0:00Welcome to Base by Base, the papalcast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. So today we are diving deep into one of the most fundamental biological problems that faces any multicellular life.
0:16Cancer. And here's the paradox I want you to chew on. If cancer is really the price we pay for having 10000000000s of cells. Why aren't the biggest, longest lived animals on Earth? I mean, think of a 100 ton blue whale or an African elephant?
0:32Why aren't they just constantly overwhelmed by tumors? It's a fantastic observations, often called Pitto's Paradox. And it basically argues that since cancer risk should go up with a number of cell divisions, these massive long-lived species must have evolved some kind of incredible, you know, hyper-effective genetic solutions to stop that from happening.
0:50But here's the thing. When scientists look into this cancer resistance, they often just lump all abnormal cell growths together. They call it neoplasia. Which is problem. A huge problem. I mean, anyone who's had a common, harmless wart knows that it is profoundly different from a lethal metastasizing cancer.
1:06Exactly. And that failure to differentiate in these big evolutionary studies, it creates this massive blind spot. So our mission today is to explore some new research that asked a really critical question.
1:18Which is? What happens when we separate the 2 types? The benign tumors, which are non-spreading, and the malignant tumors, which are the lethal cancers? Do they actually evolve under the same selective pressures?
1:29And the answer, which is just fascinating, is a resounding no. The 2 types of tumors are driven by completely divergent macro evolutionary forces. Especially when you look at how species change their body size and how fast they diversify across the tree of life.
1:46Okay, this is where it gets really interesting. So let's unpack this. Before we jump right into the findings. We do want to give special recognition to the collaborative research team that tackled this critical distinction across both birds and mammals.
1:57Yeah, this was a major effort. The study is titled divergent evolutionary dynamics of benign and malignant tumors, and it was published on November 6, 2025. The work was led by a whole team. George Butler, Joanna Baker, Sarah Aramend, Kenneth J.
2:12Pienta, and Chris Finn Diddy. And they represent some incredible institutions. University College, London Cancer Institute, Johns Hopkins School of Medicine, the University of Reading, and the Open University.
2:24It's exactly this kind of cross-disciplinary work that helps us crack these huge evolutionary questions. So to set the stage. Let's just be really clear on the terms we're using. Tumors are at their core, just abnormal cellular growths.
2:38And we classify them as either benign, meaning non-cancerous or malignant, meaning cancerous. And that one word, that classification, it means everything from an evolutionary point of view, doesn't it?
2:49Everything. The 9 tumors, you know, things like moles or warts, they generally have a very limited, if any, negative impact on an individual's ability to survive and reproduce. Right, they're usually just a minor fitness cost.
3:01Annoying maybe, but not deadly. But malignant tumors. Malignant tumors are an evolutionary catastrophe. Their ability to invade surrounding tissues, and most importantly, to metastasize. To spread to distant vital organs.
3:15Means they impose a massive, deadly selection pressure. They can just completely cut short, reproductive success and survival. So the research gap was really recognizing that this fundamental difference in lethality should mean they have fundamentally different evolutionary stories.
3:32Exactly. Previous studies had always looked at correlations with things like overall lifespan or body size, but they never separated the data for these 2 wildly different types of growth. They just threw them all in the same bucket.
3:44Right. So given that stark difference in selective pressure, the authors hypothesized that benign and malignant tumor prevalence would show divergent associations with key macro-evolutionary processes, they pick 3 big ones to test this.
3:59The 1st one is pretty straightforward. body size. Yep. Yep. We know there's a baseline correlation there. More cells, more chances for something to go wrong. But the 2nd one is much more nuanced, and really critical here.
4:10The rate of body size evolution. The paper calls it the pathwise rate. And it's not just about how big a species is, but how quickly its lineage has changed size over 1000000s of years. Okay, so, let me see if I have this right.
4:23If you have 2 species that are roughly the same size, let's say a slow evolving ancient crocodile and a rapidly evolving mammal, that mammal had to solve the cancer problem much faster. Get that big. That's precisely it.
4:37The rapid evolution implies there was this extremely strong, recent selective pressure to develop really robust cancer suppression. That makes sense. And what was the 3rd driver they looked at? The 3rd was the rate of lineage diversification, which is essentially the speciation rate minus the extinction rate.
4:54So a metric for the evolutionary success of a whole group of species. You got it. The question is, does being part of a rapidly expanding diverse lineage make you more or less vulnerable to tumors? A fascinating question.
5:06So how did they even begin to compare these dynamic evolutionary rates against disease outcomes across the entire family trees of birds and mammals? Well, to do that, they needed a really sophisticated statistical model.
5:19It's called the Besian multivariate phylogenetic, generalized, linear mix model, or MPGLMM. Okay, that is a mouthful. It is. But the concept, um, the concept is crucial. And actually pretty easy to grasp.
5:35How so? Well, think about it like this. We can't just compare human to a mouse, and then compare that mouse to a whale, as if they're completely independent points. They all share common ancestors. Right, they're related.
5:46So the phylogenetic element in that model is basically the statistical engine that accounts for that evolutionary relatedness and make sure we're comparing apples to apples across the family tree. I see.
5:56So the model corrects for that shared history, which would naturally affect shared traits like, you know, cancer susceptibility. Correct. They took previously compiled data on tumor prevalence, so how often tumors are found across different species, and they mapped it onto these phylogenies, which already had the rates of body size evolution and diversification calculated.
6:14And as we always say on here, you have to be so careful with observational data like this, if you do way more medical checks on, say, domestic dogs than on wild bats, you're obviously going to find more tumors and dogs, right?
6:27Absolutely. And the rigor of this study depended on them controlling for that sampling bias. They explicitly controlled for the number of necropsies done per species. So any differences they found were based on genuine biological dynamics, not just because some animals get more medical attention.
6:44Precisely. Okay, let's get to the results. This is where that divergence between benign and malignant tumors just becomes crystal clear. Let's start with the baseline. The correlation with basic body mass.
6:56Well, they confirmed what we'd expect. The prevalence for both benign and malignant tumors increases strongly and undeniably as body mass goes up, and that's across both birds and mammals. Okay, so that confirms the foundation of the problem.
7:08Bigger animals have a bigger risk. It sets the stage. Now for the moment of truth. The pathwise rate of body size evolution, this is that key measurement of strong selective pressure. Which tumor type was affected.
7:21And this is the strongest piece of evidence supporting the whole divergence idea. They found that the prevalence of malignant tumors was significantly negatively associated with that pathwise rate. In simple terms.
7:33The faster lineage evolved to a larger size, the better they became as oppressing deadly cancers. So rapid evolution equals strong cancer defense. That's Pito's paradox, the solution to it, playing out in the data right there.
7:46It is. But now look at the counterpoint. For benign tumors, they found absolutely no significant association with this rapid evolutionary rate. None at all. None. The evolution of a large body size simply does not seem to impact the rate at which these non-lethal growths appear.
8:01That is so interesting because if benign tumors can often be precursors to malignant ones, why wouldn't the evolutionary pressure to stamp out the lethal kind, also get rid of the 9 ones? Why would evolution just leave the door open to harmless growth?
8:17That is the core question this research helps answer. Natural selection. You know, it isn't concerned with suppressing all abnormal cell growth. It only cares about the ones that kill the organism before it can reproduce.
8:27So these results suggest that the protective mechanisms that popped up during rapid body size evolution are highly targeted. Very targeted. Targeted how? They're likely specific to the critical lethal processes, things like metasis and tissue invasion, rather than just controlling the initial dysregulation of cell growth itself.
8:47So evolution allowed the initial growth, the benign tumor to exist, as long as it couldn't spread and kill the host. Exactly. The defense mechanism evolved to prevent the escape, not the initial breakout.
8:58Wow. Okay, which brings us to the 2nd major finding of divergence. This one involves the lineage diversification rate, that evolutionary success metric. And this is where a critical layer of difference between birds and mammals comes in.
9:11What happened when they looked at the diversification rate in birds? In birds, they found a strong, positive association. A higher diversification rate was linked to a a higher prevalence of both benign and malignant tumors.
9:23Wait, so for birds, rapidly diversifying evolutionarily successful lineages actually shows significantly higher tumor prevalence overall. That's what the data shows. So, in birds, evolutionary success seems to come with a higher cancer burden.
9:38But what about in mammals? In mammals, nothing. There was no significant relationship found for either tumor type. The drivers of speciation and extinction in mammals seem to be neutral when it comes to tumor prevalence.
9:50Wow. So we've got 2 major classes of vertebrates, birds, and mammals that are solving the cancer problem in fundamentally different ways depending on their evolutionary history. We have to dig into the implications of this, this bird mammal tension.
10:05Well, the primary takeaway is definitely the divergence. Malignant tumors are evolutionarily constrained by body size change, while benign tumors are not. This really confirms that the evolutionary battle is highly specific against the lethal aspects of cancer.
10:20Let's focus on that bird finding because that seems so counterintuitive. Why would evolutionary success diversification be linked to more tumors? That seems like a terrible trade-off for survival. The authors propose this might be related to fundamental differences in genome architecture.
10:35Bird genomes generally are smaller and much more compact compared to mammals. You can think of the bird genome as an incredibly optimized high performance machine. And that helps it adapt and change quickly, which drives diversification.
10:50Exactly. But with that high optimization comes a high vulnerability. How so? That architecture might make them more susceptible to certain types of genomic instability, specifically chromosomal rearrangements.
11:03And these rearrangements are known to be involved in both speciation and tumor promotion. Ah, okay. So if your genome is structurally prone to rearranging itself to create new species quickly, that same instability can open the door to tumor formation.
11:18is a double-edged sword. So for the bird lineage, it's like a genetic tug of war. They have evolved these robust adaptive mechanisms to reduce malignancy when they get bigger, that's the negative association with pathwise rate.
11:30But at the very same time, their unique genomic structure links their evolutionary success, their diversification rate to an increased baseline tumor risk. And those 2 forces basically cancel each other out, leading to a kind of neutral effect on overall cancer rates and birds.
11:47Roughly, yes. The combined net effect on malignancy prevalence in birds is approximately neutral. And the mammals. Well, mammals lacking that specific genomic vulnerability, that positive link between tumors and diversification, they just get a net benefit.
12:03They still get the strong selective pressure from rocket body size evolution, which suppresses cancer, but without that counterbalancing risk. So that leads to a net negative effect on malignancy prevalence in mammals.
12:15They just get the upside. For the most part, yes. This research really changes how we should view comparative oncology. We were missing so much critical evolutionary context by just grouping all abnormal growths together.
12:26Absolutely. And this level of analysis shows us that the solutions to Peto's paradox are specifically focused on preventing metastasis and tissue invasion, not just stopping cell growth itself. And understanding that the selective pressure is so targeted against those lethal processes, that must offer new avenues for research into fighting therapy resistance in human cancers.
12:46I think so. If the mechanisms that suppress cancer in large animals are really dedicated to preventing invasion, studying those specific pathways might be key to neutralizing the deadliest aspects of human disease.
12:58So, to summarize the core insight here, malignant tumors, because they're so lethal to fitness, face these strong specific selective pressures, they're linked negatively to how fast a species evolves as body size, forcing rapid adaptation.
13:13Well, benign tumors, since they have a limited impact, just kind of persist unconstrained by those same big mac revolutionary forces. The prevalence of cancer across the tree of life is really determined by this complex dynamic tug of war between strong adaptive cancer defense and, you know, lineage specific genomic vulnerabilities.
13:32And that creates these unique risks in groups like birds. Exactly. Which raises a really important final question. Considering these clear trade-offs we're seeing between evolutionary success like rapid diversification and cancer vulnerability, how might a deeper understanding of species specific genome architecture inform our strategy for predicting or maybe even preventing cancer risk in certain human populations?
13:54This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoyed this, follow our subscribe in your podcast app and leave a five-star rating.
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