For an animal that’s 100 times the size of a human, elephants have remarkably low rates of cancer – much, much less than would be expected for an animal with so many active and dividing cells. Dubbed Peto’s Paradox, scientists noted this phenomenon decades ago, but have been unable to answer why until now. Two recent studies, independently published, point to the solution: Elephants have 20 copies of the well-known TP53 tumor suppressor gene. This makes their cells more sensitive to DNA damage and quicker to commit cellular suicide. This discovery has rightly captured the public attention, and additional details can be found in the New York Times and Nature.
Vincent Lynch, PhD, assistant professor of human genetics, led one of the studies, which has now shed light on the functional and evolutionary reason why elephants so rarely get cancer. He and his team studied TP53 in elephants and over 60 other species, including whales, birds, fish, humans and even extinct mammoths and mastodons. Although their study, available on the open-access preprint server BioRxiv, answers many questions about the nature of cancer in elephants, it also raises many more. ScienceLife thought we’d ask Lynch a few.
How did you get involved in studying elephant cancer?
Vincent Lynch: I was just curious. There is a paradox in biology first noted by Richard Peto: large bodied and long lived organisms like elephant and whales should have lot more cancer than small, short lived organisms such as voles and mice, but there is no correlation between body size or lifespan and cancer rates. Why not?
So what is TP53 and how are extra copies helping elephants prevent cancer?
TP53 is the ‘master guardian’ of the genome, and one of a class of genes called tumor suppressors. These genes monitor DNA damage within cells, and should they detect it cause the cell to stop dividing. If the cell is able to repair the damage TP53 allows the cell to go about it’s normal business, but should that repair take too long (an indication that there is a lot of DNA damage) p53 induces the cell to undergo a process called apoptosis – essentially making the cell commit suicide rather than risk that DNA damage causing cancer.
Why did you look at this in so many other species, including mammoths and mastodons?
We wanted to be sure that our observation, that elephants had so many extra copies of p53, was really an elephant-specific trait. For example, imagine only African elephants had extra copies of p53 and Asian elephants had the expected 1 copy. Then the increase in p53 copy number couldn’t have allowed the evolution of large body sizes in the elephant lineage because the evolution of large bodies would have predated the evolution of extra p53 copies. In contrast, we found that the increase in p53 numbers evolved with the increase in body size suggesting they are casually related.
ScienceLife editor’s note: Watch a video on Lynch’s previous work, on mapping the woolly mammoth genome, below.
Is there a downside to having so many copies of TP53?
There almost has to be because there are no free lunches in evolution. Everything has a cost. The fact that only elephants, of all the species we examined, had extra copies suggests there is a tradeoff between evolving enhanced cancer protection by duplicating p53 and something else. What that something else is is unclear, but previous studies that generated transgenic mice with very active copies of p53 reported mice age prematurely. Clearly, however, elephants either found a way to pay the cost or a way to avoid it all together.
So do the headlines match the reality – do elephants hold the “key to curing cancer?”
Sadly no. But if we can understand the ways in which evolution has solved the cancer problem then maybe we can use that knowledge to treat cancer. At the very least it will help us understand cancer biology better, and that is essential for curing cancer.
But you did put one version of elephant TP53 into mouse cells and found that it cause elephant-like sensitivity to DNA damage. What should people take away from that?
We did, but not into living mice. We transferred one of the extra p53 genes from elephants into mouse cells that we grow in the lab, we then measured how well they dealt with DNA damage. Remarkably, these mouse cells responded to DNA damage in an elephant like way, meaning as soon as we induced a little damage they committed suicide like the elephant cells. This simple experiment suggests that however these extra copies of p53 work, it is transferable.
You put your study out on BioRxiv, which is completely open access and isn’t peer reviewed, before it’s published in a traditional journal. How come?
We put our manuscript on bioRxiv, an open access repository for scientific manuscripts, because the current process of peer review is extremely slow and, to be honest, no longer makes sense. Were we to submit to a traditional journal, the process of repeated peer review could be longer than a year, during which time three anonymous colleagues would read our manuscript, critique our experiments and our interpretations of those experiments.
By publishing in bioRxiv anyone can critique our work, including all of my colleagues. Thus instead of three eyes checking our work for errors, potentially hundreds of people will do so. Finally, unless the journal was open access, our paper would not be freely available once published. Now, anyone can go to bioRxiv and view our work for free… while it is in peer review at a journal that is!