Why don’t elephants get cancer?
A new genetic study shows they have genes with special powers to fix mutated DNA — and humans have slightly different versions of the same genes.
The report, published in the journal Cell Reports, could open the door to helping people fight cancer better in the future.
And the team at the University of Utah found a batch of other animal traits that shed light on human genetics.
For instance, a stretch of DNA that gives bats their distinctive pointy ears can, when mutated, cause an ear deformity in people called Stahl ear. Another mutation can also cause fused fingers in people, but may have helped bats evolve their unique wings.
And humans share genes that give ground squirrels their distinctive stripes. In people, mutations of those genes can cause Noonan or Leopard syndrome, marked in part by distinctive freckle-like spots.
Geneticist Christopher Gregg and colleagues were not looking for anything in particular in their study.
"We were working on the elephant as a positive control in our study and we discovered parts of the genome that were important for nose development," Gregg said.
"I thought that’s very funny to find in elephants, since they have these long noses."
He chatted with a colleague at Utah, Dr. Josh Schiffman, who is a pediatric oncologist and who suggested that Gregg take a different tack.
"He had been studying why elephants don’t get cancer," Gregg said.
"This is a master regulator of DNA repair."
It's a question that has bothered biologists for years. Cancer is linked with extreme body growth. Very tall people have a higher risk of some cancers, and tumors are formed by the out-of-control growth of some cells.
But elephants are far less prone to cancer than humans are, even though they are much bigger and live very long lives.
In 2015, Schiffman found that elephants have 20 copies of a gene called p53, well known for its ability to fix damaged DNA, which can lead to cancer. Humans have only one.
Now Gregg's study showed a possible way to discover more.
"He said, 'Chris, why don’t you check in your data to discover if there are any more secrets that explain why elephants don’t get cancer?'" Gregg said of Schiffman.
Gregg's team found a big one.
It was a network of genes that all mammals, including humans, have called the Fanconi anemia pathway.
"The elephants had just radically changed it," he said.
"This is a master regulator of DNA repair," Gregg said. "People with mutations in that gene pathway have very high rates of cancer."
Elephants appear to have extra elements in their genetic complex. The team tested elephant immune cells, zapping them with radiation and looking to see which genes became active. Elephant immune cells quickly repair damage to other DNA — an important mechanism for preventing cancer.
Studying these genes further in humans might lead to new ways to fight cancer, the team proposed.
"They were good candidates for why the elephant has this superpower of getting very low rates of cancer," Gregg said.
Humans share much of their genetic code with other animals, from fruit flies and worms to dogs and apes. And sometimes the precise genetic function doesn’t have much to do with evolutionary similarities.
For instance, many of the genes that cause diseases in humans can be found in macaque monkeys but not in chimpanzees — the nearest living relative to humans.
Gregg's team had a formula for making good comparisons among the genomes of humans and other animals, finding regions that have taken markedly different paths in certain species.
"Once we recognized that the method worked, we started applying it to other animals that have really interesting and distinctive traits," Gregg said.
They did what’s called a genome wide association study — sequencing all the DNA — in a bunch of animals, including elephants, bats, orcas, squirrels, dolphins and naked mole rats.
They looked for stretches of shared DNA that different species had in common with each other and with people that might provide insights into health and development.
"We looked at bats, which are the only mammals adapted for flight," Gregg said.
"We discovered new parts of the human genome that bats have changed that are candidates for developing these wings."
And the ear finding was intriguing, too. "None of us knew what Stahl ear was. We had to all get on Google and figure out what is Stahl ear and then it all makes sense, because it causes those funky ears," he said.
Naked moles rats live underground in big colonies and are blind, and changes in their vision genes might point researchers to how the visual system developed, Gregg said.
"Once we recognized that the method worked, we started applying it to other animals that have really interesting and distinctive traits."
They also looked at dolphins and orcas — mammals that have evolved to live in water. "They can do deep dives underwater and hold their breath for very long periods of time," Gregg said.
"They must have some way of carrying more oxygen in their blood," he hypothesized.
If humans try holding their breath for too long, they can change the blood chemistry and develop blood clots.
It turns out orcas and dolphins have changes in the genes involved in the production of erythropoietin, a hormone that stimulates production of red blood cells, which carry oxygen. "We are interesting in following that up," he said.
Now it will take years of hard laboratory work to see if the genes really do what the team thinks they do.
"We need to do real functional studies in the lab with human cells and animal models to test these elements," Gregg said. "Do they really prevent cancer? Do they really shape ear morphology?"