Peto's Paradox: How Nature's Giants Defy Cancer

Written by Emir Taha Macit

Given the primary mechanisms of cancer, one would assume that organisms with larger bodies that occupy more cells for a longer lifespan would have a tremendous increase in cancer risk. For instance, if we were to scale human colorectal cancer risk to that of a blue whale, we would conclude that every blue whale would have a 100% chance of developing cancer by age 80, yet they rarely do. Oxford statistician Sir Richard Peto pointed out this contradiction in the 1970s after discovering similar cancer rates in humans and mice despite differences in size and lifespan, a contradiction named after him as Peto’s Paradox. Recent studies following Sir Richard Peto’s proposed paradox have shown almost no increase in cancer risk in larger creatures, findings that apply to the majority of the mammalian world. Having led to the discovery of advanced genetic defense mechanisms in large vertebrates on a cellular level, this revelation opens a new world of possibilities for human cancer prevention and treatment.

To understand cancer risk, we must first analyse its mechanisms. Disregarding external causes such as radiation, a cell can become cancerous during mitosis after specific DNA damage to proto-oncogenes and tumor suppressors. The damage to proto-oncogenes, genes that promote cell growth and division, is called an oncogenic mutation. The mutation drives the genes into hyperactivity, thereby making them oncogenes. These oncogenes lead to rapid mitosis, a cellular condition called hyperplasia that serves as an early step to tumor formation. Damage to tumor suppressors prevents the p53 protein coded by the TP53 gene from detecting any newly formed faulty cells in this hyperplastic group. The rapidly multiplying cells can destabilize their chromosomes during any of the many divisions and form a tumorous mass, harming nearby healthy cells and spreading exponentially.

This explanation would lead to the assumption that a larger creature would be more susceptible to cancer due to its higher overall cell count and longer lifespan. As any extra cell division can lead to tumors, an organism with more room and time for the abnormality to occur would suffer a great risk of not reaching the later stages of its life. This leads to the conclusion that large creatures have advanced mechanisms to prevent cancer from claiming their lives prematurely. Realising that megafauna could not have reached their current population otherwise, comparative oncologists and geneticists conducted various studies to determine differences in cellular defense between humans and mammals across varying sizes. These studies resulted in groundbreaking discoveries that could permanently alter our cancer research.

As diploid organisms that inherit a chromosome set from each parent, humans have one TP53 gene locus on Chromosome 17 that holds two TP53 alleles. The aforementioned damage to tumor suppressors is caused by the mutation or loss of these alleles. Across species, possessing fewer TP53 gene copies increases the risk of complete loss of p53 protection and, as a result, the risk of cancer. 

When looking at creatures smaller than us, we can see that mice share our 2-alleled system. While their version of TP53, Trp53, functions similarly to ours, their faster metabolisms producing reactive oxygen species (ROS) and their prioritization of reproduction over longevity leave them with vulnerable cells, resulting in weaker cancer protection and thus higher cancer rates.

However, studies have shown that in contrast to our single gene copy of TP53, elephants possess 20 across 20 loci. This gives them a total of 40 TP53 alleles, resulting in a vast number of genetic backups for their regulatory system. Most of these copies are not the same as ours, though. While one copy is the primary ancestral gene, the other 19 copies are retrogenes. Retrogenes of TP53 are created when messenger RNA (mRNA) from the TP53 gene is converted into DNA and inserted across various chromosomes. These retrogenes normally lack a genetic switch, remaining as dead, inactive genes called pseudogenes. In the case of elephants, evolution has helped them activate these genes by placing them near functioning regulatory regions. Furthermore, possessing an abundance of active TP53 genes has led the elephant's defense mechanism to heavily favor apoptosis, or intentional cell suicide, to prevent cancerous outbreaks. Since apoptosis requires p53 levels to exceed a certain threshold to take effect, possessing a faster production of the protein almost immediately causes the compromised cell to trigger self-destruction before tumors can form. This evolutionary trait has resulted in a stronger defense mechanism than ours, whose first response is to attempt to repair the cell before apoptosis.

By uncovering the details of Peto’s Paradox, researchers are creating blueprints for cancer treatment. Loss or mutation of the TP53 gene function is the primary cause of around half of cancer cases worldwide. Studying the elephant’s retrogenic system offers great potential in medicine, particularly for individuals suffering from Li-Fraumeni Syndrome, a condition in which only a single functional TP53 allele is inherited. Ultimately, Peto’s Paradox has proven to be a prominent path toward cancer treatment and is another example of the importance of studying and replicating nature’s millions of years of evolutionary strengths.

References:

1. Thomasy, A. (2025). Peto’s Paradox: How Gigantic Species Evolved to Beat Cancer. The Scientist https://www.the-scientist.com/peto-s-paradox-how-gigantic-species-evolved-to-beat-cancer-72725

2. Caulin, A. F., & Maley, C. C. (2011). Peto's Paradox: evolution's prescription for cancer prevention. Trends in ecology & evolution, 26(4), 175–182. https://doi.org/10.1016/j.tree.2011.01.002

3. Koeffler, H. P., McCormick, F., & Denny, C. (1991). Molecular mechanisms of cancer. The Western journal of medicine, 155(5), 505–514.

4. Tollis, M., Boddy, A.M. & Maley, C.C. Peto’s Paradox: how has evolution solved the problem of cancer prevention?. BMC Biol 15, 60 (2017). https://doi.org/10.1186/s12915-017-0401-7