Elephants and other large animals have a lower incidence of cancer than would be expected statistically, suggesting that they have evolved ways to protect themselves against the disease. A new study reveals how elephants do it: An old gene that was no longer functional was recycled from the vast “genome junkyard” to increase the sensitivity of elephant cells to DNA damage, enabling them to cull potentially cancerous cells early.

In multicellular animals, cells go through many cycles of growth and division. At each division, cells copy their entire genome, and inevitably a few mistakes creep in. Some of those mutations can lead to cancer. One might think that animals with larger bodies and longer lives would therefore have a greater risk of developing cancer. But that’s not what researchers see when they compare species across a wide range of body sizes: The incidence of cancer does not appear to correlate with the number of cells in an organism or its lifespan. In fact, researchers find that larger, longer-lived mammals have fewer cases of cancer. In the 1970s, the cancer epidemiologist Richard Peto, now a professor of medical statistics and epidemiology at the University of Oxford, articulated this surprising phenomenon, which has come to be known as Peto’s paradox.

The fact that larger animals like elephants do not have high rates of cancer suggests that they have evolved special cancer suppression mechanisms. In 2015, Joshua Schiffman at the University of Utah School of Medicine and Carlo Maley at Arizona State University headed a team of researchers who showed that the elephant genome has about 20 extra duplicates of p53, a canonical tumor suppressor gene. They went on to suggest that these extra copies of p53 could account, at least in part, for the elephants’ enhanced cancer suppression capabilities. Currently, Lisa M. Abegglen, a cell biologist at the Utah School of Medicine who contributed to the study, is leading a project to find out whether the copies of p53 have different functions.

Yet extra copies of p53 are not the elephants’ only source of protection. New work led by Vincent Lynch, a geneticist at the University of Chicago, shows that elephants and their smaller-bodied relatives (such as hyraxes, armadillos and aardvarks) also have duplicate copies of the LIF gene, which encodes for leukemia inhibitory factor. This signaling protein is normally involved in fertility and reproduction and also stimulates the growth of embryonic stem cells. Lynch presented his work at the Pan-American Society for Evolutionary Developmental Biology meeting in Calgary in August 2017, and it is currently posted on biorxiv.org.

Lynch found that the 11 duplicates of LIF differ from one another but are all incomplete: At a minimum they all lack the initial block of protein-encoding information as well as a promoter sequence to regulate the activity of the gene. These deficiencies suggested to Lynch that none of the duplicates should be able to perform the normal functions of a LIF gene, or even be expressed by cells.

But when Lynch looked in cells, he found RNA transcripts from at least one of the duplicates, LIF6, which indicated that it must have a promoter sequence somewhere to turn it on. Indeed, a few thousand bases upstream of LIF6 in the genome, Lynch and his collaborators discovered a sequence of DNA that looked like a binding site for p53 protein. It suggested to them that p53 (but not any of the p53 duplicates) might be regulating the expression of LIF6. Subsequent experiments on elephant cells confirmed this hunch.

To discover what LIF6 was doing, the researchers blocked the gene’s activity and subjected the cells to DNA-damaging conditions. The result was that the cells became less likely to destroy themselves through a process called apoptosis (programmed cell death), which organisms often use as a kind of quality control system for eliminating defective tissue. LIF6 therefore seems to help eradicate potentially malignant cells. Further experiments indicated that LIF6 triggers cell death by creating leaks in the membranes around mitochondria, the vital energy-producing organelles of cells.

To find out more about the evolutionary history of LIF and its duplicates, Lynch found their counterparts in the genomes of closely related species: manatees, hyraxes and extinct mammoths and mastodons. His analysis suggested that the LIF gene was duplicated 17 times and lost 14 times during the evolution of the elephant’s lineage. Hyraxes and manatees have LIF duplicates, but the p53 duplicates appear only in living and extinct elephants, which suggests that the LIF duplications happened earlier in evolution.