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| Dr Kawaoka's GOF Experiments in the hands of Dr Zhou Peng created The deadly Wuhan Virus. |
Kawaoka is one of a small number of researchers tinkering with the genomes of bird-flu strains to model how they might acquire human pandemic potential. Many fear these hubristic microbiologists might trigger a man-made plague if the synthetic bugs ever escape from their laboratories.
In another project, Kawaoka developed a version of one of the most dangerous influenza viruses yet known. Bird-flu strains contain genes highly similar to the 1918 Spanish flu (which was resurrected from permafrost in 2005), and Kawaoka’s team selected the most similar from eight avian viruses to create a viable 1918-like hybrid.
When inoculated into ferrets, this proved far more virulent than a wild duck virus, but less so than the 1918 virus, which killed one ferret. However, unlike the 1918 virus, it did not transmit between them.
They then spliced in entire 1918 genes, focusing on proteins critical for transmission. Two of three ferrets died, but crucially, they infected other ferrets in neighbouring cages. Through successive mutations, the team selected ever more transmissible strains in a “forced evolution” towards infecting mammalian and human hosts, by adapting the viruses to the lower temperature and pH environment of the human nose and throat.
To flu virologists, this paper delivers a cascade of data on the mechanisms by which avian viruses hop the species barrier. But the risk of a man-made pandemic has startled other virologists and epidemiologists.
Simon Wain-Hobson of the Pasteur Institute in Paris chairs the Foundation for Vaccine Research, which has petitioned US president Barack Obama and president of the European Commission Manuel Barroso in a letter signed by 56 microbiologists, including Nobel laureate Richard Roberts. They call for an urgent review of the dangers of such “gain-of-function” research and claim the science is speculative and of little use in producing vaccines or anti-viral drugs.
Meanwhile, the Centers for Disease Control in Atlanta have just closed down their biosafety level-three labs (such as Kawaoka heads at Wisconsin) due to safety breaches there. Eighty-four workers were exposed to live anthrax last month and there was an accidental release in March of an avian flu cross-contaminated with the lethal H5N1 strain.
The Atlanta centre’s own 2012 analysis reported 727 US incidents of theft, loss or release of “select agents and toxins” from 2004 to 2010, causing 11 lab-acquired infections. A May report in PLoS Medicine cited the 1977 pandemic, which many scientists believe escaped a lab, causing “significant mortality” over many years.
The new dual-use regulations arose after late 2011, when the US National Science Advisory Board for Biosecurity declared a Kawaoka paper (and one by Ron Fouchier in Rotterdam) too dangerous to publish.
Both had enhanced the human transmissibility of the deadly H5N1 bird flu, Kawaoka by “reassorting” it with the contagious 2009 swine flu. Fouchier had publicly quipped that his was “probably one of the most dangerous viruses you can make”, alarming anthrax expert Paul Keim, chair of the US advisory board. Both the World Health Organisation and the advisory board called for key sections of the papers to be redacted. However, after the FBI screened Kawaoka’s team, both bodies backed full publication.
Biosafety rules were tightened in Canada, Germany and the UK, and the dual-use policies were revised. A moratorium on such research was lifted, and last year a Chinese lab ( the Wuhan Institute of Virology?) again mixed H5N1 with the 2009 pandemic strain, achieving airborne transmission between guinea pigs.
Most recently, the London Independent revealed Kawaoka’s latest unpublished feat: successfully engineering a 2009 H1N1 virus to “escape” the human immune system and all vaccines developed since its emergence. Worse, this was done at biosafety level two, which stipulates little more than “lab coats, gloves, face and eye protection, as needed”. The news was met with incredulity by a lengthening list of senior scientists.
Dr Kim Roberts, Trinity College’s assistant virology professor, has followed the controversy closely. “There are strong arguments on both sides, and I tend to agree with both.” She has done gain-of-function work on attenuated H5N1 at Imperial College London and now does loss-of-function work on human flu, knocking out genes to see how this impairs the virus. “Kawaoka’s paper is pure basic research, which may not be directly translatable into short-term results, but it has told us incremental things we didn’t know.”
Influenza, with its aches, misery and mucus, is not the common cold. It is a far more dangerous virus that rapidly evolves and has been with us since we domesticated beasts. Seasonal epidemics ripple across human populations, as new strains evolve in the perpetual arms race with the human immune system.
Every 10-40 years, major pandemics emerge. The 1918 H1N1 Spanish flu killed an estimated 50 million people; the 1957 H2N2 Asian flu two million; the 1968 H3N2 Hong Kong flu one million, and so on, in what some optimistically interpret as a trend towards decreasing severity.
All the above are believed to have emerged from the vast reservoir of influenza strains that exists among waterbirds and migratory fowl and often causes outbreaks in poultry. Epidemiologists anxiously monitor emerging strains from southeast Asia, where bird flu is endemic, but they were wrong-footed in 2009 when the latest H1N1 pandemic erupted in Mexico, ultimately from pigs, killing perhaps 550,000 people.
Attention has now returned to Asia, where deadly new poultry-to-human infections have been linked to live bird markets: 2003’s lethal H5N1 (of 650 confirmed cases, there were 386 deaths); or, in early 2013, H7N9, which cross-infects much faster from chickens (450 cases in 18 months, with 25-30 per cent mortality). The dread is that these viruses might adapt to interhuman transmission, and become truly pandemic.
Controversial lab studies that modify bird flu viruses in ways that could make them more risky to humans will soon resume after being on hold for more than 4 years. ScienceInsider has learned that last year, a U.S. government review panel quietly approved experiments proposed by two labs that were previously considered so dangerous that federal officials had imposed an unusual top-down moratorium on such research.
One of the projects has already received funding from the National Institutes of Health’s (NIH’s) National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, and will start in a few weeks; the other is awaiting funding.
The outcome may not satisfy scientists who believe certain studies that aim to make pathogens more potent or more likely to spread in mammals are so risky they should be limited or even banned. Some are upset because the government’s review will not be made public.
“After a deliberative process that cost $1 million for [a consultant’s] external study and consumed countless weeks and months of time for many scientists, we are now being asked to trust a completely opaque process where the outcome is to permit the continuation of dangerous experiments,“ says Harvard University epidemiologist Marc Lipsitch.
One of the investigators leading the studies, however, says he’s happy he can resume his experiments. “We are glad the United States government weighed the risks and benefits … and developed new oversight mechanisms. We know that it does carry risks. We also believe it is important work to protect human health,” says Yoshihiro Kawaoka of the University of Wisconsin in Madison and the University of Tokyo. The other group that got the green light is led by Ron Fouchier at Erasmus University Medical Center in Rotterdam, the Netherlands.
In 2011, Fouchier and Kawaoka alarmed the world by revealing they had separately modified the deadly avian H5N1 influenza virus so that it spread between ferrets. Advocates of such gain of function (GOF) studies say they can help public health experts better understand how viruses might spread and plan for pandemics.
But by enabling the bird virus to more easily spread among mammals, the experiments also raised fears that the pathogen could jump to humans. And critics of the work worried that such a souped-up virus could spark a pandemic if it escaped from a lab or was intentionally released by a bioterrorist.
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| Drs. Kawaoka & Fouchier the evil scientists. |
But concerns reignited after more papers and a series of accidents at federal biocontainment labs. In October 2014, U.S. officials announced an unprecedented “pause” on funding for 18 GOF studies involving influenza or the Middle East respiratory syndrome or severe acute respiratory syndrome viruses. (About half were later allowed to continue because the work didn’t fit the definition or was deemed essential to public health.)
There followed two National Academy of Sciences workshops, recommendations from a federal advisory board, and a new U.S. policy for evaluating proposed studies involving “enhanced potential pandemic pathogens” (known as ePPPs). In December 2017, NIH lifted the funding pause and invited new GOF proposals that would be reviewed by a committee with wide-ranging expertise drawn from the Department of Health and Human Services (HHS) in Washington, D.C., and other federal agencies.
Now, the HHS committee has approved the same type of work in the Kawaoka and Fouchier labs that set off the furor 8 years ago. Last summer, the committee reviewed the projects and made recommendations about risk-benefit analyses, safety measures to avoid exposures, and communications plans, an HHS spokesperson says.
After the investigators revised their plans, the HHS committee recommended that they proceed. Kawaoka learned from NIH on 10 January that his grant has been funded. Fouchier expects the agency may hold off on making a funding decision until after a routine U.S. inspection of his lab in March.
Kawaoka’s grant is the same one on H5N1 that was paused in 2014. It includes identifying mutations in H5N1 that allow it to be transmitted by respiratory droplets in ferrets. He shared a list of reporting requirements that appear to reflect the new HHS review criteria.
For example, he must immediately notify NIAID if he identifies an H5N1 strain that is both able to spread via respiratory droplets in ferrets and is highly pathogenic, or if he develops an EPPP that is resistant to antiviral drugs. Under the HHS framework, his grant now specifies reporting timelines and who he must notify at the NIAID and his university.
Fouchier’s proposed projects are part of a contract led by virologists at the Icahn School of Medicine at Mount Sinai in New York City. They include identifying molecular changes that make flu viruses more virulent and mutations that emerge when H5N1 is passaged through ferrets.
The HHS panel did not ask that any proposed experiments be removed or modified. Suggestions included clarifying how his team will monitor workers for possible exposures and justifying the strains they plan to work with, which include H7N9 viruses, Fouchier says.
HHS cannot make the panel’s reviews public because they contain proprietary and grant competition information, says the spokesperson. But critics say that isn’t acceptable. “Details regarding the decision to approve and fund this work should be made transparent,” says Thomas Inglesby, director of Center for Health Security of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.
The lack of openness "is disturbing. And indefensible,” says microbiologist Richard Ebright of Rutgers University in Piscataway, New Jersey. The critics say the HHS panel should at least publicly explain why it thought the same questions could not be answered using safer alternative methods.
One researcher who has sympathized with both sides in the debate finds the safety conditions imposed on Kawaoka reassuring. “That list… makes a lot of sense,” says virologist Michael Imperiale of the University of Michigan in Ann Arbor. “At this point I’m willing to trust the system.”
Dr Kawaoka's Speech On His G-O-F Experiments (Youtube Video)