Prepared for a Pandemic

When the first news of what would become a global pandemic emerged from China, the world’s leaders immediately turned to researchers at the Columbia Mailman School, who moved with lightning speed to begin unraveling the mysteries of the novel coronavirus. The scientists were tapping a deep well of innovative research and policy expertise going back decades. From discerning who is particularly vulnerable to the virus and why, to determining how an infection spreads, to developing diagnostic methods and treatments, Columbia Mailman School experts supplied critical data and advice to governments, nonprofit 

organizations, and private sector entities. Even as the campus and the city closed down, the School’s researchers, staff, and students worked into the night building vital knowledge that decision-makers would use to determine how to address the rapidly evolving crisis.

For many of those at Columbia Mailman School, the battle against COVID-19 was only the latest in a decades-long fight to prevent and combat deadly outbreaks. But this one was unlike any others. For a long time now, Earth has been primed for a pandemic: Airplanes speed pathogens across borders; humans encroach on animal habitats (COVID-19 likely started with an animal infection); and climate change expands the range of disease-carrying insects. Meanwhile, countries, including the United States, have disinvested in public health systems that prevent disease in recent decades. Despite all the ingredients for a perfect storm, “you always wonder if you’re really going to see something like this,” says Jeffrey Shaman, PhD, the director of the Climate and Health Program and an expert on disease transmission. “I hate to say it, but this is the worst respiratory viral pathogen we’ve faced since 1918."

Virus Hunter vs. Virus

It was only natural that W. Ian Lipkin, MD, the John Snow Professor and director of the Center for Infection and Immunity (CII), heard about the novel virus from a colleague in Guangzhou a month before the rest of the world became aware of it. One of the foremost authorities on infectious agents, Lipkin has hopscotched the globe helping tamp down outbreaks over three decades. In late January, he spent a week in China advising the Chinese government and top scientists about its response to the mysterious illness. He and his team at CII collaborated with Chinese scientists to identify and control the SARS coronavirus outbreak there in 2003. “Methods that we’ve piloted over the past 15 years enabled the discovery of this new coronavirus,” he says. “These techniques allow researchers to take samples from individuals who had an unknown disease and to identify the causative agent very quickly.”

Lipkin has earned the title of “virus hunter” for revolutionary research that has transformed the speed at which health authorities respond to emerging infections. He and his team have discovered more than 1,800 infectious agents. In recent years, they worked on outbreaks of West Nile virus, SARS, MERS, and others. (In the 2011 movie Contagion,for which Lipkin served as scientific consultant, Elliott Gould’s character, a scientist named Dr. Ian Sussman, was based on Lipkin.)

Until October of last year, CII was deeply engaged in PREDICT, the United States Agency for International Development-funded decadelong program to detect viruses with pandemic potential in animal hosts and to examine how they make the leap into humans. CII researchers were among the first to show that bats were an animal reservoir for coronaviruses such as SARS-CoV-1, MERS CoV, and SARS-CoV-2. A significant source of support for their work with bats, the PREDICT study was abruptly shuttered, its funding pulled only weeks before the first cases of the novel coronavirus were reported in China. This would prove to be just one example of how poorly prepared the United States was to face new viral threats.

When Lipkin began his work, it took years to identify a virus. Now, it takes hours. He rose to prominence by using molecular methods to identify viruses, infecting rats with a disease and then subtracting the rats’ DNA, leaving the virus. He developed MassTagPCR (polymerase chain reaction), which detects multiple viruses at once, and GreeneChip, a glass slide containing 500,000 genes that tests for known pathogens. He then pioneered the use of high throughput sequencing for pathogen surveillance and discovery. The tests, fast and cheap, are needed when pathogens travel thousands of miles in mere hours.

Earlier this year, after returning from China, Lipkin made television appearances, promoting isolation of patients, testing, and contact tracing, among other critical containment measures he had seen in China. Meanwhile, working in CII’s high-security, pressurized Biosafety Level 3 laboratory, he and the CII team, including Nischay Mishra, PhD, an assistant professor in Epidemiology, developed an antibody test for SARS-CoV-2 as well as a PCR assay that can simultaneously detect influenza A, influenza B, and SARS-CoV-2 viruses. Generous donors stepped up to fund this work; at press time the School had raised $10 million for COVID-19-related science.

Later in the spring, Lipkin and Mishra examined the therapeutic effects of convalescent plasma for COVID-19 in a study funded by a $2.5 million award from Amazon. The U.S. Food and Drug Administration later authorized emergency use of plasma. The CII team is also studying the repurposing of previously approved drugs for COVID-19 treatment, investigating the appearance of multisystem inflammatory syndrome in children after COVID-19 infection, and examining the effect of ultraviolet light and other disinfectants.

While helping to stop one pandemic, CII is preparing for the next ones, planning a surveillance system, the Global Infectious Diseases and Epidemiology Network (GIDEON). With initial support from the Skoll Foundation, the network, which involves epidemiologists in more than a dozen countries, is designed to equip scientists with biomolecular tools to quickly identify novel pathogens and to raise early alarms. “We’re not done,” says Lipkin. “This is not the last threat. It may not even be the worst.”

Predictions from the Past

While Lipkin and his team broke new ground in the lab, Jeffrey Shaman looked back, turning for insight to a groundbreaking study he had conducted before the crisis with the aim of advancing understanding of how disease is transmitted, even by seemingly healthy people, and improving experts’ ability to forecast spread. From 2016 through 2018, during his Virome of Manhattan project, Shaman and his team tracked respiratory viruses throughout the borough by following 214 people. “Until the Virome project, we didn’t realize to what extent the rapid movement of a virus is fueled by undocumented infections. That project informed the way we thought about this coronavirus,” says Shaman.

Shaman and his team concluded by late February that “stealth transmission” by asymptomatic yet unidentified carriers was driving the spread of SARS-CoV-2, a headline-making turning point in understanding the virus. They determined that in China, a stunning 86 percent of early infections were not documented. “That’s what led to its rapid spread,” he says. “People who, because their symptoms are mild or nonexistent, are out and about, going shopping, going to work or to school, and bringing the virus to new populations.”

Shaman and his team, including Sen Pei, PhD, associate research scientist in Environmental Health Sciences, then built models projecting the disease’s spread in the United States using data provided by The New York Times. Their calculations laid bare the destructive potential of the virus, and exposed the fact that had mitigation measures been used just one week earlier, 36,000 lives could have been saved. “We’re looking at something that’s catastrophic,” Shaman told the Times. They weren’t done, though. With support from the Morris-Singer Foundation, they accurately predicted a large resurgence of cases and deaths starting in June. Shaman advised policymakers across the U.S. and his models served as a foundation for data visualizations of critical care capacity developed by Charles Branas, PhD, chair of the Department of Epidemiology, and Andrew Rundle, MPH, DrPH, associate professor of epidemiology.

Shaman continued to mine his earlier work for insight into reinfection, another pressing concern. His Virome project had found that 12 of 137 people who were infected with a coronavirus that causes the common cold were reinfected. That, Shaman says, was a signal to policymakers and others to proceed cautiously when considering whether those infected had immunity from SARS-CoV-2 and for how long. “It opens lots of questions,” he says, “for example, are repeat infections going to be milder, about the same, or worse?”

Later in the summer, as wildfires raged across California and hurricanes displaced hundreds of thousands of Americans, Shaman examined the possible intersection between the pandemic and climate change. An expert in climate and disease, Shaman published projections on the potential spread of the novel coronavirus following an evacuation from a hurricane, which also has implications for evacuations from wildfires.

Helping Africa Face the Fight

Columbia Mailman School’s long history of fighting infectious diseases extends into the field worldwide. As news of the virus broke, Wafaa El-Sadr, MD, MPH ’91, MPA, the Dr. Mathilde Krim-amfAR Chair of Global Health, a professor of epidemiology and medicine, and the founder and director of ICAP, a global research and capacity-building center at Columbia Mailman School, was already focused on the world’s most under-resourced countries in Africa, Asia, and the Americas. ICAP quickly moved to assist national ministries of health in developing and implementing a response plan, while at the same time working on the ground to help health workers and health facilities prepare to address COVID-19.

El-Sadr brought decades of experience translating scientific best practices into reality in resource-limited environments. She led the Division of Infectious Diseases at Harlem Hospital Center in the early years of the AIDS epidemic, when support for patients with another mysterious disease was hampered by limited resources, stigma, systemic discrimination, and community distrust of the medical establishment. In response, she launched community- and family-centered models for HIV and tuberculosis (TB) management. She remembers caring for a woman with HIV in Harlem who was reluctant to accept treatment and was deteriorating rapidly. Ironically, the patient was vigilant about taking care of her young child with HIV. “It made me realize that we needed a family-focused model of care. We started a clinic where she’d be seen at the same time as her child.”

El-Sadr was among the first to integrate research and care, in response to feedback from the community. That model became the precursor to groundbreaking interventions for HIV, and later TB and malaria and other public health priorities, that she and her team initiated in sub-Saharan Africa. In 2003, El-Sadr founded ICAP, which now works in more than 30 countries. Its vision is centered on the following principles: true partnership with in-country leadership, as well as a focus on strengthening health systems and on building indigenous capacity. “We provide the technical assistance and support,” she says. “We’re not there to do the work for the people on the ground. The people we work with bring great ideas. They just need the support to do what they know needs to be done. We offer training and resources to enable them to move forward.”

That work earned El-Sadr a MacArthur “genius” grant, and it positioned ICAP to be ready to assist countries in responding to COVID-19. “When HIV spread like wildfire across the African continent, it took decades for the global community to mobilize a response,” says El-Sadr. “We certainly did not want such a delay in response to this new pandemic.” In a passionate New England Journal of Medicine Perspective article about COVID-19, she wrote, “Epidemics know no borders, and success in controlling the epidemic in any one country will be limited if epidemics continue to rage elsewhere.” Throughout the spring, El- Sadr and ICAP mobilized, supplying some form of COVID-19 support in 23 countries ranging from Angola to Zambia. ICAP helped to set up laboratories and isolation units, conducted surveys to assess the infection’s spread, procured personal protective equipment, trained frontline workers on infection prevention and COVID-19 diagnosis and management, and pursued participation in vaccine development. Closer to home, El-Sadr also chaired the public health response group guiding Columbia University’s COVID-19 Task Force. More recently, ICAP launched a major study to understand the impact of COVID-19 on hard-hit communities in New York City and on older adults in particular. El-Sadr worries that even though the infection may have lagged in reaching some countries, it is raging in others. “Global partnership and commitment are critical, combined with rapid action on the ground,” she says. “So much is at stake, which compels us to act now.”

How to "Think” Like a Pathogen

Barun Mathema, PhD ’11, assistant professor of epidemiology, views risk through the eyes of the pathogen adapting to find a host, and explores how housing, and the design of a city and its transportation systems, can have an outsized effect on transmission. He quickly joined a study earlier this year to explore evolution and transmission of SARS-CoV-2 using data from a New Jersey hospital system. That work follows a path Mathema has blazed toward understanding the transmission of  TB.

Since getting his PhD at Columbia Mailman School, Mathema has spent almost a decade researching the multiple dimensions of how TB transmission is influenced by culture, geography, and economics. His research involves populations in New York and China, as well as in South Africa. “Transmission is really the interface between how people behave and how a bug can adapt in that environment, and I’ve always been interested in both aspects,” Mathema says. “How do infectious diseases originate and propagate? What drives epidemics? Who are the people who are really infecting people?” Pathogens like TB and COVID-19 are interwoven into society. Looking at their transmission raises major questions. “How do we design our cities to reduce transmission? Housing has a measurable impact on diseases, for example,” he says. Last year, Mathema published a study in Proceedings of the National Academy of Sciences of the United States of America that traced an outbreak of drug-resistant TB in a South African province, finding that the origins of the outbreak had begun more than a decade before the outbreak surfaced. His work on TB informs his thinking on how COVID-19 spreads.

His long-term COVID-19 study is tracking the evolution of the virus and how that affects patient outcomes as vaccines and new drug therapies become available. As the virus encounters those barriers, it likely will evolve, he says. New techniques like high throughput sequencing and global sharing of data, things not readily available even as recently as the H1N1 pandemic in 2009, make his work possible.

The idea is to pick up a dangerous strain of the virus before it spreads and give public health leaders information so they can act. “One of our hard lessons with drug-resistant TB has been that we find out when the cat’s out of the bag,” he says. “That’s really difficult. The basic idea is to know earlier so we can prepare.”

Predicting the Ebb and Flow of the Virus

For Micaela Martinez, PhD, an assistant professor in Environmental Health Sciences, the new coronavirus offered an opportunity to explore questions that she has delved into for several years, using cutting-edge statistical inference techniques and mathematical models. Martinez won a National Institutes of Health Director’s Early Independence Award to explore fluctuations in the body’s biological rhythms over the course of the seasons. In 2018, she published a calendar showing the seasonality of 69 infectious diseases. She also found that geography mattered. Syphilis thrived during winter in China, while gonorrhea peaks in summer and autumn in the United States. “I wasn’t expecting seasonality in things like herpesviruses, tuberculosis, HIV,” she says. “I was very struck by this.”

That led to her ongoing research project evaluating how immune systems change over a day as well as over a year. Each season, volunteers spend 24 hours at the University of Surrey, United Kingdom having their noses swabbed and blood sampled to check for 16 respiratory viruses. The pandemic interrupted the analysis of samples, but she reports that there are indications that the immune reactions of the body change with the seasons and even within a 24-hour cycle. The applications of this knowledge could include administering vaccines during a particular season and time of day to get the best protection possible.

Ultimately, those projects prepared Martinez to dive deep into the mysteries of the novel coronavirus, participating in a National Science Foundation–funded study examining its transmission and immunity, a key to understanding whether people could be reinfected, and creating a timeline of infection in New York to better understand transmission. Her team’s first paper examined differences in disease related to neighborhood and race: The researchers found that Black New Yorkers were two times more likely to die of COVID-19 and Hispanics were 1.8 times more likely compared to whites. “In New York City, we were seeing quite early on that Queens and the Bronx were being hit harder, and we suspected health disparities played a role,” Martinez says. The top three COVID-19 comorbidities—hypertension, diabetes, and obesity—were also more prevalent in the Bronx than in Lower Manhattan, for example. Martinez’s work also brought to light inequities in testing that were potentially driven by race: Despite higher rates of infection in the Bronx and Queens, majority-white Staten Island had the highest rate of testing.

Watching Predictions Play Out

It’s hard to believe it in the midst of this pandemic, but a few decades ago, the concept of “emerging infectious diseases” didn’t exist. Stephen Morse, PhD, a professor of epidemiology and the director of the Infectious Disease Epidemiology Certificate Program, coined the term before a conference he chaired on emerging viruses at the National Institutes of Health in 1989. As far back as 1991, Morse warned that viral traffic was increasing. Today, he is in demand to educate the public about the emergence of SARS-CoV-2. In the early months of the pandemic, he and other faculty gave interviews on COVID-19 that appeared in more than 2,000 news articles worldwide. 

In the intervening years, Morse became a trailblazer, building the foundation for research not only at Columbia Mailman School but also in laboratories around the world. In 1994 he was a founder and chair of ProMED, the Program for Monitoring Emerging Diseases, an innovative global surveillance effort. He wrote the lead article in the first issue of the new Emerging Infectious Diseases journal in 1995. In that paper, he pointed out that high-fatality zoonotic viruses (those which jump from animals to people) would emerge as ecological changes and agricultural development placed people closer to animals. The evolution of known human viruses, he contended, was less important than the threat of viruses moving from animals to humans and from one location to another. Four decades ago, “focusing on this was a sort of a big leap into the unknown,” he says. But in the years since, there has been one outbreak after another of zoonotic viruses: Ebola, SARS, MERS, Nipah, Zika ... the list goes on.

Morse recalls Anthony Lake, the national security advisor in the Clinton administration, saying he thought biological threats were national security threats. “A lot of people scoffed at that. I was not among them,” he says. “We can see now how devastating something like this can be—the effect on the economy, on travel, on international relations. Maybe at least for a few years we’ll start taking these infections seriously and make sure we have the resources and don’t waste time.” In the darkness of the COVID-19 pandemic, he takes comfort in this: Former students in his longstanding course on emerging infectious diseases are now working in labs, health departments, and agencies across the country, unraveling the mysteries of COVID-19 and looking beyond this pandemic, to predict the next one.

Jim Morrison writes about the environment, health, and other topics for Smithsonian, The New York Times, and The Washington Post.