Mel Greaves, Institute of Cancer Research
Kat - In 1977, the biologist Richard Peto noticed an unusual paradox - if we assume that the chances of an individual cell in the body turning into a cancer cell is the same across all animal species, then humans should get more cancers than mice, and even larger longer-lived species such as elephants and whales should get many more than us. Yet this isnít the case - whales and elephants hardly ever get cancer - so whatís going on? According to the speakers at a recent meeting about Petoís Paradox at The Institute of Cancer Research, hosted by Professor Mel Greaves, to solve it we need to take a wider look at cancer across species, including taking an evolutionary perspective, as Mel explained to me.
Mel - I, like many people in the field were very influenced by a paper published in 1976 by an American clinician called Peter Nowell who made the argument that had been developing for a few years that tumours seem to evolve through genetic change and selection over time in patients. I thought this was a complete paradigm shift and a new perspective on cancer. It didnít mention donors, it didnít mention ecosystems, some would say it was very simplistic view but it struck me that this was an absolutely fascinating and interesting way to think about cancer. And since then, I've tried to take the perspective my own work on leukaemia and cancer in general, to think about cancer as a problem in evolutionary biology and evolution of cells.
Kat - Itís almost like the idea of it being a rogue organism within the body thatís sort of evolving and changing, or a population of rogue organisms.
Mel - When multicellularity was invented 600 million years ago, and the deal was, weíve all got our different jobs to do with these different cell types, but will all work together for the common good, for the health and fitness of the individual. So, we call these metaphors, cancer cells or individual cells behaving almost as if they're a parasitic species. They're now selfish, they're ignoring the signals for restraint, and enjoying their lifestyle at the expense of the organisms. So, there are selfish types of cell and in essence they're a cellular parasite.
Kat - In terms of a wider evolutionary perspective of humans as part of the branch of the massive tree of life, how does one cancer risk fit in compared to other organisms?
Mel - We donít have a terrific amount of data on cancer in wild animals. In zoos, we have some information but in so far as that information exists, we seem to have vastly more cancer than other species.
Kat - Why do you think that is?
Mel - Well, my thought about that comes from that epidemiological observations that cancer rates appear to be low in people, indigenous populations like hunter-gatherers. It looks that the very high rates are relatively recent in human history. We see high rates of different cancers in different countries, and different people. It doesnít look as though itís primarily genetic because when populations move to another country as migrants, or when lifestyles change over time, it looks that the high risk is very much related to lifestyle, to exotic lifestyle. So, itís not too difficult to imagine - humans compared with other species have rapidly evolved essentially. Weíve recreated completely artificially unique ecosystems for ourselves Ė in our diet, in our reproductive lifestyles, the way we interact with the sun, and everything. Smoking is the obvious example. I donít know an animal smokes and there probably arenít any. So, weíve recreated this artificial environment which has many beneficial effects Ė that's why we've done it. People like smoking, people like eating a lot, and people like sitting in the sun without thinking of long term consequences. So, I'm afraid we are seriously maladapted. We have lots of cancer restraints as all animals do, that have evolved millions of years. But weíve overwhelmed them with all these regulation of the body through stress to tissues through behaviour patterns that have evolved very, very rapidly.
Kat - Lots of people say that cancer is just a disease of our modern lifestyle, but given that at least some wild animals seem to be afflicted by cancer and that there have been sort of old specimens found, does it seem fair to say that we have always had cancer, but the rates are increasing?
Mel - I think cancer in one sense is intrinsic to the design of multicellular life because what happened in deal 600 million years ago is that cells would organise themselves socially with some form of restraint. But you still needed to allow certain cells to divide quite a lot and we call them stem cells. So, there's a kind of contract there. So, every time a stem cell divides, there's a risk DNA will mutate because DNA is sloppy. It does mutate. If it didnít have mutation, it would have no evolution. So, there's always intrinsic risk of cancer which is why we have some readout of cancer in almost all the species. But there's a balance between those risks and the evolve restraints that can recognise the problem and deal with. So, I think cancer is intrinsic to multicellular life. Itís one of the risks, but itís relatively modest or low. Humans are simply overwhelmed that they tip the balance in terms of risk versus restraint.
Kat - Where do you think we need to go next with bringing our understanding of evolution together with our understanding of cancer biology and cancer genetics? What are the big questions for you now?
Mel - Well, I want to have something that's the antithesis of the magic bullet because I don't like that idea, and idea I have is a sort of analogy with signal lights. So, the best thing would be, if the problem is evolution, evolution of robust clones of parasitic-like cells and what are we going to do about it? Ao, solution number one is plan A, B, and C. the red light is, we stop it getting going before it gets started. So, thatís prevention. So probably, two thirds or maybe up to 90 per cent of cancers are potentially preventable and we should be much more assiduous and active in trying to do that. So, smoking, exposure to the sun, prophylactic vaccines of various cancers, et cetera. We need to think very seriously about whether breast cancer is preventable or not. So prevention is the red light. Stop it. Some cancers are not preventable and yet, with current knowledge, we should catch them early because we know from evolutionary point of view, when they're less evolved and less diverse then more drug sensitive. So, there should be and there is a major effort in early diagnosis because then other surgeon can deal with or radiotherapy or a simple drug combination. So, when the diversity in evolutionary progression is limited, you stand a much better chance. So, thatís the red plus yellow light Ė things are starting to go.
But the fact is that even if you are incredibly successful with that, about 15 per cent of cancers are going to present out of the blue in a very malignant advanced state. Pancreas does it, brain tumours do that, many ovarian cancers do that. So, thatís why we just need to have a reality check and say, ďThese are advanced, highly diverse, weed-like parasitic species of cells that are going to have drug-resistance on board. How can we treat those?Ē And thatís where weíre having a revolution in treatment, thinking about novel combinations of therapy using the immune system, use novel drugs that take advantage of understanding the complexity of the system. So, our argument is, we look at the phylogenetic evolutionary tree of the cancer and say, well this type of tree structure with all of these branches and this trunk, what's the best route of attack? And what we say is we donít want to just chop a few branches, a few clones, because that will achieve nothing. You want to attack it at its roots or at its trunk, and there are ways that we might be able to do that. So, there's a three-pronged approach Ė traffic-light style - of prevention, early diagnosis, and more sophisticated combinatorial treatme
Kat - Mel Greaves, from The Institute of Cancer Research.