p53 (3 page)

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.

***

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 his 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.

A DISEASE OF THE GENES?

Notable among these others are Michael Bishop and Harold Varmus who, working together at the University of California at San Francisco in the early 1970s, made such momentous
discoveries with RSV that they too won the Nobel Prize for Medicine, in 1989. Bishop had begun work with the virus in 1968, just two years after Rous’s Nobel award, and says of that event
that it ‘dramatised the great mystery of how RSV might cause cancer. It was a mystery whose solution lay in genetics.’

This was an assessment shared by Varmus, then doing postgraduate training in medical research on the other side of the country at the National Institutes of Health, NIH, in Bethesda, Maryland.
Varmus had become excited at the potential for approaching the mind-boggling complexity of human genetics – particularly in relation to disease – through
the
study of much simpler organisms. ‘From some dilatory reading in the early 1960s, I knew enough about viruses and their association with tumours in animals to understand that they might
provide a relatively simple entry into a problem as complex as cancer,’ he wrote in his autobiographical account of his work. ‘In fact, for anyone interested in the genetic basis of
cancer, viruses seemed to be the only game in town.’ The little scraps of life contain around five to ten genes all told, compared with 20,500 or so in our cells.

In the summer of 1969, Varmus and his journalist wife Connie combined a backpacking trip to California with the search for opportunities to study viruses on the West Coast. Visiting Mike Bishop
in his lab at UCSF, he found a fellow book addict with wide tastes in literature, and a keen writer also. Bishop, too, had been ambivalent about becoming a doctor, but had discovered almost by
chance the thrill of laboratory science and not looked back. In Bishop, Varmus had discovered a kindred spirit and he agreed to join him the following year. ‘Harold’s arrival changed my
life and career,’ Bishop recalled during his Nobel address. ‘Our relationship evolved rapidly to one of co-equals and the result was surely greater than the sum of the two
parts.’

When they started their work together the two scientists were somewhat out on a limb, for in 1970 many of their peers were still sceptical, even frankly disbelieving, of the theory that cancer
is a disease of the genes, since there was no direct evidence for it. But that very summer, a young postgraduate student from California named Steve Martin appeared at the Gordon Conference, an
annual event that brings together scientists at the cutting edge of their field internationally to brainstorm ideas in the informal setting of an old boarding school in Tilton, New Hampshire. The
topic at that year’s conference was animal cells and viruses, and Martin – a ‘bookish’ young man, ‘with dark curls, a cherubic face and an enthusiastic manner’,
according to Varmus – had come to tell his colleagues that he had managed to isolate the gene in
the Rous sarcoma virus responsible for turning infected cells
delinquent, and to explain how he had done so. The gene – soon given the name Src (pronounced ‘sark’) after the type of tumour it causes – was the first example of what
became known as ‘oncogenes’.

Derived from the Greek word
onkos
meaning ‘mass’, and describing a gene that can transform a normal cell into a tumour cell, oncogenes are at the very heart of the story of
p53. What earned Bishop and Varmus their Nobel Prize was the discovery in 1974 that the
normal
cells of uninfected chickens have copies of a gene almost identical to the Src found in the
virus. What is more, the two scientists soon found that many other bird species – including ducks, turkeys, quails and even an emu from the Sacramento Zoo – did too. In due course,
Src-like genes would be detected in fruit flies and worms and many species of mammals, indicating that this was a gene that could be traced back through eons of evolutionary history and that must
therefore have an essential role to play in the cell.

But in 1974, the evidence from bird species alone was enough for Bishop, Varmus and their team to suggest a revolutionary idea: that, rather than being the carrier of an alien gene with which it
corrupts host cells, the virus had, some time in the course of its evolution, picked up the gene from its chicken host and incorporated it into its own genome – a process that caused the gene
to become dangerous to its original bird host. Could it be, they speculated further, that there are other genes – perhaps many of them – in normal animal cells that are capable of
becoming oncogenes when picked up and spread around by viruses?