Given their size, you’d think cancer would be more common in elephants, whales and other large, long living mammals. But it’s not; many of these animals have dramatically lower cancer rates than humans.
This conundrum has been termed Peto’s paradox, and has raised questions about the evolution of cellular mechanisms that suppress cancer. It has even inspired interest in designing novel therapies for human cancers by co-opting the anti-cancer mechanisms that seem to be highly effective in the wild.
“It’s a paradox because we know that essentially in all species, age is the largest risk factor for cancer development. So, a large animal with a lot of cells at risk of becoming mutated, living a long time, just mathematically should have a higher cancer rate,” says Geoffrey Wood, Professor in the Department of Pathobiology at the University of Guelph.
For instance, elephants have an estimated cancer risk of five per cent, while the risk is somewhere between 11 and 25 per cent among humans.
Although in its early days, evolutionary biology-inspired drug development is the driving force behind enterprises such as Peel Therapeutics, a biotech company based in Utah. The company aims to develop treatments for cancer and immune-related diseases by learning from evolutionary solutions found in nature.
As a former intern at the GSI Helmholtz Centre for Heavy Ion Research, Sophie Blokland took cells from three humans and three elephants and analyzed how they responded to cancer-inducing radiation. Among the elephant-specific genes, those with greatest expression levels were related to immune function and apoptosis, the cellular death pathway critical for keeping cell division in check.
“It’s a very small experiment,” says Blokland, “and we need more experiments to really prove the promising mechanisms in elephants because the final goal, of course, is to learn from the mechanisms which play an important role in cancer suppression in elephants and apply that in medical research.”
Blue whales and fin whales were also found to have extra immune-related genes, according to a study recently published in Gene.
“These guys are top notch when it comes to the immune system,” says Gabrielle Genty, first author of the paper and a PhD student at Flinders University in Australia. With the immune system better equipped to screen cells and flag them as cancerous, these whale species may remain relatively cancer-free even with their enormous size.
Conducting research to draw comparisons between human and whale cancers is not easy.
“Nobody looks at whales as much as we do for humans,” says Martin Haulena, head veterinarian at the Vancouver Aquarium. “We’ve got billions of humans, and our humans tend to get for the most part looked at, diagnosed and treated. Whales certainly do get cancer, but we don’t have any clue at all as to what the rate of cancer is, especially as they age.”
Whale samples that do get analyzed post-mortem are normally bloated, digested by enzymes or decomposed. Analysis is often restricted to those that happen to wash up on shore or are small enough to enter a rehabilitation centre.
“Ahere really is quite a low incidence of cancer in many wild whales.”
In elephants, multiple copies of the TP53 gene were identified in 2015, a seminal finding that stimulated renewed interest in Peto’s paradox. While humans have only one copy of the TP53 gene, a well-known tumor suppressor, elephants may have as many as 20. Wood, however, adds that the genomic sequencing on large mammals has not been ideal. Of the 19 extra copies of the TP53 gene thought to be present in elephants, four were found to be duplicates of existing copies and three were withdrawn entirely from an online genome browser in April this year.
Despite these limitations, the benefit of these studies, according to Wood, is to understand evolutionary history and how genes evolve more broadly. It turns out that all of the extra TP53 copies in the elephant genome are pseudogenes – chunks of DNA that structurally resemble bona fide genes but have lost their ability to code for proteins that carry out cellular processes.
What these pseudogenes are doing functionally is not clear. Wood says one possibility could be that cancer cells interfere with normal processes that prevent messenger RNA production from pseudogenes. This would allow cancer cells to make products from genetic material that is normally turned off in healthy cells.
In whales, while samples remain scarce, Wood says more tissue is now available.
“At first, we were kind of thinking maybe there’s a sampling problem. But I think we have enough data now that there really is quite a low incidence of cancer in many wild whales.”
Investigations following the initial 2015 studies on elephants on TP53 gene copies have been sparse.
“There’s not been a lot of follow-up work, and I’m not really sure why that is, but we do have elephant samples now. It’s taken many years to acquire the whale and elephant samples and taken so long to build up the capacity and collaborations to look at those,” says Wood.
It’s a reversal of the usual direction of information flow – usually, clinicians and researchers studying human cancers are consulted when treating veterinary tumors. Now, labs may have the capacity to translate animal cancer insights to human health.
“These are naturally occurring systems where you know these animals have evolved to resist cancer and live a long time and they don’t have anything we would consider a side effect,” says Wood. Knowing how cancer suppression mechanisms evolved in the wild could inform the treatment of human cancers with the help of modern molecular biology.
“The experiment’s been done. We just have to analyze it now,” says Wood.
