The Mere Existence of Whales

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Strictly speaking, there should be no blue whales.

Blue whales can weigh over a thousand times more than a human being. That’s a lot of extra cells, and as those cells grow and divide, there’s a small chance that each one will mutate. A mutation can be harmless, or it can be the first step towards cancer. As the descendants of a precancerous cell continue to divide, they run a risk of taking a further step towards a full-blown tumor. To some extent, cancer is a lottery, and a 100-foot blue whale has a lot more tickets than we do.

Aleah Caulin of the University of Pennsylvania and Carlo Maley of the University of California, San Francisco, have done some calculations of the risk of cancer for blue whales thanks to their huge size. We don’t know a lot about cancer in blue whales, because blue whale oncology wards would be a wee bit awkward for everyone involved. So Caulin and Maley extrapolated up from humans.

About thirty percent of all people will get cancer by the end of their life. Scientists have been able to build good models for the odds of developing certain forms of the disease. For example, Peter Calabrese and Darryl Shibata of USC put one together last year for colorectal cancer. The colon is made up of a series of pockets called crypts. Inside of each crypt are a few stem cells that continually produce new cells that act as the lining for the colon.Calabrese and Shibata reasoned that the odds of getting colorectal cancer at a certain age depend on the odds of mutation at each cell division, the number of stem cell divisions a person has experienced, how many mutations are required to develop full blown cancer, the number of stem cells in each crypt, and the numuber of crypts in the colon.

Calabrese and Shibata found that their equation churns out results that are close to actual medical records. (Five percent of people get colon cancer by the time they’re ninety.) Their equation doesn’t just match the overall rise in colorectal cancer through life for the population as a whole. It also accurately predicts that tall women are more prone to colorectal cancer than short women–because they’ve got longer colons.

In a review in the journal Trends in Ecology and EvolutionIn a review in the journal Trends in Ecology and Evolution, Caulin and Maley took Calabrese and Shibata’s model and ramped it up to blue-whale scale. They found that the huge size of the animals means that by the age of fifty, about half of all blue whales should have colorectal cancer. By age 80, all of them should have it. It’s likely that blue whales should have far higher rates of other kinds of cancer, too.

Blue whales do get cancer, but it’s hard to believe that they get it at the rates that come out of Caulin and Maley’s calculations. Blue whales are known to live well over a century. Bowhead whales have reached at least 211 years. If blue whales really did get cancer as fast as the models would suggest, they ought to be extinct.

The failure of the model means that blue whales must have some secrets for fighting cancer. “The mere existence of whales suggests that is possible to suppress cancer many-fold better than is done in humans,” Caulin and Maley write.

The mere existence of whales is the most glaring example of what biologists call Peto’s Paradox. There seems to be no correlation between body size and cancer rates among animal species. We run a thirty percent risk of getting cancer over our life time. So do mice, despite the fact that they’re 1000 times smaller than we are. All animals studied so far have cancer rates in that ballpark. (And yes, sharks do get cancer.)

Caulin and Maley argue that when animals evolve to larger sizes, they must evolve a better way to fight against cancer. It’s possible that a blue whale simply has a souped-up version of our own defenses. We have proteins that monitor our cells for over-eager growth, for example; they can kill or zombify cells that on the road to cancer. When the genes for these gatekeeper proteins mutate, a cell becomes more likely to become cancerous. The opposite also seems to be true: Scientists have engineered mice to have extra copies of these gatekeeper genes, and they’ve found that the animals become more resistant to tumors.

Caulin and Maley suggest that nature has carried out this experiment as well. We have one copy of a gatekeeper gene called TP53, for example. Elephants–which are at a greater risk for cancer–have a dozen copies of the same gene.

Other defenses might include a more powerful immune system that can destroy new tumors. Big animals may have also lost some genes that make them particularly prone to developing cancer. And anatomy itself can offer a defense, Caulin and Maley point out. As the cells in each colon crypt divide, for example, the older ones get pushed up to the top and get sloughed off. As a result, there are few steps from stem cell to the final cell in a lineage. With fewer steps, we run a lower risk of developing cancer. Bigger animals may have evolved even more effective architectures.

It’s also conceivable that big animals enjoy defenses to cancer merely by being big. Big animals have a lower metabolic rate for their weight than smaller animals. With a lower metabolic rate, big animals produce fewer harmful byproducts that can cause mutations. One pretty wild benefit of being big has been proposed by John Nagy and his colleagues: big animals can kill cancer with cancer. Nagy’s idea is that tumors can develop “hypertumors”–cancer cells that parasitize their fellow cancer cells. Hypertumors would slow down their host tumors, making them less harmful to an animal. And since big animals can handle bigger tumors, their bodies would allow cancer enough time to develop hypertumors. It’s an interesting idea, but Caulin and Maley note that it has yet to be tested.

Then again, few of the other ideas they offer have been tested yet. But Caulin and Maley lay out a roadmap for doing so. Scientists could look at closely related species that span a big range of sizes, searching for telling differences in their cancer defences. Whales and dolphins would be a good pick, since blue whales are 2,000 times bigger than the petite Commerson’s dolpin.

But such an undertaking would have to overcome a lot of inertia in the world of cancer research. Cancer biologists don’t look to big animals as models to study–which is one reason there’s not a single fully-sequenced genome of a whale or a dolphin for scientists to look at. For most cancer researchers, mice are the animals of choice.

But if we want to find inspiration for cancer-fighting medicines, mice are the last animal we’d want to consider. It’s like learning how to play baseball from a bench-cooler at a Little League game, when Willie Mays is waiting to dispense his wisdom.

[Update: various typos fixed, and a link to the paper added.]