Peto's Paradox, and how it could be solved in the future
Written by: Darren Kan, Edited by Ivan Suen
Cancer has been there since the beginning of time, yet not all animals are affected in the same way. Elephants and naked mole rats, for example, seldom get cancer, whereas ferrets and dogs have very high rates of cancer.
Richard Peto, a British epidemiologist, proposed in 1977 that large-bodied animals with long lives have cells that undergo more cell divisions, with each cell division posing a modest but significant chance of transmitting mutations in the daughter cells. Some of these mutations have the potential to cause cancer. So, if all other factors are equal, one would expect large-bodied animals with long lives to have a higher cancer risk than small animals with short lives. However, when Peto looked into the occurrence of cancer in some of these animals, he discovered that this was not the case in fact, the number of cells in an organism does not appear to be related to the incidence of cancer. For example, despite having more cells than humans, the rate of cancer in humans is substantially higher than the incidence of cancer in whales. This phenomenon is called Peto’s Paradox.
From one point of view, the answer to Peto's paradox is straightforward: evolution. When individuals in populations are subjected to the selective pressure of cancer risk, cancer suppression must evolve as an adaptation or the population would suffer fitness losses and even extinction. However, this just tells us that evolution has solved the puzzle, not how those animals are preventing cancer.
Discovering the mechanisms underlying these Peto's Paradox answers the use of tools from a variety of biological disciplines, including genomics, comparative approaches, and cell assays. The African savannah elephant (Loxodonta africana) genome, for example, contains 20 copies, or 40 alleles, of the most recognized tumor suppressor gene TP53, according to genomic analysis.
Yet only one copy of TP53 exists in the human genome, and two functioning TP53 alleles are necessary for appropriate cancer progression checks. When cells are stressed and their DNA is damaged, they can either try to repair the damage or self-destruct by going through apopotosis (planned cell death). The TP53 gene produces a protein that is required to activate the apoptotic pathway. Because they can't properly shut down cells with DNA damage, humans with one faulty TP53 allele have Li Fraumeni syndrome and a 90% lifetime risk of several malignancies.
Meanwhile, investigations found that elephant cells subjected to ionizing radiation behave in a way that is consistent with all those TP53 copies—they are significantly more likely to activate the apoptotic pathway and hence kill cells rather than accumulate cancerous mutations.
Because enormous body size has evolved independently so many times over the history of life, there are likely various answers to Peto's paradox in nature. Whales, unlike elephants, did not develop extra copies of TP53. In fact, no evidence exists that whales, even the massive bowhead whale (Balaena mysticetus) with a lifespan of over 200 years, evolved extra copies of any tumor suppressor gene. Large body size is frequently correlated with improved fitness in populations, implying better access to resources or partners, as well as better predator avoidance. As a result, it's not surprising that large body size has developed multiple times throughout evolutionary history. Consider hippopotami and polar bears, walruses and giraffes, elephants and whales. Because various lineages faced the trade-off between high body size and cancer risk during their evolution, cancer suppression is likely to have developed in a variety of ways.
Although Peto's paradox has yet to be fully resolved, research into the phenomenon has shown to be fruitful. According to Joshua Schiffman, a pediatric oncologist, studying the tactics that different animals have evolved could lead to a range of therapy options, each tailored to a certain subset of cancer patients. "I believe it's extremely thrilling," he says, "that each animal takes a distinct path through nature, through evolution."
References
Peto's paradox. (n.d.). https://en.wikipedia.org/wiki/Peto%27s_paradox
Peto's Paradox: how has evolution solved the problem of cancer prevention? (n.d.). https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0401-7
Peto's paradox put to the test. (n.d.). https://www.nature.com/articles/s41568-022-00447-4
Solving Peto's Paradox to better understand cancer. (n.d.). https://www.pnas.org/doi/10.1073/pnas.1821517116
Why Blue Whales Don't Get Cancer - Peto's Paradox. (n.d.). https://www.youtube.com/watch?v=1AElONvi9WQ
very interesting