Scientists searching for novel ways to fight cancer think they may have uncovered a promising new lead tucked away inside the cells of the bowhead whale.
The findings, published in the journal Nature, are part of a growing field examining the ways that long-lived animals like the bowhead manage to keep on trucking without being felled by malignant cells.
In cancer biology, there's a conundrum known as Peto's paradox: Large animals have lots of cells, which in theory should mean more chances to develop cancer. And long-lived organisms have more time to acquire the mutations needed to transform healthy cells into cancerous ones.
And yet — "that's not what happens," says Vera Gorbunova, a biologist at the University of Rochester. "It suggests that these large and longer-lived animals have additional protections from cancer that they evolved."
Gorbunova and her colleagues now say that they've found one such protection in the bowhead whale, a long-lived leviathan. These animals utilize a protein — which they produce in abundance — that excels at repairing broken DNA.
"Instead of eliminating malignant cells," says Gorbunova, "they maintain their cells better so they don't accumulate as many mutations."
Vincent Lynch, an evolutionary biologist at the University of Buffalo who wasn't involved in the study, argues the findings may one day have broader applications. "The translation to human health and disease is really complicated," he says, "but you might be able to develop a treatment that mimics what we learn from other species."
Living two human lifetimes
In other work, researchers have found that elephants have their own approach to reducing the risk of cancer. They have 20 copies of a tumor suppressor gene, which is sometimes called the "guardian of the genome." It produces a protein called p53. Humans have just one copy.
This protein helps eliminate cells that turn pre-cancerous and start growing abnormally. "[The] p53 protein can trigger cell death," says Gorbunova. "Cells would commit suicide." This protein can also initiate DNA repair and keep cells from dividing.
With more copies of this gene, the thinking goes, elephants eliminate more potentially problematic cells, and keep their cancer rates down.
Gorbunova and her colleagues wanted to take the research to an extreme. "We decided: What if we look at whales that are even larger than elephants?" she says.
They set their sights on bowhead whales. They're not the biggest cetaceans out there but Gorbunova says they are the longest lived, with animals capable of surpassing 200 years of age. This is something the Alaskan Inuit have known for generations — according to one account, local whaling captains have told biologists that these animals live two human lifetimes.
Scientists have confirmed the observation by examining proteins in the eye lenses of the whales and dating harpoons embedded in the flesh of these animals.
Gorbunova was especially interested in bowheads because "I can tell you that there were no reports of malignant tumors," she says.
She got in touch with the Iñupiaq community of Barrow, Alaska, who hunt bowheads for subsistence. "They use their traditional methods like rowboats to harvest a very small number of whales every year," she says. "They very kindly agreed to share very small pieces with us so we could do our research. So all this would not have been possible without the generosity of Alaskan Inuit whalers."
In fact, Gorbunova says that in the future, this research might benefit the Inuit, a community grappling with rising cancer rates.
A little protein with a big impact
With fresh bowhead tissue in hand, Gorbunova and her team began their experiments. She figured that since bowheads are bigger than elephants, maybe they just had even more copies of the tumor suppressor gene that makes p53.
"But that's not what we found," she says with a chuckle. "We can build some hypothesis but then nature proves us wrong."
The researchers considered what else the whales might be doing to avoid cancer. "Maybe they don't allow the cells to accumulate mutations in the first place," says Gorbunova. "Just don't let things deteriorate to where the cell needs to be eliminated."
Such a strategy might involve, Gorbunova thought, better DNA repair, since breaks in DNA can be dangerous and lead to cancer. That turned out to be the case.
"Humans are pretty good at repairing DNA breaks," says Gorbunova. "But whale was even better than human — almost like two to three times better. They were not losing pieces of DNA. They were fusing the ends correctly."
The bowheads derive this ability, at least in part, from a protein called CIRBP (which stands for cold-inducible RNA-binding protein). Gorbunova says it's way more abundant in bowhead cells than in other species and it's produced by a gene that's activated by the cold.
She explains the logic this way: "For a bowhead whale that can live for more than two centuries, maintaining healthy cells by repairing damage may be more advantageous than killing those cells off, like an elephant does. The strategy of the whale is to invest in maintenance rather than clean up."
When the researchers caused human cells to overproduce the protein, those cells repaired DNA breaks more efficiently. And when they caused live fruit flies to make a lot of the protein, "they started living longer and they also became more resistant to DNA damage," says Gorbunova. "The most important take home message for us humans is that there is room for improvement."
She says that boosting the level of this protein in humans might one day help slow down the rate at which our cells accumulate mutations. "If we understand the mechanism of longevity in this exceptionally long-lived mammal," she argues, "maybe we can find a way to clinically translate this mechanism to benefit human health."
An ocean of possibilities
Amy Boddy, an evolutionary biologist at UC Santa Barbara who didn't participate in the research, found the results impressive and helpful for those in comparative oncology, a field focused on cancer and tumor formation, growth and suppression across species.
"We want to be able to treat cancer better in humans," she says. "And so it's really exciting to know that animals have evolved different pathways to live long and defend against cancer, tested through evolution."
In addition, drawing connections between possible advances in human health that long-lived animals may gift us could pack a powerful conservation message, argues Boddy, who studies elephants, among other species. That's especially true for animals that are vulnerable to extinction, she adds. "We should protect against poaching because they are these amazing, magical creatures that can maybe one day help human health."
Still, Boddy points out that with any anti-cancer strategy, there's bound to be compromise. "What these whale cells are doing is fixing damage," she says. "But what's the trade off in that? Because there must be a lot of energy and investment."
Lynch, who wasn't involved in the research either, finds the results convincing and suggests they're just the beginning. He believes that animals like bowhead whales and elephants (not to mention some anomalous smaller organisms like bats and naked mole rats) have likely evolved additional ways to keep cancer at bay.
"We have literally uncovered a handful of the mechanisms that are responsible for their cancer resistance," he says. "There's going to be a whole lot more to identify, which is cool because it gives us something to do."
Gorbunova says this is the power of looking beyond typical lab animals like mice and fruit flies. "If we only study very short-lived organisms, we cannot really find longevity mechanisms because they don't have them," she says.
In contrast, whales and elephants appear to have much to teach us from their many years on this planet.
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