Why don't elephants get cancer?
Animals like elephants and whales are made up of many more cells than a human, or a mouse, and they live far longer. Yet they hardly ever get cancer - and the big question is why? Plus, revolutions in genetics, and a magical gene of the month.
In this episode
01:04 - Mel Greaves - Evolving cancer
Mel Greaves - Evolving cancer
with 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 isn't the case - whales and elephants hardly ever get cancer - so what's going on? According to the speakers at a recent meeting about Peto's 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 didn't mention donors, it didn't 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 - It's almost like the idea of it being a rogue organism within the body that's sort of evolving and changing, or a population of rogue organisms.
Mel - When multicellularity was invented 600 million years ago, and the deal was, we've 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 don't 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 doesn't look as though it's 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, it's not too difficult to imagine - humans compared with other species have rapidly evolved essentially. We've recreated completely artificially unique ecosystems for ourselves - in our diet, in our reproductive lifestyles, the way we interact with the sun, and everything. Smoking is the obvious example. I don't know an animal smokes and there probably aren't any. So, we've recreated this artificial environment which has many beneficial effects - 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 we've 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 didn't 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. It's one of the risks, but it's 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, that's 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, that's the red plus yellow light - 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, that's why we just need to have a reality check and say, "These are advanced, highly diverse, weed-like parasitic species of cells that are going to have drug-resistance on board. How can we treat those?" And that's where we're 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 don't 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 - traffic-light style - of prevention, early diagnosis, and more sophisticated combinatorial treatme
Kat - Mel Greaves, from The Institute of Cancer Research.
09:07 - Athena Aktipis - Cancer across kingdom
Athena Aktipis - Cancer across kingdom
with Athena Aktipis, Arizona State University
Kat - Another researcher who's trying to solve Peto's Paradox by taking an evolutionary view is Athena Aktipis from Arizona State University, who's been looking in more depth at cancer rates across the animal kingdom.
Athena - I see cancer really as a fundamental problem for the evolution of multicellularity because in order to build a multicellular body, the cells have to cooperate to inhibit the cell proliferation, control cell death. But also, distribute resources and divide labour, and do all sorts of other things that you need to do in order to make a large body that can be effective. And really, cancer is this fundamental breakdown of cooperation in a multicellular body.
Kat - It's kind of cells going rogue and saying, "I'm not going to be brain cell or a skin cell. I'm just going to do my own thing."
Athena - Yeah. You could sort of think of it in that way. Having a multicellular body work well means that the cells within it are following certain rules, and those rules are encoded genetically with tumour suppressor genes that are making sure cells aren't dividing out of control, making sure that cells are expressing the right genes for the tissues that they're in, and making sure that they're producing the right proteins. So, all of those things break down in cancer and what you get are really misbehaving cells and the result of that is that you can get a malignant growth that can take over and eventually kill a patient if it's not treated properly.
Kat - Are cancer cells really kind of cheaters? They'd be getting around the rules of the society the body and doing what they want.
Athena - Yeah. So, you can think about cancer cells as cheaters in the sense that in general, we can think of cheating as breaking some shared rules. You break some shared rules that you have with a group. In cancer, the shared rules are being broken and those shared rules are actually encoded in our DNA. There are DNA repair mechanisms that are literally getting broken and allowing those cells to get around the shared rules that enabled multicellularity in the first place.
Kat - You're studying the links between cancer and evolution. What do we know sort of where cancers comes from and where is it going, and how do we fit in as humans to the rest of life?
Athena - There are two different answers to that question. So one, is the question of, where does cancer come from for any given individual? The answer is that cancer is a result of a sort of evolutionary process within the body where the cells that are proliferating more quickly, the cells that are monopolising the resources better, that cells that aren't dying when they have too much DNA damage. They're increasing in frequency in the population and that means that what happens over the course of a lifetime is that within the body, selection actually favour cells that are neoplastic, cells that are not behaving properly unless immune system is able to get them under control. So, within an individual, cancer comes from that evolutionary process. But then if we look at the evolution of life in general, what we see is that just the formation of multicellularity. In order to do that, you have to suppress cancer or at least the primordial version of cancer which is cells not inhibiting their proliferation properly, cells not sharing resources with neighbouring cells, cells not cleaning up after themselves. All of those things are sort of the primordial elements of multicellularity. And really, suppressing cancer is a problem that goes back to the evolution of multicellularity and even earlier, even before multicellularity was necessarily about discrete organisms. But when cells started living nearby each other enough that they had to start behaving a little better than they might if they were just on their own.
Kat - There were lots and lots of different species in the world of all sorts of different sizes and there's this famous paradox that you expect bigger organisms because they've got more cells, maybe they should get more cancer and particularly if they live longer, small organisms should maybe get less. But that's not what we see. Tell me about the kind of patterns that we see in cancers across different species and where humans fit in.
Athena - Yeah. Well, you know, if we look across species, we do see the sort of general trend in this paper that we just recently published, Cancer Across the Tree of Life, where the more complex forms of multicellularity and the species that are larger compared to much simpler species do seem to have more cancer reported. But if you actually look at say, within mammals or animals more generally, if you would just look at body size and cancer, you might expect larger organisms to get more cancer because they have more cells, but that isn't the case. So, elephants for example have really low rates of cancer. One of the ideas of why that might be the case is that if you have an organism that reproduces really late and has to grow really large, it's probably worth it for that organism to invest more in suppressing cancer than field mouse that runs about for a year and then gets picked off by a predator. For an animal that is only going to live that long and is going to start reproducing when it's a few months old, it doesn't necessarily make sense to invest in all those cancer suppression mechanisms especially if they come at some cost to reproduction or to wound healing or whatever the trade-offs might be.
Kat - In terms of where humans fit in to that picture - we don't really live fast and die young like a field mouse, we're not as big as an elephant - does our cancer risk kind of fit somewhere in the middle?
Athena - Modern humans do have higher cancer risk than we might expect. I think there's open questions about the extent to which those are driven by environmental exposures that sort of have to do with mismatch between the environment that we evolved in and our current environment. But there are some cancers for which it does seem like a pretty convincing case. There might be some contribution that really is coming from the fact that we live in a world that's really different from the world that we evolved in.
Kat - We're starting to understand a lot more about cancer, about how to treat it, how it starts, looking at the genetics of cancer. It seems quite a recent advance to be bringing evolution into this mix. Why do you think it's important that we do bring an evolutionary view to our studies of cancer?
Athena - Interestingly, evolution has been accepted as a theory of cancer for decades. I think recently it has made a resurgence because it's become much easier to look at the evolutionary process because of how inexpensive it's become to look at genomics and to have huge datasets at our fingertips to examine some of these evolutionary questions.
Kat - Arizona State University's Athena Aktipis.
16:51 - Josh Schiffman - Elephants and cancer
Josh Schiffman - Elephants and cancer
with Josh Schiffman, University of Utah
Kat - So we've heard about the importance of studying cancer from an evolutionary perspective, and looking across different species - but that still leaves our original question unanswered: why don't elephants get cancer? Josh Schiffman, a children's cancer doctor working at the University of Utah, has found out - publishing his findings last month in the Journal of the American Medical Association - and it all boils down to an important protector gene called p53.
Josh - Elephants, when you look at their genome, seem to have evolved extra copies of a gene called p53. P53 is known as the guardian of the genome. It's one of the most important genes in our body. It's a superhero of the genome. It actually works hard to prevent cancer. It has two main functions: one is to stop our cells from dividing so they can be fixed and all of the mutations repaired. If the cell is not able to be fixed then p53 helps coordinate the death and destruction of the cell. In fact, some of the families that we care for back in Utah have something called Li-Fraumeni syndrome actually, a hereditary risk for cancer based on p53 mutation. If they don't have p53, they go on to develop cancer at very high rates, 80 to 90 per cent lifetime risk of cancer, many cancers at a young age, multiple cancers over the course of their lifetime. Wouldn't it be wonderful if we could try to figure out if the extra copies of p53 in elephants are what's protecting them from cancer? What if we could somehow get some elephant blood and compare the elephant blood to the Li-Fraumeni blood and look to see if we can understand why don't elephants get cancer.
Kat - How on earth do you go about getting hold of elephant blood?
Josh - Several weeks later, I was back home visiting Utah's Hogle Zoo where they have three African elephants. I was watching the elephant show with my children when they explained during the course of this elephant display that elephants have large ears. They have large ears because they have large veins in the back of their ears to circulate their blood and to keep them cool in the African heat. They also went on to explain that once a week at the zoo, they draw blood from these veins in the African elephant ears and they draw the blood to make sure that the elephants are healthy and their hormones are in balance. When I heard that, I said, "I've got to talk to this elephant keeper."
So immediately, after the elephant show, I went right up. I introduced myself. I explained that I'm a paediatric oncologist. I explained about Li-Fraumeni syndrome. I explained about Peto's Paradox and I asked a question. At which point, the elephant keeper said, "Go ahead. We love questions. Please ask a question. What's your question?" I said, "My question is, how can I get me some of that elephant blood?" Fortunately, the elephant keeper didn't call security but rather explained that there was an ethical review process and a scientific review board at the zoo. And if I filled out all the paper work, it was possible to get some elephant blood at the same time they were drawing it for their own reasons at the zoo.
It took about two and a half months of paper work, but since that time, once a week, my clinical study coordinators, instead of drawing blood from our patients with Li-Fraumeni syndrome, actually go down to the zoo which is located only 15 minutes away from our laboratory, get the blood, rush it back to the laboratory where we've done the experiments and we think we figured out why elephants don't get cancer.
Kat - So, what is the answer? What have you found when you compare the cells in the elephant's blood to the cells in your patients or to normal human cells?
Josh - We take that elephant blood, we take the blood from the patients, and from healthy humans, and we bombard them with radiation to cause DNA damage. We look and we see how did the elephant cells respond to that DNA damage - which obviously, in normal situations would lead to cancer - and how do human cells respond to that? What we found surprised us. What we found was that the elephant cells didn't actually stop the cells from dividing or repaired the DNA damage any faster than the human cells like we were expecting. But instead, what we saw is that they had increased cell death. The majority of all of the elephant cells underwent cell death suicide. They underwent apoptosis. It's as if the elephant has said over evolutionary time, "Listen. It's so important that we don't develop cancer. We can't take any chances. If we stop the cell from dividing and we try to repair it, we might make a mistake and we might let a few of these mutations go on by and turn into cancer. But if we just kill the cell and get it over with then there's no way that cell can go on and cause cancer. We're elephants - we have plenty more cells where that came from. We'll just start over." And now, we're trying to figure out a way to use that information to help the children and families who develop cancer to make sure that they could live a long and healthy life.
Kat - So that's elephants. What do some of the other animals in the zoo maybe have inside that could help us understand human cancers?
Josh - Absolutely. That's an excellent question. One of the things that we're most excited about in the lab and also, when we're talking with patients is the field of comparative oncology. We're learning that all animals develop cancer. Some more than others - some are resistant like the elephants, whales also turns out are resistant. But there are other animals that are more likely to get cancer. So for instance, dogs develop cancer at 11 times the rate of people. Now, we never give cancer to dogs in the laboratory, but once they develop their cancer, we're able to look and see what is it about the dog cancer that's similar to human cancer or paediatric cancer so we can see what's in common and then target those genes.
Kat - Josh Schiffman, from the University of Utah.
23:08 - Alison Woollard - Genetic revolutions
Alison Woollard - Genetic revolutions
with Alison Wollard, University of Oxford
Kat - Every year the Genetics Society recognises a person with an outstanding ability to communicate genetics through the JBS Haldane lecture and award. This year's winner is Professor Alison Woollard from Oxford University, whose work focuses on the genetics of ageing, using nematode worms as a model. She gave her lecture at the beginning of November at the Royal Institution, focusing on key revolutions in genetic thinking. I caught up with her afterwards to find out more about Haldane himself, and her revolutionary ideas.
Alison - JBS Haldane was a very interesting scientist who was working in the UK in the 1930s and '40s, and '50s, and beyond actually. He was fascinated in population genetics. He was very interested in how to relate Mendel's ideas of heredity into whole populations and he applied maths to work that out. He was one of the real proponents of the importance of quantitative analysis in biology.
Kat - He was also kind of quite cool. He was very into debating about ideas and talking about them.
Alison - Yeah, he was amazing. People say that JBS Haldane was the best read of all scientists of his age. And then people say that in order to become the best read of all scientists of his age, he only had to read his own work because he was so prolific.
Kat - He was kind of a bit of a hippie as well. I love reading about him. He's my favourite, I think.
Alison - Yeah. He's like everyone's favourite granddad I think. He was very left wing, he was a Marxist, he was a great socialist. He believed in equality, he was a great believer in the welfare state. He was a great believer and passionate about education at all levels, and how education is a great liberator. He had weird and wacky ideas about all manner of things. He spent a lot of time in India on the hippie trail and wrote some fascinating books about his experiences there, and many other things besides.
Kat - But moving from JBS Haldane to you, you've just delivered the JBS Haldane lecture. Tell me about what you were trying to get across in the talk today?
Alison - Haldane was very well-known for his skills in public communication and so, the Haldane lecture of the Genetic Society is a public lecture where we try to bring genetic ideas to a very wide audience. My sort of take on this was to really think about genetics as revolutionary because I think Haldane was a revolutionary. And so, I wanted to have this idea of revolution in my lecture. And so, I decided I would pick on what I considered to be the most important revolutions in genetics. I was probably a little bit ambitious because I started in 400 BC and ended up in the future. That struck me as a problem when I was desperately trying to finish this last week. But nevertheless, I sort of tried to pick out the most important revolution in terms of genetic ideas that have happened, really starting with Mendel and then moving on from that.
Kat - You had 7 revolutionary ideas. Tell me about some of them.
Alison - Well, there was Mendel's Principles of Heredity. Mendel proposed a mechanism for heredity that was missing from Darwin's Theory of Evolution by Natural Selection. So, that was really, really important. And then we have the idea of relating these hereditary principles to actual tangible things in cells i.e. the behaviour of chromosomes. And that was the third big revolution. That's what Thomas Hunt Morgan was really involved in.
Kat - That's all the fruit fly guys - the fly guys.
Alison - The fly guys, lots of fly stuff, great fly stuff. And then after that sort of came the molecular biology revolution. So, all the guys, Watson and Crick, but all the people before him that showed that DNA is the hereditary material, and then that came after him that showed how gene expression works, how genes can be switched on and off. There was such a lot of molecular biology that went on it. It was an absolute ferment in the 1940s and the 1950s, and into the '60s. The molecular revolution I think is massive. And then after that, people understood the mechanism of heredity and how that works even at the level of molecules, but they didn't understand the rest of biology. And so, people started to use genetic techniques to understand other things in biology like cell division and development, how cells end up in the right place doing the right thing, what differentiates one cell from another. And so, that was a really important thing.
Kat - And then we get to the genome, the era of genomics.
Alison - Yeah, absolutely. So, that's very late 20th century, 21st century idea that you can sequence whole genomes and then you can understand the entire genetic makeup of an organism, and really drill down into what it is that distinguishes one organism from another and what distinguishes one disease from another within an organism. And so, we're in a really new era now of understanding genomes and also are beginning to manipulate them. So, that's my last revolution. It was genome editing. This idea that we can now interfere, modify our genetic destiny, and thinking about whether or not that's a good thing, or a bad thing, or an inevitable thing, whether it's a good way of eradicating disease or whether it's dangerous. It might lead to designer babies and so on. So I think people need to understand the science behind those kinds of ideas if they're to contribute to the debate about whether or not it should happen in the future.
Kat - Alison Woollard from Oxford University - this year's Genetics Society JBS Haldane lecturer.
28:36 - Gene of the Month - Merlin
Gene of the Month - Merlin
with Kat Arney
And finally it's time for our Gene of the Month, and this time it's Merlin. Rather than being named after King Arthur's legendary wizard, Merlin is an acronym, short for "Moesin-Ezrin-Radixin-Like Protein" - you can see why it's a useful nickname. Also known as Neurofibromin 2 or NF2, after the name of the gene that encodes it, the Merlin protein plays a part in the biological scaffolding inside nerve cells, helping them to keep their shape. Faults in its gene, NF2, cause tumours in the nervous system, particular in nerves in the ear. So it seems that just like the protecting force of its namesake, Merlin also helps to protect us against cancer.