GOF: Game Over
"On reading," by Simon Wain-Hobson, is a weekly discussion of scientific papers and news articles around gain of function research in virology.
Since January 2024, Dr. Wain-Hobson has written weekly essays for Biosafety Now discussing risky research in virology. You can read his entire series here.
On reading The shifting sands gain-of-function research, by Amber Dance, Nature 2021; 598:554
Now, gain-of-function research is once again centre stage, thanks to SARS-CoV-2 and a divisive debate about where it came from… The arguments have highlighted questions about gain-of-function (GOF) research. But the classification is hard to define precisely. “What we mean by the term depends on who’s using the term,”
It is never good when a term depends on the speaker. We’ve been over the meaning of GOF in the first essay (Deconstructing the portrait). As this feature is in Nature and far more widely read, it’s worth revisiting. After all, Some dance to remember, some dance to forget.
We learn that GOF research starts to ring alarm bells when it involves dangerous human pathogens… As indeed it should. The sentence continues such as those on the US government’s ‘select agents’ list, which includes Ebola virus and the bacteria responsible for anthrax and botulism. These microbes are way dangerous enough. Making them more lethal was never on the cards for any rational person.
We’re treated to an analysis of changing nomenclature surrounding risky pathogen research, yet the article never refers to dual use research of concern (DURC) which was the established term at the start of the century before it was rebranded GOF circa 2012.
Of course, the real issue concerns research that would make a pathogen likely to spread widely or cause significant disease in humans. This, the committee decided, was the only type of GOF work so risky it would require extra regulatory oversight. The committee here being the US National Science Advisory Board for Biosecurity (NSABB). One of its past members, the virologist Michael Imperiale makes the useful point GOF studies with those viruses are “a really tiny part” of virology. And he’s right. Furthermore, this places the argument that constraining GOF research will damage virology into its rightful place. This tiny part is not even 0.1% of what happens in a year’s worth of virology worldwide.
The article goes into a long section entitled How GOF can help. The examples are interesting but borderline at best. Extrapolating from tissue culture and mice to humans is hard at best (Spanish lookalikes; 1918 and all that). That said, mouse models are excellent for pre-clinical screening of antivirals although success here is necessary but not sufficient. Ditto for vaccine candidates although on this issue specialists know of the frequent disconnect between mice and humans.
And while referring to a bunch of good virology, a statement like “All that great stuff that is going to benefit humanity is a gain of function,” says Vincent Racaniello, a virologist at Columbia University in New York City is heavily misleading because the vast majority of all that good stuff doesn’t fall under DURC. Dixit Imperiale above. On reading suspects the NSABB never reviewed any of the examples in this section. All that great stuff is simply playing on the definition of GOF (Deconstructing the portrait). Courting ambiguity is antithetical to science. Case closed.
Next up, a section entitled The big questions about GOF. It starts with Treatments and vaccines are clear benefits of GOF research. Really? Then, as has been oft mentioned in these essays, how come the former head of Merck Vaccines said there is no scientific basis for the claim that gain-of-function research on H7N9 may lead to the development of more effective vaccines? He probably knew, right? For info, he was referring to Fouchier & Kawaoka research, not All that great stuff H7N9 refers to an avian flu virus that has spilled over to humans more frequently than the better known H5N1 virus. Onwards.
The section continues with a brief description of the H5N1 bird flu GOF experiments. We learn that Scientists wanted to know, however, what it would take to make that happen. “That’s the kind of question you can only answer with a gain-of-function experiment,” says the virologist Angela Rasmussen who we have encountered before (Going places). That wasn’t the rationale of the work according to Fouchier & Kawaoka.
Apparently, the new viruses were weakened and non-lethal. There are problems embedded within these few words: how predictive is the ferret model for flu transmission for human disease? Even supposing it was accurate, these weakened viruses are mutation machines and could easily adapt to humans and produce more severe disease. Just think of the seriousness of the Delta variant compared to the initial COVID-19 coronavirus.
A good counter argument is that a weakened but more transmissible virus will exact more deaths than the parental H5N1 bird flu virus (Chilled virology). In fact, both are possible. Proof? Independently of where the COVID virus came from it morphed quickly into the Alpha variant followed by the horrible Delta variant which gave serious pneumonia. In turn it was supplanted by Omicron, a milder disease provoked by a virus that was far more transmissible. As such it probably killed more than Delta (Chilled virology).
Then we’re hit hard. As for whether it was worth it, opinions differ. “Their practical importance, wasn’t, in my mind, very extraordinary,” says David Morens, senior adviser to the director at NIAID. “They don’t help us answer the questions of whether H5N1 might become pandemic or what we would need to do to recognize or prevent it.” (The corresponding authors of these two studies did not respond to, or declined, interview requests from Nature.)
Dr. Morens has been a close collaborator of Dr. Fauci with many scientific papers together. Courageous given that the NIH top brass had de facto approved H5N1 GOF virology (Chilled virology). H5N1 GOF virology doesn’t help us with predicting a pandemic which was precisely the claim of the work from Fouchier and Kawaoka. Note that after having been so voluble over a decade ago, these gents are no longer game even for an interview.
Imperiale has a go at countering this courageous comment. “We learned the determinants of mammalian transmission,” he says. For example, the work supported suspicions that for a flu virus to infect a mammalian host, it must adapt to the temperature of the host’s lungs and to the pH of that host cell’s interior compartments. Nooooo. Body temperature and pH issues were known before the controversial H5N1 GOF papers were published. Morens’ rock remains.
The shifting sands finish with, With all the challenges inherent in GOF studies, why do them? Because, some virologists say, the viruses are constantly mutating on their own, effectively doing GOF experiments at a rate that scientists could never match. “We can either wait for something to arise, and then fight it, or we can anticipate that certain things will arise, and instead we can preemptively build our arsenals,” says Morrison. “That’s where gain-of function research can come in handy.” This recycles the pipedream that GOF research can help us look into the future. It was discredited long before this article was published and, apologies for repeating it, is confirmed by Morens’ rock.
When ideas fail, words come in handy. This phrase has been attributed to Goethe, but it doesn’t matter who.
Aside
An earlier published version of this article was entitled “The truth about gain-of function research.”
Post scriptum
This essay was completed before the May 7, 2024 release of a USG policy change which has dumped the ambiguous term GOF for DURC which is welcome. The policy is better than before although there are contradictions while some practices are destined to fail. This policy document will be discussed at a later date as there is much to say which requires thought.
Just dwell for a second on 12 years of prevarications, ambiguities and justifications of what all that great GOF did for science, when all along what bothered some of us was ‘a tiny part of virology.’ Why the deliberate obfuscation, resistance, waste of valuable time and energy, not to mention the needles space taken up in top journals like Nature?
Onwards, GOF is behind us. The struggle for plain speaking and reason isn’t.
