Cancer Is One Worry Elephants Can Feel Free to Forget

The gentle giants’ cells contain a tumor-fighting self-destruct button.

Elephants, which can weigh up to 100 times as much as humans, should be riddled with cancer—but they aren't. Wikimedia Commons

Elephants are one of nature’s biggest improbabilities—literally. Their colossal bodies somehow manage to defy the odds: Despite the fact that their cells outnumber humans’ by a factor of about 100, elephant cancer mortality is somehow only a third of ours.

This baffling inconsistency has plagued scientists for decades. It even has a name: Peto’s paradox, a nod to the epidemiologist who first noted the phenomenon in the 1970s, studying humans and mice. But new research published today in Cell Reports shows that, to keep cancer at bay, elephants have a devious trick up their trunks—a molecular self-destruct button, reanimated from beyond the grave.

At first glance, being multicellular seems like a pretty great gig. It allows the existence of stronger, more complex organisms that can climb the food chain. But quantity is a double-edged sword.

Imagine a deck of cards. The fifty-two hearts, spades, clubs and diamonds are perfectly healthy cells, but the two jokers—those are cancer. Building a body is like picking cards one by one from this unavoidably stacked deck. The bigger the body, the more cards must be drawn—and the lower the odds of staying safe. Each additional card is another potential point of corruption.

All cancer needs is a single cell—one devious joker—to mutate and run amok, eventually creating an insatiable army that hoards the body’s natural resources and crowds out vital organs.

Science has often confirmed this unsettling pattern: When it comes to dogs, bulkier breeds have higher rates of tumors, while punier pups are spared. In humans, simply being a few inches taller ups your risk of cancer.

Behemoths like elephants and whales, however, turn their often-considerable noses up at this trend. Somehow, these gargantuan species either have fewer jokers in their deck—or have devised some way of screening them out of the final product.

Peto’s paradox has weighed on the mind of Vincent Lynch, a professor of evolutionary biology at the University of Chicago, for years. So Lynch and his research group were thrilled to unveil a piece of the puzzle in 2015, when they and others reported that elephants carry extra copies of a cancer-fighting gene called TP53.

To safeguard against the perils of tumorous growth, even the busiest of cells are constantly pausing to check their progress. If a cell senses damage or catches an error, like damage to its DNA code that could lead to cancer, it must make a rapid choice: Is a repair in order? If so, is it worth the time and energy? Sometimes, the answer is no, and the cell catapults itself onto a path of self-destruction. Forestalling cancer is all about nipping it in the bud, even if that means saying goodbye to an otherwise useful cell.

TP53 produces a protein that is the scrupulous schoolmarm of the cell, diligently pausing the assembly line to perform routine checks and quality control. Under TP53’s watchful eye, cells are expected to show their work and double-check their answers. If TP53 catches an particularly severe error, the cells will be commanded to commit suicide in a process called apoptosis. While extreme, such a sacrifice may be a worthwhile price to pay to avoid propagating a lineage of cancerous clones.

With a veritable cavalry of TP53s20 pairs in each cell—elephants are well-equipped for cellular surveillance. But as a top delegator, TP53 mostly blares through the intercom—and it remained unclear what exactly was carrying out its marching orders, and how.

Juan Manuel Vazquez, a graduate student in Lynch’s research group, reasoned that a schoolmarmy army would also need minions in spades to do its dirty work. So he decided to forage through the elephant genome for other genes with multiple copies. When Vazquez ordered elephant genes by the number of duplications they had sustained, he was unsurprised to see prudish TP53 at the very top of his list. Immediately below it, however, was a gene named “leukemia inhibitory factor,” or LIF.

With a name like that, the gene might as well have been called “publishable result.” To Lynch and Vazquez, it seemed almost too good to be true. And it very well could have been; Vazquez still had to prove his candidate gene actually lived up to its moniker.

Cancer Is One Worry Elephants Can Feel Free to Forget
Whales are another example of Peto's paradox: Despite their size, they are mysteriously cancer-free. Wikimedia Commons

When the researchers scoured the genomes of 53 different species of mammals, they found that the cells of most of these animals, including humans, carried only one pair of LIF genes. But elephants, rock hyraxes and manatees—which are closely related—had between seven and 11 additional pairs of LIF. In these animals’ common ancestor, someone had left the original gene on the copier and wandered off. Most of the LIF duplicates were only partial scans, though, and had become defunct over time.

But, in this tranquil graveyard, a lone zombie stirred: Unlike the others, one copy, LIF6, resuscitated itself in only the elephant line. Somehow, elephant LIF6 had surreptitiously acquired an on-switch that made it responsive to TP53—a random, improbable mutation that transformed genetic junk into workable machinery. “It’s one of those things that’s almost unheard of,” Vazquez says.

Now, when TP53 sternly beckoned, LIF6 came running. Every time an elephant cell’s genetic integrity was compromised, TP53 would flip LIF6’s on-switch. LIF6 would then produce a protein that poked holes in the cell’s mitochondria, or energetic powerhouse. This move, which effectively gutted the cell’s engine, triggered an instantaneous cellular seppuku. And when the researchers blocked expression of LIF6 in elephant cells, they became less likely to self-destruct in response to potentially cancerous DNA damage, instead resembling the hardier cells of most other mammals. It seemed elephant cells were quick to give up the ghost—but when it came to cancer, this was a blessing in disguise.

This system, fickle though it was, appeared to protect the elephant's body. It wasn’t that elephants had fewer cancerous jokers in their decks; they were simply more apt to jettison jokers into the discard pile, and draw again. By forcing cells to die before they could become cancerous, LIF6 was protecting them from disease.

Jessica Cunningham, a cancer biologist at the Moffitt Cancer Center who was not affiliated with the study, praised the “top notch” quality of the research. “They’re using all of the best experiments you can do to research this,” she says.

From the outside, elephants seem to have it figured out. Why haven’t all life forms followed suit? As Lynch puts it, “There’s no such thing as a free lunch.”

Cunningham confirms this notion. “The cost of cancer suppression in multicellular organisms must be very expensive,” she says. “If it was cheap, then we would do it all the time.”

It turns out cellular caprice comes with significant downsides. Trigger-happy cells can be too quick to bail. Every aborted cell needs to be replaced—and starting over from scratch is a cumbersome process.

Chi Van Dang, who also studies the molecular basis of Peto’s Paradox but did not participate in this research, points out that there could be other explanations for why elephants don't get cancer. For instance, larger species tend to have slower metabolisms. Cells that take their time with growth and division might have more time to address genetic mistakes.

“The correlation [with duplications of tumor suppressors and reduced risk of cancer] is clear, but we don’t have cause and effect,” explains Dang, who is the scientific director of the Ludwig Institute for Cancer Research and a professor at The Wistar Institute in Philadelphia. The case for this may be especially true when looking at more of the tree of life: Elephants are not alone in bucking Peto’s paradox. Duplications of TP53 and LIF6 may be one way to circumvent cancer, but these genetic anomalies haven’t been found in other cancer-resistant species like whales—meaning that many more types of cancer suppression likely exist.

Additionally, according to Cunningham, cancer suppression doesn’t always go hand in hand with a big body. Pint-sized naked mole rats and bats are also unusually resistant to cancer. Still other factors may be at play—such as a hyper-efficient system of repair that can correct DNA damage before it’s too late.

Of course, these different methods of forestalling cancer aren’t mutually exclusive. Scientists tend to agree that one pathway, no matter how powerful, is unlikely to explain all of Peto’s paradox, especially across diverse species that have been evolutionarily separate for millennia.

In one of their final experiments, Vazquez and his colleagues added LIF6 to the cells of rodents, which normally carry only one pair of LIF genes. With a new set of sycophantic hall monitors to heed TP53, injured rodent cells eagerly walked the plank. But the effect was modest: Because rodent cells differ from elephant cells in many other ways (including a conspicuous lack of extra pairs of TP53), simply adding LIF6 was not enough to generate totally cancer-resistant hybrids. As such, Lisa Abegglen, a cancer biologist at the Huntsman Cancer Institute of the University of Utah, says more studies are needed to confirm that manipulating LIF6 in cells in other mammals, including humans, is of consequence.

However, Abegglen, who led one of the original studies on the abundance of TP53 in elephants in 2015 but was not involved in this research, emphasizes that differences between species don’t invalidate such important findings.

“Every species will have a different defense,” she says. “The more we understand about basic biology, the more we can manipulate human cells to be like these animals. Nature has a lot to teach us if we know where to look.”

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