About 40 years ago Richard Peto surmised that if every living cell has a theoretically equal probability of getting cancer, then large animals should have higher rates of cancer than small animals because they have many more cells and typically live longer. When he went about testing his idea, however, the University of Oxford epidemiologist, now 71 years old, found that this logic does not play out in nature. It turns out that all mammals have relatively similar rates of cancer.

Researchers have come up with multiple theories to explain Peto's Paradox. One explanation holds that the faster metabolisms of small animals generate more cancerous free radicals. Another suggests that evolution has equipped larger animals with extra tumor suppressor genes. Aris Katzourakis, an evolutionary biologist at Oxford, thinks an animal's ability to suppress viruses that jump into and out of its DNA may partially explain the paradox, a hypothesis he and his colleagues put forward in July in PLOS Pathogens.

These jumping viruses, known as endogenous retroviruses, can create cancerous mutations at the locations in the genome where they incorporate their own genes. Because the viruses have evolved with mammals for millions of years, their genetic material has come to make up 5 to 10 percent of most vertebrate genomes (including our own), although most of it is now inactive.

To understand how endogenous viruses factor into cancer risk, Katzourakis and his team of researchers studied the relation between body size and the number of endogenous retroviruses that had integrated into the genomes of 38 mammal species over the past 10 million years. The larger the animal, they found, the fewer endogenous retroviruses it acquired. For example, mice picked up 3,331, whereas humans gained 348 and dolphins, 55.

It seems that larger, longer-lived animals have evolved a protective mechanism to limit the number of these viruses. “If an animal evolves a large body size, they've got to make themselves more cancer-proof,” says Peto, who was not involved in the study. Katzourakis and his team have yet to identify the mechanism, but Katzourakis predicts that animals such as whales and elephants may have a greater number of antiviral genes that limit viral replication or ones that are more effective. “They've made a striking observation,” Peto remarks.

No single mechanism is likely to explain Peto's Paradox. Instead large animals probably evolved a variety of ways to fend off cancer. This is good news, says oncologist Carlo Maley of the University of California, San Francisco: “It would mean there are potentially many different solutions to developing cancer prevention.