The simple yet effective molecular machinery of viruses can cause devastating disease, but it also offers critical clues about the fundamental principles that govern all life, says Shira Weingarten-Gabbay, who joined the Blavatnik Institute at Harvard Medical School as an assistant professor of microbiology in January 2025.
Weingarten-Gabbay leads the new Laboratory of Systems Virology, where her team works at the intersection of virology, immunology, and systems biology to better understand the inner workings of viruses and their interaction with the immune system and apply that understanding toward preventing current and future viral diseases.
For instance, lab members are developing methods that can interrogate the genomes of hundreds of viruses simultaneously to help determine how viruses interact with their hosts.
With a multidisciplinary background in molecular genetics, bioinformatics, and systems biology, Weingarten-Gabbay joined HMS following postdoctoral fellowships in virology in the laboratories of Pardis Sabeti at the Broad Institute of MIT and Harvard and Charles Rice at The Rockefeller University. Her research has received federal and philanthropic funding support.
Harvard Medicine News spoke to Weingarten-Gabbay about the secrets you can learn from viruses’ tiny proteins.
Harvard Medicine News: What drives your interest in viruses?
Weingarten-Gabbay: Viruses are among the most fascinating entities on Earth. With a genetic code that is 10,000 times smaller than ours, they can get into our bodies, defeat our immune systems, take over the machinery of our cells, and make our biological factories work for them to infect new cells and, eventually, new hosts.
A lot of the biological tricks that we learned in the last few decades — really important additions to our fundamental understanding of biology, like how cells produce proteins — were initially discovered in viruses. But viruses are also important in their own right because of the great harm they can cause.
The goal of my research is to understand how viruses do all the remarkable things that they do and to use that knowledge to prevent disease.
HMNews: Why are these tiny proteins so important?
Weingarten-Gabbay: Over the past decade, our understanding of the coding potential of genomes has been revolutionized with the revealing of a whole universe of microproteins.
We find the genetic codes for these microproteins in human cells, cancer cells, bacteria, and yeast, and they also appear in DNA and RNA viruses.
We call this particularly mysterious group of proteins the dark proteome.
My latest study, which just came out in Science, has uncovered thousands of previously unknown microproteins encoded by the “dark matter” of viral genomes. Many of these small, mysterious molecules play important roles in the immune system’s ability to protect against pathogenic viruses, making them promising targets for vaccine development.
HMNews: How can you tackle such a fundamental shift in thinking about how viruses work?
Weingarten-Gabbay: Virologists usually study one virus at a time. That’s important because each virus is unique, and we need to understand how they function in the context of their own life cycle.
But viruses also have lots of things in common with one another. For example, every successful virus needs to interact with host cells in certain ways. By looking at a lot of viruses together, we can start identifying the underlying design principles that all viruses share. I think of it as trying to figure out the grammar of the genetic language that all viruses speak.
HMNews: Does looking at multiple viruses simultaneously just multiply the work?
Weingarten-Gabbay: The traditional methods can be very time-consuming.
If you work with a dangerous live virus, you need to follow strict safety protocols, including possibly working in a secure biosafety lab. If you avoid live viruses and use a mocked-up virus-like particle that uses some of the pathogen’s genes, it can be challenging and time-consuming to create one that works well enough to infect the target cells. For both of those approaches, you must grow host cells and keep them alive.
Using synthetic biology, we can skip a lot of those steps.
We use synthetic biology to “print” segments of the genetic code from hundreds of viruses into a single tube. We then introduce these viral sequences into cells and use next-generation sequencing to identify which proteins are synthesized from each sequence. This high-resolution method enables us to detect even very small proteins, consisting of just a few amino acids. A lot of the heavy lifting is performed by custom-written computer code that we write to manufacture the samples and analyze the test results.
HMNews: This kind of broad, big-picture pattern recognition seems like it requires a new way of thinking about virology.
Weingarten-Gabbay: Doing this work requires bringing together many different ways of thinking, including proteomics, genomics, immunology, and, of course, bioinformatics. My lab is composed of people who do both experimental and computational work.
I’m a big fan of end-to-end research. Knowing how all the pieces fit together gives you a better chance of making the project work. It also helps us understand the larger importance of the discoveries we are making.
HMNews: How many viruses can you analyze at once?
Weingarten-Gabbay: In my experiments, we can look at hundreds of viruses at the same time. In the Science paper I mentioned, which I worked on while I was a postdoctoral fellow in the Sabeti Lab, we analyzed almost 679 viral genomes and identified more than 4,000 previously unknown microproteins that viruses manufacture.
It’s also great to be able to do this relatively quickly because it allows us to respond rapidly to emerging viral threats.
HMNews: How do you move from the genome to something we can use to protect against a viral disease?
Weingarten-Gabbay: From the day we have the sequence of a virus, we can move within weeks to identify regions that encode proteins. These proteins can serve as targets for our immune system.
Early in 2020 I worked on a project on SARS-CoV-2 (the virus that causes COVID-19). Our experiments showed that these proteins would make excellent candidates for a vaccine — in fact, the unexpected proteins that we found elicited a stronger immune response than those used in vaccine production.
The other advantage of these more efficient methods of probing the unexplored regions of viral genomes is that we can study rare viruses before they start an outbreak.
The more light we can shed on the dark matter of viral genomes now, the better we can protect ourselves from viral disease in the future.
This interview has been edited for length and clarity.
