LIF6 in the Exceptional Cancer Suppression of Elephants
Elephants and whales are in their own way just as interesting a target of study for cancer researchers as naked mole-rats. Cancer risk is a numbers game, based on incidence of mutation and capacity of cancer suppression mechanisms to destroy cancerous cells before they can form a tumor. Given that elephants have many more cells than humans, but a lower rate of cancer, what are the differences in cellular biochemistry that explain that outcome? Might any one or more of those differences form the basis for therapies in human medicine? It is a little early to say at this stage whether or not the comparative biology of cancer will lead to meaningful advances in control over human cancer, but a number of lines of research are underway in this part of the field.
An estimated 17 percent of humans worldwide die from cancer, but less than five percent of captive elephants - who also live for about 70 years, and have about 100 times as many potentially cancerous cells as humans - die from the disease. Humans, like all other animals, have one copy of the master tumor suppressor gene p53. This gene enables humans and elephants to recognize unrepaired DNA damage, a precursor of cancer. Then it causes those damaged cells to die. Unexpectedly, however, researchers found that elephants have 20 copies of p53. This makes their cells significantly more sensitive to damaged DNA and quicker to engage in cellular suicide.
Now, researchers describe a second element of this process: an anti-cancer gene that returned from the dead. "Genes duplicate all the time. Sometimes they make mistakes, producing non-functional versions known as pseudogenes." While studying p53 in elephants, researchers found a former pseudogene called leukemia inhibitory factor 6 (LIF6) that had somehow evolved a new on-switch. LIF6, back from the dead, had become a valuable working gene. Its function, when activated by p53, is to respond to damaged DNA by killing the cell. The LIF6 gene makes a protein that goes, quite rapidly, to the mitochondria, the cell's main energy source. That protein pokes holes in the mitochondria, causing the cell to die.
LIF6 seems to have emerged around the time when the fossil record indicates that the small groundhog-sized precursors of today's elephants began to grow bigger. This started about 25 to 30 million years ago. This supplementary method of suppressing cancer may have been a key element enabling enormous growth, which eventually led to modern elephants. Bigger animals have vastly more cells, and they tend to live longer, which means more time and opportunities to accumulate cancer-causing mutations. When those cells divide, their DNA makes copies of itself. But those copies don't match the original. Errors get introduced and the repair process can't catch up. "Large, long-lived animals must have evolved robust mechanisms to either suppress or eliminate cancerous cells in order to live as long as they do, and reach their adult sizes."
Link: https://www.eurekalert.org/pub_releases/2018-08/uocm-zgp080818.php
If p53 works well in mammals, the following study might be interesting: create transgenic mice with multiple copies of p53 and see what happens. If it really works we might start adding extra copies during stem cells therapies in humans.
Having an error correction is much more powerful
than error prevention. During the early history of communication and computers, the error correction was non -existant , and even the specialists doubted that many layers or complex systems are possible at all. Our modern storage media (hard druve, SSD, CD, DVD, Blu-ray) heavily rely on error correction techniques. In fact, the biggest improvments of the last years in the flash drives is in algorithms and controllers to allow use of, frankly, crappy chips with high error rate with a decent error correction, which result in acceptable reliability as a whole.
Since error avoidance or prevention becomes exponentially more difficult the higher fidelity you want to achieve, it quickly becomes impossible. So even a modest error correction can do wonders.
The same principle applies to the cancer. It becomes increasingly harder to avoid cancer by taking the metabolism and prevention alone. It is much easier to do some repair, error correction, and if that fails simply detect the problem and kill the pending cell.
We have
several quite imperfect error correction mechanisms. P53 is en vogue st the moment. But we also have dna repair, anticancer immune system and, probably, a few others. I have the gut feeling that not all cancers can be stopped by p53 alone, even if it worked perfectly. But it will help with more than 90% of the cases...