Rapid Response

Illustration: Ellen Weinstein

In late February, Benjamin Pinsky’s commute became unmanageable. He was readying Stanford’s Clinical Virology Laboratory for COVID-19 testing, and he received so many urgent calls each time he drove between his home in San Francisco and Stanford that, fearing an accident, he repeatedly pulled off the highway to discuss solutions with his team and reference information on his laptop. Finally, the associate professor of pathology gave up on the drive. For the first two weeks in March, as COVID-19 community transmissions increasingly made the news in the United States and the World Health Organization debated whether to announce a pandemic, he took a hotel room next to his lab.

Since January, Pinsky had been at the forefront of a vast collaborative effort to establish COVID-19 testing in the Bay Area—an endeavor paralleled by labs across the university striving to understand the disease, develop treatments and address many of the societal challenges presented by the virus. “The university is supporting rapid mobilization for COVID,” says vice provost and dean of research Kathryn Moler, ’88, a professor of applied physics and of physics. It is offering seed grants, expanding biohazard facilities, developing ways for people to work safely and accelerating the approval process for new projects. The race to respond to the pandemic may mark a watershed in how researchers mobilize and work together to face challenges, yielding stories of perseverance and teamwork that they will be sharing for years to come.

Testing, Testing 

In determining how to respond to the pandemic, the crucial first step was having an accurate and rapid test for COVID-19 infection. Medical personnel have to know who is infected in order to prevent the spread of the virus among patients and staff. In the first weeks of 2020, as news of the virus struggled to keep pace with its spread, Pinsky began ordering supplies to create a test. “By February 4,” he says, “we actually started screening specimens that were negative for other respiratory viruses to kind of keep an eye on what was happening in our area with the idea that if we were to identify any positive patients, we would be able to ramp up testing relatively quickly.”

Portrait headshot of Benjamin Pinsky.

‘They sent an email back that afternoon, saying, “You have permission from the FDA.”’
—Benjamin Pinsky

By February 29, the day the U.S. Food and Drug Administration relaxed requirements for clinical laboratory testing, Pinsky’s team had identified patient samples that were positive for COVID-19. The following Monday, his lab notified the FDA that they had completed requirements for testing. “They sent an email back that afternoon, saying, ‘You have permission from the FDA,’” he recalls—a process that would typically take several months or more. “We went live two days later,” he says, “on Wednesday”—just in time to respond to the rise in community transmissions in the Bay Area.

By April, Pinsky was referring to this period—when his lab was rushing to increase testing capacity for many hospitals in the region—as the “early days.” That was seven weeks prior. Since then, the lab has maintained the same pace, open 24 hours a day, with three rotating shifts of dozens of scientists and assistants. Due to the high demand for equipment and supplies, the lab has repeatedly validated the test using different reagents—the chemicals used to perform the tests. “There was a shortage of the reagents,” Pinsky says. “We didn’t want to run out of any one particular component of the tests, so there was constant work to make sure we were able to continue to offer testing.” Other Stanford labs also rallied, with donations of single-stranded DNA primers and RNA extraction kits.  “There was a great outpouring of support from throughout campus,” Pinsky recalls.

Antibody Answers  

One of the next most pressing questions was how to develop accurate screening for antibodies. Since numerous infected individuals appear to be asymptomatic—as many as 60 percent, by some estimates—reliable antibody testing is crucial for knowing not only which medical personnel might have developed immunity and can most safely work with patients, but also how widespread the virus is, what its actual death rate is and how far the United States might be from developing herd immunity.

Portrait headshot of Scott Boyd.

‘There’s quite a Wild West of testing going on right now.’
—Scott Boyd

Antibodies expert Scott Boyd, an associate professor of pathology, was well suited to the challenge. A native of Winnipeg, Manitoba, he majored in biochemistry at the University of Manitoba before becoming a Rhodes Scholar and studying Renaissance literature at the University of Oxford—an experience he recalls as “a great chance to really broaden my education before I dove into medical academia.” Like many of their colleagues since the pandemic began, he and research scientist Katharina Roeltgen spent day after 16-hour day in the lab. Their goal: to develop an antibody test that would offer greater accuracy than the many point-of-care and home testing kits in the marketplace.

“There’s quite a Wild West of testing going on right now,” Boyd says. “The majority of the tests really don’t seem to have much documented evidence of how well they work.” Though the FDA has eased rules regulating the sale of such tests to make them rapidly available, a good deal of money has been wasted on shoddy products. In late March, for instance, the British government purchased 3.5 million tests that then failed to give reliable results. 

Boyd’s team released its test on April 6. In developing it, they kept the focus on maintaining standards—going through all the same steps and seeing how each version of the test performs—but doing more experiments each day than would be typical. “It’s not that the methodology or the approach has changed,” he says. “It’s just that we’re having to do it more quickly than would be comfortable usually.” 

In conjunction with Pinsky and other collaborators, Boyd is now turning his attention to determining whether antibodies confer immunity. Since working directly with the COVID-19 virus is risky, a less dangerous virus will be genetically modified to express COVID-19’s spike: the prominent surface protein that binds with receptors on human cells to inject viral genetic material into them. “You can put that on a different virus,” Pinsky says. “It’s called pseudotyping, and then you use that in experiments to see if antibodies from patients will block the virus from getting into the cell.”

Treatment Trials 

Portrait headshot of Neera Ahuja.

‘Time zones don’t matter when you’re trying to find a cure that’s affecting the world.’
—Neera Ahuja

Just as research in diagnostics has been accelerating, so too have efforts on finding effective pharmaceutical treatment for patients with COVID-19. Clinical professor of medicine Neera Ahuja, division chief of hospital medicine and medical director of general inpatient medicine, is the principal investigator of a trial to treat severe cases of COVID-19 with remdesivir, an antiviral medication first used during the West African Ebola epidemic of 2013 to 2016. Remdesivir works by interrupting the genetic replication of viruses, and while it showed promise at stopping COVID-19 infections in a trial sponsored by the drug’s maker, Gilead Sciences, and carried out at Stanford and other universities, more data was needed to show its effect on severely ill patients whose lungs were being destroyed by the extreme reaction of their immune systems. A new trial sponsored by the National Institutes of Health and including a control group that received a placebo was initiated on March 30. It enrolled more than 1,000 severely ill patients at Stanford and 63 other sites across the globe. “Time zones don’t matter when you’re trying to find a cure that’s affecting the world,” Ahuja says.

Portrait headshot of Kari Nadeau.

‘It usually takes six months to get trials activated. This trial was activated in six days.’
—Kari Nadeau

“What’s great,” says co-principal investigator and professor of medicine and of pediatrics Kari Nadeau, “is how fast the NIH was on its feet and how fast the FDA was to address the challenge of this crisis.It usually takes six months to get trials activated. This trial was activated in six days.”

With equal speed, many of Stanford’s scientists have pivoted from their usual fields of study to focus on COVID-19, with as many as 50 researchers at a time on video calls briefing one another about the virus. “The COVID crisis motivated people to work together from many different areas,” says Nadeau, who directs the Sean N. Parker Center for Allergy and Asthma Research at Stanford and is best known for developing treatment for severe food allergies. “Even though our specialty areas might not be to work routinely with one another, most important is that our tools and our approaches are similar.”

Once again, the efforts paid off. On April 29, NIH released preliminary findings from the second remdesivir trial: For severely ill patients receiving remdesivir, recovery shortened from 15 days to 11 days. In a Stanford town hall meeting that same day, Lloyd Minor, dean of the Stanford School of Medicine, announced, “These two rigorously done trials provide really the first evidence of the efficacy of any therapeutic for this disease.”

Two days later, the FDA approved remdesivir for emergency use in the treatment of COVID-19.

Outpatient Options 

Since remdesivir must be administered intravenously in a hospital, that leaves the more than 80 percent of COVID-19 patients recovering at home without a proven treatment.

Portrait headshot of Prasanna Jagannathan.

‘We don’t have a lot to offer folks when they’re positive, either asymptomatic or with mild to moderate symptoms.’
—Prasanna Jagannathan

“We don’t have a lot to offer folks when they’re positive, either asymptomatic or with mild to moderate symptoms. We basically can tell them to go home and quarantine and stay away from their family members and loved ones and wait it out,” says Prasanna Jagannathan, an assistant professor of medicine. He and Upinder Singh, professor of medicine and of microbiology and immunology, are co-leading a trial to test the efficacy of interferon-lambda, one of the body’s natural antivirals. 

When under attack from viruses, cells produce interferon, a protein that, as its name suggests, interferes with viral replication while alerting other cells. “It’s sort of like you have a burglar trying to get into your home,” Singh explains, “and you’re turning on the lights and shutting the doors and windows. Interferon basically activates the cellular immune response to fight viruses.”

Of the various types of interferon that our bodies create, interferon-lambda is of interest to scientists because receptors for it exist only in the liver, lungs and intestines—the latter two being the novel coronavirus’s primary targets. Previous studies have shown that people injected with interferon-lambda tolerate it well—much better than other forms of interferon—and that it may mitigate infections such as hepatitis, SARS and influenza.

Portrait headshot of Upinder Singh.

‘We want to help them feel better, help prevent them from going to the hospital, and then, very importantly, decrease transmission to family members and close communities.’
—Upinder Singh

For the current trial, 120 patients with mild COVID-19 will be sorted into two groups. One will be injected with interferon-lambda (which lasts for a week) and the other with a placebo. Over the next 28 days, the researchers will record patients’ symptoms, rates of hospitalization and amount of viral shedding. “We have three goals,” says Singh. “We want to help them feel better, help prevent them from going to the hospital, and then, very importantly, decrease transmission to family members and close communities.”

As soon as Singh and Jagannathan conclude the first study, they will initiate two more: one with Avigan, an antiviral drug, and the other with Camostat, a compound that blocks viruses from entering cells. Once they have completed all three trials, they will evaluate their results and, if any of the drugs show promise, will consider further studies using them in combination. 

“Like we approach HIV or hepatitis C,” says Jagannathan, “we could potentially use some of these drugs together to improve outcomes even more so.”

Still Accelerating 

Portrait headshot of Kathryn Moler.

‘We didn’t make it any easier for [faculty]. We just tried to make it faster for them.’
—Kathryn Moler

Since the pandemic began, Stanford administrators have also been working nonstop to eliminate barriers so that research can proceed rapidly. “We set up a faculty committee to review COVID-19 research and get it approved as quickly as possible for conducting on-campus research,” Moler explains. “We didn’t make it any easier for [faculty]. We just tried to make it faster for them. Actually, it was harder because in addition to getting all the approvals that they normally have to get—like if they’re using lasers, they need laser safety approval—we also ask them to get approval to work on campus. But we work really fast to make sure that those approvals get turned around really quickly.” The university has even begun an expansion of the biosafety lab capable of hosting COVID research—where chemistry professor Carolyn Bertozzi and associate professor of medicine Catherine Blish typically each conduct separate experiments on tuberculosis—since it can’t meet the current demand. Says Moler: “We’ve been prioritizing multiple shifts in that facility,” including Blish’s to study the coronavirus and potential antiviral treatments, “and also have begun an expansion of the facility that is moving quite quickly. Typically, that would take a year or two, and we’re hoping to have this expansion by the end of August.”

Also crucial: ensuring that research sponsors are on board. Projects at Stanford and SLAC National Accelerator Laboratory take in $31 million a week, largely from government agencies but also from companies and foundations. “I would say that all of those entities have been very, very thoughtful about allowing people to pivot their research when pivoting their research is appropriate,” Moler says. 

Meanwhile, the university has had to ensure the safety of the often-unseen efforts that make infectious-disease research possible, such as lab maintenance, janitorial work, and supply-chain management of personal protective equipment and other essential materials. All the while, the university has been updating its policy manuals to safeguard employee health and keep pace with state and county guidance. “We need to write policy for all of these activities during this time at a really unprecedented speed,” Moler says. “I’ve been working basically nonstop since the pandemic started. Yesterday, my first Zoom call was at 6:30 a.m., and my last one ended at 9:15 p.m.” 

Stanford faculty have initiated hundreds of research projects related to COVID-19, many of which go far beyond the lab bench to address economic, policy and social challenges arising from the pandemic. The university has launched Stanford RISE (Respond. Innovate. Scale. Empower.), a response plan to connect researchers across disciplines. “RISE is an effort to bring together all of the research across campus in one place that is relevant for not only COVID-19 as a disease but also what society is going through,” says Moler. RISE reveals the many ways the pandemic affects society—from the impact of working from home to the ways social inequality affects the disease’s spread—and suggests ways humanity can respond. 

The stories of frantic work, sharing, collaboration and cross-disciplinary efforts are far more numerous than the few mentioned here. Take, for instance, how Stephen Quake, ’91, MS ’91, professor of bioengineering and of applied physics, loaded diagnostic equipment into his car at the Chan Zuckerberg Biohub, where he is co-president, and drove it to Pinsky’s lab. Or how David Camarillo, MS ’03, PhD ’08, associate professor of bioengineering, has shifted his research from preventing concussions to designing ventilators—required for severely ill COVID-19 patients—for rapid assembly from fewer parts. Collectively, these efforts suggest that among the mixed legacies of a deadly and devastating virus may be a research community primed for agility, rapid communication and cross-disciplinary innovation. In the meantime, as Nadeau points out, “None of these labs are getting sleep.

From top: Steve Fisch/Stanford School of Medicine (2); Stanford School of Medicine (3); Steve Fisch/Stanford Medicine; David Gonzales, ’93

Deni Ellis Béchard is a senior writer at Stanford. Email him at dbechard@stanford.edu.