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'Science will lead us out of the pandemic'

OHSU quickly marshals its research expertise, resources to participate in the global scientific race to confront COVID-19
two doctors putting on personal protection equipment before entering a hospital room
Doctors at the OHSU emergency department prepare to enter a room with a patient who has not been determined to be clear of COVID-19. Within 24 hours of confirmation of the virus in Oregon, scientists began coordinating research studies that will monitor patients over time. (Kristyna Wentz-Graff)

On Friday, Feb. 28, infectious disease specialist William Messer, M.D., Ph.D., got a call from the emergency department at Hillsboro Medical Center, an Oregon Health & Science University partner, where he was on clinical service as an infectious disease specialist.

The emergency department staff suspected they had a case of COVID-19, the disease caused by the novel coronavirus SARS-CoV-2. It was the same day Oregon’s first confirmed case was announced, and they needed guidance.

“My first thought was how to instruct the team to evaluate and admit this patient safely,” said Messer. The assistant professor with appointments in the Department of Molecular Microbiology and Immunology and the Division of Infectious Diseases in the Department of Medicine, in OHSU’s School of Medicine, had been tracking the virus since it was first reported in China in December 2019.

His next thought? “I immediately thought of my research. I thought, ‘We’ve got to start studying these patients right away.’”

Messer cares for patients with infectious diseases, but much of the time, he’s a physician-scientist in the lab studying the interplay between the genetics of viruses that cause diseases such as dengue, Zika and yellow fever and the human immune response following infection with those viruses. Now, SARS-CoV-2 was practically in his backyard.

The next morning – a Saturday – Messer began a proposal to OHSU’s Institutional Review Board, the governing body that oversees human subject research. He sought permission to study the long-term immunity of COVID-19 patients over a five-year period. It is key information needed to manage the disease over time.

Within 24 hours of Oregon’s first coronavirus case, Messer had answered the call of science. And his OHSU research colleagues quickly followed suit.

What it means ‘to go viral’

As the arrival of COVID-19 in Oregon came into focus in early March, researchers across OHSU quickly pivoted, tackling simultaneous priorities. They began preparing for significant disruption to their existing labs and studies, while, at the same time, identifying expertise and skills they could bring to the COVID-19 effort.

To practice the physical distancing required to minimize the virus’ spread and to keep researchers safe and healthy, OHSU joined scientists across the country in curtailing research projects. OHSU leaders made the difficult decision to shut down most research studies and laboratory experiments beginning mid-March, ahead of the Oregon governor’s March 23rd stay-at-home order. Only a small number of designated people from each OHSU research group were allowed to access each laboratory.

Susan Hayflick, M.D.
Susan Hayflick, M.D.

“Scientists understood from the beginning that this was a pandemic,” said Susan Hayflick, M.D., professor and chair of molecular and medical genetics. “This is what it actually means for something ‘to go viral.’ It wasn’t a surprise that we’d have to dial things down, but it was still devastating. Science gets us up in the morning; we’re passionate about it. But some people lost years of work. Though we understood why, many scientists felt a personal loss with their own work and across the science community.”  

Researchers adjusted to working at home, like so many others. They performed data analyses, wrote papers and grants, exchanged ideas in online meetings and established new collaborations through virtual gatherings. Many computational scientists were able to continue their work almost uninterrupted due to the inherently digital nature of their research.

Pivoting to COVID-19 research, innovation

With so little global knowledge on SARS-CoV-2 and COVID-19, the scientific charge was clear. From the very beginning, OHSU leaders supported labs who wanted to contribute. Scientists responded with an outpouring of interest, proposing a broad variety of research and contributing in many different ways. 

Peter Barr-Gillespie, Ph.D.
Peter Barr-Gillespie, Ph.D.

“Our ability to adapt to this global crisis from a research perspective has been nothing short of heroic,” said Peter Barr-Gillespie, Ph.D., executive vice president and chief research officer.

The first priority on the research team’s agenda was the pressing need to start testing people for COVID-19. Physicians and scientists came together to develop an in-house COVID-19 testing lab in 14 days, which launched in the Department of Pathology on March 24. The lab is supported by a $7 million gift from Nike leaders and Phil and Penny Knight to expand and accelerate diagnostic testing capacity.

Labs donated extra personal protective equipment (PPE), and TRIzol reagent, a chemical solution commonly used to extract viral RNA in a polymerase chain reaction technique that is used in COVID-19 test processing. More than 800 laboratory techs volunteered to perform tests. Today, the lab conducts about 400 tests a day.

COVID-19 lab
A COVID-19 testing lab was assembled through a collaboration of multiple research teams across OHSU. (OHSU/Kristyna Wentz-Graff)

The university also quickly established a COVID-19 research task force, led by Jay Nelson, Ph.D., OHSU Vaccine and Gene Therapy Institute director, to ensure studies could be conducted safely.

OHSU’s Oregon Clinical and Translational Research Institute also jumped in to create the infrastructure required to process and catalogue studies.

David Dorr, M.D., M.S., chief research information officer, led a team that rapidly stood up a COVID-19 research data mart – a repository of data designed to serve researchers – approved by the governing body that oversees human research to facilitate using patient data from OHSU’s electronic health record for research purposes.

“It is our intent to make de-identified data available both locally and nationally to help predict who is most at risk and what approaches are working to reduce the impact,” said Dorr.

In quick order, an operational foundation was laid for the COVID-19 research task force to greenlight nearly 175 individual research projects to date addressing all aspects of the disease, ranging from basic science and clinical research to epidemiology and community health studies.

Diagnostics, therapeutics, vaccines

In addition to the new on-site COVID-19 diagnostic lab, researchers including Donna Hansel M.D., Ph.D., chair and professor of pathology, Guang Fan, M.D., Ph.D., professor of pathology and associate medical director for OHSU laboratory medicine, Dan Streblow, Ph.D., associate professor at the OHSU Vaccine and Gene Therapy Institute, and Steve Kazmierczak, Ph.D., professor of pathology, are now working to offer several blood tests to identify the presence of antibodies produced in response to infection by SARS-CoV-2. These could include a rapid, point-of-care test as well as an enzyme-linked test. They are also conducting research to determine when antibodies arise following infection, how long antibodies last, and if specific types of antibodies confer resistance to re-infection.

man with blue mask, wearing gloves, holding up a vial of plasma and looking at it
Daniel Streblow, Ph.D., holds a vial of plasma that contains COVID-19 antibodies to be evaluated in OHSU’s in-house COVID-19 testing lab. Researchers are looking for antibody testing approaches, as well as hoping to find out if people can be re-infected, and how long antibodies remain in the body following infection. (OHSU/Kristyna Wentz-Graff)

Investigators are also participating in national multicenter clinical trials to research better treatments, enrolling patients at every stage of disease. They’re investigating multiple therapeutics, including those that may offer ways to block pathways involved in the ‘cytokine storm’ – the inflammatory response that leads to organ failure in the sickest patients. They’re also studying antiviral treatments, the much-discussed drug hydroxychloroquine, and how to best provide ventilation for patients experiencing respiratory failure.   

Above all, investigators are starting innovative trials at OHSU that harness unique areas of expertise. Many of these trials are randomized, placebo-controlled studies, which are considered the gold standard to demonstrate if and how well a treatment works.

Tom Beer, M.D., F.A.C.P.
Tom Beer, M.D., F.A.C.P.

For example, Tom Beer, M.D., deputy director of the OHSU Knight Cancer Institute, is initiating a clinical trial to test whether a drug that inhibits testosterone may reduce the virus’s ability to invade the lungs. 

“Worldwide, we are seeing a higher mortality rate among men than women,” said Beer. “We’ve hypothesized that one of the mechanisms for viral entry into human cells is enhanced by male hormones, so-called androgens. We’re proposing to test whether enzalutamide, an androgen blocker commonly used to treat prostate cancer, can reduce viral infectivity.”

Researchers have mobilized efforts to contribute to a COVID-19 vaccine. Scientists at the OHSU Vaccine and Gene Therapy Institute are investigating use of the cytomegalovirus and gamma herpesviruses as potential vaccine platforms and identifying adjuvants, or substances to help a vaccine create a stronger immune response, among other projects.

Other investigators are delving deep into the structure of SARS-CoV-2 with goal of creating a structural vaccine design and deploying nanoparticles for vaccine delivery.

Understanding the mystery of SARS-CoV-2

Diagnostics, therapeutics and vaccines are only possible with a deep knowledge of the virus. OHSU researchers rapidly pivoted to join in the worldwide hunt to understand SARS-CoV-2.

David Ellison, M.D., associate vice president for research, is collaborating with nephrologist and physician-scientist Susan Gurley, M.D., Ph.D., to investigate ACE-2 – a protein highly expressed in the kidney that serves as a receptor for SARS-CoV-2 so the virus can invade cells – to understand heart and kidney complications that some COVID-19 patients experience.

Brian O’Roak, Ph.D., associate professor of molecular and medical genetics, Andrew Adey, Ph.D., associate professor of molecular and medical genetics, and Benjamin Bimber, Ph.D., research assistant professor, Oregon National Primate Research Center at OHSU, are sequencing SARS-CoV-2 genomes to track the virus in Oregon, as well as analyzing its evolution over time and in response to novel treatments, which may provide information about the antiviral immune response. Their team released the first set of sequences identifying 13 viral transmission chains in Oregon. 

COVID-19 genome sequencing
Brendan O'Connell isolates viral RNA from a sputum sample from a patient positive for COVID-19/SARS-CoV-2. Researchers at OHSU are sequencing COVID-19-positive samples and comparing genomes to characterize how COVID-19 is spreading around the country and world and how it entered and is spreading in Oregon. (OHSU)

Other researchers are investigating the nature of SARS-CoV-2 to map sites on the virus that could be used as targets for new drugs called inhibitors that could prevent the virus from spreading. Some are developing neutralizing antibodies and nanobodies, while others are evaluating novel antiviral agents, creating automated platforms for drug and antibody screening, and studying changes in platelets and lipids or the immune system’s response to the infection. 

All of these studies are critical for informing the development of effective vaccines and treatments – for both the virus and complications that result from the disease. 

Innovative technologies to meet urgent needs

To make inroads against COVID-19, researchers are also engineering a wide range of equipment and technologies, including new masks with improved biopolymers that offer enhanced protection against infection.

3D-printed ventilator
Dr. Albert Chi, left, and Whitney Menzel look over a new ventilator created with 3D-printing technology, at OHSU, April 22, 2020. The design does not require electricity and operates off of a standard oxygen tank. (OHSU/Kristyna Wentz-Graff)

Trauma surgeon Albert Chi, M.D., M.S.E., is leading a team that designed a low-cost, 3D-printed ventilator. These ventilators could be useful in hot spots around the world experiencing an overwhelming surge of critically ill patients.

Emergency medicine physicians Craig Newgard, M.D., M.P.H., and Esther Choo, M.D., M.P.H., are using smartphone technology for COVID-19 patients seen in the emergency department but who aren’t sick enough to be hospitalized. The system tracks patient symptoms at home and could warn of potential problems.

A group led by trauma surgeon David Zonies, M.D., M.P.H., created a website and dashboard featuring real-time information to coordinate the regional availability of extracorporeal membrane oxygenation, or ECMO, a lifesaving machine that infuses blood with oxygen when a ventilator isn’t enough.

To expedite promising new technologies, OHSU joined other universities and academic medical centers across the country to ease licensing requirements.

Data to inform clinical practice, public health

Researchers are also employing evidence to support best clinical practices and generating data to inform public policy.

The World Health Organization funded an evidence review led by Roger Chou, M.D., director of the Pacific Northwest Evidence-based Practice Center at OHSU and a professor of medicine (internal medicine and geriatrics) in the OHSU School of Medicine, confirming that combining  PPE use with proper training in infection control lowers the rate of infection in health care workers.

Peter Graven, Ph.D.
Lead data scientist in OHSUs Business Intelligence unit, Peter Graven, Ph.D., uses numbers and advanced analytics to forecast health-related outcomes. (OHSU/Kristyna Wentz-Graff)

Data scientist Peter Graven, Ph.D., modeled the projected spread of the virus and began sharing those projections with health care leaders and policymakers in mid-March. These projections helped inform Oregon’s “Stay Home, Save Lives” campaign to reduce the spread of the virus and ensure it doesn’t exceed the capacity of health systems to treat a surge of patients who required hospitalization.

And Gov. Kate Brown tapped an OHSU team to help lead a community-based testing effort called “Key to Oregon” to gather data about the virus across the state, identify new cases at their earliest stage, identify asymptomatic individuals and locate emerging hot spots for containment – all of which are critically important for restoring the economy and protecting public health. 

The road ahead

But this is just the start. OHSU’s COVID-19 research efforts will grow and unfold over the coming months and years – fueled by an extra sense of urgency as scientists, like people everywhere, experience the pandemic.

Research leaders are looking ahead and planning how to slowly and safely resume all studies and experiments on campus in accordance with state orders.

“The overarching goal will be to get people safely back to work by prioritizing critical tasks so that progress is being made but with minimal risk,” said Barr-Gillespie. “As the situation improves, we will gradually increase activities and move toward a ‘new normal.’”

Ellison likens the situation to the HIV/AIDS crisis of the 1980s and 90s. “It was science that transformed a uniformly fatal disease into a manageable one with the development of effective therapeutics. Science is central to solving this crisis.”

With its deep wells of expertise, its relationships to collaborating institutions and access to exceptional resources such as OHSU’s Oregon National Primate Research Center and Vaccine and Gene Therapy Institute, the university is poised to make significant biomedical contributions.

“Oregon is uniquely positioned,” said Messer, who also has an appointment in the OHSU-PSU School of Public Health’s Program in Epidemiology. “We should all pat ourselves on the back because we’ve kept the virus at bay by staying at home. And, because not everyone got sick, we’ve created the headroom to study this disease, unlike other places where they’re just surviving. We can actually think.”

“Science will tell us how to stop the virus and how to heal people,” added Hayflick. “Science will even tell us how to get the economy rolling again. It’s all science.

“Science will lead us out of the pandemic.”

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