Peto’s paradox: Why do whales and elephants very rarely develop cancer?

• Cancer occurs due to uncontrollable cell multiplication.
• Large animals with more cells should have higher cancer rates, but they don't.
• Elephants, whales, and even smaller animals like the naked mole rat, have evolved with certain cancer-resistant mechanisms.

Cancer is an extremely common disease that affects millions of people around the world each year. According to the World Health Organization, it is one of the leading causes of death worldwide, accounting for almost 10 million fatalities (one in six) in 2020.

Cancer occurs when alterations in the genes lead to abnormal, uncontrollable cell growth that forms an invasive mass or tumor. The condition was first described in an ancient Egyptian medical text from 1600 BC known as the Edwin Smith Papyrus. The ancient Greek physician Hippocrates (who lived circa 460 BC to 370 BC) also wrote about it.

There is no definite cure for cancer to this day. Although there are a wide number of treatment options (such as surgery, immunotherapy, or chemotherapy), survival rates often depend on the type of cancer and how advanced it is when it is diagnosed. Cancer researchers are working to find more effective diagnostic techniques all the time, along with new methods for prevention and treatment of the disease.

In this regard, the realization that there are large animals for whom cancer is not a major cause of mortality —such as blue whales and elephants— has opened a new research window.

What do these animals have to teach us about cancer?

What is Peto's paradox?

Peto’s Paradox is named after epidemiologist Richard Peto, who studied how tumors form in mice. Peto observed that the probability of cancer progression in mice was related to the duration of exposure to a carcinogen. He later considered body mass and wondered why humans both contain 1000 times more cells and live 30 times longer than mice, yet have a similar probability of developing cancer as the tiny mice. How can this be?

We, as individuals, are believed to have more or less the same overall risk of cancer. However, this risk then increases or decreases due to individual gene mutations.

These gene mutations can be influenced by:

• Certain health conditions (such as obesity)
• Environmental factors (such as exposure to cancer-causing chemicals or radiation)
• Lifestyle choices (smoking, drinking, eating a high-fat diet, not doing enough exercise, etc.)
• Hereditary genetics (cancer itself is not hereditary but you can inherit a risk of certain gene mutations that can increase your cancer risk).

Gene mutations can also result from random errors in the process of cell division.

Different animals have different cancer rates. For example, According to the American Veterinary Medical Association, almost half of dogs over the age of 10 will develop cancer (with slight variations among breeds).

But there are other mammals that have extremely low cancer rates. Naked mole rats are very interesting for scientists because they appear to be highly cancer resistant. So are some much larger mammals, such as elephants and whales, which have many more cells than naked mole rats or even humans, yet develop cancer at much lower rates.

Cancer develops due to an accumulation of mutated genes in the cells. Theoretically, if an organism has more cells, it should have a higher chance of accumulating mutations, and eventually developing cancer —especially if it is long-lived, because it would go through more cell division processes in its lifetime.

According to a 2017 research paper published in the journal BMC Biology, "If every cell division carries a particular chance that a cancer-causing mutation could occur, then the risk of developing cancer should be a function of the number of cell divisions in an organism’s lifetime. Therefore, large-bodied and long-lived organisms should face a higher lifetime risk of cancer simply due to the fact that their bodies contain more cells and will undergo more cell divisions over the course of their lifespan."

However, elephants and blue whales —which have a lifespan of 80 years on average— have proved that logic wrong. In fact, the evidence suggests that larger, long-lived mammals actually get less cancer.

Peto’s paradox refers to this lack of correlation between the number of cells of an organism and its cancer risk at a species level.

When was Peto's paradox discovered?

English statistician and epidemiologist Richard Peto articulated this paradox in 1977 while writing an overview of the Armitage–Doll model, a statistical model of carcinogenesis developed by statistician Peter Armitage and physician Richard Doll in 1954.

This multistage model shows how a series of mutations can accumulate in the cells and eventually result in cancer (this is the generally accepted theory of carcinogenesis even to this day). Richard Peto, who studied tumor formation in mice, noticed that mice and humans had similar cancer rates in spite of having very different numbers of cells. Conversely, large-bodied, long-lived animals had lower cancer risk than mice or humans.

Realizing that these observations were inconsistent with the Armitage-Doll model, Richard Peto formulated what we now know as Peto's paradox.

How to resolve Peto’s paradox?

To resolve the paradox, Richard Peto himself proposed that evolution needs to be taken into account.

Basically, he theorized that elephants, whales, and other cancer-resistant animals must have acquired certain cancer-suppressing mechanisms in order to develop their larger, longer-lived bodies. Without these mechanisms, he reasoned, these large, long-lived animals would accumulate mutations too rapidly and die from cancer at a rapid rate. It was plain and simple adaptation to avoid their own extinction.

In 2015, a team of scientists from seven different research institutions found evidence that supported Peto’s theory. Analyzing the genome of Asian and African elephants, the team discovered that these elephants had 20 copies of a tumor suppressor gene called TP53.

The TP53 gene contains instructions for the production of the p53 protein, which determines whether an abnormal cell will be repaired or programmed to self-destruct. This decision is fundamental for the prevention of tumors, as damaged cells should not be allowed to reproduce.

Humans only have one copy of the TP53 gene, and it is actually one of the most common genes that appear mutated in cases of human cancer.

A separate research study also conducted in Lynch’s laboratory came to the conclusion that, in addition to this, elephants have 11 extra copies of a gene called Leukemia Inhibitory Factor (LIF). This gene is up-regulated by TS53 and its mission is to induce cell death in response to DNA damage.

Overall, researchers speculate that even if an elephant develops cancer, they rarely die from it because their bodies are more efficient at fighting it. In fact, cancer mortality in elephants is as low as 4%, while it's about 25% in humans.

In the case of the naked mole rats, a 2013 study found that their tissues are very rich with high molecular weight hyaluronan, which has a role in fighting cancer.

The team also identified a gene, named HAS2, which is responsible for making HMW-HA in the naked mole rat and which was different from HAS2 in all other animals. They also found that naked mole rats recycle HMW-HA very slowly, which allows the chemical to build up in the animals' tissues.

As an evolutionary mechanism, it could be that naked mole rats needed higher hyaluronic acid levels so that they could develop their super elastic skin, which allows them to slide in tight underground tunnels without harming themselves.

Apparently, this trait is also responsible for the rats’ incredible cancer resistance, as it also made them more sensitive to contact inhibition —a process in which cell proliferation stops when cells come in contact with each other. In fact, the authors of the study tried to stimulate tumor growth in the naked mole rats but they couldn't achieve it until they reduced the hyaluronic acid concentrations in the rats’ bodies.

These findings do not necessarily mean that Peto’s paradox is solved, but they support the idea that evolution can provide some answers for it, and if that’s the case, perhaps we could also use them to help us prevent and treat human cancer one day.