She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (54 page)

If it had been an ordinary tumor, CTVT might have endured for a few years, until its host died. Instead, it escaped mortality's trap and endured a thousand times longer than a typical dog. In different parts of the world, the tumor cells acquired new mutations that they passed on to their descendants. Those mutations sketched out a map of the tumor's journey. It began somewhere in the Old World; when Europeans brought dogs on ships to new continents like Australia and North America, they brought CTVT
with them. While devil facial tumor may be limited to a corner of the world,
humans have spread CTVT everywhere they brought their dogs.

Two cases of contagious cancer would have been extraordinary enough. But as Murchison was studying dogs and devils, another case came to light—not on land, but
in the sea.

In the 1960s, marine biologists discovered a leukemia-like cancer in some species of clams. Their immune cells multiplied explosively, invading all of the animal's tissues. It typically took just a few weeks for the cancer to claim a clam's life.

The biologists had never seen anything quite like the cancer before. What made it especially baffling was how quickly new cases turned up. Once one clam in a population got sick, it didn't take long before almost all the animals died. This cancer roared up the East Coast until, by the 2000s, it was killing soft-shell clams from New York all the way north to Prince Edward Island in Canada.

Two biologists at Columbia University, Stephen Goff and Michael Metzger, studied the clams to see if a virus was triggering them to form tumors. They found no sign of cancer-causing viruses. And when Metzger and his colleagues looked at DNA from the cancer cells, they were flummoxed to find that the cells in different clams shared a common set of genetic markers. It looked as if the scientists had stumbled across a third contagious cancer.

To test this idea, Metzger brought clams into Goff's lab and put them into tanks. If he put a healthy clam in a tank with a cancerous one, it became cancerous, too.

Surveying cancer cells from along the East Coast of North America, Metzger could find mutations in some of them and not others, allowing him to draw a genealogical tree. Some long-ago clam had developed leukemia, Metzger and Goff concluded, and it expelled some of its cancer cells into the ocean currents. As nearby clams filtered seawater for bits of food, they also sucked in the cancer. Over the years, the outbreak had hopscotched its way hundreds of miles from its origin.

Metzger and his colleagues knew that marine biologists had been finding fast-spreading cancers in some other species of clams as well as other bivalves. In all these cases, scientists had tried to find a cancer-causing virus and had come up empty-handed. Metzger got in touch with colleagues around the world and was able to get hold of three sickened species to study: mussels, cockles, and golden carpet shell clams. All three of their cancers also turned out to be contagious.

The cockles proved to have not one strain of contagious cancer but two. And the cancer in the golden carpet shell clams had particularly weird DNA: It didn't start out as a golden carpet shell clam. Instead, it came from pullet shell clams, another species that lives in the same intertidal beds off the coast of Spain as the golden carpet shell clam. That discovery led the scientists to inspect pullet shell clams, but they failed to find any of the cancer cells in them. They concluded that a strain of contagious cancer must have started in pullet shell clams and then jumped species, infecting golden carpet shell clams. It killed off all the vulnerable pullet shell clams, leaving only resistant ones behind.

Meanwhile, back in Tasmania, biologists were busy trying to protect the devils from extinction. They built colonies of healthy animals at zoos and turned a small island off the coast of Tasmania into a refuge. If the devil facial tumor did kill off all the wild devils of Tasmania, the protected animals could be brought back. But in March 2014, a University of Tasmania graduate student named Ruth Pye made an ominous discovery. She was analyzing cancer cells from a devil caught south of the city of Hobart and found something in them that shouldn't have been there: a Y chromosome. Murchison and her colleagues had already established that the progenitor of the disease had been a female devil. Pye's new cancer looked as if it had started in a male.

A close examination of its entire genome revealed a wealth of unique mutations not found in any of the other tumors. The data pointed to an inescapable conclusion: Pye had discovered
a second devil facial tumor. Later she and her colleagues found another seven sick devils in the region with the same form. They dubbed the two lines of contagious cancer DFT1 and DFT2.

While DFT1 arose around 1990, DFT2 has fewer mutations of its own, suggesting it emerged more recently. It's a worrying finding, because it means that the process by which contagious cancers emerge in devils may be more common than previously thought. If conservation biologists manage to save the devils from DFT1 and DFT2, who's to say they won't face DFT3 before long?

From the cancers identified so far, scientists can start developing hypotheses for how they emerge and manage to break heredity's rules. It looks as if the ability to become a contagious cancer is not limited to one particular type of cell. It just has to start down the road to cancer. One of the biggest challenges to a developing tumor is the immune system, which continually patrols the body for suspicious-looking cells. Cancer cells can evolve a range of tricks to evade detection. They can cut back on their production of surface proteins such as HLA that immune cells recognize in order to tell good cells from bad, for example.

No one knows yet what sort of adaptations cancer cells need to survive the first
journey from one host to another. Perhaps it all comes down to an accidental mutation that keeps them from desiccating in the dry air. Once they've made the first jump, their immune evasions become even more valuable, because now they are clearly foreigners, rather than traitors from within. And once the contagious cancer cells move into a new host, some of the adaptations they gained in their normal existence as a tumor may turn out to help them once more. They can send out signals to the surrounding tissue, hypnotizing cells into helping them get nourishment.

Contagious cancer is not all that different from an ordinary tumor that becomes metastatic and spreads from one organ to another. The new organ is, in effect, another animal. But unlike ordinary tumors, contagious cancers no longer face an inescapable death. Instead of gaining a few years' worth of mutations, they can gain centuries of them. After eleven thousand years circulating among dogs, for example, CTVT has acquired an impressive arsenal of mutations in
genes linked to immune surveillance. And just like ordinary cancer cells,
CTVT cells have stolen mitochondria to replace their own. The only difference is that they steal mitochondria from a series of dogs—at least five different dogs over the past two thousand years. From
the days of the Roman Empire onward, CTVT has recharged itself like a vampire, with the youth of its canine victims.

Contagious cancers were a scientific secret hiding in plain sight for two centuries. Once scientists realized what they were and started to wonder if there were others, they started finding more. It's almost certain that
the eight cases identified so far are not the last. No one knows just how many there will be. It's possible that some species will prove to be more prone to them than others. The small population of Tasmanian devils may make them vulnerable, because they have a low level of genetic diversity. In such a species, it's easier for a contagious cancer to hide inside new hosts, because it doesn't look so suspiciously foreign. Contagious cancers also need an easy route from one host to the next. Dogs have long bouts of sex that can last half an hour and leave them with broken skin. That's a promising route for a tumor adapted to growing around the genitals. But we shouldn't underestimate the lengths that contagious cancer cells can go to in order to get into new hosts. After all, now we know they can swim.

Indeed, even if scientists come across more cases of contagious cancers, the true rate may be far higher. Perhaps, like gene drives, contagious cancers are regularly emerging from animals, only to disappear—either because the immune systems of their hosts evolve a potent defense or because they drive their hosts to extinction.

All of which raises the disturbing question: Could we humans develop a plague of contagious cancer? I'm not talking about an epidemic of cancer-causing viruses, such as HPV, which can cause cervical cancer. I'm talking about human cells taking up residence in other humans: tumors that travel across the social planet.

The scientific literature is sprinkled with intriguing
cases of cancer cells moving from one person to another. A transplanted kidney turned out to contain a tumor. A surgeon accidentally nicked his hand, allowing his patient's skin cancer to slip into his body. A few pregnant women with leukemia
passed some of their cancerous immune cells to their fetuses. In an
exceptionally bizarre case, a man in Medellín, Colombia,
got infected with a tapeworm from which a cell grew into a tumorlike mass.

Yet all of these cases only document cancer making a single leap. There's no evidence of the same lineage of cancer cells moving on to a third victim. It may be that our immune systems are so strong that cancers never get the chance to evolve into parasites that can leap from host to host.

Why our immune system should react so violently to foreign tissue is puzzling. For the most part, our immune system is exquisitely adapted to particular threats. Our cells can sense invading viruses and commit suicide to stop their infection. We can make antibodies to destroy a strain of bad bacteria while sparing our beneficial bugs. These are the products of evolution, which gave our ancestors better odds of surviving and reproducing. But our ancestors were not constantly transplanting lungs and spleens into each other.

So why should our immune system be so well prepared to respond? One way to make sense of this enigma is the risk of contagious cancers. Perhaps our early animal ancestors 700 million years ago regularly faced invasions of parasitic offshoots of other animals. They had to fight off the heredities of others, or die and lose their
own.

W
HEN THE DARK
of moonless nights arrives,
the one-fin flashlight fish emerges from its hiding place.

This fish (scientifically known as
Photoblepharon palpebratus
) lives in the waters off the Banda Islands, a scattered archipelago in Indonesia. It spends the daylight hours resting in caves a hundred feet or more underwater. When the sea turns black, the fish swims out of its caves, up to the surface waters. As it hunts for little invertebrates, its body emits a cream-colored light.

Like any animal, the flashlight fish is actually a collection of organs. Its skin acts as a barrier, protecting it from the surrounding sea. Its gills draw oxygen. Its stomach digests its prey. Each organ is distinct, because its cells produce a distinctive collection of molecules and operate a distinctive network of genes. The light made by the fish comes from a pair of jelly-bean–shaped structures under each eye. To produce their light, the cells in those jelly beans manufacture proteins that glow.

Shining a light might not seem a very smart thing to do when you're a small fish swimming in a sea of predators. But flashlight fish can actually use it to escape their enemies. To flee, they dash straight ahead for a while, their light organs tracing a forward-moving line. They then roll each light organ into a pocket in their head. The fish suddenly go dark and then break away from their straight line, leaving predators barreling forward into empty water.

Their light organs thus help the fish survive long enough to reproduce. The males cast sperm into the water to fertilize female eggs, which develop into larvae and finally into mature fish.
Like engenders like
is as true for flashlight fish as for any other animal. Every new generation developed fins like their ancestors did, along with eyes, jaws, and gills. And light organs.

In 1971, a pair of scientists—Yata Haneda of the Yokosuka City Museum and Frederick Tsuji of the University of Pittsburgh—journeyed to the Banda Islands to investigate the one-fin flashlight fish. In the evenings, they would push off from shore in a canoe. Eventually they would extinguish their lights and gaze into the water, searching for the fish's gleam. When Haneda and Tsuji caught some in a net, they put the animals in jars of seawater and later dissected the light organs. Even after they were carved out of the animals, the organs still glowed. (Banda fishermen use the light organ as a lure, putting it on a hook, where it can glow for hours.)

Haneda and Tsuji inspected the light organ cells under a microscope to understand how they worked. It was possible that the fish produced their light like fireflies. Fireflies carry a gene in their DNA for a protein called luciferin. The insects store luciferin in the cells in their tail. When they want to send a signal to their fellow fireflies, they use other proteins to alter the luciferin, unleashing its stored light. Fireflies inherit the luciferin gene from their parents, along with the rest of their genes.

But the one-fin flashlight fish has no genes for making light, Haneda and Tsuji discovered. The glowing cells in their light organ do not belong to the fish itself. They are bacteria.

They are not just any bacteria, however. If you look in the light organs of any one-fin flashlight fish
,
the glowing microbes always belong to the same strain, known as
Candidatus
Photodesmus blepharus. And if you want to find
Candidatus
Photodesmus blepharus, the one-fin flashlight fish is the only species on Earth where you'll find it. The same waters around the Banda Islands are also home to a nearly identical species, the two-fin flashlight fish, with its own bacteria-loaded light organ. But the bacteria glowing inside them is different. Each species of flashlight fish inherits its own exquisitely rare microbial partner.

All species of animals and plants are shot through with microbes, ourselves included. By one estimate, each human being contains
about 37 trillion human cells and about the same number of bacteria. It's easy to ignore our bacterial half, because human cells are hundreds of times bigger than microbes. Yet that's no reason to ignore them. We have thousands of species of bacteria within us, each carrying thousands of its own genes that are fundamentally unlike our own. In this respect,
we are no different from any other animal—any Portuguese man-of-war, any desert scorpion, any elephant seal. We're not even very different from a sugar maple tree or an evening crocus.

The bacteria we're most familiar with are those that cause diseases, chewing through our skin and raging through our guts. Yet even in the best of health, we are still rife with permanent lodgers. Some harmlessly cling to their hosts, scavenging molecular scraps. Others perform tasks on which their hosts depend for their survival. If the flashlight fish had no bacteria, it would have no flashlight. Other microbes carry out tasks that are harder to see but no less important. They synthesize vitamins, they nurture a well-tempered immune system, they form a living barrier against dangerous pathogens. The microbiome, as this collective is known, blurs any simple notion of what it means to be an individual organism. If we turned into true individuals, sterilized of our microbiome, we'd become sick and might well die.

In each species, every new generation acquires a microbiome. In some regards,
this cycle of renewal looks a lot like heredity. A new animal does not acquire its own genes out of the blue, synthesized from scratch. Its genes have been duplicated over and over again inside the cells of its ancestors, taking an extraordinary journey to get to each new animal. A man, for example, starts off as a zygote full of genes, which are copied each time that fertilized egg divides. The genes end up in totipotent cells, and then in pluripotent cells, and then in cells destined for different tissues. Some of those cells end up as germ cells. As these cells migrate through the
body, they bring their genes to the region where the testicles will later develop. Years later, the descendants of these cells may develop into long-tailed sperm, each containing only one copy of each of the man's genes. Although a man makes billions of sperm over the course of his life, only a tiny fraction of them at most will ever manage to leave his body and enter a woman's reproductive tract, and fewer still will deliver his genes into an egg.

The genes of bacteria can take strikingly similar routes of their own through the generations of their hosts. One of the most remarkable of these journeys takes place thousands of feet underwater, where
thick beds of vesicomyid clams thrive around cracks in the seafloor. The clams soak up hydrogen sulfide—the toxic chemical that gives rotten eggs their awful smell—rising out of the cracks. They absorb it into their muscles, and then their circulatory system delivers the compound to their gills. Special cells in the gills—cells that don't exist in other species of clams—split sulfur atoms from the hydrogen sulfide molecules, releasing the energy stored in their bonds. The clam uses this energy to combine carbon, hydrogen, and oxygen into sugar molecules. The clams act much like trees, except that they capture a subterranean chemical energy instead of sunlight.

To be precise, it's not the clams themselves that seize the seafloor's energy. The specialized cells in their gills are actually bacteria. They carry the gene for an enzyme that can break down hydrogen sulfide. In exchange for this service, the clams supply the bacteria with a well-appointed home. Without those bacteria, the clams would starve; without the clams, the bacteria would barely eke out an existence.

This relationship is remarkable for many reasons, not the least of which is geography. Because vesicomyid clams can grow only where hydrogen sulfide seeps out of the seafloor, clam beds may be miles from each other. The clams broadcast their sex cells into the surrounding water, and after fertilization the clam larvae drift through the sea. Most of them will land in the marine desert and die. Only a few will end up at a site where they can grow. They bring with them the bacteria they need to survive, as their ancestors did.

To understand how the clams manage to hold on to their partners is difficult, because it's nearly impossible to rear a deep-sea creature in the comfort of a laboratory. Instead, scientists haul up clams from the seafloor and pick apart their dead bodies for clues. In 1993,
S. Craig Cary and Stephen Giovannoni of Oregon State University mapped the bacteria inside clams by searching for their DNA. They found some in the gill cells that house the microbes. But they also found some bacterial DNA in the ovary-like organs where clam eggs develop. Somehow the bacteria were traveling through the clams from the gills to the eggs, which they could invade in order to get into the next generation. The new clams are born infected, inheriting an expanded set of genes—some animal and some bacterial.

It's hard not to wonder what Darwin would have thought of these clams. When he pictured heredity, he saw gemmules streaming from across the body to the germ cells, coming together to carry on the body's traits to the next generation. His theory of pangenesis turned out to be wrong, and biologists set it aside as one of his exceptional blunders. They turned instead to August Weismann's stark division between the germ line and the soma. Now researchers are finding that deep-sea clams use a gemmule-like form of heredity to carry their partners into the future.

If these deep-sea clams were the only species on Earth to inherit a vital trait this way, it might be possible to dismiss them as an oddity, in the same way it was once possible to dismiss contagious cancers as a Tasmanian fluke. But they have company. Many animals ensure that essential bacteria get inside their eggs. And some of them—like
cockroaches—are a lot easier to study than deep-sea clams.

Among the microbes that live inside cockroaches is one called
Blattabacterium.
Just like clams, cockroaches develop special cells inside of which
Blattabacterium
can dwell. Instead of feeding on chemical-laden seawater, cockroaches graze on organic matter on land, able to survive on what they find on the floor of a forest or a New York apartment.
Blattabacterium
is essential to their global conquest. As the insects eat, they store away nitrogen in an organ in the cockroach abdomen, called the fat body. Inside the fat body are some cells infected with
Blattabacterium.
The bacteria
convert that nitrogen into amino acids and other building blocks that the cockroach needs to grow.

Sometimes the cells housing
Blattabacterium
will take a trip. They crawl out of the fat body and seek out the cockroach's eggs. They attach themselves to the eggs for a few days before ripping themselves open. Their resident bacteria spill out, to be swallowed up by the eggs, so that a new generation of cockroaches can continue to conquer the world.

These strictly in-house bacteria—known as endosymbionts—did not always live this way. Their ancestors lived outside of hosts. The free-living cousins of endosymbionts have helped researchers learn about how some bacteria have evolved into such intimate partners. In case after case, the microbes took
a gradual slide into a life inside.

This research shows that when the free-living ancestors of endosymbionts came into contact with a host—be it a roach, a clam, or one of millions of other species—they could grow on it by good fortune, or even inside it. By sheer coincidence, these bacteria provided some benefit to their hosts—perhaps casting off a useful amino acid in their waste. If their hosts did well as a result, the bacteria had more opportunity to reproduce in them. Natural selection favored bacteria that could do their hosts more favors because their interests were becoming aligned. Likewise, their hosts evolved to nurture the bacteria. Evolving special cells to shelter the bacteria ensured that animals could enjoy their services.

As the bacteria grew ever more pampered, genes that were once essential in the outside world became useless. Mutations that broke these newly superfluous genes no longer guaranteed extinction. The bacteria became genetically streamlined, their genomes shrinking in size by 90 percent or more. Some endosymbionts have lost the ability to do just about anything except the one thing that their host can't do.

Both the bacteria and their animal hosts became trapped in an evolutionary rabbit hole from which there is no escape. Once they were locked in symbiosis, their evolution began to follow identical paths. When an insect
species split in two, its endosymbionts split as well. Their evolutionary trees became mirror images, with identical branches splitting from each other for tens of millions of years.

The story of the one-fin flashlight fish is a lot like those of the clams and the cockroaches. It also builds a special shelter—the light organ—where its bacteria can thrive. Every new generation of flashlight fish inherits a fresh supply of the same species of bacteria. In effect, the fish are expanding their genomes to include light-producing genes. Those genes just so happen to belong to a separate species. As the bacteria have adapted to life inside light organs, they have lost
80 percent of their genome.

There is one important difference, however. A female flashlight fish does not carefully move bacteria inside her body, transferring them from her light organ into her eggs. Her offspring hatch from their eggs lacking the microbes they need to glow. To gain their own flashlight, they have to get infected.

Each day, as an adult one-fin flashlight fish hunkers down in a cave, it sheds some of its bacteria. While
Candidatus
Photodesmus blepharus has lost most of the genes required to live outside an animal, it still clings to a few. Some of the genes enable it to build tails it can whip back and forth to swim through the sea. It also still retains genes for making chemical-sensing proteins, which it likely uses as a molecular nose, sniffing its way to young flashlight fish that it can invade. Ultimately, though, it's up to the fish to let the bacteria into their light organ. They've got a strict admission policy: The same waters also teem with the bacteria that give light to the two-fin flashlight fish, but those microbes can't get in.