Uniting against an invisible foe

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 Senior 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.”

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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 months 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 trace 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% 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.

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And while trials and drug development take time, adequate testing was something that Penn was able to push for faster, the University leading in efforts to develop new tests that can be deployed rapidly and easily.

Many scientists around Penn have contributed to making a saliva test a reality. Executive vice dean and chief scientific officer Jonathan Epstein of Penn Medicine issued a challenge to faculty to create one early in the pandemic. A committee led by Bushman set to the task. The result was a test that uses an alternative DNA amplification method to traditional PCR-based tests. Using this technique, the testing program COVID SAFE rolled out at the start of the fall semester, giving essential staff of the Med School who were on campus the option of getting tested quickly, right on campus. Geneticist Arupa Ganguly is running the COVID SAFE lab and Penn Medicine Nudge Unit director Mitesh Patel is conducting a clinical trial to evaluate the screening program.

Other faculty around campus have made contributions to testing innovations, including the School of Engineering and Applied Science’s Haim Bau, and Cesar de la Fuente and Ping Wang of Penn Medicine. Wang, for instance, built on her past experience of crafting highly sensitive, specific, point-of-care tests for other biomarkers and rapidly turned toward developing a similar assay for SARS-CoV-2, in partnership with faculty from the engineering and dental schools and with support from the Penn Center for Innovation.

Nimble shifts to face a novel challenge

In nearly every corner of campus, one can find researchers applying their time, resources, and expertise to the problem of COVID. Early on, in the pandemic, the generosity of the community was on display. Students, staff, and faculty mobilized massive efforts to share PPE and, at the engineering school, even put 3-D printers to work to manufacture it. The School of Veterinary Medicine loaned ventilators to the human hospitals on campus, and Penn Health-Tech purchased ultrasound machines for emergency departments to speed diagnoses of COVID-19-associated lung disease.

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That same ingenuity and altruistic spirit is apparent in scientists’ work at the lab bench as well. A number of basic scientists at Penn Vet, including Andrew Vaughan and Montserrat Anguera, shifted gears early in the pandemic to study the effects of the novel coronavirus on lung cells and sex disparities in severity, while virologist Ronald Harty has been applying his background in developing inhibitors for other viruses, such as HIV and Ebola, to curtail the effects of SARS-CoV-2.

Similarly, at Penn Dental Medicine, Rob Ricciardi has been harnessing insights from his long experience identifying treatments for other viral diseases, such as a pox virus closely related to smallpox, to developing an antiviral for COVID.

At Penn Vet, some, too, are focusing on the disease’s “One Health” aspect. “One really important aspect of this disease is that it’s not just a human disease,” says Elizabeth Lennon, a small animal veterinarian. “It affects animals and can be passed back and forth between species.”

With funding from Penn Vet for pilot research, Lennon is testing cats and dogs seen at the School’s Ryan Veterinary Hospital for COVID-19 to get a sense of infection rates in the pet community. She’s also in the early stages of a community-based testing study of pets in Philadelphia to reach more pet owners.

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Another vet school scientist, Eman Anis, is studying the animals believed to have enabled SARS-CoV-2 to make the jump to humans—bats—as a way of assessing the presence of the virus in the wildlife population and identifying risks to wildlife rehabilitators.

Even dogs are changing their focus to the pandemic. Working Dog Center director Cynthia Otto is leading an effort to determine whether dogs can discern the scent of COVID-19 from other odors. Using T-shirts worn by people who have been tested for COVID-19 to capture scent, the study’s outcome could lead to dogs helping with screening for infected individuals, perhaps in public areas like airports, train stations, or office buildings.

In parallel, physicist Charlie Johnson of the School of Arts & Sciences is using the T-shirt samples and other COVID-19 testing materials to refine an “electronic nose” that uses the profiles of molecules in the sebum or sweat of COVID-positive individuals to diagnose disease, an approach his lab has previously deployed to detect the signature of biomarkers for other diseases, such as ovarian cancer.

“In our early tests we’ve been able to detect a sample from an individual who was COVID-positive but had minimal symptoms,” Johnson says. “In the longer term, we could see using a hand-held version of this device to be used on people directly, rather than the T-shirts.”

The long haul

As the pandemic stretches into a second year, work will continue apace on vaccines, therapeutics, and testing technologies. New initiatives like Penn’s coronavirus research center and emerging database platforms are enabling Penn scientists to share the findings they’re generating from clinical and laboratory studies openly with researchers worldwide, who can mine data for patterns and initiate new collaborations.

Many University efforts are centered around keeping our own community safe, including PennOpen Pass, COVID SAFE, close oversight and support from Penn Environmental Health and Radiation Safety and the Office of the Vice Provost for Research, and Project Quaker, an umbrella under which various testing operations around campus will run, particularly as more students return in the spring semester.

“A big focus of ours is creating a safe work environment, so we can get work done not only on COVID, but on the other diseases that are continuing to occur amid the pandemic,” says Epstein.

This, like the task of taking on COVID-19 from every conceivable angle, has and will continue to be a team effort on the part of the Penn research community.

“Our expertise in a whole host of domains has been phenomenal,” says Emma Meagher, vice dean and chief clinical research officer at Penn Medicine. “We have an enormous breadth of highly collaborative innovative scientists and talented clinician investigators, likely unmatched in any other academic institution in the country.”

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Dawn Bonnell is Senior Vice Provost for Research and the Henry Robinson Towne Professor of Engineering and Applied Science in the School of Engineering and Applied Science.

Frederic Bushman is the William Maul Measley Professor in Microbiology at the Perelman School of Medicine.

Henry Daniell is vice-chair and the W.D. Miller Professor in the School of Dental Medicine’s Department of Basic and Translational Sciences.

Jon Epstein is executive vice dean, chief scientific officer, and William Wikof Smith Professor of Cardiovascular Research in the Perelman School of Medicine.

Charlie Johnson is the Rebecca W. Bushnell Professor of Physics and Astronomy in the School of Arts & Sciences.

Scott Hensley is an associate professor of microbiology in the Perelman School of Medicine.

Elizabeth Lennon is the Pamela Cole Assistant Professor of Internal Medicine at the School of Veterinary Medicine.

Emma Meagher is vice dean, senior associate vice provost for human research, and professor of medicine and pharmacology at the Perelman School of Medicine.

Jason Moore is the Edward Rose, M.D. and Elizabeth Kirk Rose, M.D. Professor in the Perelman School of Medicine and Director of the Penn Institute for Biomedical Informatics.

Susan Weiss is professor of microbiology in the Perelman School of Medicine.