Elephants have 100 times as many cells as humans. But they seldom get cancer. This is surprising, because cancer is a result of cell division gone wrong, and the more cells an organism has, the higher the chances that some will mutate into tumors.
Also, because elephants live so long - between 60 and 70 years - their cells have more opportunities to mutate.
The counterintuitive observation that cancer risk does not always correlate with a species' size or longevity is known as Peto's Paradox, named after British epidemiologist Richard Peto, who first noted the phenomenon in 1977.
It turns out that cancer does not strike all species equally: Some animals have evolved powerful strategies to keep the disease at bay, while others are particularly vulnerable.
Scientists are increasingly exploring this interspecies variation in cancer rates, hoping to learn more about how cancer works in humans and to identify better ways of treating or preventing it.
"Elephants should be getting cancer all the time," said University of Utah cancer researcher Joshua Schiffman, who has been studying the topic for the past decade. "But they don't. They've evolved some really effective anti-cancer strategies."
Schiffman - a pediatric oncologist who also treats humans with cancer - and colleagues have found that elephants have 40 copies of the TP53 gene, which suppresses tumor cells before they can grow and spread. By comparison, humans and most other animals have only two copies.
Schiffman and research partner Carlo Maley of Arizona State University say they suspect that the extra copies may give elephants a powerful ability to keep mutant cells at bay. Scientists have long known that TP53 helps the body kill rogue cells before they can transform into tumors. But until Schiffman and Maley's work, no one realized that any animal had 40 copies of the gene. The elephants' approach appears to be a unique evolutionary strategy for fighting cancer.
Schiffman and colleagues found that elephants also have other anti-cancer mechanisms. Elephant cells respond differently when exposed to substances that damage DNA. Instead of trying to repair the damage, they tend to simply die. With cancer, this is a much safer approach: Cells that try to heal themselves are more likely to mutate and then transform into cancer cells. In a paper published in March, Schiffman and University of Utah scientist Christopher Gregg identified three genes that prevent mutations by fostering DNA repair.
Together, these genetic adjustments may give elephants multiple weapons against the disease.
Elephants are not the only animal with unusually low rates of cancer. Using data from zoos and veterinarians as well as anecdotal reports from the wild and lab research, scientists know or suspect that other creatures, including mole rats, gray squirrels, horses, whales and bats, rarely get cancer.
It is not entirely clear where humans fall on the spectrum of risk. For humans, the lifetime probability of having cancer is about 50 percent. While we do have some cancer-suppressing genes, we also tend to live for a relatively long time. For most animals, the lifetime cancer risk is probably between 20 and 40 percent, with outliers on each end - elephants on one side and dogs, mice and cheetahs on the other.
Of course, cancer is tracked much more systematically in humans than in other species. "We just don't have that much data from nature," said University of California at Riverside biologist Leonard Nunney, who studies evolution, animals and cancer, and coined the term "Peto's Paradox." "So it's very hard to compare."
Perhaps the strangest animal being studied for its cancer-fighting abilities is the naked mole rat, a five-inch-long, hairless, pinkish rodent that lives in burrows in East Africa. These creatures survive far longer than most rodents - up to 32 years - and seldom get tumors.
Over decades, scientists have studied thousands of naked mole rats in labs and zoos around the world; in that time, they have documented only six cases of cancer. For the past 13 years, University of Rochester scientists Vera Gorbunova and her husband, Andrei Seluanov, have been trying to unravel how the animals accomplish this.
The ultimate goal is to develop new ways to fight human cancer. Eventually, it may be possible to use gene therapy, genetic engineering or pharmacology to apply animals' cancer strategies to humans.
This work has already begun: Gorbunova and Seluanov are now testing whether hyaluronic acid can prevent the disease in mice. Other anti-cancer strategies of animals have not reached the testing stage, but Schiffman said the potential is clearly there.
"This is a whole new field," he said. "We are at the tip of the iceberg. Nature has come up with these solutions over hundreds of millions of years of evolution. Now we need to analyze that and apply it to humans."