Off target
"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.
The team screened English language papers involving pathogens from 2002 to mid-2022, then used some AI tools to focus on gain of function (GOF) and loss of function (LOF) work. They found around 7000 studies and picked 1000 at random. These were filtered, hopefully by being read by a human, which left 488 scientific publications.
As we have seen from the very first essay (Deconstructing the portrait) there has been a deliberate attempt to muddy the waters by assimilating dual use research of concern (DURC) as GOF 1.0 (Crossing the line) when in fact there is only one “really tiny part” of virology that needs attention, GOF 2.0. Other essays have chipped away at this ongoing attempt to be unclear for the term DURC has mutated as fast as any flu virus.
By the end of the first paragraph of the executive summary we find that this group played along with, or were confused by, the muddy waters churned up by a few scientists.
Gain-of-function (GOF) and loss-of-function (LOF) research are two valuable methodologies that allow scientists to study pathogens… allowing scientists to examine and better understand how pathogens function and develop new vaccines and therapies. LOF is irrelevant to the controversy that ignited in 2012. No, GOF 2.0 research hasn’t contributed to the development of vaccines. The attenuation of viruses, arguably LOF research, has.
Why proceed? Why make an essay out of smoke?
• There is culture of pushback to anything but self-regulation by scientists, learned societies, journals, funders and academics. Maybe it was always there; no doubt it is true of all human activities – think of the guild mentality. But. When the gains from GOF 2.0 research activities are private while the risks are public, rising to a future pandemic (Ethics of GOF virology), it is necessary to call out nonsense.
• The shock of reading the independent report of the UK’s handling of the COVID pandemic. Just one quote: Across the UK, systems had grown to be overly bureaucratic. Instead of focusing on skills, technology and infrastructure, they were focused on creating groups, sub-groups and documents. (UK COVID response report). Blistering. Any self-reflecting scientist must be cringing. So you step up.
Now where were we? Ah, the key findings.
1. Gain- and loss-of-function research is ongoing, global, and collaborative with U.S.-affiliated researchers contributing to approximately half of identified publications between 2000 and mid-2022. As they are using the broad GOF 1.0 definition this could simply reflect the fact that the US is a powerhouse for biomedical research. Hardly a scoop.
2. Gain- and loss-of-function research frequently co-occur in the same study. That said, LOF research appears in more publications than GOF research. LOF is irrelevant to the issue which represents a really tiny part of virology, aka GOF 2.0. Yet this is a key finding. Oh dear.
3. Gain- and loss-of-function research is conducted over a range of different experimental methodologies, pathogens, and applications. The methodology is irrelevant. Only GOF 2.0 matters. Do you have a position on making novel human pathogens available to malevolent minds curtesy of the US taxpayer? Is it ethical? (Ethics of GOF virology). A pity, for those are the questions.
In this methodology section we’re treated to a veneer of science: The use of serial passage is more frequent in GOF publications than LOF publications. Such a remark can only arise from a consideration of key words, not content. In More GOOFing we saw that three passages of Canine Distemper Virus were enough to recover a virus that grew well on human cells. Sabin’s attenuated polioviruses were generated by multiple passaging. Theiler’s yellow fever vaccine strain was attenuated by innumerable passages in the lab and in animals, and so on. It depends. This is an unimportant remark that might go in an appendix, but hardly in the executive summary. It shows that the authors know not what they are about.
All this is context for Based on our analysis, we assess that GOF and LOF research will be difficult to regulate because: Quite how that follows on from the key findings we’ve breezed through is unclear, however read on.
1. Gain- and loss-of-function research are widely used in public health applications. Regulations will need to target the types of research that cause the most risk without impeding disease research or therapy development. Author emphasis here and below. If you use a poor and vague definition, then any legislation may well have deleterious effect. Remedy? Use a much tighter definition.
2. Gain- and loss-of-function research are intertwined. Regulations that restrict GOF research will also restrict less risky LOF research, potentially delaying public health developments without achieving the desired safety enhancements. Not axiomatic; see 1.
3. Researchers cannot always predict whether an experiment will cause a pathogen to become more or less virulent. Experiments that were not anticipated to be GOF research may not be prevented by proactive regulatory requirements. We do experiments because we can’t predict outcomes, even if you use AI. Scientists must be the eyes and ears of the regulators (Ethics of GOF virology).
4. Gain-of-function research can be conducted without access to gene editing technologies. Regulating gene editing technologies, including CRISPR or DNA synthesis, would not affect the approximately 21 percent of experiments that were conducted using serial passaging. It is the end result that matters, not the methodologies used to get there. If you feel they need regulating, that’s another issue.
5. Risk varies among GOF studies and should not be uniformly regulated. The risk level of GOF and LOF research changes based on experimental factors including the pathogen’s biosafety level, methodology, and the animal model(s) used. Regulations will need to target the types of research that cause the most risk rather than impose a one-size-fits-all regulatory policy that does not account for these vital differences.
You got there by the end of the Executive Summary! Regulations will need to target the types of research that cause the most risk, something obvious since 2012. Science has clambered over clichés like one-size-fits-all eons ago. You could have spared us this blandness; after all, three of you are science PhDs.
It is more pushback although there is no aspersion here that this work was part of a coordinated effort; more just that they couldn’t see in the muddy waters. This report shows - once again - the extent to which the Fouchier & Kawaoka work, accompanied with a disinformation campaign from the top echelons of science has been misunderstood by so many. Top echelons? NIH, journals and the majority of virology professors who acquiesced and kept quiet.
It highlights the need to pushback on pushback and get back to the data. This needs time, effort and repeating for, as any teacher knows, important points need to be said at least twice.
This would be a good point to finish, except that the top scientific journal Nature covered this report in a news item. Unfortunately, it’s still paywalled. The writer, Max Kozolov, identifies the key point fast: But only a small fraction of the research involves agents that are dangerous enough to require the strictest biosafety precautions in laboratories.
Yet you remember pushback? “I was so relieved to see a data-driven approach” to assessing GOF research, says Felicia Goodrum, a virologist at the University of Arizona in Tucson. It helps to support the argument that GOF studies are paramount in molecular virology and are necessary to study the impact of genetic mutations that pathogens acquire in nature through evolution, she says. For info Dr. Goodrum is co-editor in chief of the Journal of Virology and a staunch supporter of research in that “really tiny part” of virology, aka GOF 2.0, a champion of regulatory pushback and censorship (Flights from reason; Perilous posturing; We the virologists; and most recently in Some housekeeping).
The problem is GOF 2.0 research didn’t help with understanding the evolution of H5N1 bird flu virus. Dr. Kawaoka has come round to this so undercutting Dr. Goodrum.
Passing through the one-size-fits-all moment, Although the report makes this argument nicely, says Gigi Gronvall, a biosecurity specialist at Johns Hopkins University in Baltimore, Maryland, it’s unlikely that it will change many minds. The report doesn’t “get to the heart of what makes people so upset about these issues”, she says - adding that, for many, “it’s about whether we should go against nature [by manipulating pathogens] to try to determine whether something is likely to become a pandemic threat”.
Utter nonsense. Going against nature is what virologists are paid to do! Smallpox and rinderpest have been eradicated while polio is down but not out. Thanks be to vaccination. Microbiologists have been beating the hell out of viruses and bacteria since the germ theory of Pasteur (Crossing the line). Yet astonishingly, making new human viruses is, to some, a risk worth taking according to the NIH (Chilled virology).
As to try to determine whether something is likely to become a pandemic threat, we’ve been there. Prediction is too complex and integrates elements of chance. Even Drs. Fouchier and Kawaoka have moved on from predicting the next pandemic which was not anchored in serious virology.
On reading was tough on two journalists from the Los Angeles Times (Some housekeeping). They were not scientists and so had difficulties grappling with issues that even the experienced and former New York Times science reporter like Donald McNeil encountered. Their difficulties are understandable.
Here, three authors have science PhDs while the remaining three have an MS. No doubt they too had the same problem. This shows that the narrative spun by a few scientists to deflect from the colossal dangers of GOF 2.0 virology is derailing people.
Conclusions
You underperformed. You’re not paid to make gross mistakes like this. Next time, be far more critical of what you’re writing about, or else your time and work will be wasted, again, which is not amusing.
Aside 1
The science on GOF 2.0 virology is clear. That most don’t go along with this comes back to Chilled virology.
Aside 2
Thomas Pynchon came up with Why should things be easy to understand? Having been up against the unknown for an entire career, amen. With a small a.
Aside 3
We’ve encountered Dr. Gronwall pushing back and being imprecise before (Why words matter).
Aside 4
DURC was rebranded to GOF, GOFROC, P3CO before coming back to DURC in the USG’s recent policy document. Then there was PPP, ePPP followed by PePP. Be clear, time is short. Share information, don’t keep things to yourself. The way things are, benefits are private while risks are public. Been there read that.
There’s a perspective - here, a non-scientist POV - that as virology has matured, if it were a bunch of pets, certain ones are clearly evolving to have the traits of unpredictable, deadly wild animals. And the scientists aren’t considering all the options-cage the animals or put them down. They are in love with them, of course, and are bent on trying to manage their behavior. Or do nothing. But suffer through with a debate that seems stuck in status quo.
The easy target answer for us non-scientists is that we kill off these new dangerous pets and be content with only the lesser creature. We‘re not so sure we trust that cages even can be built and managed. Only takes one sloppy move, one escapes. Logic. Was fine the way it was. We think you aren’t letting your group think, which is a must and not evil, take in just how horrible this might all turn out.
You’re a virologist? Sorry, we say, get comfortable with our knowing everything you do, spying on you 24-7. Same with labs. This is logic. Sounds like ridiculous overkill?
What about CRISPR, DNA synthesizers? Need em? They increase the odds of pandemic happening? More likely than not seems fair estimate.
Consider the bio labs at Universities. For we the public, we may come down saying get rid of them. Is this truly unwise? You say there are upsides, which you can’t measure. But we can measure a downside. There is a non-zero chance for each one of these labs that it enables a worldwide pandemic, of even apocalyptic scale. Get rid of them. Every university will lobby that they are the exception. No, non-zero is non-zero.
Destroy virus sequences, databases. Outlaw collecting of viruses from the wild. There are next to no laws pertaining to GoF which includes a prison sentence!
Group think is slowly shifting to incorporate the new truth of science being discovered. Consider Elon Musk giving AI a 10-20% chance of killing us off. Yet that remark causes no major public alarm, no blaring headlines, no endless debates over dinner, panics. 10-20%? Where is the POV saying- too bad, we gotta play it safe, put this dog down, 10% is 10%, it’s wishful thinking to assume with effort we can managing it, bring that percentage down to 0%.
Ask Grok for odds of another man-made virus, without any accounting of big shifts in group think, it guesses 10-20% in next 5yrs, 50-50% next 10yrs, and 75%+ next 20yrs. And this isn’t issue #1 on everyone’s mind? Nursery schoolers are likely to be dead before completing high school? Could be mistaken for a gigantic death wish.
Congress represents the people, it listens, hears zero interest in GoF laws, so does nothing. But that will change, the group think about science is adapting. Predict awareness and action will pick up hugely here in 2025.
Future generations will come to their own decisions, first we got to deliver the next generation.