by Nick Lane
This discrepancy is partly responsible for the schism that has opened between Margulis and neo-Darwinists like Dawkins. As we have seen, Dawkins’ ideas about selfish genes are equivocal when applied to bacteria (which he does not try to do). For Margulis, however, the whole tapestry of evolution is woven by the collaborations of bacteria, which form not just colonies but the very fabric of individual bodies and minds, responsible even for our consciousness, via the threadlike networks of microtubules in the brain. Indeed, Margulis pictures the entire biosphere as the construct of collaborating bacteria—Gaia, the concept that she pioneered with James Lovelock. In her most recent book, Acquiring Genomes: A Theory of the Origins of Species, written with her son Dorion Sagan, Margulis argues that even among plants and animals, new species are formed by means of a bacterial-style merging of genomes, rather than the gradual divergence pictured by Darwin, and accepted by virtually every other biologist. Such a theory of merging genomes might be true in some instances, but in most cases it flies in the face of a century of careful evolutionary analysis. In dismissing neo-Darwinism, Margulis deliberately provokes the majority of mainstream evolutionists.1 Few have the patience displayed by the late Ernst Mayr, who contributed a wise foreword to the book, in which he commended Margulis’s vision of bacterial evolution, while cautioning the reader that her ideas don’t apply to the overwhelming majority of multicellular organisms, including all 9000 species of bird, Mayr’s own particular field of expertise. The reality of sexual reproduction means that genes must compete for space on the chromosomes; and the rise of predation in the eukaryotes means that nature, at this level, really is red in tooth and claw, however much we may wish it otherwise.
Given their different perspectives, it’s ironic that the views of Dawkins and Margulis do not diverge as far as one might think when it comes to the individual. As we have seen, Dawkins wrote of the individual as a colony of collaborating genes, while Margulis thinks of an individual as a colony of collaborating bacteria, which might be construed as a colony of collaborating bacterial genes. Both see the individual as a fundamentally collaborative entity. Here is Dawkins, for example, in his splendid book The Ancestor’s Tale: ‘My first book, The Selfish Gene, could equally have been called The Cooperative Gene without a word of the book itself needing to be changed… Selfishness and cooperation are two sides of a Darwinian coin. Each gene promotes its own selfish welfare, by cooperating with other genes in the sexually stirred gene pool which is the gene’s environment, to build shared bodies.’
But the ideal of collaboration does not give proper weight to the conflict between the various selfish entities that make up an individual, and in particular to the cells and mitochondria within the cells. While conflict between various selfish entities is entirely in keeping with Dawkins’s philosophy, he did not develop the idea in The Selfish Gene—these ideas awaited his own later book The Extended Phenotype, and in the 1980s and 1990s the important work of Yale biologist Leo Buss and others. Thanks to the exploration of such conflicts and their resolutions, evolutionary biologists now appreciate that colonies of cells (or genes, if you like) do not constitute true individuals, but rather form a looser association, in which individual cells may still act independently. For example, multicellular colonies like sponges often fragment into bits, each of which is able to establish a new colony. Any commonality of purpose is transitory, for the fate of individual cells is not tied to the fate of the multicellular colony.
Such cavalier behaviour is ruthlessly suppressed in true individuals, in whom all selfish interests are subordinated to a common purpose. Various means are employed to guarantee a common purpose, including the early sequestration of a dedicated germ-cell line, so that the great majority of cells in the body (so-called somatic cells) never pass on their own genes directly, and can only participate in the next generation voyeuristically, as it were. Such voyeurism could not possibly work if the individual cells within the body did not share identical genetic bonds—all derive from a single parent cell, the fertilized egg (the zygote), by asexual, or clonal, replication. Although their own genes are not passed on directly to the next generation, the germ-line cells do pass on exact copies of them, which is the next best thing, and ultimately little different. Even so, carrot measures are not enough: stick measures are also needed. The resolution of selfish conflicts between the cells themselves, even though they are genetically identical, can only be achieved by the imposition of a police state reminiscent of Stalinist Russia. Offenders are not prosecuted but eliminated.
The consequence of this draconian system is that natural selection ceases to pick and choose between the independent entities that make up an individual, and begins to operate at a new and higher level, now choosing between the competing individuals themselves. Yet even within apparently robust individuals, we can still detect echoes of dissent, a reminder that the unity of an individual was hard won, and all too easily lost. One such echo of the past is cancer, and it is to this, and the lessons we can learn from it, that we turn in the next chapter.
11
Conflict in the Body
Cancer is a chilling ghost of conflict within an individual. A single cell opts out of the body’s centralized control and proliferates like a bacterium. At a molecular level, the sequence of events is one of the most graphic illustrations of natural selection at work. Let’s consider briefly what happens.
Cancer is usually, but not always, the result of genetic mutations. A single mutation is rarely enough. Typically, a cell must accumulate eight to ten mutations in rather specific genes before it can transform into a malignant cell, whereupon the transformed cell puts its own interests before those of the body. Genetic mutations tend to accumulate at random as we grow older, but it takes a particular combination to cause cancer: mostly the mutations must be in two sets of genes known as oncogenes and tumour-suppressor genes. Both sets code for proteins that control the normal ‘cell cycle’—the way in which cells proliferate or die in response to signals from elsewhere in the body. The products of oncogenes normally signal a cell to divide in response to a particular stimulus (for example, to replace dead cells after an infection) but in cancer they get stuck in the ‘on’ position. Conversely, the products of tumour suppressor genes normally act as a brake on uncontrolled cell division: they countermand the signals for proliferation, making cells quiescent, or forcing them to commit suicide instead. In cancer, they tend to get stuck in the ‘off’ position. There are numerous checks and balances in cells, which is why it takes an average of eight to ten particular mutations before a cell transforms into a cancer cell. People with a genetic predisposition to cancer may inherit some of these mutations from their parents, leaving them with a lower threshold of ‘new’ mutations that must accumulate before the onset of cancer.
Transformed cells no longer respond normally to the body’s instructions. As they proliferate, they form into a tumour. Yet there is still a big distinction between a benign growth and a malignant tumour: many other changes still have to take place for a cancer to spread. First of all, to grow larger than a couple of millimetres across, the tumour requires sustenance. Slow absorption of nutrients across the surface of the tumour is no longer enough—the tumour cells need an internal blood supply. To acquire a blood supply, they need to produce the right chemical messengers (or growth factors) in appropriate quantities to stimulate the growth of new blood vessels into the tumour. Further growth requires digestion of the surrounding tissues, giving the tumour space to invade: the cells need to spray potent enzymes that break down the tissue structure. Perhaps the most feared step is the leap to remote sites elsewhere in the body—metastasis. The properties required are opposing and specific. Cells must be slippery enough to escape the clutches of the tumour, and yet sticky enough to bind to the walls of blood vessels elsewhere in the body. They must be able to evade the attentions of the immune system during their passage through the blood or lymph system, often by ‘sheltering’ in a clump of cells that bind to
gether despite their slipperiness. On arrival, the cells must be able to bore their way through the vessel walls, into the safe haven of the tissue behind—but then stop there. And throughout this hazardous solo journey they must retain their ability to proliferate, to found a cancerous outpost in the new continent of a different organ.
Luckily very few cells come equipped with the dialectical qualities needed to cause metastatic cancer. Yet few of us are untouched by cancer, if not ourselves, then our family, relatives, and friends. How, then, do cells acquire all the properties needed? The answer is that cancer cells evolve by natural selection. In the course of our lifetime, cells acquire hundreds of mutations, some of which may just happen to affect the oncogenes and tumour-suppressor genes that control the cell cycle. If a single cell is freed from the shackles that normally prohibit its proliferation, it proliferates. Soon it is not a single cell but a colony of cells, all of which are busily picking up new mutations. Many of these mutations are neutral, others are detrimental to the cells, but in time a few will cause a single cell to take the next step down the road to malignancy, then the next, and the next. Each time, the descendents proliferate: what had been a singular mutant becomes a heaving population, until this, too, is displaced by another single cell adapted to the next step. In the space of a few years, even a few months, the body becomes riddled with cancer. The cancer cells have no prospects—they are doomed to die as surely as we are. They simply do what they must, grow and change, a progression dictated by the inexorable blind logic of variation and selection.
What is the unit of selection in cancer, the gene or the cell? As we saw with bacteria, it makes more sense to think of the cells themselves as the selfish unit. The cells do not replicate by sex, but in the manner of bacteria, by asexual replication. The genes may change faster than the phenotype of the cell, which at least for a period retains many aspects of its provenance, including its appearance down the microscope. Even metastatic cancers betray their origins: if we scrutinize a tumour in the lung, it is usually possible to tell whether it is a ‘primary’ tumour, derived from the lung cells, or a ‘secondary’ tumour, a metastatic outpost of cells from a distant tissue such as the breast. We know because they still retain some atavistic traits of ‘breast’ cells, such as hormone production. At the same time, cancer cells are notorious for their genetic instability: chromosomes are lost, or broken, or cobbled together in wild rearrangements. So while the cells retain a semblance of their former appearance, their genes are scrambled out of recognition by mutations and rearrangements. If there is a ‘selfish’ evolutionary unit, surely it is the cell, which leaps all hurdles in its way until finally killing its master, a course as heavily laden with fate as that of Macbeth.
In cancer, the word ‘selfish’ rings hollow. There is no sense in which a malignant tumour is making a bid for freedom—it is simply a ghost in the machine, a pointless reversion to an earlier type, which ruled before the evolution of the ‘individual’—that of cells doing their own thing. In this sense, cancer gives a dull and empty sense of the sheer meaninglessness of evolution. Cells replicate, and the cells that replicate best leave the most descendants. That’s it. It’s hard to think of any deeper meaning for cancer: it is mindless mechanics and no more. This contrasts with that other revealing view of evolution in microcosm, bacterial infection, where for all the grinding levers of bacterial replication there is still a strong whiff of purpose: we may find infections abhorrent, but we do accept that bacteria have a point—a life cycle, a future, an ‘objective’. They’re not doomed, but go on to infect another individual. (Of course, this distinction is in itself imaginary—neither bacteria nor cancer cells have any ‘purpose’. However, cancer is a useful example, for it is plain that cancer cells are not equipped to outlive the body, and so the futility of their short-term success in self-replication is transparent.)
If cancer has no meaning, it does at least illustrate the obstacles that must be overcome to forge an individual. If today we still succumb to the lawlessness of cancer, what hope had the first individuals? In those days of looser associations, deserters had the same chance as bacteria of making it alone: desertion was not futile. How did the first individuals quell the strong tendency of their own cells to rebel? It seems they did so in the same way that we do today: they killed the transgressors via a mechanism known as programmed cell death, or apoptosis—they forced the dissident cells to commit suicide. Apoptosis exists even in cells that spend part of the time as independent free-living cells, and part of the time in colonies, begging the question: how and why did apoptosis evolve in single-celled organisms? Why would a potentially independent cell ‘agree’ to kill itself?
Much of our understanding of apoptosis comes from the study of its role in cancer. The more we learn, the more we appreciate that mitochondria play the title role in apoptosis. And as we trace our way back through evolutionary time, it emerges that apoptosis evolved out of the manipulative campaigns between mitochondria and their host cells in the first eukaryotes—at a time when colonies were far from the rule.
Chronicle of a death foretold
There are two main forms of cell death: the violent, unexpected, swift demise known as necrosis, in which the carpet is left stained with blood and gore; and the silent, premeditated swallow of a cyanide pill, apoptosis, in which all evidence of the deed is spirited away. This is the spooks’ end, and it seems appropriate in the Stalinist state of the body. In contrast, death by necrosis incites an unruly inflammatory reaction, equivalent to an incendiary police investigation, in which more bodies turn up, and the ructions take a long time to fade.
Historically, there has been a curious reluctance among biologists to cede full significance to apoptosis. Biology, after all, is the study of life and there is a sense in which death, the absence of life, is beyond the remit of biology. Many of the early observations of programmed cell death were treated as curiosities without wider meaning. One of the earliest observations was in 1842, from the German revolutionary, savant, and materialist philosopher, Karl Vogt, whose politics had forced him to flee to Geneva, and whose dealings with Napoleon III later made him the target of Karl Marx’s brilliant polemical pamphlet, Herr Vogt (1860). Perhaps it’s more edifying to remember Vogt for his careful studies of the metamorphosis of the midwife toad, from the tadpole into the adult. In particular, Vogt used a microscope to follow the fate of the flexible, primitive backbone of the tadpole, the notochord: did the cells of the notochord transform into the spinal column of the adult toad, or did they disappear, making way for new cells which formed the spinal column? The answer turned out to be the latter: the cells of the notochord die off, by apoptosis as we now know, and are replaced by new cells.
Other ninteenth-century observations also concerned metamorphosis. The great German pioneer of evolutionary biology, August Weismann, noted in the 1860s that many cells die off quietly during the transformation of the caterpillar into the moth, but curiously he did not discuss his findings in relation to ageing and death, subjects that later made him famous. Most subsequent descriptions of orderly cell death also came from embryology—the changes that take place during development. Most strikingly, whole populations of neurons (nerve cells) were found to die off in fish and chick embryos. The same applies to us. Neurons disappear in successive waves during embryonic development. In some regions of the brain, more than 80 per cent of the neurons formed during the early phases of development disappear before birth! Cell death allows the brain to be ‘wired’ with great precision: functional connections are made between specific neurons, enabling the formation of neuronal networks. But the same general theme of sculpting pervades all of embryology. Just as the sculptor chips away at a block of marble to create a work of art, so too the sculpting of the body is achieved by subtraction rather than addition. Our fingers and toes, for example, are formed by orderly cell death between the digits, not by forming discrete extensions to a ‘stump’. In web-footed animals such as ducks, some of the cells do no
t die, so the feet remain webbed.
Despite its importance in embryology, the role of apoptosis in adults was not appreciated until much later. The name itself was coined in 1972 by John Kerr, Andrew Wyllie, and Alastair Currie, all then at Aberdeen University, following the suggestion of James Cormack, professor of Greek at that university. It means ‘falling off’, and was introduced in the title of their paper in the British Journal of Cancer: ‘Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics.’ Being Greek, the second ‘p’ is silent, so the term should be pronounced ‘ape-oh-toe-sis’. The word had been used by the ancient Greeks, originally Hippocrates, to mean ‘the falling off of the bones’, an opaque phrase that referred to the erosion of fractured bone beneath gangrenous bandages; while Galen later extended its meaning to ‘the dropping off of scabs’.
In modern times, John Kerr noticed that in rats the size of the liver was not fixed, but changed dynamically with fluctuations in blood flow. If blood flow was impaired to certain lobes of the liver, the affected lobes compensated by becoming gradually smaller over a period of weeks, as cells were lost by apoptosis. Conversely, if blood flow was restored, the corresponding lobes gained in weight, again over weeks, as cells proliferated in response. This balancing act is generally applicable. Every day in the human body, some 10 billion cells die and are replaced by new cells. The cells that die do not meet a violent unpremeditated end, but are removed silently and unnoticed by apoptosis, all evidence of their demise eaten by neighbouring cells. This means that apoptosis balances cell division in the body. It follows that apoptosis is just as important as cell division in normal physiology.