Question asked by Le Mutin on October 18, 2022.

On October 17, an article from the English tabloid Daily mail showed a particularly sensational headline: ‘EXCLUSIVE: ‘It’s playing with fire – it could trigger a lab-generated pandemic’: Experts crack down on Boston lab where scientists created deadly new strain of Covid with 80% fatality rate. The article, widely shared on social networks, claims to report on a study presented in pre-publication on October 14 by a team of researchers from Boston University.

What did the study actually consist of? Its authors tried to determine which mutations of the omicron BA.1 variant give it a different virulence than the strain of Sars-CoV-2 that circulated at the start of the epidemic. More specifically, they wanted to test the hypothesis that omicron’s infectious properties would depend on mutations occurring in its “tip” protein (the protein that allows the virus to bind to human cells).

To test this hypothesis, they introduced the omicron spike protein onto the strain discovered in 2019, creating a hybrid virus. Several series of experiments were carried out, in vitro or on animals, to compare the capacity of this new virus with the capacity of omicron BA.1 and with the capacity of the ancestral virus.

Thus, the authors observe that this hybrid coronavirus, exposed in vitro to serum from vaccinated patients, has an immune escape capacity equivalent to omicrons (which is hardly surprising since most of the available mRNA vaccines are based on exposure of the organism to a spike protein sequenced in 2020, significantly different from omicron BA.1).

Another experience caught the attention in particular Daily mail. The hybrid virus, omicron BA.1 and the ancestral virus were inoculated in large quantities into ten, ten and six mice respectively “humanized”. In fact, these animals have been genetically modified to express on the surface of their cells the same “ACE2” receptor as the one that spike binds to in the human body (“K18-hACE2” mice).

Lethal… to genetically modified mice

Whereas the infection of the ten mice exposed to omicron BA.1 was “light and non-lethal”, eight out of ten humanized mice exposed to the hybrid virus died. In turn, the six mice exposed to the ancestral virus died. In other words, the omicron BA.1 virus does not appear to be dangerous to these mice that present this human ACE2 receptor on the surface of their cells, while the two viruses that exhibit ancestral characteristics (regardless of the spike protein they expresses), are fatal to them. The authors conclude that the virulence properties of omicron BA.1 are not based—at least not solely—on mutations present on its spike protein.

At the inoculated doses – 10,000 PFU – the parent virus is identified as being lethal to K18-hACE2 mice. The researchers note that the hybrid virus at the same doses spared two of the ten inoculated mice.

When Daily mail mentions a virus in its title “with 80% death rate”, the tabloid omits to specify that this mortality relates to an experiment on only ten mice, genetically modified to have a very strong sensitivity to Sars-CoV-2. A sensitivity such that the virus circulating at the beginning of 2020, in the doses inoculated in these experiments, has a mortality of 100% in these animals. Fortunately, this is not the case with humans.

Boston University responded to the article in Daily mail call it a “false and inaccurate”, and considers that it distorted the results obtained by the researchers. “They sensationalized the message, they distorted the entire investigation and its objectives,” thus declared Ronald Corley, director of the laboratories on which the authors of the study depend. The university also pointed out that the research had been reviewed and approved by a biosafety committee and by the Boston Public Health Commission.

Increasing function

In its press release, the university also attacks another claim from Daily mail : these works would be a “search for functional recovery”, defined in the article with these words: “When viruses are deliberately manipulated to be more infectious or lethal.”

In practice, a search for “gain of function” refers to any work aimed at causing an organism to acquire new functions, generally by inducing mutations and selecting new traits, but also by hybridization or by targeted genetic manipulation. All such research, especially on low-risk organisms, is not cause for concern. On the other hand, when the studied organism is particularly sensitive and the manipulations carried out tend to increase its dangerousness, we easily talk about GoFROC, the abbreviation for “regarding gain-of-function research”. However, there is no consensual and universally accepted definition of GoFROC that would define its contours without any ambiguity.

“Everyone has difficulty with the definition of this research”, comment to Release Bruno Canard, CNRS Research Director at the Architecture and Functions of Biological Macromolecules Laboratory at Aix-Marseille University. “There hasn’t been a big debate on this topic, and nobody really agrees on what should lie behind these terms. One of the topics is also that the research activity in this field is itself uncertain: one can very well predict a loss of function and achieve a gain of function, and vice versa…”

For Boston University, however, things would be simple, as she writes: “This research is not gain-of-function research, in the sense that it did not involve amplification of the Sars-CoV-2 virus strain [ancestrale], and that it did not make it more dangerous. In fact, this research has made the replication of the virus less dangerous. (referring to the fact that only eight out of ten mice died with the hybrid virus, compared to six out of six with the ancestral virus).

However, this argument presents several problems. First, it is based on an arbitrary and narrow definition of gain-of-function research (here reduced to two criteria, application of a technique “reinforcement” to produce the viruses used in the experiment and above all to the production of a more dangerous virus). In addition, the university hides the fact that the hybrid virus provides a greater immune escape than the ancestral strain (as demonstrated by the experiment performed in vitro). This corresponds to a new function assigned to the virus which makes it more dangerous.

Finally, the argument that the lethality of the hybrid virus is lower (for humanized mice) than that of the ancestral virus… is an observation that results from the conduct of the experiment. In the event that the researchers had described a virus as deadly as the ancestral strain, and with more significant pathogenic properties than the original virus, the university would then have judged this to be a “gain-of-function research” ? In other words, does this qualification depend on the outcome of the experiment or on the simple implementation of an experimental protocol? Intent or result?

An answer is given in the university’s press release, in a passage that explains why this work was not the subject of a prior declaration to the National Institute of Infectious Diseases (Niaid): “Firstly, because the experiments were carried out with funds from the university […] and secondly because this research did not lead to an increase in function. If at any point there was evidence of a gain in functionality, according to Niaid protocols and ours, we would stop and report the research immediately.”

Similar research published recently in “Nature Communications”

Boston University also wants to be reassuring by specifying that this research was conducted in the laboratories of “biosafety level 3” : “All studies are conducted in a biosafety cabinet, where researchers enter their work area through a series of locked doors. All floors and walls are sealed, and the lab is equipped with sophisticated filtration and decontamination technology. And if the researchers had seen anything abnormal during the study, they immediately stopped it and reported it.”

While gain-of-function research involving infectious pathogens raises legitimate questions, one might be surprised by the attention paid to the Boston study when similar, but larger, works are published without generating the minor media reaction. In fact, a Chinese team presented at the end of September in the review Nature communication the results of experiments performed with different hybrid viruses integrating the spike proteins of the alpha, beta, gamma, kappa, delta, lambda, omicron and N.1.618 variants of an ancestral Sars-CoV-2.

With the usual caveats related to the fact that these results have not yet been peer-reviewed, Bruno Canard assesses the experiment conducted in the Boston laboratory, “which was carried out under proper safety conditions”, “makes it possible to obtain interesting scientific information”. “It shows that there are additional mutations in the backbone of the virus that play a role in increasing innate immunity, or in the ability of the virus to replicate, etc.”

Because this study “was performed on viruses that are already circulating, of which we already know the tip and skeleton, and to which populations have already been exposed”, Bruno Canard reviews this research “clearly much less worrying than others”. “In particular, it is much less dangerous than looking for new viruses – under often not very well-defined safety conditions – to bring them back to the laboratory and have them cross the species barrier to determine whether they will one day pass to man.”A type of research that he insists on, “has never made it possible to predict an epidemic”,and returns, according to him, “looking for a gas leak with a lighter”.

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