Biomolecular weapons for fighting COVID-19

By Chris Woolston

Years before the novel coronavirus turned into a global pandemic, Susan Daniel was already looking for ways to defeat it. Daniel, a professor in Cornell’s Robert Frederick Smith School of Chemical and Biomolecular Engineering, had created models of the host membrane to gain new insights into the virus SARS-CoV. Now referred to informally as SARS-CoV-1, the virus is a precursor and close relative of the new coronavirus, SARS-CoV-2 or SARS 2.

A dangerous virus in its own right, SARS 1 infected more than 8,000 people around the world in an outbreak in 2002 and 2003. That particular outbreak has long faded, but Daniel was intrigued by this virus and wanted to know exactly how it enters its host’s cells, a crucial step toward infection. The work was scientifically interesting—these viruses have a lot of tricks—but the arrival of the novel coronavirus suddenly put her work at the center of a global crisis. “Never has my research been so relevant to the world,” she says.

The new virus wasn’t a complete surprise, says Tiffany Tang, a fifth-year Ph.D. student in Daniel’s lab. She notes that new strains of coronavirus tend to emerge every decade or so, and the latest version was overdue. “When we heard there was a new virus in December, we figured it was about time,” she says. Of course, nobody could have anticipated the new virus’s devastating spread. “Part of me is still in shock over the impact,” she says.

The novel coronavirus is far more contagious and deadly than its predecessor, but the two viruses also share much in common. The strains look alike under a microscope—picture tiny spheres bristling with spikes—and the similarities go deep down into the genome. By studying SARS 1, Daniel was learning much about unique features of coronaviruses that would help her understand SARS 2, even before it emerged.

“It was an easy pivot,” she says. “We could essentially deploy all of the techniques that we were already using.” With a new sense of urgency, Daniel and her team are collaborating with other Cornell researchers to expand their coronavirus studies in an effort that blends engineering with virology and data science. “Understanding virus infection requires people of all different expertise coming together,” she says. “It’s truly an interdisciplinary effort.”

Discovering coronavirus’s vulnerability

Much of the work in Daniel’s lab looks at the spiky projections—appropriately called spike proteins—that give coronaviruses their tell-tale appearance. These pointy proteins reach out to grab nearby cells (Daniel calls it “harpooning”), the first step towards an infection. Once the spikes have snagged a cell, the virus can deliver its genetic payload, essentially turning the infected cell into a virus factory. If there was a way to stop these spike proteins from doing their job, the virus would be essentially disarmed. “If the virus doesn’t fuse with the cell, the genome is never transferred, and the infection doesn’t proceed,” she says.

Daniel and her team believe they may have identified a potential vulnerability in the spike proteins. Studies of the original SARS 1 virus showed that the spikes depend on the mineral calcium to effectively do their job. As Daniel explains, calcium ions fit neatly within a particular region of the spike that controls the harpooning process. That extra fortification seems to help make the spike tips strong and rigid, qualities that are important for attaching to a cell. Without calcium, the spikes tend to be floppy, potentially making it more difficult for the virus to infect a cell. In theory, reducing calcium levels at the point of virus entry could stop infections before they start. Daniel and colleagues discussed the role of calcium in coronavirus infection in a paper published online in Antiviral Research in April 6, 2020.

When the new virus first arrived on the scene, Cornell researchers knew where they wanted to look. Daniel—along with her frequent collaborators Gary Whittaker, professor of virology at the College of Veterinary Medicine, and Nicholas Abbott, the Tisch University Professor of chemical and biomolecular engineering—received a $200,000 “rapid” grant from the National Science Foundation in April to study the spike proteins of the new virus. The team brings different skills and viewpoints. Whittaker’s lab had been studying the spike proteins in coronaviruses, including varieties that infect dogs, cats, pigs and horses. Abbott’s lab studies a type of interaction—called a hydrophobic interaction—that coronaviruses use to harpoon cells.

The researchers are paying particularly close attention to the section of the protein, called the fusion peptide, that actually initiates a process called membrane fusion, where the host and viral surfaces merge, forming an opening where the genome escapes into the cell. After comparing the sequences for the fusion peptides in SARS 1 and SARS 2, they quickly realized that this novel threat was in many ways surprisingly familiar. “They are nearly an identical match,” Daniel says. “And because we knew that calcium was crucial for SARS 1 entry, we posited that SARS 2 would require it too.”

If the new coronavirus really does need calcium to infect a cell, an arsenal of FDA-approved calcium-blocking drugs could potentially be called into action. The drugs, often prescribed to treat high blood pressure and heart issues, work by reducing the concentration of calcium ions around the cell. If Daniel’s theory about calcium and spike proteins is correct, those drugs at the right concentrations in the right patients could slow or even prevent infection of the novel coronavirus.

As a first test of the hypothesis, Daniel and her team have been studying the effects of calcium-blocking drugs on lung cells and kidney cells that are exposed to the new coronavirus in the laboratory. The findings are not yet published, but Daniel is already excited. “We’ve had phenomenal results,” she says. “In some cases, we’ve had undetectable levels of infection.”

Turning to big data, nature

Daniel is quick to point out that there’s a huge gulf  between showing that drugs work in a petri dish and showing that they work in real patients. For that reason, she cautions that it’s far too soon for people to take such medicines for the purpose of fighting or preventing coronavirus infection. As a next step, she’s hoping to build on ongoing collaborations with other Cornell researchers to test the theory in more realistic models. “I would love to team up with researchers in the clinic and veterinary school to see how this treatment works in mice and guinea pigs,” she says.

There may be another way to test the possible effects of calcium-blocking drugs on Covid-19 infection. Daniel notes that many people already take such drugs for other conditions. By mining data in medical records, it might be possible to find out of if those patients are any less likely than others to succumb to the infection. The comparison would be complicated by the fact that people taking the drugs are by definition already somewhat unhealthy. But if there’s any benefit to calcium-blocking drugs, the numbers should tell the story. “We’ll need to turn to someone with the right computational toolbox to tease that out,” she says, “Luckily, we know some great people down at Weill Cornell Medicine.”

In another line of investigation, Daniel and team are looking at the interaction between spike proteins and antibodies produced by the immune system. So far, they’ve managed to show that mere fragments of the spike protein were enough to trigger the production of antibodies in mice. What’s more, some of those antibodies seemed to zone in on the fusion peptides of invading viruses. In a sense, the immune system seems to be targeting the same parts of virus that scientists have in their own sights. Understanding how nature fends off coronaviruses could offer important insights for researchers who are trying to accomplish the same goal, Daniel says.

Rising to the challenge

After building her career on bioengineering techniques, including the cell-free membranes that she developed to study the infection mechanisms of SARS 1, Daniel had to move slightly beyond her comfort zone to a more clinical world of cell cultures and animal studies. She embraced the challenge. “If I were to focus solely on the technology that I developed, I’d be missing the bigger picture,” she says. “As an engineer, my role is bringing my toolbox to the field of virology, and then to help synthesize the information from all inputs to better understand these viruses.”

The ongoing collaborations with Whittaker, Abbott and other researchers have been a great experience, says Miya Bidon, a third-year Ph.D. student in Daniel’s lab. “We’re learning all sorts of different techniques,” she says. Bidon continues to work on her original project—studying fusion peptides in SARS 1—but like everyone else, she has also turned her attention to SARS 2, too. Among other things, she’s participating in the cell studies of calcium-blocking drugs. The arrival of the new coronavirus brought new energy and urgency to the lab, she says. While other labs temporarily shut down in April because of the pandemic, the Daniel lab earned an “essential research” designation and reopened after a two-week hiatus.

“The importance of the work is clear to everyone, even people who never set foot in a lab. My friends and family ask me a lot of questions about it,” Bidon says. “It’s really exciting.”