Peto’s Paradox: Insights into cancer through elephants, naked mole rats, and the Animal Kingdom

elephants

As cells become cancerous randomly, we would expect that organisms with more cells have a greater cancer incidence. Peto’s paradox refers to the fact that this is not the case. Photo credit: Cecilia Jay, The Oxford Scientist


Elephants, whales, and other large species are not known for their mysterious cancer-fighting abilities. But when compared to humans, their ability to avoid cancer is nothing short of impressive. Cancers are formed when a cell mutates and starts to grow independently of cell cycle signals. Given that these transitions to cancerous cells happen at random, one would think that a greater number of cells would correlate with a greater cancer risk. 

The distinct absence of cancers in large creatures like elephants and whales is an exception to this rule—this is known as Peto’s Paradox. Peto’s Paradox (named after the first researcher to characterise the phenomenon, Sir Richard Peto, Emeritus Professor of Medical Statistics and Epidemiology at the University of Oxford), refers to the puzzling idea that more cells do not necessarily correlate with more cancer. So, how do these animals avoid cancer? Looking at the differences in their biochemistry could help researchers to further understand cancer and ultimately inspire the development of novel treatments. 

Cells typically grow on a specific timeline regulated by local signals. This is known as the cell cycle, and is what allows cells to grow and divide. Normally, a cell will only progress through each checkpoint of the cell cycle in the presence of a specific chemical signal. But some mutations can prevent the cell from recognising or responding to the body’s signals. 

DNA proofreading can be conducted by molecules like polymerases to recognise mistakes in genetic code. If mutations evade the cell’s proofreading machinery and accumulate, the cell may start dividing rapidly. When cancer cells mutate in a way which allows them to escape normal regulation by the body and grow independently of external signals, this rapid division may result in tumours (masses of rapidly dividing tissue).

There are two types of gene that are typically mutated in cancers—oncogenes and tumour suppressor genes. Oncogenes (genes involved in cell growth and division) can become upregulated and constantly fire a signal within the cell, meaning the original signal to progress through the cell cycle is no longer needed. Examples of these include growth factor receptors, responsible for responding to a stimulating signal known as a growth factor, or transcription factors, which activate genes involved in the growth and division process. 

Tumour suppressor genes (TSGs) are genes that, as their name implies, prevent the formation of tumours. Thus, it is the down-regulation or abnormal function of these genes that result in cancer. Cancerous cells can grow faster if tumour suppressor genes are suppressed or lost. But all copies of the gene must be inactivated or removed for loss of function. The “two-hit hypothesis” supposes that the need to have dysfunction of two genes rather than one inherently reduces the chances of TSG loss, leading to cancer activation. 

Every cell has the potential to suffer a mutation in its DNA and create a cancerous cell that can go on to form a tumour. In theory, a greater number of cells living for a longer amount of time would be more likely to develop cancer. It therefore follows that the probability of cancer increases with a species’ lifespan and size: for example, even small increases in human height can be associated with higher incidences of cancer. 

If the cells in a blue whale behaved the same way as human cells, statistical models have indicated all whales would develop cancer by age 80. But this is not the case. Peto’s Paradox offers an explanation for the discrepancy between these mathematical models and what is observed in nature. The hypothesis suggests that larger, longer-lived animals have evolved mechanisms to prevent cancer.

If the cells in a blue whale behaved the same way as human cells, statistical models have indicated all whales would develop cancer by age 80. But this is not the case.

There are many physical differences between larger animals and humans that provide some explanation for why organism size does not seem to correlate with cancer incidence. One such potential explanation could lie in the larger cell sizes of more sizable creatures. Indeed, larger cell sizes have slower cell division, meaning the cell has more time to repair DNA damage before it proceeds to the next stage of the cell cycle. 

The diversity of animal immune systems could also provide more information as to why some have lower incidences of cancer. The immune system plays an important role in recognising and destroying cancerous cells, but some cancerous cells can avoid immune recognition. When this occurs, cancer cells can then continue to multiply and develop into tumours. One theory suggests that certain organisms have simply developed a better system of recognising cancerous cells. 

Naked mole rats—animals known for being impressively resistant to disease and cancer—have far more myeloid cells than mice. Myeloid cells are blood cells originating from the bone marrow which are involved in the innate immune response, while natural killer cells typically fight off viruses. Researchers attribute these immune differences to the fact that naked mole rates are exposed to more bacteria than viruses in their underground homes. The differences in exposure have resulted in notable differences in their immune system composition that relate back to their disease-fighting ability. 

Another reason large animals are less likely to develop cancer could be due to differing metabolic rates. A common cause of DNA damage are reactive oxygen species, a group of molecules generated as by-products of metabolism which have the ability to attack and mutate DNA. Large, long-lived animals typically have a lower basal metabolic rate (BMR), meaning fewer reactive oxygen species are produced. Therefore, the chance of cancer originating from damage by these molecules is far lower. The mass-specific BMR is usually correlated to an animal’s size; however, the naked mole-rat has a lower mass-specific BMR than expected. This could relate to its unusually low rates of cancer. 

An alternative way of thinking about Peto’s Paradox is through the analysis of the specific genetic makeup of each animal. In this way, researchers have been able to pinpoint key genes that are either increased or decreased in copy number. Examples of genetic advantages could be the presence of more instances of tumour suppressor genes than normal (making it harder to turn them off), or oncogenes that do not mutate as easily. For example, researchers have demonstrated that bowhead whales have frequent duplications in genes relating to DNA repair and the cell cycle. This allows for a more efficient response to DNA damage before mutations can accumulate to form cancers. 

A specific gene allowing elephants to avoid cancer is TP53. This is a tumour suppressor gene, and the protein it codes for (“p53”) is a key junction in the pathway to repair DNA before mutations accumulate. The protein p53 senses signals like radiation or replication issues that could suggest the formation of mutations. It can then signal a pause in the cell cycle to give the cell time to repair these damaged pieces of DNA. Alternatively, it can initiate cell self-destruction in a process known as “apoptosis”. By inducing apoptosis, the cell will die, rather than continue to grow independently of the body’s signals.

Alone, the presence of TP53 in elephants is unsurprising—the gene is found in many organisms, and mutations in the TP53 gene are the most common mutations found in human cancers. What is unusual about the elephant is that it has twenty copies of the gene, while humans have just one. It is thought that this makes elephant cells far more sensitive to DNA damage; rather than allowing uncontrolled growth, these cells will be more likely to pause the cell cycle or die. Knowing the functions of TP53, it is unsurprising to learn that elephant cells seem to conduct apoptosis at a higher rate than human cells. It’s possible that observed levels of apoptosis may then correlate to rates of cancer.

Peto’s Paradox does not have any one clear explanation.

Peto’s Paradox does not have any one clear explanation. Rather, it is likely that animals such as whales, elephants, and naked mole rats have an arsenal of different cancer-fighting mechanisms. This makes biochemical information about genetically diverse animals extremely valuable to researchers. Studying the differences between species may help us to better understand the pathways that malfunction in cancer, ultimately increasing our knowledge of the disease. Our understanding of the impressive anti-cancer strategies employed in complex animals may later be used to explore potential applications in drug design and treatment.