Why don’t elephants get cancer? The curious case of TP53
Elephant Side Profile, Simoneemanphotogrpahy via Envato
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There aren’t many great scientific stories that start with a trip to the zoo, but this family outing certainly made a big impact on the world of cancer research, in more ways than one.
In our previous story we raised the issue of Peto’s paradox - namely that we would expect large long lived animals that are made of lots of cells that have lots of opportunity to multiply to get more cancers then small animals, whereas in reality the opposite is true. The story of one species’ solution to the problem starts a few years back with Josh Schiffman, a children's cancer doctor working at the University of Utah.
Some of the families that Josh and his team were caring for had a condition called Li-Fraumeni syndrome, which is caused by an inherited alteration in a gene called TP53, sometimes known as the ‘guardian of the genome’. TP53 encodes a protein called p53, obviously enough, which helps to protect against cancer. When the DNA in cells gets damaged, p53 swings into action triggering a cascade of events that either end up in the cell repairing any damage to its DNA or dying through a process called apoptosis - a kind of cellular suicide - in order to protect the rest of the organism.
We all have two copies of TP53, one from mum and one from dad. But people with Li-Fraumeni syndrome only have one functional copy, meaning that their cells struggle to repair DNA damage effectively. As a result, they have a very high risk of developing cancer, often starting at a young age and suffering from multiple different cancers over their lifetime.
While Schiffman was working with these individuals whose lack of p53 led them to have an incredibly high chance of getting cancer, he started wondering what role p53 might be playing in species at the other end of the spectrum - namely those that don't seem to get many cases of cancer at all.
A few weeks later he's visiting Utah’s Hogle zoo with his family, and they're checking out the elephant show. During the course of the demonstration, the elephant keepers explain that once a week at the zoo they draw blood from the veins in the African elephants’ ears to make sure that their charges are healthy. When Schiffman hears that, his ears instantly prick up.
“How can I get me some of that elephant blood?”
Immediately after the show he heads over to the keepers and explains that he's a paediatric oncologist but to bear with him. He tells them about Li-Fraumeni syndrome, and about Peto’s paradox, and he says that he has a question. Intrigued the elephant keeper says, “Go ahead, we love questions - what's yours?” Straight away, Schiffman replies, “My question is: how can I get me some of that elephant blood?”
Several months of paperwork later, including scientific and ethical review, and Schiffman finally gets his hands on the prized elephant blood, rushing it back to the laboratory to try and understand why elephants don't get cancer. After carrying out genetic testing and experiments on elephant cells grown in the lab they make an intriguing finding.
Whereas humans have two copies of a single version of the TP53 gene - one from mum and one from dad - African elephants have a staggering 20 different versions of the gene, making 40 copies in total. One version is the original, with the extra 19 having arisen as a result of genetic shenanigans some time in the elephant’s evolutionary history, with genes getting copied and pasted around the genome by accident.
Looking more closely at the elephant cells, Schiffman and his team discovered that when the cells experienced DNA damage, rather than stopping to repair it, the elephant cells rapidly underwent apoptosis far more frequently than human cells, preferring to die rather than try and fix the damage. This makes sense if you're an organism as big as an elephant.
As Schiffman told me when I interviewed him about his work a few years back, "Listen. It's so important that we don't develop cancer. We can't take any chances. If we stop the cell from dividing and we try to repair it, we might make a mistake and we might let a few of these mutations go on by and turn into cancer. But if we just kill the cell and get it over with then there's no way that cell can go on and cause cancer. We're elephants - we have plenty more cells where that came from. We'll just start over."
At the same time that Schiffman and his team published their findings in the Journal of the American Medical Association in October 2015, another team of scientists at the University of Chicago, led by Vincent Lynch, also published a paper showing paper showing the same thing: not one but 20 different versions of TP53 in the African elephant genome.
Intrigued by when this duplication might have happened - and if it had anything to do with the evolution of the elephant’s mighty size - Lynch and his team compared the number of copies of TP53 in African and Asian elephants with DNA sequences from preserved remains of three long-gone giant elephant ancestors: the American mastodon, woolly mammoth, and Columbian mammoth.
As might be expected, all these species had the regular TP53 gene. But while the African elephant had 19 extra versions, the Asian elephant had around 12–17, and their relatively recent relatives the Columbian and woolly mammoth boasted around 14 copies. However, there were just 3–8 in the American mastodon genome - a smaller species that lived around 50,000–130,000 years ago and split off from the ancestors of elephants roughly 25 million years ago. This is a pretty good indicator that being able to evolve an enormous body size, for elephants at least, is linked to having extra copies of TP53 in your genome.
So far, so fascinating. But that’s not the end of the story.
‘Zombie genes’ and cancer risk
A couple of years later, a graduate student in Lynch’s lab - Juan Manuel Vazquez - discovered that elephants also have nine extra copies of another gene, called LIF, lurking in their genome.
Like the extra copies of TP53, these bonus versions of LIF have ended up scattered through the elephant genome as a result of genetic copying and pasting sometime back in the evolutionary history of the species. In most cases this has resulted in what's known as pseudogenes, so-called ‘zombie genes’ that are effectively dead or dormant because they don't have the control switches around them necessary to turn them on and off.
However, there was a notable exception. One of these nine extra LIF genes, known as LIF6, happened to have landed next to the ‘on switch’ for another gene, allowing it to become activated again. Not only that but the on switch is responsive to p53, so when a cell is damaged p53 switches on LIF6 and triggers the cells self-destruction pathway. Using genetic engineering techniques to knockout the LIF6 gene made the elephant cells less sensitive to DNA damage, although only slightly, suggesting that there are other cancer protection mechanisms at work in these gigantic animals.
There's another final twist in this tale. While having extra copies of genes like TP53 and LIF seems to have been very useful for elephants in enabling them to grow large, live long, and avoid cancer it doesn't seem to be a mechanism that's used by other large long-lived animals such as whales. Instead, it seems that each species has evolved to solve Peto’s paradox in its own way - a menagerie of malignancy that we can learn from.
Studying cancer - and cancer resistance - in other species allows us to open nature’s toolbox, revealing the recipes and ingredients that have evolved over millions of years to produce different cancer defence mechanisms and modify risk. In turn, this helps us to gain deeper insights into the vulnerabilities in our own human cells and how we might one day overcome them.
