p53 (29 page)

Campisi, dark haired and petite, with dangly earrings and the graceful posture of a ballet dancer, uses her hands and eyes expressively as she speaks. She began her research career focusing on
cancer, and it was here she first encountered senescent cells, in the context of tumour suppression. But she soon became fascinated by their possible role in the normal processes of ageing –
an idea that all but a small ‘crazy contingent’ of scientists had dismissed for a long time. ‘I didn’t buy [the theory] for a minute,’ she said in an interview with
one of her colleagues at the Buck Institute in early 2013. ‘[But] sure enough, we started working on this problem and I had to realise that this “crazy contingent” was actually
correct!’

To the uninitiated, the scientists’ original doubts seem strange, since the very term ‘senescence’ implies ageing. This was clearly intended by Leonard Hayflick, the man who
discovered and named the cells in 1961 – but he was putting himself out on a fragile limb scientifically, Campisi told me. ‘Len Hayflick was a cell biologist, and he was studying cell
proliferation for a very specific reason: he was interested in growing viruses in human cell cultures as opposed to animal cell cultures, and virologists were having a helluva time. They would get
these cultures and initially they’d do great, and then eventually they wouldn’t do so great, and they’d throw them out and start again.’ Hayflick decided to study this in
much more detail, and he made the startling discovery that, in contrast to most cancer cells, normal human cells have a finite ability to undergo cell division in culture. ‘Now that finite
ability is huge,’ said Campisi. ‘For stem cells taken from a human embryo we’re talking 40, 50, 60 population doublings. So you can see why you’d be fooled –
you’d do an experiment for three months, the cells are growing great and then they start not to do so great and then they stop.

‘Hayflick made two interesting observations,’ she continued. ‘One of them was obvious and was immediately accepted, and that is, “My God, tumour cells don’t do
this. Maybe this is a way of stopping cancer.” It fuelled a whole area of research to think about the senescence process, which is controlled by this famous suppressor gene, p53, as stopping
cancer, and I think there’s very little controversy about that now. But he also made another observation that was totally unscientific, totally intuitive, based only on his sense as a cell
biologist. He looked in the microscope; he looked at these cells and said, “They look old.” Now what on earth does that mean, that a cell looks “old”? I mean it’s an
unquantifiable observation. But he said, “Maybe what’s also happening is that we are recapitulating some aspects of ageing in a culture dish.” That observation, that comment, went
largely unnoticed except for a few, again pretty imaginative, people in the field who picked this up and began to study senescence, not as a tumour-suppressive mechanism but as an ageing process.
It is still somewhat controversial – less so than it was 50 years ago, but still controversial, though it’s also gained a lot of momentum.’

The number of divisions a normal cell can undergo before becoming senescent is known today as the Hayflick Limit, and it is measured by the telomeres on the ends of the chromosomes. Telomeres
are protective tips to the chromosomes that are rather like the little plastic caps put on the ends of shoelaces to stop them unravelling. Every time a cell divides, the telomeres shorten, until
they are no longer able to protect the chromosomes and the cell goes into permanent arrest. And though this is not the only route to cell senescence, dangerously shortened telomeres are one of the
stressors that trigger the p53 response.

Today Judith Campisi is a world leader in the field of cell senescence, and she is in no doubt that these cells are at the pivotal point of a mechanism that can tip either way. ‘What my
work tries to do is to reconcile the two very different views of senescence. One says it’s really good for you, it stops cancer. The other says it happens during ageing and it looks like
it’s bad for you because the cells look kind of old and ragged.’

Her lab has discovered recently that senescent cells provoke inflammation – a condition that underlies almost every major age-related disease, she told her interviewer at the Buck
Institute. ‘We’ve shown now very clearly that one senescent cell sitting in a sea of non-senescent cells will provoke an inflammation that will spread to other cells. So it’s a
very appealing hypothesis that you don’t need very many senescent cells to be able to drive the degenerative changes that are a characteristic of ageing organisms.’

Senescent cells are also highly resistant to apoptosis and the ultimate irony is that, with time, they themselves become a cancer risk, helping to drive the process of uncontrolled growth. But
how? ‘In the last couple of years we’ve learnt that the senescence response has another life, and that is to promote tissue repair when needed,’ said Campisi. ‘That’s
where it begins to be problematic in later life.’ As senescent cells become dysfunctional with time, she explained, they can start to send out signals to initiate tissue repair and
proliferation of cells in the absence of real injury, thus driving the development of tumours.

This, of course, is not inevitable. As researchers have found with every aspect of tumour suppression, context is all important: different cell types and tissues follow different paths on
activation of p53. Scott Lowe, another mouse-model man, whom we met in the chapter on apoptosis, is also at the cutting edge of cell-senescence research; he discovered that, although these cells
are indeed resistant to killing by apoptosis, they don’t always hang around in the tissue to become toxic. In some tissues they communicate with the immune system, which sends in the
scavenger cells to clear them away.

‘We had this study in 2007, in which if you had no p53 you had a cancer cell; if you flipped p53 on, the cancer cell went senescent,’ Lowe explained. ‘We could see this in the
Petri dish and also in the animal. But whereas in the Petri dish the cells just sat there – they never divided, they didn’t die but they didn’t grow – in the animal the
tumour went away.’ This was perplexing: surely, the researchers figured, if the cells weren’t dividing, nor were they dying, the tumour should stay the same size. So what was happening
here? Digging more deeply into the mechanism, they found that proteins secreted by the senescent cells were triggering an immune response that was removing them as effectively as apoptosis.
What’s more, they could watch this happening in the lab, watch the scavenger cells engulf senescent cells, if they put the two together in the Petri dish and allowed them to communicate
– in effect creating a simplified version of the community of cells you would find in a living body.

As with their discovery of dead cells and apoptosis, this was a surprising result, not what they were expecting to see at all, but Lowe found it strangely pleasing intellectually. ‘For 15,
20 years, we studied how p53 affects the cell that it’s turned on in, but now we realised it does more than that . . . It also can send signals that affect the surrounding tissue.’

Still today no one knows exactly why the stress response leads to different outcomes under different circumstances. ‘Part of it is tissue-dependent: lymphoid cells will, by and large,
apoptose, and connective tissue will senesce,’ said Lowe. ‘But it isn’t completely that. There are other factors that influence it, some of which we know, but none in a way that
you can satisfyingly say is decisively the answer . . . And it’s not even that p53 is turning on different sets of genes when the cells die versus when they arrest, so it’s also
something about how the cell
interprets
the genes that p53 turns on. This is a really interesting question for what we now call “systems biology” – how the cell
integrates multiple signals to make a yes or no decision to go down a certain path – and it’s stuff we study to this day.’

Researchers interested in the gene’s role in ageing believe that both apoptosis and senescence are significant to the process – senescence for all the reasons discussed above, and
apoptosis because it gradually depletes the pool of stem cells our bodies need for repair and maintenance. ‘The simplest model would be that you’re born with a limited number of stem
cells,’ explained David Lane. ‘Those stem cells are very easily killed off by DNA damage, so they’re the ones most tightly controlled by p53. If you set a stress-response
threshold where they’re too easily killed, then you don’t get cancer but you run out of stem cells more quickly. If you set the threshold such that they’re hard to kill, then you
could live a long time, but you’re more likely to get cancer.’

Age researchers also have a theory, drawn from evolutionary biology, to explain the paradox of why a system designed to preserve life by protecting us from cancer should also drive the mechanism
that leads inexorably to our decline. Basically, nature only cares about perpetuating the species, so evolutionary pressures to select for advantageous traits – and weed out ones that are
harmful – operate only up to and across our reproductive years. Beyond that we are living on borrowed time: nature no longer has a use for us, and natural selection is a spent force.

Ageing is anyway a modern phenomenon. During the great majority of our time on Earth, humans didn’t die of ageing: we didn’t die of cancer or Alzheimer’s disease, or even
cardiovascular disease; we died of accidents and predators and infection and starvation. Thus for millennia, ageing operated below the radar of evolution by natural selection. It’s only
today, as we’ve conquered infection, hunger and predation in much of the world, that the damaging flip-side of tumour suppression has been able to play itself out to full effect. But
understanding the roots of ageing holds promise for the future. ‘People are beginning to ask: can I manipulate the system to get the best of both worlds?’ commented David Lane.
‘Can I sensitise the gene for short periods (to eliminate cancerous cells) and can I suppress it (to keep ageing at bay)? I think one can imagine really quite extraordinary results as we
begin to be able to control this system.’

***

‘If you peer into cancer cells – and we’ve got amazing technologies now to catalogue all the things that are happening – and you look at them from an
evolutionary point of view, it turns out that even within a single tumour there are many, many different subspecies of cells that have evolved in slightly different ways,’ says Gerard Evan,
whose remarks about the rarity of cancer opened this book. ‘And here we are, basically trying to wipe out the entire tumour while keeping the patient alive at the same time. It’s a
tough deal!’

But Evan is not disheartened. Indeed, as evidence mounts that cancer is an even more complex disease than anyone realised – a hotbed of evolution that makes of tumours a constantly moving
target for therapy – he remains decidedly optimistic. Why? ‘Let me give you an analogy,’ he says. ‘Absent of cancer, human beings have been subject to terrible diseases of
cells that grow inside them and invade and spread. These cells are genetically very heterogeneous, they exchange genetic information one with the other, and they grow like crazy . . . They’re
called bacteria, right?

‘A hundred years ago you’d have looked at all the infectious diseases and said, “Oh my God, we’ve got to have a cure for each one – there’s TB in the lung,
and in the bone, and then there’s this and that . . .” But it turns out they share a great deal of commonality, and if we hit them with antibiotics we can more or less eradicate, at
least for a time, infectious disease due to bacteria. Now the fact is, bacteria are much,
much
more genetically complex and heterogeneous and hardy and resourceful in the evolutionary
sense than cancer cells.’

The task for drug developers, Evan believes, is to find the commonality of cancer – the ‘mission critical’ mutation without which no tumour can survive. Not everyone agrees
with this analysis; most cancer researchers are still backing the idea of targeted therapy tailored to the individual patient’s tumour characteristics. But whatever the perspective, tumour
suppressors are obvious candidates for investigation, and much of the effort of academic researchers and their counterparts in the pharmaceutical industry is focused on repairing or enhancing the
body’s natural capacity to single out and eliminate rogue cells.

People have high hopes and many imaginative ideas for p53-based therapies, though the journey from the lab to the patient’s bedside is often frustratingly slow. Ironically, as the
explosive speed of technological advance makes it ever easier and quicker for scientists to develop potential new drugs, the rules and regulations governing the process get ever more tight: it
typically takes a decade or more for a promising new therapy to be approved for use on patients. Very many prototypes never make it that far; drug development is, by its very nature, a painstaking
process of trial and error, but even the ‘failures’ teach valuable lessons along the way.

VIRUSES AS DRUGS

The first person to try p53-based therapy in humans was Jack Roth, who in 1996 recruited to his study nine patients with inoperable lung cancer whose tumours were no longer
responding to conventional therapy. In a pleasing twist to the story, Roth’s therapy made a virtue of the pernicious properties of viruses – the fact that the only way they can survive
and reproduce is to invade the living cells of the host organism and hijack the machinery of replication. Using genetic engineering, he and his colleagues converted a common virus into a vehicle
for transporting good copies of p53 into cells where the gene is dysfunctional. This engineered virus they injected direct into the patients’ tumours and found, to their gratification, that
the strategy worked: the p53 gene was successfully transferred to the tumour cells; it switched on to produce healthy protein, and the patients suffered no significant side effects.