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One can hardly look at a newspaper these days without encountering cancer—sometimes in a tragic or uplifting story; too often, still, the story of some alleged breakthrough that will lead to false hopes in patients and their relatives. I have been struck by the increasing sophistication of such reports. A few months ago in one of the major tabloids a feature writer was commenting on the inadequate treatment of someone with early breast cancer whose primary was a high-grade tumour, discussing the prognostic importance of tumour grade as a separate feature from node status. Just recently the London Evening Standard, in a 3-page spread, took us through the function of the p53 gene (with an update from David Lane), via the importance of psychosocial research in measuring cancer outcomes and patient communication, to the current state of systemic treatment and the difficulties of paying for it within the National Health Service budget. And in almost any outpatient clinic nowadays you see patients or their companions, Internet experts, who arrive equipped with in-depth information from websites around the world. The time is ripe for a book that embraces the science and art in non-patronizing style, and with Cancer—the Evolutionary Legacy1 Mel Greaves has succeeded brilliantly.
Greaves steps back from his work as a cell biologist to delve into the shifting cultural mores that have informed our perceptions of cancer throughout recorded history. In so doing, he sets up numerous targets, and some people will have fun trying to knock them down. The basic thesis is that cancer is an inevitable consequence of our make-up as a multicellular sexually reproductive animal. Since multicellular organisms have been around for 700 million years there has been a long time for cancer to evolve; and, without DNA mutation, we ourselves would not have evolved and adapted into what we are. Greaves rephrases Jacques Monod's comment on evolution to state that ‘Cancer becomes a statistical inevitability of nature—a matter of chance and necessity’ (my italics).
The paradigm of reductionist biology and the neo-Darwinian view of evolution proselytized by Steve Jones and Richard Dawkins is founded on the modern concept of DNA. Particularly in the last two decades, as the tools have become increasingly available, Watson and Crick's discovery has driven basic cancer research and has culminated in the Human Genome Project. Many believe that this must finally provide the detailed blueprint to allow the development of the precise instruments to put right the disordered biology of the cancer cell. For a start, Greaves rejects the very name we give this spectrum of over 200 diseases; disinvention of the word cancer would certainly dispel some of the demonology. Chapter 2 plunges into history and molecular diagnostics, with the story of poor King Ferranti of Naples with his mutated RAS gene, probably the cause of his lethal bowel cancer in 1494; for this information we can thank the miraculous power of the polymerase chain reaction to interrogate ancient DNA. Egyptians with phenotypic features of inherited predisposition to cancer appear later; as does, inevitably, Percival Pott with his famous observations on scrotal cancer in the chimney sweeps of England. But why were the sweeps of Holland and Germany spared? If you want to know, buy the book. Fascinating anecdotes reveal the depth of the historical research, including information from the Cincinnati Transplant Registry of accidentally imported cancers and the case of a ‘successful’ and lethal take of a melanoma transplanted from dying daughter to 80-year-old mother. In one particular the book already seems out of date. Greaves estimates the number of potential targets (i.e. genes) that could mutate as 70 000-100 000; but the initial results of HUGO suggest about half that number. This does not materially undermine his argument—especially since he surmises that only a small number of critical, larger(?) genes are vulnerable and important in cancer initiation. A more important matter on which some will take issue with Greaves is his dismissal of the potential importance of the immune system in surveillance and prevention of clinical disease. Can the high incidence of some cancers following therapeutic immunosuppression really be explained, as he suggests, by the permissive environment for herpesviruses? What about simple histopathology evidence of immune response? What about spontaneous regression of cancer? Admittedly, the vision of Macfarlane Burnet and others—that manipulation of the immune system would be an effective means to control cancer—has not been realized clinically; but the promise is not yet exhausted. Since the time of Burnet we have learned much about the physiology of the immune system and how to manipulate it. Two humanized murine monoclonal antibodies that target cell surface proteins—one in breast cancer (an oncoprotein, HER2) and a second against a differentiation antigen on lymphoma cells (CD20)—are of great significance in terms of proof of principle as well as practical benefit for thousands of patients in the UK. They are now under scrutiny by the National Institute for Clinical Excellence, after trials and licensing. Although this is some way from Burnet's vision of re-educating the immune system it is a good start. In addition, vaccines are under investigation for several common cancers.
Dealing with the environmental contributions to cancer causation Greaves offers a superb chapter on the benign social and evolutionary effects of fire, as well as the malign consequences of its misuse. In one of the many humorous asides that leaven the book he quotes Bob Newhart's immortal monologue about Walt Raleigh's effort to sell his noxious weed to an official from the British West India Company. The front cover of the book suggests that Greaves the evolutionary biologist gives quite a lot of weight to culture and environment, with his illustration of a pair of native North Americans enjoying their Romeo y Giulliettas. Looking ahead, Greaves tempers his enthusiasm for the reductionists' magic bullets with pragmatic information on simpler remedies, from non-steroidal anti-inflammatory drugs upwards in the evolutionary scale of drugs. He describes himself and others of his ilk as inveterate optimists. (I too am an optimist; though, nearer the clinical coalface, my adjective is ‘incurable’). Most oncologists now practising have been trained at the dawn of systemic anticancer therapy, which began in earnest in the USA in the 1970s and later, against much professional scepticism, in the UK. Even with the poor knowledge base and the crude technology, we have come a long way in my 25 years of practice. Clinical oncologists of every hue would be delighted to consign to the dustbin of history treatments that are expensive, frightening and toxic. If Greaves and others like him are right, we are on the verge of a new era in which dysfunctional proteins will be targeted precisely and missing pieces will be placed in the incomplete cellular jigsaw that characterizes many of these diseases. As I worked through this magnificent book, so my enthusiasm for the message and its philosophy grew. It is intended for non-scientists; but I can think of few clinicians or scientists, specialized as we all are nowadays, who would not learn something useful from it.