The dangers of mongrel viruses

Jim Pipas is a professor in my department and the co-mentor of Sandlin, one of the graduate students in my lab. Because his lab is two floors above ours, I’ve never had much to do with him, but sometimes the things Sandlin says in passing pique my interest.

“No, Jim’s not even here this week. He’s still in Siberia.”

or

“Jim’s having trouble importing his tiger poop.”

Jim studies cancer in the lab using the tumor-causing virus SV40 and I couldn’t figure out why that meant he was always in Borneo or China or Malawi.

Another time, our lab manager was driving us home and started singing along to the CD she was playing.

“I’ve got those SV40 Lab-ratory, undesirous adenovirus, polyoma – Take me homa Blues!”

“What the hell?” I asked.

“It’s Jim and his brother’s band,” she explained.

“What the hell?” I asked again, since I’m never satisfied by explanations.

So when I decided that I should write about someone in my department to give me some practice interviewing people and writing on topics that I have no clue about, I figured this was a good excuse to find out what Jim was up to.

Jim Pipas, Department of Biological Sciences, University of Pittsburgh

Figuring out what he was up to took several interviews and some adventures in suburban bars, but I think I got a good story for The Original. In the process, the editor became so enthusiastic about Jim and his stories that she ended up writing a companion piece about his musical persona, ‘Dr Space’. In fact, we got so many good stories I’m going to have to use this post as the ‘Supplementary Data’ section, to give the full science story.

Let’s start by thinking about your body as a viral landscape. Right now, you are playing host to billions of viruses. If you’re unlucky, you might have the sniffles or some horrific intestinal disease, but more likely you don’t. These viral guests are living quietly in your guts, on your mucus membranes, inside your cells and inside your genome. They live inside the countless bacteria and fungi that have colonized every nook and cranny of your body, as well as the plant cells you are digesting after eating that salad. Some of your viral guests may even be playing host to their own viruses.

And yet you are not the most complex viral landscape in the world. By one estimate, there are a few thousand kinds of viruses in a typical human, compared to a million kinds in a kilogram of seafloor. Jim has started taking stock of this dizzying viral diversity, sampling everywhere from Barcelona sewers to Phillipino bat caves, because he has a radical idea about one way that dangerous new viruses can arise. He thinks that all those millions of kinds of viruses are continually engaged in a haphazard game of gene mix-n-match, in which every so often, one hits the viral jackpot that lets them infect a new kind of host, wreaking havoc on that host’s defenses.

Jim’s radical idea was born from his decades of studying how viruses manipulate hosts. Specifically, he studies how SV40 interacts with its host cells, inadvertently causing them to become cancerous. SV40 is a monkey virus that you might have heard of because millions of people were exposed to it from contaminated polio vaccines in the ’50s. I really wish the top Google hit for “SV40 polio vaccine” was this CDC site, rather than all the conspiracy theory sites. Despite the hysteria, it turns out to be unlikely to cause cancer in humans, although it is quite effective at doing so in non-primate hosts like rodents.

Jim’s specialty is the veritable swiss-army-knife of a protein (T-antigen), that SV40 uses to manipulate its host into replicating the tiny virus genome. Recently, he has branched out to look for proteins in other viruses that are also used to manipulate the host.  Actually ‘other viruses’ is an understatement; what I meant was all other viruses. They have searched all of the several thousand known virus genomes for clues as to which genes encode proteins that interact with host biology. They call these proteins ‘Host Interacting Proteins’ or HIPs, and the possession of certain host-specific HIPs is what allows a virus to infect its chosen host.

But in the process of searching thousands of viral genomes for HIPs, they kept finding evidence for the exchange of HIPs between completely unrelated viruses.

“Gene recombination across different virus families makes no sense, we don’t know how it happens,” he says. This phenomenon is nothing like the relatively orderly process of gene shuffling that gives the flu virus a new edge every year. This is more like genome butchery, with random bits of DNA from one virus being pasted into another’s genome. The strangest thing was that they saw evidence for this process even between viruses that cannot infect the same host cells. Contrary to what is normally assumed, Jim realized that in such gene exchange events, some of the DNA could come from an inactive virus.

“Only one virus has to be able to grow in the cell, the other one just has to be in the cell.”

This means that the viruses of all kinds of different hosts could, in theory, be exchanging genes all the time, until one virus suddenly gains the ability to jump between hosts.

“Is this a mechanism for the emergence of new viruses? And where in nature does this mixing happen?” To answer these questions, Jim and his colleagues are preparing to take environmental samples, isolate all the viral DNA, then sequence everything that comes out. This will give a comprehensive overview of the viral genomes present.

The reason why Sandlin’s accounts of Jim’s travels were always so bizarre was because he used computational prediction to select environments that will favour his ability to detect any viral gene exchange. Because the computational algorithm takes into account features like biodiversity, species density, endemism and animal migration, the list of sites it generated tended towards the exotic. Like Siberia.

“You think of Sibera as frozen tundra,” he says. “I know that’s what you’re thinking. And most of it is.”

But not all of it – in the alpine areas of the South, Siberia offers hot summers followed by bitter cold winters. One of the potential sites in Siberia is Lake Chany, an enormous shallow marsh that is a summer destination for migratory birds arriving from Africa and Asia. The area swarms with biting insects that feed on the summer visitors, as well as the local wildlife, all of which conveniently defecate into the waters of the lake. In contrast, another of their potential Siberian sites is much more biologically isolated; Lake Baikal is the largest freshwater lake in the world, but 40% of the species found there are found nowhere else. By choosing a variety of sites with different kinds of hosts, they hope to more easily spot gene exchange between very different kinds of viruses. Jim has spent several years visiting the sites, establishing collaborations with local scientists that can help collect and process the samples.

But even once the samples start arriving, the most challenging aspect will still be ahead of them: analyzing all the sequence data to find evidence for gene exchange. To test their sampling methods and start developing the computational tools for analysis, Jim and his lab have sequenced raw sewage from Ethiopia, Barcelona and Pittsburgh. So far they have identified 234 known viruses, which is almost 10% of all viruses ever detected previously. But they also found between 10,000 and 50,000 times as many kinds of unknown viruses. Most of them are viruses that infect bacteria, and 90% of the rest are plant viruses. Yes, that’s right, plant viruses. Apparently, animal stools typically contain enormous numbers of plant viruses from the animal’s diet. But because Jim thinks that gene exchange between different virus families doesn’t require infection, these plant viruses are fair game for their hunt for evidence of these events. What kind of evidence might he find?

Eastern Barred Bandicoot, Australia. Wikimedia commons, http://www.noodlesnacks.com/

Take the virus that has been ravaging a cute, but endangered, Australian marsupial called the Bandicoot. Efforts to protect the dwindling Bandicoot population have been hampered by the rapid spread of a viral disease that results in debilitating skin cancer-like masses. When scientists isolated the virus causing all the trouble they found a curious mongrel between a papillomavirus and a polyomavirus. Papillomaviruses, like the human virus linked to cervical cancer, are sometimes associated with cancer-like diseases. In contrast, polyomaviruses are mostly well-behaved house guests, only causing disease in hosts with compromised immune systems. The splicing of new combinations of genes in the Bandicoot virus gave it the structure of a papillomavirus, but also bestowed it with a protein closely related to SV40’s T-antigen, the protein that causes cancer in SV40-infected mice.

To understand why such mixed-up viruses might be so dangerous, you need to consider how viruses make their host sick. If you remember your high school biology, you might be tempted to say it’s because viruses lyse the cells in which they reproduce in order to escape and spread to new cells and new hosts. But in most cases the loss of these cells is insignificant; the real culprit behind the wooziness/snot/tingles/headaches/what-have-you is your own body’s response to invasion.

So in the case of a virus that has been co-evolving with its host, its ability manipulate the biology of the host has been finely tuned; some viruses benefit from disease symptoms like coughing and sneezing, but most do best by keeping their heads down and escaping immune system surveillance. A virus that has suddenly been bestowed with a magical new HIP that allows it to infect a new host has evolved for a totally different environment, and is likely to cause all kinds of problems as it starts interacting with host biology in all kinds of new ways.

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