Researchers have long struggled to understand why certain animals are predisposed to cancer and others are not.
Naked mole rats, for instance, can live for more than 30 years, yet never have a single incidence of cancer.
Elephants, similarly, present an even more mystifying conundrum. Despite their size and nearly comparable lifespan to humans — a whopping 50 to 70 years — they have a shockingly low occurrence of the disease.
This fact raises a high-stakes scientific question: What kind of cellular ammunition do large animals such as elephants have to combat cancer that humans do not?
A new study, published Oct. 8 in the Journal of the American Medical Association, provides a tantalizing answer to this question by first scrutinizing exactly how resistant large animals like elephants are to cancer, and then determining what arsenal they may have hidden in their DNA that provides this evolutionary advantage.
"Nature has already figured out how to prevent cancer," study author Joshua Schiffman, a pediatric oncologist at the University of Utah School of Medicine and Primary Children's Hospital, said in a press release. "It's up to us to learn how different animals tackle the problem so we can adapt those strategies to prevent cancer in people."
Cancer arises when a mutation — or an error in a cell's DNA sequence — causes that cell or another one to replicate out of control.
When the trillions of cells in your body replicate and divide, the machinery that copies your original strand of DNA into two separate copies is bound to make some mistakes. If a mistake happens in a gene that prevents tumor formation, such as the incredibly important tumor suppressor gene p53, the protein that the gene encodes would stop working — and could eventually fail to respond to unchecked tumor growth.
Since elephants are much larger than humans, we might expect them to have a higher lifetime risk of cancer. They have 100 times more cells than humans, which means that theoretically there should be many more chances for a cancer-causing mistake.
So why are they relatively healthy?
To rule out the idea that cancer incidence increases with body size, Schiffman's team analyzed 14 years-worth of autopsy data from 36 mammalian species of zoo animals. They found that a large body size was not, in fact, a risk factor for cancer. That observation squares with previous findings showing no relationship between body size and cancer risk, a counterintuitive idea known as Peto's paradox.
Elephants are no exception to that strange rule, the team found. Of the nearly 650 elephants analyzed, Schiffman's team found that only about 5% died from cancer. That's an incredible statistic, considering the cancer mortality rate in humans ranges from 11% to 25%.
Then they searched for potential anti-cancer agents that might be hiding in an elephant's DNA. After examining and comparing the genetic sequence of African and Asian elephants with those of humans, they found that elephants had extra copies of a gene that is crucial for thwarting cancer: the p53 gene.
Compared to the one pair of p53 genes that humans have, the team found that elephants have a whopping 20 pairs.
The human p53 gene prevents cancer by responding to DNA damage in a few ways: It turns off cellular replication, encourages cell suicide, or repairs the damage.
The importance of the gene is illustrated by a disease called Li-Fraumeni Syndrome (LFS), in which patients only have one good copy out of the normal two copies of p53. Those with LFS have a nearly 100% risk of cancer across their lifetime.
To see if the extra pairs of p53 in elephants helped to thwart cancer, the team analyzed how their cells respond to damage. Lo and behold, after battering the cells with cancer-causing radiation and chemicals, the extra genes didn't try to repair the damage, but simply spurred the cells to commit suicide. That suggests that the elephant p53 gene may be different, and more specialized, than that found in humans.
"It's as if the elephants said, 'It's so important that we don't get cancer, we're going to kill this cell and start over fresh,'" Schiffman said in a press release. "If you kill the damaged cell, it's gone, and it can't turn into cancer. This may be more effective of an approach to cancer prevention than trying to stop a mutated cell from dividing and not being able to completely repair itself."
The team thinks that elephants are much less prone to cancer because they have 20 times as many p53 genes as humans. But the study, while intriguing, still doesn't indicate how these extra genes prevent cancer.
"One possibility is that the extra copies don’t actually cause cells to commit suicide," journalist Carl Zimmer wrote for The New York Times. "Instead, they may act as decoys for enzymes that destroy p53 proteins."
Though the exact mechanism of protection is still a mystery, "whatever's going on is special to the elephant lineage," Vincent J. Lynch, an evolutionary biologist at the University of Chicago, told The New York Times. Other animals, like mole rats and whales, seem to have evolved entirely distinct strategies for cancer prevention.
Clinical trials targeting p53 are underway, though even before this — based on animal studies — scientists were wary: One line of mice bred to have extra copies of p53 paid a price of aging prematurely; another developed shrunken kidneys, Lynch explained in a Reddit AMA.
But what's happening in elephants suggests something slightly different than what's been seen before. Perhaps one day, according to the study authors, scientists can start tailoring drugs for humans that can mimic the elephants' remarkable survival strategy.
Even if that doesn't happen soon, the JAMA study is still exciting new evidence of a toolkit that nature has evolved to overcome one of the most destructive diseases of our time.
