Why elephants aren’t riddled with tumors poses a weighty problem for researchers. A new study shows that the animals harbor dozens of extra copies of one of the most powerful cancer-preventing genes. These bonus genes might enable elephants to weed out potentially cancerous cells before they can grow into tumors.
When it comes to cancer, elephants appear to have several strikes against them. At up to 4800 kg, an African elephant packs about 100 times as many cells as you do. The more cells an animal carries, the higher the odds that one of them will suffer the DNA damage that can lead to cancer. Producing all those cells also entails numerous rounds of cell division, each of which can result in a tumor-triggering DNA break. Moreover, elephants can survive for more than 60 years in the wild, providing plenty of time for tumors to arise. “Long-lived animals with lots of cells should all be dropping dead of cancer,” says pediatric oncologist Joshua Schiffman of the University of Utah’s Huntsman Cancer Institute in Salt Lake City, who is a co-author on the new study. “But they don’t or they’d go extinct.”
The surprisingly low cancer rates in elephants and other hefty, long-lived animals such as whales—known as Peto’s paradox after one of the scientists who first described it—have nettled scientists since the mid-1970s. So far, researchers have made little progress in solving the mystery or determining how other long-lived species beat cancer. One exception involves naked mole rats. Although these African rodents aren’t massive, they survive for up to 28 years, almost 10 times longer than lab rats, and they don’t develop cancer. Two years ago, cell and molecular biologists Vera Gorbunova and Andrei Seluanov of the University of Rochester in New York and colleagues reported that one of naked mole rats’ defenses against cancer was a complex sugar called hyaluronan, which prevents their cells from clumping together to form tumors.
In the new study, Schiffman teamed up with Carlo Maley, an evolutionary cancer biologist at Arizona State University, Tempe, and colleagues. To put elephants’ cancer-fighting abilities into perspective, the researchers wanted to pin down different species’ vulnerability to tumors. The team used data from the Elephant Encyclopedia, which tallies the births and deaths of all captive elephants worldwide, and from necropsies performed on animals of more than 30 species at the San Diego Zoo in California. Fewer than 5% of elephants die from cancer, the scientists estimated, a lower rate than for smaller animals such as African wild dogs (8%) and humans (up to 25%).
A possible reason for pachyderms’ reduced susceptibility to cancer turned up in the genome of the African elephant. The researchers found that it contains 40 copies of the gene that encodes the protein p53, one of the most important mechanisms for preventing cancer. If cells have DNA damage that could spawn tumors, p53 prevents them from dividing until they make repairs or spurs them to commit suicide. Asian elephants harbor 30 to 40 copies of the gene, the team reports online today in the Journal of the American Medical Association.
In contrast, humans sport only two copies of the gene for p53, and so does elephants’ closest living relative, the rock hyrax. The extra copies probably accumulated millions of years ago as the gene was accidentally duplicated many times in the ancestors of elephants, the researchers suggest.
To investigate how the extra copies of the p53 gene fend off tumors, the team dosed African elephant cells with radiation, damaging their DNA. “We expected to see that elephants were repairing DNA like nobody’s business,” Schiffman says. But the animals’ cells weren’t any better than human cells at fixing broken DNA. Instead, the elephant cells were twice as likely to die after radiation exposure than were human cells. “We think we’ve figured out—maybe—why elephants don’t get cancer,” Schiffman says. The extra copies of the p53 gene enable elephants to kill off potentially cancerous cells before they form tumors. The study is consistent with a paper published earlier this week on the preprint server bioRxiv, which also found 40 copies of the gene for p53 in the elephant genome.
“This is exciting evidence for how [Peto’s] paradox is resolved by one giant animal,” says Gorbunova, who wasn’t connected to the new study. However, biochemist Vadim Gladyshev of Harvard Medical School says he’s skeptical because the researchers haven’t demonstrated that the extra genes produce working versions of p53. “My question is whether any of these genes have a function.”
Schiffman says that he and his colleagues are trying to determine whether they can make human cells more elephantlike, for example by inserting additional copies of the p53 gene or by identifying compounds that duplicate the effects of the extra copies.
Naked mole rats and elephants protect against cancer in different ways, Seluanov notes. “We need to look at long-lived, usually big animals,” he says, and we might find yet more ways of preventing cancer that that could potentially be useful for our cells.