Lucky old Dumbo! Elephants and their cancer resistance

 

Elephant
“Waaahheeeyyy!”

Evolution has come up with a pretty nifty trick to control cancer development in larger animals, by stocking up on important genes.

 

 

Okay, get your pencil out

There are an estimated 37.2 trillion cells in the human body, each cell will divide approximately 50-70 times in its lifetime, and each time must correctly copy somewhere in the region of 3.2 billion nucleotides – the “letters” the genetic code is written in. Is your head hurting yet? In essence, there is a HUGE potential for little mistakes which give rise to genetic mutations, which, if not caught, accumulate and eventually can give rise to cancer. Cancer is a genetic disease that is caused by the accumulation of mutations in genes that are critical for our cells. While some of these mutations can be inherited, the vast majority of them are either random copy mistakes or caused by DNA mutating agents (mutagenic chemicals, UV light, asbestos, etc.).

Given this mathematical element, one could logically speculate that in larger animals (increased number of cells), or with increasing life span (more cellular divisions), that the risk of cancer would increase. Many people have pondered this issue and it’s been termed the “Peto paradox” (after Richard Peto, a Professor of Medical Statistics and Epidemiology, University of Oxford). “Paradox” because it doesn’t stand true. In truth, there is actually no trend where increased animal size leads to an increased cancer risk. Although we’ve known about this paradox for a while, we have had no actual evidence to answer the question of why.

Recently, two independent research groups published their work investigating this and came to very similar conclusions. While the human risk of dying due to cancer is something around 25%, only around 5% of elephant deaths are due to cancer. It looks like this is because elephants have an increased number of p53 genes.

p-whaaat? 

Okay, lets reverse a little.

We commonly use two terms to describe genes which are important in cancer:
“Oncogene” and “Tumor Suppressor”.

An Oncogene is a gene that drives cancer, normally these oncogenes aren’t activated, they are in a “normal” form, sometimes termed proto-oncogenes. They behave themselves. On the other hand, a Tumor Suppressor, as the name suggests, suppresses or inhibits cancer development. Normally, these are fully functional and keep us safe from cancer, but if lost or dysfunctional, can lead to cancer. You can think of the cell as a car, an oncogene is like pressing down hard on the accelerator – the cellular division drives forward. But, as long as tumor suppressor genes are functional, they act as breaks, the cell is kept in check. Loose the tumor suppressor gene, the breaks are dysfunctional, the accelerator is in overdrive; and you will crash.

Onco.Car
Image courtesy of the National Cancer Institute

p53 is a really important tumor suppressor gene. It inhibits the development of cancer because it checks that DNA replication has been carried out correctly, and if not, if there are mistakes, it stops the cell cycle and makes a choice between attempting repair (if the mistakes are few) or cell death (if the mistakes are abundant). It’s so important that it is often given the rather spiffing nickname “Guardian of the Genome”. People who are born with one defective p53 allele, have a disease called Li-Fraumeni Syndrome, and they acquire lots of cancers at a very early age.

This recent research uncovers the fact that elephants have 20 copies (40 alleles) of this p53 gene in their genome, whereas humans have 1 (2 alleles). The researchers looked at what difference this made, and found that the elephant cells were more sensitive to DNA damage than human cells. Basically, when confronted with the genetic mistakes, they choose cell death (“apoptosis”) more often than attempting repair. This results in a lower “mutation load” overall, and healthier cells. Less mutations = Less cancer.

Worth mentioning, are the possible limitations of these studies. We must always look at science with a critical eye. Firstly, a lot of the elephant disease and death data we have access to is from elephants living in captivity or wildlife reserves, and there is the possibility that in the wild, elephants live longer and hence our cancer data might not be completely accurate.

But altogether, really interesting stuff.

Lucky old elephants!

 
 

 

✉ caitrin.crudden@ki.se
 

For those eager beavers amongst you; further reading can be found here:

The two research papers:

More on Peto and his paradox:

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