Read the next installment: “Outbreak: Our next global pandemic”
Read the previous installment: “Evolution: How a virus becomes a threat“
In 2011 Ron Fouchier took a pipette in one hand, a ferret in the other, and squeezed a few drops of liquid into the creature’s quivering nostril. This was a routine procedure for Fouchier, one of the world’s leading virologists at the Erasmus Medical Center in Rotterdam. He had spent his career studying the ways in which deadly viruses mutate as they pass between animals and people. Nevertheless, as he squeezed the pipette, he could not have anticipated the fallout from his actions.
The liquid contained microbes of the deadly bird flu virus H5N1. By 2011, H5N1 had infected close to 600 humans and killed more than half of them, a proportion that far exceeded that of the 1918 influenza pandemic, which killed as many as 100 million people. This new strain of avian flu was also unusually virulent, but at that moment, it required direct contact with infected birds–or the bodily fluids of infected humans–in order to spread. For the few weeks prior, Fouchier and his team had been increasing the virus’s potency by fiddling with its genetic code in the laboratory. The idea was to see how it might mutate in the wild and if it could become airborne–an evolutionary upgrade that would vastly increase the pandemic threat.
Researchers have played with viruses in this way since the mid-1980s. It takes around six months to develop treatment for a new strain of flu virus, so by anticipating the ways in which H5N1 could evolve and become deadlier and more transmissible, Fouchier and his team hoped to give humanity a head start. “Modifying different parts of the virus allows us to learn about functions of different proteins,” he told me recently. “This is super important because only if you understand a virus well is it possible to design efficient vaccines and therapeutics.”
The environment was safe and secure. Fouchier’s Dutch laboratory, specially constructed for him by the university, was a so-called ABSL-3+ facility, designed to contain lethal microbes. Anyone entering the virological laboratory, one of the most highly regarded in Europe, was subject to a security check. Workers were required to wear special suits and breathe through respirators. None of these precautions, however, would protect Fouchier from the forthcoming events–ones he would later characterize as no less than an “international witch hunt.”
Viruses have an extraordinarily high rate of mutation compared to other organisms–on average, it’s one per every 4,000 genetic building blocks within a single virus. More complicated life, such as bacteria, plants, and animals, have a kind of proofreading ability when it comes to reproduction that enables them to produce a small number of offspring with a low rate of mutation and a high rate of success. A virus, however, takes the opposite approach, producing as many offspring with as many mutations as is possible. This approach offers an obvious evolutionary advantage. For every “child” virus that dies due to a harmful mutation, there will be one that flourishes due to an advantageous mutation. In this way, the beneficial mutations survive and propagate.
Back and forth, back and forth, the virus passed between the ferrets in Fouchier’s lab, transported by researchers using swabs who hoped to mimic the chain of infection that occurs between people. As the days passed, Fouchier and his team observed that at each stage of the infection process, some strains of H5N1 were becoming more adapted to surviving and replicating in the ferrets’ upper respiratory tracts, a key evolutionary stage to enable the virus to spread by cough or sneeze.
By the end of the experiment this new, hyper-virulent strain of H5N1 had gained the one ability that keeps virologists up at night. No longer did it require physical contact to pass between mammals. A new version of H5N1, just five mutations different to its precursor, had become airborne–passing between ferrets kept in separate cages, on the chasing wind of a sneeze.
In Malta in September, 2011, Fouchier took to the stage at the European Scientific Working Group on Influenza. In a keynote speech, he outlined his experiments and findings to a roomful of his peers. The crowd fell silent as Fouchier reported the news: the deadliest bird flu virus known to humankind had, in laboratory conditions at least, become airborne. When Fouchier finished, the crowd applauded for what seemed like an age. “Many researchers had tried to achieve the same, with no success,” says Fouchier.
The implications were clear to everybody in the room: Fouchier had engineered a virus that, if it ever escaped the confines of the laboratory, could potentially kill more than half of the world’s population. Yet in the hallway outside the lecture hall, a queue of excited researchers formed, each person wanting to shake Fouchier’s hand, or to ask him questions.
Three months later, Fouchier was preparing to publish his findings in a scientific journal when the National Science Advisory Board for Biosecurity reviewed his research. The NSABB, formed in 2001, is a panel of public-health experts who provide guidance on scientific research. An unprecedented request followed. Most scientific journals publish research findings without much fanfare or, outside of scientists who work within the same area, much attention. With Fouchier’s research, however, the panel asked that the authors omit any details about their process that might help terrorists create their own strain of the deadly virus.
On January 7, 2012, The New York Times published an editorial titled “An Engineered Doomsday” that stated, bluntly, that the potential harm of Fouchier’s research was “so catastrophic” and the potential benefits “so speculative” that the research, simply, “should never have been undertaken.”
Fouchier was incensed by these reactions, but nevertheless, he agreed to a 60-day moratorium on the project. “To attempt to prevent this research from reaching the largest number of scientists is bullshit,” he told The New Yorker a few months later.
Fouchier’s anger was heightened by what he considered to be an inevitable mischaracterization of the work by the media, which had been denied access to the facts. For example, the Times piece argued that, “it is highly uncertain, even improbable, that the virus would mutate in nature along the pathways prodded in a laboratory environment.” In fact, Fouchier told me when I spoke with him, his team’s strain of H5N1 had evolved via biological traits and mutations that “appear to have occurred in every pandemic and mammal-transmissible strain of flu to date.”
Five months later, in June 2012, Fouchier’s research was finally published–but the cost was steep. The U.S. government almost simultaneously issued a blanket ban on research where mutations are encouraged within lab conditions (called “Gain of Function” research) for a host of viruses, including bird flu.
While the scientists, policy-makers, and publishers of scientific journals reckoned with the social, medical, and ethical implications of their work, H5N1 continued its chaotic spread. Thanks to improved practices around chicken farming–the supply of chickens to major cities like Hong Kong was completely overhauled–infection rates had slowed in China. But elsewhere, in particular in Cambodia, Egypt, and Indonesia, the rates of infection and human deaths were continuing to rise steeply.
Then, in late March 2013, something at once unthinkable and inevitable happened: a new variant of deadly bird flu was detected in humans. On March 26, the World Health Organization announced that this new variant had killed 11 of 17 people infected, including a man in Britain who fell ill after traveling to Saudi Arabia and Pakistan.
Unlike H5N1, a form of bird flu that had been under observation for some time, this new strain, which became known as H7N9, produced no symptoms in birds. (Initially, at least; in 2017 it acquired a mutation that enabled it to kill birds, and possibly people, much faster.) But the two variants shared more similarities than differences: both viruses infect poultry and wild birds and both viruses can prove fatal when caught by humans (although H7N9 has, as one researcher put it to me, “a weird preference for older men”).
There was another key difference, however. H7N9 was spreading much more quickly than its predecessor. Within eight weeks it had infected 130 people in mainland China, killing 36. This time, the response of the Chinese government, which had invested $97 million into the poultry industry since the emergence of H5N1, was quick and decisive. Live poultry markets in 10 provinces were immediately shut down and 60,000 samples were taken from birds housed at chicken farms across the country in order to isolate where the virus was concentrated.
More than 20,000 birds were destroyed at a wholesale market in Shanghai, where the virus was detected in a pigeon. The public, now familiar with bird flu emergencies, was also quick to act. The New York Times reported that at a KFC restaurant in Beijing, “employees stood idle as mounds of fried chicken went largely unsold.”
The U.S. promptly declared H7N9 the greatest pandemic threat in the world, and researchers who were already working on the H5N1 virus suddenly had a new focus for their studies.
As soon as Jim Paulson heard about H7N9, his team began to work on the virus. Paulson is a professor at the Department of Molecular Medicine at The Scripps Research Institute in California, and like Fouchier, he wanted to see how quickly it could mutate to become airborne. But since Fouchier’s work had prompted the ban in 2012, things proceeded considerably more slowly for Paulson and his team.
“Normally what is done now is a new virus is sequenced and the genetic information is put into a database,” Paulson told me. “Everyone can access that information, so, you are able now to just write down genetic code and send it to a laboratory who will synthesize the gene for you at a very cheap cost and then that allows you to produce the protein in the laboratory, study it and make mutations.”
With the H7N9 protein in hand, Paulson ran some initial tests before turning his attention to the same question that had inspired Fouchier’s research. Namely, how many more mutations would it take for this virus to become airborne?
Four years later, in June of this year, Paulson published his team’s key findings: a mere two mutations (in addition to one found in wild H7N9 since his work began) will allow the virus to bind well to human cells. The results, unlike Fouchier’s tests with H5N1, are speculative, since they remain untested in mammals. “Without animal infection studies, we can only speculate what might happen,” Paulson recently told New Scientist. “We can’t move forward.” For now, any further work must be carried out in laboratories that do not rely on U.S. government funding.
Five years on, Fouchier remains adamant that this kind of research is essential to our preparedness for a global pandemic, and that the U.S. ban works against human safety, not for it. “We do this [work] to understand how viruses replicate, cause disease, evade immunity,” he says. “It has led to new drugs, vaccines, therapies against viruses and other diseases such as cancer. If we know how a disease works to the finest level of detail we are more likely to know how to stop the disease. There are no arguments against this practice.”
The restrictions for researchers working on bird flu viruses in laboratories that receive U.S. funding remain in place. “Security experts fear that our knowledge could be misused and safety experts fear that our viruses could escape from our labs and kill people,” says Fouchier. “Both fears–in my humble opinion–are unjustified. The knowledge gain is terrific, the risks have been properly mitigated. Naturally evolving virus variants represent the real threat to humans and animals.”
Dr. Florian Krammer, who works at the Department of Microbiology at the Icahn School of Medicine in New York, agrees. “The moratorium is controversial because these experiments help us to understand key mechanisms of virus biology and pathogenicity,” he says, adding that they present a significant roadblock to the prompt development of vaccines for new viruses. “The world would be vulnerable for about six months and even then it is questionable if enough vaccine for everybody can be made and distributed.”
The threat, meanwhile, intensifies. H7N9 has just enjoyed its deadliest year yet, infecting more people in China in the past 12 months than in the previous four years combined (more than a third of whom have died). And the virus is thought to be causing milder, undiagnosed disease in far greater numbers of people, particularly during the winter months.
With each new infection, the H7N9 virus has the opportunity to mix its genomic segments with common human flu virus strains such as H1N1 or H3N2, which are particularly prevalent in winter. Every infection offers a new opportunity for the virus to evolve. “Do I think there will be another pandemic?” says Paulson. “Absolutely yes. It’s just a matter of time. Will it come from H7N9? You know, I think, right now, if we had to pick one that is most likely I would choose this one. As human infections increase it becomes more likely the mutations will occur and catch on.”
With researchers in U.S.-funded labs restricted in their work, it now falls to other organizations and initiatives to ensure our preparedness for a pandemic that most experts agree is coming, sooner or later. Solving this problem requires deep international collaboration–for countries to generously share data, knowledge, and resources in order to ensure our collective survival in the face of a global health crisis.
Yet recent months have been characterized–in part through the rhetoric of the Trump presidency, and Britain’s vote to leave the European Union–by the exact opposite. Many countries are retreating to isolationist policies, closing borders, and substantial cuts to foreign aid. In this climate, what will happen if the worst happens?
Read the next installment: “Outbreak: Our next global pandemic”
Read the previous installment: “Evolution: How a virus becomes a threat“
How We Get To Next was a magazine that explored the future of science, technology, and culture from 2014 to 2019. Fowl Plague is a five-part series that explores the history of deadly global pandemics–and asks whether we’re ready to respond to the next one.
