When it became clear in the spring of 2020 that SARS-CoV-2 was spreading around the world, University of Chicago’s Pritzker School of Molecular Engineering (PME) faculty joined a campus-wide effort at the University of Chicago to gather and donate personal protective equipment—N95 face masks, face shields, gowns, surgical gloves, and boot covers from their labs—to health care works both locally and around the country.
At the same time, Pritzker Molecular Engineering faculty quickly pivoted their work to focus on pressing research questions around vaccines, diagnostic tests, drugs, and other technology to help the world cope with the deadly pathogen.
Virus in the air
Even with faculty donating protecting equipment from their labs early on, there was still a shortage of N95 respirators, considered the gold standard for filtering out pathogens. To help healthcare and other frontline workers reuse such masks, PME researchers joined a team of scientists and engineers, students and clinicians from both the private sector and universities to create N95decon.org, a website that synthesizes the scientific literature about mask decontamination to create a set of best practices to decontaminate and reuse the protective face covering.
Meanwhile, members of the public were making or buying homemade masks. This prompted Prof. Supratik Guha, also a senior scientist at Argonne National Laboratory, to research what might be the best pathogen-filtering fabric for such masks. He and his colleagues found that one layer of a tightly woven cotton sheet, combined with two layers of polyester-based chiffon—a sheer fabric often used in evening gowns—filtered out the most aerosol particles (80% to 99%, depending on particle size).
While Guha was focused on how people might best protect themselves from inhaling infected airborne viral particles, others such as Assoc. Prof. Savas Tay were trying to understand how far and wide those particles might travel in the air. Tay and colleagues collected air samples from hospital ICU rooms, then measured the amount of virus in the samples and how far it traveled from the patient.
They hoped to gain insight into whether patients exhaled less viral particles into the air over time as they received treatments for COVID-19. They also want to know how different treatments affected patient exhalation of virus particle. Did some treatments lead to increased viral load in the air and some to decreased?
Better ways to diagnose
Because people with COVID-19 can be asymptomatic and still spread the disease, PME researchers also put effort into finding better and faster ways to diagnose the disease. Early on in the pandemic, healthcare workers took nasal swabs of patients, then ran those samples through a machine that used a technique called quantitative polymerase chain reaction to look for the virus's DNA in the sample.
Later scientists began testing a newer detection system called droplet-digital PCR or ddPCR. One of those was Tay, who collected saliva samples from people who came to UChicago for curbside nasal swab testing. When he and his colleagues compared early data from their samples/COVID-19 diagnoses with those of the hospital, they found the saliva ddPCR tests matched up exactly with the hospital’s results.
At the same time, Asst. Prof. Jun Huang and Junhong Chen, Crown Family Professor of Molecular Engineering, started working on a handheld device that people could use to test for COVID-19 at home. They planned to program it with step-by-step prompts on an LCD screen, allowing for easy use without any prior training. The device would use various specimens from patients (e.g., nasal and saliva samples) to test for both infection and antibodies.
Nanoparticles and drugs to fight COVID-19
As SAR-CoV-2 infected and sickened hundreds of thousands of people, PME scientists also began investigating how to treat COVID-19. Some began researching methods of nanoparticle-based drug delivery, which distributes pharmaceutical treatments more efficiently in the body.
Dean Matthew Tirrell, for instance, wanted to address acute respiratory distress syndrome, a life-threatening form of lung failure that can develop in patients with COVID-19. So he and Yun Fang, an associate professor in UChicago’s Pritzker School of Medicine, are testing innovative nanomedicine approaches that would use nanoparticles to deliver therapeutic nucleotides to the lungs that, in turn, would reduce viral replication and promote lung health against COVID-19.
Another nanoparticle approach came from Huang and colleagues who unveiled a completely novel potential treatment: nanoparticles that capture SARS-CoV-2 viruses within the body, then use the body's own immune system to destroy them. They tested the safety of the system in a mouse model and found no toxicity. They then tested these “nanotraps” against a SARS-CoV-2 pseudovirus - a less potent model of a virus that doesn't replicate—using the most advanced system available—living human lungs maintained by ex vivo lung perfusion, a process by which a pair of lungs is kept alive outside the body. Using this model, they found that nanotraps can completely block SARS-CoV-2 infection to human lungs.
Finding the best drugs
Over at Juan de Pablo’s lab, the focus is on using machine learning and artificial intelligence to better understand COVID-19 at the molecular level. de Pablo, Liew Family Professor of Molecular Engineering, also advanced computational techniques to sift through key candidate drugs that are already used to treat other diseases and could be repurposed to inhibit those processes in SARS-CoV-2.
For instance, he uncovered how the antiviral drug remdesivir works at a molecular level—the drug disrupts the virus’s ability to replicate, but its exact mechanism had remained a mystery and it was not always effective on every patient. This discovery, he said, means scientists can now focus on finding better strategies to deliver the drug more effectively.
Also using advanced computational techniques, as well as modeling and supercomputer simulations, they discovered that ebselen, a drug used to treat bipolar disorders and hearing loss and that has antiviral and anti-inflammatory properties, could be a good candidate drug for treating COVID-19. Specifically, they found, ebselen decreased the efficacy of Mpro, a key enzyme inside the virus that helps it to replicate in host cells. Their work, which still must be validated in clinical studies, revealed a new vulnerability in the virus that was previously not known.
Understanding complications of severe COVID-19
PME researchers also collaborated with UChicago clinicians to evaluate patient samples and uncover new aspects of disease pathophysiology. Using tissue sections from autopsies of COVID-19 patients, Prof. Melody Swartz and her lab discovered widespread clotting in the lymphatic vessels of the lung and lung-draining lymph nodes. This was a crucial finding because lymphatic drainage to the lymph nodes is critical for the body to mount effective immune responses.
Next, Swartz and her colleagues discovered that the lymph nodes of patients with more lymphatic clotting had more extensive loss of germinal centers—tiny structures that form in lymphoid tissues that produce protective antibodies.
After that they analyzed the blood of dozens of patients collected by Thomas Gajewki, AbbVie Foundation Professor of Cancer Immunotherapy, and his lab in UChicago's Prtizker School of Medicine. Through that work, the researchers found a strong correlation between markers of lymphatic clotting and lack of antibodies against SARS-CoV-2.
Swartz said these discoveries offer evidence that patients who are unable to mount strong antibody responses, or those that lose antibodies quickly, could potentially benefit from anti-clotting therapies.
Innovative vaccine approaches
While Pfizer, Merck, Johnson & Johnson and other pharmaceutical companies worked on developing a COVID-19 vaccine, PME investigators researched how to make those immunizations better with the goal of informing second-generation vaccines, inoculations that would be more effective than the first wave, to protect against SARS-CoV-2.
Assoc. Prof. Aaron Esser-Kahn, for instance, searched for ways to boost the efficacy of vaccines, trying things such as adding in molecules that activate CD4+ cells which protect the lungs in flu, SARS and Zika infections and might do the same in COVID-19.
He also researched molecules that would tweak human cells’ signaling processes to help the body better respond to COVID-19 with less chance of side effects. And he looked at using molecules to boost the immune system without a vaccine—buying time while the immune system makes specific antibodies to COVID-19.
Jeffrey Hubbell, Eugene Bell Professor in Tissue Engineering, and Melody Swartz, William B. Ogden Professor of Molecular Engineering also worked on vaccines, specifically ways to deliver a vaccine via a nanoparticle to the lymph nodes, the organs in the body that are one of the frontlines for the immune system. Within the node, there are specific cells that trigger different types of responses; Swartz and Hubbell want to induce the production of a particular kind of antibody called “broadly neutralizing antibodies.” These are antibodies that seem to act on a variety of virus strains, and thus may be able to clear several strains of the virus.
“We have shown in advanced preclinical studies in nonhuman primates that nanoparticle vaccination can be very powerful for malaria vaccines, and we are exploring how this can be extended to SARS-CoV-2,” said Hubbell, who has led extensive testing of this technology in mice.
The work continues
Today, PME researchers are continuing their pandemic-related research. They know that even as the current pandemic slows down, there’s a need for more information and more technologies.
“We’ve seen that the virus is not going away and is in fact starting to mutate,” de Pablo said. “Efforts to find the best therapies, and the best ways to administer them, have to continue.”