Gain of Function? Not So Fast
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So what's the definition of gain of function? Does it have to add a function that isn't found in the wild? I'm struggling to come up with a definition that excludes this experiment but includes everything that is considered gain of function.
The gain-of-function debate began in the 2010s over a specific set of experiments that were done on influenza. The term is used to describe changes that render a virus that has the potential to become a pandemic more virulent or more transmissive.
Gain of function as described, has to increase the virulence of a potential human pandemic-causing pathogen.
To those who might counter that this definition needs to be changed: I don't disagree, but until it is, scientists are going to grade themselves on the scales they are given by the funding and regulatory agencies.
The example Wikipedia gives explicitly states specifies, and I quote, a "situation would be considered a gain-of-function experiment, as the virus did not previously have that function."
The journal Nature states that gain of function is "GOF is a classic genetics term to describe mutations that give a gene, RNA or protein new abilities". Not much different from what OP stated, unless there is a nuance you wish to point out:
https://www.nature.com/articles/d41586-021-02903-x
NIH's website states gain of function (as well as loss of function) research is any selection process involving the alteration of a genotype in order to produce a corresponding change in phenotype:
https://www.ncbi.nlm.nih.gov/books/NBK285579
That is a much more technical way of saying gain of function research is what happens when you modify genes to produce a change in phenotype, which is the technical term for the observable behavior and characteristics of an organism, ie. function.
So anyhow, it's possible OP is wrong, Wikipedia is wrong, and a host of comments/sources are wrong, in fact it may very well be likely, but without a better source available it does seem like gain of function research is fairly open-ended research that attempts to modify an organism's genetics so as to add additional functions that it did not otherwise have.
GoF is aquisition of a new tool or capability.
So I’m not really sure how that excludes this research. The Ba1 spike is new function.
if its something that the virus already did, but now does it to greater extent that is attenuation of function
This research seemed to accomplish that, unless I'm missing something, which I might well be. But if we're nuancing the definition of GoF to say this research was not GoF, then I think we've lost track of what the concern was in the first place.
the function of "lethality" was reduced in association with the recombination, thus attenuated in summary, if you look hard enough you may be able to find gains, but overall it is attenuation.
this isnt the research you seem to be concerned about.
you should be more concerned with codon scale editing of the nonstructural features of the virus as there is a direct influence upon interferon dynamics that is understood, and can be easily influenced by editing additional codons into the code at the "region" associated with interferon cascade mediated lethality.
i will not give details here, but i you choose to look around and do some hard reading, you will discover, that the recipe for extremely lethal corona virus is not complex, but requires a lab capable of keeping and using the accesory biochemicals that allow primary sequence editing- that is to say any molecular genetics lab
He's not circling the wagons defending natural origins in the above.
Then you read a bit about virology, and you realize that most virological research involves altering viruses, and that these sorts of experiments are orders of magnitude less likely to lead to a super strain outbreak than the millions of people around the world who right now have SARS-CoV-2 replicating in their throats, and who are walking around maskless, breathing at other people.
If you want to gain a bit of familiarity with virology in your free time or during your commute, I recommend listening to This Week in Virology: https://www.microbe.tv/twiv/
I agree, Vincent and his regulars are fantastic science communicators. I started listening to TWiV just before the Coronavirus kicked off when there were early reports of something going on in Wuhan. I also liked that he published his virology lectures with updates each year on YouTube.
The Q&A livestream[0] is also quite entertaining, Amy Rosenfeld is quite a character (it sadly doesn't get published as a podcast).
[0]: https://www.youtube.com/playlist?list=PLGhmZX2NKiNmAaXoQ4kCU...
"In other words, any selection process involving an alteration of genotypes and their resulting phenotypes is considered a type of Gain-of-Function (GoF) research, even if the U.S. policy is intended to apply to only a small subset of such work." [0]
"...experiments that encompass all influenza viruses, SARS-CoV, and MERS-CoV that can be reasonably anticipated to increase pathogenicity or transmissibility in mammalian species" [1]
[0] https://www.ncbi.nlm.nih.gov/books/NBK285579/#sec_28 [1] https://www.ncbi.nlm.nih.gov/books/NBK285579/#sec_30
Not to be too harsh, but if you don't know about the experiments conducted by Sabin that led to the live attenuated oral polio vaccine, then you don't know enough about virology to comment on the gain-of-function debate.
This is the equivalent of wading into a highly technical debate among computer scientists and then saying that you've never heard of the concept of a Turing Machine.
> Fifty-seven nucleotide substitutions distinguish the attenuated Sabin 1 strain from its virulent parent (the Mahoney serotype), two nucleotide substitutions attenuate the Sabin 2 strain, and 10 substitutions are involved in attenuating the Sabin 3 strain.
> The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of infection and replication, but is unable to replicate efficiently within nervous system tissue.
[Note that the injectable polio vaccine uses inactivated ("dead") virus, that is safer but not effective to stop contagion.]
Sabin developed the original attenuated vaccine in the 1950s-60s, which is basically the stone ages, as far as genetics goes.
We now know that the attenuated vaccine reverts to a more dangerous form of polio after it's administered, but that the time it takes to revert is long enough that the vast majority of people develop a robust immune response and don't develop paralysis. The problem is that there is an evolutionary path that the virus can take to revert, and that that path is heavily favored once the virus is actually inside a human gut.
However, using modern genetic engineering techniques, it is possible to introduce a set of mutations into the polio virus that make it much more difficult for the virus to revert to a dangerous form. Scientists engineering viruses in a lab could sound scary to laypeople, but it's vital work that might lead to the final eradication of polio.
My point is that claiming the BU experiments on ePPP were not GOF because they didn't produce a more deadly pathogen is a somewhat nonsensical definition (whether NIAID promotes it or not) and an ineffective defense of the work. Derek Lowe can do much better, but he didn't. In the process, he misses addressing the real concerns of critics and fails to understand or acknowledge their fears (which have nothing to do with the precise definition of GOF as used by Derek Lowe).
In this case, it does, because those are some of the most famous experiments in the history of virology. Everyone who learns the basics of virology knows about those experiments. As I said, this is the equivalent of saying one knows the fundamentals of computer science, but not knowing about the Turing Machine. Or imagine someone expressing very strong opinions about programming, but then saying they've never heard of C.
I raise this because I'm always shocked in these discussions on HN by how many people who don't seem to know the basics of virology weigh in with such strong opinions. Virology has come under significant attack, and most of it has been very poorly informed.
About the experiments themselves, they do not look similar to the experiments that have historically been considered GOF, and which sparked the GOF debate (look up the debate from the 2010s over research into the 1918 pandemic flu strain, if you want to know what the original debate was about). Taking a spike protein from a variant and putting it onto wild-type SARS-CoV-2 is a fairly straightforward way to try to isolate the effect of the changes in the spike protein from other changes in the virus. The Omicron spike is already out there. Omicron is already out there. This isn't adding anything to SARS-CoV-2 that isn't already massively spreading in the real world, and there's no particular reason to think that this experiment will create a more deadly or transmissible virus.
Derek Lowe chose to focus on defining GOF in a rather narrow way - one that can only be applied retroactively if the outcome is critical to the definition -- and uses that definition to say that criticism of the BU experiments is overblown. The general fear around experiments involving ePPP doesn't care about the exact definition of GOF. Just saying that it doesn't qualify as GOF is not going to convince people that fear it. Derek Lowe should have focused more on the points you raise in your last paragraph.
>The Omicron spike is already out there. Omicron is already out there. This isn't adding anything to SARS-CoV-2 that isn't already massively spreading in the real world, and there's no particular reason to think that this experiment will create a more deadly or transmissible virus.
Nobody intends to create a more dangerous virus on purpose. But if the outcome were so fully understood and completely predictable, then it's a waste of time and money doing the experiment just to confirm a conclusion that everyone fully agrees on and understands. And if there's little to no risk, why take precautions? Why use BSL3? Why does NIAID feel it should have been alerted? That's what Derk Lowe should have addressed, not a definition!
I think "understands the basics of virology" is a reasonable litmus test for who should be commenting on whether a given virology experiment is safe or not.
> Nobody intends to create a more dangerous virus on purpose.
This is not true. It's actually what the original GOF debate (focusing on influenza) was about in the 2010s.
> And if there's little to no risk, why take precautions? Why use BSL3?
Honestly? Partly to appease people like you. The scientists are being extraordinarily cautious, with a set of experiments that are highly unlikely to lead to anything particularly concerning in the first place. The danger posed by everyday people walking around with CoVID-19 is far greater than the danger posed by this experiment. Inside of labs, SARS-CoV-2 is treated like an incredibly dangerous substance. Outside of labs, people are walking into restaurants and bars and exhaling SARS-CoV-2 onto everyone around them.
> So this was not a gain-of-function experiment, and it did not appear to make a more dangerous virus.
He seems to be making two separate claims:
1. This research is not GOF 2. This research did accidentally make a more dangerous strain.
And that because of both reasons we should not be worried.
The article up to this point was explaining why the research was unlikely to produce a more dangerous strain, and hence why he could describe it as "not GOF". This is not based on outcomes, but on a reasonable assessment of the risks ahead of time.
Well that's not the only reason, but it's probably the biggest if we're being honest.
The risk of millions dying is not worth the possible benefit of gaining better understanding.
The only thing you are missing is the hubris of the researchers involved, typified by the attitude of the author in this piece. In my opinion, the preponderance of the evidence available today strongly suggests that Covid was indeed created in a lab. Countless millions are dead and the lives of billions have been permanently upended. The fact is that there is no such thing as perfect safety, and there is always a risk that whatever viruses they are creating and/or modifying in a lab will be released into the wild. These researchers are risking the lives of millions with their franken-virus research - which is why it was halted by the Obama administration years ago. The engineering/modification of dangerous viruses should be completely banned with extremely harsh criminal penalties for anyone violating this ban. The fact that we are still letting these so-called scientists gamble with the lives of millions after Covid is an extremely withering indictment on our society.
I’m not quite convinced.
this sort of manipulation can produce gain of function when there is interplay between the recombined elements, most often it is simply a recombination of functions. to split hairs, the wuhan "backbone" [not spike] gained function of omicron spike, but lost function of wuhan spike.
gain of function doesnt have to be so dramatic. there is a non spike region, of coronavirus that modulates virus/interferon signaling dynamics, modification of a small number of, [as in 2-3] codons will produce lethality
that itself is not gain of function it is potentiation.
a clear cut case of gain of function would be a recombination of wuhan backbone with chimeric SARS-MERS spike that retains both target specificities [ACE2-DPP4]
> That's how they do, they play games with words. I can imagine them making an airborne version of HIV that only kills 80% of infected "well its not gain of function because it kills less than the original strain"
stay classy with your censorship.
edit: and apparently someone has a script that auto downvotes. doubt anyone read this days old comment section within seconds of my post.
I'm going to quote one of the scientists the article actually quoted themselves:
"Now, the outcome of the experiment was not clear. You could have assumed that the virus, compared to the ancestral virus is less pathogenic (which was the case). But it could also have been more pathogenic. Therefore, these experiments need to be done in appropriate biosafety laboratories. And, if the virus can become more pathogenic and falls into certain categories, you also need permission from the US government to perform the experiment - especially if they fund your research. And that is what was not done here."
Later on, on the same subject, he literally says: "Having said all that, I absolutely think GOF research should be tightly regulated and controlled."
Our scientific institutions surely have become wholly corrupted by politics. This is gain-of-function research. Whether you think that type of research should be conducted or not is moot. The scientist quoted said he thinks this was not dangerous GOF research, but still needed to be tightly regulated.
Second, would you classify Derek Lowe as a scientist, or a "scientist"? (If you think there's no difference, then you're reading the parent comment differently from me, which is useful information.)
Assuming Derek Lowe the author of the article, I feel like my first comment covered your question He's playing with the definition of a politically-charged word, claiming that a GOF experiment isn't so unless it successfully creates a more virulent virus. I get that the definition of words isn't set in stone and there can be ambiguity involved, but this seems like a very dishonest take on what GOF research actually is.
He even quoted a scientist whose conclusion is the exact opposite of his, that this is in fact GOF research, and failed to mention the fact!
To add to my original comment, he used the phrase "real virologist" at least three times. This is charged language that implies a lot of people in these conversations don't know what they are talking about. This is not the behavior I expect out of scientists. Well, that's not true anymore. Nowadays, this is unfortunately the kind of behavior I do expect out of scientists that write articles for sites like science.org.
You also want to accuse him of not engaging with your main point. But from your posts, I would say your main point is that some of those who claim to be scientists are more akin to politicians than scientists. And if that is not your intention, then I would say that is a failure on your part to convey what point you actually wanted to make.
You want to knock his use of the term "real virologist", but he's using it to distinguish the people as people who work in virology and not random people on the internet arguing about the semantics of an apparently ill-defined term.
And, to slightly correct your summary, I'm saying scientists are often conducting politics, or operating in the political arena (or moral arena), while, either explicitly or implicitly, taking advantage of the scientific credibility that society gives them by default. It's articles like these that land in leftwing fact-checking sites like Politifact that are then used as solid evidence that a particular claim is "misleading" or "mostly false."
I don't think you understand what I'm asking.
Edit: Oh wow. I just read gp's comment below. It was the original intent of GP.
Yes, that's more or less the definition of the term.
> Playing with the definitions of words is a class political tactic!
I definitely get the feeling that there are people that like to twist words to suit their goals.
> This is gain-of-function research.
From where are you sourcing your definition of the term?
This doesn't appear to be gain of function research (from the strict definition of the term) but in this day and age when the virus is ground-zero for politics, it's probably not politically wise to do research on it along these lines. To this end, where what's politically favorable influences the science we do, I do agree that politics is inevitably corrupting good research.
It is not constrained to virulence.
You can't characterize a type of research by its results for purposes of evaluating its methods. If we want to say "GOF research should only be carried out in a lab that meets such and such criteria", or "we shouldn't fund GOF research at all", then the definition must be related to what the research may do, since we need to evaluate it before we know it's result.
You just copied a new function moreEffectiveImmuneDodge() into a viral substrate that was previously lessEffectiveImmuneDodge()
This act of composition apparently created willStillTryToKillYou().withAMoreEffectiveImmuneDodge()
Look, I get it, you've gotta run a trial.
Do it in BSL4. Not BSL3. You are mixing snippets from two known, highly transmissable, highly pathogenic set of substrates. You should not be going into utilizing either of these ingredients as a chimera under the misguidedly optimistic thought you won't make something worse. The least you could do is demonstrate an elevated level of caution of your treatment of it until your experimental results prove the end result isn't as bad or worse than the originals.
How is that so hard an assumption to work under? If we're locking GoF behind "I succesfully created a more dangerous pathogen" rather than "I'm adding a feature to a virus that wasn't there", then GoF is a useless term.
There are things that you COULD do with scientific procedure that would absolutely have some beneficial results where the potential human cost is simply too high to ethically justify (for example, see: a ton of science performed under the Third Reich). Perhaps some day we can do some of this work in a safe manner off-planet (ideally, without even needing humans on board the platforms where the virii are being manipulated). We're not there yet, and ethicists need to be willing to step in to keep things in check.
By this logic, if they didn't gave a BSL3 lab they should have still done it in a BSL2 lab, and by the same logic, utlimately in their garage.
If you don't have access to the proper facilities, don't do the research. Anything else should be a career-ending move.
The "aim" or the intention is entirely irrelevant.
>If you want to classify this study as GOF then you might as well do the same with any study of a virus where even a point mutation is made - good luck doing any virology under those conditions.
Good, let's stop mutating viruses in labs. Better to have no virology at all than to let these madmen continue to gamble with all of our lives.
"The term GOF didn’t have much to do with virology until the past decade. Then, the ferret influenza studies came along. In trying to advise the federal government on the nature of such research, the US National Science Advisory Board for Biosecurity (NSABB) borrowed the term … From that usage, it came to mean any research that improves a pathogen’s abilities to cause disease or spread from host to host."
https://www.nature.com/articles/d41586-021-02903-x
The actual regulations sensibly avoid the term, targeting "enhanced potentially pandemic pathogens".
https://www.nih.gov/news-events/research-involving-potential...
> Examples of pathogens that have the potential to cause human pandemics, or have caused a human pandemic, include the H5N1 or H7N9 influenza viruses(link is external), also referred to as bird or avian influenzas, SARS-CoV(link is external), which caused an epidemic in several countries in 2003, and SARS-CoV-2(link is external), also known as Severe Acute Respiratory Syndrome Coronavirus 2, which causes COVID-19 disease.
[0] https://www.nih.gov/about-nih/who-we-are/nih-director/statem...
Well that is very different to the first news I saw about this. Tim Pool reported that in the first test no mice died. I guess I have to be more careful about what I listen to.
Easy money printing machine: keep making new viruses, keep making new vaccines, make $$$