This interview by Bruce Goldman was originally published by the Stanford School of Medicine.

On May 13, the journal Science published a letter, signed by 18 scientists, stating that it was still unclear whether the virus that causes COVID-19 emerged naturally or was the result of a laboratory accident, but that neither cause could be ruled out. David Relman, MD, the Thomas C. and Joan M. Merigan Professor and professor of microbiology and immunology, spearheaded the effort.

Relman is no stranger to complicated microbial threat scenarios and illness of unclear origin. He has advised the U.S. government on emerging infectious diseases and potential biological threats. He served as vice chair of a National Academy of Sciences committee reviewing the FBI investigation of letters containing anthrax that were sent in 2001. Recently, he chaired another academy committee that assessed a cluster of poorly explained illnesses in U.S. embassy employees. He is a past president of the Infectious Diseases Society of America.

Stanford Medicine science writer Bruce Goldman asked Relman to explain what remains unknown about the coronavirus’s emergence, what we may learn and what’s at stake.

1. How might SARS-CoV-2, which causes COVID-19, have first infected humans?

Relman: We know very little about its origins. The virus’s closest known relatives were discovered in bats in Yunnan Province, China, yet the first known cases of COVID-19 were detected in Wuhan, about 1,000 miles away.

There are two general scenarios by which this virus could have made the jump to humans. First, the jump, or “spillover,” might have happened directly from an animal to a human, by means of an encounter that took place within, say, a bat-inhabited cave or mine, or closer to human dwellings — say, at an animal market. Or it could have happened indirectly, through a human encounter with some other animal to which the primary host, presumably a bat, had transmitted the virus.

Bats and other potential SARS-CoV-2 hosts are known to be shipped across China, including to Wuhan. But if there were any infected animals near or in Wuhan, they haven’t been publicly identified.

Maybe someone became infected after contact with an infected animal in or near Yunnan, and moved on to Wuhan. But then, because of the high transmissibility of this virus, you’d have expected to see other infected people at or near the site of this initial encounter, whether through similar animal exposure or because of transmission from this person.

2. What’s the other scenario?

Relman: SARS-CoV-2 could have spent some time in a laboratory before encountering humans. We know that some of the largest collections of bat coronaviruses in the world — and a vigorous research program involving the creation of “chimeric” bat coronaviruses by integrating unfamiliar coronavirus genomic sequences into other, known coronaviruses — are located in downtown Wuhan. And we know that laboratory accidents happen everywhere there are laboratories.

All scientists need to acknowledge a simple fact: Humans are fallible, and laboratory accidents happen — far more often than we care to admit. Several years ago, an investigative reporter uncovered evidence of hundreds of lab accidents across the United States involving dangerous, disease-causing microbes in academic institutions and government centers of excellence alike — including the Centers for Disease Control and Prevention and the National Institutes of Health.

SARS-CoV-2 might have been lurking in a sample collected from a bat or other infected animal, brought to a laboratory, perhaps stored in a freezer, then propagated in the laboratory as part of an effort to resurrect and study bat-associated viruses. The materials might have been discarded as a failed experiment. Or SARS-CoV-2 could have been created through commonly used laboratory techniques to study novel viruses, starting with closely related coronaviruses that have not yet been revealed to the public. Either way, SARS-CoV-2 could have easily infected an unsuspecting lab worker and then caused a mild or asymptomatic infection that was carried out of the laboratory.

3. Why is it important to understand SARS-CoV-2’s origins?

Relman: Some argue that we would be best served by focusing on countering the dire impacts of the pandemic and not diverting resources to ascertaining its origins. I agree that addressing the pandemic’s calamitous effects deserves high priority. But it’s possible and important for us to pursue both. Greater clarity about the origins will help guide efforts to prevent a next pandemic. Such prevention efforts would look very different depending on which of these scenarios proves to be the most likely.

Evidence favoring a natural spillover should prompt a wide variety of measures to minimize human contact with high-risk animal hosts. Evidence favoring a laboratory spillover should prompt intensified review and oversight of high-risk laboratory work and should strengthen efforts to improve laboratory safety. Both kinds of risk-mitigation efforts will be resource intensive, so it’s worth knowing which scenario is most likely.

4. What attempts at investigating SARS-CoV-2’s origin have been made so far, with what outcomes?

Relman: There’s a glaring paucity of data. The SARS-CoV-2 genome sequence, and those of a handful of not-so-closely-related bat coronaviruses, have been analyzed ad nauseam. But the near ancestors of SARS-CoV-2 remain missing in action. Absent that knowledge, it’s impossible to discern the origins of this virus from its genome sequence alone. SARS-CoV-2 hasn’t been reliably detected anywhere prior to the first reported cases of disease in humans in Wuhan at the end of 2019. The whole enterprise has been made even more difficult by the Chinese national authorities’ efforts to control and limit the release of public health records and data pertaining to laboratory research on coronaviruses.

In mid-2020, the World Health Organization organized an investigation into the origins of COVID-19, resulting in a fact-finding trip to Wuhan in January 2021. But the terms of reference laying out the purposes and structure of the visit made no mention of a possible laboratory-based scenario. Each investigating team member had to be individually approved by the Chinese government. And much of the data the investigators got to see was selected prior to the visit and aggregated and presented to the team by their hosts.

The recently released final report from the WHO concluded — despite the absence of dispositive evidence for either scenario — that a natural origin was “likely to very likely” and a laboratory accident “extremely unlikely.” The report dedicated only 4 of its 313 pages to the possibility of a laboratory scenario, much of it under a header entitled “conspiracy theories.” Multiple statements by one of the investigators lambasted any discussion of a laboratory origin as the work of dark conspiracy theorists. (Notably, that investigator — the only American selected to be on the team — has a pronounced conflict of interest.)

Given all this, it’s tough to give this WHO report much credibility. Its lack of objectivity and its failure to follow basic principles of scientific investigation are troubling. Fortunately, WHO’s director-general recognizes some of the shortcomings of the WHO effort and has called for a more robust investigation, as have the governments of the United States, 13 other countries and the European Union.

5. What’s key to an effective investigation of the virus’s origins?

Relman: A credible investigation should address all plausible scenarios in a deliberate manner, involve a wide variety of expertise and disciplines and follow the evidence. In order to critically evaluate other scientists’ conclusions, we must demand their original primary data and the exact methods they used — regardless of how we feel about the topic or about those whose conclusions we seek to assess. Prior assumptions or beliefs, in the absence of supporting evidence, must be set aside.

Investigators should not have any significant conflicts of interest in the outcome of the investigation, such as standing to gain or lose anything of value should the evidence point to any particular scenario.

There are myriad possible sources of valuable data and information, some of them still preserved and protected, that could make greater clarity about the origins feasible. For all of these forms of data and information, one needs proof of place and time of origin, and proof of provenance.

To understand the place and time of the first human cases, we need original records from clinical care facilities and public health institutions as well as archived clinical laboratory data and leftover clinical samples on which new analyses can be performed. One might expect to find samples of wildlife, records of animal die-offs and supply-chain documents.

Efforts to explore possible laboratory origins will require that all laboratories known to be working on coronaviruses, or collecting relevant animal or clinical samples, provide original records of experimental work, internal communications, all forms of data — especially all genetic-sequence data — and all viruses, both natural and recombinant. One might expect to find archived sequence databases and laboratory records.

Needless to say, the politicized nature of the origins issue will make a proper investigation very difficult to pull off. But this doesn’t mean that we shouldn’t try our best. Scientists are inquisitive, capable, clever, determined when motivated, and inclined to share their insights and findings. This should not be a finger-pointing exercise, nor an indictment of one country or an abdication of the important mission to discover biological threats in nature before they cause harm. Scientists are also committed to the pursuit of truth and knowledge. If we have the will, we can and will learn much more about where and how this pandemic arose.  

During the severe acute respiratory syndrome (SARS) outbreak in 2003, Taiwan reported 346 confirmed cases and 73 deaths. Of all known infections, 94% were transmitted inside hospitals. Nine major hospitals were fully or partially shut down, and many doctors and nurses quit for fear of becoming infected. The Taipei Municipal Ho-Ping Hospital was most severely affected. Its index patient, a 42-year-old undocumented hospital laundry worker who interacted with staff and patients for 6 days before being hospitalized, became a superspreader, infecting at least 20 other patients and 10 staff members. The entire 450-bed hospital was ordered to shut down, and all 930 staff and 240 patients were quarantined within the hospital. The central government appointed the previous Minister of Health as head of the Anti-SARS Taskforce. Ultimately the hospital was evacuated; the outbreak resulted in 26 deaths. Events surrounding the hospital’s evacuation offer important lessons for hospitals struggling to cope with the COVID-19 pandemic, which has been caused by spread of a similar coronavirus.

Read the Full Study in the Journal of Hospital Medicine

What is COVID-19? 
COVID-19 comes from the same family as severe acute respiratory syndrome (SARS), a respiratory illness first identified in southern China in 2003 that killed more than 700 people; and Middle East respiratory syndrome (MERS), which emerged in Saudi Arabia in 2012. Scientists still aren’t sure how humans first became infected with COVID-19, but suspect that the virus arose from bats, Relman said.

“That’s the best guess, simply because all of the most closely related viruses we know of in the world are ‘bat viruses,’” said Relman, who is a senior fellow at FSI and an expert on emerging infectious diseases.

Where Did the Virus Come From?
While many of the first cases of COVID-19 have been linked to the Huanan Seafood Market in Wuhan, recent data suggests that about half of the earliest cases appear to have no obvious connection to the market.

“Could they have been indirectly connected somehow, or could they too have been exposed through the movement of animals that ended up in the market? These are things that are unknown,” Relman said. 

Meanwhile, there has been speculation that the virus did not originate at the market and was instead created in a laboratory. Relman acknowledged that while he thinks it’s possible that scientists in China could have been studying the virus and let it out by mistake, he doesn’t think that’s what happened in this case.

Why Has COVID-19 Spread So Quickly?
The rapid transmission of the virus likely has to do with how it interacts with the human host. Most likely, it is growing to large numbers in the upper parts of the respiratory tract, and is therefore primed to be transmitted more easily, Relman noted.

“One of the biggest questions is whether people are contagious before they have symptoms,” Relman said. “And that is perhaps the most critical question as to whether this is going to be contained in the very near term or not.” 

What’s Been the Effect on China?
China was much better prepared for this epidemic than it was 17 years ago for SARS, said Eggleston, who is also a senior fellow at FSI and director of the Stanford Asia Health Policy Program. Still, China’s economy and connectivity within the global economy mean that this time around, it’s even more of a crisis, Eggleston said.

Many of the people who have died from the virus were healthcare workers who weren’t properly protected, due to a combination of strained resources and a shortage of testing kits and protective gear, she added. 

How Damaging is COVID-19 Going to Be?
If COVID-19 can be transmitted before people are exhibiting symptoms, it’s much more likely that the virus will spread broadly within China and be passed on to more people in other countries, said Eggleston.

Relman predicted that the number of new cases of the virus will decline over the next few months into the summer, but that it will continue to pop up in certain parts — or “hotspots” — around the world.

“We’re probably looking at a future that now includes the persistence of this virus periodically, especially in winters for the next several years,” he warned.  

Taiwan is only 81 miles off the coast of mainland China and was expected to be hard hit by the coronavirus, due to its proximity and the number of flights between the island nation and its massive neighbor to the west.

Yet it has so far managed to prevent the coronavirus from heavily impacting its 23 million citizens, despite hundreds of thousands of them working and residing in China.

According to the Johns Hopkins Coronavirus COVID-19 Global Cases map, as of Tuesday there were only 42 cases and one death in Taiwan, far behind China, with more than 80,000 cases and more than 2,900 deaths. The country also lags far behind its other Asian neighbors and ranks 17^th in the world for the number of global cases. As of this writing, South Korea was second, with 5,186 cases; followed by Iran with 2,336 and Italy with 2,036 people infected with the virus.

The United States currently stands at 107 known cases and six deaths.

The viral outbreak in China occurred just before the Lunar New Year, during which time millions of Chinese and Taiwanese were expected to travel for the holidays.

So what steps did Taiwan take to protect its people? And could those steps be replicated here at home?

Stanford Health Policy’s Jason Wang, MD, PhD, an associate professor of pediatrics at Stanford Medicine who also has a PhD in policy analysis, credits his native Taiwan with using new technology and a robust pandemic prevention plan put into place at the 2003 SARS outbreak.

“The Taiwan government established the National Health Command Center (NHCC) after SARS and it’s become part of a disaster management center that focuses on large-outbreak responses and acts as the operational command point for direct communications,” said Wang, a pediatrician and the director of the Center for Policy, Outcomes, and Prevention at Stanford. The NHCC also established the Central Epidemic Command Center, which was activated in early January.

“And Taiwan rapidly produced and implemented a list of at least 124 action items in the past five weeks to protect public health,” Wang said. “The policies and actions go beyond border control because they recognized that that wasn’t enough.”

Wang outlines the measures Taiwan took in the last six weeks in an article published Tuesday in the Journal of the American Medical Association.

“Given the continual spread of COVID-19 around the world, understanding the action items that were implemented quickly in Taiwan, and the effectiveness of these actions in preventing a large-scale epidemic, may be instructive for other countries,” Wang and his co-authors wrote.

Within the last five weeks, Wang said, the Taiwan epidemic command center rapidly implemented those 124 action items, including border control from the air and sea, case identification using new data and technology, quarantine of suspicious cases, educating the public while fighting misinformation, negotiating with other countries — and formulating policies for schools and businesses to follow.

Big Data Analytics

The authors note that Taiwan integrated its national health insurance database with its immigration and customs database to begin the creation of big data for analytics. That allowed them case identification by generating real-time alerts during a clinical visit based on travel history and clinical symptoms.

Taipei also used Quick Response (QR) code scanning and online reporting of travel history and health symptoms to classify travelers’ infectious risks based on flight origin and travel history in the last 14 days. People who had not traveled to high-risk areas were sent a health declaration border pass via SMS for faster immigration clearance; those who had traveled to high-risk areas were quarantined at home and tracked through their mobile phones to ensure that they stayed home during the incubation period.

The country also instituted a toll-free hotline for citizens to report suspicious symptoms in themselves or others. As the disease progressed, the government called on major cities to establish their own hotlines so that the main hotline would not become jammed.

Some might say that because Taiwan is such a small country — about 19 times smaller than Texas — it is easier to mobilize during emergencies. Yet Taiwan is particularly challenged by its proximity to China and the fact that 850,000 of its citizens reside on the mainland; another 400,000 work there. Taiwan had 2.71 million visitors from China last year.

So when the WHO was notified on Dec. 31, 2019, of a pneumonia of unknown cause in Wuhan, China, Taiwanese officials began to board planes and assess passengers on direct flights from Wuhan for fever and pneumonia symptoms before passengers could deplane.

As early as Jan. 5, notification was expanded to include any individual who had traveled to Wuhan in the past 14 days and had a fever or symptoms of upper respiratory tract infection at the point of entry. Suspected cases were screened for 26 viruses, including SARS and MERS. Passengers displaying symptoms were quarantined at home and assessed whether medical attention at a hospital was necessary.

What the U.S. Could Learn

One of Wang’s co-authors, Robert H. Brook, M.D., ScD., of the David Geffen School of Medicine at the University of California, Los Angeles, said Washington could learn a great deal from Taiwan’s so-far successful management of the virus.

“In Taiwan, diverse political parties were willing to work together to produce an immediate response to the danger,” said Brook, also of the nonprofit RAND Corporation. “Transparency was critical and frequent communication to the public from a trusted official was paramount to reducing public panic.”

The other co-author of their study is Chun Y. Ng, MBA, MPH, of The New School for Leadership in Health Care, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.

Brook said Taiwan got out ahead of the epidemic by setting up a physical command center to facilitate rapid communications. The command center set the price of masks and used government funds and military personnel to increase mask production. By Jan. 20, the Taiwan CDC announced that it had a stockpile of 44 million surgical masks, 1.9 million N95 masks and 1,100 negative pressure isolation rooms.

“In a country as complex as the United States,” Brook said, “there needs to be a sharing of intelligence on a real-time basis among states and the federal government so that action is not delayed by going through formal channels.”

Please contact Beth Duff-Brown for media requests.