For those involved in fighting the coronavirus pandemic, these are frightening times. Health care providers, sometimes working in improvised protective equipment, risk exposure to the coronavirus from patients and worry about carrying it home to their families. Even Americans whose jobs don’t bring them into contact with COVID-19 patients are frightened of contracting the coronavirus at work, if they still have work to go to.
But Sara Cherry, a microbiologist at the University of Pennsylvania, feels safer at work than almost anywhere else. That’s because she works inside a biosafety level 3 laboratory on the Penn campus in Philadelphia, where she is the scientific director of the High-Throughput Screening Core. Level 3 is used for research on potentially lethal microbes, and ones that can be easily transmitted through the air, including tuberculosis and plague. There is only one higher level, which is required for a few extremely dangerous viruses, including Ebola and smallpox.
Cherry’s workplace, with no more than three other people inside at a time, is a sanitized, negative-pressurized space in which ambient air is being continuously expelled from the room. She works in full biohazard gear, including a sealed hood, breathing high-efficiency particulate air (HEPA) from a battery-powered blower she carries on her waist.
It takes two months to train someone to work in the lab. “Once you get the hang of it, it’s really not that dangerous,” Cherry says modestly. “In fact, it’s probably about the safest place to be.” She finds that a hood, which conveys a gentle stream of cool air to her face, is more comfortable than a respirator mask.
She is, of course, working on the coronavirus. In March, the university shut down almost all ongoing research, including the work Cherry had been doing on emerging mosquito-borne viruses, including Zika and West Nile. If you’re accustomed to handling those in a BSL-3 lab, the coronavirus, although not to be taken lightly, holds no special terror.
Researchers around the world are attacking COVID-19 on every imaginable front, and some that are beyond imagining, including irradiating the lungs with ultraviolet light, which was one of the ideas tossed out by President Trump at a recent White House briefing, and which one Colorado medical device company says it’s researching.
In broad terms, there are two ways to go about the effort. One is a targeted approach, which builds on what we know about the virus. This is the approach of vaccine researchers, who start with the coronavirus genome and try to engineer an agent that resembles the virus in a way that can trick the body into mounting an immune defense against the real thing when it encounters it.
The other is the brute-force approach, which acknowledges that there is a lot we don’t know about the virus and amounts to testing thousands of different substances and hoping one of them will work.
For all the advances in biology over the last century, scientists still don’t understand many diseases in enough detail to accurately predict what will work against them. Hydroxychloroquine, a drug that is being used experimentally for COVID-19, was originally synthesized to treat malaria, which is caused by a parasite spread by mosquitoes. It was later discovered to work in the treatment of non-infectious autoimmune disorders such as lupus.
What do these diseases have in common with an airborne coronavirus, or with each other? Basically, nothing.
Cherry is using the brute-force approach. Her laboratory is one of a handful in the country equipped to do high-throughput screening, an automated process that can test hundreds of compounds at a time to determine if they are active against the SARS-CoV-2 coronavirus strain, which causes COVID-19. What you need for this, besides the machinery, are the following:
A supply of living cells that can easily be cultured and infected with SARS-CoV-2. Most laboratory research is conducted on cell lines derived from human cancers, because they can replicate themselves outside the body indefinitely. But Cherry found many cell lines were resistant to infection with the coronavirus, making them useless for research. “We have a lot more that we can’t infect with this than we can,” she notes. Finding and growing the right cells is an ongoing process of trial and error. She found that human lung cell lines and normal human lung cells, although harder to keep alive outside the body, make better subjects for research.
A “library” of drugs for testing that are known to be safe. “We’re starting with FDA-approved drugs,” she says, “because the only way to have a big impact now is with a molecule that has already been used in humans” and therefore can skip the initial safety testing. These are known as “small molecules,” with a molecular weight below about 500, which generally can be synthesized and mass-produced easily and taken by mouth.
The other main category of drugs is “biologics,” much larger and more complex molecules that are generally extracted from living organisms. Hydroxychloroquine is a small molecule; remdesivir, another promising drug being researched, with a molecular weight around 600, has to be administered intravenously, limiting its use (for now) to hospital and clinic settings. Cherry’s lab started by testing around 4,000 drugs that have been tested and/or used in animals and humans.
A supply of SARS-CoV-2 viruses. The reference virus for research was obtained by the Centers for Disease Control and Prevention on Jan. 22 from the first patient diagnosed with COVID-19 in the United States, and made available to researchers beginning in February. Cherry’s lab grows it in a cell line called “vero,” derived from African green monkeys, that she calls “the virologist’s workhorse.”
If you have those things, and access to a BSL-3 laboratory, you too could save millions of lives. Put a few thousand human cells — a microscopic quantity — into each of the wells on the machine’s tray and inoculate them with the coronavirus. Leave some untreated, as a negative control, and treat some with remdesivir as a positive control. Each of the remaining wells — the machine in this lab can test 384 samples at one time — is dosed with one of the small molecules you want to research.
Let the plates incubate for a day or so, then stain them to make the virus visible under a fluorescent microscope, and examine them — using an automated microscope and automated image analysis to count the number of cells and the number of infected cells.
Do this over and over — four times, so far, with more than 4,000 compounds in Cherry’s lab — to winnow the field to around 30, and then the real work begins: figuring out how those drugs actually work — by preventing the virus from infecting the cell or inhibiting its replication inside the cell, or by some other mechanism.
And then you might have a candidate for testing in animals, or clinical trials in human subjects. Cherry doesn’t know when that will be, but she hopes it will be soon. When it happens, though, it will be someone else’s project.
“Am I motivated to do this? Very much so,” Cherry says. “I’m working pretty much seven days a week, but I’m still putting my daughter to bed at night. We all really want to make a difference. We have this expertise, the screening platform, and I’m optimistic we can find something that will benefit.”
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