1918 And All That
"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 first part is good at explaining what the resurrection of this virus was all about. There were two steps – first obtaining the genetic data and then making the virus using established technology called reverse genetics. Clues to the virulence of the 1918 virus were not apparent by scanning the genome, prompting efforts to reconstruct the virus for further characterization. OK, although this is actually the norm. The sequence of hepatitis B virus genome published some 25 years earlier opened a big door on serum hepatitis. Coming in at 3200 genetic building blocks and a handful of genes it is one of the smallest viral genomes but didn’t explain the disease back then. Genomes are necessary but not sufficient.
Back to flu, paradoxically, the 1918 virus lacked the usual genetic features associated with the ability to replicate in the absence of trypsin. The 1918 HA gene did not have a series of basic amino acids at the HA cleavage site. This is a little ironic. The analogous region of the COVID-19 virus Spike protein does have several basic amino acids and is cleaved by the enzyme furin. This fact alone has sparked endless discussion and speculation across all forms of media.
The key takes on the reconstruction of the Spanish flu virus are (a) the virulence of the 1918 virus was polygenic, where the constellation of all eight genes together produced an exceptionally virulent virus in the model systems examined, and (b) bacterial coinfection contributed significantly to the lung disease associated with the 1918 pandemic.
That virulence involved many genes should not be a surprise. Simple genetic traits like uptake of foreign RNA into the genome of bovine viral diarrhea virus are relatively rare. As to the synergy between bacterial and flu viral coinfections, this has been known experimentally since at least 1935.
Note that there is nothing to do with helping making vaccines, even though an editorial accompanying the 2005 paper describing the resurrection of the Spanish flu virus said, The good news is that we now have the sequence of this virus, perhaps permitting the development of new therapies and vaccines to protect against another such pandemic. The concern is that a terrorist group or a careless investigator could convert this new knowledge into another pandemic. Eighteen years on, no vaccine enhancing research is cited in the present paper. The second sentence has gone unaddressed.
The second part of the review is a disconnect spanning the COVID-19 virus and GOF research. It lacks close reasoning, unlike the first part. It starts with the bird flu H5N1 virus that has eked bedlam on poultry farms and onwards to land and sea mammals even though it poses little risk to humans as of writing.
As we learned during the COVID-19 pandemic, a pathogen that is capable of airborne spread can have devastating consequences. Readers of these lines close to 70 years old will have lived through four influenza pandemics and don’t need COVID-19 to learn about the dangers of respiratory viral infections.
The last paragraph on H5N1 flu notes the Fouchier and Kawaoka experiments also shed light on other compelling research questions relevant to global health and pandemic preparedness. Please, do discuss. However, it finishes with This leads us to conclude that there is insufficient evidence to answer these important questions about influenza viruses. So there’s nothing to discuss.
Under the development of countermeasures, we learn that the efficacy of vaccines can be limited by the emergence of escape mutants or novel viruses (and by low vaccine uptake). This is textbook stuff, so no problem with that. By contrast, nothing is said about the intrinsic difficulty of making some vaccines, notably to the agents of tuberculosis, AIDS and hepatitis C, although there is finally progress with malaria.
Of course, if GOF is used once again in its historical sense and not limited to dual use research (DURC) of concern that set off the controversy, then this is unhelpful and a disservice (Deconstructing the Portrait).
We are reminded that not all mutations are equal and depend on gene context. Concerning the Fouchier and Kawaoka DURC/GOF we learn that the potential problem of focusing on the exact changes identified in the 2012 studies is that other mutations might also be capable of conferring the same phenotype, and there may be other genetic pathways to transmissibility. Exactly!
How many pathways, or combinations of mutations will give a comparable result? We’ll probably never know the number, although On reading’s hunch is many hundreds for H5N1 bird flu which effectively puts it beyond the practical bounds of experimentation and prediction.
The authors respond to this conundrum with, The counterview is that our current inability to accurately predict phenotype from genotype must be overcome.
This counterview is a belief or a wish nobody in infectious diseases would take issue with. Yet it is a belief, a goal at best. It assumes the outcome is possible. Let’s go back to the key takes of resurrecting the Spanish flu virus mentioned above; a) multiple genes working in concert prohibited genotype to phenotype conclusions and b) bacterial coinfections. By their own admission a) is a tough challenge, hence the need to resurrect the virus, while there is no way b) can be read from the influenza genome.
So it’s a belief. The problem with beliefs is that not only can they morph over time, but also anyone who disagrees with them comes under fire as a defeatist, which is an ad hominem remark, not based in scientific evidence.
Let’s step aside for a few sentences and look at another pandemic. After 40 years of molecular genetics, we still cannot ‘read’ the disease AIDS from the HIV genome. It depends on human genetics, epigenetics and whether the individual has a heavy microbial burden, particularly Mycobacterium tuberculosis.
Science must counter arguments with hypotheses built on more or better data, not beliefs. Engineers can’t make smartphones out of beliefs. Things work, or they
don’t. Endless soft- and hardware updates illustrate well the incremental advances typical of science and technology.
Under checks and balances we read that for DURC the benefits outweigh the risks and the strategies that are in place to mitigate these risks including regulations and safeguards, and the checks and balances that are in place to ensure biosafety and biosecurity. In the United States, the National Science Advisory Board for Biosecurity (NSABB) provides biosecurity oversight… This dense sentence is full of affirmations. No benefit/risk analysis has ever published for the controversial H5N1 bird flu experiments. Scientists overestimate the benefits of their work and underestimate risk, so care is needed. And if the NSABB does provide oversight, why are there numerous pushback articles to their recent recommendations? One of these articles is signed by the senior author of this article (Flights from reason).
Their concluding remarks harbour a mix of unreferenced statements such as Insights gained from sequencing the genome of the 1918 virus … have provided practical and clinical knowledge to improve the management of public health today. On reading begs to disagree; generalisations were already out there but nothing specific and tangible has emerged. Or Knowledge obtained from reconstruction of the 1918 virus has provided valuable information for future pandemic preparedness. Please mention just one example.
We learn that Given the diversity of viruses in animal hosts, it is difficult to predict which influenza or CoV may cause the next pandemic. Many thanks especially as this comes from two flu virologists. Actually, we knew this years ago. Furthermore, nobody has ever predicted a pandemic beyond ‘one day soon’. So why were virologists expected to swallow the Fouchier and Kawaoka argument that their experiments would predict the next pandemic strain?
Quickly we’re back to another counterview. The value of scientific information cannot always be judged with current understanding or knowledge. We proceed with the information around us. Scientists with 20 years of baggage have all had the experience of their field partly discombobulated by a new paper that necessitated rethinking. Understanding the natural world can be hellishly difficult. If scientists just churn out data and make no attempt to find the internal logic for fear of being exposed 20 years down the line, this will cause no end of problems and stifle innovation and technology.
After 12 years of intense discussion, DURC/GOF research à la Fouchier and Kawaoka has not delivered (Deconstructing the portrait). There are no compelling public health benefits. Good arguments are needed to continue along this path, if only to spend precious research dollars on other experiments with a higher probability of perceived success.
It is the misuse or malicious use of viral RG that is the concern. This crops up in the text and reappears in a boxed summary at the end of the paper, as well as in the Science editorial mentioned above. No attempt was made to grapple with the malicious use of academic work which is at the core of DURC. Virologists feel their job is to tackle questions and publish their results. Period. Maybe patent some of the better findings. Very few are aware of the IAP statement on biosecurity or other appeals (Do no harm 1, Nuclear parallels) where the scientist is exhorted to go beyond the bench and think about the impact of their work on society, the immediate funder of their work.
This blind spot shows up again in the sentence Dual use research continues to have great potential to advance biological sciences, provided there is a compelling public health benefit for the research and appropriate biosafety. The malicious mind is forgotten, conveniently no doubt, because virologists are not equipped to handle it. The obvious corollary is that self-governance doesn’t work when the stakes are high, which is why the DURC/GOF work on bird flu viruses sparked a controversy. The pushback from virologists to the NSABB report (Going places) makes no sense precisely because they don’t have the knowledge to handle the Dual Use component.
Houston, we have a problem.
Aside 1
The title is variant of 1066 and all that by WC Sellar & RJ Yeatman (1930). We’re treated to an irreverent look at English history, including the sharp one-liner History is not what you thought. It is what you remember.
Aside 2
Under a section devoted to new technologies we learn that since reverse genetics (RG) was used to reconstruct the Spanish flu virus in 1999, RG technology has advanced rapidly, with platforms available for rescue of positive- and negative-sense RNA viruses. This is way too flu centric. And years out of phase. RG was used to generate the positive-sense RNA poliovirus in 1981, while others did so for the negative-sense RNA measles virus back in 1995. Both papers were preceded by a couple of years by work on other RNA viruses.
Aside 3
We’re given to believe once again that necessity is the mother of invention. Some of the greatest advances in RG technology have occurred recently for CoVs, spawned out of necessity by the COVID-19 pandemic. The method in question is called circular polymerase extension reaction and was originally developed for flaviviruses back in 2013 well before COVID. For info, yellow fever and hepatitis C viruses are well-known flaviviruses.
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