Elephant cancer resistance linked to ‘zombie’ gene
A gene present but inactive in many species has been revived by the world’s largest land mammal – to very good effect. Ben Lewis reports.
Elephants possess a weaponised zombie gene that protects them from cancer by preventing rogue cells from forming, according to new research published in the journal Cell Reports.
The discovery, made by a team led by geneticist Vincent Lynch from the University of Chicago in the US, goes a long way to answering one of the great questions of biology: Why don’t elephants get cancer as often as other animals?
They should get cancer. During cell division, genetic mutations can creep in due to mistakes in the replication of the DNA, and a large, long-lived animal has a much larger number of cell divisions than a small, short-lived one. And yet, even with 100-times more cells than a human, elephants remain almost cancer-free.
Many mammals have multiple copies of a cancer-suppressing gene named LIF, and in most cases, those genes are non-functioning. But elephants (Loxodonta africana), Lynch and his colleagues discovered, have evolved with one of those copies brought back from the dead.
That gene, LIF6, responds to DNA damage such as that caused by mistakes during cell division, or by ultraviolet rays, killing those poised to become cancerous.
To investigate the elephant’s prodigal cancer-resistance, the researchers first looked towards their smaller relatives, such as the manatee (Trichechus senegalensis) and groundhog-sized hyrax (Procavia capensis).
Using cells from elephant and its smaller relatives, the researchers looked to see if there was an inherent difference in the way that elephant cells responded to cancer-causing DNA damage.
What they saw was a rapid suicide by the elephant cells, while the others continued to survive.
“The elephant cells just died,” says Lynch. “They were entirely intolerant of DNA damage in a way their relatives' cells were not.”
“Because the elephant cells died as soon as their DNA was damaged, there was no risk of them ever becoming cancerous.”
But that then led to a new question – just what caused the elephant cells to commit suicide so quickly?
Examining the animal’s genome, the researchers noticed several copies of the LIF gene, which is known to produce a protein that acts as to suppress tumour growth. However, nearly all of them were inactive, missing critical parts that prevented them from being used by the cell.
Apart from one.
Taking a close look, they noticed that LIF6 had been brought back from the dead and was available to the cell.
Blocking LIF6 in the elephant cells made them survive with DNA damage the same way non-elephant cells did, while producing it in cells of animals with inactive LIF genes – such as mice – caused them to immediately die after sustaining damage.
That, say the researchers, points directly to LIF6 as the reason for the elephant’s oncological resistance.
When Lynch and his team investigated the evolution of LIF6, they found that it had most likely been refunctionalised. In other words, the animal had faced selection pressures that brought it back from the dead. At some point in the development of the modern elephant, the gene had been reactivated, and that, say the researchers, could have been the advantage needed to allow elephants to increase in size.
But elephants aren't the only animals that have evolved cancer resistance.
“Species like whales, bats, and naked mole rats don't have these zombie LIF genes, which means that they have evolved cancer resistance using a different strategy, and that there are many ways animals can combat cancer,” Lynch explains.
Earlier this year researchers at the University of Utah, US, also identified three other genes likely involved with elephant’s cancer-free lives: FANCL, VRK2 and BCL11A. These genes are involved in DNA repair, and suggests that the elephant’s resistance to cancer may involve evolutionary several advantages.
The researchers now hope that they can manipulate human cells to reactivate cancer-suppressing genes.
“Maybe we can find ways of developing drugs that mimic the behaviours of the elephant's LIF6 or of getting cancerous cells to turn on their existing zombie copies of the LIF gene,” says Lynch.