Fatal Cancer Threatens Tasmanian Devil Populations

A voracious cancer threatens to wipe out an iconic Tasmanian species and destabilize the island's ecosystem. Can biologists trick the disease into taming itself? 

By Julie Rehmeyer|Monday, March 31, 2014
A Tasmanian devil.

Menna Jones peered into a trap, and a Tasmanian devil peered back at her. Its gaze was somehow off. The devil’s face seemed misshapen, and its jaw was raw and red. Perhaps, she thought, the swelling was an infected wound. Many devils are torn up by the end of the breeding season, after a month of winning and defending mates.

Jones, a biologist at the University of Tasmania, was trying to decipher the social structure of the island’s iconic creature, the largest meat-eating marsupial in existence. Were the devils promiscuous, as many researchers suspected? Which ones were studly and prolific, and which ones were losing the reproductive race? This fellow was one of many helping Jones answer those questions in June 2001 at her study site on the Freycinet Peninsula, a crooked finger of land in eastern Tasmania.

Jones reached for a canvas sack, tipped the cage gently and shook the black, beagle-size animal into the bag. Then she sat on the ground, legs wrapped around the bagged animal. Gripping him firmly, she pulled the bag back to measure his head. It was a dance she’d performed hundreds of times, moving smoothly and predictably so the devils knew what to expect.

Sometimes after she released a devil, it stayed in her lap and sniffed the sunscreen on her arm or buried its furry face in her armpit to hide from the sun. Although this devil was new to her — he was at the neck of the peninsula, which she visited only once a year — she often trapped the same devils dozens of times over the years, watching them grow from tiny imps in their mothers’ pouches to the grizzled old age of about 5.

When she pulled the bag back from this devil’s face, her soothing ritual faltered. A mass obliterated his right eye and erupted into an oozing, red-and-black cauliflower across his cheek. Another swelling deformed his left cheek into a deceptive chipmunk-chubbiness.

These facial growths were ominously familiar to Jones, though few others had ever seen one. Two years earlier, she’d observed strange tumors on a third of the devils she’d trapped 100 miles to the north. At the time, she thought perhaps they’d been exposed to some toxin.

Lacking a camera, she could take only measurements and descriptions to a wildlife veterinarian. He told her the only way he could figure out what ailed her devils would be if she were to euthanize one and bring it to him. “I was horrified at the thought that you’d euthanize a devil just to find out what it was sick with,” Jones told me, sitting in her office in the port town of Hobart. “Interesting to think back on that now that tens of thousands have died.”

Over the remainder of Jones’ 2001 trip to Freycinet, two more strapping 3-year-old males appeared in her traps with tumors on their faces. One of these tumors spread across the devil’s jaw and then dissolved, leaving a gaping hole. He could no longer eat. With no qualms about putting this doomed creature out of his misery, Jones brought him to a veterinary pathologist. Cancer, the veterinarian confirmed, but he wasn’t sure what kind.

Biologist Menna Jones of the University of Tasmania has led the charge to thwart the contagious cancer that threatens Tasmanian devils.
University of Tasmania

The following January, Jones spotted tumors blooming on the faces of devils five miles farther down the peninsula — devils she’d known for years. When she returned in April 2002, the blight had marched still farther. By June, when she returned to the neck of Freycinet, she caught only 14 devils, rather than her usual 50. A third of them had tumors.

The disease was spreading. Somehow, it seemed, this cancer had evolved to become contagious.

Now, more than a decade later, the tumor is finally beginning to reveal its tricks. These devils are suffering from a malady so odd many researchers scarcely thought it possible: One devil’s cancer has learned how to survive in other devils’ bodies, and that one tumor is now threatening to wipe out an entire species. This would undermine the Tasmanian ecosystem and likely cause the extinction of many other marsupials that survive only in Tasmania, an island state off the southern coast of mainland Australia.

Fearing such a calamity, the Tasmanian government, working with a network of biologists, has begun quarantining healthy devils in zoos and on isolated islands. If the cancer kills off all other wild devils, this “insurance population” could, in theory, help reboot the species. (See “A Tasmanian Devil Insurance Policy” below.) Meanwhile, some of Jones’ colleagues are trying to decipher how the cancer evolved in hopes of using the information to create a vaccine. But Jones puts better odds on figuring out how to hack evolution itself, so the tumor can coexist with the devil.

The big question is whether researchers can do that before the disease wipes out wild Tasmanian devils altogether.

Unraveling the mystery will do more than save a few furry creatures at the bottom of the world. The tragedy has given researchers a backstage pass to see the evolution of cancer itself. No ordinary cancer can live as long or divide as many times as that of the “immortal devil,” the long-dead animal that spawned the current plague. All cancers are products of natural selection played out on the level of cells rather than species. So understanding the strange tricks that devil facial tumor disease, or DFTD, has evolved to ensure its survival should shed new light on cancer writ large.

An estimated 5,000 devils are infected with devil facial tumor disease, which typically causes death within six months of the appearance of a tumor.
Menna Jones
Life Raft

Watching the Freycinet devil population crash in 2001 and 2002, Jones worried the survival of the species might be at risk. It seemed almost unimaginable. After all, devils were so common many considered them pests. Their nighttime screeches (frightening enough to have inspired the name the early Tasmanian settlers gave the small, shy creatures) startled people awake. Dead devils littered the roads, having fed on roadkill until meeting the same fate as their dinner. Farmers complained the devils ate their chickens and lambs. Most rural Tasmanians viewed devils like Americans tend to regard raccoons or squirrels: ubiquitous, occasionally annoying, worthy of little thought.

But the devils’ ubiquity was no guarantee of their survival. Biologists believe a new and virulent disease can eradicate even a well-established species if the pathogen continues spreading after the population becomes sparse. So in late 2002, Jones sounded the alarm to the state government.

Conducting a quick-and-dirty survey of devil populations, officials found that devils in the northeast, where Jones first saw the disease, were nearly wiped out. Of the few survivors, many were already infected. The disease seemed to spread during mating season, when female devils fight off suitors and males compete for females. Devils bite each other on the face as they scrabble, and malignant cells can crumble off tumors like feta cheese, dropping into bite wounds.

Over the next several years, Jones watched the populations at her study sites fall by 50 percent a year. She kept feeding the new data into mathematical models that factored in the animals’ age, migration patterns and disease prevalence in the population, among other things. The models’ predictions were bleak: Once the disease arrived in an area, devils there would vanish within 10 to 15 years.

Grim as the outlook was for the devils themselves, Jones’ deepest concern was that if the Tasmanian devil vanished from the wild, it could take a big chunk of Australia’s dwindling biodiversity with it.

Like the Tasmanian devil, the Tasmanian tiger, or thylacine (Thylacinus cynocephalus), survived in the wild only in Tasmania after being wiped out from mainland Australia. But by the 1930s, Tasmanian sheep farmers slaughtered thylacines to extinction in an effort to prevent them from preying on lambs. In a 2006 article contemplating the fate of the Tasmanian devils, Menna Jones riffed on Oscar Wilde: “To lose one large marsupial carnivore may be regarded as a misfortune; to lose both would look like carelessness.”
Zoological Society of London

More mammals have gone extinct from Australia than from any other continent. Nineteen mammal species have disappeared over the past 200 years, and more than a hundred more are threatened or endangered. Tasmania is Australia’s one exception. Since it was settled in 1803, the island has lost only one mammal, the Tasmanian tiger (or thylacine) — a wolfish, striped, carnivorous marsupial. And the island state serves as a life raft: Four Australian species survive only here, having been completely or nearly wiped out from the mainland. Tasmania also offers a safe haven for nine more species that are threatened on the mainland. Many of these creatures’ names sound as if they’ve leapt from children’s fables: the eastern barred bandicoot, the Tasmanian pademelon, the eastern quoll, the long-nosed potoroo, the eastern bettong.

The devil, which went extinct on the mainland about 5,000 years ago, is one of these Tasmanian survivors. And it is the thumb in the dam, preventing many other creatures from being swept from the Tasmanian landscape into extinction. Devils suppress feral cats and foxes (repeatedly and illegally introduced to the island) by preying on their young and competing for habitat and resources. If populations of cats and foxes were to spread, as they did long ago on the mainland, they would slash a hole in the marsupials’ life raft. “It’s just like taking wolves out of Yellowstone,” Jones says. “Losing the top predator sends the ecosystem out of balance.”

The Spread of a Killer Cancer

Since its first recorded sighting in 1996, devil facial tumor disease (DFTD) has maintained a steady westward march in Tasmania, depleting devil populations by as much as 90 percent in some areas.

Kellie Jaeger/Discover

Cancer as a Parasite

Jones’ warning spurred the Tasmanian government to action, leading to the 2003 formation of the Save the Tasmanian Devil (STTD) program, with Jones as an adviser. The program’s goals were to suss out the threat and find a way to address it.

News reports about the devils’ plight sprang up around the globe. Anne-Maree Pearse, a retired cancer researcher living in Launceston, Tasmania, heard a radio story about the disease and called the Save the Tasmanian Devil program offering to help.

Pearse was uniquely qualified: Decades earlier, she began her scientific career studying the genetic makeup of a species of flea that had a special taste for the Tasmanian devil. Then she applied her expertise to humans, studying chromosomal rearrangements in leukemia cells. As a result, Pearse was perhaps the only person in the world with expertise in both cancer and devils — and, though the relevance was not yet apparent, in parasites as well.

The STTD program jumped at Pearse’s offer and gave her devil cancer cells to analyze. When Pearse put the first one under her microscope, she found that, as is common in cancer, its chromosomes were mangled: One pair of chromosomes was missing entirely, one lacked a partner, one was chomped off, and some leftover bits were jammed together into extra chromosomes.

When she looked at a cancer cell from another devil, she saw the same pattern — chromosomes that had shattered and reformed in precisely the same way. The third, too. The chromosomes from all 11 devils she studied had the same deletions and the same extra bits put together in the same exact way.

The similarity could mean only one thing: These cells were clones of one another. Later, a different group found that the sex chromosomes in the jammed-together leftovers were always of the XX variety — female — regardless of the devil host’s gender. That confirmed the cancer cells weren’t mutations from the sickened devil, the way cancer ordinarily works. They had come from another devil entirely, a female undoubtedly dead for years. Her cells, though, lived on. The cancer cell line had become an organism that survived by sucking nutrients from other devils’ bodies. It was, in other words, a parasite.

A healthy male devil has 14 chromosomes, including an XY (male) chromosome (top). All the diseased devils Anne-Maree Pearse first studied had the same pattern of missing and mangled chromosomes; other researchers found they also all had XX (female) genetic material (bottom).
A.M. Pearse and K. Swift/Adapted by permission from Macmillan Publishers Ltd. Nature 439, 549 (2 February 2006)

News of Pearse’s discovery quickly spread to the Australian mainland, where it reached University of Sydney immunologist Kathy Belov. Belov had just earned her Ph.D. showing that marsupial immune systems were vigorous, much like humans’. So it seemed shocking that devil immune systems would fail to recognize and stomp out something as obviously foreign as another devil’s cancer cells.

She wouldn’t have been so surprised if the cancer were spread by a virus, since viruses (such as the papillomavirus, which turns human cervical cells cancerous) have had millions of years to evolve ways of evading the immune system. But Pearse had shown that no virus was involved; the cancer cells had transferred directly from one animal to the next. So why hadn’t the devils’ cytotoxic (or “killer”) T cells, their immune systems’ designated cancer assassins, detected the invasion?

One plausible explanation was that over the course of successive population crashes, the devils had become so inbred that their cells look identical — at least to the animals’ immune systems. Belov knew how to check this. An animal’s immune system detects foreign cells by scanning for proteins, called antigens, that stick out from the surface of each cell. These molecular identity cards are produced by a set of genes collectively known as the major histocompatibility complex, or MHC. That’s why identical twins make perfect organ donors for each other: Only they have perfectly matched MHC genes.

Perhaps, Belov reasoned, all devils were like identical twins. If so, then different devils’ perfectly matched “identity cards” would prevent their killer T cells from recognizing each other’s tissues as foreign.

Fellow Island Survivors

Like the devil, the eastern quoll (left), Tasmanian pademelon (center) and Tasmanian bettong (right) have all gone extinct from mainland Australia. They exist only in Tasmania, where the devil helps protect them from feral cats and foxes.

Left to right: Dave Watts/naturepl.com (2); Peter Oxford/naturepl.com

Analysis of the identity cards initially supported her theory, showing only the tiniest of differences. But when Belov and her collaborators transplanted skin between pairs of devils, the edges of the grafts grew pink and scabbed over. The animals’ immune systems were recognizing and rejecting the foreign skin after all. Their genetic similarity wasn’t enough to explain the cancer’s voracious spread.

Belov turned to another possibility: that the tumor was somehow obscuring its foreign identity card from the immune system. That is the case in another rare contagious cancer, canine transmissible venereal tumor (CTVT), a sexually transmitted disease in dogs traced to a single animal now dead for millennia. Instead of displaying the full complement of incriminating proteins on the tumor cell’s surface, the dog cancer displays just a few, obfuscating the invasion underway.

One of Belov’s students, immunologist Hannah Siddle, now at the University of Southampton in the U.K., jumped at the chance to investigate this possibility. To learn how the devil cancer cells might be blurring their identities, Siddle, with the help of Jim Kaufman at the University of Cambridge*, examined cells from multiple devils’ tumors and saw they were doing something even more radical. The tumor cells’ surfaces presented no antigens and thus, no identity card at all. As a result, the devils’ immune systems were giving them a free pass, for reasons that remain mysterious.

If the cells displayed no identity card, Siddle figured, the MHC genes that produced the identity cards had to be missing. But no: They were intact, just inactive. “This was really exciting because it raised the possibility that we might be able to turn them back on, restore the proteins to the [cells’] surface and use those cells as a vaccine,” says Siddle.

Indeed, after Siddle added a squirt of interferon-gamma — a chemical messenger that activates numerous genes involved in producing MHC antigens — to cells cultured from devil tumors, the MHC genes functioned normally again, and the tumor cells’ identity cards showed up, plain as day. She even found evidence that the devils’ immune systems were occasionally performing this interferon-gamma trick themselves: In some instances, tumor cells near the edge of the tumor, in close proximity to white blood cells, showed MHC antigens that cells farther within the tumor mass lacked. This suggested to Siddle that in rare cases, the devils’ immune systems were recognizing the tumor cells enough to release interferon-gamma and activate their MHC expression.

Alison Mackey/Discover
In this microscopic image, DFTD tumor cells (in blue) have low levels of MHC protein, so they do not pick up a brown stain that adheres to the protein. Host cells (brown) in tissue adjacent to the tumor cells show the MHC protein strongly.
Hannah Siddle/University of Southhampton, U.K.
Alison Mackey/Discover

The Tumor That Won't Die

How it spreads: Unlike normal cancers, where the disease-causing mutation is confined to one organism, devil facial tumor disease (DFTD) cells have evolved the ability to spread from devil to devil. The blight started with one long-dead female devil, known as the "founder" or "immortal" devil. Her cells live on in animals infected with DFTD today.

How it hides: In a normal cell, genes encode instructions for surface proteins known as the major histocompatibility complex (MHC). These molecules acts as "ID cards" that the animal's immune system can detect and target with cytotoxic ("killer") T cells.

In a DFTD cell, inactive MHC genes present no identifiers, so the animal's killer T cells ignore the threat.

Siddle believes the results may offer all the pieces needed to develop a vaccine against DFTD. One strategy would be to take devil tumor cells from the wild and turn on their MHC genes in the lab, making them recognizable to devils’ immune systems. Then, with their evasion strategy disabled, those cells could be injected into healthy devils, whose immune systems could learn to mount a defense when they encounter the cancer in the wild.

“I think there’s a good chance that this vaccine will work,” Siddle says. “Whether we get something that’s effective and cost-effective [enough] to be used in the field before DFTD moves through all of Tasmania is another question.”

Even if researchers could protect large numbers of Tasmanian devils with a vaccine that was 100 percent effective, those animals’ immunity would not be passed on to their offspring; any vaccination program would need to go on indefinitely, a formidable challenge.

Evolution in Fast-Forward

While Jones hopes Siddle and Belov succeed in developing a DFTD vaccine, she’s not expecting the devils’ salvation to be delivered through a needle. Instead, she looks to another strategy: helping the devil and the cancer evolve their way into peace.

Currently, the devil cancer is far too deadly for its own good: By killing its host, the cancer is limiting its future prospects. That glaring evolutionary stumbling block should cause it to become less virulent, while also causing the devil to become more resistant over time.

CTVT, the infectious cancer that affects dogs, may point to the devil tumor’s future. At perhaps 11,000 years old, CTVT is the oldest known line of mammalian cells on Earth, so it’s no longer evolving much. Through random mutations in the past, it has already found the most advantageous arrangement of its DNA. In particular, it has evolved to show itself three to nine months after infection, allowing its own destruction by displaying antigens on its cell surfaces so the dog’s immune system can destroy it. It’s a smart evolutionary tactic, allowing infected dogs to survive and breed, thus continuing their own species and providing future hosts for the tumor.

With time, most parasites pick up similar tricks, killing their hosts more slowly or not at all. Left to its own devices, the devil tumor may likewise evolve to be less deadly. The problem is time. Because the devils are so geographically restricted and because there are so few of them, the cancer may kill them all before it has time to evolve in the ways CTVT has.

Jones’ colleague Elizabeth Murchison, a geneticist at the University of Cambridge in the U.K. (and a Tasmanian expat), is working to understand the evolutionary process. The tumor is indeed evolving rapidly, she has found. Sequencing the cancer in 2007, she found that the tumor had picked up about 20,000 mutations. (By now, it undoubtedly has many more.) Most of those mutations are irrelevant, but a few of them are key, including those allowing the cancer to spread among devils. She has sequenced hundreds of tumor samples from across the island in an effort to understand how it evolves and how that affects the devils’ survival rates.

Jones and Pearse hope that with this genetic knowledge in hand, it might be possible to nudge evolution along by selectively breeding devils that are particularly resistant to the cancer, or to cancers altogether. “I think there is a light at the end of the tunnel, but it’s a very long tunnel,” Pearse says.

Such insights could not only help rescue the devils, Murchison hopes they might help advance cancer biology more generally. A cell that evolves a mutation allowing it to divide endlessly will outgrow its neighbors. One of its progeny might pick up a mutation giving it the ability to gobble up nutrients faster; or to enslave other cells and force them to form blood vessels to feed it; or to hide from the immune system; or to resist a particular chemotherapy. Each of these mutations gives the cell an advantage over its brethren, which it then outcompetes.

The cells from that one, long-dead female devil somehow picked up another highly valuable evolutionary trick: the ability to survive in another devil’s body. Researchers studying the devil tumor hope to learn what cancer does when the inconvenient obstacle of its host’s death isn’t enough to stop it. “Cancers are evolution in action,” Murchison says. “Understanding the underlying evolutionary mechanisms that drive all cancers, not just the devil cancer, will help us understand and treat the disease.”

A Tasmanian Devil Insurance Policy

Even if wild Tasmanian devils are wiped out despite all of scientists’ efforts, the devil won’t go extinct. In 2005, a consortium of researchers began a massive captive breeding program to create an “insurance population” of healthy animals that could be reintroduced to Tasmania if devils go extinct in the wild. The program now has 600 devils in zoos and parks across Australia (and a small number elsewhere in the world).

But captivity changes animals, even genetically. Shyer, fiercer, more anxious animals may prosper best in the wild, but they often won’t breed in captivity.

To preserve genetic diversity and guide breeding, geneticist Kathy Belov is sequencing portions of the DNA of every captive devil — an unprecedented level of sophistication for any captive breeding program. The current population includes 99 percent of the genetic diversity of all devils.

Still, devil populations in captivity for many generations may lose their wild behaviors. Small islands off the coast of Tasmania provide an opportunity for protected devils to live in the wild. In 2012, the Tasmanian government released 15 healthy devils onto Maria Island, a national park off Tasmania’s coast. So far these animals — the only wild devils safe from the disease — are thriving. — JR

[1] An employee of Devil Ark, a protected habitat and breeding facility that houses about 130 healthy devils, cradles a resident. [2] Devils at the park roam in large, free-range enclosures. [3] Devil imps must compete from the day they’re born as they try to out-wriggle their littermates to secure a berth in their mother’s pouch. Later, only the fiercest manage to mate and evade predators. At Devil Ark, imps are isolated after weaning so adults can’t cannibalize them. [4] Devil Ark attempts to help devils retain wild behaviors such as scavenging. [5] STTD personnel moved 15 healthy Tasmanian Devils to Maria Island in 2012. [6] Each devil traveled in a tubular trap. [7, 8] After their traps were opened, the devils snoozed, then crept out and vanished into the woods, the only devils in the world both safe from the cancer and free.
Clockwise from left: John Kadlecek; Devil Ark; STTD; Devil Ark/Gary Johnston; Simon DeSalis/Devil Ark (4)
Tasmanian Devil Sanctuary Cradle Mountain

Hope For a Truce

Even without that artificial nudge, nature appears to be turning a corner. After years of watching the cancer relentlessly take her beloved devils, Jones has seen some tentative signs of a truce between the devils and the tumor. Even in the hardest-hit areas, the devils haven’t disappeared entirely, the way Jones’ models predicted a decade ago. Populations have fallen by 90 percent, but no more than that, and Jones believes some of those surviving devils may be acquiring a kind of resistance.

Jones’ other source of hope, though tenuous, comes from a population of devils in the north-central part of the state, on the front lines of the cancer’s steady westward march. Devils in the west are somewhat genetically distinct from those in the east, where the disease began, and these western devils might be more resistant to the disease.

Jones herself is now far too busy orchestrating research projects to spend much time in the field. But her research assistant Rodrigo Hamede Ross has been studying this population since before the disease hit the area in 2006. On a November day I joined him at his study site near Cradle Mountain, one of Tasmania’s most popular national parks. Finding a devil in one of his traps, he repeats Jones’ dance from many years before, shaking it out into a burlap bag, sitting on the ground and placing it firmly between his legs. He blows on the devil’s nose and it opens its mouth. His assistant moves its tongue aside with a stick, and Hamede Ross peers inside its mouth. “Mara’s healthy,” he says of the 3-year-old mom, her teats full of milk.

When he started at this site, he braced himself for the decimation he’d seen in other parts of the island, knowing the disease would arrive soon. But by 2008, it was clear that something was different here. He occasionally found tumors on the animals in his traps, but it was rare. The population wasn’t crashing. Devils were still making it to old age. Then Hamede Ross saw something even more remarkable: In five devils, the tumors got smaller and went away.

He pricks Mara’s ear and squeezes out enough blood to fill a small vial. Murchison — sneaking in a field trip while home in Tasmania visiting family — watches over his shoulder. The vial may eventually come to her lab for sequencing, to help figure out what shields this population from the cancer decimating devils elsewhere.

A few traps after we leave Mara, Hamede Ross recognizes a 3-year-old male on sight: Bariloche. He isn’t so lucky. Bariloche first showed up in Hamede Ross’ traps with a tumor six months earlier, in May. Now, the tumor pushes out from his cheek. After examining him, Hamede Ross lets him go. “He hasn’t lost molars and canines, so he can still feed,” he says. “I’d guess he’ll still be around in February but not in May.”

Hamede Ross started seeing more sick animals like Bariloche in 2011, and testing of the tumors showed that a new, more virulent strain of the cancer had arrived. But his concern has been alleviated a bit since then. “It’s still pretty different from other places,” Hamede Ross says. Devil populations in the Cradle Mountain region have dropped only 35 to 40 percent, compared with 90 percent declines elsewhere.

Right now, there’s nothing the scientists can do to stop the spread of the cancer. They can only work to understand how it’s behaving and watch for an opportunity to intervene. “We’re trying to identify the mechanisms of evolution as it’s occurring in the wild” and translate it into a strategy to save the devils, Jones says. “Can we speed up the process to get coexistence?”

Sitting at her desk in Hobart, Jones isn’t as tan as in earlier pictures, and it’s been years since a devil has sniffed her sunscreen. But her mind is always on the devils that rely on her — along with the potoroos and bandicoots and pademelons that rely on them. For the first time in more than a decade, she feels a cautious hope for their future. “If you asked me five years ago,” she says, “I would have said that things look quite dire. If you ask me now, I feel quite optimistic ... but we’re not going to see recovery overnight. It may take 20 to 30 years.” Then her voice lowers as she considers the life raft. “And in the meantime, we don’t want to lose anything.”


*This story has been updated to include attribution to Jim Kaufman at the University of Cambridge.

[This article originally appeared in print as "The Immortal Devil."]

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