In the fall of 2011, the world almost succumbed to pandemic. Scientists were playing God, having engineered a virus too dangerous to be toyed with.
At least, that was the tenor of headlines at the time. Ron Fouchier, lead scientist of the Dutch study that caused the ruckus, had inflamed the press with comments that he “mutated the hell” out of the Bird Flu. His research team had artificially engineered and H5N1 flu that was both airborne and lethal, the ripe conditions for a pandemic.
His statements prompted widespread public fear, criticism from security experts and accusations of scientific callousness. Bowing to public pressure and fearing top-down government oversight, Fouchier and other flu scientists called a halt to research and publication of the results of their work on the H5N1 strain. It was the first world-wide scientific moratorium since 1975, when genetic researchers called a time-out on recombinant DNA studies, fearing misuse of the results.
Although the H5N1researchers eventually published a revised version of their results after hundreds of hours of meetings, they now face a surfeit of regulatory hoops that create a distinct deterrent to future research. Unfortunately, the domino effect of public fear, self-censorship and beefed-up regulation was triggered by a gross misunderstanding of Fouchier’s work.
This misunderstanding unleashed an infection more dangerous than any virus: fear.
Fouchier’s work was based on a scientific discipline known as “gain of function” (GOF) research, which involves manipulating viruses in a lab to learn about the kinds of mutations that can happen in nature. This can give scientists hints about the imminence of a naturally-occurring bird flu outbreaks and can contribute to disease surveillance and prevention. However, this research also qualifies as “dual use research of concern,” or research on any pathogen that could double as a biological weapon. Since the 2001 anthrax attack, when weapons-grade anthrax samples were mailed to members of Congress and the White House, the government has kept tabs on a list of pathogens that pose potential public health threats including the contemporary Avian Flu (H5N1) and the Spanish Flu of 1918 (H1N1).
The 2001 anthrax attack also prompted a famous and much-cited document in the biosecurity community, Biotechnology Research in an Age of Terrorism. Colloquially known as the Fink Report, the 2004 paper by MIT’s Gerald Fink detailed seven dangerous classes of experiments requiring additional oversight, such as dual-use research. Based on the Fink Report’s recommendations, the U.S. government created the National Science Advisory Board for Biosecurity, or NSABB, to provide scientists with guidelines for publishing results of dangerous experiments. But without the power to enforce recommendations, NSABB struggled to provide consistent oversight that would protect scientific exchange and manage true biosecurity risks. Fink‘s clearly defined set of risky experiments, paired with a toothless advisory panel, set the stage for the moratorium that unfolded after Fouchier’s ill-said comments.
In nature, the H5N1 flu strain is often deadly but it does not pass easily from person to person, preventing a very serious outbreak. Fouchier’s experiment induced five mutations to the H5N1 genetic sequence and used it to infect a group of ferrets. According to reporting at the time by New Scientist, ABC and others,the mutations created the key ingredient for pandemic-like conditions by making the strain lethal and capable of airborne transmission. When the manuscript was submitted to Science as part of the peer review process, editors at the journal recognized it as one of Fink’s seven risky experiments and alerted NSABB.
NSABB requested censorship of Fouchier’s results and of another, similar publication submitted to Nature by the University of Wisconsin’s Yoshihiro Kawaoka. Both research groups, realizing growing public panic and the potential for government intervention, voluntarily called a 60-day moratorium in January 2012 to discuss the implications of their research. What was meant to be a temporary pause turned into a year-long discussion organized by the World Health Organization and the U.S. National Institute for Allergy & Infectious Disease (NIAID).
Although both papers were ultimately published, scientists studying the influenza virus now face a crippling maze of domestic and international safety protocols. These regulations, spearheaded by the U.S. and adopted by most countries, require additional scientific justification for government funding, pre-screening of results by the scientists themselves, and possible enhanced lab security measures to prevent accidental outbreak. There is also an international layer of regulation, because the publication of dual-use research itself can be considered a weapon. That makes it subject to export control laws governing weapons-sharing between countries. Essentially, H5N1 gain-of-function research will only take place if it meets an extremely rigorous set of funding criteria, is vetted by several government agencies and is treated as a potential weapon.
With the clarity of 20/20 hindsight, it appears that NSABB was reacting based on a misunderstanding of Fouchier’s results. David Morens, the Scientific Advisor the Director of NIAID, agreed that the results were initially misinterpreted.
“Before I read the paper, I heard what people said about it, including journalists, and it didn’t all add up to me,” Morens said. “And then I read the paper and I realized that everyone had misunderstood.”
There were actually two separate pieces of Fouchier’s study. The first was to artificially mutate H5N1 on a lab bench and then put that virus in the noses of ferrets to let it replicate and mutate on its own. Then, scientists separated ferrets in cages to see if the infection could pass in the air, which it did. However, none of the ferrets that inhaled the airborne virus died. It was only when scientists physically inserted the mutated H5N1 virus into the ferrets‘ tracheas that they died.
“People made the connection that it killed and it was easily transmissible: big mistake,” Morens said.
Vincent Racaniello, a Higgins Professor of microbiology at Columbia University who has blogged extensively on the subject, pinpoints the problem to Fouchier’s November 2011 interview in an article published in Science Insider. Fouchier reported that the aerosol transmitted viruses were deadly but failed to note that ferret death only happened when the virus was shoved in the trachea.
David Malakoff, a reporter for Science who has covered the H5N1 controversy from the start, agreed that “Fouchier was hyping results” and the NSABB members “had a vast misunderstanding of what they were meeting about.” He said the distinction between lethality and airborne transmission was not truly understood until February 2012 when Anthony Fauci, Director of NIAID, asked Fouchier to clarify his results, point-blank at a meeting hosted by the American Society of Microbiology. Malakoff said that when Fouchier confirmed to the meeting attendees that none of the ferrets that breathed in the virus actually died, “the entire room went silent.”
“Fouchier was hyping results,” Malakoff said.
But by that time, the moratorium was already in full swing and would continue for almost a year, despite the fact that the biosecurity threats were ill-founded. National security personnel were examining the dangers of this kind of research, and one of the greatest fears raised was that terrorist groups would use the genetic code to create a biological weapon. However, many flu scientists have said that the actual censorship of the genetic sequence was a moot point by the time the moratorium kicked into high gear.
“I suspect that if I wanted to have the sequence at that time, I easily could have gotten it,” said Gundi Ertl, Chair of the Immunology Department and Director of the Vaccine Center at the Wistar Institute. The mutated H5N1 sequence had already been presented at conferences, meaning it could be easily found by some asking-around in the flu research community. Ertl, echoing many flu scientists, also finds it unlikely that a terrorist group would be able to re-engineer the virus to create highly contagious human-killer because even Fouchier had not been able to fully engineer this disaster in ferrets. Moreover, other similar research slipped past the NSABB radar, such as a January 2012 publication in Virology by Chen and colleagues with similar implications to Fouchier’s study. But without scientists spouting outlandish comments to the press, that paper was published with less of a fuss from NSABB.
While gain-of-function research does present risks if conducted irresponsibly, more red-tape only prevents advanced understanding of one of the most deadly infections that exists. In fact, the ban on research had a direct negative effect on the current attempts to learn more about Avian Flu mutations. Because of the moratorium, Chinese researchers were not able to study the transmissibility in ferret models, the best human analogue, according to a report published in CIDRAP News on May 2. The Chinese scientists instead used guinea pigs, and discovered that mutated H5N1 could achieve mammal to mammal transmission, although did not prove lethality. This research is especially crucial now that a new strain of bird flu (H7N9) has emerged in China through naturally-occurring mutations; according to the Chinese government this strain has already killed 24 people and infected 125. If it can pass from human to human, and not just from bird to human, H7N9 could potentially generate its own pandemic. Gain-of-function research could be the best way to stay ahead of the curve by engineering mutations safely in a lab to see what might happen in nature.
David Ozonoff, Professor of Environmental Health at Boston University and one of the main activists for the 1975 scientific moratorium on recombinant DNA, said that he believes the two studies that sparked the moratorium were critically important for our understanding of the bird flu. He said that neither contagion or lethality are well understood, and this research is essential “if any means of control is to be undertaken.” Fouchier has already used lessons learned from his H5N1 mutation research to shed light on this new H7N9 genetic sequence, currently taking lives in China.
There is no doubt that research on the highly contagious flu virus needs to be executed carefully. Scientists must agree on common safety protocols around biosecurity and biocontainment. Admittedly, the censorship could have been worse; scientists are still free to publish their results, but now face mountains of red tape. Some argue that these regulations are necessary to ensure public safety, but the cost of over-regulation exceeds the supposed benefit to public safety. Ultimately, the tragedy of this situation is that the entire decision-making process rested on a web of misinformation and whipped-up public fear of bioterrorism threats. The better way to move forward is to educate scientist about responsible communication of high-risk/high-reward research.