Around noon one August day in 2011, a familiar dorsal fin rose from the sea off the coast of Massachusetts. Flecked with tiny white scars, it belonged to Salt, a female humpback whale who scientists had been studying since the 1970s and who was named for those distinctive markings.
Aboard the research vessel Shearwater, Jooke Robbins—director of humpback whale research at the Center for Coastal Studies in Provincetown, Massachusetts—loaded a crossbow with a dart, modified with a specialized tip and yellow float, and took aim. The bolt went flying. It hit its target but, by design, bounced harmlessly off the whale’s bulk, taking with it only a few cubic millimeters of flesh—almost like a mosquito bite, relative to the whale’s size.
Robbins and her team collected the sample, preserved it in liquid nitrogen, then sent it away to be analyzed. Now, eight years later, a team supported by the Arizona Cancer Evolution Center (ACE) at Arizona State University has discovered that Salt and other cetaceans—the group of mammals that includes whales, dolphins, and porpoises—evolved clever ways of dealing with cancer, including an array of tumor-suppressing genes. The team published its findings in May in the journal Molecular Biology and Evolution.
The findings, along with similar work on elephants, suggest that somewhere, hiding in the genetic code and evolutionary history of large mammals, there could be a new cancer treatment for humans. But if the researchers are correct, their window to study these megafauna may be closing as humans continue to threaten the animals’ populations and the biodiversity of their habitats.
That whales like Salt had value was never in doubt for Robbins. There are many valid reasons to conserve large mammals, from ethical to ecological. But the idea that their genes could be useful for cancer research was a new one for her.
“I did not think years ago that one of the things we would be studying with this population would be cancer, in general, let alone any kinds of cancer implications for humans,” she said. “It’s unexpected, and very valuable, but I never would have planned it.”
In theory, large, long-lived creatures like Salt should have high cancer rates. At its core, cancer begins when a cell splits—it divides incorrectly, the potentially fatal mutation spreads to neighboring cells, and, if left unchecked, throughout the body.
Compared to humans, whales and elephants can have hundreds of times the number of cells—and have similarly long natural lifespans—but their cells mutate, become cancerous, and kill them less frequently. This quirk of nature, which the ACE team is studying, is called Peto’s Paradox, named for Richard Peto, a British epidemiologist. In the late 1970s, he proposed that there must be some kind of natural selection for cancer suppression, because humans live longer and are much larger than mice, but the species have similar rates of the disease.
In 2011, ACE researchers, along with scientists at 11 other institutions worldwide, first started looking at how Peto’s Paradox manifests itself in the genomes of humpback whales by comparing the information in Salt’s genes to those of other cetaceans. According to the results reported this year, the parts of a whale’s genome that determine how and when a cell splits evolved quickly and coincided with when the animals grew to their enormous size. Marc Tollis—a biologist at Northern Arizona University’s School of Informatics, Computing, and Cyber Systems who joined and began leading the ACE study in 2015—hopes that taking one of the amped up, cancer-fighting whale genes and putting it in the body of a smaller creature will help the latter fight off these cellular mutations: a mouse as a test, a human as a hopeful end result.
Other scientists are also studying Peto’s Paradox in a different group of huge animals: elephants. In 2012, Joshua Schiffman, a pediatric oncologist at the University of Utah, began investigating cancer defenses in the animals after learning that they had extra copies of a gene responsible for fighting off tumors. It was this same gene that his patients with Li-Fraumeni syndrome, a rare hereditary disorder that predisposes sufferers to cancer development, lacked.
Collaborating with ACE’s Carlo Maley, Schiffman and his team worked with local zoos and the Ringling Bros. and Barnum & Bailey Circus—before the circus ceased using elephants in its acts—and its Center for Elephant Conservation to gather blood samples during regular checkups with veterinarians. In their 2015 paper in the Journal of the American Medical Association, they reported that the elephants’ extra copies of this tumor-squashing gene triggers a type of programmed cell death and a defense against cancer called apoptosis. When a cell splits and experiences some kind of DNA damage—from chemical agents, for example—the cell will either try to fix itself, or self destruct to prevent the mutations from spreading to other cells. Both whale and elephant cells are also likely to undergo apoptosis more often compared to humans.
“People are smart, but nature is much smarter,” said Schiffman. “Nature has figured out the solutions to some of our health problems over hundreds of millions of years of evolution.”
It’s clear elephants and whales have managed to find their resistance to cancer over countless generations, Schiffman added. His team is also looking for other cancer defenses in elephant genetics and trying to transfer this phenomenon to humans.
“What’s even more exciting than that [these animals] found the cure,” he added, “is that, through nature, they evolved ways to prevent cancer in the first place.”
So far, 22 of the 90 or so existing cetacean species have had their genomes sequenced and added to the National Center for Biotechnology Information database, with more being added all the time. When Tollis began working on Salt’s genome in 2015, there were only five. The field moves quickly, he said, with new technologies making the process cheaper and easier.
Scientists have also sequenced the genomes of all three elephant species alive today. While it’s a start, scientists may not have enough data to get a full picture of how the animals thwart cancer. As human activity eats away at these populations—through ecosystem destruction, climate change, and more—researchers get fewer and fewer chances to collect samples. The creatures become harder to find and the regulations protecting them grow tighter, delaying research by years.
Considering the rate these species are in decline, Tollis also hopes the research will also make people consider the importance for both cancer research and the environment.
“Generally, since we’re living in a mass-extinction event right now,” he said, “we need every reason for conservation we can get.”
The conservation status of these large mammals is a mixed bag, according to data from the International Union for Conservation of Nature (IUCN), which, among other projects, tracks population health of the world’s animals. Some whale species, like the humpback, have recovered from centuries of hunting while others, like the North Atlantic right whale and Sei whale, are still endangered. African and Asian elephants are listed as vulnerable and endangered, respectively.
Recently, Botswana lifted its five-year ban on elephant hunting and Japan resumed commercial whaling in July. However, conservation experts are even more concerned with habitat loss and other less violent, but thoroughly insidious dangers to the species.
Elephants suffer as their former stomping grounds are turned into industrial areas or farmland, which also leads to “human-elephant conflicts,” said Chris Thouless, strategic advisor with Save the Elephants, a research and conservation organization based out of Kenya.
In the ocean, whales are increasingly put at risk by marine microplastics and noise from shipping, said Hal Whitehead, a cetacean specialist with the IUCN. Cetaceans use sound to hunt for food and form social bonds, as neither sight nor smell work particularly well under water, and the noise stresses out the creatures.
“The species which have been hit the worst are those with the closest contact with humans,” Whitehead added.
Even if these species’ populations recover, there are other challenges for collecting genetic data from a wealth of species. A sample from only one animal isn’t necessarily representative of an entire species, said David Baillie, a molecular biologist at Simon Fraser University in Burnaby, British Columbia.
While having an accurate, representative genome of a species gleaned from many samples is valuable, so too are some of the oddities that can arise in the genomes of individuals. Genetic diversity and large population numbers leave a good deal of wiggle room for mutations that could benefit both the creature and—further down the line and with the right understanding—humans.
“The more genomes we have, the better we come to understand the residual diversity that underlies the population structure,” Baillie wrote in an email to Undark. He added that rare mutations “can be very important when trying to understand disease resistance, for example.”
There’s evidence that points to robust genetic variation between regional groups within the same species, and more effort is needed to catalog the genes of an animal’s distant cousins, Tollis said. Similarly, according to Schiffman, poaching, habitat loss, and inbreeding have caused a bottleneck that has stifled genetic diversity in many species—and among the world’s largest creatures in particular.
According to Cristiana Pașca Palmer, executive secretary at the UN’s Convention on Biological Diversity, the impact of habitat and species loss on medical research more broadly is still unknown.
“The loss of large species like elephants and whales is just a microcosm of the cataclysmic species diversity loss happening in ecosystems the world over,” she wrote in an email. “Really, when we act to preserve biodiversity, we are acting to preserve ourselves.”
It’s also unknown how, over generations, human activities are changing these animals’ genomes, and the potentially useful data they hold. Research out of the University of Southampton in the UK suggests the median size of mammals will shrink by a quarter as humans continue to pave over untamed habitats, for example. As the genetics of the world’s animals adjust to humanity’s tightening grasp on the planet, the genes a species use to defeat any number of diseases and other valuable mutations could be, effectively and inadvertently, bred out of existence.
“If we lost the opportunity to study these animals in the wild, and if we don’t protect them,” Schiffman said, “we could be losing cures for many different diseases to come.”
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