Friday, August 2, 2019

One of the strangest living things on the planet started as a dog, but has turned into something else entirely.

It originated somewhere in Asia about 6,000 years ago, when a cell in the genitals of an unknown dog developed mutations that allowed it to multiply uncontrollably. That is, it became a tumor. But unlike almost every other cancer, which ultimately goes down with its host, this one did not. Somehow, it gained the ability to spread from one dog to another through sexual contact. And in doing so, it achieved a kind of immortality. The original dog is long gone, but its contagious cancer—known as canine transmissible venereal tumor, or CTVT—lives on, having hopped around the world on the junk of humanity’s best friend.

To clarify, several cancers can be caused by infectious entities; cervical cancer, for example, is the work of HPV, a sexually transmitted virus. But in those cases, the cancer itself is not infectious and cannot spread. CTVT is different: Each cancer cell is a free-living parasite that can set up another tumor on another dog. Among wild animals, there are only eight known examples of such transmissible tumors. Two grow on the faces of the unlucky Tasmanian devils. Five spread between shellfish. None are as ancient, prolific, or successful as CTVT.

Now, a team led by Elizabeth Murchison of the University of Cambridge has finished the largest study of CTVT yet, comparing the DNA of 546 tumors collected from dogs around the world. The team’s study reads like an epic biography of this unusual cancer, and it shows just how strange an entity CTVT really is.

As a typical tumor grows, it also evolves. New cells inherit the mutations of their parents, before picking up new ones of their own. This process of constant change means that cells at opposite ends of a tumor can be genetically different, as can those that spread (or metastasize) to other organs. By comparing these patterns of mutations and working backwards, scientists can identify which mutations arose when and where, and work out how a tumor originated, evolved, and spread. But they usually do this for samples collected from a single body. Murchison’s team did it for samples collected from six continents. “We mapped out a metastasis on a global scale, over thousands of years,” she says.

Her team calculated that CTVT arose 4,000 to 8,500 years ago, somewhere in Central Asia. It then stayed there for millennia, perhaps because it emerged in a population of dogs that were isolated from others. For whatever reason, that seclusion broke about 1,900 years ago, and the tumor slowly spread west through Asia to Europe.

Its movements accelerated about 500 years ago, when it hitched a ride to the Americas on the genitals of colonizers’ dogs and spread quickly once it arrived. In the 18th century, one particular lineage of CTVT made the return trip, and swept through Europe and Africa. Most of today’s CTVT tumors are descended from that American lineage. Colonization, globalization, and homogenization: The recent history of CTVT is not unlike our own.

The tumor’s genes reveal not just the route of its travels, but also some of its encounters along the way. Many carcinogens mutate DNA in distinctive ways: Sunlight, for example, creates a very different pattern of mutations than cigarette smoke. Murchison’s team found that CTVT contains a lot of those sunlight signatures, especially at lower latitudes, where the sun is stronger. For example, CTVT in Mauritius has more sunlight-induced mutations than the same tumor in Russia. Based on that trend, the team could calculate how many sunlight-related mutations the original CTVT tumors would have had and, from that, the latitude at which the founder dog probably lived. “It points to China as a likely origin,” Murchison says.

But one pattern of mutations was less clear-cut. Repeatedly, the team saw stretches of DNA where one particular quintet—GTCCA—had changed into GTTCA. (DNA is a chain of four building blocks that can be represented by the letters A, C, G, and T.) And that pattern has never been seen before, in any other cancer, from any other species. Weirder still, that signature accounted for a third of CTVT’s mutations during its early past, but hasn’t cropped up again in the past two millennia.

“It’s very mysterious,” Murchison says. “This cancer was exposed to something that caused this very particular mutation, and has never been seen in any human cancer ever, and that seems to have stopped 2,000 years ago. We don’t know what that carcinogen is, and we’d love to. I guess it was probably something in the dogs’ environment? This is a very crazy idea and we don’t really believe it, but maybe ancient people who owned the dogs tried to treat [their tumors] with some kind of chemical?”

                                                         
Regardless of the source of CTVT’s mutations, it has clearly accumulated a lot of them. Put it this way: Today’s tumors are about as genetically different from the founder dog as two distantly related dogs are to each other. “CTVT is like its own organism,” Murchison says. “It isn’t really a dog. Is it a cancer, still?”

There’s good reason to think that the answer is no. Sure, it’s a tumor, but one that behaves in very strange ways. For example, one of the hallmarks of cancer is genomic instability. That is, it is constantly mutating, duplicating or deleting genes, rearranging entire chromosomes. To look at a cancer genome is to stare at chaos. CTVT, by contrast, is a picture of stability. Yes, it has a lot of mutations, but that’s because it’s been around for thousands of years. If anything, it acquires new ones at a slower rate than you’d expect for a cancer.

Also, the majority of those mutations, including almost all of the recent ones, are neutral. They don’t seem to benefit the tumor in any way. Again, that’s very different from most cancers, which are constantly adapting to outfox their hosts’ immune systems, or to grow a little faster, or to spread to new areas. Not so with CTVT. “We think that the cancer is not adapting anymore,” says Adrian Baez-Ortega, who was one of the main researchers on the study. “Maybe it doesn’t really need to.”

Perhaps, early on in CTVT’s history, it found such thorough ways of escaping the immune system and jumping into new hosts that no further tweaks were necessary. Or perhaps it no longer imposes enough harm on its hosts to warrant a counterattack. It’s rarely fatal, after all, and if dogs are otherwise healthy, it doesn’t grow very fast. “The tumor and the dogs aren’t competing against each other anymore,” Baez-Ortega says. “They’re coexisting. The cells behave like cancer cells, but the ecology of the tumor is that of a parasite.” And a fairly benign one at that.

Doctors should take note. In lieu of aggressive chemotherapy, which drives the evolution of resistant and recurrent tumors, some researchers are looking at a strategy called adaptive therapy. Their plan is to treat cancers intermittently and gently, enough to control them, but not enough to trigger the rise of resistance. The goal is not to cure, but to tame—to turn a tumor into a long-term but manageable problem. And CTVT shows that “a tumor can be tamed by evolution,” Baez-Ortega says. It can evolve toward low-key survival instead of aggressive growth.

Its future is uncertain, though. While failing to acquire beneficial mutations, CTVT is also failing to weed out harmful ones. That’s understandable, because much of its DNA comprises genes for building a dog. It can afford to let those mutate into obsolescence. But over time, the genes that it still needs will also take hits. Slowly, the tumor will become weaker and less efficient.

Evolutionary biologists have long predicted that purely asexual organisms—those that reproduce by cloning themselves instead of having sex—are doomed to this fate, which is why they’re incredibly rare. CTVT seems to be proving them right. “Is it an evolutionary dead end?” wonders Hannah Siddle of the University of Southampton, who studies contagious cancers. “Is it gradually becoming more unstable under its increasing random mutational burden?” Baez-Ortega thinks so: “I don’t see this surviving for millions of years,” he says.
                                                     
Humans have sped up the tumor’s demise by treating it with chemotherapy—a surprisingly easy feat because, unlike most cancers, it doesn’t seem to evolve resistance to drugs. Indeed, almost all the 546 dogs sampled in Murchison’s study were cured, even when their tumors had metastasized. “That’s astounding,” she says. “CTVT is probably one of the most curable cancers we know of.”

But I wonder, when we talk about cure, do we really mean extinction? CTVT is a unique biological entity—not quite a cancer, not quite a dog, and not quite like anything else. There’s a growing movement to protect unglamorous parasites alongside more charismatic fauna. Is CTVT, with genetic collapse on its horizon, a case for conservation instead of cure? Would anyone seriously propose saving a tumor?

“I think you could make that argument, but not at the expense of dogs’ welfare,” Murchison says. “They do recover, but chemotherapy is not nice. I wouldn’t personally be concerned if CTVT was eradicated from the dog population, but if it was kept in a museum, that would be ideal.

“It would be very sad if it disappeared from the planet,” she adds.


Source : The Atlantic

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