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Is there a reasonable reading according to which Baric, Shi et al 2015 isn't gain-of-function research?

by ChristianKl1 min read21st Jul 20215 comments

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From the A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence by Baric, Shi et al:

Wild-type SARS-CoV (Urbani), mouse-adapted SARS-CoV (MA15) and chimeric SARS-like CoVs were cultured on Vero E6 cells (obtained from United States Army Medical Research Institute of Infectious Diseases), grown in Dulbecco's modified Eagle's medium (DMEM) (Gibco, CA) and 5% fetal clone serum (FCS) (Hyclone, South Logan, UT) along with antibiotic/antimycotic (Gibco, Carlsbad, CA). DBT cells (Baric laboratory, source unknown) expressing ACE2 orthologs have been previously described for both human and civet; bat Ace2 sequence was based on that from Rhinolophus leschenaulti, and DBT cells expressing bat Ace2 were established as described previously8. Pseudotyping experiments were similar to those using an HIV-based pseudovirus, prepared as previously described10, and examined on HeLa cells (Wuhan Institute of Virology) that expressed ACE2 orthologs. 

To me building chimeric viruses and then infact human cells (HeLa cells are human cells) looks like dangerous gain-of-function research. Fauci seems to argue that someone the NIH is able to define this work as not being gain-of-function research. To me this redefinition seems to be the bureaucratic way they circumvent the gain-of-function moratorium. Before the moratorium was imposed Fauci was arguing against it and the moratorium wasn't imposed by anyone in the NIH or the HHS but the Office of Science and Technology Policy. To me that looks like a way to evade safety regulation by the NIH by dedefining terms because the NIH didn't like the moratorium.

This question is about more then just assigning guilt for things that happened in 2015. If we want to prevent further risk, getting the NIH to accept that growing chimeric viruses that infect human cells is what the gain-of-function regulation is supposed to prevent seems to me to be very important. 

It's likely also a good case study for evading safety regulation and we should think about it in other context as well. If we end up with AI safety regulation, how do we prevent the people causing problems from just redefining the terms so that it doesn't apply to them?

If anyone has a defense of not classifying this work as gain-of-function research I'm also happy to hear that.

 

 


 

 

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Disclaimer: I know essentially nothing about US legislation, scientific ethical frameworks, etc. as I am not American. I just read the paper and have some background in genetics. 

tl;dr: No, this is classic gain-of-function research as far as I can tell

From the paper, I can see two vaguely plausible arguments for why this isn't gain-of-function research:

  1.  SARS-CoV is already (obviously) already capable of infecting human cells. Using SARS-CoV as a vector to test other spike proteins' ability to infect humans doesn't increase the number of hosts
  2. Prior to the chimeric testing referred to, it seem like the authors did not expect the altered spike protein used (SHC014) was likely to successfully infect human cells; host-range regions were different from SARS-CoV, and it was unable to enter human cells when in a pseudovirus (which, as I understand it, are not fully replication-competent, making an outbreak unlikely)

However, neither of these arguments really holds water in my opinion. The first seems the strongest-- my main concern is that introducing a different spike protein could plausibly increase transmissibility or pathogenicity, but I don't know enough about that topic specifically to confidently evaluate that claim. If anybody does know I'd be interested to hear (for instance, do any SARS-CoV-2 variants have spike mutations?).

As to the second point; if you didn't think it was plausible that SHC014-MA15 (the chimeric virus) would be capable of infecting human cells... why did you do the test in the first place?

Some relevant things in the paper:

  • Previous expectations had been (at least, according to the paper; I haven't checked that they aren't lying) that viruses like the one they made should not be able to infect humans. They found evidence that it might be possible after all, so maybe it ended up being research that produced gain of function, but I think "gain of function research" is usually taken to mean research intended or at least expected to produce gain of function.
  • Their modified virus (SHC014-MA15), if I'm understanding right, was a sort of combination of an existing SARS virus adapted to be more suitable for infecting mice rather than humans (SARS-MA15) and an existing bat coronavirus (SHC014-CoV). The modified virus was less harmful to mice than the pre-existing SARS-MA15, not more.
  • They explicitly discuss GoF concerns and say (I paraphrase) "what we did isn't technically GoF research, but in view of what we found it seems like we should consider not doing this stuff in future".

It's certainly "GoF-adjacent" research at least, but I don't think it's unreasonable to say that (1) it's not exactly GoF research and (2) it doesn't fall into the categories forbidden by US policy from 2014 to 2017. (The moratorium was on research "that may be reasonably anticipated to confer attributes to influenza, MERS, or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route". This research did modify a SARS virus, namely SARS-MA15, but in a way that wasn't expected to make it more harmful or more transmissible in mammals via the respiratory route; it in fact seems to have made the virus less harmful to the animals it's best suited to, namely mice, but it turned out that it did make it more able to infect humans. I guess a lot turns on what counts as "reasonably anticipated".)

[I am neither a biologist nor a lawyer.]

3 comments, sorted by Highlighting new comments since Today at 2:14 PM

Do we know on what basis the NIH classified this as not GoF research? It might be worth separating out "the NIH uses unexpected/weird/just-plain-wrong criteria" from "the NIH's criteria are not being applied correctly in this case".

I don't know on what basis the NIH made that classification or when it made it. If someone knows I would be interested in reading the underlying NIH analysis.

While I could have linked to the more political claims I decided against it, to keep the politics in the question to the minimum.

I agree that trying to keep politics out of it as far as possible was a wise move.