Giant whales have few cancer relative to their body size. It is a biological mismatch known as Peto’s paradoxwhich describes how large, long-lived animals, despite having trillions more cells than humans or tiny creatures, do not develop more cancers.
Cancer is a disease of rampant cell division, where genetic mutations cause cells to divide and divide, forming masses called tumors. One might therefore think that the bigger an animal, the more cells it has and the more likely these cells are to accumulate genetic errors that lead to cancer, especially over a long life.
But the famous British statistician Richard Peto noticed when comparing mice and men in the late 1970s that this was not the case. Later studies have shown that among creatures large and small, cancer does not become more common the more a species a of cells. Elephants, like whales, don’t have a ton of cancers.
It may seem like biologists are clinging to a decades-old paradox that is just a quirk of nature — but it is an important quirk. Resolving this paradox can help develop new strategies to prevent or suppress cancer in humans.
Now a team of researchers from the University of Rochester in New York has found a solution to the paradox in bowhead whales, baleen baleen, the second largest but most living animal on Earth.
“By studying a mammal capable of maintaining its health and avoiding death from cancer for more than two centuries”, to write Biologist Denis Firsanov and colleagues in their preprint article, “We are offered a unique glimpse behind the curtain of a global evolutionary experiment that has tested more mechanisms affecting cancer and aging than humans could ever hope to approach.”
In a series of lab experiments, researchers found that bowhead whale cells were better at repairing DNA damage than human, mouse and cow cells. Whales, it seems, nip DNA damage in the bud “with exceptional efficiency and precision compared to other mammals,” Firsanov and colleagues to write.
Simply put, bowhead whales can tolerate more knocks on their genomes because they have a fast, well-tuned repair system to repair DNA damage. The researchers found that in a region of DNA that whales, humans, mice and cows share, whale cells were more likely to repair DNA breaks (cut by CRISPR) without mistakes.
Bowhead whale cells also pumped out a DNA repair protein called CIRBP at much higher levels than the other species studied. And when lab-grown human cells were engineered to produce CIRBP in bulk, this genetic modification enhanced their ability to repair DNA error-free.
“This strategy that does not eliminate cells but repairs them may be essential for the long and cancer-free lifespan of bowhead whales,” Firsanov and colleagues conclude.
Jason Sheltzer, a cancer biologist at Yale University, who was not involved in the work, said the “fascinating” preprint – which has yet to be peer-reviewed – “provides a new model for how large animals stave off cancer”.
“Maybe they’re just better than us at DNA repair?” Sheltzer pondered on Twitter. “As a next step,” he added, “I would like to see this validated in an animal model – if you drive high expression of the CIRBP whale [protein] in mice, are they resistant to cancer?”
Of course, as past research shows, translating a discovery like this into cancer therapy isn’t easy.
When scientists discovered in 2015 that elephants had extra copies of a tumor suppressor gene called TP53, the next logical step was to test whether increasing TP53 activity in mice also alleviated cancer. Tumor suppressor genes effectively “blow up” any cells they find harboring too much DNA damage, and it turns out elephants have very low thresholds to wage war on damaged cells.
However, overexpression of a form of the TP53 protein in mice, while suppressing cancer, also induced premature aging with the animals. Other studies may have found a workaround – and scientists continue to search for other possibilities.
“There are probably many solutions to Peto’s paradox in nature, because large body size has evolved independently so many times in the history of life,” REMARK Marc Tollis, a geneticist at Northern Arizona University, in a 2017 article with two other researchers.
In other words, every long-lived or large animal, from naked mole rats to African elephants, has evolved its own means of suppressing cancer that scientists are eager to discover.
Other explanations could be that tumors in large animals grow slowly and are less lethal or that large animals have better immune surveillance. However, these solutions have not yet been observed in large-bodied species and require further research.
“Each time we uncover a potential mechanism for cancer suppression in a species, we have the opportunity to find new therapeutic targets and new cancer prevention approaches to save human lives,” Tollis and colleagues said. to write. But this will undoubtedly require “substantial efforts to translate recent findings into effective therapies for humans.”
The University of Rochester study is available on the biorXiv preprint server Before peer review.