p53

by Sue Armstrong

  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 PubMed1 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:

  • the forces pushing them to grow and divide come from within the corrupted cell itself, rather than being signals from outside;

  • cancer cells are insensitive to forces that normally stop cell division at appropriate times;

  • they are resistant to being killed by the mechanisms that normally remove corrupted cells;

  • they are immortal, meaning they can divide indefinitely, whereas normal cells have a finite number of divisions controlled by an internal ‘clock’ before they stop dividing, become senescent and eventually die off;

  • they develop and maintain their own blood supply;

  • they can spread to other organs and tissues and set up satellite colonies, or metastases.

  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.

  Hippocrates, living in ancient Greece around 460 BC, was the first person to recognise the difference between benign tumours that don’t invade surrounding tissue or spread to other parts of the body, and malignant tumours that do. The blood vessels branching out from the fleshy growths he found in his patients so reminded him of the claws of a crab that he gave this mysterious disease the name karkinos, the Greek word for crab, which has translated into English as carcinoma. Hippocrates and his contemporary physicians believed cancer was a side effect of melancholia. And up to the Middle Ages and beyond, medics and patients alike reckoned the causes were supernatural and related to demons and sin and the accumulation of black bile.

  This menacing theory of cancer prevailed for nearly 2,000 years before it was exploded by Andreas Versalius, a Flemish doctor and anatomist working in Padua, Italy, in the early 16th century. Versalius performed post-mortems on his patients, as well as dissecting the corpses of executed criminals supplied to him by a judge in Padua fascinated by his work: black bile, he announced, was nowhere to be found in the human body, diseased or healthy.

  But it was another two centuries and more before anyone suggested that agents in our environment might be playing a part in the development of tumours. In 1761 John Hill, a London physician and botanist, produced a paper, ‘Caution Against Immoderate Use of Snuff’, in which he described patients with tumours of the nasal passages as a consequence of sniffing tobacco. And in 1775 an English surgeon, Percivall Pott, reported a number of cases of cancer of the scrotum in unusually young men whose only link was that they had been chimney sweeps as small boys and were likely to have gathered soot in the nooks and crannies of their bodies as they squeezed themselves up the narrow flues of homes and factories in Georgian Britain – a practice that lasted for two centuries and frequently involved children as young as four years old. In 1779, the world’s first cancer hospital was set up in Reims, France – at a fair distance from the city because people feared the disease was contagious.

  The foundation of our modern understanding of cancer as a disease of the cells was laid in the mid-19th century by Rudolf Virchow, a German doctor born into a farming family, who won a scholarship to study medicine and chemistry at the Prussian Military Academy. Often referred to as the father of modern pathology, Virchow was much less interested in his suffering patients than in what they suffered from – the mechanics of disease – and preferred to spend his time in the lab poring over his microscope and doing animal experiments than visiting the sick. The idea that living cells arise from other living cells through division had been around for many decades but had been almost universally rejected, perhaps because it offended religious sensibilities about creation – in those days people really believed that maggots appeared spontaneously in rotting meat.

  It was not until the strong and independent-minded Virchow, who was active in politics as well as in science and medicine, published his own observations of cell division and coined the phrase omnis cellula e cellula – which translates roughly as ‘all cells arise from other cells’ in a continuous process of generation – that the idea finally caught on. But it was the advent of molecular biology in the mid-20th century that has allowed scientists to peer ever deeper into the cell – to study the machinery of life itself in the DNA – and to begin to crack the code of cancer.

  CHAPTER TWO

  The Enemy Within

  In which we hear a) about a virus that causes cancer in chickens that can be passed on to other birds in the DNA and b) of the discovery of the first genes responsible for driving cancer – the so-called oncogenes.

  ***

  Now more ambitious questions arose . . . Might all cancers arise from the wayward action of genes? Can the complexities of human cancer be reduced to the chemical vocabulary of DNA?

  Michael Bishop

  At the cutting edge of research in the mid-1900s was the idea – incredibly controversial at the time because there was no direct evidence for it – that viruses could cause cancer in humans. The central figure in this story is Peyton Rous, born a full century earlier in Texas, who studied medicine at Johns Hopkins in Baltimore and was very nearly lost to science before he began. While still a student, Rous contracted tuberculosis from a cadaver he was dissecting when he cut his finger on a tuberculous bone. He had surgery to remove infected lymph glands, and was sent home to recuperate under the big skies and fresh air of a Texas ranch. A year spent rounding up cattle on horseback and sleeping out under the cold stars on the range with the other cowboys – a profound experience from which he drew pleasure for the rest of his life – restored him to health and he returned to Johns Hopkins Medical School.

  Rous qualified in 1905, but during his first year on the wards he, like Virchow before him, decided he was not cut out to care for the sick, and he retreated from the front line to the pathology lab to study disease. By 1909, he found himself in charge of the cancer laboratory at the Rockefeller Institute of Medical Research – a post vacated by the institute’s director, Simon Flexner, who wanted to turn his attention to the more pressing problem, as he saw it, of polio, which was crippling millions of American children.

  A trawl through the history of cancer research draws one up sharp: almost everything we know today about cancer – as a disease of the cells and of the genes – was suggested by someone way back before scientists had any way of testing their ideas, and who is often forgotten by those who later reveal them as facts when the world is more ready to listen. However, in 1909, precious little had been established about how cancer works and, apart from surgery and the newly discovered but not yet widely available use of X-ray radiation, there was no treatment. Much of the research effort at that time went into expanding the insights of people like John Hill and Percivall Pott that chemicals cause cancer, and identifying these carcinogenic agents.

  But Rous was interested in exploring another idea: whether or not viruses could cause malignancy. He could hardly have asked a more difficult question to investigate, for at that time viruses were more of a concept than a reality, known by their footprints only. Viruses had been ‘discovered’ in the 1890s when scientists working on infectious agents developed filters that could block the passage of bacteria. When they found that a filtered solution from which all pathogens then known had been removed remained infectious, they scratched their heads in perplexity and concluded that whatever was causing the infection must be a chemical. They then gave it the Latin name for poison: ‘virus’.

  By the time Rous was asking his questions, the idea of viruses as living entities was more or less accepted by the scientific world, and a few that caused diseases in plants had already been identified. But viruses could neither be seen, nor cultured, nor caught in filters. They could be identified as the infectious agent only by exclusion – when other, larger pathogens had been caught in the net.2 A virus that causes leukaemia in chickens had already been discovered, in 1908, but the finding caused hardly a stir in the cancer community because leukaemia was not then recognised as a malignant disease. Rous, however, was intrigued and in his search for a cancer-causing virus he turned his attention to barnyard fowl. Very quickly he struck lucky. In 1910 he discovered a sarcoma – a cancer of the connective tissue – in chickens that could be induced in healthy birds by injecting a filtered extract of the tumour from a sick bird into a healthy one, where in time it produced exactly the same type of tumour as the original. What’s more, his experiment worked over and over again, and he believed he could detect signs of the virus in the tumour cells.

  Rous published h
is findings in 1911 but they were roughly and widely dismissed, as he told his audience at the Swedish Academy on receiving the Nobel Prize for Medicine decades later in 1966. ‘Numerous workers had already tried by then to get extraneous causes from transplanted mouse and rat tumours, but the transferred cells had held their secret close. Hence the findings with the sarcoma were met with downright disbelief.’ This was despite the fact that the experiment with barnyard fowl had been repeated successfully on several more occasions, and a virus found each time. ‘Not until after some 15 years of disputation amongst oncologists were the findings with chickens deemed valid – and then they were relegated to a category distinct from that of mammals because from them no viruses could be obtained.’

  In the event, Rous’s work with chicken viruses was to spawn one of the most exciting and productive fields ever in cancer research. But he died in 1970, just too early to see it truly bear fruit. ‘Tumours are the most concrete and formidable of human maladies, yet despite more than 70 years of experimental study they remain the least understood,’ he told his Nobel audience, musing a little later, ‘We term the lawless cells neoplastic because they form new tissue, and the growth itself a neoplasm; but on looking into medical dictionaries, hoping for more information, we are told, in effect, that neoplastic means “of or pertaining to a neoplasm”, and turning to neoplasm learn that it is “a growth which consists of neoplastic cells”. Ignorance could scarcely be more stark.’

  After experiencing the same failure as others to repeat his chicken results with rats and mice, Rous quit virus research for more obviously rewarding fields of pathology. It fell to others to tease out what Rous sarcoma virus, RSV, as it had been named, was doing in cells to make them malignant, and to see what lessons this might hold for understanding the mechanics of cancer in humans.