Photo by Robert Hood / Fred Hutch News Service
A few years back, Dr. Alex Greninger was playing Frisbee with some friends in a park. It was a sunny summer day not long after the scientist had moved to Seattle, and Greninger soon noticed one of the city’s key, if not often celebrated, features. The park was full of Canada geese — and their leavings.
Greninger’s first reaction was typical of Seattle newcomers: “Oh, my God, I had no idea how much crap they generate,” he said.
His second reaction was also likely typical: He wondered whether there was anything infectious in that poop, which in the course of the game had smeared itself all over the Frisbee.
So Greninger, a resident in laboratory medicine at the University of Washington Medical Center and an expert in virus discovery, decided to find out. He took some of the goose poop the few blocks back to the laboratory of Fred Hutchinson Cancer Research Center virologist Dr. Keith Jerome, where just that week he’d helped install a new type of genome sequencing machine known as a next-generation sequencer.
Into the machine went the genetic material extracted from a gram of goose poop. Out popped the genome of a previously undiscovered virus, which Greninger and Jerome dubbed “goose dicistrovirus.”
Jerome leads the laboratory group that can test for — and diagnose — a huge range of human viral infections. He’s also been leading a push to get this next-generation technology, which has already made its mark in research labs, into diagnostic use. These machines capture the entire collection of the molecular letters that make up a human’s (or a virus’s) genome faster and with less expense than the older sequencing techniques.
In fact, they can read the genetic sequence of pretty much anything. And that meant that Jerome and his colleagues suddenly found themselves exploring viruses they hadn’t expected to be studying.
Photo by Robert Hood / Fred Hutch News Service
“Once you have this capacity and start to talk with folks, then opportunities come up that aren’t necessarily things that we thought of ahead of time,” Jerome said. The goose poop virus was Greninger’s idea. But soon after, Greninger and Jerome started working with other Seattle-area scientists to identify other local animal viruses — from salmon to spiders to mosquitoes.
“As a field, we’ve only sampled a fraction of the viral world that’s around us. There are always new things to learn and there are always surprises,” Jerome said.
Studying the entire genetic sequence of one creature is called genomics. What Greninger, Jerome and their colleagues are doing is known as “metagenomics,” or capturing all the genetic information from an entire community of organisms. The goose poop-derived genomes that went into the sequencing machine contained the genes of the new virus, but it also carried genetic material from the goose’s gut microbiome, plants the goose had eaten and the bird’s own cells. Metagenomics allows the researchers to see all of it.
There’s a lot you can glean just from the string of letters that make up a tiny bug’s unique genome and by understanding how it compares to the genes of other viruses out there. For example, Greninger is pretty sure this particular virus is not actually a goose virus because dicistroviruses almost exclusively infect insects.
There’s nothing to say residents of the Pacific Northwest should start worrying about getting sick from visiting our local parks. This virus almost certainly wouldn’t infect humans, Greninger said. There are no examples of this type of virus jumping from insect (or goose poop) to us.
Photo by Robert Hood / Fred Hutch News Service
But the work of understanding new viruses that infect animals in the world around us — even if those particular viruses will never make us sick — is still an important pursuit, the researchers believe. Uncovering animal viruses can help researchers like Greninger and Jerome better understand evolution, improve existing lab techniques and be better prepared for viral outbreaks that do infect humans.
When we think of viruses, most of us would think of the really bad ones, those that kill people, cause deformities and sometimes make headlines. HIV. Ebola. Zika. Flu. But the viruses that cause human illness are just the tip of the infectious iceberg. Viruses are everywhere, and not just in us. Every living thing you see around you can carry viruses you can’t see, and most of them are uniquely adapted to the specific creature they infect. There are grass viruses, spider viruses, cat viruses, even viruses that only infect bacteria.
“You could call it backyard metagenomics,” Greninger said. “There’s so much new stuff to be found that literally you could just walk outside, sample anything, and find some viruses.”
That’s plenty of material on which budding virologists could cut their teeth.
Greninger tapped two UW undergraduate trainees, Negar Makhsous and Ryan Shean, to investigate the viral variety that surrounds us.
“Viral discovery is really the gateway drug to science,” he said.
Greninger’s next inspiration for viral discovery also came from nearby the lab. One evening after dark, he was walking home from the Fred Hutch lab along Seattle’s Lake Union waterfront. Certain types of web-spinning spiders are plentiful in late summer in Seattle, and they caught his eye in the streetlights. Against the dark water, it looked like the spiders and their webs were spotlighted in midair, all around him.
“It's just these illuminated spiders hanging out,” Greninger said. “It’s kind of creepy, actually.”
Photo courtesy of Rod Crawford / Burke Museum
Did Crawford have any extra spiders sitting around that Greninger could throw in his sequencer? Crawford did. (That was the first time in his 46 years running the Burke’s spider collection that any of his specimens had been used in a virology study, Crawford said.)
Several tubes of spiders went into the virology lab. Six new spider viruses — from six different Washington state spider species — came out.
The idea that we’re all surrounded by thousands or even millions of viruses, all the time, could be mildly terrifying. But to Greninger, it’s inspiring. To him, the coolest part about the millions or billions of viruses that inhabit the world is that they’re like a carbon copy of the evolution of life itself, only much simpler. Viruses have been around since life began, and they’ve been evolving along with their hosts ever since. When the first single-celled creature eventually evolved into two different single-celled creatures, viruses were tucked away inside, quietly changing their own genes to hitch an evolutionary ride.
A fishy mystery
When he was describing his animal virus work, Greninger ticked off his local collaborators on his fingers. There was Crawford, the spider guy. There is also a “moth guy” — David Droppers, a volunteer with the Washington Butterfly Association, who would meet Greninger in the parking lot of the UW hospital with envelopes full of local moths (six new viruses found there too). Most recently, Greninger connected with Dr. James Winton, the salmon guy.
Unlike Crawford and Droppers, Winton is actually also an expert in animal viruses — in this case, fish viruses. He is recently retired from the U.S. Geological Survey and spent his career studying viruses and other pathogens in both wild and farm-raised fish. As part of his job, he helps identify viruses from wild salmon in Washington state when they return from the ocean to freshwater to spawn. This is the point in the fish’s life cycle when they are most vulnerable to infection. Because they die after spawning, the fish put all their body’s energy toward egg production, sapping the reserves used for immune defense.
Local researchers sample some of these fish to survey for any possible emerging epidemics that might affect the local wild populations. Two years ago, Winton and his colleagues had been sent a salmon virus that they couldn’t identify with the techniques they had available at the time. So the test tubes containing that mysterious virus were left sitting in their lab freezer ever since. Through a colleague, Greninger heard about the unidentified virus.
“And Alex had never met an unknown virus he didn’t like,” Winton said.
Greninger, Makhsous and their colleagues sequenced it — “literally like shooting fish viruses in a barrel,” Greninger quipped — and it turned out to be a type of aquareovirus, a virus of a class that Winton had actually discovered himself.
These viruses are typically harmless, although some types of aquareovirus found in China can be deadly to the fish, Winton said. They don’t spread to humans.
The team published a study about the new salmon virus in the Virology Journal in September. It’s more a story of collaboration and new techniques than anything that will affect local conservation efforts, Winton said. Recently, he and other USGS researchers have begun working with the Hutch’s Shared Resources teams to identify and characterize other new fish viruses.
Filling in the viral puzzle
In general, the researchers aren’t in it for the glory of discovering new viruses — of the 50 new viruses they’ve uncovered in the past two years, most haven’t even been published in scientific journals. Their sequences are immediately put in a publicly available database, though, for other scientists to use.
But the work, which Greninger has mostly been conducting on nights and weekends or whenever he can squeeze it in around his busy schedule in the hospital as a laboratory medicine resident, isn’t meant to be headline-grabbing. Rather, it’s about information-gathering.
Photo courtesy of David Droppers / Washington Butterfly Association
You might think of the entire collection the millions upon millions of nonhuman viruses in the world as a massive puzzle. Researchers like Greninger are quietly and methodically filling in the background, the hundreds of plain blue pieces that make up the sky, and making them publicly available for other scientists to use. Their hope: When a new animal virus makes the jump to humans and starts wreaking havoc — the next Zika, Ebola, or West Nile virus — researchers will already know where that piece fits into the whole.
“Nobody’s scared of moths, but in the time of Zika, everybody’s worried about mosquito viruses and tick viruses,” Greninger said. “So rather than waiting for someone to get sick and sequencing their blood … you sequence the mosquitoes.”
And they have found some new viruses in local populations of animals that can harbor pathogens known to cause human disease, such as mosquitoes, bats and ticks. But Greninger doesn’t want to stir up panic. These animals also carry plenty of viruses that will never cause harm to humans. There’s no evidence that any of the new viruses he found will ever pose a threat.
“There are odd cases of people with what appear to be viral illnesses that have been diagnosed through metagenomics. These are rare but fascinating cases,” Jerome said. “Our longer-term goal is to be prepared to contribute to cases like that, and to contribute to [understanding] outbreaks of viral illnesses.”
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.
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