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 22.214.171.124b 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.