Why are some viruses harmless and others fatal? AJ te Velthuis is on the case.


Viruses outnumber humans by about 400 trillion to one, yet pandemics are rare. Why? Why do a few viruses inflict so much damage, when the vast majority are harmless or even useful?

These questions lead AJ te Velthuis, a virologist who joined Princeton’s Faculty of Molecular Biology in January 2021.

“AJ is the future of virology,” said Bonnie Bassler, Squibb professor of molecular biology and department chair. “Our service has always been a driving force in virology. When it was time to recruit a new assistant professor, our senior virologists – an incredible group of academics and intellectuals – helped us understand where the future of this field was going, and they identified it.

“I’ve been working on RNA viruses, and I’ve been doing it for a very long time,” te Velthuis said. “I’m particularly interested in why some new viruses, when they jump on humans, suddenly trigger serious illnesses, whereas when they were in bats or other species, they almost seemed harmless. “

He studies the fundamental mechanisms of virus replication and confusion in our immune system. He’s also working on new masks that inactivate viruses, antivirals that stop viral replication, and how variants of the same virus – such as Omicron or Delta – can arise and cause more damage than others. He underlined the key role played by immunization programs around the world.

“Unvaccinated people act as a reservoir from which the virus causing COVID-19 can continue to return to vaccinated people,” te Velthuis said. “It’s a perfect breeding model for the new variants, unfortunately. “

Defend the coronavirus

Early in the pandemic, researchers experimented with live specimens of SARS-CoV-2, the virus that causes COVID-19, at great personal risk. Te Velthuis has found a way to change that – to edit the genome of the new strain of SARS so that he and his colleagues around the world can study the virus without exposing themselves and their loved ones to the deadly disease.

To do this, he took advantage of the fact that it is an unusually complex virus, with an elaborate pattern encoded in a long sequence of RNA (the single-stranded cousin of DNA).

The long genome can be thought of as a train, with a locomotive and a long chain of interconnected cars behind it. When the virus wants to give instructions to the cells it invades, it has to highlight the most relevant part of its genome, so it splices this “wagon” and reattaches it in the front. Researchers at te Velthuis’ lab used this property to isolate a locomotive and a wagon, resulting in a micro-virus that cannot infect new cells but can still be useful for testing antiviral treatments and studying new mutations..

“It’s no longer deadly, because you need all the other ‘train cars’ to create a complete, infectious virus particle,” Te Velhuis said. “If you only have one single car, it can’t produce anything infectious, but it gives you information on the running of the wheels, the strength of the locomotive. “

At the start of the pandemic, researchers experimented with live specimens of the virus at great personal risk. Te Velthuis has found a way to change that – to edit the genome of the new strain of SARS so that he and his colleagues around the world can study the virus without exposing themselves and their loved ones to the deadly disease. SARS-CoV-2, the virus that causes COVID-19, has a long RNA genome that can be thought of as a train, with a locomotive and a long line of cars. When the virus wants to give instructions to a cell it invades, it splices the affected “wagon” and reattaches it to the front. Te Velthuis and his team used this property to isolate a locomotive and a wagon, creating a micro virus that cannot infect new cells but can still be useful for testing anti-COVID treatments and studying new mutations. “It’s no longer deadly, because you need all the other ‘train cars’ to create a complete, infectious virus particle,” Te Velhuis said.

In many ways, te Velthuis thinks like an engineer, which he says comes from a childhood filled with construction toys. “Structural biology has progressed in such a way that you can start to look at molecules almost like Legos in the way they fit together and how we can build with them. It’s a lot of fun to think about it, draw it and teach it to the students. It’s so visual, and so, so beautiful.

This love of looking at these tiny structures was part of what drew him to Princeton, with its extraordinary community of microscopy researchers. “A picture says a lot more than some of the biochemical work we do – both for scientists and when communicating with students and the wider community,” Te Velthuis said. “So working with them and finding new ways to look at viruses is really inspiring. “

He arrived in Princeton in January 2021 to find a mountain of boxed equipment and a construction area where his lab should be. He already had a graduate student, Kimberly Sabsay, whom he co-supervises with Ned Wingreen, Princeton’s Howard A. Prior Professor of Life Sciences, who is also a Professor of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics.

Sabsay and te Velthuis had the struggle – and joy – of building the lab from scratch, despite construction delays and supply issues related to COVID.

“Unpacking the boxes for the new equipment was like Christmas, and it kept us sane as construction delay after delay extended,” said Sabsay. “The experience I gained from working one-on-one with AJ to design and set up his dream lab has been invaluable. The process was painfully slow, riddled with frustration and failure, but ultimately turned out to be more rewarding than I could have imagined, much like science itself.

Kimberly Sabsay and Karishma Bisht work in the lab

Graduate student Kimberly Sabsay (left) and postdoctoral research associate Karishma Bisht work with te Velthuis to find out how viruses replicate and how they disrupt the immune system, causing it to get out of hand.

A swab to predict pneumonia?

Long before the current pandemic, te Velthuis studied coronaviruses as well as various strains of influenza, comparing one seasonal influenza (H1N1) to two pandemics: the 1918 influenza and avian influenza (H5N1). While the seasonal flu usually causes mild symptoms, the other two flu can trigger an overreaction by the immune system that fills the lungs with fluid (pneumonia). As the world learned in early 2020, the coronavirus family of viruses has a similar pattern: While most coronaviruses only cause mild symptoms of the common cold, some can cause pneumonia, including SARS-CoV- 2.

Te Velthuis and his team discovered that the molecular trigger that turns influenza into pneumonia is a tiny molecule of viral RNA. They can detect it in vitro, in ferrets infected with the 1918 flu, and in saliva swabs from hospital patients; Further research, Te Velthuis hopes, could lead to a rapid test to predict severe flu, ultimately resulting in faster and better treatment.

He also wants to go further. His team are now working to uncover the mechanism behind this trigger, with the goal of finding drugs that inactivate this process, turning a serious health threat into a minor inconvenience.

“If we can have a tool, like a drug, that we can use when a pathogenic virus appears, we can immediately turn it into a more manageable seasonal virus, and we wouldn’t see so much pressure on hospitals and other care. health. institutes ”, declared te Velthuis, whose work is funded in part by the National Institutes of Health. “It’s the biggest dream, the biggest goal. “

Teacher and researcher

This spring, te Velthuis will teach “Pathogens, Pandemics and Technologies” with Cameron Myhrvold, also Assistant Professor of Molecular Biology.

The course will look at pandemics from several angles, Te Velthuis said. “How to study a virus? How do you develop ways to protect yourself from it? What does a virus need to enter a cell? What makes them sick? What causes a pandemic? “

Virus are very different from each other, but they all have to solve the same problems, Te Velthuis explained – getting into cells, interacting with proteins, escaping immune defenses – which means viruses often use similar mechanisms. That’s part of why he’s so excited to join the Princeton research community. “The virus tries to solve engineering issues when it jumps between environments, so it’s really helpful to hear how physicists and engineers think about these things,” he said.

It’s no coincidence that Princeton’s last two coronavirus researchers are teaching a course on pandemics, of course.

“In the Department of Molecular Biology, we place great importance on being excellent teachers, in all manifestations of this role – in the classroom, in the lab, with the doctoral students,” said Bassler, director of the Department of Molecular Biology. department. “In our department, many students become co-authors of published articles, because they make central discoveries in their final thesis work. Research by students at Princeton’s Department of Molecular Biology is the real deal. We’re totally immersed in research and in the thrill of discovery – we’re not kidding with that here. “

AJ gives us the freedom to prepare our wildest experimental dreams, ”said Sabsay, who continued in her lab. “And when our delusional plans fail us, he’s there with us to help them resuscitate them and keep our fantasy alive for as long as possible.”

“AJ never says no to anything I want to try,” agreed Elizaveta Elshina, who was his first graduate student and came with te Velthuis from the University of Cambridge.

“Science is all about trying different things,” said Karishma Bisht, a postdoctoral researcher who joined her lab in the fall of 2021. “Not everything will work, but you wouldn’t know unless and until you do. ‘try – and AJ is willing to take the risk with you to explore these scientific questions by sharing his knowledge, expertise and resources. “

Bassler said the Velthuis has already been a valuable addition to its many research communities – within its lab, within their department and across the University. “Because of our commitment to education, Princeton itself selects those people who believe part of the scientist’s social contract is to teach the next generation of scientists to be scientists,” she said. . “And AJ is already contributing to the collaborative and stimulating spirit of our“ All for one and one for all ”department. It happened quickly, especially given the COVID restrictions. It’s hard to immerse yourself in a department on Zoom, but it did.


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