João Pedro de Magalhães: Old whale, new tricks
Image Courtesy of João Pedro de Magalhães
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We’ve just heard about how breakthroughs in understanding human heart attacks can come from some of the smallest mammals like the 13 lined ground squirrel. Well now let’s take it up a notch and see what we can learn from some of the biggest mammals on the planet, like the bowhead whale.
João Pedro de Magalhães, is a professor of Molecular Biogerontology at the University of Birmingham, studying the mechanisms of ageing, and again he’s not restricting himself to just studying humans. To get us started, I asked him what exactly do we mean when we’re talking about ageing:
Joao Pedro: So I tend to define ageing as an inevitable and irreversible process of loss of viability and increase in vulnerability, which is a very broad definition, which kind of encompasses multiple changes, physiological, molecular, cellular changes, and encompasses also pathologies and mortality that increases exponentially with age.
Sally: I noticed how the word inevitable is right up there in your definition. So ageing is inevitable, is it?
Joao Pedro: It is inevitable in human beings for sure. Yes. It is not inevitable in the animal kingdom. I mean, there are species that appear not to age. So you have animals like the rockfish or some species of rockfish, you have some species of turtles and tortoises, quite unusual species that appear not to age.
Sally: How old are these individuals? How old is the oldest rockfish that we know about?
Joao Pedro: That's a great question, we don't know for sure because we don't have methods of assessing their age. I mean, they don't have ID documents, right? So it's all based on indirect methods.
Joao Pedro: In mammals, the longest lived mammal is thought to be the bowhead whale, which has been estimated to live over 200 years. And in the wild, you know, without hospitals, without medicine, they just live longer than us and they're protected from cancer!
Sally: So when it comes to thinking about human ageing and how we can improve our own ageing as a species, why is it useful to look at all of these other animals?
Joao Pedro: I think there's a lot that we can learn from different species. I suppose from a biomedical perspective, if you think about biomedical research, it mostly focuses on short-lived animals like mice. Mice developed diseases like cancer very rapidly, so we study the mechanisms of disease and genes associated with diseases in these short-lived, disease-prone animals.
Joao Pedro: The idea of studying these long-lived disease-resistant species is that it's a complimentary paradigm then. So whales for example, they must have tumour-suppressive mechanisms that we lack. So if we can identify, if we can figure out what makes them cancer-resistant compared to humans, that may have human applications.
Sally: So do whales not get cancer?
Joao Pedro: They do get cancer, but if you think about a whale: thousand times heavier, a thousand times more cells than human beings. Then, well, cancer starts in one rogue cell, right? So all things being equal, an animal that has a thousand times more cells than a human being would on average develop cancer earlier in life. But they don't, they actually live longer than human beings. So they must have natural mechanisms for tumour suppressor that we lack.
Sally: How do you study a whale? You can't exactly keep a whole bunch of them in the lab. I come from a fruit fly background, so I just have loads of genetic mutants. Super easy. You can't really do that for whales, I imagine.
Joao Pedro: No, you can't. No, I don't think my head of department would be too happy if I just started having whales in a lab. So that's one of the advantages of genomics and genome sequencing is that now it's much cheaper, quicker, and easier to sequence a genome. So we were the first to sequence the bowhead whale genome, for instance.
Joao Pedro: Just by sequencing the genome of these amazing animals, you can gather insights and derive hypotheses for what may be their secrets to disease resistance and longevity. And then you can even take some of those insights and try to apply them. You can create cells with genes from whales, for instance, human cells or mouse cells. So there's all sorts of analyses you can then do that don't involve actually getting a whale to do experiments.
Sally: So once you've got, say, the bowhead whale genome, where do you even begin to start with looking for kind of anti-cancer genes?
Joao Pedro: So one way to start is by looking at existing or known tumour-suppressor genes, oncogenes. So cancer-associated genes or ageing-associated genes in whales. So you compare the human genes to the whale ones, and then you're trying to find evolutionary innovations. You try to find changes that based on a computational analysis, indicate that this could be important.
Joao Pedro: You can make 3D models of proteins from the bowhead whale, for example, based on the changes, on the mutations that were observed in the bowhead whale compared to other mammals. And based on that, you can make predictions about what the impact of those changes in the bowhead whale are.
Sally: I was gonna ask, how do you separate out just random mutation drift. Things mutate all the time and things mutate and it doesn't make any difference. You are going to expect, even if you're looking at the same gene in a whale and in a human, you're going to expect differences. How do you work out which ones matter?
Joao Pedro: There's a lot of tools for that actually. So that's a challenge also in analysing human genomes. I mean, if you sequence your genome, you will have changes. So how do you figure which are important and which aren't?
Joao Pedro: First of all, there are not that many differences, particularly in protein coding regions. So in the functional regions, there's not that many differences between a whale and a human being.
Joao Pedro: And then for the changes you find, you can say, okay, so do you see these changes in any other mammals? I mean, if there's like a particular nucleotide or residue that changes a lot, then you know, that's probably not a very important nucleotide. I mean, it can mutate a lot without phenotypic consequences. But if you have a particular nucleotide, a particular residue in a protein that's very well conserved amongst mammals, then chances are that's quite an important one. That's why it doesn't mutate, ever. But if it mutates in whales, then you can say, okay, that probably has some sort of functional consequence.
Sally: And what do these cancer-related proteins do? Do they go around killing cancer cells, preventing them from forming? How do they act?
Joao Pedro: So by and large, these are cell cycle regulators. They regulate whether cells divide or not. Some of them are involved in DNA damage responses. So how cells respond to DNA damage, whether they stop proliferating, and so on.
Sally: And you mentioned it's possible to take then some of these genes that you find in whales and put them in human cells in vitro. Have you tried that?
Joao Pedro: We haven't tried it with bowhead whales yet, but one of the things kind of similar that we have tried is to take some genes from the naked mole rat. The naked mole rat is the longest lived rodent, it can live over 30 years. And it's very cancer-resistant.
Joao Pedro: So we have taken some cancer-related genes from the naked mole rat, and we replaced the mouse gene with the naked mole rat equivalent gene. So we've done that for some well-known cancer-related genes like p53 in mouse cells. And actually what I would like to do is actually make a mouse with naked mole rat genes and see if they live longer, if they're cancer resistant. That's what I would really like to do.
Sally: Do we know why, in terms of adaptations and evolution, why some animals live for so much longer than others? Like why should a naked mole rat have evolved to live so much longer than its other rodent relatives.
Joao Pedro: I think from an evolutionary ecological perspective, animals mostly die because they're eaten by other animals. That's the number one cause of mortality in mice or rats or lots of other species.
Joao Pedro: And if that's the case, and particularly if you are heavily predated on, then you need to have a very short sexual maturity. You need to grow very rapidly, make babies very rapidly, just have to push that offspring out rapidly because your life is gonna be very short.
Joao Pedro: On the other hand, when you look at the long lived animals, well let's take naked mole rats as an example, they live in very protective environments in which that external mortality like predation, it's much, much reduced when compared to other rodents. And hence they can evolve this longer lifespan, longer reproductive period, and so on.
Sally: And where do humans fall on that scale?
Joao Pedro: We are quite long-lived as a species. Evolutionary and biologically and compared to other species, including related species of primates, we are a long-lived species.
Joao Pedro: The way I see it, ageing is a product of civilisation and technology. It's actually an excellent product of civilisation and technology! You don't have to look very far into the past. You just look 150 years ago, life expectancy was about 40. Most children died. Throughout human history, most children died, which was horrible! We now live in times where childhood mortality is very low and people can live much longer lives. And that is an outcome of these various technological and societal changes and civilisation development as a whole, which, yes, it has its drawbacks because now we develop all of these age-related diseases later in life.
Joao Pedro: But it's really the result of great progress that was made over past centuries that now allow us to have these much longer lives than ever before in human history.
Sally: So do you think that by studying other animals will be able to "cure ageing"?
Joao Pedro: I think cure ageing is even more complicated from a technical perspective. There is also a broader issue of why we age, which we haven't been able to answer yet.
Joao Pedro: I think that the comparative approach can provide insights on that. It can provide insights on why different species age at different paces, and potentially into mechanisms for longevity and disease resistance that we may apply to humans. Now, curing ageing, it's, you know, one step ahead. It's much more complicated than that, in part because we don't well understand the process of ageing or why we age.
