Molecular Mimicry

A geodesic dome, a soccer ball, a herpes virus. What do they share? The shape of an icosahedron. Certain crystals and microscopic organisms do too. “It’s a structure repeated again and again throughout the natural world and the human-designed world,” says Britt Glaunsinger, a virologist in the Department of Plant and Microbial Biology. “There’s a beauty to it, and there’s a logic to it.”

It’s a structure also encountered on Glaunsinger’s office walls, on T-shirts worn at her lab’s retreats, and on a former student’s arm in the form of a simple black tattoo. “We know it’s a useful shape because it appears so often,” Glaunsinger says. “For viruses, it’s one of the most popular solutions that they’ve come up with to house their genome.”

Among the many viruses that use an icosahedral protein shell to enclose their genetic material are household names like rotavirus, human papillomavirus, and polio. But the primary object of Glaunsinger’s attention is a subset of herpes viruses known as gammaherpesviruses, and in particular one called Kaposi’s sarcoma–associated herpesvirus, a major cause of AIDS-associated cancers worldwide and especially in sub-Saharan Africa. What she and others in her lab learn about the virus could help reduce its reach—as well as that of viruses with similar approaches, like influenza and SARS.

Glaunsinger and her team study the creative tactics these viruses use to manipulate gene expression in host cells during infection. They seek to understand more about how viruses and their mammalian hosts interact, as well as about human-specific pathways to disease—in the hope of discovering something that can be used in the development of drug treatments or that would otherwise be beneficial to human health.

That mission will become more critical as climate change, deforestation, and urban development continue to force animals and the viruses they carry into greater contact with humans. Viruses that evolve within one animal species and then jump to a new animal or a human—as occurred with HIV and Ebola—can be especially dangerous, Glaunsinger says.

We can also study viruses to learn more about ourselves, she adds. In a nutshell, viruses steal what host cells have and make it work for them. So if you want to find the most important components of a particular cellular pathway, Glaunsinger says, you look for the components that viruses target. “Viruses find the crux of how a cell works. Follow those molecules, and you can learn a lot about how the host works, be it a plant or a bacteria or a human or some other animal.”

Viruses are not living organisms but minuscule bundles of genetic code often coated by a space-efficient icosahedral shell. They’re so small that we can see them only through powerful electron microscopes, but they can wreak havoc on our bodies. When coming into contact with a host cell, which is orders of magnitude larger, a virus can use its genetic code to take over the cell and force it to produce more viruses.

Some viruses, like smallpox and certain strains of Ebola and influenza, can be so potent that they effectively put themselves out of business by killing their hosts. Others, like certain herpes viruses, are typically much less harmful but can still cause chronic pain or severe illness in individuals with weakened immune systems.

While her work is ultimately geared toward protecting us from them, Glaunsinger also expresses a certain admiration for viruses. “From the moment I started learning about them, I found viruses to be the most fascinating biological entities out there,” she says.

This moment she speaks of was not an abstraction, any more than the viruses themselves are, no matter how tiny and mysterious. It came in 1994, via the best-selling nonfiction thriller The Hot Zone. The book tells the story of viral hemorrhagic fevers like Ebola, including their origins and past outbreaks.

An undergraduate at the University of Arizona at the time, Glaunsinger was intrigued by the book’s tales of scientists risking their lives to study viruses in the hope of reducing their human toll. But that wasn’t all that captured her, Glaunsinger says. “What I found more interesting is what viruses can do with an incredibly small amount of genetic information.” After reading the book, she went on to enroll in a virology class and later majored in molecular and cell biology.

Over the course of her studies, she also learned that, as captivating as they are, viruses are just half the story. The other partner in the intimate dance of exposure and infection is the host cell. Today, research in Glaunsinger’s lab is aimed squarely at this interaction, investigating how cells detect and then attempt to stop an infection, as well as how viruses respond in kind. Other work is targeted at understanding how the Kaposi’s sarcoma herpesvirus uses what Glaunsinger calls “molecular mimicry” to slip past host cells’ built-in defense systems.

It’s complex stuff, but Glaunsinger has a gift for making virus-host interactions sound less like an encyclopedia entry and more like a stage play. When discussing her work and the habits of viruses, she jumps back and forth between our world and theirs, or slips in and out of the perspective of a cell, explaining with passion and enthusiasm all the drama at the microscopic scale.

Granted, at first glance there may not be much there. While humans have more than 20,000 genes, some viruses have fewer than 10. But by pilfering from our DNA, they can be powerful and persistent. Herpes viruses, for example, which have been around for 200 million years, are endemic in the human population worldwide: everybody is infected with at least one herpes strain, even if, to the virus’s advantage, most of us don’t get too sick.

“What makes the virus so successful, and how has it been able to strike that balance where it can invade an entire population and yet not burn itself out?” Glaunsinger says. “That’s something we want to know more about.”

When Glaunsinger speaks of viruses as “thieves” and “masters of genetic economy” and boasts of their “ingenuity,” it’s easy to be pulled into the world of her research. Much of her lab’s exploration could be called basic or fundamental science, geared toward gaining greater insight into exactly how viruses behave and cells respond. But it’s all done with an eye to the possibility of informing a breakthrough in medical science: a molecule that could be targeted by an antiviral drug, or an insight that could help someone design a vaccine or a diagnostic test.

“That’s always the possibility and the hope, but it could be something that’s far removed from the virus you are studying,” she says. “It’s extremely difficult to predict which of your findings are going to lead to therapies, even if you go looking in a very directed way.”

The key, she says, is being able to persevere in the face of what can feel like constant failure. “The answers are not always obvious. You’re searching, and you’re failing, and then you’re searching and you’re failing again.”

Don Ganem, Glaunsinger’s postdoctoral adviser at UC San Francisco, remembers her as not only talented but also bold. “Together we dreamed up what we thought was a pretty risky project to try to identify genes in the Kaposi’s sarcoma–associated herpesvirus that might be responsible for shutting off host gene expression,” he says. As is often the case, they didn’t know how the project would pan out, Ganem notes. “Not all postdocs want to take on a high level of risk in their research, but that instantly resonated with Britt. She was all for it, because she’s a person who likes to ask big questions.”

And as it turned out, the research was fruitful. She found what she was looking for, both in the study and in her career trajectory. “I still remember seeing the early results of that study,” she says. “It’s led us down a lot of really interesting paths and resulted in years of discoveries in many areas of science related to this virus and to RNA biology in general.”

If Glaunsinger were solely a scientist, she’d be a successful one. In 2015, she was one of just 26 biomedical researchers nationwide to be named a Howard Hughes Medical Institute Investigator. The appointment is designed to encourage creativity in research, in particular ideas whose risky nature makes them difficult to support through traditional means—in other words, the sort of work that has become Glaunsinger’s hallmark.

But along the path she took from reading The Hot Zone  to leading a lab, she also honed her skills as a teacher and mentor. One of her most popular courses is an annual graduate seminar called Making Yourself Clear: How to Give an Engaging Science Talk, which helps students practice relaying their science to a wider audience. In 2018, she was one of five faculty members across campus to be recognized for outstanding mentorship of graduate students. A student nomination letter noted that “she encourages curiosity and exploration while ensuring that we don’t lose sight of the ultimate goal.”

Marta Gaglia, who worked in Glaunsinger’s lab as a postdoctoral fellow from 2009 to 2013, now runs her own lab as an assistant professor in the Department of Molecular Biology and Microbiology at Tufts University. “She really thought about each of us as a whole person. She met with us to discuss not just where our research project was but where we wanted to go in general,” Gaglia says. “I now follow that mentorship model in my lab.”

Another former student, Renuka Kumar, PhD ’12 Microbiology, says it’s no accident that her time as a graduate student researcher in Glaunsinger’s lab led to two postdoctoral fellowships and ultimately her current position as a virologist at Chan Zuckerberg Biohub in San Francisco. “What struck me about Britt was her pure excitement for molecular interaction. It was contagious,” says Kumar. “I knew I wanted to focus on virus-host interactions after falling in love with them in her lab.”

Love may not be too strong a word. Glaunsinger’s work teaches us that viruses are something to fear, certainly, but also something to behold with wonder, to learn from, and even to thank. They are, in the end, a part of us.