Authors: Carl Zimmer
It's also possible that being a chimera can be
good for your health. Bianchi's first clue that chimerism might have an upside came in the late 1990s, when she was searching for fetal cells in various organs. She discovered a mother's thyroid gland packed with fetal cells carrying Y chromosomes. Her gland was badly damaged by goiter, and yet it still managed to secrete normal levels of thyroid hormones. The evidence pointed to a startling conclusion: A fetal cell from her son had wended its way through her body to her diseased thyroid gland. It had sensed the damage there and responded by multiplying into new thyroid cells, regenerating the gland.
In another woman, Bianchi discovered that an entire lobe of her liver was made up of Y-chromosomeâbearing cells. Bianchi was even able to trace the paternity of the cells to the woman's boyfriend. She had had an abortion years before, but some of the cells from the fetus still remained inside her. When her liver was damaged later by hepatitis C, Bianchi's research suggested, her son's cells rebuilt it.
It's also possible that fetal cells help mothers fight cancer. In 2013,
Peter Geck of Tufts University and his colleagues looked for cells with Y chromosomes in the breast tissue from 114 women who died of breast cancer and 68 women who died of other causes. Fifty-six percent of the healthy samples had male fetal cells in them. Only 20 percent of the cancerous tissue had them. Geck speculated that fetal cells swooped into the niches of breast tissue that are good for proliferating cells. Those may be the same niches cancer cells need to find in order to grow into tumors.
As chimerism rises out of the freak category, it also raises unexpected ethical questions. Somewhere around a thousand children a year are born
to surrogate mothers in the United States alone. As
Ruth Fischbach and John Loike, two bioethicists at Columbia University, have observed, the rules for surrogacy are based on an old-fashioned notion of pregnancy. They treat people as bundles of genes. As a society, we are comfortable with a woman nourishing another couple's embryo and then parting ways with it, because she does not share the hereditary bond that a biological mother would. If the pregnancy goes smoothly, the surrogate mother is supposed to leave the experience no different than before the procedure.
But Fischbach and Loike observed that a surrogate mother and a baby may end up connected in the most profound way possible. Cells from the fetus may embed themselves throughout her body, perhaps for life. And she may bequeath some of her cells to the child. This is not merely a thought experiment. In 2009, researchers at Harvard did a study on eleven surrogate mothers who carried boys but who never had sons of their own. After the women gave birth, the scientists found Y chromosomes in the bloodstreams of five of them.
Fischbach and Loike don't argue that surrogacy should be banned because of chimerism. But they do think that surrogates-to-be need to give informed consent that's truly informed. It may come as a surprise to them that their own DNA could have a long-term influence on the health of an unrelated child, and that they may end up with some of the child's cellsâcomplete with a separate genome. These women need to know that heredity's tendrils can't be pruned as easily as we might imagine.
The Tasmanian devil couldn't have been dead long.
Elizabeth Murchison got out of her car in a cool, damp gully. It was the summer of 2006, and Murchison had just spent a week hiking the Central Highlands of Tasmania. Now she appreciated the shady break from the heat. She noticed a cloud of flies swirling over a black creature the size of a Jack Russell terrier. A wound on its neck was still trickling blood, presumably from a recent collision with some vehicle. Murchison turned over its body, hoping to see something. And there it was: a pea-size lump of pink flesh swelling from its face.
Murchison had grown up in Tasmania listening to the howls of devils in the night. When it came time for college, she headed to mainland Australia to study genetics, and in 2002 she traveled to Cold Spring Harbor in New York to earn her PhD. Murchison studied microRNAs, molecules made by our cells to silence genes when needed. Not surprisingly, she was the only Tasmanian in Cold Spring Harbor, and so she often found herself answering questions about Tasmanian devils. She would explain how the real animals were nothing like the Looney Tunes version, the drooling cartoon tornado that swept across American television screens. Tasmanian devils were actually the largest living species of marsupial predators, and a tough species at that. They have a habit of biting off pieces of each other's faces, whether in a fight over food or a courtship.
Tough as they might be, though, Tasmanian devils were in trouble.
A singular epidemic was sweeping across the island, not quite like anything veterinarians had seen before. A devil would develop a fleshy growth in or around its mouth. In a matter of weeks, the growth would balloon, and within a few months, the animal would starve or suffocate.
These growths were first observed in 1996 in the northeast corner of Tasmania, and over the next few years they spread over most of the island, killing off tens of thousands of devils. By the early 2000s, the species looked like it might become extinct in a matter of decades, killed by a disease scientists didn't understand. It would take them years to realize that these devils were chimeras, and that their cancers descended from the cells of a long-dead animal.
Murchison and her fellow graduate students would try to guess at the diagnosis for the devils. On an individual animal, the disease looked like a tumor (hence its name, devil facial tumor disease). But, as Boveri first recognized, a typical tumor is a mosaic. It arises from an animal's own body, thanks to a series of mutations that pile up along a lineage of cells. The reports of new devil facial tumor cases formed a wavelike pattern, as if they were a contagious epidemic.
Some of Murchison's colleagues guessed a virus was to blame. Some
viruses do cause cancer by infecting cells and disrupting their biochemistry. But once a virus infects its host, it can take years to produce cancer. Devil facial tumor disease was moving far faster. An even bigger problem with the virus hypothesis arose when scientists closely examined the tumors themselves. The tumor cells were not mosaics, descended from a devil's own zygote. They had an entirely different pattern of bands in their chromosomes, indicating that they came from a different animal altogether. The devils were actually chimeras.
Soon afterward, an Australian geneticist named Kathy Belov led a more detailed study on the disease. She and her colleagues sequenced microsatellites from tumors and healthy tissues taken from a number of devils. The DNA fingerprint from tumor cells didn't match the healthy cells from the same devil's body. Instead, they matched cancer cells from devils who died dozens of miles away. It was as if all the sick devils had gotten a cancer transplant from a single tumor.
When Murchison encountered the roadkill devil in the Tasmanian forests, she decided then and there she would study the tumors. At the time, powerful new technologies for reading genomes were just becoming affordable enough for small groups of scientists to use. In 2009, Murchison brought samples from the roadkill devil to the Wellcome Trust Sanger Institute in England to read its DNA more closely than anyone had read the tumor DNA before.
The genome in the tumors had undergone many changes, but Murchison could trace back its history through earlier generations. She found a pair of X chromosomes in the cells, and no trace of a Y chromosome. So the cancer must have begun in a female devil. Murchison then looked for clues about which kind of cell it started out as. She sequenced the microRNAs from tumor cells. The cells were making a combination of molecules typically only found in one kind of cell. It's
a type of nerve known as a Schwann cell, which normally wraps an insulating sleeve around other neurons to help them send their signals.
At some point in the early 1990s, Murchison's research showed, a single
Tasmanian devil in the northeast corner of the island got cancer. The mutations may have initially arisen in a Schwann cell. The descendants of that original cancer cell grew into a tumor. During a fight, another devil bit off the tumor. The cancer cells did not end up digested in the attacker's stomach. Instead, they likely lingered in the devil's mouth, where they were able to burrow into the cheek lining and work their way metastatically into the other tissues in the devil's head.
The cancer cells continued dividing and mutating, until they broke through the skin of the second devil's face. At some point, that new victim also got bit, and its own attacker took in the cells from the original cancer. A single carrier could pass the cancer on to several other devils if it was especially aggressive, and thus help accelerate its spread. Passing through host after host, the tumor cells gained about twenty thousand new mutations.
As strange as it had become, the devil's contagious cancer has not escaped the bonds of heredity. All the tumors that grew in thousands of Tasmanian devils were united along an unbroken line to their female Schwann cell ancestor. But the conventional language we use to describe heredity fails to describe what is happening in Tasmania.
August Weismann had crystallized our conception of heredity by giving germ cells a chance for immortality. Now a batch of somatic cells from a mammal had gained an immortality of its own by moving out of its original body and ending up in new ones. The original cancerous Schwann cell died inside a Tasmanian devil decades ago, as did the subsequent victims of its cancer. But the tumors endured because they were in the right place for another Tasmanian devil to bite off a chunk of them and let them live on in a new home.
Murchison's research showed just how cobbled together heredity is. It's not a cosmic imperative but a process that emerged from biological ingredients and has been modified into new forms. And yet, on their own, devil facial tumors might have ended up as little more than a philosophical curiosity. It was easy to dismiss them as the product of a weird species restricted to a remote corner of the world. In fact, contagious cancers were cosmopolitan, spanning the planet.
Murchison knew that there was at least one other form of contagious cancer: a disease in dogs known as canine transmissible venereal tumor (CTVT for short). It's a particularly ugly disease, causing oozing tumors to grow around the genitals. The disease is found in many countries and is most common in stray dogs. Because it's disgustingly obvious, pet owners quickly take their animals to the vet for treatment.
While devil facial tumors only came to light in the 1990s, the symptoms of CTVT were already known by 1810. In a book called
A Domestic Treatise on the Diseases of Horses and Dogs
, the British veterinarian
Delabere Blaine described a “fungous excrescence” that formed around the genitals of dogs. At the time, some physicians believed the growths were caused by bad humors, while others thought they spread like the plague.
It wasn't until 1876 that a Russian veterinarian named
Mstislav Novinski carried out the first successful transplant of the cancer. He cut pieces of a canine transmissible venereal tumor from a sick dog and inserted them in the skin of two puppies. After a month, each puppy had a tumor of its own. Novinski then cut off a piece of one of the new tumors and grafted it to another dog. The second-generation tumor grew as well.
Later generations of scientists carried out more detailed versions of Novinski's experiment.
In 1934, a veterinarian and a pathologist reported carrying the cancer forward through eleven dogs. But they could succeed only when they used living cancer cells. Dead cells wouldn't do the trick, nor the fluid from tumors. In a few cases, the cancer became metastatic and killed the dogs, but most of the time it grew for a few months before disappearing. “The origin of the cells forming this tumor is unknown,” the researchers wrote. They suspected that sometimes dogs could spontaneously develop the cancer and then pass it to other dogs through mating.
Cancer biologists paid CTVT little mind, because it didn't work like standard cancerâwhich is caused either by random mutations or by certain viruses. But the discovery of contagious cancers in Tasmanian devils led a number of scientists to take another look. In 2006, a British biologist
Robin Weiss and his colleagues collected CTVT tumors from forty dogs on five continents. They sequenced short pieces of DNA from each one, along with healthy cells from other parts of the dogs. Weiss and his colleagues found that the dogs were also chimeras, not mosaics. All the cancer cells shared a common set of genetic variantsâvariants that couldn't be found in the healthy cells in any of the dogs. Rather than cropping up from time to time in different dogs, the scientists realized, the disease had arisen just once.
Murchison followed up on Weiss's study with one of her own. Instead of looking at snippets of DNA, she and her colleagues sequenced the entire genomes of two tumor cells. One came from a cocker spaniel in Brazil and the other from an Aboriginal camp dog in Australia. Each tumor cell had just over 100,000 unique mutations not shared by the other one. But the two cells shared 1.9 million mutations in common that Murchison didn't find in ordinary dog DNA.
The cancer cells still carry clues about their origins. Murchison suspects that they descend from some kind of immune cells, based on the genes they use and the ones they keep quiet. That signature may be a distant echo from the origin of CTVT: An immune cell in an ancient dog turned cancerous, and eventually the cancer found a way to other dogs.
Murchison and her colleagues also discovered that CTVT is far, far older than devil facial tumor. Mutations accumulate in cancer cells at a roughly clock-like rate. Based on the mutations in different CTVT cells, Murchison and her colleagues estimated that the cancer arose in a single dog about eleven thousand years ago, around the end of the Ice Age.