Why Blue Whales Don't Get Cancer - Peto's Paradox

Cancer is a creepy and mysterious thing. In the process of trying to understand it, to get better at killing it, we discovered a biological paradox that remains unsolved to this day: Large animals seem to be immune to cancer, which doesn't make any sense. The bigger a being, the more cancer it should have. To understand why, we first need to take a look at the nature of cancer itself.

(Kurzgesagt intro music)

Kurzgesagt in a Nutshell. Our cells are protein robots made out of hundreds of millions of parts. Guided only by chemical reactions, they create and dismantle structures, sustain a metabolism to gain energy, or make almost perfect copies of themselves. We call these complex chemical reactions pathways. They are biochemical networks upon networks, intertwined and stacked on top of each other. Most of them can barely be comprehended by a single human mind and yet they functioned perfectly... Until... they don't.

With billions of trillions of reactions happening in thousands of networks over many years, the question is not if something will go wrong, but when. Tiny mistakes add up until the grandiose machinery gets corrupted. To prevent this from getting out of hand, our cells have kill switches that make them commit suicide. But these kill switches are not infallible. If they fail, a cell can turn into a cancer cell. Most of them are slain by the immune system very quickly. But this is a numbers game. Given enough time, a cell would accrue enough mistakes, slipped by unnoticed, and begin making more of itself.

All animals have to deal with this problem. In general, the cells of different animals are the same size. The cells of a mouse aren't smaller than yours. It just has fewer cells in total and a shorter lifespan. Fewer cells and a short life means a lower chance of things going wrong or cells mutating, or at least it should mean that. Humans live about 50 times longer and have 3,000 times more cells than mice, yet the rate of cancer is basically the same in humans and in mice. Even larger blue whales, with about 3,000 times more cells than humans, don't seem to get cancer at all, really.

This is PETO'S PARADOX: The baffling realization that large animals have much, much less cancer than they should. Scientists think there are two main ways of explaining the paradox: evolution and hyper tumors.

Solution one: evolve or become a blob of cancer. As multicellular beings developed 600 million years ago, animals became bigger and bigger, which added more and more cells and hence more and more chances that cells could be corrupted. So the collective had to invest in better and better cancer defenses. The ones that did not died out. But cancer doesn't just happen. It's a process that involves many individual mistakes and mutations in several specific genes within the same cell. These genes are called proto-oncogenes, and when they mutate, it's bad news.

For example, with the right mutation, a cell will lose its ability to kill itself. Another mutation and it will develop the ability to hide. Another and it will send out calls for resources. Another one and it will multiply quickly. These oncogenes have an antagonist, though; tumor suppressor genes. They prevent these critical mutations from happening or order the cell to kill itself if they decide it's beyond repair. It turns out that large animals have an increased number of them.

Because of this, elephant cells require more mutations than mice cells to develop a tumor. They are not immune but more resilient. This adaptation probably comes with a cost in some form, but researchers still aren't sure what it is. Maybe tumor suppressors make elephants age quicker later in life or slow down how quickly injuries heal. We don't know yet.

But the solution to the paradox may actually be something different.

Hypertumors. Solution 2: Hypertumors. Solution 2: Hypertumors (Yes). Solution 2: Hypertumors (Yes, really). Hypertumors are named after hyperparasites: the parasites of parasites. Hypertumors are the tumors of tumors.

Cancer can be thought of as a breakdown in cooperation. Normally, cells work together to form structures like organs, tissue, or elements of the immune system. But cancer cells are selfish and only work for their own short-term benefit. If they're successful, they form tumors; huge cancer collectives that can be very hard to kill. Making a tumor is hard work, though. Millions or billions of cancer cells multiply rapidly, which requires a lot of resources and energy.

The amount of nutrients they can steal from the body becomes the limiting factor for growth. So the tumor cells trick the body to build new blood vessels directly to the tumor, to feed the thing killing it. And here, the nature of cancer cells may become their own undoing. Cancer cells are inherently unstable and so they can continue to mutate. Some of them faster than their buddies.

If they do this for a while, at some point one of the copies of the copies of the original cancer cell might suddenly think of itself as an individual again and stop cooperating. Which means, just like the body, the original tumor suddenly becomes an enemy, fighting for the same scarce nutrients and resources. So the newly mutated cells can create a hypertumor. Instead of helping, they cut off the blood supply to their former buddies, which will starve and kill the original cancer cells. Cancer is killing cancer.

This process can repeat over and over, and this may prevent cancer from becoming a problem for a large organism. It is possible that large animals have more of these hyper tumors than we realize; they might just not become big enough to notice. Which makes sense: a two-gram tumor is 10% of a mouse's body weight, while it's less than 0.002% of a human and 0.000002% of a blue whale. All three tumors require the same number of cell divisions and have the same number of cells.

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 don't know. Scientists are working on the problem. Figuring out how large animals are so resilient to one of the most deadly diseases we know could open the path to new therapies and treatments.

Cancer has always been a challenge. Today, we are finally beginning to understand it, and by doing so, one day we might finally overcome it.