Gladstone Institute's BSL-3 lab director Mauricio Montano demonstrates one of the new lab's biosafety cabinets, in which researchers will work with live coronavirus. (Peter Arcuni/KQED)
There’s so much scientists still don’t know about the novel coronavirus: basic stuff, like how exactly it invades a host’s healthy cells, the molecular interactions that enable it to spread through the body and why it affects some people more than others.
But a handful of labs in the Bay Area, including ones at UCSF and UC Berkeley, are trying to gain a better understanding of how SARS-CoV-2 behaves by doing basic research with live virus. The work could help scientists develop and test new treatments or vaccines to target the virus more effectively.
To handle live coronavirus and other potential deadly airborne pathogens, these labs must meet strict Biosafety Level 3 (BSL-3) containment requirements set by the Centers for Disease Control and Prevention.
On a recent visit to San Francisco’s Gladstone Institutes, we got a look inside its newly launched BSL-3 lab (before any live virus arrived) with Dr. Melanie Ott, director of the Gladstone Institute of Virology, and lab director Mauricio Montano.
As I learned, getting into a BSL-3 lab requires a few extra steps.
From Surgical Mask to ‘Space Suit’
These days, a basic cloth facial covering or surgical mask is required even to enter Gladstone’s Mission Bay headquarters. But gaining access to the BSL-3 lab requires two more wardrobe changes.
The first takes place in a locker room, where researchers go from street clothes into scrubs, gloves and a bonnet that resembles a gauzy shower cap.
“That's part of the sacrifice of making sure everybody's safe and clean,” Montano said. Then he walked me through the protocol for putting a pair of booties on over my sneakers, before stepping over a line of yellow tape on the floor.
“You’ll put a booty on one foot, and then you'll be able to plant your foot into this clean space. And then you'll put the other booty on and you'll be able to walk in here,” he coached.
It took me a few tries to get it right.
“Even very experienced Ph.D.-level virologists who come in here for the first time will have the same experience,” Montano said. “The environment requires a really hyperactive vigilance.”
Next we head down the hall to the BSL-3 lab’s secure anteroom. A digital monitor by the door showed the air pressure as negative, which ensures that no aerosolized particles (stuff floating in the air) can escape. Instead, a high-powered HVAC system draws in the lab’s air and cleans it with a series of filters.
“A BSL-3 is like a giant vacuum cleaner,” Montano said. “No pathogens or anything could come out of that room.”
The lab’s safety is closely monitored by officials at UCSF, as well as state and federal health regulators.
Once inside with the anteroom’s outer door shut, scientists will don Tyvek hazmat suits — or “space suits,” as Montano calls them — and respiratory purifiers to filter out potential pathogens. Only then can they enter the lab’s inner workspace. (Because there was no live virus present during our visit, we skipped this last step.)
Here researchers will work with the virus with gloved hands reaching inside glass-shielded biosafety cabinets that resemble laboratory hoods from chemistry class.
Any physical waste, like used reagents, that needs to leave the room must first be sterilized by the lab’s autoclave, which is essentially a high-temperature medical-grade pressure cooker.
“Anything to come out of here basically has to be dead and has to be clean,” Montano said.
“As I always say, I feel much safer here than I feel at the local grocery store,” Ott added.
‘We Know Very Little About This Virus’
Ott says the ability to work with active SARS-CoV-2 opens up avenues of inquiry that aren’t possible using inactive viral fragments or looking at genomic sequences.
“A Biosafety Level 3 lab is allowing you to work with dangerous viruses that are actually fully functional and replicating,” Ott said. “So you can study the virus, the full viral life cycle, in an animal or in a cell.”
The lab is equipped to run animal studies using mice, which will be housed in cages inside.
The approach, she says, can uncover ways to interfere with that life cycle either by attacking the virus itself or by targeting parts of the host cells that the virus interacts with to block it.
“We’re coming really from the mechanistic side,” Ott said. “You're diving deep into the interaction of the virus with the host.”
Ott says scientists still don't fully understand precisely how the coronavirus spreads throughout the body.
“We have to learn how it engages the upper airway, how it gets into the lower airway and how it disseminates into other organs from there,” she said. “There's a lot that we don't know.”
To tackle this, Ott says the lab plans to culture the types of cells that are the primary or secondary targets of the virus. These include lung, gut, liver and heart cells.
“So we are trying to reconstruct the more complex cell systems in a dish and then see how the virus behaves,” Ott said. “Is it infecting everybody? Is it infecting dependent on a certain factor, like an important entry factor and receptor? Is that all mediated by this molecule?"
Gladstone’s BSL-3 lab, Ott says, can also serve as a place to test potential treatments and vaccines before they are tested in human subjects.
“Before you go into a clinical trial, you want to make sure that what you're doing is efficient, that it’s actually doing what it's supposed to do,” Ott said. “These preclinical studies can give you a much better idea about what exactly is happening when you give that drug to a patient.”
‘Too Many Questions to Answer At Once’
Gladstone’s new facility will allow virologists to gain a better understanding of SARS-CoV-2, but the virus is a puzzle with many pieces.
“There's too many questions to answer at once,” Ott said. “Collaboration, I think, is absolutely essential. ... This has been unprecedented, at least in my experience, how people have come together around this virus.”
In preparation for the new lab’s launch, Ott partnered with UCSF’s BSL-3 to culture cells and prepare the virus for transfer to Gladstone. She’s collaborating with other researchers at the university who have identified more than 300 interactions between SARS-CoV-2 and human proteins.
“We are in very good relationship with all the BSL-3s here in the Bay Area,” Ott said. “Stanford, Berkeley, UCSF, I think everybody recognizes that these laboratories are in short supply.”
There are roughly 200 BSL-3 labs throughout the U.S., according to a 2018 report.
At this point, Ott says, the coronavirus pandemic has affected everyone. Her brother-in-law, a physician in a small Austrian village, contracted the virus and became seriously ill. But the science, she says, gives her hope.
“You see all the politics, you see all the rush. But at the end," she says, "you settle down, you look at your data and you see that you're making progress.”
The basic coronavirus research done by Gladstone and its collaborators, Ott says, could help fight not only this virus, but the next wave as well.
“It's a constant evolutionary battle,” says Ott. “There will be other clever viruses, whether they're coronaviruses or influenza viruses or even something like HIV. So it's important to have facilities like this where we can prepare for the future pandemics that are coming.”
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