On reading Virology – the path forward by Angela Rasmussen and 77 others. Journal of Virology, Jan 3, 2024.

The old farmhouse, gouache on paper by Joseph-Marius Avy (1871-1939).

This might take a little longer.

Nobody likes regulations. They cost time and money but without regulations global warming would be even worse. Raw sewage would be pumped into rivers and seas. Much still is in the UK. Pesticides would be even more omnipresent. The list is very long.

You might imagine that scientists, at least, would be somewhat less resistant. Nope, they loath them.

Ever since On reading has been working in the life sciences circa 1974, there has been a steady stream of new regulations. This was inevitable for there was precious little back then. The Asilomar conference and a self-imposed moratorium on US genetic engineering was a wake-up call. Of course, this newfound self-awareness paled in compaison to the scrutiny heaped upon nuclear research following the first two atom bombs. Ditto chemistry and chemical weapons.

Today the genetic toolbox is so powerful you can synthesize the genome of any virus in a week or two at most, leading to production of infectious virus. See asides. Extinct viruses have been resurrected, notably Spanish flu, although this is not the only one. To reassure the reader, research on the smallpox virus is very tightly controlled.

So it is not surprising that proposed regulations by the US National Science Advisory Board for Biosecurity (NSABB) that will impact certain types of research in microbiology are under discussion with a decision expected soon. It has provoked a series of pushback articles in journals from the American Society of Microbiology.

That of Rasmussen and colleagues is written by the first four authors, the remaining 74 reviewed and edited the manuscript. It covers a lot of ground yet generally favors the status quo. Some arguments are not the best.

We learn that, ‘New oversight must not impede the scientific mission of identifying and addressing well-evidenced natural threats.’ OK but how does it square with the strong sentence from the abstract? ‘Safety in virology research is paramount and oversight frameworks should be reviewed periodically.’ If safety is paramount, then if ever it collides with the scientific mission, the former must trump the latter.

What are the following sentences doing in this paper? ‘Decades of research on diverse viral pathogens tell us that the risks posed by even presently unknown pathogens are highly mitigatable. As one example, all viral pathogens can be completely inactivated by standard laboratory reagents and practices, including autoclaving, bleach, or other chemical disinfectants.’ They omit to say that occasionally scientists do get infected by the pathogen they were working on. Fortunately, they rarely die. And while former President Trump had an issue with bleach, all microbiologists from thesis level up knew the above.

Another questionable sentence is, ‘The proposed NSABB rules would isolate American research internationally and discourage collaborations in other countries with fewer resources to bear increased laboratory and administrative burdens.’ The whole point of regulations is to level up, not dumb down. Ask yourself why other countries are building BSL3 & BSL4 labs. There are some nasty microbes out there and in the interests of national safety and security, some countries don’t want to rely on others all the time. Yes, lab biosafety varies across institutions and around the globe, but everybody is trying to level up. Yet it was the NIH that promoted contemporary Gain Of Function (GOF) virology which generated novel transmissible human viruses of unknown potential/risk despite a wealth to top-level biosafety labs.

We are asked to believe that cumbersome oversight policies will deter essential research as investigators and institutions choose to focus their efforts elsewhere.’ This is an old chestnut to be thrown into the fire. On reading first came across it during the 2012 Royal Society conference on the Fouchier and Kawaoka GOF influenza papers. It’s been wheeled many times out since. With the 2019 COVID pandemic researchers from across virology shifted to coronaviruses. Fast, and in droves.

People who left virology came back – for example, a former PhD student of mine. So long as there is funding, virologists will be on hand. And with viruses regularly in the news – pandemic flu, SARS1, MERS, Chikungunya, Zika, SARS2, monkeypox – it’s a vibrant and attractive field.

‘The resulting contraction of this field was detrimental to our understanding of coronaviruses and left us less well-prepared for the emergence of SARS-CoV-2.’ One of the things that continues to amaze is that pre-COVID field studies failed to pick up any bat coronavirus remotely close to SARS-CoV-2. Oddly, even four years later there are far too few SARS2-related bat coronavirus sequences, which makes no sense. This the more surprising as by 2019 virology was already heavily into high throughput sequencing. Field studies are much less impacted by the NSABB recommendations than research labs or BSL-3 facilities.

Re: the human measles virus vaccine, we learn that Work in laboratories resulted in a virus that replicated to much higher yields. Technically this represents a gain of function.’ The Edmonston strain that led to the measles vaccine was grown on chicken embryo fibroblasts. As the innate immune systems of humans and chicken cells are different, it is possible that measles virus was less shackled in chicken cells so resulting in high titers. In addition, microbiology regorges examples of subtle adaptation of microbes to lab culture conditions. So no, it was not a gain of function; simply the goal posts had moved.

Measles virus for vaccines was later grown on Vero cells which has a defect in interferon signaling meaning that the cells produced more virus – great for making vaccine stocks. A couple of molecular papers on measles virus vaccine (paper 1 and 2) might interest a few.

See On reading January 31, 2024 for a discussion of the confusion surrounding the term GOF.

Rasmussen and colleagues touch very briefly on the key flu virus work that ignited the GOF controversy; ‘while H5N1 influenzavirus has been considered a potential pandemic threat for decades, some researchers had predicted that it would not be possible for the virus to become transmissible between mammals because it lacked the genetic potential for mammalian transmissibility. This prediction was disproven in the laboratory and in nature.’ Drs. Fouchier and Kawaoka claimed their work would predict the next pandemic virus allowing the development of preventive drugs and vaccines to nip any pandemic in the bud.

It was never about transmission. That’s different and surprisingly difficult. Lest this sound like an opinion, a couple of examples: H3N8 and H3N2 influenza A viruses have been in dogs for a number of years. That must mean hundreds of billions of licks and hugs with owners. Likewise, H3N8 influenza A virus has been in horses since the early 1960s. Despite this, very few clearly documented spillovers to humans have been documented.

‘In light of the challenges inherent to predicting biological outcomes, new policy should focus on observed outcomes of concern. Investigators should be tasked with alerting oversight bodies to experimental results that may pose heightened risk to humans.’ First, many thanks for admitting that predicting biological outcomes is challenging. Second, agreed that the focus should be on the outcomes rather than the starting point. It is amazing that this has only recently been appreciated. Third, this greenlights GOF research in virology and shifts the responsibility to oversight bodies in the event of success – creation of a novel human microbe that could spark a pandemic no less.

The outcome is a foregone conclusion. Regulatory bodies will be inundated with requests such as, it’s profoundly destabilizing. If a research proposal is funded, then results should be published. PhD students and post docs need papers. Blocking publication will harm their careers.

Funding bodies will be riled by the former, while the latter is guaranteed to frighten away young researchers. Both are unfair.

It’s far better to discuss up front whether:

  • the grant proposal has the foggiest chance of answering the biological questions addressed in anything other than a contrived experimental setting;
  • the risk/benefit ratio can be computed, sort of;
  • there are alternative ways of generating similar anticipated data, with all the difficulties surrounding the word anticipated.

It goes without saying that the biosecurity level must be commensurate with the anticipated outcome.

It is worth remembering that the intent of the Fouchier and Kawaoka GOF research was to create novel human transmissible agents out of avian influenza viruses. Intent should have been obvious from reading the grant proposal. The consequences were to create human risk, to make the world a more dangerous place.

As the purported goals could not be obtained why commit research $$$ to work? And while the risk of a lab leak is very small, it is not the same as not returning home in the evening. It could be anywhere up to catastrophic risk with deaths in the millions, not to mention endless pain and economic impact.

Upon reflection, On reading wants to reboot. This sentence does not maintain the status quo. It goes backwards and present regulators with a fait accompli and the world with potential catastrophic risk.

On reading had a problem with ‘Meanwhile, other nations will take the lead in understanding important characteristics of emerging pathogens that are critical for effective responses and vaccine development. International norms will be set by them, not by US scientists. Moreover, this will leave the US beholden to potentially adversarial countries for data and information to mount responses and develop vaccines.’ This is the sovereignty argument talked up by many nations these days. On reading has no problem with excellent US science but doesn’t see why equally excellent scholarship from around the world, much from NATO ally countries, cannot be absorbed by the US following publication. There is much unsaid within these lines making them difficult to plumb.

For the record, GOF (aka DURC) research will not lead to making new vaccines.

At this point On reading switched off.

 

Aside 1. Cytomegalovirus DNA alone, devoid of viral proteins, was shown to be infectious back in the early 1960s, way before the gene cloning revolution. Fraenkel-Conrat showed in 1956 that purified tobacco mosaic virus RNA was infectious. This was a rock to get around given the Hershey-Chase paper of 1952 on DNA as the hereditary molecule, followed by the Watson Crick papers of 1953 with all their implications. Over time it dawned that there were two distinct molecules for encoding hereditary information.

 

Aside 2. Poliovirus was the first virus to be produced by chemical synthesis of its genome circa 2002. The reason Eckard Wimmer did this was to show that if humans succeeded in eradicating polioviruses 1, 2 and 3 by vaccination, some malicious mind could bring them back by way of genome synthesis. Hence the need to keep the world’s population vaccinated. A clear public health issue. Of course, in 2005 the CDC brought Spanish flu virus back from the dead.

However, the stunning aspect of Eckhard’s work was elsewhere. Between bacteria and the reader of these lines, there is an uninterrupted chain of replication spanning billions of years. The chemical synthesis of poliovirus was the first hiatus in descent with modification – Darwin’s words. Biological information moved into knowledge, the conception and programming of machines to make the nucleic acid fragments which were assembled as a DNA genome that was ultimately copied to RNA by a cell – poliovirus has an RNA genome like tobacco mosaic virus.

 

Only in virology!

Leave a Reply