[germanjoey]

The actual impact of gain-of-function research papers isn't actually what is being critiqued here. That's putting the cart before the horse. What is being criticized is that the authors of such papers are pushing their research efforts into this area because they see it as their highest expected value avenue for generating the "impact" they need to secure funding, tenure, etc.

[jpeloquin]

But if the gain-of-function research really is high-impact in the sense that is valuable to society, isn't it a good thing that incentives push scientists to work in this area? It would be an example of careerism "impact" lining up with actual impact; i.e., the system working as intended.

[pdonis]

> if the gain-of-function research really is high-impact in the sense that is valuable to society

So far its net impact seems to be extremely negative (one pandemic, zero help with any treatments or preventive measures). So by your own argument, we should stop it immediately, right?

[jpeloquin]

I'm not sure whether on the balance gain of function research is a good idea or not. The point of my comment was just that discussing the impact is highly relevant, and isn't "putting the cart before the horse". But I guess I should expand on it.

Regarding whether gain of function research is a good idea: Creating synthetic variants (to see if there is gain or loss in function) is very helpful in that it allows well-controlled experiments, which is necessary to establish causation. As I said elsewhere, I don't think the risk is appreciably different whether the lab's collection of dangerous viruses is all-natural or not. That is, if we ban gain of function research we should probably stop studying the unmodified variants also. There have been near-misses with accidental releases of SARS-CoV-1 and Guanarito [0]; no gain of function required. And the 1977 release of H1N1 came from vaccine development.

Regarding describing the net impact of gain of function research as one pandemic, zero help:

I don't know what would be different if gain of function research had been banned. The underlying methods have been used since at least 1999 on, among other things, MERS and SARS-2003 [0], so they have contributed to the general knowledge base that permitted extremely rapid development of the COVID-19 vaccine. This was a significant help, not zero help. On a technical and scientific level we were very well prepared for COVID-19. Its biology was well-understood almost immediately. Our failures were on the social and organizational levels.

Was gain of function research genuinely necessary to achieve that level of preparedness? To answer that one of us would have to sift through the body of work on COVID-19 vaccine development and trialed treatments to see if the people involved used information from mutagenesis or infectious clone technology experiments (the work that is being referred to as "gain of function"). I haven't done that, so I can't give a definitive reply on that point.

There is also the matter of side effects from a ban. Creating synthetic variants within the scope of naturally occurring traits seems acceptable given the benefits. But there's no guarantee what a given edit will do in advance. If you ban all genetic engineering that could lead to gain of function then that will severely hamper research, including development of vaccines and antivirals.

So overall I guess I favor a restriction on deliberately increasing pathogenicity, virulence, and transmissibility beyond levels that occur in similar natural viruses, but allowing the possibility that this could still happen unintentionally. I also think synthetic variants should be destroyed as soon as their purpose is complete, and facilities where these viruses are studied should have a test/trace/isolate plan in continuous operation.

Edit: We also have to keep in mind that COVID-19 wasn't necessarily leaked from a lab, and even it was, it may be a naturally occurring variant. Which would make much of this speculation pointless.

[0] https://yurideigin.medium.com/lab-made-cov2-genealogy-throug...

[pdonis]

> allowing the possibility that this could still happen unintentionally

Btw, this is also a key point: if we are going to do research that could unintentionally result in the release of a deadly pathogen, we need to agree as a society in advance on what countermeasures we will put in place if that happens. Leaders of society should not be having to "wing it" about these things after the release has occurred. For example, if the only way to stop a pandemic once the release reaches a certain stage is to stop all international travel, then everyone needs to agree in advance that if there is a release, and it reaches that stage (which in the case of COVID-19 would have been roughly mid-January 2020, when it was clear that infected people were making it from China to other countries), all international travel gets stopped until the outbreak is contained, no exceptions. (Imagine if that had been done in January 2020--we might have had no pandemic at all, and a lot less economic disruption overall to boot, since China, if you believe their numbers, had their outbreak under control by February 2020.) And if that gives a lot of people second thoughts about whether such research should be allowed at all, if that kind of drastic consequence has to be planned for, good.

[pdonis]

> Creating synthetic variants (to see if there is gain or loss in function) is very helpful in that it allows well-controlled experiments

Only if, as I responded to another post of yours elsewhere in this discussion, the experiments consist of infecting humans with different strains and seeing what happens to them. And even then there are a huge number of possible confounders.

> There have been near-misses with accidental releases of SARS-CoV-1 and Guanarito [0]; no gain of function required

Indeed. The fact that this problem has been around for a while doesn't make it any less of a problem. Plus, those releases had a much smaller impact because those previous viruses were not as well adapted to human infection when they first appeared--a feature that SARS-CoV-2 does not share (see further comments below).

> I don't know what would be different if gain of function research had been banned

If the lab escape theory is correct, we would not have had this pandemic because the lab would not have done the research in the first place. Seems like a pretty major negative consequence to me.

> On a technical and scientific level we were very well prepared for COVID-19. Its biology was well-understood almost immediately. Our failures were on the social and organizational levels.

The decision to do gain of function research in the first place, particularly in a lab in China where US officials could not hope to have any useful oversight of safety procedures, was also a social and organizational failure. (So was our failure to get a vaccine widely distributed even though, as you note, we understood the biology of the virus very quickly.) Doesn't make the pandemic any less devastating.

> they have contributed to the general knowledge base that permitted extremely rapid development of the COVID-19 vaccine

I don't know what knowledge base you're talking about. DNA sequencing technology, and generating mRNA from a given DNA sequence, which is how Pfizer and Moderna were able to produce a COVID-19 vaccine in a matter of hours, were around before any of the research you refer to was done, and that research added nothing new.

If you mean knowledge about the spike protein being important, that was known before any gain of function research was done, so I don't see how that research helps. Simple research into "how does this type of virus infect a human cell" would have been enough.

> I guess I favor a restriction on deliberately increasing pathogenicity, virulence, and transmissibility beyond levels that occur in similar natural viruses, but allowing the possibility that this could still happen unintentionally. I also think synthetic variants should be destroyed as soon as their purpose is complete, and facilities where these viruses are studied should have a test/trace/isolate plan in continuous operation.

While these are nice ideas, the problem is that they would have to be implemented with the same grossly failed institutions that got us into this mess.

To me this is similar to an argument I agree with against allowing capital punishment in our society: while I agree in principle that there can be cases where capital punishment is justified, the institutions in our society have shown that they are incapable of exercising the kind of discipline required to make sure that, when a person is sentenced to death, we know to a moral certainty that they are guilty of a crime that merits that punishment. Similarly, while in principle it might be the case that we could gain benefits from dangerous research with viruses, the institutions in our society have shown that they are incapable of exercising the kind of discipline required to do that safely.

> COVID-19 wasn't necessarily leaked from a lab, and even it was, it may be a naturally occurring variant

The fact that even the earliest samples obtained, in late 2019, were already highly infective to humans, is a huge indicator to me that this virus was not only leaked from a lab, but leaked from a lab that was doing gain of function research, not a naturally occurring variant. As I noted above, previous accidentally released viruses, which were believed to be naturally occurring variants, did not have this property, and, as we can see by comparing the respective outbreaks that followed, it makes a huge difference in the impact.

[jpeloquin]

I think you may be approaching the discussion more from the standpoint of where to assign blame specifically regarding COVID-19, and I'm more interested in the benefits from infectious clone technology and infection experiments in general, which covers the last 50 years [0], not just the work in 2R01AI110964 that is currently under criticism. So I yield on all Wuhan-related points.

One thing that really confuses me though is why you say human testing is a requirement, when almost all work is done in cell & animal models. Usually human tests are restricted to treatments, and only those that have already gone through cell and animal testing to ensure as much safety as possible. I just want to emphasize this point because the thought of doing infectious clone testing on people is awful and the Common Rule is meant to prevent this kind of abuse [1].

Regarding "previous accidentally released viruses, which were believed to be naturally occurring variants, did not have this [highly infectious to humans] property." The ones that are notable enough to make it into reports kind of do. The 1977 H1N1 leak affected "20-70% of those under 20 years of age in school or military camp outbreaks in the first year" [2]. There were also several leaks of the 2002 SARS virus that could easily have gone the same way COVID-19 (SARS-CoV-2) did. China was the source of several of these leaks, so feel free to use this as evidence for a lax safety culture.

[0] https://www.virology.ws/2009/02/12/infectious-dna-clones/

[1] https://www.hhs.gov/ohrp/regulations-and-policy/regulations/...

[2] https://armscontrolcenter.org/wp-content/uploads/2016/02/Esc...

[pdonis]

> I think you may be approaching the discussion more from the standpoint of where to assign blame specifically regarding COVID-19

No, I'm approaching it from the standpoint of how to not have a pandemic like this happen again.

> I'm more interested in the benefits from infectious clone technology and infection experiments in general

What are the benefits? What benefits have we gained specifically from this research, that we wouldn't have gained without it?

> why you say human testing is a requirement, when almost all work is done in cell & animal models

Because we can't reliably predict what a virus will do to humans unless humans have been infected with it. Cell and animal models are nice, but they aren't the same as actual human patients.

> Usually human tests are restricted to treatments

Exactly. And that's for good reasons. And my point is that testing treatments isn't the same as testing the viruses themselves. The Wuhan lab wasn't testing treatments, they were testing viruses. So how treatments are tested, and how confident we feel that they are safe based on cell and animal testing, is irrelevant to work with viruses themselves.

> and only those that have already gone through cell and animal testing to ensure as much safety as possible.

And even then we find effects in humans that we didn't expect. And that's for treatments, where we have more control over the variables than we do with viruses themselves.

> The ones that are notable enough to make it into reports kind of do.

"Kind of" isn't the same thing. I'm not talking about how infective they got in the first year. I'm talking about the way SARS-CoV-2 was in the very first human patients we have records of, back in late 2019. The strains isolated from that time were already highly infective. Initial strains of previous viruses were not; they increased in infectivity as they spread in humans and evolved to adapt. That's what we expect to happen for a virus that naturally jumps to humans from some other source. But when we see a virus that is already highly infective in the first human cases we know of, that's an indication that it did not naturally jump to humans, but was specifically engineered in a lab to be more infective to humans.

> There were also several leaks of the 2002 SARS virus that could easily have gone the same way COVID-19 (SARS-CoV-2) did.

How do we know they could have?