The following information is taken from a story that appeared in Qanta Magazine, a publication devoted to illuminating basic science and math research. The story by Viviane Callier, “A Zombie Gene Protects Elephants From Cancer,” was reprinted on wired.com on November 12, 2017.
Gene mutations and cancer
Let’s start with cells. Animals, including humans, are made up of millions, billions, or even (in the case of humans) trillions of cells. We know from basic biology that cells grow and divide, and in the process each new cell contains a copy of its entire genome. However, copies are subject to error (if you ever tried to make a Xerox of a Xerox, then repeat it with another Xerox from the second one, and so on, the quality of the final document will be somewhat degraded from the original). Errors result in cell mutations, which are a bit like natural experiments. Some are beneficial (e.g. enhanced immunity), some are neutral (e.g. blue eyes), and some are harmful (e.g. sickle cell anemia). Some genes that are broken due to copy errors, or that no longer serve a survival function, remain in the genome and are called “pseudogenes” – a kind of genetic junk. In many cases, cells that carry errors are programmed to die off, so mutated cells never make it to the stage where they duplicate themselves. However, some mutations can lead to cancer, and cancer cells have the ability to override the “die-off” programming.
Common sense suggests that the bigger the animal, the greater number of cells—and therefore the greater chance of developing cancer. However, in the 1970s an Oxford University professor, Richard Peto, identified a paradoxical phenomenon: the bigger the animal, the less incidence of cancer. Elephants have a 4.8% death rate from cancer, while humans have an 11-25% cancer mortality rate.[i]Since then, scientists have been trying to explain why elephants and other large-bodied creatures appear better protected against cancer.
Elephants seem like a good place to start. Elephants weren’t always huge. They have smaller relatives on the family tree that include armadillos, aardvarks and even a small mammal called a hyrax that never evolved into large creatures – but about 30 million years ago, elephants branched off and began evolving into the giants we know them as today.
The genome of modern elephants offers two possible explanations for why elephants rarely get cancer:
- Their genome has over 20 copies of a tumor suppressor gene, p53, that helps control potentially cancerous cells by programming them to die off.
- According to the Callier article, “elephants and their smaller-bodied relatives … also have duplicate copies of the LIF gene, which encodes for leukemia inhibitory factor. This signaling protein is normally involved in fertility and reproduction and also stimulates the growth of embryonic stem cells.” The copies appear to be incomplete and unable to perform any known function, so they may be some old genetic junk (pseudogenes). However, a copy called LIF6 seems to have a binding site for p53, when can activate LIF6. Experiments showed that when activated, LIF6 plays a role in programming the death of cells with DNA damage that makes them precancerous.
Researchers hypothesize that LIF6 was also a pseudogene, but that natural selection had preserved it without accumulated mutations or errors – as if it were in deep storage. Then, around 30 million years ago, or roughly the same time period when elephants began gaining species size, it came back into play. This theory that LIF6 “came back from the dead” earned it the nickname “zombie gene.” Other elephant relatives also have extra copies of LIF, but none of them have LIF6, suggesting that it was resurrected only after elephants branched away from the ancestors of aardvarks, armadillos, hyraxes, etc. In addition, only elephants carry the p53 gene, another factor that sets them apart from their more diminutive cousins. It seems that by protecting elephants from cancer, they were able to eventually become giants.
We are learning a lot from elephants, but more research needs to be done. Whales also have low rates of cancer and cancer death. They carry LIF and p53, but it’s unknown how – or even if – these genes help maintain cancer resistance in the ocean giants. A very small creature, the bat, is also under study. Some bat species live for 20-30 years, with low cancer mortality. What is their secret?
Many questions remain unanswered. One thing is certain: the more we understand how nature protects some animals against cancer, the greater our potential to one day protect ourselves from this disease.
[i] Abegglen LM, Caulin AF, Chan A et al. Potential mechanism for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA. 2015;314(17):1850-1860.