Why Elephants Don't Get Cancer--and What That Means for Humans
10/22/2015, Alexander Nazaryan, Newsweek
Every police officer knows he might have to save his partner’s life. Few will have to do so in the manner of Nick Belliveau, a 28-year-old cop in the small northern California town of Sebastopol.
Belliveau works with a German shepherd named Frank, an energetic 7-year-old who does what Belliveau calls “find-and-bite kind of work.” Nestled in the gentle hills of wine country, Sebastopol is generally a calm place, but it has its cast of small-time crooks. Once, in February 2014, about an hour before midnight, Belliveau encountered one of these when he tried to accost a belligerent drunk in an alley behind a bar. The drunk, swinging a bottle, proved difficult to subdue, so Belliveau pressed a button that released Frank from the squad car. The German shepherd sprinted toward the two men and promptly clamped down on the suspect’s hand, breaking it. That quickly ended the struggle.
Though Frank is a weapon, he is also a pet who comes home with Belliveau at the end of each shift. Last winter, Belliveau’s wife was running her hands through Frank’s thick mane when she noticed a “big old lump under his neck.” This could mean many things, none of them auspicious. Belliveau took Frank to a veterinarian, who ran some tests and placed him on antibiotics.
We asked readers to submit via social media their questions about what studying cancer in animals can mean for humans. The two experts in our story weighed in. You can view the reader questions and expert responses here.
The antibiotics did not help. Belliveau was working a graveyard shift several days later when his wife called. Frank was lethargic, eating nothing, cowering in a corner of the garage. This was uncharacteristic behavior for a dog who otherwise brims with energy; when Belliveau makes a traffic stop and leaves Frank back in the car, the barking is incessant. This was not a meek dog. Something was amiss.
Belliveau rushed home and took Frank back to the vet. This time, the German shepherd was diagnosed with lymphoma, a cancer of white blood cells whose telltale sign is enlarged lymph nodes. Belliveau now faced several options, including doing nothing. But if he did nothing, Frank would die, quickly. The most promising course of treatment involved 19 weeks of chemotherapy. This would cost $10,000, more than three times what Frank had cost the Sebastopol Police Department.
“I didn’t really think twice about it,” Belliveau told me as we rode around in his patrol car through the crisp Northern California night. Frank had once saved him; now it was his turn to save Frank. The Sebastopol Police Department told him it could defray some of the costs, but that departmental funds would probably not be able to cover the full cost of the chemotherapy. So Belliveau turned to the Internet.
When I met him in February, he told me he’d made about $20,000 through the online appeal. This seemed to please and stun him. Many of the donors, Belliveau says, shared a common trait: They too had owned dogs who had suffered from cancer. Dogs are highly susceptible to cancer, with certain varieties of the disorder plaguing certain canine breeds. For example, the shaggy Bernese mountain dog is routinely felled by histiocytic sarcoma, while the puffy chow chow is one of several breeds prone to oral melanoma. Canines’ plight highlights the deep genetic roots of cancer: breeding dogs for certain traits, like a golden mane or elongated snout, inadvertently passes other, undesirable, genetic traits from generation to generation, with cancer effectively piggybacking on the good looks we associate with pure breeds. Similar forces work on humans too: For example, women of Ashkenazi background are at increased risk for breast cancer stemming from the BRCA genetic mutation.
But while some dog breeds routinely get cancers, others do not. In their bookZoobiquity: The Astonishing Connection Between Human and Animal Health, the evolutionary biologist and cardiologist Dr. Barbara J. Natterson-Horowitz and science journalist Kathryn Bowers note that beagles and dachshunds are relatively cancer-free. Natterson-Horowitz and Bowers write that “these extra-healthy dog breeds may point to behaviors or physiology that offer cancer protection.” What those behaviors or mechanisms may be, we do not know.
Lately, Breen has been trying to map canine cancer clusters across the United States. He explains that if an environmental pollutant—a toxin in the groundwater, say, or particulate matter in the air from a nearby factory—is present in a community, any resulting cancer would show up in dogs before showing up in humans. And since nearly half of American households have dogs, 80 million of them, Breen calls these beloved pets “the ultimate canary in the mine.”
Breen is one of an increasing number of researchers looking to animals for answers about cancer. “The failure to pursue this path is scientifically irresponsible,” says Natterson-Horowitz, the Zoobiquity co-author. “Every single minute of every single day, bird, fish, terrestrial mammals develop disease, and many of those diseases overlap with the diseases we have.” Doctor Dolittle, in other words, may have plenty to teach us about human illness.
And then there are the mammals who do not get cancer at all, the anti-Franks, those super-dachshunds. The ones Dr. Harold E. Varmus, the former head of the National Cancer Institute, told The New York Times last spring he wants to know more about. The ones who have an innate armor against the disease that afflicts some 1.7 million Americans each year.
Those are the ones that fascinate Dr. Joshua D. Schiffman.
Dr. Joshua Schiffman, an oncologist, had cancer when he was a teen, and after watching a pet dog die of cancer years later, committed his career to unraveling the mystery of elephants and the Big C. In his research he uses blood collected from elephants at the Hogle Zoo in Salt Lake City, Utah, to figure out what makes them resistant to cancer.?
SCHIFFMAN KNOWS ALL about cancer, of both the human and animal variety. He grew up in Providence, Rhode Island, the son of an oncologist who worked at the National Institutes of Health and at Yale before taking a position at Brown that he holds to this day. His father was a clinician, not a researcher. On the map of the human body, he knew exactly what cancer would look like, where it sprouted, where it went. His job was not to find out where the cancer came from, or why it came, but to simply make it go away so that his patients could live another day, and then another day after that.
Schiffman told me about one day in the early summer of 1989, when he was 15 years old. He came down from his room for dinner, and his father wrapped his hands tightly around Schiffman’s neck. Schiffman thought he was being strangled by a parent not otherwise prone to violence, in which case he must have done something truly terrible. He hadn’t: The older Schiffman was feeling the lymph nodes in his son’s neck. Their enlargement, he well knew, was often a first sign of cancer. His fingers confirmed the first suspicion of his eyes. He did subsequent tests, which confirmed that Josh had Hodgkin lymphoma, a blood cancer that afflicts teenagers, a cancer similar to the one that paid a recent visit to Frank, the German shepherd.
What followed, Schiffman calls “a summer of R and R: rest and radiation.” He was treated at a hospital in Boston. He and his father would drive there each day for the radiation therapy, then drive back to Providence. Schiffman says he would spend his evenings vomiting from the radiation, which touched on the area postrema of his brain, where the nausea response is triggered. Then, the next morning, they would do it all over again. It was a summer of curative brutality. Yet the cancer went away, and it has never come back.
Today, Schiffman is 41 years old. He lives in Salt Lake City with his wife, Maureen, and their three children. After his bout with lymphoma, Schiffman wanted nothing more to do with medicine, especially the sort his father practiced. He was done with doctors, and he was certainly done with cancer.
Except it hasn’t worked out that way: Schiffman is the director of the pediatric cancer genetics clinic at Intermountain Primary Children’s Medical Center and the Huntsman Cancer Institute at the University of Utah. He treats children who are sick in much the same way he was 26 years ago, frightened kids facing death. A lot of his time, though, is spent trying to unravel the genetic and hereditary workings of cancer, figuring out how we inherit cancer risk, much like the chow chows marked for melanoma from birth. His only complaint about Salt Lake City is that the bagels are inedible. One can’t be much surprised about that.
As his teenage experience with cancer receded, Schiffman’s aversion to medicine eased. For college, he decided to attend the Program in Liberal Medical Education at Brown University, an eight-year course of study that emphasizes a humanistic approach to medicine, with classes taught by poets and playwrights. In a decision that was either improbable or inevitable, Schiffman became interested in pediatric cancer.
While at Brown, he started volunteering at a local hospital, where he met a patient named Derek Cute who had just turned 7. He had leukemia, and he was going to die from it soon. This was obvious to those who were treating him. Other volunteers warned Schiffman against becoming attached to Derek, but he didn’t listen, perhaps recognizing something of himself in the ailing boy. He became increasingly close to Derek. Once, when Schiffman was visiting him at home, Derek said, “You know, Josh, you’re my only friend.” Derek died shortly thereafter; Schiffman was shattered.
Derek’s death led Schiffman to a simple conclusion that continues to guide his work today: “Cancer sucks. And we have to do something about it.” After graduating with a medical degree from Brown, Schiffman went on to Stanford University, where he became interested in pediatric palliative care, helping kids die if he could no longer heal them. In 2003, he and Maureen bought a house in Menlo Park, California, near the Stanford campus. Now that they had a house, they could also have a dog. They got a Bernese, Rhody, so named for the Schiffmans’ home state of Rhode Island. Someone alerted Schiffman to the breed’s susceptibility to histiocytic sarcoma, but he brushed the warning aside, thinking, What are the chances of an oncologist having a dog with cancer?
The Schiffmans were settling into Salt Lake life when, in 2010, Rhody developed a limp. Schiffman remembered the warning about Bernese mountain dogs and sarcoma, how easily he had ignored what turned out to be a statement of deep-seated genetic risk. The warning had not been prescient but merely factual. Unlike Frank, the Sebastopol police dog, Rhody had little hope for treatment. “He was dead within a couple of months,” Schiffman says.
In the wake of Rhody’s death, Schiffman developed a new interest: finding out why his dog had gotten sick. Once a dog hits the age of 10, its chance of dying from cancer is a striking 50 percent. There were lessons here that Schiffman thought could be valuable to all people, not just dog lovers. Schiffman was “still healing” from Rhody’s death when he went to a conference on genetics in Washington, D.C. There, he saw a poster for a paper on the genetic risk of Bernese mountain dogs for cancer. He began, at once, to interrogate the poor graduate student presenting the research, explaining why he had to get in touch with the study’s authors (Schiffman’s approach to science can be described as accost-and-collaborate). Not only had his Bernese died of cancer, but he was studying genetic predisposition to cancer, albeit in humans. Like the love affairs in Meg Ryan–Tom Hanks movies, this was meant to be.
In the summer of 2012, Schiffman attended a conference about evolutionary medicine and comparative oncology, the study of cancer across different species. One of the presenters was Carlo C. Maley, an associate professor at Arizona State who researches cancer and evolution. Maley, in turn, introduced Schiffman to one of the great conundrums of cancer: Peto’s Paradox.
Peto’s Paradox is named after Sir Richard Peto, the Oxford University medical statistician and epidemiologist whose work in the 1970s pointed to the link between smoking and cancer. Like all paradoxes, Peto’s is incredibly complex precisely because it is so incredibly simple: Why don’t big animals get more cancer than small animals? Cancer is the unregulated division of cells. The more cells an animal has, the more likely any one of those cells is to go rogue, turning into a tumor. Huge mammals like whales and elephants have many more cells than humans do, which should make them much more prone to cancer. A whale has 1,000 times more cells than humans, which should mark it for cancer right from birth. But for some reason, the whale evades that fate better than we do. Not only that, but the whale evades cancer for a very long time, with some bowhead whales living for 200 years. Some elephants live for 60 years, carrying 100 times more cells than we do.
“Evolution has solved the problem” of cancer in large mammals, Maley explained when we spoke on the phone last spring. Species survive via reproduction, and large mammals have much longer gestation periods: An elephant spends about 22 months in the womb, while whale gestation can last about 18 months. Moreover, elephants can keep reproducing until what is, for them, senescence: after 50. Elephants that are able to suppress cancer long enough to reproduce end up passing those cancer-suppressing genes to their progeny. Nature will conversely make short work of the mouse, but because it reproduces early and often, the mouse will have already passed on its genes to the next generation. Most humans also get cancer in late middle age, after they have fulfilled their reproductive duties. We benefit from the legacy of ancestors who were generally able to suppress cancer until they finished reproducing (and raising their young), which is why, in Schiffman’s words, “cancer is a disease of aging.” It is evolution’s cruel way of thanking us for parenthood.
The evolutionary legacy of elephants and whales, with their hardy genomes, may hold the key to suppressing cancer in older humans, who are the humans most likely to get cancer. What happens inside the body of an elephant or a whale that keeps it cancer-free for all those decades? Why do almost 25 percent of Americans die from cancer, but only 18 percent of belugas do, though a specimen of the latter species can easily weigh 3,000 pounds? What secret mechanism protects the beluga, and how can we copy it?
Maley, today a close collaborator of Schiffman, says that cancer medicine has been so focused on the molecular particulars of the disease, we’ve failed to fully account for the fact that elephants and whales manage to avoid cancer without vitamin supplements or chemotherapy regimens. “How did evolution solve,” Maley asks, “this problem that’s vexing humans?”
SMALL, TALKATIVE AND DEEPLY INTENSE, Schiffman says he has “permanent hat-head” from the many professional hats he constantly dons and doffs: ministering to sick children, unraveling the genomic pattern of cancer, teaching at the University of Utah. He is also starting a company,ItRunsInMyFamily.com, that wants to digitize family medical histories and mine them for predictive potential, a sort of Facebook for heritable disease. When we met in Salt Lake City several months ago, he was on the cusp of leaving for Boston, to meet with a researcher who wants to clone the woolly mammoth. Schiffman told me that his curriculum vitae was 36 pages long. I thought he was exaggerating. It turned out that I was correct: The CV he sent me was a mere 32 pages in length.
One day in 2012, Maureen Schiffman told her husband he needed to spend more time with their three children. Joshua Schiffman’s motto is that cancer doesn’t sleep, so neither should he. And because no cancer is more terrible than the one that afflicts a child, he has the tendency to become consumed by his research. But on this morning, he knew that his wife was right. So he drove his beloved brood to the zoo.
The Hogle Zoo is on the edge of Salt Lake City, near Emigration Canyon, through which Mormon exiles fleeing the Midwest, led by Brigham Young, passed a century-and-a-half ago. Across the street from the museum is This Is the Place Heritage Park, on the spot where Young declared his scorned flock had found its new home.
At the zoo, they went to see the elephants, where Schiffman saw a caretaker explaining to the crowd that elephants have large ears because flapping them circulates cooler blood throughout the body, which is important since elephants don’t perspire. The caretaker added that his staff collected blood from the elephants once a week.
The answer to Peto’s Paradox, Schiffman realized, was flowing through the elephants’ thick ear veins. Whatever genetic advantage the elephant had would almost certainly be present in its blood cells. Forgetting his wife’s injunction, Schiffman approached the caretaker. The unsuspecting zoo employee was Eric Peterson, who today oversees the care of Hogle’s two elephants. He is almost comically the opposite of Schiffman: huge, goateed and bald, a native of Utah who looks like a Viking warrior but loves animals and nature photography. He was conscripted into Schiffman’s research on the spot, with the young oncologist pleading with him for elephant blood. Peterson could have taken him for a madman, but did not. They have been working together ever since.
An elephant trainer works with Christie, an African elephant in Schiffman's study, at the Elephant Encounters exhibit at the Hogle Zoo in Salt Lake City, March 30. KIM RAFF FOR NEWSWEEK
Peterson has his reasons for the collaboration. About 96 elephants are killed by poachers in Africa each day for the ivory in their tusks. Peterson thinks that if people realized that elephants possessed the cure for cancer, they’d take greater care to save them. “Who’d want to throw away the cure for childhood cancer? This is our chance to save people and elephants.”
Since 2012, the procedure has always been the same: Peterson draws elephant blood at Hogle, which then travels the short distance to Huntsman. There, in Schiffman’s lab, researchers pull the cells apart, trying to understand what makes elephants resistant to cancer.
The answer almost certainly has to do with TP53, “the single most studied gene in molecular biology,” according to Sue Armstrong, a British science journalist who just wrote a book about it. A tumor suppressor gene, TP53 is the police officer of the cellular world. If a cell with faulty DNA is replicating, the TP53 gene encodes a protein called p53, which can arrest the process and allow it to move forward only once the DNA is fixed. Or it can shoot to kill, getting rid of the cell with bad DNA. P53 is, as one of its discoverers famously declared, “the guardian of the genome.”
Humans have two copies of TP53, one from each parent. It resides near the edge of chromosome 17, between base pairs 7,668,401 and 7,687,549. But the elephant has 20 versions (that is, 40 copies) of TP53, potentially giving the pachyderm body 20 times more tumor-suppressing powers than the human one. Nineteen of those extra elephant TP53 versions are retrogenes, meaning they were copied back onto the DNA from the RNA, in a sort of reverse transcription. Schiffman and his colleagues, however, do not believe that TP53 retrogenes are any less capable of keeping cancer at bay (other experts I spoke to disagree).
Considering that human cells are always dividing, TP53 does a pretty good job of forfending cancer. Having two copies of TP53 is “good but not great,” says Dr. Giridharan Ramsingh, an oncologist at the Keck School of Medicine of USC who has studied how mutated TP53 can actually lead to cancer instead of preventing it. “When you have 20 copies, it’s fantastic.”
Ramsingh has also conducted research that may explain why dogs are more susceptible to cancer than other mammalian species. Though canines have two copies of TP53 just like humans, their genome is more vulnerable to the introduction of retrotransposons, which Ramsingh explains are DNA segments that, if inserted into the right section of the genome, can cause “genomic instability” and lead to cancer—that is, unless checked by p53. He says that dogs are subject to “very active transposition” in their genomes. “In dogs, two [copies of TP53] doesn’t seem to be enough.”
Schiffman and his collaborators, who just published a paper in JAMA, found that p53 does not work in elephants quite like it works in humans. Instead of expending extra energy on fixing bad DNA, elephant p53 simply kills the cell with faulty DNA. “It’s like buying a new car rather than fixing an old one,” explains Trent Fowler, the young manager of Schiffman’s lab. Killing cells, the elephant models suggests, is a better bet than trying to set them straight.
How this knowledge will translate into human treatment isn’t yet clear, not even to the irrepressibly optimistic Schiffman. To some, the research into elephant cancer immunity is fascinating but not terribly instructive. Alan Ashworth, president of the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, cautions that the kind of comparative oncology Schiffman practices may yield “great insights” without defeating cancer. “It’s going to be quite a long time before there's any solid application,” he told me. “If ever.”
Schiffman thinks medicine could eventually arrive at a compound that replicates the p53-rich environment of elephants, or even find a way to insert elephant p53 into people. But first, he wants to figure out exactly how all those extra copies of TP53 work in concert to keep elephants cancer-free. He brushes aside suggestions of a silver bullet, that long-sought cancer therapy to cure the disease without leaving patients bald, emaciated and throwing up. The silver bullet holds no interest for him. “This will give us the whole gun,” Schiffman says.
Eric Peterson, elephant manager at the Hogle Zoo, shows blood he took from Christie's ear in the Elephant Encounters exhibit at the Hogle Zoo in Salt Lake City, March 30. Researchers periodically draw blood from one of the ears of Christie, and the other African elephants being used in Schiffman’s study. KIM RAFF FOR NEWSWEEK
Schiffman inevitably returns to a sort of childish wonder at these enormous creatures that have conquered the world’s most unconquerable disease. He routinely sees toddlers and teens fighting losing battles against brain tumors and blood cancers. Meanwhile, down the road at the Hogle Zoo, there are mammals whose cancer fatality rate is less than 5 percent. “They’re so big, they have so many cells pulsing through their body,” Schiffman says, “they should all be dead of cancer. Every time I look at an elephant, I’m amazed.”
CANCER IS EVERYWHERE. As Schiffman told me his story of fighting lymphoma over breakfast, I could hear the two women at an adjacent table discussing the particulars of a breast cancer treatment: lost hair, marital strife, the usual dreadful stuff. About a week later, Schiffman was vacationing at Lake Tahoe with his family when he walked into a store with his golden retriever. A stranger approached and started talking about her dog of the same breed, who had been claimed by a bone tumor. Cancer has crept into Schiffman’s family life, too. He told me it took him many years to get over the notion that every time one of his children coughed, the feared diagnosis was at hand.
After breakfast, we drove to the Hogle Zoo, where we were met by Peterson, the elephant keeper, and about a dozen members of the extended Means family. As is inevitably the case in Utah, the Means children far outnumbered the Means adults. But young and old, they were all eager to see the elephants. They had been aware of Schiffman’s work with creatures. But they had never seen that work firsthand, despite its potential to save their own lives.
Looking at the Means family, you wouldn’t know that many of its members are afflicted with Li-Fraumeni Syndrome, a germ line (i.e., inherited) mutation that knocks out one of the two copies of TP53 in every cell in the body. That makes it virtually certain that someone with Li-Fraumeni will get cancer. Because they will get it early and often, cancer will probably kill them, one way or another.
The patriarch of the Means family is Von, a fit airline employee in his mid-50s who does not have LFS. But his wife, Sharese, did and died of breast cancer at a very young age in 1994. She came from a family, the Thompsons, in which LFS has killed several members. Those with an LFS mutation have a 50 percent chance of passing it on to progeny; Sharese gave it to all three of her children, Tony, Andrew and Lindsay. Tony has had brain cancer, which recently returned; Lindsay has had a prophylactic double mastectomy. Tony gave all three of his children the LFS mutation; one of them currently has a brain tumor. Andrew gave one of his children the LFS mutation. He has not had cancer, though there was a worrying growth on his neck a little while back. He knows that he can get cancer any day. So can any of us, for that matter, though our odds are a little better without LFS.
Elephants are the picture of cancer resistance; the Means family is the picture of cancer susceptibility. Someone with LFS has a 90 percent chance of developing cancer, more than twice the rate for the American population at large (43 percent for men and 38 percent for women). So while the average person may think about cancer only occasionally, those with LFS have to think about it incessantly. Late last year, the Deseret News, the daily newspaper of the Mormon Church, profiled the Thompson family (of which the Means family is an offshoot) and its struggles with LFS, the desire to have children balanced against the knowledge that any one of those children could become a certain cancer victim. “Doctors have recommended that family members with the gene have annual full-body and brain MRIs, as well as blood tests and bone marrow biopsies,” the Deseret News reported. “Doctors also told them to avoid red meat, barbecued and microwaved foods, and X-rays, and encouraged them to cook with stainless-steel pots and pans.”
Li-Fraumeni Syndrome is one of Schiffman’s seemingly endless enthusiasms. Of the genetic predispositions to cancer he has been studying since arriving to Utah, none is as extreme or deadly. He treats the Means family while they, in return, treat him like one of their own. His work with them clearly dovetails with his interest in both the hereditary nature of cancer and the role of TP53 in preventing the disease.
The Means children crowded against the railings as Peterson and his fellow keepers had the elephants do tricks while he performed a physical check on them. All of the Means children are too young to understand much of anything about TP53. But the adults all knew what they were looking at. Andrew, Tony’s younger brother, later revealed what was going through his mind: “Lucky elephants.”
Schiffman was right up against the elephants, pacing back and forth like a mad scientist anxious to get a world-changing experiment just right. “No cancer, no cancer,” he whispered in something between jealousy and admiration.
“That’s the cure to cancer right there,” he said a little later, as Peterson found a vein in one of the elephants’ ears and a vial filled quickly with maroon liquid.
In 2013, the University of Utah awarded Schiffman an endowed chair in pediatric research, a distinction rarely bestowed at such relative youth. It was an unambiguous sign of confidence. He has also partnered with the Ringling Bros. and Barnum & Bailey Center for Elephant Conservation in Polk City, Florida, home to the largest herd of Asian elephants in North America, which will give him a treasure trove of new genetic data.
Yet to some, Schiffman’s work with elephants is nothing more than an amusing detour. His paper on how TP53 works in elephants (which he authored with Arizona State University’s Maley and several other collaborators) was rejected by some of the nation’s most prestigious publications before finally finding a plenty prestigious home at JAMA.
I talked to Schiffman after each of these rejections. He was invariably disappointed, but never doubted the purpose of his work, its potential to help beat back a foe not used to defeat. “Nature’s figured it out,” he says. “Why can’t we?”
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