Question asked by Le Mutin on October 18, 2022.
On October 17, an article from the English tabloid DailyMail displayed a particularly sensationalist headline: ‘EXCLUSIVE: ‘It’s playing with fire – it could trigger a lab-generated pandemic’: Experts slam Boston lab where scientists created deadly new strain of Covid with 80% case 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 really consist of? Its authors sought to determine which mutations of the omicron BA.1 variant give it a different virulence from the strain of Sars-CoV-2 which was circulating at the start of the epidemic. More specifically, they wanted to test the hypothesis that the infectious properties of omicron would depend on mutations occurring in its “spike” protein (the protein that allows the virus to bind to human cells).
To test this hypothesis, they introduced the omicron spike protein on the strain discovered in 2019, creating a hybrid virus. Several series of experiments were carried out, in vitro or on animals, to compare the capacities of this new virus with those of omicron BA.1 and with that of the ancestral virus.
The authors thus observe that this hybrid coronavirus, exposed in vitro to the serum of vaccinated patients, has an immune escape capacity similar to that of omicron (which is hardly surprising, since most of the mRNA vaccines available are based on exposure of the organism to a spike protein sequenced in 2020, significantly different from that of omicron BA.1).
A second experience particularly caught the attention of the DailyMail. The hybrid virus, the omicron BA.1 and the ancestral virus were respectively inoculated, in large quantities, to ten, ten and six mice “humanized”. In fact, these animals have been genetically modified to express, on the surface of their cells, the same “ACE2” receptor as that to which spike binds in the human body (“K18-hACE2” mice).
Lethal… for genetically modified mice
Whereas for the ten mice exposed to omicron BA.1, the infection was “lightweight and non-lethal”, eight of ten humanized mice exposed to the hybrid virus died. For their part, the six mice exposed to the ancestral virus died. In other words, the omicron BA.1 virus does not appear dangerous for these mice presenting this human ACE2 receptor on the surface of their cells, while the two viruses displaying ancestral characteristics (regardless of the spike protein they express) are fatal to them. The authors conclude that the virulence characteristics 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 ancestral virus is identified as being lethal for K18-hACE2 mice. The researchers note that at the same doses, the hybrid virus spared two of the ten inoculated mice.
When the DailyMail mentions in its title a virus “with an 80% fatality rate”, the tabloid omits to specify that this lethality concerns an experiment on only ten mice, genetically modified to have a very strong sensitivity to Sars-CoV-2. A sensitivity such that the virus which circulated at the beginning of 2020, at the doses where it is inoculated in these experiments, has a lethality of 100% on these animals. Fortunately, this is not the case with humans.
Boston University reacted to the article in the DailyMail calling it a “false and inaccurate”, and judging that it distorted the results obtained by the researchers. “They sensationalized the message, they misrepresented the entire study 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.
Gain of function
In its press release, the university also attacks a second assertion by the DailyMail : these works would be a “search for gain of function”, defined in the article by these words: “When viruses are deliberately manipulated to be more infectious or deadly.”
In practice, a search for “gain of function” refers to all work that aims to make an organism acquire new functions, generally by inducing mutations and selecting emerging traits, but also by hybridization, or by targeted genetic manipulation. All such research, especially that on low-hazard organisms, is not cause for concern. On the other hand, when the organism studied is particularly sensitive, and the manipulations carried out tend to increase its dangerousness, we readily speak of GoFROC, the acronym for “concerning gain-of-function research”. However, there is no consensual and universally accepted definition of GoFROC, which 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 great debate on this subject, and no one really agrees on what to include behind these terms. One of the subjects is moreover that the research activity, in this field, is itself uncertain: one can very well predict a loss of function and obtain 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 amplifying 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 poses several problems. Firstly, it is based on an arbitrary and narrow definition of gain-of-function research (reduced here to two criteria, recourse to a technique “amplification” 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 does present a greater immune escape than the ancestral strain (as demonstrated by the experiment carried out in vitro). This corresponds to a new function conferred on 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 lethal as the ancestral strain, and presenting more significant pathogenic characteristics than the initial virus, would the university have then judged that this was a “gain-of-function research” ? In other words, does this qualifier depend on the result of the experiment, or on the simple implementation of an experimental protocol? Intention or result?
An answer is given in the university press release, in a passage explaining 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 second, because this research did not lead to a gain of function. If at any time there was evidence of a gain in functionality, per Niaid protocols and ours, we would stop and report the research immediately.”
Similar research recently published in “Nature Communications”
Boston University also wants to be reassuring by specifying that this research was carried out in laboratories of “biosafety level 3” : “All studies are conducted in a biosafety cabinet, with researchers entering their workspace through a series of locked doors. All floors and walls are sealed, and the laboratory is equipped with sophisticated filtration and decontamination technology. And if the researchers had seen anything abnormal during the study, they would have immediately stopped it and reported it.”
While gain-of-function research involving infectious pathogens raises legitimate questions, one may be surprised at the attention given to the Boston study, when similar, but larger, work is published without generating the less media reaction. Indeed, at the end of September, a Chinese team presented in the review NatureCommunications the results of experiments carried out with various hybrid viruses, integrating into an ancestral Sars-CoV-2 the spike proteins of the alpha, beta, gamma, kappa, delta, lambda, omicron and N.1.618 variants.
With the usual reservations related to the fact that these results have not yet been reviewed by peers, Bruno Canard judges the experiment carried out in the Boston laboratory, “which was carried out under correct safety conditions”, “allows to obtain interesting scientific information”. “It shows that there are additional mutations in the backbone of the virus that play a role in boosting innate immunity, or in the ability of viruses to replicate, etc.”
Because this study “was carried out on viruses that are already circulating, of which we already know the spike and the skeleton, and to which populations have already been exposed”, Bruno Canard judges this research “clearly much less of a concern than others”. “It is notably much less dangerous than going to look for new viruses – in often not very well defined security conditions – to bring them back to the laboratory, and to make them cross the species barrier to determine if they will , one day, pass to the man.”A type of research which, he insists, “never made it possible to predict an epidemic”,and returns, according to him, “looking for a gas leak with a lighter”.