Cancer research: Zombie genes and elephants

An intriguing deep dive into elephant genetics helps explain why they are less susceptible to cancer than humans. The answer comes in the form of a reanimated "zombie gene."

Around 17 percent of people die from cancer, but the disease is not a problem restricted to humans; it affects a wide range of species.

From cats and dogs to fish and Tasmanian devils — even duck-billed dinosaurs seem to have been afflicted.

Interestingly, under 5 percent of elephants in captivity die from cancer. This is surprising because they live for an average of 70 years and have roughly 100 times as many cells.

Living a long life and having more cells can make cancer more likely to appear. This is due to the fact that each time a cell divides, its DNA is copied, which increases the possibility of errors. As these errors mount up over a long life, cancer is more likely to develop.

The more cells you have, the more opportunities that cancer has. For instance, taller people have a slightly higher cancer risk than shorter people, and the overall number of cells in their body may be part of the reason why.

So, within a species, the number of cells correlates with a greater cancer risk, but between species, this correlation does not appear. This is referred to as Peto's paradox, named after the cancer epidemiologist Richard Peto who first described this conundrum in the 1970s.

Understanding just what makes larger species more resilient to cancer is both interesting and important; if we can understand how elephant cells outfox tumors, perhaps we can use that knowledge to help reduce humanity's odds of cancer.

Elephant DNA damage control

In 2015, scientists working independently at the University of Chicago in Illinois and the University of Utah in Salt Lake City made a breakthrough in understanding elephants' resilience to cancer.

In humans and many other animals, a gene called p53 works as a tumor suppressor; it identifies DNA damage that has not been repaired and triggers cell death. In this way, cells that have the potential to turn rogue are nipped in the bud.

When scientists looked at elephant genomes, they found that they carry at least 20 copies of p53. In comparison, most animals, including us, carry just one copy. The elephant's extra copies mean that cells with damaged DNA are identified and destroyed more swiftly and efficiently.

Wanting to build on this surprising finding, a team from the University of Chicago recently published a new paper in the journal Cell Reports. The study outlines a second part to the puzzle, explaining further how elephants appear to be able to prevent the development of cancer.

Its authors describe an anticancer gene that has come back from the dead. As senior study author Vincent Lynch, Ph.D., an assistant professor of human genetics, explains, "Genes duplicate all the time. Sometimes they make mistakes, producing nonfunctional versions known as pseudogenes. We often refer to these dismissively as dead genes."

The rise of the zombie gene

When investigating p53 in elephants, they found that a pseudogene known as leukemia inhibitory factor 6 (LIF6) was no longer a pseudogene and had "come back to life;" it had "evolved a new on-switch."

The revived function of LIF6 provided another piece of the puzzle; once activated by p53, LIF6 can respond to damaged DNA by attacking and killing the cell. It does this by producing a protein that punctures mitochondrial membranes, thereby destroying the cell's power supply and swiftly killing it.

"This dead gene came back to life. [...] This is beneficial because it acts in response to genetic mistakes, errors made when the DNA is being repaired. Getting rid of that cell can prevent a subsequent cancer."

Vincent Lynch, Ph.D.

This zombie gene appears to have been helping elephants evade cancer for a long time: from 25–30 million years ago. "We can use the tricks of evolution to try to figure out when this defunct gene became functional again," Lynch explains.

They surmised that the LIF6 gene got turned back on at roughly the same time that the elephant's groundhog-sized distant relatives started growing in stature. Genetic mutations such as this may have helped elephants evolve into the behemoths they are today.

"Large, long-lived animals must have evolved robust mechanisms to either suppress or eliminate cancerous cells in order to live as long as they do and reach their adult sizes," explains study co-author Juan Manuel Vazquez.

The findings are intriguing; not only do they provide new insight into cancer, they also give us a glimpse into the evolution of the elephant. Next, the team plans to investigate LIF6, focusing on exactly how it triggers apoptosis.