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With cancer, the main thing to worry about is something going awry when a cell copies itself. So you would expect bigger animals with more cells and longer lives to get cancer more often.

But the weird thing is, they don’t. This biological puzzle is called Peto’s Paradox. And researchers are working on solving it.

Like, we’ve learned that bigger, longer-lived animals have evolved better ways of dealing with cells that start to grow out of control. But we don’t really know how they do it… except for elephants. A few years ago, two groups of scientists discovered that elephants have 20 copies of a tumor-suppressor gene called TP53.

Most animals, including us, have one copy. The gene makes the protein p53, which can help fix damaged DNA and even kill cells if the DNA is messed up beyond repair. So because elephants have more of this protein, they have some extra protection from cancerous growths.

In fact, it’s so much protection that they have around 100 times as many cells as us, and still get tumors less often. But it turns out: that’s not only thanks to TP53. This week, geneticists at the University of Chicago reported that elephants have another trick up their trunks: zombie genes.

If you’re unfamiliar with the term, don’t worry. It seems like these researchers came up with it just for the paper. Which, by the way, sure, do that, go and you be you scientists.

And, actually, “zombie” pretty much nails what it is and does. The gene was reanimated over the course of evolution, and its job is to kill, to kill cells. Basically, the researchers noticed that elephants have extra copies of another gene called leukemia inhibitory factor, or LIF.

A few elephant relatives do too, like manatees and a rabbit-like African mammal called the rock hyrax. But in those animals, the extra copies of LIF don’t seem to work. The geneticists think that most of the copies are pseudogenes, basically flawed versions of genes that came about because of either sloppy gene duplication or mutation after duplication.

So they’re recognizable bits and pieces when we look at the DNA, but they don’t do anything. One of the elephant copies of LIF does seem to work, though. Normally LIF can either help cells survive or self-destruct, depending on how much of its sequence is turned into protein.

The working extra copy in elephants only has the part that helps kill cells, which could help stop cancerous ones from spreading. It’s called LIF6. To find out what LIF6 does, the researchers grew elephant cells in petri dishes.

Elephant cells are incredibly sensitive to DNA damage, so they die really easily when scientists add toxic chemicals. But when the team reduced the amount of LIF6 protein the cells could make, the cells were less sensitive. And when the team jacked up the protein, the cells were so sensitive that the scientists didn’t even need to add toxic chemicals to make them die.

This reveals a downside to being cancer-resistant. Sure, you want to avoid letting a tumor grow, but you also don’t want to make it too easy for your cells to die, either. The good thing for elephants is that their restored LIF6 gene evolved sequences that let it be controlled by p53.

So this cell-killing gene doesn’t normally do much unless there’s DNA damage. When that happens, good ol’ p53 can swing into action, bind to the LIF6 gene, and crank its expression way up. The LIF6 protein then probably punctures the mitochondria, turning those cellular powerhouses into death machines that release chemicals that trigger the demise of the damaged cells.

It’s killer, but, you know, the helpful kind of killing. Using DNA samples from extinct and living elephants and their relatives, the researchers were also able to roughly piece together when this LIF gene came back to life. Creatures like mastodons and woolly mammoths share what looks like the functional LIF6 gene with today’s African and Asian elephants, whereas manatees and hyraxes don’t.

That suggests zombification happened sometime between 60 and 30 million years ago. And that timing is especially interesting because this is when elephant ancestors started to really pack on the pounds and get real big. LIF6 could be one way the animals were able to do that, since it prevented them from getting tumors all over the place.

And TP53 duplication could have helped too. So, thanks to this research, we now have an even better sense of how elephants came to be so big and relatively cancer-free. We still don’t entirely know how other massive animals like whales, or long-lived creatures like bats, pull it off.

But who knows, maybe there are more zombie genes or other genetic tricks out there. Thanks for watching and learning with us, and a big thank-you to our. Patreon President of Space Matthew Brant.

Thank you Matthew for helping us make SciShow. If you want to join our Patreon community, go to Patreon.com/SciShow to learn more. [♪ OUTRO].