The Szpara Lab needs more data.
That’s because finding a cure for Herpes is a very complicated challenge. For nearly a century, researchers have been proposing vaccine candidates but despite some promising leads, nothing has ever been established as a definitive method to stop Herpes Simplex Virus 1 and 2.
Research Technologist Chris Bowen tees up one of the key driving questions of the lab’s inquiry — the one that makes their task so daunting: “How much genetic diversity is present in HSV strains circulating in the public?”
Unlike many viruses—like say, the flu—which affect people for short periods of time and are killed off, the Herpes viruses (Herpes Simplex Virus 1 and 2) stay with their hosts for their lifetimes, evolving and adapting. This means herpes is more genetically varied than a lot of those other, short-lived viruses, and there’s a wide variation in how it manifests. For some infected people, minor symptoms might occur one time but never again, or flare up periodically. In others, symptoms can be severe, painful, and recurring—and especially in infants, potentially life-threatening.
A lot of the lab’s work takes place in the swirl around the causes and implications of this diversity.
“Each person that has an HSV-1 infection has slightly different version of that virus from everybody else,” says Principal Investigator Moriah Szpara, Associate Professor of Biology, and Biochemistry & Molecular Biology. “That means not only are they carrying a slightly genetically different pathogen, but the way it manifests in them could also be slightly different.
“We need a vaccine that encompasses not just one really bad thing, but the million versions of this virus that are out there,” says Szpara. “If you’re protected against a hundred thousand of them, you’re going to interact, at some point, with something that breaks through your vaccine immunity.”
To address this wide range of potential infection, Szpara Lab approaches HSV and a few other viruses in a very thorough manner, combining traditional virology with genetic analysis and a wholehearted embrace of big data. But to do that kind of analysis, they need more samples of the viruses, from more people, from all around the world. And they need the most up-to-date information possible. “We need to know what’s out here now, not 30 years ago.” says Szpara.
Part of the problem is the ethnocentrism of the research on a disease with global impact. Experts estimate 7 in 10 people worldwide carry a form of HSV, but very little research has included people from the global South.
“For the most part throughout history, Europe and North America have been the predominant sampling sites,” says Bowen. “But that leaves large portions of the human population under-represented.”
Another issue is the availability of the most important data sources: neonatal viral infections are considered the highest-priority cases, but collecting samples from newborns is a tricky, delicate business. For Szpara, that means building up credibility and proving their methods at a smaller scale.
“Infected infants are small human beings,” says Szpara. “They are precious, and you cannot sample them more than once. You don’t touch or intervene unless you really have to, to save their lives. You can’t just say ‘I want to sequence from infected babies,’ and have people offer you an array of data. You have to prove that your sample analysis is worth a tiny fraction what’s available to study.”
Chad Kuny. Credit: Huck Institutes of the Life Sciences
Her group began by working with animals, specifically chickens through a collaboration with Andrew Read, now director of the Huck Institutes. From there, they moved on to adult humans, refining their methods and building confidence from their eventual collaborators.
“Five years ago, those clinical collaborators wouldn’t have trusted us with those samples.”
For each project, Szpara starts small. She had a paper just about one patient, but that one patient has become the foundation for an analysis of 10 people and 30 samples for the next paper, which laid the groundwork for a study with 40 people and hundreds of samples. “That’s not made-up numbers, that’s really Molly’s papers,” Szpara said.
“Molly” is Biochemistry, Microbiology, and Molecular Biology graduate student Molly Rathbun, a fellow in the Huck Institutes-administered Computation, Bioinformatics, and Statistics NIH training program.
“I’m investigating the comparative genomics aspects of HNV1 infections,” said Rathbun. “What I think is really exciting about what we’re doing with these studies is that we can sample viral genomes directly from clinical isolates, rather than having to expand the virus in a laboratory cultured environment, and that makes it really useful for us to ask questions about the natural genetic variation of HSV1 that circulates around the world, and how that develops, and then what that might mean in the context of infection outcomes.”
Credit: Huck Institutes of the Life Sciences
The difference between lab samples of HSV and “wild” strains is another important wrinkle in the Szpara Lab’s approach. Because HSV is so long-lived and has so much opportunity for adaptation, old strains isolated years ago for study can be very different from the bugs making people sick.
“What the virus looks like in the real world is much more wild and has much more variability than what happens when you domesticate it in the lab,” says Szpara. “It’s a wolf versus a little puppy.”
“We have to be smarter than the viruses if we want to beat them. Everything that’s been done thus far to make a vaccine has failed. All of that was based on these domesticated, lab-adapted strains. It’s not a guarantee that if you study the wild ones that you will get to a vaccine strain, but everything else that’s been tried hasn’t been good enough. It’s the next best hope to say ‘well, if that vaccine maybe was inducing some good immunity to the lab strain, that’s a start,’ but let’s get something that can induce immunity to the actual diversity of things out there and that can protect a human despite the fact that these viruses are evolved to be genetically flexible.”
Szpara values classic virology but recognizes that success will require her to push things further.
“I think it’s great that there are labs that work only at the computational level or only doing epidemiology, but we’re trying to integrate all that data. It’s hard, and challenging, so each person here is working on a slice of that, but that’s the only way we’re going to get there.”
Szpara has carefully assembled a team that shares her passion for and feeds off her enthusiasm for the work.
“I might colloquially refer to them as ‘my people,’” says Szpara, “but I try to make it really clear that they’re all independent scientists, and we’re functioning as a team. It’s not any one person who can ever pull off any one of these projects. Nor is there any one person who has all the best ideas. It’s better that we all acknowledge what we don’t know and then recognize who else has the expertise.”
“She’s spooky good at finding the right fits for the lab,” says postdoc Chad Kuny. “She’s very good at not taking the lab culture for granted.”
“I’m looking for people who fit with the awesome thing we’ve already created,” agrees Szpara.
“A lot of it is Moriah’s mentorship,” says the lab’s newest member, Molecular, Cellular, and Integrative Biosciences graduate student Sarah Dweikat, “But it’s also the way that the lab functions. She has set up a dynamic where the whole lab will mentor new people.”
At one point, posing for promotional photos with Rathbun and Computational Scientist Daniel Renner, someone makes a joke. Szpara cracks and within seconds, goes deep red in the face, wiping away tears as she and her team laugh.
“Her energy level can be infectious,” admits Bowen. “I find myself wanting to move projects along faster so that I can have the data to show, because she’s always so ‘up’ and cheerleading for us to get good results. I’m motivated to try and match those energy levels, but I never do.”
“We work well together,” says Szpara. “Because we’re sharing data and ideas all the time, we can be more productive and efficient about pushing forward the ideas that matter. The ideas we can’t sort out now—we don’t throw them out. We save them and we often circle back and realize, two years later, aha—we can do something with that! We pick those up and keep them going and thus, the lab has this forward momentum that I think has worked really well.”
In targeting HSV, Moriah Szpara picked a tough fight. But she realizes that such a dynamic disease requires more than just her own considerable brainpower. She’s building a team whose tenacity and diversity of thought might just match that of the disease. Herpes had better watch its back.
This article originally appeared in the Huck Institutes of the Life Sciences eNewsletter.