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In 2011, a tall, confident Dutch scientist, Ron Fouchier, using grant money from Fauci’s group at NIH, created a mutant form of highly pathogenic avian influenza, H5N1, and passaged it ten times through ferrets in order to prove that he could “force” (his word) this potentially fatal disease to infect mammals, including humans, “via aerosols or respiratory droplets.” Fouchier said his findings indicated that these avian influenza viruses, thus forced, “pose a risk of becoming pandemic in humans.”
This experiment was too much for some scientists: Why, out of a desire to prove that something extremely infectious could happen, would you make it happen? And why would the U.S. government feel compelled to pay for it to happen? Late in 2011, Marc Lipsitch of the Harvard School of Public Health got together with several other dismayed onlookers to ring the gong for caution. On January 8, 2012, the New York Times published a scorcher of an editorial, “An Engineered Doomsday.” “We cannot say there would be no benefits at all from studying the virus,” the Times said. “But the consequences, should the virus escape, are too devastating to risk.”
These gain-of-function experiments were an important part of the NIH’s approach to vaccine development, and Anthony Fauci was reluctant to stop funding them. He and Francis Collins, director of the National Institutes of Health, along with Gary Nabel, NIAID director of vaccine research, published an opinion piece in the Washington Post in which they contended that the ferret flu experiments, and others like them, were “a risk worth taking.” “Important information and insights can come from generating a potentially dangerous virus in the laboratory,” they wrote; the work can “help delineate the principles of virus transmission between species.” The work was safe because the viruses were stored in a high-security lab, they believed, and the work was necessary because nature was always coming up with new threats. “Nature is the worst bioterrorist,” Fauci told a reporter. “We know that through history.”
Soon afterward, there followed some distressing screwups in secure federal laboratories involving live anthrax, live smallpox, and live avian influenza. These got attention in the science press. Then Lipsitch’s activists (calling themselves the Cambridge Working Group) sent around a strong statement on the perils of research with “Potential Pandemic Pathogens,” signed by more than a hundred scientists. The work might “trigger outbreaks that would be difficult or impossible to control,” the signers said. Fauci reconsidered, and the White House in 2014 announced that there would be a “pause” in the funding of new influenza, SARS, and MERS gain-of-function research.
Baric, in North Carolina, was not happy. He had a number of gain-of-function experiments with pathogenic viruses in progress. “It took me ten seconds to realize that most of them were going to be affected,” he told NPR. Baric and a former colleague from Vanderbilt University wrote a long letter to an NIH review board expressing their “profound concerns.” “This decision will significantly inhibit our capacity to respond quickly and effectively to future outbreaks of SARS-like or MERS-like coronaviruses, which continue to circulate in bat populations and camels,” they wrote. The funding ban was itself dangerous, they argued. “Emerging coronaviruses in nature do not observe a mandated pause.”
Hoping to smooth over controversy by showing due diligence, the National Science Advisory Board for Biosecurity, founded in the BioShield era under President Bush, paid a consulting firm, Gryphon Scientific, to write a report on gain-of-function research, which by now was simply referred to as GoF. In chapter six of this thousand-page dissertation, published in April 2016, the consultants take up the question of coronaviruses. “Increasing the transmissibility of the coronaviruses could significantly increase the chance of a global pandemic due to a laboratory accident,” they wrote.
The Cambridge Working Group continued to write letters of protest and plead for restraint and sanity. Steven Salzberg, a professor of biomedical engineering at Johns Hopkins, said, “We have enough problems simply keeping up with the current flu outbreaks — and now with Ebola — without scientists creating incredibly deadly new viruses that might accidentally escape their labs.” David Relman of Stanford Medical School said, “It is unethical to place so many members of the public at risk and then consult only scientists — or, even worse, just a small subset of scientists — and exclude others from the decision-making and oversight process.” Richard Ebright wrote that creating and evaluating new threats very seldom increases security: “Doing so in biology — where the number of potential threats is nearly infinite, and where the asymmetry between the ease of creating threats and the difficulty of addressing threats is nearly absolute — is especially counterproductive.” Lynn Klotz wrote, “Awful as a pandemic brought on by the escape of a variant H5N1 virus might be, it is SARS that now presents the greatest risk. The worry is less about recurrence of a natural SARS outbreak than of yet another escape from a laboratory researching it to help protect against a natural outbreak.” Marc Lipsitch argued that gain-of-function experiments can mislead, “resulting in worse not better decisions,” and that the entire gain-of-function debate as overseen by the NIH was heavily weighted in favor of scientific insiders and “distinctly unwelcoming of public participation.”
Nariyoshi Shinomiya, a professor of physiology and nano-medicine at the National Defense Medical College in Japan, offered this warning: “Similar to nuclear or chemical weapons there is no going back once we get a thing in our hands.”
But in the end, Baric was allowed to proceed with his experiments, and the research papers that resulted, showered with money, became a sort of Anarchist’s Cookbook for the rest of the scientific world. In November 2015, Baric and colleagues published a collaboration paper with Shi Zhengli titled “A SARS-like Cluster of Circulating Bat Coronaviruses Shows Potential for Human Emergence.” Into a human SARS virus that they had adapted so that it would work in mice, Baric and Shi et al. inserted the spike protein of a bat virus, SHC014, discovered by Shi in southern China. They dabbed the mice nasally with virus and waited, looking for signs of sickness: “hunching, ruffled fur.” They also infected human airway cells with the mouse-adapted bat-spike-in-a-human-virus backbone. In both mice and human airway cells, the chimeric virus caused a “robust infection.”
This proved, Baric and Shi believed, that you did not need civets or other intermediate hosts in order for bats to cause an epidemic in humans and that therefore all the SARS-like viruses circulating in bat populations “may pose a future threat.” Peter Daszak, who had used Predict funds to pay Shi for her work on the paper, was impressed by this conclusion; the findings, he said, “move this virus from a candidate emerging pathogen to a clear and present danger.”
Richard Ebright was trenchantly unenthusiastic. “The only impact of this work,” he said, “is the creation, in a lab, of a new, non-natural risk.”
Early in 2016, Baric and Shi again collaborated. Shi sent Baric a fresh bat virus spike protein, and Baric inserted it into the backbone of a human SARS virus and then used that infectious clone to attack human airway cells. “The virus readily and efficiently replicated in cultured human airway tissues, suggesting an ability to potentially jump directly to humans,” reported the UNC’s website. This time, they also used the bat-human hybrid virus to infect transgenic humanized mice that grew human ACE2 protein. The mice, young and old, lost weight and died, proving, again, that this particular bat virus was potentially “poised to emerge in human populations.” It was “an ongoing threat,” Baric wrote. But was it? Civets and camels that are exposed to a lot of bat-guano dust may be an ongoing threat and a manageable one. But the bats themselves just want to hang in their caves and not be bothered by frowning sightseers in spacesuits who want to poke Q-tips in their bottoms. This 2016 “poised for human emergence” paper was supported by eight different NIH grants. In 2015, Baric’s lab received $8.3 million from the NIH; in 2016, it received $10.5 million.
Gain-of-function research came roaring back under Trump and Fauci. “The National Institutes of Health will again fund research that makes viruses more dangerous,” said an article in Nature in December 2017. Carrie Wolinetz of the NIH’s office of science policy defended the decision. “These experiments will help us get ahead of viruses that are already out there and pose a real and present danger to human health,” she told The Lancet. The NIH, Wolinetz said, was committed to a leadership role with gain-of-function research internationally. “If we are pursuing this research in an active way, we will be much better positioned to develop protection and countermeasures should something bad happen in another country.”
A reporter asked Marc Lipsitch what he thought of the resumption of NIH funding. Gain-of-function experiments “have done almost nothing to improve our preparedness for pandemics,” he said, “yet they risked creating an accidental pandemic.”