Drawing on the assumptions of the “viral traffic” framework, international health authorities sought to implement a global surveillance system that could detect and rapidly contain novel pathogens.
Epidemiologist Donald Henderson, who had led the W.H.O. smallpox eradication campaign in the 1970s, provided an initial vision of a global infrastructure for detecting the onset of emerging diseases.
Henderson’s vision built on the field of “epidemic intelligence,” developed at the Center for Disease Control during the Cold War, which involved training field epidemiologists to track reports of outbreaks and quickly respond to contain them.
The goal was to extend the tools of epidemic intelligence — which were designed to detect outbreaks of existing diseases — to anticipate the emergence of novel ones.
Such a system, Henderson and others argued, would be of use not only for monitoring emerging diseases, but also for the early detection of a bioterrorist attack.
In the aftermath of the 2001 anthrax letters, this “dual use” approach to biological threats attracted increasing support from the national security establishment.
There were political as well as technical challenges to building a global system to monitor the emergence of infectious diseases.
National governments were often hesitant to report outbreaks to international authorities.
At the outset of the 2003 SARS epidemic, the Chinese government refused to allow outside experts to investigate, underlining the need for a system that would enable rapid response to the appearance of a novel and deadly infectious disease.
Soon after, the specter of an avian influenza pandemic accelerated efforts to construct such a system, including the adoption of revised International Health Regulations that enabled the W.H.O. to declare a “public health emergency of international concern” based on the appearance of an as-yet-unknown pathogen.
The goal was to push W.H.O. member states to rapidly report any such outbreaks and to allow international health authorities to investigate them.
“Experimental virologists argued that it would be possible to simulate the natural process of viral evolution in the laboratory.”
A number of entrepreneurial scientists claimed to have developed tools that would enable the early detection of future viral disease outbreaks, making it possible to “stop the next pandemic before it starts.”
Epidemiologist Larry Brilliant pitched a digital surveillance system that would crawl the internet and global news to detect signs of developing health threats.
Primatologist Nathan Wolfe promoted a system of “viral forecasting” that involved collecting samples of bushmeat from local markets across sub-Saharan Africa.
Zoologist Peter Daszak at EcoHealth Alliance conducted genetic analyses of samples taken from wildlife around the world with the aim of predicting the onset of emerging diseases.
The concern among health authorities that avian influenza would mutate to become more easily transmissible among humans drove an intensification of research on viral emergence.
Disease ecologists thought that a pandemic strain would likely emerge at the duck-pig interface in East Asia and then be carried around the world by migratory waterfowl.
To track potentially dangerous mutations of the virus, they regularly conducted genetic analyses of samples taken from migratory birds.
But such molecular surveillance efforts posed a familiar question: How could scientists know which viral strains to look for? What were the signs that a virus was becoming more easily transmissible among humans?
Here a new set of scientific actors entered the picture: experimental virologists, who argued that it would be possible to simulate the natural process of viral evolution in the laboratory.
The premise was that pushing H5N1 in the direction of human transmissibility would help molecular surveillance efforts by making it possible to identify genetic sequences linked to the ability to infect humans.
This goal was taken up as part of the U.S. government’s 2005 national pandemic preparedness plan. In an appendix to the plan, the National Institutes of Health pledged support for basic research in influenza virology, including projects to understand the “genetic changes that permit an influenza virus to suddenly acquire the ability to transmit between species.”
This clause referred to a subfield of virology that would become known as “gain of function research,” in which researchers experimentally manipulated viruses in order to study characteristics such as virulence and transmissibility.
Between 2001 and 2007, annual federal funding for basic research on influenza, managed by the National Institute of Allergy and Infectious Disease (NIAID), jumped from $15 million to $212 million.
Gain Of Function
When the H1N1 (swine flu) pandemic began in the spring of 2009, it seemed at first to be “the next pandemic” that health authorities had been anticipating.
But H1N1 turned out to have relatively mild effects on human populations, and W.H.O. officials were accused of overreacting to the appearance of the new strain — of having pushed governments to invest huge sums in what turned out to be unnecessary mass vaccination campaigns.
By this time, meanwhile, the dire threat of an avian influenza pandemic seemed to be waning. Perhaps H5N1 was unlikely, after all, to mutate to become easily transmissible among humans.
However, experimental virologists continued to make the case for its viability as a pandemic threat.
In late 2011, when Dutch virologist Ron Fouchier announced that his laboratory had created a strain of H5N1 that could be passed via aerosol transmission among ferrets, he explained the rationale for creating what he described as “one of the most dangerous viruses you can make.”
While there were respected scientists who thought “that H5N1 could never become airborne between mammals,” he said, “I wasn’t convinced. To prove these guys wrong, we needed to make a virus that is transmissible.”
Fouchier’s announcement sparked a public debate among life scientists and biosafety specialists over the risks and benefits of gain-of-function research on dangerous pathogens.
According to advocates of the research, experimentally manipulating viruses to make them more virulent or transmissible would contribute to pandemic preparedness by enabling molecular surveillance efforts — such as sampling migratory birds for avian influenza — to recognize the emergence of dangerous pathogens in time to contain them.
“In defining the mutations required for mammalian transmission,” as NIAID director Anthony Fauci and two co-authors wrote in a Washington Post op-ed,
“public health officials are provided with genetic signatures that, like fingerprints, could help scientists more readily identify newly emergent, potentially harmful viruses, track their spread and detect threatening outbreaks.”
“The key concern was that this type of research might spawn exactly what it was meant to prevent.”
Critics, meanwhile, charged that the rationale for such research was tenuous at best.
First, they argued, it took for granted a vast technical capacity for the molecular surveillance of potential animal hosts that was completely unrealistic given limited resources.
Second, it assumed that what was created in the laboratory through gain-of-function research would in fact mimic what was likely to emerge in “nature.”
But there was no basis for such an assumption. As one scientist memorably put it, “Would nature have come up with the dachshund?”
Critics also argued that a significant recent record of laboratory accidents resulting in the release of dangerous viruses and a woefully insufficient regulatory apparatus militated against providing government support for gain-of-function research.
The key concern was that this type of research might spawn exactly what it was meant to prevent.
As a group of scientists concerned with biosafety wrote in 2014, the lab-based creation of pathogens with pandemic potential “entails a unique risk that a laboratory accident could spark a pandemic killing millions.”
For these critics, the hypothetical benefit of assessing pandemic potential did not outweigh the catastrophic risk of unleashing an actual pandemic.
Two catastrophic scenarios confronted one another with no means of technical resolution: a naturally emerging virus whose onset might be anticipated and even prevented through the results of viral transmission research, versus the accidental release of a pandemic virus as a result of this very research.
In this uncertain terrain, government funding agencies struggled to find an agreed-upon method of risk assessment that could guide regulatory decisions.
Meanwhile, despite an official moratorium on federal support for gain-of-function research from 2014 to 2017, such experimentation continued and extended to new areas.
The Route To Wuhan
The two major strands of research on viral emergence — disease ecologists studying wildlife in the field and experimental virologists manipulating pathogens in the laboratory — converged in the investigation of bat coronaviruses found in caves in southern China.
In June 2014, NIH funded a proposal for research on “understanding the risk of bat coronavirus emergence,” led by Peter Daszak of EcoHealth Alliance in collaboration with the Wuhan Institute of Virology.
The proposed research would address questions on “the origin, diversity, capacity to cause illness and risk of spillover” of bat coronaviruses, and involved “conducting laboratory experiments to analyze and predict which newly discovered viruses pose the greatest threat to human health.”
Such “emergence potential” — that is, the potential for “interspecies transmission” of novel coronaviruses — would be tested “using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice,” as the proposal put it.
Thus, the project sought to address the question that Stephen Morse had posed three decades earlier: How to assess “the likelihood that a given animal virus will emerge as a pathogen”?
Seven years later, in mid-2021, there were two ways to understand the retrospective significance of this research program — as either the prescient forecast or the dangerous progenitor of the COVID-19 pandemic.
In this sense, we can understand our current situation of diagnostic uncertainty as a question of which route of viral traffic to follow: zoonotic spillover, as exemplified by the movement of SARS in the early 2000s from bats to civet cats to humans via the trade in wildlife; or a new potential route, from the bat caves of southern China to a virology laboratory in Wuhan, as part of a cosmopolitan project in the life sciences—initially proposed in 1989—to investigate the pandemic potential of emerging viruses.
The stakes of this assessment are high, not only for determining the sites of failure that led to the present catastrophe, but also in targeting interventions designed to forestall “the next one.”