fleeting intermediates produced by radiation and respiration are called free radicals.
• The problem is that we are not dealing with a chemical reaction between two molecules, but with an interaction between radiation energy and a single water molecule. Ionizing radiation always interacts with matter at the level of individual atoms, and it cannot produce hydrogen and oxygen molecules ‘just like that’. What it does produce stimulated debate throughout the twentieth century, as the products are normally so short-lived.
• •OH is a free radical called the hydroxyl radical — a ferocious molecule that is among the most reactive substances known... This is a fundamental feature of all free radical reactions — one radical always begets another, and if this radical is also reactive, then a chain reaction will ensue. Thus the cardinal feature of a free radical is an unpaired electron, while the cardinal feature of free-radical chemistry is the chain reaction. <> We are all familiar with free-radical chain reactions when they happen in fatty foods such as butter: they are responsible for rancidity.
• A dramatic non-biological example of the power of free-radical chain reactions is the hole in the ozone layer... CFCs are shredded by ultraviolet rays in the upper atmosphere, and disintegrate to release chlorine atoms... They can steal electrons from almost anything. Just one chlorine atom can set in motion a chain reaction that might destroy 100 000 ozone molecules.
• There are only two ways for a free-radical chain reaction to end: when two radicals react with each other, and their unpaired electrons conjoin in blissful chemical union; or when the free radical product is so feebly reactive that the chain reactions fizzle out, like handbag thieves overcome with remorse. Some well-known antioxidants, such as vitamin C and vitamin E, act in this way. Although the products of their reactions with a free radical are themselves free radicals, they are so poorly reactive that the chain reactions squib out before too much damage is done.
• If radiation strips a second electron from water, the next fleeting intermediate is hydrogen peroxide (H2O2) ... The oxidizing properties of hydrogen peroxide can kill bacteria, and are in part responsible for the mildly antiseptic properties of honey, which has been used to treat wounds since ancient times... (H2O2) can go either way in its reactions (losing or gaining electrons) depending on the chemical company it keeps. It can even go both ways at once, when reacting with another hydrogen peroxide molecule... A far more dangerous and significant reaction, however, takes place in the presence of iron, which can pass electrons one at a time to hydrogen peroxide to generate hydroxyl radicals. If dissolved iron is present, hydrogen peroxide is a real hazard. Organisms go to great lengths to avoid contamination with dissolved iron. The reaction between hydrogen peroxide and iron is called the Fenton reaction
• with oxygen all around us, the fact that living things do not burst spontaneously into flame betrays an odd reluctance on the part of oxygen to react. The reason for its reticence is buried within the bonds of the oxygen molecule itself... the great Scottish chemist Sir James Dewar, who found that oxygen is magnetic... In 1925, Robert Mulliken finally explained why oxygen is magnetic, using recently developed quantum theory. Magnetism results from the spin of unpaired electrons, and Mulliken showed that molecular oxygen normally has two unpaired electrons.4 These electrons dominate the chemistry of oxygen and make it hard for the gas to receive a bonding pair of electrons; hence the reluctance of oxygen to react by forming new chemical bonds... On the basis of bond strengths and magnetism, oxygen has three bonds rather than two: one bond has two electrons, while the other two bonds have three electrons, one of which is unpaired in each bond... The second way of coaxing oxygen to react is to feed it with electrons one at a time, so that each of the unpaired electrons receives a suitable partner independently. Iron can do this, as it has its own unpaired electrons (which makes it magnetic too). Iron loses these electrons without becoming unstable because it has several different ‘oxidation states’,
• The continual production of superoxide radicals by cells means that, despite the emotive associations of radiation sickness, breathing oxygen carries a qualitatively similar risk. <> Estimates suggest that, at rest, about 1 or 2 per cent of the total oxygen consumed by cells escapes as superoxide radicals,... breathing for a year would seem to be 10 000 times more dangerous than a chest x-ray,
• Photosynthesis uses light to split water, a trick that we have seen is neither easy nor safe: it amounts to the same thing as irradiation. A catalyst such as chlorophyll gives ordinary sunlight the destructive potency of x-rays. The waste product is oxygen, a toxic gas in its own right.
• the invention of oxygenic (oxygen-producing) photosynthesis surely increased global organic productivity by two or three orders of magnitude. Once life had invented oxygenic photosynthesis, there was no looking back. But this is with hindsight. Darwinian selection, the driving force of evolution, notoriously has no foresight.
• There is good circumstantial evidence that oxidative stress, produced by solar radiation as on Mars (see Chapter 6, page 129), lies behind the evolution of photosynthesis on the Earth.
• The interaction of light with any molecule always takes place at the level of the photon. In photosynthesis, chlorophyll is the molecule that absorbs photons. It cannot absorb any photon — it is constrained by the structure of its bonds to absorb photons with very particular quantities of energy. Plant chlorophyll absorbs photons of red light, with a wavelength of 680 nanometres... To extract electrons from water requires extra energy, which must be acquired from higher-energy photons. To do this requires a change in the structure of chlorophyll, so it can absorb red-light photons instead of infrared light.
• Inside a modern plant leaf the oxygen concentration can reach three times atmospheric levels. Tiny cyanobacteria pollute themselves and their immediate surroundings in a similar fashion... Some of this excess oxygen inevitably steals stray electrons to form superoxide radicals. The risks are huge. Chaos could break out at any moment. The closest analogy is a nuclear power station... If photosynthesis is to work at all, the reactive intermediates from water must be sealed inside a structure that immobilizes them, preventing them from escaping before oxygen is released.
• It is the exact equivalent of the natural reaction between two molecules of hydrogen peroxide, but is speeded up 100 million times by the enzyme. The need for two molecules of hydrogen peroxide means that catalase is extremely effective at removing hydrogen peroxide when concentrations are high, when it is easy to bring two molecules together... Catalase is thus swift to remove high concentrations of hydrogen peroxide, but is poor at mopping up trace amounts or at maintaining a stable low-level equilibrium.
• In the shallow seas and freshwater lakes, however, there was much less iron. These low levels of iron could plausibly have been depleted, or exhausted, by a steady drizzle of hydrogen peroxide. With the loss of iron and hydrogen sulphide, such secluded environments would have grown steadily more oxidized...
• oxygenic photosynthesis only ever evolved once. All algae, all plants, the entire green planet, use exactly the same system. All of them inherited it from the cyanobacteria, which invented it once, perhaps 3.5 billion years ago. No other cells on Earth ever learnt to split water... Without catalase, oxygenic photosynthesis never evolved. Without photosynthesis, free oxygen never accumulated in the air.
• The detailed structure of eukaryotic genes came as one of the greatest surprises of molecular biology in the last quarter of the twentieth century. Far from being continuous compact coding sequences, neatly lined up like beads on a string, as we once imagined (and as bacterial genes had been shown to be), eukaryotic genes are discontinuous and comprise just a few per cent of the cell’s total DNA.
• Bacteria have a fraction of the number of genes of most eukaryotes — a few thousand, instead of tens of thousands. They organize these genes into groups with similar function, known as operons, and carry very little junk DNA. Nor are they encumbered with stacks of internal membranes, protein skeletons or organelles such as mitochondria. This lack of clutter allows them to divide at huge speeds simply by binary fission, or splitting in half. They can also recombine their genes with those of other bacteria by what amounts to copulation — the direct injection of genes into a neighbouring bacterium in a process known technically as conjugation. This allows genetic innovations, such as resistance to antibiotics, to spread rapidly through an entire bacterial population.
• The conclusion from all this — that all life on Earth has a common ancestor — is backed up, most convincingly of all, by the surprising unity of life at its most basic level: the ‘handedness’ of individual molecules... All life is right-handed in its molecular preference. The only sensible explanation for this extreme conservatism is that LUCA herself was right-handed — a historical accident — and that all her descendants have been obliged to follow suit.
• It is now accepted, as one of the basic tenets of biology, that chloroplasts and mitochondria (the energy ‘power-houses’ of eukaryotic cells) were once free-living bacteria. Many details betray their former status. <> Both, for example, retain a genetic apparatus,.. Mitochondrial DNA, for example, like bacterial DNA, comes packaged as a single circular chromosome, and is naked (not wrapped in proteins)... Mitochondria are also purple, and are in fact one of the few coloured components of the cell. In a vivid aside in The Energy of Life, Guy Brown remarks that ‘were it not for the melanin in our skin, myoglobin in our muscles and haemoglobin in our blood, we would be the colour of mitochondria.
• For example, the genes encoding the oxygen-carrying haemoglobins have diverged at a rate of about 1 per cent every 5 million years. This means that close relatives, which diverged only recently, have similar haemoglobin sequences, whereas distant relatives have quite different haemoglobins. Similar patterns apply to other essential and widely shared genes, such as that for the respiratory protein cytochrome c.
• Woese recognized that of all the components of a cell, ribosomes were the closest approximation to a cantilever — absolutely indispensable to all aspects of cellular function — and were therefore highly unlikely to undergo rapid mutation or wander around the gene pool. Furthermore, because the sequence of letters in ribosomal RNA is an exact replica of the gene, ribosomal RNA sequences could be compared directly, without recourse to the genes themselves... Woese therefore settled on ribosomal RNA as a yardstick of evolution... This could only mean that the split between bacteria and eukaryotes had taken place very early indeed, perhaps not long after the first stirrings of life itself. This in turn meant that the eukaryotes could not have evolved gradually from bacteria over 2 billion years, as everyone had expected.
• Today, instead of five kingdoms, we recognize three great domains of life: the Bacteria, the Archaea and the Eukaryotes.
• Enzymes that function normally at high temperatures and pressures are an answer begging for an application. Already enzymes extracted from archaea have been added to detergents and have been used for cleaning up contaminated sites such as oil spills. ... These sequences at once confirm the great antiquity of archaea, and their splendid isolation over the aeons. But the greatest surprise is how many genes the archaea do have in common with bacteria.
• Our obvious dependency on oxygen conceals the fact that individual cells within internal organs are not at all adapted to bathe in an oxygen bath. The development of multicellular organisms can even be considered an antioxidant response, which has the effect of lowering oxygen levels inside individual cells. Our elegant circulatory system, which is usually presented as a means of distributing oxygen to individual cells, can be seen equally as a means of restricting, or at least regulating, oxygen delivery to the correct amount.
• This is essentially how leghaemoglobin works in the root-nodule system — it maintains intracellular oxygen at a low level, releasing its own oxygen on demand... Whales and other diving mammals have very large muscular stores of myoglobin, which can pool large quantities of oxygen, allowing them to remain under water without breathing for an hour at a time.
• here’s a summary of the new evolutionary scheme. LUCA lived in a world scorched by radiation... if LUCA was metabolically versatile, then she must have lived in a world demanding versatility, and this must have included the surface layer of the oceans.
• As such, antioxidants maintain oxygen levels within physiological limits, rather than simply mopping up free radicals. This is a crucial distinction. Antioxidant treatments often aim to eliminate free radicals, but by doing so may instead strain the regulatory balance.
• VC proponent Linus Pauling: Only in 1954, when he won the Nobel Prize for Chemistry, and the New York Times brought the controversy to light, was he permitted to travel again. Similar struggles plagued his position at the California Institute of Technology.
• They note that gulonolactone oxidase produces hydrogen peroxide as a by-product of vitamin C synthesis. This means that high rates of vitamin C synthesis in animals such as the rat could, ironically, impose an oxidative stress.
• lemons might have done as much as Nelson to defeat Napoleon. The situation did not last long. In a cost-cutting measure typical of the British over the ages, the Admiralty replaced lemons with cheaper limes, which contain barely a quarter as much vitamin C. Scurvy soon reappeared. To add insult to injury, British sailors acquired the nickname ‘limeys’.
• Budd prophesied that scurvy was due to the “lack of an essential element, which it is hardly too sanguine to state will be discovered by organic chemistry or the experiments of physiologists in a not too distant future”. <> In the event, fulfilment of Budd’s prophesy had to wait another 93 years, in part because the concept of deficiency diseases was set back by Pasteur’s germ theory of disease, which was then applied with indiscriminate enthusiasm to almost any condition.
• In the course of this defence, neutrophils vacuum up vitamin C from their surroundings... finally, we see an action of vitamin C that seems to be an antioxidant effect... Neutrophils need this extra protection to survive the wrath of their own assault, as they turn their immediate environment into a battlefield. The effect is a little like soldiers strapping on their gas masks before releasing chlorine gas onto the enemy. Instead of chlorine gas, neutrophils produce a burst of free radicals and other powerful oxidants (including hypochlorous acid, derived from chlorine), which are responsible for bacterial killing.
• Why is vitamin C used so extensively as an electron donor?... First, vitamin C is very soluble in water, so it can be concentrated in confined spaces surrounded by membranes... The second reason... is that the reaction product is fairly stable and unreactive.
• the darker side of vitamin C. We have noted the link between iron, vitamin C and oxygen. When vitamin C interacts with iron and oxygen, it is acting as an electron donor, but not as an antioxidant. Quite the contrary. By regenerating the active form of iron inside an enzyme, vitamin C aids and abets the addition of oxygen — in other words, it helps to oxidize the substrate.
• Rather surprisingly, we have no specific mechanism for removing excess iron from the body, save menstrual bleeding or the shedding of gut-lining cells. The rate of absorption of iron therefore needs to be regulated tightly.
• the third broad conclusion that we can draw from vitamin C. The precise behaviour of an antioxidant depends on its surroundings. Whether vitamin C acts as an antioxidant, or a pro-oxidant, or somewhere in between, depends primarily on its interactions with other molecules.
• By protecting against free-radical damage, mucus goes some way towards explaining the remarkable ability of bacteria to survive in outer space and in other highly irradiated environments... Bacterial mucus is a mixture of long-chain polymers, analogous to plastics, which have one thing in common: they all carry a negative electrical charge... Yet by stockpiling iron in their jackets, bacteria make sure that any dangerous free-radical reactions take place at arms length, rather than inside the cell itself. The mucus acts as a sacrificial target and the iron is converted into biologically inactive rust... The presence of hollow microscopic pits in the structure of some banded iron formations suggests that these rocks might have been formed from the buried corpses of innumerable iron-encrusted bacteria. As the bacteria themselves dissolved away, only the metal jackets remained to testify to the existence of a mass graveyard.
• We too hide behind a layer of dead cells, otherwise known as the skin. Like the ciliates, we too use haem proteins as sensors to maintain internal oxygen at a constant low level. Like the sulphate-reducing bacteria, we too use sulphur as a buffer against oxygen
• The increase in body size compensates for the higher external oxygen levels, especially in diffusion-limited creatures such as the Bolsover dragonfly. An increase in size presumably lowers the oxygen levels within the end-users, the mitochondria.
• A different balance must be found, in which the dangerous effects of free radicals are prevented or contained by antioxidant enzymes and free-radical scavengers — the second and third defence mechanisms on our list.
• Moreover, the rate at which it disposed of superoxide almost beggared belief. Superoxide radicals are unstable and react with each other within seconds to produce hydrogen peroxide, but haemocuprein sped up this natural reaction by a factor of a billion. Surely this could not be accidental!1 McCord and Fridovich renamed the protein superoxide dismutase (SOD)... The implications transformed the field. If an enzyme as efficient as SOD evolved specifically to eliminate superoxide radicals, then superoxide radicals must be biologically important... People with Down syndrome therefore make too much SOD.
• Many of the best-known antioxidants, including carotenoids, flavenoids, phenols and tannins, must be obtained in the diet from plants. Their relative importance in the body’s antioxidant balance is tricky to determine, but their overall contribution is generally held to be responsible for the benefits of fruit and vegetables.
• Some conditions that we tend to think of as pathological, such as jaundice in newborn babies, may really be an evolved physiological adaptation. In the case of jaundice, evidence suggests that bilirubin is stockpiled in the skin to protect against the oxidative stress of birth. The baby emerges from the cloistered security of the womb into the high-oxygen world outside,.. Similarly, the disfiguring colours of a bruise — courtesy, again, of bilirubin — help to protect against the oxidative stress of traumatic injury,
• the balance of risks and benefits with chain-breaking antioxidants is far from clear. Take uric acid, for example — a potent antioxidant, certainly, but one that at high levels causes the painful inflammation of gout as it crystallizes in the joints.
• The point is that few things serve a single purpose, least of all in biology, and we must fight our instinct to impose one... we saw that vitamin C is used in diverse ways, united only by the same molecular action. This also applies to SOD, catalase or haem oxygenase.
• it is quite possible that the benefits of fruit also relate to other factors, such as mild doses of toxins that stimulate the production of stress proteins like haem oxygenase...
• He began transplanting testicles (removed from recently executed prisoners) into inmates in 1918. Some of the recipients reported full recovery of their sexual potency. By 1920, the scarcity of human gonads induced Stanley to substitute ram, goat, deer and boar testes, which he said worked equally well.
• ‘Doctor’ John R. Brinkley, transplanted hundreds of sliced goat testicles into his ageing customers in Milford, Kansas, where he became so popular that he was nearly voted governor in 1930. Each patient had the privilege of selecting his own goat from the doctor’s herd. The financial success of this venture enabled him to build and operate the first radio station in Kansas — KFKB, or Kansas’ First, Kansas’ Best — through which he brazenly promoted his own secret remedies, including goat gland transplants. After a series of court cases, and opposition from both the American Medical Association and the Federal Radio Commission, Brinkley fled to the Mexican borderlands, where he set up a new, even more powerful, radio station
• Each time a stress-resistant cell reproduces itself, it must replicate multiple copies of its genes, and it is also funnelling a substantial proportion of its energy into the production of more stress proteins... Bacteria, for the most part, do not age. There is no reason for them to do so. They maintain the integrity of their genes by rapid reproduction... The critical point is that the survival of bacterial life involves death on a massive scale.
• When death outweighs life on such a massive scale, natural selection cleanses the population of genetic damage. Only the fittest survive. Perverse as it may sound, the main criterion for immortality is death... If senescence evolved, then it must be determined at least partly by genes,
• Indeed, the males of many species of Hymenoptera, including some wasps, bees and ants, are entirely haploid — they develop from an unfertilized egg. In contrast, the females develop from a fertilized egg, and are diploid... Within six hours of emergence, the worker bees actually find and eat all of the diploid males... Atmar argued that haploid males act as ‘auxiliary defect sieves’, to purge the population of genetic error by exposing latent gene defects to selection. In other words, because genetic errors cannot be concealed in haploid animals, any haploid males with demonstrable vigour must possess a near-perfect complement of genes... Atmar also notes that men are haploid for the X and Y chromosomes, whereas women are diploid for the X chromosome. To the extent that only men suffer from genetic disorders caused by mutations on the Y or X chromosome, such as haemophilia and colour blindness, it may be that we too use a mild form of haploidy to clean up our germ line (the inheritable DNA in sex cells).
• At the most basic level, the function of sex cells is to pass on undamaged DNA to the next generation, while the function of the soma, the body, is to be selected for vigour, not to be perpetuated itself. The origins of this differentiation between sex cells and somatic cells stretch back to the earliest days of sex... The body is a useful but ultimately redundant subsidiary to the germ line — not only mortal, but designed from the very beginning to be thrown away. The advantages are obvious: a body enables the specialization of individual cells — a specialized team has every advantage over the individual amateur — and physical protection for the germ cells. But there is no need for the body to outlast its usefulness.
• The idea is known as the disposable soma theory of ageing,... Kirkwood and Holliday considered the dichotomy between the germ line and the soma as the outcome of a trade-off between survival and reproduction. In essence, to be of any use, the body must survive at least to reproductive age. Survival costs... there is indeed a strong inverse relationship between fecundity and maximum lifespan.
• The discrepancy is simply explained: in primates, longevity has been purchased by deferring sexual maturity, by slowing down the rate of growth to adulthood. Humans live twice as long as gorillas, but take a third longer to reach sexual maturity... they still found that “the longest-lived aristocrats tended, on the average, to have had the greatest trouble with fertility”
• Since resources are limited, said Weismann, it is imperative that parents do not compete with their offspring. Weismann argued that ageing was a means of ridding the population of worn-out individuals, thereby clearing space for offspring, but not so fast as to lose the social benefits of experience... The problem is that a genetically static population is a sitting target for pathogens and predators... even if group selection does not explain the origins of ageing, it remains possible that group selection could maintain ageing once it had evolved.
• If an organ works well enough for its deficiencies not to constitute an adverse selective pressure, then natural selection has no way to improve on it. Conversely, if an organ works better than required (in new circumstances), the random accumulation of negative mutations over generations will gradually degrade its performance to that required, at which point selection pressure will maintain the standard.
• The risk of childbirth is dangerously high for older women, whereas their prolonged survival benefits existing children or grandchildren; hence the menopause.
• A number of genes, so-called gerontogenes, have now been discovered, whose effects can double or even triple the lifespan of simple animals like nematode worms. At first sight, these genes have bemusingly diverse effects, but as we have learned more we have come to see that they are linked by a common factor — oxygen.
• Insulin induces a shift in metabolism towards growth... glucose is taken up rapidly by all cells in the body and stored as the carbohydrate glycogen. Protein and fat synthesis is stimulated, leading to a gain in weight. Breakdown of glycogen and proteins for energy is inhibited. As glucose is used up, blood glucose levels fall. The actions of insulin are countered by the hormone glucagon, which restores blood glucose levels to normal... Here, if anywhere, is the switch between reproduction and longevity, which underpins the disposable soma theory of ageing. In the presence of plentiful food, insulin and the IGFs are produced. The organism gears up for sexual maturation and reproduction, throwing longevity to the wind.
• When almost all babies are born with low birth weight, however, those most likely to survive are insulin-resistant. As in nematodes, insulin-resistance confers general stress-resistance. Children who are genetically insulin-resistant are thus more likely to survive into adulthood, and to pass on their genes for insulin-resistance. This only becomes a problem when a high-carbohydrate diet is imposed on a thrifty genotype.
• others, notably the native Americans and the Pacific Islanders, never herded milk cattle, and remained predominantly lactose intolerant. They were therefore denied the most plentiful source of sugar in a farming community. Whether lactose tolerance signalled the demise of the thrifty genotype in Europeans is unknown, but the fact is that all populations with lactose tolerance have a low susceptibility to diabetes. Conversely, all populations that are lactose intolerant are highly susceptible to diabetes.
• Denham Harman's argument: Ageing and the degenerative diseases associated with it are attributed basic-ally to the deleterious side attacks of free radicals on cell constituents and on the connective tissues. The free radicals probably arise largely through reactions involving molecular oxygen catalysed in the cell by oxidative enzymes and in the connective tissues by traces of metals such as iron, cobalt, and manganese... The problem with the free-radical theory, from the very beginning, was that correlations say nothing about causality.
• The effects of calorie restriction are mediated by concerted changes in gene expression. The benefits are well worth queuing for. In all animals studied so far, calorie restriction delays ageing, not just the timing of death. This is true for more than 80 per cent of the 300 indices of ageing tested in rodents... The net effect of calorie restriction is to increase stress-resistance.
• We saw in Chapter 8 that mitochondria have retained vestiges of their independent past, in particular their own DNA and their ancestral way of dividing, simply splitting in two by binary fission: an asexual process. Mitochondria are therefore asexual genetic systems that replicate themselves within a sexually reproducing organism... Mitochondrial DNA evolves over thousands of years, but is not recombined through sex. Thus, there is no ‘mixing’ of mitochondrial genes... This is the basis of ‘mitochondrial Eve’, the mythical mother of mankind who passed her mitochondrial DNA to all those living on the planet today.
• One possibility put forward by John Allen (who we shall meet later in the chapter) is that mitochondrial genes allow a rapid response to sudden changes in oxygen level, nutrient supply or the presence of respiratory poisons. The energy status of the cell is so critical that cells need to respond swiftly and appropriately to sudden change. Having to rely on bureau-cratic nuclear genes to do this is like waiting on the government
• The story of the Hayflick limit came to a head in 1990, when Cal Harley, founder of the Californian biotechnology company Geron Corporation, made a connection between the ability of cells to count and the length of their telomeres — the ‘tips’ at the ends of individual chromosomes... Telomeres are a characteristic biological fudge: they are needed because our DNA replication machinery was inherited from bacterial ancestors with circular chromosomes, whereas those of all eukaryotes are linear. Because of the way the biochemical machinery for replicating DNA works, it is impossible to replicate the extreme ends of a linear DNA molecule... it is easy enough to add a bit of extra non-coding DNA to each end of the chromosome,
• How do cancer cells escape? It seems they make use of an enzyme, called telomerase, which regenerates the telomeres, so that their length is not perpetually truncated.
• In short, it seems fair to say that, for all the hullabaloo, telomerase does not hold the secret of eternal life.
• My cultured cells had no brush border, and I could see no more than a handful of mitochondria. There was nothing for it but to turn to the textbooks and the original papers. I was in for another shock. My sad cells were exactly what kidney tubule cells were supposed to look like in culture!
• To survive, get rid of your mitochondria — throw them overboard like so much ballast. Cancer cells do. Cancer cells become less differentiated as they multiply, and lose their mitochondria in the process. They thrive on anaerobic respiration. Most tumours are a dense mass of tissue with a low requirement for oxygen. Indeed, oxygen is toxic to many tumours: radiotherapy is three or four times more effective when the tumour is oxygenated.
• Why male mitochondria are not passed on to the next generation? ... Essentially, if mitochondria are inherited from both parents, the stage is set for the evolution of ‘selfish’ organelles. The argument is as follows. When a cell divides, all its nuclear DNA is replicated, with half going to each daughter cell: the two daughters have identical sets of genes, so there is no unequal competition. This is not true of mitochondria, which have their own DNA and use it to replicate independently. The overall make-up of the mitochondrial population in a cell therefore depends on the speed at which individual mitochondria replicate (or break down), and this makes the cell vulnerable to abuse.
• Allen draws on the logic of the mitochondrial theory of ageing to explain the evolution of two sexes. In essence, he argues that male mitochondria are not passed on to the next generation because they are time bombs: they have been fatally damaged by oxygen, and if passed on would cause the birth of prematurely aged babies. Breathing oxygen dictates the need for two sexes. If so, then oxygen is the ultimate gender bender... 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... 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... 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.
• 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, ... 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.
• 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.
• I suggest that there is a trade-off between oxidative stress as a signalling pathway that musters our defences against infection, and oxidative stress as a cause of ageing. In effect, the diseases of old age are the price we pay for the way in which we are set up to handle infections and other forms of stress in our youth... The outcomes are diametrically opposed: resistance to disease in youth and vulnerability to disease in old age.
• Now think what happens during ageing. Our mitochondria leak free radicals, bringing about an insidious rise in oxidative stress as we get older. There comes a point when the oxidative stress is severe enough to activate transcription factors like NFB. We begin to go through a low-grade stress response and inflammation.
• Thus, for most people with Alzheimer’s disease, oxidative stress is the earliest pathological change, and is responsible for producing both main features, the tangles and the plaques.
• Cigarette smoke is dangerous because it is the most dastardly free-radical generator known
• Glucose reacts in a complex manner with proteins to form brownish caramels that accumulate with age, known as advanced glycation end-products, or AGEs (this is also why meat browns when it is cooked). Such caramels account for the clouding of the lens of the eye in a cataract. Caramelization of proteins is accelerated by oxygen, and most AGEs are really oxidation products.
• After the Carboniferous, the climate grew cooler and drier, and the great coal swamps dried up. The first reptiles developed scales and shelled eggs to escape the constraints suffered by amphibians, which depended on water. Eggs with shells could be laid on land and did not dry out... As a related historical accident, the hard shell made copulation necessary. The shell forms before the egg is laid, so fertilization has to take place internally.
• recap: On Earth, photosynthetic cyanobacteria injected oxygen into the air, and fast: faster than the volcanoes could spew out sulphurous gases, faster than erosion could expose virgin rocks to the air... As oxygen built up, an ozone layer formed, which blocked the penetration of ultraviolet radiation into the lower atmosphere. The loss of oceans slowed to a trickle on Earth but continued apace on Mars and Venus, where no oxygen buffer had formed... In the next, larger, injection, which followed the snowball Earth and mountain-building episodes around 2.3 to 2.2 billion years ago, the eukaryotes made their first robust appearance in the fossil record. Soon after, the fossil record began to show signs of multicellular algae; but little else happened in the next billion years. Then came the greatest of all geological roller-coaster rides: a succession of at least two snowball Earths, in which ice shrouded the Earth episodically over a 160 million-year period and finally pushed atmospheric oxygen up to modern levels.
• Then one day a eukaryotic cell happened to swallow an oxygen-guzzling purple bacterium. Suddenly it could swim with apparent impunity through the shallow seas, protected from oxygen by its internal vacuum cleaner. The insider deal blossomed into a Mephistophelean pact: as the purple bacteria turned into modern mitochondria, they exchanged their surplus energy for a life spent dicing with death. Oxygen mutated DNA, forcing genes to change and evolve. It must have been one of the factors that drove the evolution of the most efficient of all genetic cleansing mechanisms, sexual recombination. But mitochondria presented a unique and profound problem of their own: they retained some genes that were necessary for the function of the eukaryotic cell as a whole... The solution was not sex but sexes. Given two sex cells that would combine to form the next generation, one cell could be powered by mitochondria destined for disposal, like the fuel tanks of a rocket, while the other could maintain its mitochondrial population in a dormant state
• So long as we avoid really serious illness, a weak disposition might perhaps lend itself to persistent immunosuppression, which reaps its reward in old age.
• there is a dilemma at the heart of immune modulation, however refined it is: the benefits are always part of a trade-off between susceptibility to infections, on the one hand, and to age-related diseases on the other. Any benefits will depend on a delicate balancing act in which genes, diet, environment, behaviour and luck all have a role.
• It is hopeful, as it shows us that ageing is neither programmed nor inevitable, even if it cannot easily be put off. It is corrective, for it shows us the fallacy of chasing ‘susceptibility’ genes for the diseases of old age. It is constructive, in that it points us to the fields of research that might best tackle the problem of ageing — immune modulation and mitochondrial medicine. And it is practical, for it offers us a rational guide to good health in old age: eat widely, but not too much, don’t be obsessively clean or get overly stressed, don’t smoke, take regular exercise, and keep an active mind.