Still life, 1975 by André Lwoff. Nobel Prize in Physiology and Medicine 1965 along with Jacques Monod and François Jacob.
This article emphasizes the need to use words precisely; to make them do work. After all, if scientists can’t use words precisely, then how can we describe accurately what we’re studying?
The paper is the latest commentary on a controversy that erupted in the fall of 2011 and has been going on ever since. The fuse was lit by two groups who had adapted highly pathogenic avian H5N1 strains of avian influenza virus to droplet transmission between ferrets. This is considered a reasonable surrogate marker of human-to-to human transmission. Details of this controversy can be readily found on the web, in published papers, some by this author, as well as on the Biosafety Now site.
The paper propagates a word play that has muddied the waters. Going back to 2011-12, two manuscripts written by researchers Ron Fouchier and Yoshi Kawaoka were flagged as examples of dual use research of concern, or DURC, and referred to the US National Science Advisory Board for Biosecurity (NSABB). Two meetings and some vote changes later, unredacted manuscripts were eventually published in the top journals Nature and Science.
For some reason this work, DURC by any name, was rebranded Gain of Function research, or GOF. Obviously the avian H5N1 viruses had gained the ability to transmit between ferrets, something that the parental viruses did extremely rarely. The positive sounding GOF quickly ousted DURC with its anxiogenic research of concern.
The problem was GOF, and its counterpart Loss of Function (LOF) are terms that have been used in biology for eons. Quickly some of us virologists were harangued by bacteriologists complaining they were getting tarred with the controversial brush being used by supporters of the work by Fouchier and Kawaoka. As this started to sink in, a second rebranding occurred, this time GOFROC, for gain of function research of concern. With its research of concern, co-opted from dual use research of concern, GOFROC was proof of the emerging negative effects rebranding of DURC was having on virology.
This proved to be fleeting to say the least. The work was rebranded PPP research for potential pandemic pathogen research, which was quickly morphed to ePPP, for enhanced potential pandemic pathogen research. There is no need to belabor the vagueness of these terms except to point out that they gave rise to an HHS decision framework called P3CO for potential pandemic pathogen care and oversight.
The rebranding was obfuscation. We’ve seen it before when a new entity emerges from the ashes of another after a tragedy. An example is from my country, France, where the National Blood Transfusion Center was rebranded the French Blood Establishment after the ignominious HIV tainted blood scandal that started 1984.
People are not stupid. Words matter.
Despite top-down attempts at rebranding, GOF stuck. The paper in mSphere covers Fouchier and Kawaoka style GOF research while praising the merits of classical GOF research in biology. In a nutshell, as the latter has been highly successful, the former is to be supported.
The GOF controversy in virology was never about prior GOF research in biology. It was specifically about the Fouchier and Kawaoka papers. Period. The flippant language and anxiogenic message of Ron Fouchier didn’t help.
The questions were, and still are, what are the benefits, risks and is the work ethical?
We are treated to some general statements such as ‘Here, we would like to discuss what GOF is and why it is an essential tool for microbiologists.’ This is a straw man for GOF/LOF research is widely accepted in biology. There is a consensus; the community is for it. Move on.
The work of Fouchier and Kawaoka was clearly DURC which is why the manuscripts were referred to the NSABB. Yes, their work does represent a subset of classical GOF; this was never contested. The two gents claimed that their work would help predict the next pandemic. Consequently, this would help in the generation of preventive drugs and vaccines. This was the mantra used to justify the work. The debate was whether those claims were valid and was the risk worth the benefits stated?
There is nothing new in the paper on this although I know quite a few infectious disease researchers who don’t buy into the claim that the work of Fouchier and Kawaoka would help predict the next pandemic. Sadly, they remain stubbornly silent in public. We do learn that ‘these experiments provided new information by unequivocally establishing that this virus has the genetic potential for mammalian transmissibility and could thus launch a devastating human pandemic.’ Note my highlights. 1) Indeed, it is reasonable to propose that the virus would transmit between humans, although proof in the rigorous scientific sense of the word is lacking for it would entail infecting humans. Accordingly, the genetic potential will always remain a potential. Which is imprecise. 2) Proving that the virus could generate a pandemic is also ethically impossible. This is an extrapolation at best, hence the word could.
We do have a good example of the difficulties fathoming what viruses do when they spill over to humans. Of all the simian immunodeficiency viruses that crossed over, only HIV-1 M went pandemic. HIV-1 O and HIV-2 were regionally localized. Some appear to be extremely limited in transmission like HIV-1 N or HIV-1 P, while a few appear to be dead-end infections. There is no consensus why HIV-1 M out competed the others – lots of interesting hypotheses and discussion, but no consensus.
The authors are aware of this and note, ‘Transmissibility is a complex trait that cannot be predicted from genotype or tissue culture studies,’ meaning that animal experimentation is necessary. Yet how predictive is the ferret model? Humans and ferrets diverged some 60 million years ago. The innate and acquired immune system are different, so the tempo of host/virus dynamics will be different. Microbiology has thrown up umpteen cases of subtle adaptation to new niches, environments and experimental conditions. Indeed, the authors treat us to many such examples. All this means that extrapolation from experimental conditions, and this includes animal models of infection, must be treated with care.
Certainly, there was nothing in the Fouchier and Kawaoka papers to help advise a Health Ministry. Indeed, the overall recent risk assessment from the European CDC of avian influenza H5 clade 2.3.4.4b viruses, the one circulating in winter 2023-24, was ‘low for the general public in EU countries.’
A few more details from the ECDC are worth noting:
‘The likelihood of travel-related importation of human avian influenza cases from countries where the viruses are detected in poultry or wild birds, is considered to be very low.’
‘Mutations associated with mammalian adaptation have been identified sporadically in a few birds, but emerged more frequently in mammalian hosts after infection. No mutations or reassortment have been identified that would modify the virus to become human-adapted and transmissible between humans.’
Contemporaneous data do not support avian H5N1 to be a looming pandemic. It just shows–once again–how hard it is to predict virus evolution. Going over the top was not merited. That said, no virologist I know would write off H5N1. Indeed, we should be very wary of H5N1.
Back to the paper by Casadevall and colleagues which has some good one-liners; ‘just because an experiment can be done doesn’t mean that it should be done.’ Absolutely, no doubt all review bodies will agree. ‘The vast majority of GOF/LOF experiments pose no risk for humanity.’ Agree again. Apart from the spurious claims about drugs and vaccines, the GOF controversy post 2012 was mostly about risk. This is why rebranding DURC GOF was an error, a source of confusion and a disservice. We need to ditch GOF now and go back to DURC which is shored up by the detailed Fink report.
It’s reminiscent of a Picasso portrait showing multiple and complex facets of human nature. And fascinating. However, when the public health world is clamoring for a risk assessment on a microbe circulating in an animal population somewhere, DURC along the lines of Fouchier and Kawaoka didn’t come up trumps.
Dr. Wain-Hobson’s primary criticism of our article appears to be a semantic one. Dr. Wain-Hobson is concerned that our article propagates ‘a word play that has muddied the waters’ by confounding dual research of concern (DURC) with gain-of-function (GOF) research. But in fact, we agree with Dr. Wain-Hobson that GOF research is not always DURC. The primary point of our article was to highlight the epistemic value of GOF experiments in biomedical research, only a small minority of which fall under the rubric of DURC. We are concerned that recent proposed legislation to regulate GOF research fails to clearly make this crucial distinction.
The 2012 Fouchier and Kawaoka experiments qualify as both GOF experiments and DURC. Those experiments selected for influenza H5N1 virus variants with mammalian transmissibility. They gained a new function, mammalian transmissibility, meeting GOF criteria. Dr. Wain-Hobson appears to concur when he writes that ‘The work of Fouchier and Kawaoka was clearly DURC which is why the manuscripts were referred to the NSABB. Yes, their work does represent a subset of classical GOF; this was never contested.’
Dr. Wain-Hobson also criticizes our acknowledgment that the Fouchier and Kawaoka experiments provided new and potentially important information on mammalian transmissibility. Whatever the wisdom of those experiments, it is inarguable that these experiments showed that H5N1 is capable of mammalian transmissibility. This was not known prior to 2012, since all human cases could be traced to contact with an infected bird. We agree that ferret transmissibility does not necessarily imply human transmissibility. However, ferrets, like humans, are mammals and are a widely accepted model for human respiratory viruses, and the demonstration of transmissibility in mammals certainly raises the concern that human-to-human transmission could unleash an epidemic. We are currently witnessing a global panzootic outbreak of avian H5N1 that has already spilled into several mammalian species such as minks and seals and there are worrisome signs that mammalian transmission may have already occurred in these animals (https://jamanetwork.com/journals/jama/article-abstract/2801499). Hence, we stand by the wording of our sentence. We are not arguing that gaining this knowledge provides a sufficient justification for performing these experiments. However, an impartial risk-benefit assessment must consider epistemic benefits as well as hazards.
In summary, we agree with Dr. Wain-Hobson that DURC and GOF research should not be conflated. We also agree that research with potential pandemic pathogens is dangerous and warrants a careful risk-benefit assessment. However, it is false to suggest that we are using the value of GOF research in biology to justify the Fouchier-Kawaoka experiments.
Arturo Casadevall
Ferric C. Fang
Michael J. Imperiale
From the mid-2000s and into the 2010s I was closely involved in the negotiations that resulted in the WHO Pandemic Influenza Preparedness Framework, and the transformation of the Global Influenza Surveillance Network (GISN) into the Global Influenza Surveillance and Response System (GISRS). This required me to pay rather close attention to public health efforts to collect potentially pandemic flu viruses, characterize them, and to develop diagnostics and prototype human vaccines.
Casadevall and friends want their GOF cake and to eat it too. They prevaricate, writing that they are not arguing that Kawaoka and Fouchier’s results provided “a sufficient justification for performing these experiments” yet they also, more prominently, argue that the experiments “provided new and potentially important information.” and that “whatever the wisdom of those experiments, it is inarguable that [they] showed that H5N1 is capable of mammalian transmissibility,” They then underscore the significance they attribute to the latter point on transmissibility by noting that it was previously unknown.
Meh, not really.
An honest evaluation of the purported value of Yoshi and Ron’s “inarguable” demonstration of mammalian transmission needs context, particularly on how the public health community perceived the H5N1 threat before the GOF experiments took place.
In reality, the experiments, while shocking, where not a wake up call for anybody. For many years before 2012, the public health community that is charged with virus surveillance, collection, characterization, and vaccine prototyping had no question that H5N1 posed sufficient mammalian, including human, pandemic potential, to warrant the collection and characterization of every new strain, whenever possible. As such, long before the GOF experiments, great efforts were already being put forth to collect and characterize real world H5N1 viruses everywhere they appeared. This included not only those viruses that had infected humans (WHO), but also strains collected from birds in a number of countries (OIE and FAO).
What then was the added value of the GOF viruses? Little to nothing, and less than nothing when one considers that the experiments themselves generated novel pathogens with pandemic potential. The effort to collect, characterize, and the other steps of response with H5N1 strains from nature were already a highest priority.
Thus the public health response to H5N1 by the critical global public health laboratory networks certainly did not require GOF. Those networks’ full-on response measures were in place for many years before Fouchier and Kawaoka dosed the ferrets. Nor was the public health response informed by or aided by GOF once it happened.
We know today that the “epistemic” value of the GOF experiments was nil for public health. Honestly most of us not making excuses for the research establishment already knew as much back then, more than a decade ago. The dangerous demonstration of transmission was unnecessary and uninformative: GISN / GISRS and the other response networks weren’t sitting around waiting for GOF results, they had long before decided to closely surveil a novel influenza in birds known to infect humans.
I think continuing to make a fundamentally pro-GOF argument by purporting that Fouchier and Kawaoka’s creation of novel pandemic pathogens was of value – and yes, then trying to also hedge that statement – is obviously an error, maybe a cynical one too. Time has made even clearer that the experiments created new risk yet provided no value to the public health systems charged with surveillance and response to potentially pandemic influenza. There’s no “there” “there” and there never was one. Just the purported benefit, “epistemic” or otherwise was as false then as it is today – the public health system already treated H5N1, for good reason, as if it would move into mammals. And obviously still does.
The primary relevant concerns with GOF are not the definition of some possibly arcane but almost inevitably weak “epistemic” value among an interested and intertwined group of researchers, but rather those of public health. Those concerns are much wider, impact far more people, and are less risk tolerant, than the classical, closed, risk-benefit analysis that Casadevall et al endorse.
A particularly clear explanation. Many thanks.
There is little for me to add to Hammond’s compelling (and very informative) response.
I’ll just focus on certain statements in Casadevall et al’s response that struck me as rather odd, especially in light of
the authors’ previous letter (“Virology under the microscope…”)
* “We are concerned that recent proposed legislation to regulate GOF research fails to clearly make this crucial distinction.”
As far as I know, *none* of the recent proposals/bills (the NSABB recommendations, the Florida / Texas / Wisconsin bills) has failed to clarify
that the GoF of concern is on potential pandemic pathogens (PPP). Whether this is a subset of DURC is a separate matter. My point is this: ignoring the PPP clause and attacking the strawman of “regulating GoF research” comes across as disingenuous, whatever your intent.
* “However, it is false to suggest that we are using the value of GOF research in biology to justify the Fouchier-Kawaoka experiments.”
Table 2 (“Examples of useful gain-of-function experiments”) in their earlier letter “Virology under the microscope…” has 19 entries, of which *only* two
(the Fouchier-Kawaoka and the Baric-Shi-Daszak experiments) would qualify as GoF on PPP viruses.
Among the other 17 entries are “Faster computers” and “Enhanced lithium batteries” !
What is the reader supposed to take from a table that clubs these with two of the most controversial GOFROC experiments ever?
The pandemic has affected the entire planet and people are paying close attention to risky virology.
Whatever Casadevall and Imperiale are campaigning for, I suggest that they come up with more intelligent and
realistic arguments for the same.
Harish Seshadri is not correct. Our mSphere commentary begins with a reference to H.R. 1827, a bill in the U.S. Congress that proposed to prohibit the NIH from conducting or supporting GOF research, with GOF referring to ‘any research that could enhance the transmissibility, virulence, or pathogenicity of any pathogen (whether or not classified as a pathogen of pandemic potential) or non-pathogen agent’.
You are correct – to an extent. Namely, I forgot to look at House Bill H. R. 1827, which you talk about in your article.
But please note that your article opens with “Federal and STATE (my emphasis) efforts have been recently introduced to legislate against or otherwise regulate “gain of function” research,…” and you only cite H.R. 1827, not the state bills.
This omission is all the more striking considering that the only bill that has become a law, Florida Act 381.875, does not work with that definition.
There is a more serious problem with your article (apart from the grossly misleading statement that the possibility that SARS-CoV-2 might have been genetically engineered at the Wuhan Institute of Virology in China is an “unsubstantiated speculation”). Instead of confining yourself to the widely accepted practical benefits of GoF in microbiology, you again try to justify the Fouchier-Kawaoka experiments in the same breath.
Variants of “This increases the urgency of developing measures to prepare for and prevent an H5N1 influenza pandemic and identifies some of the possible genetic and functional changes that might herald such a pandemic” have been repeated (and countered) ad nauseam since 2012. At best, it is a vacuous homily with no relevance to public health.
If (as you claim in your reply to Wain-Hobson) your intention is not to justify the Fouchier-Kawaoka experiments, then why do you persist in these ridiculous justifications of the same? It looks all the more ridiculous in contrast to the other genuinely beneficial works you discuss in your article.