We all know that cancer is one of the common diseases and a significant cause of death in any country. We also know that cancer tends to get commoner with increasing age. Many of us probably also know that the term “cancer” is derived from the Latin word for a crab, which would appear to imply that it is a creeping thing that, like the splay of the crab’s many legs, spreads and invades our tissues. In fact, let me assure readers that many cancers are eminently treatable, far more so than when I first qualified as a doctor, and some are even completely curable. As with anything that frightens us, it becomes a good deal less frightening when we come to understand it better. And there can be no doubt at all that the logical approach to cancer, and its treatment, comes from exactly that – from understanding.
Our body is composed of organs and tissues, such as the brain, heart, and the glandular tissues that line the breast, or the prostate, and these in turn are made up of many different types of cells. As part of the wear and tear of life, cells die and must be replaced by the division of neighbouring cells. The first step in understanding cancers is to grasp the fact that nearly all cancers are caused by disturbance in the way genes, and other regulatory factors, exert control over this pattern of reproduction of cells.
Two groups of genes appear to be particularly important in controlling the way cells reproduce themselves. One group, known as “oncogenes” (onco here means tumour), are so-called because if they are inappropriately activated they increase the risk of developing a cancer. A second group are known as “tumour suppressor genes”. As the name suggests, these normally suppress the tendency towards uncontrolled cell proliferation that is such a prominent feature of cancers. Mutations that inappropriately switch on oncogenes or inappropriately switch off tumour suppressor genes are thus a potent cause of cancer. The decoding of the human genome has highlighted the genetic alterations that underlie cancers in such unprecedented detail that it has led two American oncologists, Vogelstein and Kinzler, to declare that ‘cancer is, in essence, a genetic disease’.5 They have summarised the mutated genes responsible for various cancers, together with the ways in which these mutations have perverted the normal genetic mechanisms to do so. For example, one in five familial breast cancers have been linked to mutations in the genes BRCA1 and BRCA2. Geneticists can further predict that women who carry these mutations have an 80% risk of developing breast cancer during their lifetime, so that pre-emptive surgery offers the potential of prevention. Recently, PGD has also been extended to help such families, and embryological screening has been made increasingly available for BRCA1 and BRCA2, with the first assisted babies, freed from the terrible risk, already born in a number of countries.
In 2006, a multi-centre screening programme in the USA looked at more than 13,000 genes taken from human breast and colon cancer cells, enabling authorities to compare the genes they found in the two cancers with the normal, and revealing that individual tumours accumulate an average of 90 mutant genes.6 Meanwhile, they concluded that a much smaller number of mutations are critical to the early stages of the cancer process, in their estimation perhaps 11 mutations for each of breast and colon cancer. Encouraged by these findings, the US National Institutes of Health is drawing up an atlas of cancer genomes – the Cancer Genome Atlas, or TCGA – with the aim of decoding the genomes of every human cancer and, by comparing these to the normal, extrapolating the genetic abnormalities that underlie all cancers.7 A pilot study has begun with cancers of the lung, brain and ovary.
It is not unreasonable to anticipate, as our knowledge of mutation grows, that important preventive and therapeutic aspects will come from it. However, though the understanding and medical applications of mutation have proved to be helpful, mutation is neither the exclusive mechanism of hereditary change in evolution nor the exclusive explanation of the genetic underpinning of disease, including cancer.
Sit down before fact as a little child, be prepared to give up every preconceived notion, follow humbly wherever and to whatever abysses nature leads, or you shall learn nothing.
THOMAS HENRY HUXLEY2
When, on a hot afternoon in September 1994, I arrived at the Rockefeller University, New York, with an appointment to interview its distinguished president, and Nobel Laureate, Joshua Lederberg, I considered myself fortunate that he had agreed to see me, since he was one of the busiest men I was ever likely to meet. The meeting with Terry Yates, two months earlier, had radically altered my perspective on viruses, and, on my return to England, I had consumed what literature I could lay my hands on concerning what for me was a new topic of inspiration – the possibility that what we were observing in pandemic plagues, including AIDS, might best be interpreted as evolutionary phenomena. I had arrived early so I took a walk down York Avenue to 68th Street, turning towards the river by the twin-fronted colossus of the New York Hospital, until I reached a low concrete parapet on which I could lean and gaze out over the wide East River, with its turbid, black-green water.
I had been here once before, while working on my book on tuberculosis, and the sight of the hospital brought back poignant memories. Rene Dubos, a scientist I greatly admired, had worked at the Rockefeller University for most of his life. A scientist-philosopher, and twice a Pulitzer Prize winner for his writing, Dubos was one of the most original thinkers among the scientists involved in the antibiotic story. He had pioneered the discovery of the soil-derived antibiotics, such as streptomycin and neomycin, and had played an important part in the discovery of the cure for tuberculosis. I knew that it was my writing about Dubos in my book on tuberculosis that had opened Lederberg’s door to my interviewing him. But Dubos’s contribution to the discovery of antibiotics, and the cure for tuberculosis, had ended abruptly, and tragically, right here, in the New York Hospital, where his first wife, Marie Louise, had died from the disease. I couldn’t help reflecting now on Dubos, and his highly original way of thinking about microbes, including viruses, as I gazed upriver towards the looming ironwork of the Queens-boro Bridge. Viruses appeared to be omnipresent. In fact, whenever we bothered to probe any life form on Earth for the presence of viruses, we seemed to find them. It made little sense that at this time only some 5,000 strains, or species equivalents, of viruses were known. Only recently had we discovered that viruses teemed in the oceans, where we had little or no knowledge of what they were doing – yet the vast numbers alone suggested that their presence was significant. We knew, by now, that most, if not all, life forms had viruses that invaded them, and, given that there were millions of different species inhabiting the Earth, it was clear that our knowledge of viruses, even at this very basic level, was inadequate. Those two months of intense background reading and research had convinced me of this. It had also convinced me that, in our blinkered vision of viruses, we were missing something very important. These questions troubled me as I stood in Founders’ Hall, pausing in the reception area before a painting of its first medical director, Simon Flexner, who had earned a distinction that perhaps only a doctor would appreciate – of having the dysentery bacterium, Shigella flexneri, named after him. I climbed into a battered green-and-black elevator old enough to have been familiar to Flexner, and I widened my stance, a trifle warily, as it rattled and groaned on its way to the fourth floor.
I shook hands with Lederberg in a room cluttered with boxes of scientific papers and lantern slides, its walls be-decked with a proliferation of certificates and diplomas. He sat down opposite me, bald-headed and stolid as a Buddha. ‘Well,’ he remarked, his eyes following my gaze with a slight twinkle, ‘they are rather an idiosyncratic collection … I got to microbiology through genetics – through biochemical genetics in particular. My first experience in that area was with your namesake, Francis Ryan, who was my mentor at Columbia University. You don’t have Joseph after your first name?’