A Scientist’s Journey from Virology to Neuroscience

Ivan Marazzi didn’t set out to study neurodegenerative diseases. As a virologist, he studies how cells respond to pathogens, particularly a family of RNA viruses that includes influenza. So he knows these amazingly diverse organisms are full of surprises. Still, his most recent discovery — an act of microbial espionage that hasn’t been documented before — has given him a new appreciation of their biology and the evolutionary adaptations that have given rise to it.

Working with a multinational research team, Marazzi found that some viruses steal genetic material from human cells and combine it with their own to make genes that are part virus, part human. Using this tactic, the viruses can generate a new set of genes — genes that may make them more infectious or better at evading an immune system bent on eliminating tiny invaders.

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Ivan Marazzi at the Neurodegeneration Challenge Network meeting in February 2019 | Photo by CZI

This discovery underscores that our understanding of viruses and their interactions with humans is still incomplete — even for those viruses that, like influenza, sweep the globe and infect millions of people annually.

Marazzi calls the hypothesis that led to the discovery a “simple idea,” but it is characteristic of the scientific sleuthing he has been doing over the last seven years since he opened his lab at the Icahn School of Medicine at Mount Sinai in New York City. “The goal in my lab is to try to connect things that are seemingly unconnected,” he says.

Some of those connections have led Marazzi into neuroscience, where he is investigating the role of the innate immune system in motor neuron diseases like amyotrophic lateral sclerosis (ALS). Last year, Marazzi received a Chan Zuckerberg Initiative (CZI) Ben Barres Early Acceleration Award, a grant to support early career investigators studying neurodegenerative disorders, especially those who are new to neuroscience.

Microbial Detective

Viruses consist of genetic information — either DNA or RNA — wrapped in a protein coat. They cannot reproduce nor make their own proteins. Instead, they rely on a host cell’s replication machinery to translate their genetic information into viral proteins.

RNA viruses — the ones Marazzi is most interested in — are a special case. To replicate, they take short strands of RNA from the host and tack it onto their own RNA — a phenomenon known as “cap-snatching.” The term refers to the cap, or end of the host RNA strand, which contains a molecular “start” signal. Once combined, the host cell reads the hybrid RNA strand from that “start” signal, and a viral protein is born.

Scientists have known about this mash-up of cellular and non-cellular life for a few decades. But Marazzi and his team wondered if there was more to the mechanism. What if the virus actually uses genetic material from the host to make a new set of genes? And what if some of those genes encode proteins that change the way the virus functions?

Marazzi’s research team ran with the idea. More than four years later, they proved their hypothesis that viruses can produce previously unknown genes by stealing genetic signals from their host cells. They also showed that some of these hybrid RNA strands are translated into proteins, and that those proteins trigger an immune response and may even affect how virulent a pathogen is.

“This is one mechanism of gene origination that nobody knew about. It’s an important discovery because it shows a new way that we make genes in symbiosis with a virus,” explains Marazzi. “We might think about how to leverage this knowledge to design therapeutics or vaccines to combat viral infection.”

The results were published last month in the journal Cell.

Though Marazzi’s team worked intensely on the problem, it wasn’t a solo effort. Spurred in part by CZI’s commitment to open science — a movement to make scientific knowledge and outputs accessible to all — they posted their results to the preprint server bioRxiv. That decision proved consequential: within days, Marazzi was connected to Edward Hutchinson, PhD, a researcher at the MRC-University of Glasgow Centre for Virus Research who studies viral replication and had made a similar discovery.

Instead of racing to publish their results independently, the two decided to combine their findings into a single paper. The result, a scientific story with 54 authors at more than a dozen institutions across the globe, represents the kind of collaborative, open science that is reshaping biomedical research.

A Pivot to Neurodegeneration

When Marazzi was just starting out as a principal investigator, he made the discovery that would lead him into neurodegeneration. He was studying senataxin, a gene involved in viral replication, as well as the body’s immune response to viral infection. However, mutations in the senataxin gene were also known to cause early onset amyotrophic lateral sclerosis (ALS Type 4) and several other rare neurodegenerative disorders. Marazzi’s research team found that cells from individuals with those disorders that carried senataxin mutations generated high levels of inflammation compared to control cells.

He has been studying the connection between the infection, inflammation, and neurodegeneration ever since, and exploring the possibility that viral infection can trigger these diseases.

“This line of research is inspired by a family in Italy who have children affected by ALS Type 4 and have come to visit my lab in New York twice. I felt like I had to do it — to build on that first discovery,” he says.

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(L-R) Cori Bargmann, Ivan Marazzi, and Adrienne Sussman at the Neurodegeneration Challenge Network Meeting in February 2019 | Photo by CZI

Since joining CZI’s Neurodegeneration Challenge Network (NDCN) about a year ago, Marazzi says he has struck up a series of collaborations with other scientists in the network to help drive forward research into the role of the immune system in neurodegenerative diseases. He also wants to help develop the NDCN itself, so that it can benefit other early-career researchers.

“I want to grow within the Network with fellow researchers and help the Network become a solid place where you can do transformative, collaborative research, because there is a big need for it.”

Learn more about CZI’s work in science.

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