With a Thousand Times More Cells Than Humans, Why Don't Whales Get Cancer More?

If you are a US citizen, according to the US government's Surveillance, Epidemiology and End Results Program data from 2010-2012, there is approximately a 40 percent chance that you can expect to be diagnosed with some form of cancer in your lifetime.

As a citizen of the US myself, I don't like those odds—and neither do a lot of scientists, although for reasons that have more to do with statistics than a fear of death.

To put it simply, for creatures of our size, such a high rate of cancer incidence doesn't make much sense. And yes, this statistical anomaly is good news, as it may illuminate new, natural ways for preventing cancer in humans.

Cancer, the catchall term for a disease characterized by the abnormal and selfish reproduction of cells in the body, affects a staggering variety of fauna, albeit at wildly varying rates. Just what accounts for this variation in cancer incidence across species is the subject of some contention, although common sense suggests that organisms with more cells, longer lifespans, and/or a higher metabolic rate would as such be more susceptible to cancer-inducing cell mutations, simply by playing the numbers.

While both humans and whales are mammals—the class of vertebrae which has been suggested to be the most susceptible to cancer—humans exhibit a far higher rate of the disease than their cetacean counterparts, despite whales having approximately 1,000 times more cells than humans and with lifespans that commonly break 100 years (in some instances even surpassing 200 years).

This lack of correlation between body size, longevity, and cancer risk is a conundrum that has become known as "Peto's Paradox." The paradox derives its name from Richard Peto, an epidemiologist at Oxford who first noted that the number of cells in an organism does not appear to be correlated to the rate of cancerous mutations in a 1975 paper published in The British Journal of Cancer.

"I think [Peto's Paradox] is one of these beautiful questions that is simple and precise, yet implies important discoveries that have yet to be made," said Carlo C. Maley, an associate professor of biology at Arizona State University who has been doing research related to the paradox since 2009. "It's been around since the 70s but finally people are addressing it. That's exciting [because] it might reveal mechanisms that translate to doing better cancer prevention in humans."

Despite the intriguing nature of the hypotheses raised in Peto's paper, relatively little work was done to address this emerging paradox until recent years. According to Maley, the surge of interest in this 40-year-old paradox can be attributed to a number of causes, such as the fact that evolutionary approaches to cancer research becoming more commonplace, although perhaps none so much as recent strides forward in genomics.

Maley, who was one of the editors on the June issue of Philosophical Transactions of the Royal Society B which was dedicated exclusively to the paradox, is working on sequencing the genome of the humpback whale in the hopes of discovering what genetic factors are present in whales that allow them to suppress cancers so much more effectively than humans and other smaller mammals.

According to Maley, mammals all have essentially the same genes and this includes the variety of tumor-suppressing genes (called "antioncogenes"). The question then becomes, how have antioncogenes evolved to become so effective in whales, but not in humans? The first step is to simply look for extra copies of these antioncogenes, a redundancy that could help explain the low incidence of cancer in the species.

"It's possible that whales, which don't seem to have a lot of extra copies of tumor suppressing genes, might've optimized them to be better than the human versions," said Maley. "It's [also] quite possible that whales have adapted other genes to be cancer suppressing. We just wouldn't know that because we don't have the experiments to discover it yet."

Maley's research also involves studying elephants, another species with a long lifespan and about 100 times more cells than a human, yet which are not exhibiting a rate of cancer incidence that is 100 times higher than their anthropic counterparts.

While Maley and his team did not notice any telling duplication of genes which might account for low cancer rates among humpback whales, their work with both elephants and whales has revealed other suggestive findings.

Among these is a noticeable selective pressure on some antioncogenes such as ubiquitin, which functions as a "garbage collector for cells" by chewing up and recycling old proteins. In some studies, it has been linked to longevity. According to Maley, these findings suggest that there has been the parallel evolution of ubiquitin in both whales and elephants, although whether or not this is related to cancer suppression is yet to be seen.

Despite a few notable similarities between whales and elephants, it is still the differences that remain the most striking. For instance, elephants have many extra copies of an important tumor suppressor gene called p53, a notable genetic feature that is absent in whales.

"The initial question is: have [whales and elephants] all solved the problem in the same way or have they developed different ways of suppressing cancer?" said Maley. "The picture that is emerging is that elephants are suppressing cancer differently than whales are."

This is both good and bad news for those concerned with solving the paradox, as it can potentially provide a variety of avenues for applying future discoveries to preventing cancer in humans, but also makes the direction of focused inquiry less certain. The primary methodological problem remains in the realm of data collection for both species, which despite advances in genomics is still difficult and time-consuming.

"It's very hard to get cancer incidence data in wildlife, but also in captivity. The records across zoos are not collated and electronically available," said Maley. "There's been a sort of rough, almost anecdotal observations that there aren't particularly large cancer incidences in large organisms, [but] as scientists we want to be on a little bit more firm ground."

Since there is very little data available on the rate of cancer incidence in whales and elephants, it is difficult to say just how much lower their rates are compared to the rate of cancer incidence in humans. (A 2003 study on the high rate of cancer among a certain population of Beluga whales pegged the total number of documented cancer cases among wild whales, dolphins and porpoises at 33.) The important thing, according to Maley, is the fact that elephants and whales are not 100 to 1,000 times more likely to get cancer than humans, despite having 100 to 1,000 times more cells.

"We need a lot more investment in studying cancer in wild animals," he said. "There is virtually nothing happening in that area of research."

There is also the question of just why large mammals like elephants and whales seem to develop more effective cancer suppressing genes than humans or mice, given that improved cancer suppression would seem to be a positive genetic selection for all species.

As it turns out, however, improved cancer-suppressing genes may lead to certain negative health effects in larger organisms, such as decreased fertility. A team of scientists at the Institute of Research for Development modeled 100 possible genetic mutations of proto-oncogenes (which play a role in a cell's transition from "normal" to "cancerous") and tumor-suppressing genes over 4000 generations. What they found is that in mammals of intermediate size, the decreased fertility associated with stronger cancer suppressing genes could actually be disadvantageous to a given population. In other words, the evolutionary cost of keeping cancer in check was greater than the advantages favoring cancer suppressing genes.

Thus, as Maley explained, varying selective pressures on organisms lead to different strategies for reproduction and survival, which belong on a continuum whose poles are fast-life history and slow-life history strategies. The basic idea here is that organisms have a limited amount of energy, which they can either allocate for greater somatic reproduction (fast-life history) or maintenance (slow-life history).

For those species belonging more on the slow-life history end of the spectrum(that's us), genetic selection favors those mutations which produce fewer offspring with the ability to survive and adapt to conditions where resources are restricted. According to Maley, a notable facet of the slow-life history category is the development of cancer suppressing genes, which allow these organisms "to build a body that can last a long time and invest in its offspring," but possibly at the expense of the organism's fertility.

The evolutionary approaches to tackling Peto's Paradox are still in their infancy, yet according to Maley such approaches may hold massive potential for our understanding cancer not only as a disease, but as a "driving force in biological systems."

The first step in this process—finding out how hosts' cancer suppression mechanisms have evolved—is well underway. Once researchers have a better grip on just what genetic factors are at play in preventing cancer in other species, it will be time to bring it to the lab.

The research currently being conducted on natural cancer suppressing mechanisms in whales and elephants is still in the discovery phase, which according to Maley means it will probably be a good 20 years before we seen any of this research being utilized in the clinic. Just what clinical use of this research might look like still remains highly speculative, but Maley can imagine a future in which we can take a drug that effectively "flushes out" mutated cells, similar to what elephants do naturally. Less is known about whales' cancer suppressing mechanisms than elephants' so its difficult to say just how our increasing knowledge of whales' genetics might help humans suppress cancer in the future, but Maley is optimistic on the subject.

"Evolution has spent the last billion years discovering and refining ways to suppress cancer. Each time a large or long lived organism evolved, they discovered a way to do this," he said. "[There are] powerful discoveries that mother nature has already made to prevent cancer and we should be mining them to improve human health."