This interview is with Professor Mel Greaves, for CANCERactive and was originally published in July-August 2004 icon
Childhood Cancer Specialist - An Optimist Searching For Solutions
When cancer breaks into your world, the inevitable question is "Why?" closely followed by "What could I have done to prevent it?"
Nobel prizes and knighthoods aplenty await scientists who deliver definitive answers - as in time they will, maintains our icons icon Mel Greaves, Professor of Cell Biology at the Institute of Cancer Research, London.
"Like most scientists I am an optimist" he says. "I wouldnt have spent my life working on the very complex problems of cancer (and specifically on childhood leukaemias) if I didnt think they could be solved."
In the years to come, Professor Greaves expects scientific solutions - perhaps including a smart vaccine - to go hand in hand with conscious lifestyle adjustments from our affluent society. How long will it take before we have the knowhow to protect ourselves and, above all, our children from the various cancers?
"By, say, 2025 I would expect the prognosis to be very favourable" writes Mel Greaves in his book Cancer the Evolutionary Legacy (OUP), "and by 2050 for the evidence to be indisputable."
We are all impatient for this cancer-cleared future. But as Mel Greaves explains, scientists cant start with prevention - they have first to understand the biology and mechanisms of the different cancers. As far as childhood leukaemias are concerned "Its taken the research community 30 years of effort to improve treatment from 100 per cent fatality to 75 per cent cure - Recently weve really made headway so that in the next five years I think we will finally be identifying the major causal factors of this disease - the exposures that matter, the genetic and dietary factors that matter. Once the bigger picture is less fuzzy, we can then take some concrete steps towards prevention. But the natural pace of these things is slow."
By 2025 I would expect the prognosis to be very favourable
Prof Greaves trained as a biologist at University College in the sixties. An interest in evolution and immunology drew him to medicine, and a PhD at the Middlesex Hospital. He planned a career applying the technologies and ideas of science to medical problems and thought that be would maybe focus on auto-immune diseases such as diabetes. But besides scholarly rigour and a puckish sense of humour, Mel Greaves has a big heart. It was emotion, rather than pure science that drew him into lifelong research into cancer. "I had a colleague working at Barts Hospital who took me round the wards at a time when my own (now adult) children were three and four years old. I saw children the same age stricken with Leukaemia and found it appalling. When I asked "What is leukaemia? What is the underlying problem here?" it was absolutely dear that ignorance was pretty rampant. We had no idea about the nature of the disease except that an expanding population of cells was damaging the bone marrow and children were dying. I felt that this must be a tractable problem, so I started asking simple biological questions such as "What sort of cell is involved?" One thing led to another and Ive spent the last three decades continuing the enquiry"
Mel Greaves makes no single-handed claims of success, but says modestly that as part of a worldwide research effort - "almost entirely funded by charities such as the Leukaemia Research Fund. I havent had a penny from government" - he has found it immensely rewarding to help unravel the underlying genetic abnormalities of childhood eukaemia. "We have shown that the mutant genes driving the disease start with the developing baby in the womb, and that other mechanisms come into play after birth. Being able to plot the development of the disease, understanding its biology and mechanics has had an impact on diagnosis and therapies. But though Ive been very pleased with the advances in treatment, it comes at a price: it takes a huge toll on families, its toxic and not everyone is cured. So prevention remains my overriding ambition."
The Obstacles To Childhood Cancer Research
We have shown that the mutant genes driving the disease start with the developing baby in the womb
Childrens cancers represent only one per cent of the cancer spectrum, and their very rarity, says Mel Greaves, makes them difficu~t to study. "Its really only in the past 10 years that we in the UK and USA have begun to design studies of a sufficient size to start addressing the causes. Its extremely difficult to design appropriate studies because there are many types of childhood cancers, even many types of leukaemia. And the answer to the problem of causation will never be that cancer stems from stuff x or agent y. There is always a multi-factorial or multi-component causing mechanism, which various things interact, in order for any individual to get cancer. My view about all cancers, including childrens cancers, is that you get the disease because of a combination of circumstance - genetics, exposures, dietary factors, energy balance - and sheer bad luck."
The Genetic Component
"I dont mean the inheritance of nasty mutant genes, although that can happen, and very occasionally in childhood cancers too" says Prof Greaves. "I mean that the set of genes you get from Mum and Dad which will determine how susceptible you are to cancer as to many other things in life such as the shape of your nose and the colour of your eyes. We are only now beginning to ask questions about the particular genes that affect predisposition to leukaemia or to brain tumours in childhood. Genetic background is just one major factor: 90 per cent of cancers are not inevitable. Malignant cancer may be a product of evolutionary ancient design limitations but most are still potentially avoidable."
Indecent Exposures
Hearing the words exposure and cancer in a single breath puts most lay people - and indeed many epidemiologists, in mind of environmental pollutants. But Mel Greaves suggests that this is by and large a false trail and that concentrating on carcinogens in the environment is like staring in the dark: Forget" he says "about the chemicals or the radiation we make such a fuss about. We dont need to go looking for man-made and unnatural substances that damage DNA because Planet Earth is simply bathed in DNA damaging agents from the sun and the solar system, from rocks and from the plants we eat. If they were all so terrible, we wouldnt, of course, have evolved as we have. Nature has invented lots of tricks to deal with these agents, so our bodies are well equipped with mechanisms for restricting and repairing DNA damage.
Genetic background is just one major factor: 90 per cent of cancers are not inevitable
Of course some of these things such as benzopyrenes, the chemicals in cigarette tar, do cause cancer. Cigarettes are a maior cause of cancer - theres no doubt about it. But its misleading in so far as it leads people to think that there is a singular cause of cancer. If there were, wed have solved the problems of breast and childhood cancers by now - Its not that simple. Theres a tendency among patients, among activist groups, even some scientists, to believe that breast cancer, for instance, is so unnatural and dreadful a thing that some noxious external and man-made pollutant must surely be at fault. But turn the picture around and you come up with a completely different set of explanations to do with current lifestyles which are so divorced from those we were adapted to when evolving. Internal problems of the body connected to hormone levels and diet can disrupt the activity of the breast so fundamentally that cancer is a consequence. The total calorie intake of young womens diet in relation to their physical exercise can result In a huge imbalance. This has major consequences for the amount of cell proliferation that goes on in the breast. Women now compound that with the fact that they are now not having early pregnancies and breastfeeding which remove some of the damaged cells and resets the system."
Again Professor Greaves stresses that lifestyle and genetics play a role in the development of cancer, and both interact with dietary factors. "Thats why theres a real challenge in this field: how do you put together the jigsaw puzzle to get a serious answer instead of a glib supposition that chemical x is to blame? These behavioural lifestyles seem perfectly natural but biologically they are grossly divorced from the way our physiology was set up to function early in our evolution.
Dietary Laws
Some dietary factors, says Professor Greaves, may be a common influence across the cancer board. Hes interested in folate "as current thinking suggests that a good healthy input is to some extent protective especially for colon cancer and to a lesser extent for breast". An Australian study has also found that women who took folate throughout pregnancy had children with a lowered risk of leukaemia. The reason this makes some sense says Prof Greaves is that folate is a B vitamin and its level in the cell affects the integrity of your genetic DNA material and its capacity for repair. But again one cant be simplistic - its not the case that taking a lot of folate means you wont get cancer because the genes that control your metabolism of folate vary from person to person.
The Random Element
Some dietary factors may be a common influence across the cancer board
Chance is an element in all these disease processes" says Professor Greaves "Its whether a combination of circumstances including background genetics, exposures and dietary factors come together or not in a particular individual, and sheer chance tips the balance. Potential causes are brewing every day in everybody. But you can only get a cancer if particular genes are damaged in particular cells. That damage occurs indiscriminately in the same way as trying to bit a target with a bow and arrow, blindfolded. It does come down to bad luck."
The challenge of preventing childhood cancers is heightened not only because the incidence is mercifully rare; another problem is that the cause of leukaemia in babies is different from that in older children - though in the past they were lumped together. "The type of cell involved and the abnormality in DNA is quite different as is the response to drugs and the possibility of cure. Only in the past couple of years have we discovered that some of the genetic factors that influence risk of leukaemia in babies have no effect whatsoever on your risk of leukaemia as an older child. The genes we are talking about now are not inherently mutant genes like BRCA1 and 2 which come with as high a probability 70 per cent chance of breast cancer. Rather, these are among the 30,000 variant genes that govern looks, all our individuality, as well as how potent our immune systems are and how good you are at detoxifying chemicals - or DNA repair. Your risk can vary according to the genetic lottery of which particular genes you have from Mum and Dad. But having a particular variant, for example, of the gene weve studied in infant leukaemia, still doesnt mean you are going to get that disease: it simply pushes your odds up or down. It sounds complicated, but there is probably a set of 10 or more genes that determines your risk genetically for each and every type of childhood cancer. So in order to prevent childhood cancers we have got to do specific genetic screening to find which sent of gene variants influences your risk, which exposure might affect your risk and which dietary factors."
Professor Greaves is impressed by some credible worldwide evidence that may explain the unusual pattern of disease in the children of affluent societies and the proliferation of allergies and type 1 diabetes as well as leukaemia. "Some years ago, we discovered that a common type of leukaemia we see in children here is quite common among white African children, but rare in black African children. Other studies in Europe and Australia also showed a gradient of risk that more or less went along with affluence."
Why should this be? "As an immunologist originally, Im interested in the patterns of infection among babies and how the immune system has evolved to cope. The immune system is still unstructured in the newborn; its a bit like the brain in the first year of life, before its bad all the sensory input. The Immune system learns its job by becoming exposed to infections. Once exposed, its primed so that when a child later gets infections, the immune system knows just bow to mount a balanced response. But in affluent societies now, we are very clean. Instead of five or six children in a house there are one or two. We are simply not exposing infants to what used to be endemic infections.
Firstborn children are considerably more at risk than third or fourth
children
"Of course theres a huge benefit in that there is no longer 25 per cent childhood mortality. But the consequences could include some modern diseases: infants who dont go to nursery in the first year of life but then pick up lots of infections later. If a child is then of the genetic background that reacts particularly strongly to those infections this, we suspect, can precipitate a very pronounced inflammatory reaction that damages the bone marrow. The argument is that the "delayed infection precipitates damage to the bone marrow which is the precipitating factor for leukaemia. And although we need early infection, the paradox is that persistent infection generates chemical products that damage DNA."
Mel Greaves is the first to acknowledge that this idea may sound esoteric, but cites four or five positive studies against one negative, supporting the theory that children exposed to other children or infections in the first year of life receive significant protection to allergies, type one diabetes and leukaemia. Another study - the largest ever to look at birth order and family size, finds that firstborn children are considerably more at risk than third or fourth children.
The wind of social change
The next step is to prove that children need infection in the first year of life. "If we can pin that down what next can we do about it? Encouraging social contact and more creches and nurseries is one route, which of course has huge social and economic implications for working mums. From a scientific point of view we could also consider concocting a vaccine that really does mimic natural infections. Allergists too are interested in this, because their explanation for the epidemic of allergies is very similar to what Ive described. They take the line that it should be possible to concoct a protective vaccine that would reprogramme the whole immune system."
Between 15-20 per cent of all worldwide cancers are caused by infection, including liver cancer, cervical cancers and some skin cancers. "As specialists we tend to be blinkered" says Mel Greaves, "but the real challenge ahead is how to look at the interaction of multiple factors and fit the bits of the cancer puzzle together. Even with the technology to look at the human genome and the capacity of huge consortium studies, the challenge is great - but theres now less of an excuse not to see the bigger picture.
Interview by Madeleine Kingsley