Zombie Gene Protects Elephants From Cancer

Large mammals, such as whales and elephants, have very low rates of cancer compared to smaller mammals, such as humans. Scientists believe they have found the genetic answer to this paradox. fhm/Getty Images

You have no idea what your DNA is up to right now. You might not be able to see it or feel it working, but it's there, it never sleeps and it's basically got you hogtied. You can't see your genetic material, but it's an entire universe of biological instructions — and a lot of the time they're not even very good instructions. Your DNA could be making coarse black hairs grow out of your palms right now; it could also be nonchalantly protecting you from cancer. It could also be doing absolutely nothing. There's no telling.

Here's the thing: Evolution doesn't have some great plan for you, personally. Whether or not you have genes that tell your palms to grow whiskers and your body to fight cancer — that's mostly just happenstance. Mostly. But from time to time, DNA has been known to pull incredible Hail Marys.

Take elephants, for instance. They very rarely get cancer — an elephant's cancer mortality rate is just under 5 percent, while we die of cancer between 11 and 25 percent of the time. Whales have very low rates of cancer too — in fact, large animals of all kinds seem to succumb to cancer way less than one might imagine. This puzzled cancer researchers in the 1950s and '60s because the early understanding of why cancer happens has to do with how many cells an animal has, coupled with its longevity.

Large and long-lived animals, scientists theorized, have lots of cells and/or more time in which cells could potentially start doing their jobs wrong. Conversely, small animals have fewer cells and generally don't live as long as larger animals, thus there are fewer chances and less time for cells to mutate in ways that would result in cancer. This line of reasoning makes a good bit of sense, right? Yet in the 1970s, statistical epidemiologist Richard Peto observed that we don't see a higher incidence of cancer in humans than we do in mice, even though human bodies contain 1,000 times more cells and live 30 times as long.

It was in this way that science was introduced to Peto's Paradox, the mystery that's bedeviled cancer researchers for nearly half a century. Even though cancer reliably shows up in larger individuals within a species more often than in little ones — for instance, a couple inches of height on a human can significantly raise her chances of getting some types of cancer — for whatever reason, huge and long-lived animals have cancer rates comparable to or lower than our own.

Because being humongous has evolved countless times over the eons, there are probably as many solutions to Peto's Paradox as there are gigantic-bodied animals. However, a new study published in the Aug. 14, 2018, issue of Cell Reports finds that the reason for Peto's Paradox in elephants is, in reality, completely bonkers.

Previous research reported that African savannah elephants (Loxodonta africana) have a whole bunch of copies of a specific cancer-fighting gene called TP53. This gene produces a protein that combs cells looking for potential DNA damage. Humans (and most other animals) have only one copy of this gene — elephants, it happens, have 20 copies. So, T53 lends the elephant a lot of capacity to see that there is a problem, but not the ability to do anything about it.

The University of Chicago research team rummaged around in the elephant genome to see if they could find any clue as to who would be carrying out the cell repairs or cell destruction that gives elephants their cancer-fighting powers, and they found something pretty obvious: Elephants have between seven and 11 copies of a type of gene known as "leukemia inhibitory factor," or LIF. The problem was, these copies were old — many of them had probably been useful to the elephant's evolutionary progenitors, but they were so degraded they were probably completely useless.

And this is where things start getting weird.

"What we actually found was a copy of LIF — LIF6 — which had integrated into the genome in the common ancestor of elephants and manatees," says lead author Juan Manuel Vazquez, graduate student in the Department of Human Genetics at the University of Chicago. "Manatees still have this piece of DNA, but it's what we'd traditionally consider 'junk.' But elephants took this junk DNA and, right before it lost any and all coding potential for the correct protein, it evolved a new way of inducing its activation and expression into a functional protein again. It was pure luck."

So, as a last-ditch attempt to cut down on the accumulation of bad cells, the elephant resurrected a piece of DNA that's capable of killing cells that have been flagged for execution by TP53 and put it to work culling cells with DNA damage.

"We coined the term 'zombie gene' because we couldn't find any other case where this has happened — right before a piece of junk DNA becomes purely junk or evolves into something useful," says Vazquez.

And, you know, it could have gone wrong. What's amazing is the elephant was able to both reactivate the gene and control it — to tell LIF6 to kill, not every cell, but just the ones that seemed the most dangerous.

You can't control your DNA, but sometimes it can come out with some pretty cute tricks you'd never even think of.

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