Massive animals may hold secrets of cancer suppression – Peto’s Paradox

by Sibongiseni Msipa

Cancer is a creepy and mysterious thing. While we tried to understand it, to get better at killing it, we discovered a biological paradox that remains unsolved to this day: large animals are immune to cancer. Which does not make any sense – the bigger a being, the more cancer it must have. To understand why, we first need to look at the nature of cancer itself.

To understand the nature of cancer we must first understand how cells work. cells are the basic units that make up the human body. they are made from hundreds of millions of parts. Guided by chemical reactions, they build and break down structure, sustain metabolism to gain energy or make copies of themselves. These complex chemical reactions are called pathways. Pathways are biochemical networks upon networks, which intertwined with each other, and function perfectly – until they do not. With these billions of reactions occurring in thousands of networks over many years, the question is not “if” something will go wrong but when? Tiny mistakes accumulate in the DNA of cells until this “perfect” network of systems gets corrupted. To prevent this from happening our cells have kill switches that make them commit suicide when cells are corrupted, however these kill switches are fallible. If they fail a cell can turn cancerous. Given enough time a cell would accrue enough mistakes, slip by unnoticed and begin to make more itself. All animals face this ordeal.

In general, the cells of all animals are the same size. The cells of a mouse are not fewer than yours, it just has fewer cells in total and a shorter lifespan. Fewer cells and a short lifespan mean a lower chance of things going wrong or cell mutating, – or at least it should mean that. Humans live about 50 times longer and have more cells than mice, yet the rate of cancer in humans and mice is the same. Even weirder blue whales have even more cells than humans, but they do not seem to get cancer at all. This is known as Peto’s Paradox.

Peto’s paradox is the baffling realization that larger animals have much less cancer than they should. Evolutionary biologists think that this results from larger animals using protective mechanisms that many smaller animals do not have. To identify how large animals might foster such mechanisms, evolutionary biologists created a theoretical model to simulate which of 100 possible genetic-mutation strategies would become most prevalent over 4,000 generations. The model included two gene types, Tumour suppressor and proto-oncogenes. The latter when mutated is bad news. For example, with the right mutation a cell will lose its ability to kill itself, another mutation and it will develop an ability to hide, another and it will send out a call for resources and multiply quickly. These genes, however, have an antagonist, known as tumour suppressor gene.

Tumour-suppressor genes, repair cellular damage that could otherwise lead to cancer. They found that tumour-suppressor genes and proto-oncogenes react differently along a gradient of body masses. In this model, evolution always favoured tumour-suppressor genes in large animals. Proto-oncogene activation decreased steadily with increasing body mass; the team found. Because of this, whales require more mutation than mice to develop a tumour, they are not immune but more resilient.

Or the solution to this Paradox may be something different; Hyper tumours. Hyper Tumors are named after hyperparasites, the parasites of parasites, hyper tomours are Tumour-within-a-tumour. Unlike normal cells which work together, cancer cells are selfish and work for their own short-term benefit, when successful, these cells form tumours these are huge cancer collectives which are hard to kill.  These cancerous cells require a lot of energy and resources to continue multiplying rapidly. Therefore, the amount of energy needed by these cancer cells becomes its growth limiting factor.  To counter this the body is tricked into building new blood vessels directly to the tumour, to feed the thing killing it. This is where the nature of cancer cells may become its undoing. Because of how unstable they are they continue to mutate and if they do this for a while one of the copies of the copies of the original cancer cell might suddenly think of itself and stop cooperating and just like that the original tumour suddenly becomes an enemy and blood supply is cut off to the original tumour – this starves and kills the original cancer cells. Cancer is killing Cancer. This process can repeat repeatedly, this then prevents cancer from becoming a problem in large animals. It is possible that large animals have more of these hyper tumours than we realize, they might just not become big enough to notice. So, an old blue whale might be filled with tiny cancers and just not care.

There are other proposed solutions to Peto’s Paradox, such as different metabolic rates or different cellular architecture, but right now we just do not know. Figuring out how large animals are so resilient to this deadliest disease; we might open up a path to new therapies and treatments. Cancer has always been a challenge but today we are finally beginning to understand it and by doing so we will finally overcome it.

References

Nagy, D., Victor, M. & Cropper H. (2007) Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox. Integrative and Comparative Biology, (47)2, pp 317–328

Gewin, V. (2013) Massive animals may hold secrets of cancer suppression. Nature, https://doi.org/10.1038/nature.2013.12258

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