A blog about microbes, diseases and biomedical research advances. Posts in English or German.
This article was originally published in theGIST Print Magazine (Spring 2016).
Few would call the naked mole rat beautiful. The hairless, small rodent with pale, wrinkly skin and imposing front teeth is often considered one of the ugliest animals on earth. Looks are however not all that counts: naked mole rats have extraordinary qualities that go beyond what meets the eye.
Naked mole rats can live for up to 32 years, longer than any other rodent species, and about 15 times longer than mice or rats. What’s more, they do not develop cancer – ever. These features intrigued scientists, and some are now trying to work out how to use the naked mole rat’s secrets to prevent cancer and slow ageing in humans (without making us all hairless, pale, and wrinkly).
The magic goo
The naked mole rat’s secret started to be unravelled several years ago. Their small size, similar to a mouse, enabled researchers to study the animals in a laboratory environment. Here, they used modern molecular biological techniques to dissect the inner workings of naked mole rat cells – and what they found was remarkable.
When naked mole rat cells were grown outside of the animal’s body, they behaved very differently to mouse cells. Instead of growing in a neat, tightly packed layer as most other cells grown in laboratories do, naked mole rat cells stopped growing before they could fill a cell culture flask. And unlike other animal cells, they secreted a substance that made their growth media go all gooey. As it turned out, this secretion was the key to the naked mole rat’s anti-cancer defence.
The goo was created by a compound made up of a long chain of sugar molecules, called hyaluronan. Hyaluronan is a common ingredient in many organisms’ bodies, including humans, and it works as a connecting and filling agent between cells in tissues. The difference between our hyaluronan and that of the naked mole rat is its size: Hyaluronans found in the animals were exceptionally large, consisting of sugar chains about 5 times longer than in humans or mice. The long chains of hyaluronan could stop the growth of cultured naked mole rat cells before they touched one another and, in this way, prevent the formation of tightly packed, cancerous tumours. By interrupting the cellular hyaluronan factory, researchers could coax formerly cancer-resistant naked mole rat cells into growing more densely in culture. When the scientists injected these hyaluronan-low naked mole rat cells into mice, they readily formed tumours – something that they had never done before.
Perhaps the opposite strategy – increasing long-chain hyaluronan production in humans – could be used to prevent cancers. This idea is still in the early stages, and several hurdles need to be overcome to test it. Researchers first need to work out if long-chain hyaluronan produced by human cells has similar effects on cancer formation as the naked mole rat version of the molecule, and then find a way to either boost its production in our bodies or introduce it from outside. As it turns out, some forms of hyaluronan are already used for treatments on humans, just not in cancer therapy.
Hyaluronan is a common ingredient of anti-ageing creams. As a natural component of our epidermis, it helps to keep skin elastic. The naked mole rat may have evolved a way to keep its supply high because of this property: the animals live underground and their elastic skin is well suited for their constant burrowing through narrow, subterranean corridors – cancer resistance and longevity may just have been an added benefit of this adaptation.
While the naked mole rat’s evolutionary cousin, the blind mole rat, does not share it’s high hyaluronan levels, these digging animals are also long-lived and protected from cancer. When blind mole rat cells are grown in the laboratory, they are happy to grow into a dense, tight cell layer. They are, however, not happy for long: nearly all cells in the culture quickly die a sudden and concerted cell death.
The simultaneous nature of their demise hints that a signal in the liquid surrounding the cells may be responsible for this peculiar behaviour. A signalling molecule, found enriched in the media of densely grown blind mole rat cells, causes this phenomenon: interferon beta. While this compound is part of the anti-virus defense system in humans, it causes blind mole rat cells to self-destruct when they grow too densely, which could be key to preventing the formation of tightly packed cancers in the species.
Naked mole rats and blind mole rats have found different ways to beat cancer and gain longevity, but a shared feature – their underground life – may be closely tied to this development. Both animals are naturally shielded from potential predators by their lives in underground tunnels. Free from the danger of being eaten, the next biggest enemies they needed to battle were age and age-related diseases, such as cancers. While cancer-fighting adaptations would give highly hunted animals, such as mice, little advantage, they could enable ‘protected’ animals to procreate longer – and therefore create more offspring that share the longevity and cancer-protection of their parents.
Extra large protection
Low tumour rates and longevity are not limited to mole rats, and cancer protection is particularly extraordinary in giant animals. Cancers develop when a single cell in an organism goes awry and starts to grow uncontrollably. Within a species, the more cells you have the more likely you are to develop cancer, for example within humans as height increases so do cancer rates. But across species the story is a little different.
Elephants and whales, with their massive bodies made up of trillions more cells than ours, should be much more likely to develop cancer than us, but strangely they are not. In bowhead whales, the longest lived animals with life spans of more than 200 years, cancers have never actually been observed at all. On the other hand, one in three humans will develop cancer in their lifetime. This peculiar phenomenon is called Peto’s paradox.
Working out exactly why Peto’s paradox holds is still an open question, but the key seems to be that for big animals to become big in the first place, they have had to develop ways to protect themselves from cancer. And the better we understand these protections, the more likely we are to be able to find ways to use them ourselves.
New research suggests that in elephants, one protective mechanism involves the well-described “guardian of the genome”, a protein called p53. While humans have two copies of the p53-making gene – one from each parent – elephants have around 40. p53’s normal function is to stop cells from dividing or eliminate them when their DNA gets damaged. In human cancer, both copies of p53 are usually mutated in malignant cells, which allows them to keep multiplying without triggering their inbuilt suicide switch. A mutation in all copies of p53 genes of elephants is very unlikely, resulting in high cancer protection.
The research mentioned here shines a light on some of the perks of evolution. By comparing different species, we could uncover some of the evolutionary paths that lead to longer and healthier lives, and these newly gained insights might be useful in our own fight against cancer and age-related disease. No one knows what wonders still await us in the treasure trove of nature, but some of them may well be successfully used in human medicine in the future. Perhaps, some day, we will value the naked mole rat for helping us further our understanding of cancer – and for giving us a better means to fight the disease or prevent it altogether.