Power, Sex, Suicide: Mitochondria and the Meaning of Life (37 page)

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.

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 not 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.

In their 1972 paper, Kerr, Wyllie, and Currie presented evidence that the form of cell death is basically similar in numerous disparate circumstances—in normal embryonic development as well as teratogenesis (malformation of the embryo); in healthy adult tissues, cancers, and tumour regression; and in the shrinkage of tissues with disuse and ageing. Apoptosis is also critical to immune function: immune cells that react against our own body tissues commit apoptosis during development, enabling the immune system to distinguish between ‘self’ and ‘non-self’. Thereafter, immune cells exert many of their own effects by inducing damaged or infected cells to undergo apoptosis themselves. This kind of screening by immune cells eliminates incipient cancer cells before they get a chance to proliferate.

The sequence of events in apoptosis is precisely choreographed. The cell shrinks and begins to develop bubble-like blebs on its surface. The DNA and proteins in the nucleus (the chromatin) condense in the vicinity of the nuclear
membrane. Finally, the cell breaks up into small membrane-wrapped structures called apoptotic bodies, which are taken up by immune cells. Effectively, the cell packages itself into bite-sized chunks, which are then cannibalized without fanfare. Consistent with such a choreography, apoptosis requires a source of energy in the form of ATP—if deprived of ATP, a cell cannot undergo apoptosis. So the process is very different from the swelling and rupture characteristic of necrosis, the violent unpremeditated form of cell death. Also unlike necrosis, there is no aftermath to apoptosis, in particular no inflammation: nothing to mark the passing of a cell but its absence. It is a death foretold, but unremembered.

For more than a decade, Andrew Wyllie and a handful of others persevered, evangelists of apoptosis, in the face of indifference in the wider biological community. Wyllie began to convert the unbelievers through his discovery that, in apoptosis, the chromosomes break up into segments that exhibit a characteristic laddering pattern on biochemical analysis. This finding enabled apoptosis to be diagnosed in the lab, overcoming the cynical biochemists’ perpetual suspicion of electron-microscope artefact. But the real turning point came in the mid 1980s, when Bob Horvitz, at MIT in Boston, set about identifying the genes responsible for apoptosis in the nematode worm
Caenorhabditis elegans
, research for which he shared the Nobel Prize in 2002.
C. elegans
is a tiny, microscopic worm which offered several big advantages—first, it is transparent, so researchers could actually make out the fate of individual cells down the microscope; second, a small, predictable group of cells, 131 of the 1090 somatic cells (body cells, as opposed to germ-line cells) comprising the nematode, die by apoptosis during embryonic development; and third, the mean lifespan of
C. elegans
is barely 20 days, so its swift development is easily tracked in the lab.

Horvitz and his colleagues discovered several genes that coded for the effectors of cell death in nematodes—the death genes. Their findings were fascinating in their own right, but by far the most unexpected and important discovery was that there were exact equivalents of the death genes in flies, mammals, and even plants. Cancer researchers had already identified some of these genes at the time, but why or how they were involved in cancer was still unknown. The link with nematodes made their function clear, while giving another demonstration of the fundamental unity of life. Not only were the human genes unambiguously related to the nematode genes, but also they could even be genetically engineered to replace the nematode genes in the worms themselves, where they worked equally well! Mutations that disabled any of the
death genes prevented the nematodes from losing their 131 cells by apoptosis as usual. The implications for cancer were plain: if the same mutations had a similar effect in people, then incipient cancer cells would likewise fail to commit suicide, and would instead continue to proliferate to form a tumour.

By the early 1990s, researchers realized that a number of oncogenes and tumour suppressor genes, which we discussed earlier as the causes of cancer, did indeed control the fate of the cell through their effect on apoptosis. In other words, cancers arise from cells that have lost the ability to kill themselves by apoptosis, after mutations in the death genes. The death genes are any genes that normally cause a cell to commit apoptosis, and so can potentially include both oncogenes and tumour-suppressor genes, both of which can overrule a cell’s commitment to die in the interest of the body as a whole. As Wyllie put it at the time: ‘The ticket to cancer comes with a ticket to apoptosis built in; the apoptosis ticket has to be cancelled before reaching cancer.’