p53 (2 page)

‘Science without storytelling,’ wrote the American astrophysicist Janna Levin in a commentary for
New Scientist,
‘collapses to a set of equations or a ledger full of
data.’ My aim here is to stand clear of those ledgers full of data as far as possible and tell the story of some of the curious, obsessive, competitive minds that filled them, thereby helping
to unravel the deepest mysteries of cancer.

A NOTE FROM THE AUTHOR

I have tried hard to avoid jargon as far as possible. But there is one expression I am loath to replace with something more readily understood: that expression is ‘wild
type’ in reference to the status of the p53 gene. Essentially, the ‘wild-type’ gene means the ‘normal’ gene that functions as nature intended, as opposed to the
‘mutant’ gene whose behaviour is aberrant. ‘Wild type’ is a term so widely used by the biology community, and by my interviewees – and so much more vivid than
‘normal’ – that I have decided not to substitute it. I trust my readers will forgive me.

***

‘The question that’s obsessed me for the whole of my career is: why is cancer so rare?’ Gerard Evan, a professor of molecular biology at the University of
California, San Francisco, and Cambridge, England, pauses to let his comment sink in. He knows it will startle me, for the statistics most commonly quoted in the media paint a bleak picture: that
one in three of us will be diagnosed with cancer at some point in our lives and one in four of us will die of the disease. But Evan, talking to me in his office in the Sanger Building in a leafy
corner of Cambridge about his years of research at the most fundamental level of the genes, is looking at cancer from the viewpoint of the cells, not of the whole human being. It takes just one
rogue cell which has lost its normal regulatory machinery and run haywire to trigger cancer, yet billions upon billions of cells in our bodies that are growing and replicating themselves all the
time do so typically for 50, 60 years or more without producing a tumour. And in two in three of us they never do. ‘I mean, if you were doing the lottery you’d never gamble on
this!’ continues Evan. ‘Cancers do arise, but clearly we’ve evolved amazingly elaborate and
effective mechanisms to restrict the spontaneous evolution of
autonomous cells within our bodies. And even though we bomb ourselves with mutagens and carcinogens and do all sorts of things we shouldn’t do, still most people die of heart disease; they
don’t die of cancer.’

A measure of just how resistant our cells are to corruption is the fact that a goodly chunk of our DNA – nature’s instruction manual for building our bodies – can be traced
back to the original single-celled organism known as the ‘last universal common ancestor’ of all life on earth (often referred to by the acronym LUCA), whose existence was first
proposed by Charles Darwin in his book
On the Origin of Species,
published in 1859. In other words, some of our genes are more than 3.5 million years old and have been passed down
faithfully from one generation to the next over unimaginable eons of time.

The term ‘cancer’ represents not one but a collection of around 200 different diseases which share this common characteristic: they all originate from a single cell that has become
corrupted. The great majority of cancers – well over 80 per cent – are carcinomas, which means they are in the epithelial cells that form the outer membranes of all the organs, tubes
and cavities in our bodies, and include our skin. The connective tissue, which provides the structural framework for our bodies, and support and packaging for the other tissues and organs –
it includes, for example, bone, cartilage, fibrous tissue such as tendons and ligaments, collagen and fatty tissue – appears extremely resistant to turning malignant. Sarcomas, which are
cancers of the connective tissue, account for only about one in a hundred cases.

No one yet knows the reason for this bias, though speculation is intense. Could it be that epithelial cells tend to divide more often than connective tissue cells and the opportunity for
mutation is much greater? Our skin, for instance, has an intense programme of self-renewal with
cells at the base layer dividing and undergoing processes of differentiation
and maturation as they push up towards the surface, where they are eventually sloughed off (that’s what causes the tidemark around the bathtub). The lining of the gut, too, is constantly
renewing itself, and the sloughed cells are excreted. However, an argument against high rates of proliferation being the main reason why epithelial cells are at greatest risk of malignancy is the
fact that some of the most cancer-prone epithelial cells are not ones that divide most frequently. Some suggest that it is because epithelial cells are a first line of defence against the outside
world and are more likely to come into contact with cancer-causing agents. But this argument too has weaknesses, since epithelial and connective tissue cells are equally exposed to carcinogens in
some organs, notably the prostate, yet the epithelial cells are the more vulnerable.

Looking for answers to this conundrum, one lab took samples of healthy breast tissue, teased apart connective tissue cells from epithelial cells and watched what happened when they attacked them
with chemical carcinogens in their Petri dishes. To their surprise, they saw that the two cell types reacted completely differently, though they still don’t know exactly how or why.
That’s the Holy Grail, as it might point to chinks in cancer’s armour as targets for new drugs.

Tumours typically arise from the pool of stem cells in a tissue that are responsible for the repair and replacement of cells as part of the routine maintenance of our bodies. It can take years,
even decades, for a rogue cell to grow into a tumour that is detectable. This is because it depends on progressive breakdown of the cellular machinery through the mutation and/or loss of crucial
genes that regulate growth, replication, repair and timely death of cells – mutations that occur independently and, crucially, don’t result in the cell being eliminated, which is the
normal fate of damaged cells. The growing tumour is parasitic: it competes with the normal cells around it for nutrients and oxygen,
and it can’t grow much beyond
1–2mm (1/25th–1/12th of an inch) in diameter unless it develops its own blood supply.

What distinguishes a malignant tumour from a benign one is the former’s ability to spread – to send out microscopic shoots that penetrate the walls and invade neighbouring tissue,
and to seed itself in distant sites from breakaway cells carried in the bloodstream or lymph system. Blood-borne dissemination is particularly efficient at spreading cancer, with the blood
depositing its cargo of delinquent cells along natural drainage sites, most commonly the liver and lungs.

Our understanding of the mechanics of cancer has advanced at revolutionary speed in the last 40 years, as one technological breakthrough after another in molecular biology has enhanced
scientists’ ability to explore the workings of the cells – the building blocks of all life on earth. But the sheer volume of data churned out has threatened at times to overwhelm the
cancer research community. Robert (Bob) Weinberg has been involved since the early 1960s and has played a big part in the revolution. ‘The plethora of information is just overwhelming,’
he told an audience of mostly fellow scientists who had gathered in a lecture theatre at Massachusetts Institute of Technology, MIT, to hear him speak of his life in science and of the personal
experiences that had formed him.

‘When I was a graduate student there were two journals one paid any attention to: the
Journal of Molecular Biology
and
PNAS
(
Proceedings of the National Academy of
Sciences
). That was it. Today?’ Weinberg shrugged mightily and spread his hands. ‘More than the stars in the sky. I think PubMed
¹
now has 12 or 15 million papers in it, and the only way I can deal with this is to continually ask people who have distilled information in their own minds how this or that problem is
evolving.’ Laboratory scientists today can generate important data up to 10,000 times faster than he could when he started out in cancer research, Weinberg told his audience.

In his own lab at MIT, where he has spent most of his working life, Weinberg puts pressure on people to draw lessons and develop ideas from what they observe, not simply
accumulate data. It’s little surprise, then, that he should have become preoccupied with bringing some order to the explosion of information about cancer that in many ways mirrors the
disease’s own chaotic growth. Attending a conference in Hawaii in 1998, Weinberg took a walk down to the mouth of a volcano with fellow scientist Doug Hanahan, who had also caught the
molecular-biology bug at MIT as an undergraduate. Mulling over their common frustration as they walked, the two conceived the idea of writing a review that would seek to clarify what Weinberg calls
the ‘take-home lessons’ of research.

‘Cancer research as a field was a very broad and disparate collection of findings, and we thought there might be some underlying principles through which we could organise all these
disparate ideas,’ he said. ‘We came up with the notion that there were six properties of cancer cells that were shared in common with virtually all cancer cells and that defined the
state of cancerous growth.’ ‘The Hallmarks of Cancer’ was published in 2000 and far from disappearing ‘like a stone thrown into a quiet pond’, as Hanahan and Weinberg
had predicted, knowing how quickly most journal articles are read and forgotten, their paper has become the descriptive cornerstone of cancer biology and a clear framework into which new pieces of
the jigsaw can be slotted. The six characteristics they identified as being common to virtually every cancerous cell are that, in lay terms:

In 2011 the two scientists updated and refined their ‘Hallmarks’ paper, adding further general principles, including the fact that the metabolism in cancer cells
– particularly the way they use glucose to provide energy – tends to be abnormal; and that they are able to evade detection and destruction by the body’s immune system.

Crucially for the story I’m telling here, p53 plays a role in all these traits. ‘As I read the paper by Hanahan and Weinberg, I said, “This is conceptually
brilliant!”’ comments Pierre Hainaut, who spent many years investigating cancer genetics at the World Health Organization’s International Agency for Research on Cancer, IARC, in
Lyon, France. ‘But then I thought: where is the unity? Clearly it must be a more coherent programme than just a succession of boxes. What is holding it together? And then I realised: my
goodness, it’s p53!

‘There are many genes that have a mechanistic role in one hallmark trait or another, and this will spill over to two or three hallmarks. But p53 is the one that links all the hallmarks
together. This means that from a molecular viewpoint there is one basic condition to get a cancer: p53 must be switched off. If p53 is on, and hence functioning properly, cancer will not
develop.’

Hainaut – a tall, rangy Belgian with a crooked smile, boyish enthusiasm and an earnest expression behind black-rimmed specs – has been particularly intrigued by the gene’s
multiple roles in the activities of the cell. It’s an
interest that takes him frequently out of his lab and into the wider world, to investigate the connection between
mouldy peanuts and liver cancer in the Gambia, to meet families with a hereditary cancer disposition in southern Brazil, and to many other countries, from China to Iran, in pursuit of insights into
the workings of p53 in our everyday lives. ‘There are many, many ways to lose the function of p53,’ he continues. ‘Mutation is a very common one; loss of one copy of the gene is
another; but there are also other ways, such as switching it off, degrading it, putting it off-site and so on. But I repeat: if the cell is retaining a perfectly intact and fully reactive p53
function, it will not give rise to cancer.’

AN ANCIENT MALADY

Cancer is a disease as old as humankind. It is mentioned in the earliest medical texts in existence, a collection of papyri from ancient Egypt dating from 3000–1500 BC.
Actual specimens of human tumours have been found in the remains of a female skull from the Bronze Age, dating between 1900 and 1600 BC, and in the mummified remains of ancient Egyptians and
Peruvian Incas. In 1932, the palaeoanthropologist Louis Leakey, working in the Rift Valley of East Africa, found evidence suggestive of bone tumours in the fossilised remains of one of our hominid
ancestors,
Homo erectus
, who roamed the African savanna between 1.3 and 1.8 million years ago.

In fact, cancer has probably been around since LUCA first gave rise to multi-celled creatures. In 2003 a team from Northeastern Ohio Universities College of Medicine, led by radiologist Bruce
Rothschild, travelled around the museums of North America scanning the bones of 700 dinosaur exhibits. They found evidence of tumours in 29 bone samples from duck-billed dinosaurs called hadrosaurs
from the Cretaceous period some 70 million years ago. And evidence of tumours has been found also in the bones of
dinosaurs from the Jurassic period between 199 and 145
million years ago.