The latest "killer virus" panic

In which I aim to bring some sense to the latest social media panic

Two days ago twitter and the media discovered a pre-print published on 4th January which assessed the lethality of Coronavirus strain GX_P2V in humanised mice. What happened next is that lot of people got very worried and a wide range of publications started covering this in a very apocalyptic tone - I particularly like the fact that the DailyMail capitalises the word BRAIN.

This is the top comment on one of these articles. Very Frankenstein-esque sentiments.

The brightest online minds also opined on this. See for example this post by Curtis Yarvin in which he declares that everyone is so mindkilled (much like the mice whose BRAIN was attacked) - but not him! “Y’all are so mindkilled” I imagine Yarvin saying, in a Valley Girl Accent. And we’re all gonna die of a cold, probably…

Now, I must admit that at the beginning I got a bit freaked out myself. The type of damage this virus causes in the humanised mice does not sound pleasant, to put it mildly: “By the seventh day following infection, the mice displayed symptoms such as piloerection, hunched posture, and sluggish movements, and their eyes turned white”

Thankfully, the author promptly released a statement about his research, linking to some papers that offer some background and that I could personally check. After reading about the topic I became more and more convinced this is essentially a social media induced moral panic.

Now, a few points about what motivates this post and its aims:

1. I am intervening in this conversation because I am a Biologist and many of the people involved so far are not. I am not a fan of those who mindlessly recite “Trust the experts!”, and I have written at length what my issue with this attitude is. But the truth is that there are a lot of disciplines where familiarity helps, especially due to the unspoken knowledge that one gains by working in the field. Nowhere is this more true than in experimental science, where a lot of subtleties are really hard to transmit via papers. But, crucially, I am not a Virologist myself (and yes, these distinctions actually matter), and I might be missing some things. This post is intended as a starting point for debate and I am very happy to be contradicted on the points I make here.

2. This post is not a general commentary on the practical utility of academic research on viruses or a recommendation of the kind of safety-exploration trade-offs that are optimal. I am simply aiming to clarify what the implications of this specific paper are, because I think it has been misrepresented.

This is not a very special paper

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The first thing that must be said about this paper is that there’s nothing particularly special about it in terms of the methods it uses or its aims - it most certainly got so much attention solely because the effects in the humanised mice seem so dramatic. But people do awful things to mice all the time in labs, so I am not sure this is a great criterion.

I’ll explain why there is nothing particularly dangerous or special about this paper:

Firstly, the virus in this paper is not created “in a lab” as a “new virus”. The GX_PV2 is a naturally occurring variant that has been discovered in pagolins in a Nature paper surveying existing Coronavirus strains. Now, there are two mutations that were spontaneously acquired by the virus in the lab (not introduced on purpose). This was actually reported in an earlier, 2023 paper (so if you have an issue with this type of research, you should have an issue with that paper). Crucially though, these were not selected for increased virulence or lethality; in other words, the virus was not subjected to evolutionary pressure in order to become more dangerous to humans. The way in which these were acquired was via simple serial passage of the virus in cell culture, which often leads to spontaneous mutations that help the virus adapt to the cell culture conditions. In vitro passage is a common technique used to culture viruses that has been around for decades (indeed it has won the Nobel Prize in 1954). It helps in isolating specific strains of bacteria or viruses from a mixed culture, allowing for the study of a single, pure strain. Often, when this happens, viruses become “attenuated”, so less virulent, deadly etc. Incidentally, this is how a lot of vaccines were historically made!

In vitro passage: very standard technique

So, to summarise: this is a naturally occurring variant that is being studied in the standard way you would study such variants. If we were to worry about any new mutation that a bacteria or virus acquires in vitro we would have to stop a lot of research!

Clarifying some further points

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Now that I have explained in broad strokes what this research is about, I will address some other commonly encountered speculations that I found to be wrong.

Firstly, this is not Gain-of-Function research. I have found a useful definition of gain-of-function research and some examples in this paper arguing AGAINST it:

“Specifically, these refer to experiments that are reasonably anticipated to create novel viral strains that combine high virulence in humans with high transmissibility in human, especially when it is expected that the strain is likely to be unaffected by existing immunity in the general population due to antigenic novelty. Ferret passage of modified influenza A H5N1 viruses to select for droplet transmissibility is a paradigm case for such studies. More generally, such studies typically start with a particular virus that does not have a phenotype of interest: to date, this has usually been droplet transmissibility between individuals of some mammalian species. Manipulations are performed to introduce changes that might confer such transmissibility. Such manipulations might involve (1) introducing via reverse engineering mutations expected to contribute to the phenotype (2) providing novel genetic material by coinfecting cells or animals with another strain and permitting reassortment or (3) simply waiting for mutations to occur. After performing one or more of these manipulations, the next step is to exert selection for the phenotype (say by placing an infected animal near but physically separated from an uninfected ones and looking for viruses in the second animal that have moved via droplets from the first”

The current paper does not do any of the things described above. The key thing here is that they are not modifying this virus on purpose to select for a more dangerous phenotype - there is no evolutionary pressure exerted to make it more deadly or change its transmissibility. They are also not creating a virus that is “likely to be unaffected by existing immunity in the general population due to antigenic novelty”- since this virus is already naturally occurring!

The other aspect I’d like to address is that humanised mice results need to be treated with a (very) big pinch of salt. So what is a humanised mouse? It is a type of mouse model used in scientific research that has been genetically modified to express certain human genes, cells, tissues, or even organs. These modifications are made to make the mouse model more similar to humans in specific biological pathways. In this case the mice were expressing the human version of the protein ACE2¹. However, apart from this one protein, the mouse remains a mouse. If humanised mice were so good at recapitulating human biology, we’d be much closer to what the media likes to call “a cure for cancer”. What’s more, these mice usually express *much higher* levels of the ACE2 protein than humans do and in more tissues than humans, so they’re much more “primed” to be affected than a human would. So the fact that this viral strain has the effects it has in mice is not really telling us much about what it would do in humans (IF, and that’s a big IF, it managed to acquire other traits it would need to actually pose a threat, which include human transmissibility).

The last common misunderstanding I have seen is that someone is going to use a DNA synthesizer “to create a more deadly virus” based on the new information in this paper. I wish Biology were that easy! To make a more deadly virus you wouldn’t just sit in your room, like some sort of Evil Genius, reading papers and coming up with ideas based on them. You’d need access to a lab and you’d perform the kind of directed evolution experiments described in the “Gain-of-Function research” section. That’s because Biology is so complicated and you need to optimise so many variables, that only the force of evolution can really crack it. Now, you could argue that someone might have a better starting point in such an endeavour by reading about this variant. But what are we going to do then? Stop publishing the sequences of naturally occurring viruses? And certainly, if someone actually did manage to illegally get access to a lab where they would perform the experiments I described above (non-trivial!), the publication of a naturally occurring sequence is not the kind of bottleneck that will make or break their evil endeavours.

What should we do about this?

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I think there is a wider debate to be had about the benefits of such research in general. There is also a discussion to be had about actual Gain-of-Function research. For example, the kind of ferret gain of function research I mentioned above, where scientists were specifically trying to optimise for increased transmissibility in a mammalian species, seems rather misguided to me.

But freaking out about this specific paper, which does not even seem to pose particular risks, ain’t it. Essentially, the decision to pursue infectious agent research hinges on addressing two key questions:

1. What is the level of risk associated with it?

2. What potential benefits could it offer?

Now, I do not think this research is particularly dangerous, as I explain above. I am also not entirely sure the current paper we are discussing is particularly useful. Apart from torturing some mice, I don’t know that it has achieved much. I guess the best argument for carrying out this research is deciding whether it’s worth making prophylactic vaccines against specific strains, based on how bad their effects are in these “humanised” mice. Will the results from one humanised-mouse-model-that-we-are not-sure-recapitulates-human-physiology determine whether a new vaccine will be developed? I doubt it.

I think you can argue that messing with viruses at all is so dangerous that we simply should not do it, regardless of whether it’s Gain-of-Function or not. But that’s a really different discussion that has to be had about an *entire field*.

1. ACE2 gained significant attention during the COVID-19 pandemic because it is the entry receptor for SARS-CoV-2, the virus that causes COVID-19.