Most experts agree: COVID-19 is going to be with us in some form for a long time. “We’re going to be studying COVID for the rest of our lives,” says Jason Moore, director of the Institute for Bioinformatics at Penn Medicine.
At Penn, for the better part of a year, that study has evolved in quality and expanded in quantity, with more and more researchers finding application for their expertise in the fight against this formidable foe. The need to understand the SARS-CoV-2 virus and COVID-19, the disease it causes, has brought a new urgency to the scientific enterprise and inspired new collaborations that cross barriers—between schools and between basic science and clinical practice—uniting an already close-knit campus like never before.
“I think this is a moment that’s really highlighted the underlying strengths of the Penn community,” says Vice Provost for Research Dawn Bonnell. “When faced with this real emergency it was very gratifying to see people coming together from all over, and to see the underlying compassion on the part of the researchers, with people’s lives and health at stake.”
Given what she knows about the research community, Bonnell says, “It’s inspiring to see this response, but it’s not surprising.”
A timely response
In mid-March, at the same time as many research labs were going quiet and campus was emptying out in an attempt to contain the early stages of the pandemic, faculty in the Perelman School of Medicine’s Department of Microbiology were formulating a new clearinghouse to coordinate coronavirus-related research: the Center for Research on Coronavirus and Other Emerging Pathogens, co-directed by Susan Weiss and Frederic Bushman. The Center site now lists some 100 COVID-19 projects, efforts ranging from tackling the fundamentals of virology and immunology to developing more expedient diagnostics. And a new program to support additional pilot studies is in the works.
“We’re reaching out to people from all over campus,” says Weiss. “Our goal is to support more ideas that will be grist for the mill to continue making progress on this disease. The pilot study results will also hopefully allow researchers to recruit more funding from outside sources, like the National Institutes of Health.”
Weiss and Sara Cherry, a microbiologist at Penn Medicine, were among the first scientists in the country to receive samples of live virus, which they and members of their labs have been working with in Penn’s Biosafety Level 3 (BSL-3) laboratory in the months since. While Cherry’s own studies have entailed screening huge libraries of molecules for potential antiviral activity, and Weiss’s focus on the host immune response, the researchers have also distributed reagents, such as inactivated virus, to colleagues to conduct their own studies outside the confines of the BSL-3.
Bonnell reports “striking” numbers of research proposals submitted by Penn researchers in the early month of the pandemic: more than 400 to federal agencies, submitted on behalf of nearly every school on campus. “More than $13 million have been awarded so far,” Bonnell says. “That’s just tremendous.”
Data from the clinic
Meanwhile, as Penn Medicine hospitals began to admit patients with COVID-19, physician-scientists Ronald Collman, Nuala Meyer, and Daniel Rader organized a massive effort to have nurses acquire informed consent to collect blood, saliva, microbiome, and other samples. These samples are being catalogued in a biobank, supporting a host of investigations at present and more to come in the future.
“That’s been a huge spine of our effort here,” says Bushman, whose own projects in collaboration with Collman have examined the role of the lung microbiome in influencing COVID severity.
Leveraging Penn’s strength in the field of immunology, John Wherry and Michael Betts are among researchers using these samples to track immune responses in patients. In September, together with pulmonologist Meyer, they reported in Science the presence of three distinct immune profiles in hospitalized patients, trajectories which could be used to help predict each patient’s disease and guide treatment choices.
Data has also come in from tests performed in Penn Medicine hospitals, a community-based testing site at Sayre Health Center, and pop-up testing sites in West Philadelphia and beyond. Results have shed light on the unequal burden of COVID in the wider Philadelphia community. A study by Penn Medicine’s Scott Hensley and Karen Marie Puopolo of Children’s Hospital of Philadelphia, for example, analyzed COVID-19 tests given routinely to pregnant patients at Pennsylvania Hospital and the Hospital of the University of Pennsylvania (HUP). Conducted through June 2020, the results showed that Black and Latina pregnant women are five times more likely to have been exposed to SARS-CoV-2 as white and Asian women.
“Pregnant women are fairly representative of community exposure, and these data provide more evidence, on top of what we already know with COVID-19, that health and socio-economic equity are inextricably linked,” Hensley says. “Hopefully, this will help lead to policies that address these inequities.”
Getting clinical trials up and running
Scientific insights can mean lives saved, and clinical trials are where many of those ideas get tested. Numerous trials went into full swing throughout the spring and summer of 2020. By April trials on treatments such as remdesivir and convalescent plasma were up and running, and soon after Penn served as a site for a Phase I trial of a DNA-based vaccine from Inovio, based on research that David Weiner, now of The Wistar Institute, performed at Penn.
The biological insights underlying at least three other COVID-19 vaccines in various stages of development traces back to innovations from the Penn labs of Drew Weissman and Katalin Kariko, who is now with BioNTech. The mRNA-based innovation is being employed in vaccines in clinical trials by Moderna and BioNTech/Pfizer, as well as one in a preclinical stage of development in collaboration between Weissman’s lab and Thailand’s Chulalongkorn University. Last week, Pfizer released a statement that interim results of their Phase 3 clinical trial indicated their vaccine was 90 percent effective against the novel coronavirus.
“Drew and Katie [Kariko] had the key observation that if you take messenger RNA and modify it in the right way, it isn’t recognized by the cellular immune system, so it isn’t kicked out of the body,” says Bushman. “That’s been terrific as a platform for many vaccine technologies.”
The School of Dental Medicine’s Henry Daniell is developing a study to test his patented plant-based protein therapy platform to create novel therapies for COVID, with support from a $800,000 grant from the Commonwealth of Pennsylvania.
One arm of this work, pursued in collaboration with the medical school’s Kenneth Margulies, will use an orally delivered protein to increase levels of ACE2, the receptor for SARS-CoV-2, as well as one of the proteins that arises from the activity of the ACE2 protein, angiotensin 1-7, in the hopes of reducing the worst pulmonary and cardiovascular effects of COVID-19. “We are hopeful that we can do this all in a way that dramatically lowers treatment costs normally associated with protein drugs,” Daniell says. Another aspect of the work is aimed at developing a booster vaccine to complement other vaccines in development.
Treatments and tests
Until an effective vaccine is approved, therapeutics can make a difference in the severity of disease. Making use of the High-Throughput Screening Core, Cherry and colleagues reported findings in August that, among other FDA-approved drugs, the immunosuppressant cyclosporine could inhibit COVID-19 infection while also suppressing an overactive immune response in human lung cells, which can lead to poor outcomes in acutely ill patients. An active clinical trial at Penn, led by Emily Blumberg and Carl June, is currently testing the safety and efficacy of this drug in COVID patients.
“That rapid, high-throughput screening of thousands of compounds is a special capability at Penn and Sara Cherry and her team were really on top of it and getting it done,” Bonnell says.