UC Santa Cruz researcher Rebecca DuBois
Researcher Rebecca DuBois in her lab at UC Santa Cruz.
(Via Carolyn Lagattuta)
UC Santa Cruz

As the fight against RSV adds vaccines, UCSC researcher is on the cutting edge

Respiratory syncytial virus, or RSV, raged last winter, contributing to a “tripledemic” where cases of flu, COVID-19 and RSV all flooded the nation’s hospitals at once. UC Santa Cruz professor Rebecca DuBois is deep into vaccine research even as a CDC committee recommended a pair of immunizations this week. DuBois works at the molecular scale, and her research is action-packed and futuristic-sounding.

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On Wednesday, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended that older adults “may” receive one of two different vaccines for respiratory syncytial virus, or RSV.

RSV is a nasty respiratory illness that surged in 2022, contributing to a “tripledemic” where cases of flu, COVID-19 and RSV flooded the nation’s hospitals all at once.

Respiratory syncytial (sin-SISH-uhl) virus is most serious for seniors and babies. The CDC estimates that in the United States, RSV causes 2.1 million outpatient visits, up to 80,000 hospitalizations and up to 300 deaths among children under 5 each year. In adults over 65, it accounts for up to 160,000 hospitalizations and up to 10,000 annual deaths.

Two companies, GSK and Pfizer, have developed vaccines to prevent RSV, and the CDC’s advisory committee — which develops vaccine recommendations in the U.S. — gave both the green light this week. Once the CDC’s director signs off on the recommendation, which she is expected to do, both vaccines will become available.

It’s an important scientific and public health milestone. But, it’s not the end of the line for RSV research.

At UC Santa Cruz, Rebecca DuBois, a professor of biomolecular engineering who studies childhood viruses, has been working on questions about RSV and a potential vaccine for a decade. Her work nips at the heels of GSK and Pfizer, but has its own unique twist.

It focuses on a different protein than the two newly recommended vaccines. It also relies on her skills as a master 3D puzzler.

DuBois is convinced proteins — one of life’s essential building blocks, those tiny molecules that drive every process in your body from your nervous system to your digestion to your hormonal pathways — hold the key to taking on RSV. That’s because viruses like RSV also use proteins. They decorate their outer surface with proteins that help them stick to and invade our cells. To make a vaccine or a treatment against a virus, you’ve got to know exactly what those proteins look like in as much detail as possible.

So DuBois builds virtual 3D maps of viral proteins using sophisticated computer software, then uses those models to search for the virus’ “Achilles’ heels.”

But proteins are super tiny and hard to photograph. For reference, a human hair is around 100,000 nanometers thick, while the proteins DuBois studies are around 5 nanometers thick. DuBois uses powerful electron microscopes and high-power X-rays to take high-resolution pictures of them. But that’s just the start.

The pictures show only the blobby outlines of proteins, not the guts. It’s like fitting all the edge pieces of a puzzle together into an outline, but having a completely empty middle. So DuBois painstakingly works to fit individual amino acids — the building blocks of proteins — one at a time, like singular puzzle pieces, into that outline in a way that follows the laws of physics and chemistry.

DuBois knows how to do this. She has a Ph.D. in biochemistry and completed postdoctoral fellowships at the Pasteur Institute in Paris and at St. Jude Children’s Research Hospital in Memphis. A quick look at her CV reveals that she’s an expert in protein biochemistry who studies infectious diseases that harm children.

UC Santa Cruz researcher Rebecca DuBois
(Via Carolyn Lagattuta)

Her work requires meticulous attention to detail and a sharp eye for puzzle-solving. And now, her work is timely, with RSV becoming a household name, and the race to get treatments and vaccines on the market accelerating.

So DuBois is hustling to build 3D digital puzzles of RSV proteins. In her lab among the redwoods on UCSC’s Science Hill, DuBois uses her solved puzzles as maps to guide her in designing both treatments and vaccines.

DuBois invited me to her office to walk me through the basics of biomolecular engineering. We sat against a backdrop of thick biophysics, physical chemistry and cell biology textbooks. And after very carefully moving a tray of about 20 recycled pipette tip boxes that each contained a thin, clear jellylike film submerged in blue liquid — “protein gels,” she explained — we had an in-depth discussion about the new GSK and Pfizer vaccines and her own RSV vaccine research.

This interview has been edited for length and clarity.

Lookout: How do these new GSK and Pfizer vaccines affect or even align with your own work?

Rebecca DuBois: It’s really exciting to have the very first RSV vaccine after over 60 years of research trying to develop a vaccine. And the new vaccines were actually made possible because of the 3D structure of one of the proteins on the surface of the virus, so the techniques I use are very relevant.

The GSK vaccine is effective at preventing severe disease, and that’s the most important thing, but I think there’s still room to improve it — to prevent transmission and reduce infection to start with. I think that’s where the research I’m working on can potentially help.

Lookout: What kind of targets are we talking about for RSV?

DuBois: We could think of RSV as having two Achilles’ heels — the G glycoprotein, which allows the virus to attach, and the F glycoprotein, which allows it to fuse and inject its genome into the cell.

Really when it comes to RSV vaccines, we are thinking of both the F and G glycoproteins as potential targets for a vaccine. The goal is to induce an immune response — to get your own body to recognize those viral F and G glycoproteins and attack them with antibodies that will block a future infection.

Lookout: So do GSK and Pfizer’s new vaccines target those proteins?

DuBois: They both target the F glycoprotein, the membrane fusion protein. That’s the main difference between my work and these other vaccines — my lab focuses on the G glycoprotein.

Theoretically, an immune response to either the F or G glycoprotein could block infection, because both are important for the virus to infect humans. However, I think a vaccine that focuses on just one of the two proteins won’t be as effective as if we had an immune response to both. And so my lab focuses on the G glycoprotein as a potential vaccine antigen that could be used on its own, or more likely in combination with these F glycoprotein vaccines.

Lookout: So how do you study the G glycoprotein — that sticky protein that lets RSV attach to our cells?

DuBois: One way is through structural biology. We get high-resolution snapshots of these virus proteins so we can really understand what they look like.

Lookout: It can’t be easy to just take pictures of these teeny tiny proteins — how do you do it?

DuBois: Right. It is not as easy as taking pictures. Even the best light microscopes will not see any detail of these proteins. We use two different strategies to image proteins. One is called cryo-electron microscopy. The other is called X-ray crystallography.

RSV protein crystals seen under magnification
Rebecca DuBois’ lab grows protein crystals in small petri dishes. Each crystal is a couple of millimeters long or less. The team views crystals with a microscope before scooping them up for the next step.
(Via Sarah Lanning)

For the RSV project, we have mainly used X-ray crystallography. We get the proteins to form crystals, which are highly ordered — the proteins arrange themselves in repetitive 3D layers. And because of that order, when we shoot X-rays at the crystals they scatter, or diffract, X-rays in distinctive patterns. Finally, from those patterns, we can get the pictures of the proteins.

Getting the proteins to form a crystal is really no different than the sugar crystallization experiment that we did as kids — that one where you dissolve sugar in water and hang a string into the solution, then, as the water evaporates, sugar crystals form along the string.

Once we get protein crystals, we actually scoop them up and freeze them in liquid nitrogen. And then we ship them to a particle accelerator facility in the Berkeley area that holds the high-power X-ray equipment.

Lookout: Is it really scary to pick up a fragile crystal and ship it somewhere? What if it breaks on the way?

DuBois: [Laughs] Yes — while we normally think of crystals as like sugar crystals or salt crystals that are really hard, protein crystals are actually more like a little tiny speck of Jello-O. Usually the biggest protein crystals we have are less than a millimeter. So we use a microscope to even see these little tiny protein crystals.

And when we scoop them up, it’s like scooping up a little piece of Jell-O inside a little lasso of a loop. Sometimes it’s not easy to scoop them up. You can’t drink too much coffee in the morning.

But once we scoop them up and freeze them, they’re actually transported in a way that we don’t need to worry about them.

Lookout: OK, so what happens next?

DuBois: At Berkeley’s facility, we shoot the crystals with X-rays and collect the diffraction data. And from that diffraction data, we can interpret the atomic structure of the proteins that are in that crystal. And that data is really powerful and gives us just exquisite, detailed information about what that protein looks like.

Solving the structure means using that data and building a three-dimensional map of the protein. It’s almost like a 3D jigsaw puzzle. You’re building in the amino acids that form the protein into the 3D data from that protein that was in the crystal.

A 3D map of the RSV antibody structure
DuBois uses solved 3D structures as maps to figure out how to build vaccines and therapies that will attack the RSV protein. For example, she can pinpoint exactly how and where antibodies (blue) might interact or bind with the RSV G glycoprotein (yellow).
(Via Rebecca DuBois)

Lookout: What do you like about the puzzling stage?

DuBois: It’s satisfying, maybe a little therapeutic. I can sort of just go deep in my thoughts while I’m fitting amino acids into the data and 3D puzzling. It’s a zone. But it’s not actually intensive thinking itself. Almost sort of like knitting or something like that, where you can just kind of move forward and be productive without really thinking too hard about the project at hand.

Lookout: What does it feel like to solve a 3D structure of something you can’t even see with your eyes?

DuBois: It feels pretty awesome to be the first to see that protein ever. It’s a little teeny drop of science that I put my mark on.

I just love the actual 3D jigsaw puzzle — building it and seeing all these atomic interactions that really form the basis of life.

Lookout: You get to live in that space between physics and chemistry and life, and you get to actually see how it works. That’s so cool.

DuBois: Yeah, it really is. You realize that so much happening in our bodies is just based on proteins and how they interact. It’s just proteins touching one surface to another surface, and those surfaces are formed by hydrogen bonds and electrostatic interactions and hydrophobic interactions and all sorts of just tiny details that really result in life and our bodies working how they should.

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Lookout: So once you get that detailed picture, what are you trying to find?

Once we finish the structure, then we have to think deeply about what it’s telling us.

Some things that we can see are patches, three-dimensional patches, of totally conserved amino acids that never change. And when we see that on a virus, we know it’s important. Viruses are notorious for mutating and changing all the time. But they aren’t mutating strategically.

When a virus has a mutation in that important spot, that virus can no longer go on and infect another cell, and it doesn’t survive. So what we see is mutations in places that aren’t as essential, and then conserved, never-mutating places that are essential.

When specific parts of that protein never get mutated, we know that that’s an important and functional part the virus uses to cause infection. And that helps guide our decisions when it comes to designing a vaccine or designing antivirals. We want to make sure that we are targeting those absolutely conserved and essential parts of the virus.

Lookout: Do we know what those places are in the RSV G-protein?

DuBois: Yes, the RSV G-protein is notorious for having a lot of mutations in it. However, there is a stretch of about 40 out of its 300-and-something amino acids that is highly conserved, there are no mutations in any strain that we sequence. So we think that’s a really important part of the virus that it cannot mutate. It is a great target for potentially developing antiviral treatments, as well as something that we’re honing in on to develop a vaccine. We want to design a vaccine that stimulates antibodies that target that conserved spot.

Lookout: RSV isn’t the only virus you study. You also study astrovirus, which causes gastrointestinal issues like diarrhea, vomiting and nausea. Why is studying all these childhood viruses so important to you?

DuBois: We really have an incredible childhood vaccination schedule that is preventing many terrible diseases that were commonplace 100 years ago — diphtheria, polio, measles, rubella, chicken pox, just to name a few — and that’s a great thing. But there are still so many infectious diseases. There’s still a lot of work to be done.

The DuBois lab at UCSC, comprised of undergraduate and graduate students as well as postdoctoral researchers and specialists
The DuBois lab at UC Santa Cruz, comprised of undergraduate and graduate students as well as postdoctoral researchers and specialists, takes on viruses that cause childhood diseases.
(Via Rebecca DuBois)

Lookout: Who’s helping you do all this work, and what do you like about working with them?

DuBois: I’ve currently got five undergraduates, five graduate students and two postdoctoral researchers in my lab. It’s gotten to that point where this lab is way more productive than I could ever be on my own.

I love getting to see these scientists learn and grow and become independent and have ideas that I never thought of. The bigger impact of my lab is that I’m sending highly trained and creative scientists out in the world to do even more great things.

Elise Overgaard is a June 2023 graduate of UC Santa Cruz’s science communication graduate program. Her goal is to bring unheralded science stories to life. With a Ph.D. in biomolecular science, she covers topics from particle physics and the molecules of life to marine mammals and deep sea creatures, always focusing on the brilliant humans behind the lab curtains. She wrote this piece as part of UCSC professor and Lookout Community Voices editor Jody K. Biehl’s class. Find her previous Lookout Q&A here.