In Chris Basler, we have that someone.
The GRA Eminent Scholar in Microbial Pathogenesis has broken new ground in the fight against Ebola, SARS-CoV-2 and other menacing viruses. Much of this work involves pinpointing activities inside cells that give drug developers precise targets for new treatments or vaccines.
As Basler marks the fifth anniversary of his being recruited to Georgia State University from the Icahn School of Medicine at Mount Sinai in New York, we’re pulling back the curtain on his lab to look at five significant contributions he and his team have made.
The finding was seminal in the field: Basler found a protein in Ebola, called VP35, that silences a kind of siren in the body.
When Ebola infects a cell, VP35 keeps that cell from activating the “siren” – i.e., interferons produced in an invasion to signal nearby cells that an attack is underway. “This discovery opened up the question of how these viruses evade responses in the body,” Basler says.
Later, he and his team would develop a way to modify VP35 to disable its siren-blocking function. Their modified protein was shown to be less virulent – and less lethal – in animal models. That meant a new drug target was born.
In August 2021, Basler and colleagues published a paper in EMBO Journal on their discovery of three proteins inside the body that keep a key Ebola protein (VP30) from starting up its copying machinery.
“You think of Ebola as this uncontrollable virus that grows and grows until it kills you,” Basler says. “We went fishing for cell proteins in the host (humans) that would interact with the virus’s proteins to facilitate its growth. But instead, we found three host proteins that actually slow down the virus’s gene expression.”
That finding gives drug developers another new target – the Ebola protein VP30. Since it’s where replication of the virus slows down, a drug that takes aim at this spot could potentially treat infection.
In spring 2020, Basler did what so many scientists did at the time. He redirected his time, energy and expertise to battling SARS-CoV-2.
Early on, he formed a partnership with Axion Biosystems, a (recently acquired) GRA-backed startup out of Georgia Tech that makes micro-electrode arrays (MEAs). The devices connect cells and tissue to electronic circuitry so that scientists can gain an exquisite view of human biology – in a petri dish, and in real time.
Using Axion’s Maestro Z system, Basler was able to study how the coronavirus affected host cells as it replicated – and how well existing antiviral drug compounds could block that replication.
Of the dozens of compounds they tried, Basler and his team found four that disrupted the virus’s ability to replicate. Importantly, this disruption took place in different areas – again, pointing drug developers to potential new targets.
“Maestro Z gave us very detailed, very quantitative information about the growth of the virus and the antiviral activity of different compounds we tried,” Basler says. “You set up the experiment, and the machine does all the work for you in the next 2-3 days.”
Because SARS-CoV-2 is transmitted easily, studying the live virus requires a highly protective environment called a Biosafety Level 3 (BSL3) laboratory. But methods exist to deactivate the virus – essentially kill it – to make it easier to study outside such a lab.
Basler knew that many scientists like him would be pivoting their existing research to take up the fight against the coronavirus. So he and colleagues set out to define specific protocols and methods to render the virus safe for study outside the BSL-3 lab.
“These methods include things like, how much do you have to heat the virus, and for how long?” Basler says. “Much of this would be obvious to researchers who had worked on coronavirus before. But you had so many scientists who were beginning to work on it for the first time – and we had to figure all of this out for our own research – that we figured, why not share it?”
In the long list of papers Basler published, this one generated one of the highest responses.
“Many, many scientists contacted us wanting clarification on how to do this or that,” he says. “Clearly, it was something a lot of people looked at.”
A pair of highly lethal viruses emerged in the 1990s after making the leap from bats to animals to people. Nipah and Hendra viruses are closely related to each other – and while they belong to a different family of viruses, they’re every bit as deadly as Ebola. No drugs or vaccines are available to stop them.
In 2018, Basler teamed up with Australian researchers to investigate the interactions between a protein in the viruses (called W protein) and two specific proteins inside the human or animal host. They discovered that when W binds with these two host proteins, a door opens to allow the virus to enter host cells.
Infection then follows – and usually, death.
“Better understanding these interactions points to potential ways to block them from happening,” Basler says. “If you had a drug that could prevent the interaction between W protein and its target inside the body, then the virus would be less able to cause infection.”