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Not So Fast. Back To In the Pipeline * In the Pipeline * Covid-19 Gain of Function? Not So Fast. * 18 Oct 2022 * By Derek Lowe * 2 min read * Comments Share: * Twitter * Linked In * Facebook * Reddit * Wechat * Email It's been a little while since I wrote about coronaviruses per se, but some recent news (and the coverage of it, especially) prompts today's post. I'm talking about the preprint out of a Boston University research group which is being described by many as "irresponsible gain-of-function" research. I think that that's not a good characterization of it, and I think that language is likely just to scare or enrage a lot of people who don't know much about viruses or virus research. On the other side of the coverage, here's one of the best takes on it I've seen, predictably from Helen Branswell at Stat, who's been doing a great job on this sort of thing through the whole pandemic. So here are the general details of the story: the BU group (at the university's National Emerging Infectious Diseases Laboratories) created a chimeric virus, taking an "original" strain from Wuhan and putting in a current Omicron-type spike protein (a BA1, to be specific). The Omicron strains have not only that version of the spike, but numerous other mutations throughout their sequence, so this is an experiment to see how much of the differences in the early virus strains and the current ones are due to just changes in the spike itself. Recall that the spike protein is the part of the virus that recognizes human cells to infect, specifically the human ACE2 surface protein, and that it's especially the "tip" of that protein (the receptor binding domain or RBD) that is at the business end of that process. And also recall that infectious viruses in general have human cell-surface proteins that they've evolved to recognize and use as leverage to move their contents across the cell membrane and start the infection cycle. There's nothing particularly remarkable about ACE2 or the fact that the current coronavirus strains use it or that they use such a mechanism - there's a whole list of such human proteins that viruses have stumbled onto over the last few hundred million years or so and have managed to exploit. This research was partially funded by the National Institute of Allergy and Infectious Disease (NIAID), a part of the NIH, and the NIAID itself is not happy that they first learned of this work when the preprint came out. They claim that the grant application itself does not mention this experiment, but unfortunately I don't think any of us have seen it to know what it says or doesn't say or at what level of detail. It's important to realizes that this doesn't mean that this work was "illegal" or "unauthorized", either (although there's a lot of loose language like that being thrown around). As you can see from the Stat article linked above, about all the NIAID can say is that they wish the BU team would have informed them. The agency's granting policy is that work that could produce "enhanced pathogens of pandemic potential" needs to be evaluated by a committee doing a risk/benefit analysis and studying the proposed research plan. The NIAID is not saying that this work produced such a pathogen, or that it would have caused such a committee to be convened at all, just that they would have wanted to decide whether it warranted that level of examination or not. Meanwhile, the research was approved by BU's own biosafety review process and by the Boston Public Health Commission, so it's not like anyone who saw the proposed experiment would have immediately hit some sort of alarm button. So what did the team find? Did they make a more dangerous version of the coronavirus? No. In fact, contrary to many of the people who are spouting off on this on social media, the new chimeric strain was less dangerous by comparison in animal tests. Some readers may have seen the figure of 80% of the mice exposed to the chimeric virus dying (because that one is sometimes passed around in ALL CAPS, it can be hard to miss). But before jumping out of your chair, consider that when these mice were exposed to the original Wuhan coronavirus that 100% of them died. This would also be a good time to mention that "exposed", in this experiment, means "large dose sprayed directly up their noses", not wafting around in the cage like some simulation of a mouse dinner party. And as another real virologist (Marion Koopmans of the Netherlands) notes from the data in the preprint, the chimeric virus actually had lower ability to replicate deep in the lung tissue, which may be some of the reason that it was less virulent than the ancestral strain. Here's a good Twitter thread by a real virologist, Florian Krammer at Mount Sinai. He points out that the Omicron strains of the coronavirus are much less pathogenic in the mouse model than the originals, and that's what this chimeric strain showed as well: when these mice are exposed to the actual Omicron BA1 strain, they are not killed off by it at all. The BU experiment was trying to see if this weakening of Omicron in the mice was due to changes in the spike protein, and the answer is that that can't be the whole answer. The chimeric virus did get weaker than the original strain, but it didn't just drop down to mouse-nonlethal like a real Omicron strain would. So the majority of the Omicron-weakening effect in mice has to be coming from mutations in other parts of the virus. And here's another discussion from a real virologist, Stuart Neil at King's College, London. He emphasizes that this work was done not in just plain mice, but in an inbred mutated strain, K18-huACE2. That name means that the mice are expressing the human ACE2 protein (because the coronavirus doesn't really recognize the native mouse ACE2), and that this introduced protein is being expressed via the Keratin 18 promoter. If you're not a molecular biologist, all that means is that when you're getting some organism to produce a protein that's not in its own genome, you need to put some signaling sequences in as well when you splice in this new gene, to get the cellular machinery to pay attention and actually read off your new sequence instead of just ignoring it. The key thing here is that the K18 promoter makes sure that the human ACE2 protein is expressed strongly in pretty much all epithelial tissue, very much including the lining of the lungs. These mice are loaded with the stuff compared to humans - they have much wider and stronger expression of ACE2 than we do, so they are completely set up to be hit by the coronavirus. They are an animal model, in other words, not a direct reflection of the real world - in the real world, mice don't get sick from SARS-Cov-2. You will note, for example, that as the early strains of the coronavirus went into the human population that we did not see a 100% mortality rate like these transgenic mice did. The Black Death itself didn't hit 100%, even under medieval public health conditions. You build animal models like this to get fast, solid comparisons between mouse experiments, not to take the numbers from them and think that they will directly translate to human disease. But what if? What if this chimeric strain turned out to be more lethal than expected in the human population? What happens if you take an older strain of the virus and swap in the Omicron-level spike; doesn't that have the potential for trouble? Well, we've already seen a "natural experiment" like that, as Florian Krammer points out. There was a strain back in March called XD, which was a Delta that had the Omicron spike protein in it (via recombination). XD did not take off in the human population and did not seem to be more of a problem than the other strains, which is why you've probably never heard of it. That recombination domain-switching process very likely takes place in cases of infection with two viral strains at once. The various sequences can get swapped around under these circumstances while things are replicating and reassembling in the same cells, and you'd overall rather not see much of that, because it just gives the virus more lottery tickets to play with. So this was not a gain-of-function experiment, and it did not appear to make a more dangerous virus. It was approved by review committees, and it was done in a BSL3 lab facility (as any work with the pandemic coronaviruses should be!) Where things have gone wrong here is (as mentioned above) that the NIAID folks would like to know about such experiments beforehand, and to start from a sheer practical standpoint you don't want to irritate people who are providing some of your funding. But the larger problem is the way that this was rolled out. I don't think that this group through through the way that coronavirus news gets handed around in this day and age. There are extremely strong and loud opinions out there, and some of those are held by people who cannot be bothered to read the original paper. Hell, let's stop being polite about it: some of the loudest ones are held by people who are frankly unable to understand the original papers at all. So this is what happens. Rumor and misinformation is (as usual) lapping around the world while the truth is still looking for its shoes. I realize that this post falls into that category, but I felt like I needed to write it anyway. Calm down. About the author Derek Lowe Derek Lowe emailTwitter Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. --------------------------------------------------------------------- Comments Please enable JavaScript to view the comments powered by Disqus. IN THE PIPELINE Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog, all content is Derek's own, and he does not in any way speak for his employer. 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