Cells in our body have built-in mechanisms to be healthy, to correct errors, and to divide and grow to optimum size and make more copies of themselves. Each of these processes is strictly governed. But what if something goes wrong due to external insults, such as smoking, or high doses of radiation? Cancer is one such result, wherein the DNA in the cells is damaged, leading to non-stop multiplication and formation of uncontrolled large masses of tumour tissues, debilitating organs in the body. There are relevant genes and their proteins in the cells which attempt to resist such tumour growth. A gene called TP53 is one such. It is when these check and control mechanisms are tampered with that cancer results.
Peto’s Paradox
Let us also note that cell division is not error-proof. The more cells there are in a body, the more chances there are for such errors to occur — the growth error can override the protective mechanisms. Thus, if every cell has an equal chance of going cancerous, elephants which have many billions of cells in their bodies would be expected to have greater chances of getting cancer than us humans. But it turns out that elephants (with a typical body mass of around 4,800 kg) are found to have a cancer rate of 5–8%, compared to 11–25% in us humans. This is also true of whales (40,000 kg); they seldom get cancer. And the 600 kg manatees, also called sea ‘cows’ (because they are vegetarians, and live on water plants in tropical seas) too seldom get cancer. On the other hand, a mouse, which hardly weighs a few grams, is 3 times more likely to get cancer than us humans. Thus, there seems more an inverse correlation between body mass and cancer probability. This inverse relationship was first noticed by Dr. Richard Peto of Oxford University about 70 years ago, and has come to be known as Peto’s Paradox. Since then, quite a few scientists have been trying to unravel the reason behind this riddle.
A possible explanation to this paradox comes from studying the genome (the entire collection of genes in the body) of organisms. Over the course of evolution, animals such as mice, humans, manatees and mammoths have gathered a large number of genes. Many of these genes are active and generate the materials necessary for the functioning of the organisms. But if one looks at the genome carefully, one finds that anywhere between 2–20% of the DNA in the genome is hardly used at all. They are just there, not coding for any RNA or proteins, but accumulated as evolutionary, ancestral heritage or baggage. Biologists have impolitely called them ‘junk DNA’. (It is estimated that over 97% of the genetic sequence in the human genome is ‘junk’). Many of these do not carry a ‘promoter’ to activate them to function. If one were to activate these ‘non-coding genes’ by some mechanism, there could be extra functions that the cell might acquire.
Waking ‘zombie’ genes
It is this ‘waking up’ of such ‘sleeping DNA’ sequences that appears to be responsible for the remarkable ability of elephants to not get cancer. This suggestion has recently been made by a group at the University of Chicago, led by Dr. Vincent J Lynch, titled “A zombie LIF gene in elephants is upregulated by TP23 to induce apoptosis in response to DNA” (and published in Cell Reports 24, 1765-76, August 14, 2018; those interested in the paper may access it at https://doi.org/10.1016/j.cellrep.2018.07.042). By the way, the word ‘zombie’ is used here to describe a silent, sleeping gene, called LIF, in the elephant genome. Why zombie? This goes back to the folktale in the country Haiti, wherein a corpse is brought alive through voodoo or black magic, mainly for manual labour. (On an aside, it would have been better to call LIF a Kumbakarna gene. In some versions of Ramayana, Ravana’s brother Kumbakarna went off to a deep, long-lasting slumber, thanks to a spoonerist mistake he made, but had to be woken up to fight the war and he did, making Sugriva unconscious. Kumbakarna was not a corpse, but just sleeping!)
The Chicago authors found that in the elephant genome, the silent gene LIF was ‘woken up’ by an anti-cancer protein molecule called p53. The gene LIF (which is known as leukemia inhibitory factor) acts against damage to the DNA in cells, which are damaged and thus become cancer-prone. And, the elephant genome has 10 copies of the LIF gene; compare that with just one copy that we have. Once it is woken up, LIF begins its job of looking out for cells in the body whose DNA might have been damaged, making them cancer-prone. It then works with some partner proteins to kill off such damaged cells. This process is induced by the protein p53 (which is coded by the gene TP53), which is also known as an anti-cancer molecule. Elephants have 20 copies of TP53; compare this with just one copy that we humans have. In effect, elephants have reduced cancer risk by evolving extra tumour-suppressor genes.
Given that the zombie/Kumbakarna gene LIF can be upregulated, and thus lead to protection against cancer in pachyderms, should we not try and do this in humans? Sure enough, several teams are already thinking about it, once the Chicago team’s paper appeared. There is a Lasker or Nobel prize waiting for this feat.
dbala@lvpei.org
