How the elephant family is protected from cancer

A few years ago, we spoke here on the programme to Vincent Lynch. He’d solved “Peto’s Paradox” - the apparent contradiction that despite having a big body and therefore many more cells capable of turning malignant, elephants actually have very low levels of cancer. And they do it, he reported, by bulking up on copies of a protective gene, called p53, that kills off cancerous cells. Well now he’s widened the scope of that initial study both to look across the entire elephant genome for other anti-cancer genes and also to consider other members of the elephant family, as he told Chris Smith...

Vincent - So in a previous study we had shown that elephants have a bunch of extra copies of this gene called p53 - one of the master tumour suppressors. Its job is to go around all of your cells, and when it senses that the cells might give rise to cancer, causes those cells to kill itself. And we think that that's probably related to why elephants were able to evolve such large body sizes and such long lifespans. And what we did this time is say, well, instead of focusing in on the one gene p53, what happens when we look at all of the genes in the genome? So the genome includes 20 - 22,000 genes. So let's just look at all of them. It turns out that elephants have lots of extra copies of genes whose function is to surveil the cell for the kinds of damage that are associated with eventually turning into cancer, and either dealing with that damage or causing the cells to kill themselves. So it looks like one of the ways that elephants evolved their really large bodies and long lifespans is to have lots of extra copies of these anti-tumour genes.

Chris - Elephants of course, are part of a family of animals that are similar to them, but they're not all huge. So if we look at smaller animals in that same group of animals, do they also have this massive expansion or did the elephants alone as big animals have that?

Vincent - The living elephants are big and the extinct ones like mammoths and mastodons, they're even bigger. So this lineage includes lots of big animals. But their closest living relatives are pretty small, so things like manatees and animals like a Hyrax, which is about the size of a Groundhog, and then a whole bunch of things, which are pretty small - about the size of medium sized dogs or mice. And when we look at their DNA, we see similar things, they all have extra copies of these anti-tumour genes. It's just that elephants have lots and lots of additional copies even compared to their close relatives.

Chris - So that tells you then, although all these animals share a common ancestor and that common ancestor had lots of copies of these genes, it was in turning into something with a very, very big body size, i.e. an elephant or bigger that there was this very strong selection for even more copies to enable that body size to be sustained?

Vincent - Yeah, that's right. So it looks like in this whole group of animals, there is a tendency to get extra copies of anti-cancer genes, but then as elephants evolved their large bodies, there was some additional selection that probably required them to have even more additional copies of those anti-cancer genes. So that's what we're seeing when we look at their genomes.

Chris - The interesting thing is the age of reproduction in these animals, because elephants really benefit from these extra copies of genes beyond the age of which they might be reproducing don't they? So is it because they live in big families that they've managed to concentrate these genes and select for the beneficial effects?

Vincent - Yeah. So that's actually a really, really challenging question to answer. So all we can do now is compare the DNA of all the living animals, so elephants, and there's a few different species of elephants, to all their close relatives and say, okay, how many of these anti-cancer genes do they have? And obviously elephants have more. But determining the direction of causation - is it that they got all these extra genes and that allowed them to get big and get large families and live a really long time? Or did it go the other way around? Was there some selection for elephants to get big and have large families and delay reproduction, and that required them to evolve some kinetic mechanism to do that? So we call that the direction of causation. We can't really know that, but all the things that go along with being big, like having long lifespans and delaying reproduction until you're older, and in elephants in that they live in these large families where the matriarch has a lot of knowledge about how to exploit the resources in the land. All these things probably together mean that elephants had this sort of increased selection to live longer, which means you need genetic mechanisms to allow that.

Chris - Do you think cancer would have been a major problem for these animals otherwise then? Because it just seems a bit surprising that only those genes, those anticancer genes, would have been enriched. Surely there would have been other problems that they would have run into as they got older. I mean, an old person claps out with heart disease and strokes, for example. Don't elephants succumb in the same way?

Vincent - Yeah, so I don't know about strokes. It's hard to sort of ask an elephant the questions that you're asked when you have a stroke. So we can't know much about cerebral cerebral vascular diseases. But they do end up getting a lot of coronary artery disease, so a lot of the kinds of diseases that we think are associated with old age in humans and other animals. So they suffer the same sort of old age diseases, the same diseases of old age as humans. But at least with regard to cancer, they get less of it.

Chris - So in other words, because they are so gigantic, they would have a substantial disproportionately big risk of cancer because they've got all those cells that can turn cancerous. So there would have been a very profound selection pressure to defend against that.

Vincent - Yeah, that's right. So if you can imagine that if you look at the sort of cells of all these different animals, and they all have the same probability of going from a normal, healthy cell to a diseased cancer cell, then big things which just have more cells than small things should have more cancer. So that means that, because they don't, they must have evolved really, really efficient ways of reducing their cancer. But that doesn't mean that they're not going to get other diseases of old age.