Peto's paradox is the observation that, at the species level, the incidence of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

does not appear to correlate with the number of cells in an organism. For example, the incidence of cancer in

humans Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

is much higher than the incidence of cancer in

whales Whales are a widely distributed and diverse group of fully aquatic placental marine mammals. As an informal and colloquial grouping, they correspond to large members of the infraorder Cetacea, i.e. all cetaceans apart from dolphins a ...

, despite whales having more cells than humans. If the probability of

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

were constant across cells, one would expect whales to have a higher incidence of cancer than humans. Peto's paradox is named after English statistician and epidemiologist

Richard Peto Sir Richard Peto (born 14 May 1943) is an English statistician and epidemiologist who is Professor of Medical Statistics and Epidemiology at the University of Oxford, England. Education He attended Taunton's School in Southampton and subsequ ...

, who first observed the connection.

History

Peto first formulated the paradox in 1977. Writing an overview of the multistage model of cancer, Peto noted that, on a cell-for-cell basis, humans were much less susceptible to cancer than mice. Peto went on to suggest that evolutionary considerations were likely responsible for varying per-cell carcinogenesis rates across species. It remains unsolved to this day.

Same species

Within members of the same species, cancer risk and body size appear to be positively correlated, even once other risk factors are controlled for. A 25-year longitudinal study of 17,738 male British civil servants, published in 1998, showed a positive correlation between height and cancer incidence with a high degree of statistical confidence, even after risk factors like smoking were controlled for. A similar 2011 study of more than one million British women found strong statistical evidence of a relationship between cancer and height, even after controlling for a number of socioeconomic and behavioral risk factors. A 2011 analysis of the causes of death of 74,556 domesticated North American dogs found that cancer incidence was lowest in the smaller breeds, confirming the results of earlier studies.

Across species

Across species, however, the relationship breaks down. In a 2015 study, the

San Diego Zoo The San Diego Zoo is a zoo in Balboa Park, San Diego, California, housing 4000 animals of more than 650 species and subspecies on of Balboa Park leased from the City of San Diego. Its parent organization, San Diego Zoo Wildlife Alliance, is ...

surveyed results from 36 different mammalian species, ranging in size from the 51-gram

striped grass mouse ''Lemniscomys'', sometimes known as striped grass mice or zebra mice, is a genus of murine rodents from Africa. Most species are from Sub-Saharan Africa; ''Barbary Striped Grass Mouse, L. barbarus'' is the only one found north of the Sahara.Jona ...

to the nearly 100,000 times larger 4,800-kilogram

elephant Elephants are the largest existing land animals. Three living species are currently recognised: the African bush elephant, the African forest elephant, and the Asian elephant. They are the only surviving members of the family Elephantidae ...

. The study found no statistically significant relationship between body size and cancer incidence, offering empirical support for Peto's initial observation.

Evolutionary considerations

The evolution of multicellularity has required the suppression of cancer to some extent, and connections have been found between the origins of multicellularity and cancer. In order to build larger and longer-lived bodies, organisms required greater cancer suppression. Evidence suggests that large organisms such as elephants have more adaptations that allow them to evade cancer. The reason that intermediate-sized organisms have relatively few of these genes may be because the advantage of preventing cancer these genes conferred was, for moderately-sized organisms, outweighed by their disadvantages—particularly reduced

fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...

. Various species have evolved different mechanisms for suppressing cancer. A paper in ''Cell Reports'' in January 2015 claimed to have found genes in the

bowhead whale The bowhead whale (''Balaena mysticetus'') is a species of baleen whale belonging to the family Balaenidae and the only living representative of the genus '' Balaena''. They are the only baleen whale endemic to the Arctic and subarctic waters, ...

(''Balaena mysticetus'') that may be associated with longevity. Around the same time, a second team of researchers identified a

polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with ...

in the

naked mole-rat The naked mole-rat (''Heterocephalus glaber''), also known as the sand puppy, is a burrowing rodent native to the Horn of Africa and parts of Kenya, notably in Somali regions. It is closely related to the blesmols and is the only species in the ...

that appeared to block the development of tumors. In October 2015, two independent studies showed that elephants have 20 copies of tumor suppressor gene

TP53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

in their genome, where humans and other mammals have only one. Additional research showed 14 copies of the gene present in the DNA of preserved

mammoth A mammoth is any species of the extinct elephantid genus ''Mammuthus'', one of the many genera that make up the order of trunked mammals called proboscideans. The various species of mammoth were commonly equipped with long, curved tusks and ...

s, but only one copy of the gene in the DNA of

manatee Manatees (family Trichechidae, genus ''Trichechus'') are large, fully aquatic, mostly herbivorous marine mammals sometimes known as sea cows. There are three accepted living species of Trichechidae, representing three of the four living speci ...

s and

hyrax Hyraxes (), also called dassies, are small, thickset, herbivorous mammals in the order Hyracoidea. Hyraxes are well-furred, rotund animals with short tails. Typically, they measure between long and weigh between . They are superficially simil ...

es, the elephant's closest living relatives. The TP53

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

gene specifies a protein that senses damaged sites in DNA, or a cell experiencing stress. The TP53 protein then either slows the growth of the cell for a brief period during which DNA damage is repaired, or it triggers cell death ( apoptosis) if the damage is overwhelming. Enhanced capability to repair DNA damage may explain the observed cancer suppression in elephants. The results suggest an evolutionary relationship between animal size and tumor suppression, as Peto had theorized.

Metabolic and cell size considerations

A 2014 paper in ''Evolutionary Applications'' by Maciak and Michalak emphasized what they termed "a largely underappreciated relation of cell size to both metabolism and cell-division rates across species" as key factors underlying the paradox, and concluded that "larger organisms have bigger and slowly dividing cells with lower energy turnover, all significantly reducing the risk of cancer initiation." Maciak and Michalak argue that cell size is not uniform across mammalian species, making body size an imperfect proxy for the number of cells in an organism. (For example, the

volume Volume is a measure of occupied three-dimensional space. It is often quantified numerically using SI derived units (such as the cubic metre and litre) or by various imperial or US customary units (such as the gallon, quart, cubic inch). Th ...

of an individual

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

of an elephant is roughly four times that of one from a common shrew). Furthermore, larger cells divide more slowly than smaller ones, a difference which compounds exponentially over the life-span of the organism. Fewer cell divisions means fewer opportunities for cancer mutations, and mathematical models of cancer incidence are highly sensitive to cell-division rates. Additionally, larger animals generally have lower

basal metabolic rate Basal metabolic rate (BMR) is the rate of energy expenditure per unit time by endothermic animals at rest. It is reported in energy units per unit time ranging from watt (joule/second) to ml O2/min or joule per hour per kg body mass J/(h·kg). P ...

s, following a well-defined inverse logarithmic relationship. Consequently, their cells will incur less damage over time per unit of body mass. Combined, these factors may explain much of the apparent paradox.

Medical research

Large animals' apparent ability to suppress cancer across vast numbers of cells has spurred an active medical research field. In one experiment, laboratory mice were genetically altered to express "always-on" active

tumor antigens, similar to the ones found in elephants. The mutated mice exhibited increased tumor suppression ability, but also showed signs of premature aging. Another study placed p53 under normal regulatory control and did not find signs of premature aging. It is assumed that under its native promoter p53 does not cause premature aging, unlike constitutively expressed p53.

References

{{Reflist Carcinogenesis Epidemiology Health paradoxes