The Memphians Cracking the Covid-19 Code

Local research teams have been working to solve the mysteries of the coronavirus.

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As 2021 dawns, COVID-19 still ravages the land, and Memphis is in much the same straits as the rest of America. In mid-December, the time of this writing, the Shelby County Health Department reported record high case rates for practically every consecutive week in the past month and half. We’ve averaged more than 500 new cases per day for the past week; nearly a thousand cases were reported on one recent Saturday alone. At the close of 2020, Tennessee was reporting some of the nation’s highest numbers of new positive tests per capita.

We are lucky to have many front-line heroes staffing local hospitals, but Memphis is also home to others working to curtail the coronavirus in less obvious ways. This city bustles with research related to COVID-19, and the three pillars of the medical district — St. Jude Children’s Research Hospital, Le Bonheur Children’s Hospital, and the University of Tennessee Health Science Center (UTHSC) — are leading the charge.

Among these three institutions, often in collaboration with local hospitals or national researchers, scientists are conducting a host of studies. While vaccine trials receive the most media attention, many laboratories are focused on the question of therapeutics: how to respond once SARS-CoV2, aka “the novel coronavirus,” has gained traction in a human cell. This work is crucial, even as public health officials prepare to roll out the first vaccines against the virus, because vaccines are never 100 percent effective and rarely universally distributed. And then there are those who’ve already contracted the virus — more than 72 million people worldwide and counting.

Hoping to understand the strides being made to stop or slow COVID-19, the disease, I spoke with three Memphis-based researchers studying the mysteries of SARS-CoV2 and how the human immune system might best be harnessed to beat it.

Testing Molecules Old and New

Dr. Colleen Jonsson, director of the Regional Biocontainment Laboratory (RBL) at UTHSC, is working on the front lines, albeit at the microscopic level. That’s the world you inhabit if you’re a professor in the UT Department of Microbiology, Immunology and Biochemistry. But on the macro level, she relies on a crack team of researchers, and when I connect with her, she tells me she worries about them.

“They keep getting taken out of circulation, so they can’t come into the lab,” she says. “Every week I get a new one, pretty much.” One lab worker, she says, quarantined for 24 days after someone in his home tested positive. “It’s really nerve-racking,” she goes on. “But we err on the side of caution with our employees.”

Jonsson is anxious to get her lab up to speed, because her team is onto something big — if one can say that about targeting the coronavirus at the molecular level. “We now have a series of brand-new molecules developed in collaboration with the Oak Ridge National Laboratory and the University of Wisconsin, Madison,” she says. “And we have a very attractive molecule that we’re pursuing with that consortium. We’re hoping by the first of the year we’ll have new small molecules designed specifically for the SARS-CoV2. We’re very excited about that.”

To understand how important these molecules are, one has to picture human cells not as undifferentiated blobs, like bowls of plain Jell-O, but as collections of large, complex molecules called proteins — more like what the church ladies call “ambrosia,” chock-full of marshmallows, nuts, and fruit. Each protein in a cell helps direct the cell’s activities, but a virus like SARS-CoV2 arrives with its own proteins. When the virus docks to a cell, it highjacks that cell’s proteins, and directs them to do one thing: make copies of the virus. It’s as if your ambrosia turned against you.

Therapeutic treatments to slow or eradicate the coronavirus can target different proteins in this process. The new molecules being tested in Jonsson’s lab target the proteins that help the virus make copies of itself. And to get the testing process started, Jonsson relies on the high-powered computers at the Oak Ridge National Laboratory near Knoxville, where virtual models of molecular behavior can help predict what will be effective.

“They start with known collections of molecules, and dock virtual models of them to a virtual model of the SARS-CoV2 protein,” she says, “and they look for molecules that interact with those proteins and give them a score. Then, based on that scoring, they sent 400 molecules to me, and I screen them in-vitro against the live coronavirus.”

In other words, Jonsson’s lab takes the crucial step of testing how the molecules affect the coronavirus in real life. “And then from the live coronavirus,” she says, “we confirm that we have one that looks particularly attractive to follow up on, and make a new, novel molecule targeting the SARS-CoV2.” The goal is to find a molecule that disrupts the virus’s ability to make copies of itself in the cell, like a wrench thrown in the machine. If the replication machinery can’t function, the virus can’t proliferate to other cells or move on to other human victims.

Even after the lab identifies a molecule that can disrupt the virus’s functions, it’s another matter to develop a drug that can deliver that molecule to human cells. Which is where other collaborators come in.

“I’m not a medicinal chemist,” says Jonsson, “so I work with Jennifer Golden at the University of Wisconsin. She’s taken that chemical matter and now she’s building compounds around it. The reason we do that is we know you’re not going to get anything perfect right off the bat. So she’s adjusting the molecules to increase their potency.”

As complex as it may sound, that’s just one of the approaches Jonsson’s lab at UTHSC is pursuing. A similar line of inquiry is being pursued using molecular compounds found in nature, not designed in a lab. Such molecules tend to be larger and far more complex than synthetic ones. Dr. Jerome Baudry at the University of Alabama, Huntsville, used a supercomputer to test 50,000 prospective naturally occurring compounds. Now Jonsson’s lab is testing 125 of the most promising among them.

And then there’s her work with pre-existing drugs already approved for other uses. Working with Dr. Tudor Oprea of the University of New Mexico, Jonsson screened many such drugs, ultimately finding three of them — amodiaquine (an antimalarial), zuclopenthixol (an antipsychotic), and nebivolol (a blood pressure medication) — that showed promise against the coronavirus. Having already been approved and mass-produced for human use, the “repurposed” drugs have a special advantage over newly discovered compounds.

“They’re incredibly cheap,” Jonsson tells me, not to mention more easily transported. Ultimately, she says, they may be found to work in combination with remdesivir, which has not been shown to be as effective as researchers originally hoped as a stand-alone therapeutic.

The Human Response Over Time

Meanwhile, a few blocks away, St. Jude Children’s Research Hospital is conducting research that connects such molecular-level understanding with living humans. And it’s all thanks to the timely way that St. Jude took action back in March, just as the magnitude of the covid-19 threat was becoming apparent. As Dr. Josh Wolf of the infectious disease department explains, Dr. James Downing, president and chief executive officer of St. Jude, “sat in a room with a group of researchers and asked us, ‘Is there something that needs to be done to address this pandemic that only St. Jude can do, or that St. Jude can do better than anyone else in the world? If there is, then St. Jude wants to do it.’”

“The immune response is the most important component to the damage that the virus causes.” — Dr. Josh Wolf

The study that one team of researchers hit upon then took advantage of having a large pool of well-protected, regularly tested people — St. Jude’s own employees — in close proximity to the research hospital’s scientists. And starting early gave them another advantage: time. The team of about a hundred researchers moved quickly, knowing that every day counted.

“We went from having the idea of a study and being asked by Dr. Downing to produce something, to enrolling our first patient in a little under a month,” says Wolf. “That’s a process that normally takes about a year. But that’s just because everyone worked really hard on it. It wasn’t that we were allowed to skip anything or bypass any procedures,” says Wolf.

By April, the study enrolled its first subjects, all volunteers from the St. Jude labor pool. And all they had to do, for starters, was provide information and blood. This study was founded on the principle of baseline data. Wolf, who was deeply involved in planning and managing the study’s logistics, puts it this way: “What we’re looking at is two elements. First, we’ve asked people to provide baseline samples over the last several months. Almost 1,300 people provided us with a blood sample, which we then can compare with a sample if they get the coronavirus. And that’s really important, because by the time other research subjects get the coronavirus and give a blood sample, the information in it is already affected by the virus.

“Then, we have another unique characteristic,” he continues, “which is that, as a condition of working at St. Jude, people go through coronavirus screening with a nasal swab about once a week. That gives us really precise information about when people are infected with the virus, if they get infected, and also what proportion [of those infected] don’t even have symptoms, and that was a big question at the beginning of the pandemic.”

Indeed, the study was unique in establishing the health of a cohort so early in the pandemic, so as to better correlate their medical condition and history with their body’s response to the virus, should they become infected. This helps researchers understand a crucial factor in the severity of the disease: “The immune response,” Wolf says, “is the most important component to the damage that the virus causes.”

And that’s where Dr. Paul Thomas, from St. Jude’s immunology department, comes in.

“We know all of the different pieces of the virus that are being targeted by your immune system,” says Thomas, “and now we are finding how that varies from person to person. We’ve had the potential to do something special with this group of volunteers, in that we could understand how that immune response might be determined by your prior history.”

Researchers can divide the immune response in a number of different ways, Thomas notes, by way of explaining what his team looks for when running assays, or tests, of the subjects’ blood samples. “There’s the innate immune response, which is the relatively non-specific inflammatory response that you mount after any kind of infection,” he says. “And then you have your adaptive immune response that is made up of your T-cells and B-cells, that are really specifically targeted to the virus. The difficulty with the T-cell assays is that they have to be somewhat tailored to the specific person you’re looking at.”

“Because we get really well curated, large samples that we have this longitudinal data on, we can train our experimental procedures with that study group and then apply them to a more severe study group.” — Dr. Paul Thomas

This gives researchers the opportunity to study how the immune response might be determined by each person’s prior history of infection with other coronaviruses.

“We all have had other coronaviruses in our life,” says Thomas. “There are common cold coronaviruses, and you’ve had them and you make T-cell responses to them, and we know that some of them are cross-reactive to varying degrees. But the huge gap in the literature right now is, what parts are cross-reactive, to what extent are they cross-reactive, and does that cross-reactivity help you or harm you? For all of that, we needed longitudinal sampling, and a sampling that was prior to any exposure to SARS-CoV2, which is what we have in this study.”

While around 80 of the 1,300 subjects have contracted the coronavirus, discovering infection early in the St. Jude setting, along with the employees’ relative good health, has helped ensure that none have died thus far. That’s why Thomas then compares their data to more severe cases.

“We’re accumulating samples from a number of different studies,” he says, adding that the study of St. Jude employees “is actually the centerpiece of everything we’re doing. Because we get really well curated, large samples that we have this longitudinal data on, we can train our experimental procedures with that study group and then apply them to a more severe study group.”

Although no results from the study have been published yet, the comparative power of such a large, ongoing project promises to yield valuable insights over time. And thus it is that such findings, gleaned from the meticulous work carried out every day in our city’s medical community, can advance our knowledge — not only of this deadly virus, but of others yet to come.