Peto's Paradox: Why Don't Larger Animals Get Cancer More Often?

Bowhead whales can live to 200

If cancer is predominantly a random process, then why don't organisms with thousands of times more cells suffer more from cancer? Large species like whales and elephants generally live longer, not shorter lives, so how are they protected against the threat of cancer?

While we have a great deal more to learn when it comes to cancer biology, the general belief is that it arises first from mutation. It's becoming clear it's actually an incredibly complicated process, requiring a range of variable factors such as mutation, epigenetic alteration and local environment change (like inflammation). While some students may have spent sleepless nights wondering how many mutated cells they contain after learning the fallibility of our replication mechanisms, the reality is that with such an error rate we should all be ridden with cancer in childhood - but we're not. Our canine companions sadly often succumb around their 1st decade, but humans are actually comparatively good at dealing with cancer. We live a relatively long time in the mammal kingdom for our size and even in a modern environment, it's predominantly an age-related disease.

While evolution may have honed replication accuracy, life itself requires 'imperfection' to evolve. We needed those occasional errors in germ cells to allow evolution. If keeping the odd error is either preferable or essentially not worth the energy tackling when you're dealing with tens of trillions of cells, then clearly there is more to the story than mutation. In order to maintain a multi-cellular organism for a long enough period, considering that errors are essentially inevitable, other mechanisms must be in place to remove or quarantine problematic cells.

 

Elephants have around 100 times more cells than humans, but remain cancer resistant

Larger organisms are a great demonstration of this because their size requires they overcome this challenge, and scientists think we could learn a lot about cancer biology from studying the genome of species like the bowhead whale, which is the longest lived mammal on earth (the oldest recorded was 211 years old). Any estimation of maximum lifespan in wild animals is inherently tricky, but even if these numbers are lower estimates, they're still telling. So what are these animals doing differently that protects them against cancer? 

 

 

The fact that cell number doesn't correlate with cancer incidence is called Peto's paradox. This paradox suggests there are mechanisms these organisms possess which we could learn from, and indeed utilise against cancer. 

“I think Peto’s Paradox is one of these beautiful questions that is simple and precise, yet implies important discoveries that have yet to be made”

Work on these mammals so far suggests one answer may lie with 'antioncogenes' - essentially protective genes that acts as tumour suppressors or growth checkpoints. Elephants and bowhead whales also appear to have evolved different strategies to deal with the threat of cancer. Both animals appear to have undergone selective pressures on some similar mechanisms, but elephants uniquely have more copies of a particular tumour suppressor gene called p53. While many such animals may hold important clues about how to stave off cancer, the fact is research on these is relatively sparse and there is a great deal more to find out.

“We need a lot more investment in studying cancer in wild animals. There is virtually nothing happening in that area of research.”

Another theory as to why cancer is less prevalent in organisms like Bowhead whales, is that their sheer size is a barrier. In this model, cancer requires more time to become a danger and this time factor renders it more vulnerable to experiencing essentially, a 'tumour within a tumour'. Just as the original cancerous population rebels against the host, in larger organisms cancer may suffer a kind of 'rebellion in the ranks', destroying some of the original tumour and inhibiting its spread. At this point this remains a theory however.

There is also some suggestion that larger organisms contain fewer 'viral relics' in their genomes: when some viruses infect a host, they can leave injected sequences in a genome which is then passed down to the next generation (if the victim survives). Work at Oxford suggests smaller animals contain more of these retroviral traces, and that these sequences can act detrimentally. It's possible animals like whales and indeed humans have undergone more evolutionary pressure to combat this viral interference.

Credit: Brandon Vick/University of Rochester

Before we get too carried away with larger organisms alone, some smaller varieties do also buck the trend. Naked mole rats for example exhibit diminished cancer rates and live up to 30 years, despite being on the diminutive side. Research on them has revealed so far that they encode an additional tumour suppressing gene, which may account for some of their extraordinary resistance. 

While cancer resistance may seem like a pretty neat trait to have, different species are subject to different evolutionary pressures and research suggests resistance may come at a cost. Evolution is complex and context dependent, so even if a long lived species with low fertility works in some settings, a shorter lived species with high fertility might excel in another. This cost/benefit ratio is different in different environments e.g. if you're in a particularly dangerous place, tumour suppression isn't really a priority. 

'A notable facet of the slow-life history category is the development of cancer suppressing genes, which allow these organisms “to build a body that can last a long time and invest in its offspring,” but possibly at the expense of the organism’s fertility.'

If we truly want to extend our healthspan and lifespan we need to tackle cancer, and because different species with desirable traits have likely evolved different ways of tackling certain problems, more focus on comparative genomics could potentially reveal important weapons against this daunting foe. 

Read more at Motherboard