A Planet of Viruses - Carl Zimmer (2011)

EVERYWHERE, IN ALL THINGS

Our Inner Parasites

Endogenous Retroviruses

The idea that a host’s genes could have come from viruses is almost philosophical in its weirdness. We like to think of genomes as our ultimate identity. We know who our biological parents are because they gave us our DNA. In our DNA are not just the instructions for the color of our skin or our susceptibility to diabetes. Our very nature lurks there. That’s why the idea of cloning is so abhorrent: no one should have to carry secondhand genes.

But if most of an organism’s genes arrived in its genome in a virus, does it even have a distinct identity of its own? Or is it just a mishmash of genes, cobbled together by evolution? It’s as if the world was filled with hybrid monsters, with clear lines of identity blurred away.

Microbiologists have been getting used to the viral roots of the microbes they study for decades now. And as long as microbes were the only organisms with much evidence of virus-imported genes, we could try to ignore this philosophical weirdness by thinking of it merely as a fluke of “lower” life forms. But now we can no longer find comfort this way. If we look inside our own genome, we now see viruses. Thousands of them.

We have the jackalope to thank for this realization. The myth of the jackalope was one of the clues that led virologists to discover that some viruses cause cancer. In the 1960s, one of the most intensely studied cancer-causing viruses was avian leukosis virus. At the time, the virus was sweeping across chicken farms and threatening the entire poultry industry. Scientists found that avian leukosis virus belonged to a group of species known as retroviruses. Retroviruses insert their genetic material into their host cell’s DNA. When the host cell divides, it copies the virus’s DNA along with its own. Under the certain conditions, the cell is forced to produce new viruses—complete with genes and a protein shell—which can then escape to infect a new cell. Retroviruses sometimes trigger cells to turn cancerous if their genetic material is accidentally inserted in the wrong place in their host’s genome. Retroviruses have genetic “on switches” that prompt their host cell to make proteins out of nearby genes. Sometimes their switches turn on host genes that ought to be kept shut off, and cancer can result.

Avian leukosis virus proved to be a very strange retrovirus. At the time, scientists tested for the presence of the virus by screening chicken blood for one of the virus’s proteins. Sometimes they would find the avian leukosis virus protein in the blood of chickens that were perfectly healthy and never developed cancer. Stranger still, healthy hens carrying the protein could produce chicks that were also healthy and also carried the protein.

Robin Weiss, a virologist then working at the University of Washington, wondered if the virus had become a permanent, harmless part of the chicken DNA. He and his colleagues treated cells from healthy chickens with mutation-triggering chemicals and radiation to see if they could flush the virus out from its hiding place. Just as they had suspected, the mutant cells started to churn out the avian leukosis virus. In other words, these healthy chickens were not simply infected with avian leukosis virus in some of their cells; the genetic instructions for making the virus were implanted in all of their cells, and they passed those instructions down to their descendants.

These hidden viruses were not limited to just one oddball breed of chickens. Weiss and other scientists found avian leukosis virus embedded in many breeds, raising the possibility that the virus was an ancient component of chicken DNA. To see just how long ago avian leukosis viruses infected the ancestors of today’s chickens, Weiss and his colleagues travelled to the jungles of Malaysia. There they trapped red jungle fowl, the closest wild relatives of chickens. The red jungle fowl carried the same avian leukosis virus, Weiss found. On later expeditions, he found that other species of jungle fowl lacked the virus.

Out of the research on avian leukosis virus emerged a hypothesis for how it had merged with chickens. Thousands of years ago, the virus plagued the common ancestor of domesticated chickens and red jungle fowl. It invaded cells, made new copies of itself, and infected new birds, leaving tumors in its wake. But in at least one bird, something else happened. Instead of giving the bird cancer, the virus was kept in check by the bird’s immune system. As it spread harmlessly through the bird’s body, it infected the chicken’s sexual organs. When an infected bird mated, its fertilized egg also contained the virus’s DNA in its own genes.

As the infected embryo grew and divided, all of its cells also inherited the virus DNA. When the chick emerged from its shell, it was part chicken and part virus. And with the avian leukosis virus now part of its genome, it passed down the virus’s DNA to its own offspring. The virus remained a silent passenger from generation to generation for thousands of years. But under certain conditions, the virus could reactivate, create tumors, and spread to other birds.

Scientists recognized that this new virus was in a class of its own. They called it an endogenous retrovirus—endogenous meaning generated within. They soon found endogenous retroviruses in other animals. In fact, the viruses lurk in the genomes of just about every major group of vertebrates, from fish to reptiles to mammals. Some of the new endogenous retroviruses turned out to cause cancer like avian leukosis virus, but many did not. Some seemed to be effectively muzzled by their host. Certain endogenous retroviruses carried by mice cannot infect mice cells, for example, but they can readily spread among rat cells.

Other endogenous retroviruses turned out to be crippled, carrying mutations that robbed them of the ability to make full-fledged viruses. They could still make new copies of their genes, however, which were then reinserted back into their host’s genome. And scientists also discovered some endogenous retroviruses that were so riddled with mutations that they could no longer do anything at all. They had become nothing more than baggage in their host’s genome.

Endogenous retroviruses can linger in their hosts for millions of years. In 2009, Aris Katzourakis, an evolutionary biologist at the University of Oxford, discovered hundreds of copies of endogenous retroviruses in the genome of the three-toed sloth. Their genes closely matched those of foamy viruses, free-living pathogens that infect primates and other mammals. Katzourakis concluded that foamy viruses infected the common ancestor of three-toed sloths and primates, which lived a hundred million years ago. In primates, they’ve remained free-living. In the sloth lineage, however, they became trapped in their host’s DNA and have remained there ever since.

As scientists discovered endogenous retroviruses in other species, they naturally wondered about our own DNA. After all, we suffer infections from many retroviruses. Virologists tried coaxing endogenous retroviruses out of human cells without any luck. But when they scanned the human genome, they found many segments of DNA that bore a striking resemblance to retroviruses. Many of those segments resembled retrovirus-like segments in apes and monkeys, suggesting that they had infected our ancestors thirty million years ago or more. But some of the retrovirus-like segments in the human genome had no counterparts in any other species. It was possible that the segments unique to humans started out as retroviruses that infected our ancestors a million years ago.

To test this idea, Thierry Heidmann, a researcher at the Gustave Roussy Institute in Villejuif, France, tried to bring a human endogenous retrovirus back to life. Searching through the genomes of different people, he and his colleagues found slightly different versions of one retrovirus-like segment. These differences presumably arose after a retrovirus became trapped in the genomes of ancient humans. In their descendants, mutations struck different parts of the virus’s DNA.

Heidmann and his colleagues compared the variants of the virus-like sequence. It was as if they found four copies of a play by Shakespeare, each transcribed by a slightly careless clerk. Each clerk might make his own set of mistakes. Each copy might have a different version of the same word—say, wheregoreshereforewhoreforewherefrom. By comparing all four versions, an historian could figure out that the original word was wherefore.

Using this method, Heidmann and his fellow scientists were able to use the mutated versions in living humans to determine the original sequence of the DNA. They then synthesized a piece of DNA with a matching sequence and insert it into human cells they reared in a culture dish. Some of the cells produced new viruses that could infect other cells. In other words, the original sequence of the DNA had been a living, functioning virus. In 2006, Heidmann named the virus Phoenix, for the mythical bird that rose from its own ashes.

Retroviruses are a major threat to human health when they’re free-living, but even after they become endogenous they remain dangerous. Mutations can give them back the ability to make full-blown viruses that can escape and cause new infections and even cause cancer. Endogenous retroviruses that can only insert new copies of their DNA into their host genome are dangerous as well, because they can cause genes that are shut down to switch on at the wrong times. The threat from endogenous retroviruses is so great, in fact, that our ancestors evolved weapons that exist only to keep these viruses from spreading.

Paul Bieniasz, a virologist at Rockefeller University, discovered two of these weapons in 2007 by reviving an endogenous retrovirus, as Hiedmann’s team had revived Phoenix the year before. Bieniasz dubbed his resurrected virus HERV-K[con]. When he infected human cells with it, he found that the cells could fight the virus using two proteins called APOBEC3. Bieniasz’s experiments suggest that APOBEC3 homes in on endogenous retroviruses as they are making new copies of themselves destined to be inserted back into the host’s genome. The protein upsets the gene-copying process so that the new copies of the viruses pick up extra mutations. The extra mutations act like a hail of bullets. Some of them don’t cause any harm, but if one of them hits a vital spot in the virus’s DNA, it can cripple the virus so that it can no longer reproduce.

Proteins like APOBEC3 disable endogenous retroviruses, but they don’t eliminate them. Over millions of years, our genomes have picked up a vast amount of DNA from dead viruses. Each of us carries almost a hundred thousand fragments of endogenous retrovirus DNA in our genome, making up about 8 percent of our DNA. To put that figure in perspective, consider that the twenty thousand protein-coding genes in the human genome make up only 1.2 percent of our DNA. Scientists have also observed millions of smaller pieces of “jumping DNA” in the human genome. It’s possible that many of those pieces evolved from endogenous retrovirus, having been stripped down to the bare essentials required for copying DNA.

Endogenous retroviruses may be dangerous parasites, but scientists have discovered a few that we have commandeered for our own benefit. When a fertilized egg develops into a fetus, for example, some of its cells develop into the placenta, an organ that draws in nutrients from the mother’s tissues. The cells in the outer layer of the placenta fuse together, sharing their DNA and other molecules. Heidmann and other researchers have found that a human endogenous retrovirus gene plays a crucial role in that fusion. The cells in the outer placenta use the gene to produce a protein on their surface, which latches them to neighboring cells. In our most intimate moment, as new human life emerges from old, viruses are essential to our survival. There is no us and them—just a gradually blending and shifting mix of DNA.