Strange Bedfellows

Viruses make us sick, drive evolutionary change––and are part of us.

Virus is a Latin word for poison.

Appropriate enough when you consider the most recent Ebola outbreak, which, by February 2015, had killed 9,000 people in West Africa (with fewer than 20 deaths elsewhere). Far worse: the 1918-19 influenza pandemic, which killed an estimated 30-50 million people worldwide, and the HIV-AIDS epidemic in which an estimated 39 million people have perished, with Sub-Saharan Africa bearing most of the loss.

But aside from their role as virulent killers, viruses—stripped-down packets of genetic material in a protein wrapper—exist in millions of forms with wide-ranging effects, most of them escaping our notice. They’re everywhere, with a biomass thought to be equivalent to nearly 200 million blue whales.

Virus

And here’s the shocker: viruses are part of us. As much as 8 percent of human DNA is ancient genetic code from viruses that probably infected and failed to destroy the germ cells (destined to be sperm or eggs) of our distant ancestors. Most of these little hitchhikers integrated into our genome before humans diverged from other primates and have been tagging along ever since.

Once referred to as junk DNA, these relics—known as endogenous (originating from within) retroviruses, retrotransposons (elements that copy and transfer DNA from one place to another in the genome) and other mobile elements—have been the focus of Biology Professor Keith Garrison’s research career.

“There are some endogenous retroviruses that we all have,” said Garrison. “A lot of them are very old. We share them with primates and mice. But some are more recent and some unique to the individual.”

In work he began at the University of California, San Francisco, Garrison and research colleagues looked for ways that these HERVs (human endogenous retroviruses) might help in the fight against HIV (human immunodeficiency virus). They began with the hypothesis that the immune system failed to respond to viral infections, specifically HIV, because of similarities between HERVs, which are part of us, and the invading virus.

“It turned out the opposite was true,” Garrison said. “And that’s what I always tell my students. Don’t try to prove hypotheses true. That’s not how science works. Often you make the most interesting discoveries when something completely opposite happens.”

Garrison and his colleagues observed that, in some people, the presence of HIV in a cell seemed to turn on inactive sequences of fossilized retroviruses, turning them into a flag or alert that HIV was present. The hope is that study of HERVs could someday lead to a more reliable way to prevent infections by a deadly virus that mutates and adapts so quickly that it’s difficult to create a vaccine against it.

The study of fossilized virus fragments could be important in other ways—in the fight against cancer, for example. Garrison, one of a still relatively small number of researchers studying HERVs, is interested in a better understanding of the biology and history of these ancient, non-infectious scraps of genetic code. “We want to know what factors turn them on, what factors turn them off,” he said. “Could a cancerous state in a cell turn on the fossilized fragments and act as a signal for recognizing cancer cells?” By doing more basic, fundamental research, we can explore a lot of possibilities, he said. “So, we started to look at the history of these viruses and what diversity is present in the population.”

One of Garrison’s summer research students, Thomas Reynolds ’11, found a promising mutation in a segment of one of the endogenous retroviruses in the cell line. “It acted as part of an on/off switch,” Garrison said. “That’s interesting to think about. Could we learn more about what factors help to flip the switch?”

The study of viruses on a broader scale—their diversity and their behaviors—also provides clues to the origins and evolution of life on Earth. Besides making us sick, viruses have played an important evolutionary role in the natural world, functioning as major drivers of evolution in the genome, “because they’re good at passing genes around horizontally,” Garrison said. Genetics is about vertical transmission, passing genes down from parent to child. Viruses are able to grab genes and move them around within a single generation, causing the relocated genes to be passed on to future generations. “It’s a different way to think about inheritance and evolution,” Garrison said.

HERVs are part of a much larger family of so-called junk DNA called mobile elements, sequences able to move around the genome, changing their number and location, and influencing neighboring genes for both good and bad. Mobile elements account for as much 50 percent of the human genome and up to 90 percent in some plants.

“This is what I’ve looked at throughout my whole career, as a graduate student, as a post doc and as a researcher here,” Garrison said, “thinking about this autonomous component of our DNA, that’s made up of these elements that can move around. What do they do? How do we adapt to them? How do they adapt to us?”

An important example of the influence of viruses on human life is their suspected role in the evolution of mammals. The development of the mammalian placenta—which provides nutrients, oxygen and waste removal for a developing fetus—makes live birth and bigger brains possible. Some researchers think viruses are behind it all.

“One of the things viruses do very well is fuse with the host cell in order to infect it,” Garrison said. Some researchers think that cells in the placenta adopted this fusion ability from a virus and used it to make a fused cell layer that regulates blood flow and supplies nutrients for the fetus, he said, adding that this explanation is still controversial and that some placenta specialists don’t really buy it.

More recently, Garrison has become interested in viral infections in coral. Under stress they produce herpes viruses, which are well known for remaining latent and under control until something challenges their immune system.

“Coral is a stripped-down model of an organism that consists of only an outer skin and a gut,” Garrison explained. “But we understand so little about how their immune system functions that we don’t know how to help them.” He would like to find out how the coral immune system works. “Coral may alert us to problems in the ocean environment before other less fragile species are affected,” he said.

Garrison, who won a Fulbright Award in March, has also done a lot of work on viruses in plants—it was in the tobacco plant that viruses were first discovered in 1892. This fall he will take his sabbatical and use the research award in Colmar, near Strasbourg, to study disease defense genes in wine grapes. Research on plant pathogens has implications for the wine industry and other crops upon which we depend.

Finally, an idea that’s difficult to prove and debated by researchers is the role of viruses in the development of life on the planet in the first place—quite a trick for something that isn’t, itself, alive at all. And the only fossil record it leaves is entangled in the DNA of a world of organisms. Nevertheless, a 2013 report from the American Academy of Microbiology notes that while we might wish that viruses had never existed, “without viruses, life on Earth would have been very different, or perhaps there would be no life at all.”

It is interesting, Garrison said, "to think about how we can study viruses and other mobile elements as a key to unlock the past buried in the genome.”

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