Marti Head, Ph.D., had a bad feeling. It was mid-February of 2020. She’d just returned to her home in Tennessee from a work trip. Somewhere, probably in an airport, she’d picked up what she thought was just a cold.
Sure, physically she felt crappy. But the bad feeling, which she described as “itchy,” came from the news coming out of China. A career spent working with infectious diseases had given Head all the info she needed on what, exactly, the novel coronavirus might be capable of.
And so, when her nose started running and her throat got scratchy, Head quarantined herself and her husband. Instead of watching trashy TV in bed to recover, she tucked into her quarantine cocoon of a home office—with tissues and tea at hand—and started hunting.
Head is a drug hunter. A computational chemist by training, Head uses complex computer simulations to search for molecules that can gum up the gears of a virus hell-bent on infecting human cells. She focuses on therapeutics—the things doctors rely on to treat disease. Head spent decades at a major drug company searching for drugs that would combat diseases, including viruses like HIV. But in February of 2020 she was working at the Oak Ridge National Laboratory, in Oak Ridge, Tennessee. Moving to public sector meant Head had an obligation to find something, anything, that might serve the public good in this time of crisis. It also meant that she had access to one of the most powerful supercomputers in the world.
Marti Head’s Summit research may lead to drugs that treat those who get infected.
he served as the Director of Science at the Oak Ridge Leadership Computing Facility. It’s a job that required, in large part, helping other researchers achieve their data goals on Summit at the expense of his own work. Messer says he missed the research life and stepped away. But in late 2019 the job opened again. Messer knew how to do it and allowed himself to be pulled back in. What he did not know, though, was just how chaotic—and high-stakes—this role would become in two months.
Bronson Messer and his team write the code for every query that gets run through Summit.
A range of scientists from all over the country applied and got time on Summit for Covid-related projects. But perhaps two of the most important queries on the computer attacked the virus from opposite ends of the scientific spectrum. One wanted to know how Covid attacked the body, so we could better understand the disease. The other wanted to discover how we could stop the virus in its tracks.
Dan Jacobson and his team model and analyze biological systems on Oak Ridge’s supercomputers.
The lab’s own Jacobson was charged with writing the code that would get answers on exactly why Covid was behaving in ways doctors had never seen before. Jacobson is a computational biologist. His work is specifically in systems biology, which involves deciphering the interconnected complexity of living organisms at the cellular level—whether that’s in plants destined for biofuels or in the human brain, unwinding the causes of various neuropsychiatric conditions like Alzheimer’s and autism.
Jacobson was watching the pandemic well before the rest of us. Through another project, he had contacts working in the Beijing embassy when the first cases in Wuhan were reported. He instantly understood the trouble mankind might be in. “There were a few of those ruh roh moments, where we said, ‘Yeah, this could go really quite poorly,’” Jacobson says.
Jacobson looks for patterns in data that reveal what exactly is happening in the molecular relationships within and between cells. At first, there wasn’t much data to work with. But then, as so many scientists across the globe put their other research on hold to work on Covid-related projects, it was like a firehose, and Jacobson wanted all of it. He approaches biology holistically, using huge amounts of data from all types of inquiries to look for patterns and interesting interactions between systems. When it came to Covid, he hoarded everything: gene expression information, immune system information, physiology data, genetics data, protein structural data, electronic health records, environmental data, microbiome data, and autopsy data. The goal was to look for patterns that changed when people became infected, were sick, and then recovered from Covid. Looking at everything all at once “allows us to find things that often are missed otherwise. If you’re just looking at one thing at a time, you’re taking a very traditional approach,” he says. And you may find that one thing you’re looking for, but “you’ll overlook important things because you’re focused very narrowly.”
Marti Head wanted her turn, too. Before joining the Oak Ridge National Laboratory, Head spent part of her two decades at pharmaceutical giant GlaxoSmithKline hunting for drugs that would attack bacteria. Fighting Covid was going to be markedly harder. “Bacteria are alive, so you can kill them. They fight back, but you can kill them,” she says. “Viruses aren’t really alive, and it’s much harder to kill something that’s not really alive.”
Instead of going for the kill, Head’s drug-hunting hopes rested on finding molecules that could, essentially, throw a wrench in how the virus worked. In one case, she and her colleagues started looking at the main protease, an enzyme that essentially cuts the protein chain found in a cell infected with Covid into little tiny protein bits that then go off and do the virus’s bidding. Head needed a molecule that was exactly the right size and right shape to dock with a small groove they’d identified on the main protease. Step one was writing an algorithm that would essentially search for molecules that could possibly be the right size and shape to dock with the virus.
But it’s not just enough for the two parts to fit, says Head. “Proteins are not just sitting there waiting for us in a static way to do something. They’re constantly moving as part of what they are, and so we need to understand those motions.”
supercomputer is only as super as the people writing code for it. A misconception, says Messer, is that you log onto Summit and can simply click on programs that help you run your query. For the vast majority of calculations on Summit, someone has to write all the algorithms. Usually, that someone is actually a group of someones. The researcher writes some of the code, but Messer adds that the graduate students doing code development are the lifeblood of Summit.
What makes writing code for these projects hard is that there’s rarely a single answer you’re seeking. An if-then algorithm won’t work, because you don’t want just one answer. “When I run an astrophysics code, there’s no answer at the end,” says Messer. Instead, he watches as a stream of data is produced that might point him toward possible answers. “And then I have to climb inside all the data that are generated to be able to infer some scientific insight,” says Messer.
To crack exactly why Covid was making so many people so sick, Jacobson was going to have to crawl inside a whole mess of data, too.
Jacobson started at the beginning, focusing on how the virus hooks onto cells. This he already knew: Covid goes after the ACE2 protein, which isn’t a typical receptor for a virus to latch onto. When he began looking at data from other coronaviruses—like the ones that cause the common cold—he realized that many of them target proteins in the renin angiotensin system (RAS) as entry points into cells. The RAS is partially responsible for regulating blood pressure and fluid and electrolyte balance. Jacobson figured he’d start there.
Covid previously had seemed like purely a respiratory disease. So targeting the RAS was a little unexpected. His next step was to use Summit to evaluate gene expression in lung tissue samples from infected and uninfected patients. Summit went searching, plowing through 2.5 billion calculations. The analysis coughed up a trove of data on exactly how genes are normally regulated and how those regulatory patterns were dramatically altered by SARS-CoV-2 infection.
And then: “I had that eureka moment. Not many times in my career can I go back to a discovery where there was a single eureka moment,” says Jacobson. But it was right there in the data: Covid was causing a massive dysregulation in the RAS.
Back to Summit Jacobson went. Because of the computer’s massive computational abilities, Jacobson was able to see changes in many cellular functions—ranging from inflammatory and permeability responses, to hyaluronic acid synthesis and degradation, to electrolyte balance and coagulation, that connected in some way to the RAS. From that resulting data set, it became clear that something strange was happening at the intersection between the RAS and the kallikrein-kinin (bradykinin) system, which both play roles in inflammatory responses. “We then dived into the clinical literature of what happens when you dysregulate those systems,” he says. “You look at those predictive symptoms in different parts of the body and, wow, they match up really well with what’s going on in Covid-19.”
This research helped reframe the discussion of Covid being as much a vascular disease as a respiratory one. Dysregulation of the bradykinin system can cause blood vessels to essentially leak—which could explain why doctors were seeing patients with so much fluid in their lungs. Thanks to Summit and Jacobson’s research, and that of similar groups, clinicians began thinking about whether Vitamin D, a known regulator for the RAS, might help some patients. While just going outside and standing in the sunshine certainly won’t prevent Covid, there is evidence that it could reduce the severity of infections.
Likewise, the bradykinin hypothesis brought icatibant, a drug that acts as a bradykinin B2 receptor antagonist, into clinical trials. Though these drugs are not a cure-all for Covid, the bradykinin hypothesis is helping doctors understand what they’re seeing.
While Jacobson was discovering what was causing severe disease, Head was working the other side of the equation, hunting for a drug to beat back that severity.
Drug hunting takes a lot of patience. While Head has numerous patents and has taken several molecules fairly far in the drug testing process, she had yet to find a molecule that got to market as an efficacious drug. So much can go wrong in the development process: Maybe the molecule only docks with the protein in the lab. Or maybe it works when injected into mice, but won’t survive the acid of a stomach when swallowed in capsule form.
“We need it to be that one-in-a-million,” she says, describing the odds of finding a molecule that does it all.
Thanks to Summit, Head has a lead on that one-in-a-million. It’s called MCULE-5948770040, and it both binds and inhibits the main protease. In late March, she published a pre-print paper on her team’s finding. That research is currently undergoing peer review. New variants, meanwhile, have made her work even more important. So far, vaccines appear to be effective against the new variants, but should that change, therapeutics will again become a most precious tool in the fight against Covid. Highlighting the importance of the development of effective Covid drugs, in June, the Biden administration announced $3 billion in funding for drug development projects like Head’s.
But Head is thinking well beyond the variants, too. What she’s truly hoping to build is code that’s a starting point for fighting the next pandemic. Because there will be a next pandemic. “We want those platforms ready to go, so we can respond quickly to the next Zika, Ebola, influenza, and coronavirus,” she says. “When, heaven help us, SARS-CoV-3 comes along, as long as we have the will to stay invested and vigilant, we will have the data, the platforms, and the people around the globe who are going to respond.”