Scientists are homing in on one of medicine’s most baffling mysteries: why some species avoid getting cancers while others are plagued by tumours that shorten their lives.
Whales tend to have low rates of cancer but it is the leading cause of death for dogs and cats. Foxes and leopards are susceptible while sheep and antelopes are not. Bats are also relatively well protected against cancer but not mice or rats. In humans, cancer is a leading cause of death that kills around 10 million people a year.
Even more puzzling is the fact that many huge creatures, including whales and elephants, generally avoid cancer when, instead, they should be at special risk because they possess vast numbers of cells, each of which could trigger a tumour.
This is Peto’s paradox, named after the UK statistician Richard Peto who first outlined it, and it is the focus of investigations by scientists at the Wellcome Sanger Institute, in Cambridge, who are working with researchers from a number of centres, including the Zoological Society of London (ZSL).
“Cancer is a disease that occurs when a cell in the body undergoes a series of mutations in its DNA and begins to divide uncontrollably, and the body’s defences fail to stop this growth,” said project leader Alex Cagan. “The more cells that an animal possesses would suggest the greater is the risk of one becoming cancerous.”
This point is backed by Simon Spiro, ZSL’s wildlife veterinary pathologist. “Think of cells as lottery tickets: the more you have, the greater is your chance of winning a jackpot which, in this case, is cancer. So if you have a thousand times more cells than a human, then you should have a thousand times greater risk of ending up with cancer.”
From this perspective, there are some species of whale that should not be able to reach the age of one without getting cancer because they have so many cells – several quadrillion compared with humans, who only have trillions, a thousandfold reduction in numbers. But that is not what is observed. Bowhead whales have an average lifespan of 100 to 200 years, for example, while elephants have an average lifespan of around 70 years. Yet compared with humans, they all have thousands of times more cells, each a potential starting point for a mutation that would lead to cancer.
In a bid to understand this paradox, the Sanger team studied a range of animals that had died of natural causes at London Zoo. All were mammals and included lions, tigers, giraffes, ferrets and ring-tailed lemurs. In addition, naked mole rats from a different centre were included in the study.
“They look like cocktail sausages with teeth,” said Cagan. “They are the size of a mouse but live for about 30 years and almost never get cancer.”
The scientists then isolated cells known as intestinal crypt cells from each newly expired animal and studied their genomes.
“These are constantly being replenished by stem cells and are a first-rate way to compare genomes. We used them to count the numbers of mutations each species was accumulating every year,” added Cagan.
“What we found was very striking. The number of mutations each was accumulating every year varied enormously. Essentially, long-lived species were found to be accumulating mutations at a slower rate while short-lived species did so at a faster rate. For example, in humans, we get about 47 mutations a year while in the mouse, it is around 800 mutations a year. The latter live for about 4 years. The average human lifespan is 83.6 years.”
In addition, it was found that, at the end of a lifespan, all the different animals that were studied had amassed around 3,200 mutations. “The similar number of mutations at the end of the lifespans of these different animals is striking, though it is not yet clear if this is a cause of ageing,” said Cagan.
Exactly how long-living animals successfully slow down their rate of DNA mutations is unclear, however. In addition, the link between mutation rates and lifespan has only been established for animals that have low-to-middle lifespans.
“We can only study creatures that have died natural deaths, and those very long lifespans will be rare, by definition,” said Spiro. “We will have to wait to get that data.”
In addition, the first phase of the Sanger-Zoo project only looked at mammals. Now it is being extended to plants, insects and reptiles.
“Social insects like ants are particularly interesting,” said Cagan. “Worker ants and their queen have the same genome but the queen lives for 30 years whereas workers last one or two. This suggests the queen might be activating better DNA repair, though there could be other explanations.”
Cagan added that their research suggested that the mouse, which is used in cancer experiments, may not be the best model for research because of its very short lifespan.
“Now we can think about looking at much longer-living species that may be more relevant and be useful models for understanding cancer resistance.”
The crucial point is that making a link between mutation rates, tumours and ageing offers new understanding of both processes and could lead to improved cancer screening and treatments that might moderate the worst impacts of ageing, say the scientists.
