Peto’s Paradox is a captivating conundrum in the realm of evolutionary biology and cancer research, prompting scientists to ponder a perplexing question: Why don’t large-bodied or long-lived animals, like whales and elephants, with their multitude of cells and extended lifetimes, exhibit a proportionally higher incidence of cancer compared to smaller species?
Named after the epidemiologist Richard Peto (see source 2 at the bottom of this post), this paradox challenges conventional understanding, suggesting that creatures like whales or elephants, despite having many more cells that could potentially turn cancerous over longer lifespans, don’t necessarily suffer from cancer more frequently than humans do. Unraveling the mystery behind this phenomenon could offer profound insights into cancer resistance and inform future therapeutic strategies.
Peto’s Paradox and Cancer
To understand why large animals seem unlikely to get cancer, we first need to take a look at the nature of cancer itself.
Cancer essentially refers to the uncontrolled growth and division of cells. At its core, it’s a genetic disease, resulting from mutations (changes) in the DNA within cells.
- Cell Growth and Division: Normally, when our cells become damaged or old, they die and are replaced by new cells. However, cancer cells are different; they don’t die when they should, and they can form masses of tissue called tumors.
- DNA Mutations: Mutations in DNA can cause certain genes to malfunction. Some genes (oncogenes) can promote cell division, and mutations here can cause them to remain “switched on.” Others (tumor suppressor genes) normally prevent cell division or cause cell death; mutations can “switch them off.”
- Causes of Mutations: Mutations can be spontaneous, caused by errors in DNA replication, or result from external factors like UV radiation from the sun, certain chemicals, or even some viruses.
- Metastasis: Not all tumors are harmful. Benign tumors don’t spread and aren’t cancerous. Malignant tumors, on the other hand, can invade nearby tissues and spread to other parts of the body. When cancer cells break away from a tumor and move to another location in the body through the blood or lymphatic system, this is called metastasis.
More Cells, More Time, and Cancer:
- Probability and Errors: Every time a cell divides, it replicates its DNA, and there’s a small chance of an error or mutation. With more cells in an organism, there are more cell divisions and, consequently, more opportunities for errors.
- Lifespan and Accumulation: Longer-lived species have more time for mutations to accumulate. Mutations can stack up over time, with one mutation potentially making subsequent mutations more likely. Think of it as a snowball effect; the longer the lifespan, the larger the snowball can become.
- Size and Number of Divisions: Larger animals have more cells, which means there are more cells dividing and potentially accruing mutations at any given time. Over the vast number of cells in a large organism, the absolute number of mutations occurring can be substantial.
Considering these factors, it would logically follow that larger animals with longer lifespans should have a higher incidence of cancer. The fact that they often don’t, as observed in Peto’s Paradox, suggests there are additional protective mechanisms or factors at play in these animals.
Peto’s Paradox leads to several questions:
- Why don’t larger animals get cancer more frequently?
- What protective mechanisms might exist in these animals that suppress cancer?
Researchers have been studying this paradox to gain insights that might aid in cancer prevention and treatment for humans. Some hypotheses and findings related to Peto’s Paradox include:
- Evolutionary Pressure: Over millions of years, larger animals, due to the sheer number of cells in their bodies and the associated risk of cancerous mutations, might have been under stronger evolutionary pressure to develop enhanced cancer-suppressing mechanisms. Given their size and the increased potential for cellular anomalies, without these advanced mechanisms, they would face a much higher likelihood of premature death from cancer. This would naturally work against individuals without these protective measures, leading to populations where robust cancer resistance becomes a predominant trait. Over time, this evolutionary push could result in species-wide adaptations that provide an innate defense against cancer’s onset.
- Cellular Mechanisms: Emerging research indicates that larger animals, exemplified by species like elephants, possess multiple copies of specific tumor-suppressing genes, a feature not commonly found in smaller species. This genetic redundancy amplifies their defensive mechanisms, fortifying their cellular machinery against malignant transformations. The presence of these additional gene copies not only bolsters their ability to prevent initial cancerous changes but also offers a layered defense, potentially arresting the progression of any aberrant cells that might slip through the initial protective barrier. Such sophisticated cellular systems give these animals a distinctive edge in warding off cancer.
- Metabolic Rates: Smaller animals, by nature of their physiology, typically exhibit higher metabolic rates compared to their larger counterparts. This heightened metabolism results in a more rapid turnover of cells as they grow, repair, and replace tissue at a swifter pace. While this rapid cellular activity aids in their survival and adaptability, it simultaneously presents a double-edged sword. The frequent replication and division of cells amplify the opportunities for DNA replication errors or mutations. Over time, these accumulated errors can increase the risk of malignant transformations, making these smaller creatures potentially more susceptible to cancer in relation to their size.
Understanding Peto’s Paradox and the mechanisms that some animals use to suppress cancer could potentially unlock new avenues for cancer prevention and treatment in humans.
But wait, great white sharks get cancer!
We know that great white sharks, which are obviously very large animals, frequently get cancer, and this is an interesting nuance related to Peto’s Paradox.
Firstly, Peto’s Paradox doesn’t assert that large animals or long-lived species don’t get cancer at all. Instead, the paradox is centered around the observation that these animals don’t seem to get cancer as often as we’d expect, given the number of cells they have and their long lifespans.
Great white sharks, whales, elephants, and other large or long-lived species certainly can and do develop cancer. However, the rates at which they develop cancer are surprisingly low when considering their size and lifespan, especially when compared to many smaller species, like humans.
The existence of cancer in great white sharks or other large animals doesn’t contradict Peto’s Paradox. Instead, the paradox challenges researchers to uncover what unique mechanisms or adaptations these animals might possess to keep cancer rates lower than expected. For instance, as mentioned earlier, elephants have evolved multiple copies of the p53 gene, a tumor suppressor, which might help them fend off cancer more effectively.
In summary, while large animals like great white sharks can and do get cancer, the paradox lies in the observation that their cancer rates are not proportionally as high as one might expect based on their size and longevity.
Related: 10 Amazing Great White Shark Facts
Video: Why blue whales don’t get cancer [Peto’s Paradox] by Kurzgesagt
- Peto’s Paradox on Wikipedia
- Original study: “Cancer and aging in mice and men”. R Peto, F J Roe, P N Lee, L Levy, J Clack, 1975 [link]. Abstract of the study: In an experiment involving 950 mice with a normal lifespan of 2-3 years, in laboratory conditions, regular benzpyrene application to the skin was started at 10, 25, 40, or 55 weeks of age. The incidence rate of malignant epithelial tumors among the survivors in each group increased steeply with time. This increase was associated directly with the duration of exposure but, given duration, was independent of age at the start of exposure, as were the growth rates of already established tumors. In our experiment, although age per se was irrelevant, the cancer incidence rate increased approximately as a power of the duration of exposure to benzpyrene. This shows that the observed approximate power-law increase of most human adult cancer incidence rates with age could exist merely because age equals duration of exposure to background and spontaneous carcinogenic stimuli. Thus, no intrinsic effects of aging (such as failing immunological surveillance or age-related hormonal changes) need to be postulated to explain the vast increases in old age of the incidence rates of such human cancers. This result can greatly simplify speculation about the mechanisms of carcinogenesis.
- Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox. John D. Nagy, Erin M. Victor, Jenese H. Croppe. Integrative and Comparative Biology, Volume 47, Issue 2, August 2007, Pages 317-328. [link] Abstract of the study: Larger organisms have more potentially carcinogenic cells, tend to live longer, and require more ontogenic cell divisions. Therefore, intuitively one might expect cancer incidence to scale with body size. Evidence from mammals, however, suggests that the cancer risk does not correlate with body size. This observation defines “Peto’s paradox.” Here, we propose a novel hypothesis to resolve Peto’s paradox. We suggest that malignant tumors are disadvantaged in larger hosts. In particular, we hypothesize that natural selection acting on competing phenotypes among the cancer cell population will tend to favor aggressive “cheaters” that then grow as a tumor on their parent tumor, creating a hyper tumor that damages or destroys the original neoplasm. In larger organisms, tumors need more time to reach a lethal size, so hypertumors have more time to evolve. So, in large organisms, cancer may be more common and less lethal. We illustrate this hypothesis in silico using a previously published hypertumor model. Results from the model predict that malignant neoplasms in larger organisms should be disproportionately necrotic, aggressive, and vascularized than deadly tumors in small mammals. These predictions may serve as the basis on which to test the hypothesis, but to our knowledge, no one has yet performed a systematic investigation of comparative necrosis, histopathology, or vascularization among mammalian cancers.
- The real war on cancer: the evolutionary dynamics of cancer suppression. Leonard Nunney, 2013. [link] Abstract of the study: Cancer is a disease of multicellular animals caused by unregulated cell division. The prevailing model of cancer (multistage carcinogenesis) is based on the view that cancer results after a series of (generally somatic) mutations that knock out the genetic mechanisms suppressing unregulated cell growth. The chance of these mutations occurring increases with size and longevity, leading to Peto’s paradox: why don’t large animals have a higher lifetime incidence of cancer than small animals? The solution to this paradox is evolution. From an evolutionary perspective, an increasing frequency of prereproductive cancer deaths results in natural selection for enhanced cancer suppression. The expected result is a prereproductive risk of cancer across species that is independent of life history. However, within species, we still expect cancer risk to increase with size and longevity. Here, I review the evolutionary model of cancer suppression and some recent empirical evidence supporting it. Data from humans and domestic dogs confirm the expected intraspecific association between size and cancer risk, while results from interspecific comparisons between rodents provide the best evidence to date of the predicted recruitment of additional cancer suppression mechanisms as species become larger or longer lived.
- Peto’s Paradox: Evolution’s Prescription for Cancer Prevention. Aleah F. Caulin and Carlo C. Maley, 2011. [link]
- Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. Lisa M. Abegglen, Ph.D.; Aleah F. Caulin, Ph.D.; Ashley Chan, BS; et al, 2015. [link]
- Cell size and cancer: A new solution to Peto’s paradox? Sebastian Maciak and Pawel Michalak, 2015. [link] Abstract of the study: Cancer, one of the leading health concerns for humans, is by no means a human-unique malady. Accumulating evidence shows that cancer kills domestic and wild animals at a similar rate to humans and can even pose a conservation threat to certain species. Assuming that each physiologically active and proliferating cell is at risk of malignant transformation, any evolutionary increase in the number of cells (and thus body mass) will lead to a higher cancer frequency, all else being equal. However, available data fail to support the prediction that bigger animals are affected by cancer more than smaller ones. The unexpected lack of correlation between body size (and life span) and cancer risk across taxa was dubbed Peto’s paradox. In this perspective, several plausible explanations of Peto’s paradox are presented, with an emphasis on a largely underappreciated relation of cell size to both metabolism and cell division rates across species, which we believe are key factors underlying the paradox. We conclude that larger organisms have bigger and slowly dividing cells with lower energy turnover, all significantly reducing the risk of cancer initiation. Solving Peto’s paradox will enhance our understanding of the evolution of cancer and may provide new implications for cancer prevention and treatment.
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