Elephants are bringing a genetic gun to a cancer knife-fight.
The longer you live, the higher your chances of developing cancer creep toward 100 percent. Moreover, the larger you are, the greater your chances are of developing cancer as well—more cells in your body mean there are more opportunities for mutations to strike and encourage a tumor to grow. This holds true when comparing individuals within a species (including humans), but the trend falls apart when researchers compare cancer rates between different species—a mystery we call Peto's Paradox. Elephants are some of the biggest mammals who roam the Earth, so mathematically they should be hounded by cancer at 100 times the rate of humans. Yet death by cancer among these eight-ton animals hovers around five percent, compared to 11 to 25 percent of humans. What gives? Is it metabolic rates? Tumors that are able to parasitize other tumors? Certain genes?
Unsurprisingly, the answer comes down to genes. We've known for decades now that the gene that codes for a protein called p53 is a critical tumor suppressor. The protein directs the body's response against damaged DNA and prevents these cells—whose mutations could otherwise confer an ability to proliferate uncontrollably—from dividing. Problems with p53 helps give rise to many different forms of cancer, affecting the brain, colon, liver, bone, and other body parts. We've also known for a few years now that while humans only have one copy of the p53 gene, elephants have a staggering 20, which would help make the cell system much more sensitive to damaged DNA, and prioritize a cell's death over trying to repair that damaged genetic code. Elephants are bringing a genetic gun to a cancer knife-fight.
However, cancer is not driven by one or two single factors, but rather an entire web of systems that act in concert to encourage or suppress cancer. And so it turns out it's not just the cadre of p53 genes that give elephants such aggressive protection against cancer. One of the teams responsible for the p53 study went on to determine that another gene, called LIF6, gives elephants an even more unique advantage against cancer.
“We were curious if elephants had more copies of genes that have tumor suppressor functions, including LIF which is a known tumor suppressor gene,” says Vincent Lynch, an evolutionary biologist at the University of Chicago and a co-investigator of the new findings, reported in Cell Reports this week. “We zeroed in on LIF6 because, as far as we can tell, it is the only extra copy that is functional. All the other copies are dead.”
He means “dead” metaphorically. Here's the story: All mammals carry an LIF gene, which codes for something called leukemia inhibitory factor, a cell-signaling protein involved inhibiting cell differentiation. Humans, like most mammals, have one copy of the gene.
Elephants, as you probably guessed, carry multiple copies — 10, to be precise. It took 80 million years of evolution to create these multiple copies, but the newer versions lack a specific slice of DNA that can turn the gene on, which means they're just sitting there, as good as, well, dead. More formally, you can call them pseudogenes.
Anyways, at some point in the elephant species evolution, one of these gene copies, LIF6, inexplicably turned back on, for reasons yet unknown. DNA analysis from fossils shows that mastodons and mammoths retained LIF6, and Lynch expects the gene turned on when the p53 copies evolved and started their own party.
Lynch and his coauthors decided to call LIF6 a “zombie gene” since its resurrection has allowed it to function as something of a killer of living cells. “At this point, we debated calling it a Lazarus gene,” says Juan Vazquez, a graduate researcher in Lynch's lab and the lead author of the study. “But 'zombie gene' just seemed more appropriate.”
In elephants, when a cell mutates, the contingent of genes that controls p53 gets activated. The presence of those proteins turns on LIF6, and those LIF6 proteins end up blitzing cell mitochondria and allowing toxic molecules to spill out into the rest of the cell, speeding up death.
This sort of genetic resurrection an extremely rare occurrence in general, says Vazquez, especially for a gene whose function is to kill cells. “If it wasn't for the very specific nature of its expression—being regulated by p53—LIF6 probably would've ended the individuals carrying the zombie gene before it could pass it on to its offspring.”
Joshua Schiffman, a pediatric oncologist at the University of Utah who has also studied cancer in elephants and was not involved with the study, thinks the results are fascinating. “I had not heard of a zombie gene prior to this, and it's exciting to see it connected to this p53 mechanism we've previously studied. This reanimation of LIF6 occurred perhaps over 59 million years. That's an amazingly long period of time for nature to modify and perfect an anticancer mechanism.”
But he does emphasize the findings need validation before they can truly be celebrated. Because we can't just observe LIF6 and its proteins in action within a living elephant itself, the team was forced to only make observations within the cells themselves, in a laboratory setting, and the behavior of these proteins could vary in some key ways in nature. Moreover, there might very well be other genes that affect the function and role of LIF6.
“p53 is needed for LIF6 expression,” says Vazquez. “However, we also saw that lowering LIF6 levels did not lower the amount of cell death proportionally, which tells us that it's not the only way that p53 kills these cells in response to DNA damage.”
Lisa Abegglen, a cancer researcher also based at the University of Utah, also points out a few concerns with some of the study's methodological details, like the high concentrations of drugs used to induce DNA damage and activate p53, and wants to see more robust data that links LIF6 to DNA damage induced apoptosis. But like Schiffman, she thinks this study is a great start.
The most tantalizing part of the results is in figuring out what they might mean for fighting cancer in humans. It's too early to figure out how specifically LIF6 could be used to combat cancer in humans, but Schiffman thinks the new findings “offer up another avenue of research, another piece of the puzzle, in how nature decreases cancer, and could help us in finding creative ways to treat and perhaps one day prevent cancer.” A drug that mimics the LIF6 function, for example, would be a boon to cancer treatment and prevention.
“There are so many potential mechanisms contributing to the longevity of elephants,” says Schiffman. The results are another small expansion of the scope of possibilities available to us in combating cancer in the future.