P53 by Sue Armstrong
It has become the most studied single gene in the history of molecular biology, generating over 70,000 research papers
Vogelstein, who was born and brought up in the shadow of Johns Hopkins in the 1940s and went to medical school there, has been involved with p53 since its earliest days. His lab, housed today in a tall modern building of glass and light which looks out over Baltimore and down onto the warm red bricks of the old hospital, has provided some of the most important insights into the workings of the gene. ‘I think you could safely say that it’s impossible – or very difficult – to get a malignant tumour without the activity of p53 being disrupted.’
the role of p53 in nailing the tobacco industry by furnishing unequivocal proof that smoking is a direct cause of cancer.
‘The question that’s obsessed me for the whole of my career is: why is cancer so rare?’ Gerard Evan,
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 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.
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.
‘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
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.
‘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.’
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.
And in 1775 an English surgeon, Percivall Pott,