Ralph Baric Interview

Oh my, Rand Pauls file dump ruined my vacation from Substack. So let me start with the Baric interview. I’ll have to get to the Slack messages in a separate post

https://www.paul.senate.gov/wp-content/uploads/2026/07/2026.07.23_UPDATED-FINAL-FINAL_BARIC-TI_Redacted.pdf

Of course they did not discuss this

Ralph Baric-2006 paper

Will synthetic or recombinant bioweapons be developed for BW use? If the main purpose is to kill and inspire fear in human populations, natural source pathogens likely provide a more reliable source of starting material. Stealing the BW agent from a laboratory or obtaining the pathogen from natural outbreak conditions is still easier than the synthetic reconstruction of a pathogenic virus. These conditions, however, change as 1st and 2”d generation candidate vaccines and drugs are developed against this select list of pathogens, limiting future attempts to newly emerged viruses.

If notoriety, fear and directing foreign government policies are principle objectives, then the release and subsequent discovery of a synthetically derived virus bioweapon will certainly garner tremendous media coverage, inspire fear and terrorize human populations and direct severe pressure on government officials to respond in predicted ways.

https://web.archive.org/web/20210103192435id_/https://www.jcvi.org/sites/default/files/assets/projects/synthetic-genomics-options-for-governance/Baric-Synthetic-Viral-Genomics.pdf

Or this

2019 January , Ralph Baric gave a talk in Harbin, China in a  conference talking about the complexity of deliberate design of viruses.  He also gave a talk on H5N1 on behalf of USDA

Studies to alter pathogen properties of viruses can use several approaches, including selection pressure to drive evolution as well as deliberate design. Potential opportunities might include building chimeric viruses with altered structures for the receptor binding for viral entry, or those that incorporate changes to other viral determinants  or that modulate host-pathogen interactions.

  Dr Baric noted the example of adding the spike protein from a mouse coronavirus to a bat coronavirus , which can produce a strain more virulent in mice. But he cautioned, that a combination of techniques, including selection pressure from passaging in mice <humans?>is generally needed to generate virulence in a host…..

Dr. Baric also noted that predictive modeling of protein interfaces and the use of such models for structure-guided virus design has recently improved, providing advancing capabilities for affecting host-virus interactions and altering antigenic properties. Similarly, he noted that the “shopping list” of virulence determinants continues to grow as more is learned about host-virus interfaces and how they evolve as viruses move through different species.

As examples of both potential opportunities and ongoing barriers to effective engineering of viral properties, Dr. Baric referenced studies to develop a self-replicating alphavirus containing HIV sequences for use as an HIV vaccine, an approach that was abandoned when the virus was too pathogenic in mice. He also noted the barrier provided by a glycosylation site that makes it relatively easy to create mouse-adapted SARS strains but not mouse-adapted MERS. And the use of newer tools such as CRISPR/Cas-based gene editing to create a mouse model by introducing the human virus binding receptor domain into the mouse.

On the other hand, creating a virus that is super-adapted to a particular host can actually result in an attenuation of virulence, if the virus interacts overly strongly with a cellular receptor. This shows the complexity of deliberate design as well as a potential sweet spot for pathogenicity.

Other challenges to deliberate design include the fact that a large number of virus-host protein interactions occur, and changing one can have unexpected effects across the interaction networks as virus-host interactions are usually a “highly coordinated co-evolved process.” Viral packaging constraints, the effects of host genetic variation on disease severity, and other factors all add to the complexity and confound the utility of predictive design models.

https://usrtk.org/wp-content/uploads/2022/04/US-China-dialogues-report.pdf

A COVID Timeline

·

August 20, 2024

Mostly for my own reference, I realize folks have moved on from COVID

Or this

First of all, lets be clear yet again what Sars-Cov-2 really is.

Its a low pathogenic virus that is pretty harmless to children and most healthy young adults, although it can present problems to the elderly.

Baric: Could be … you know, we almost have 1 billion elderly on the planet above 60, and coronaviruses like to replicate in old people.

https://alumni.unc.edu/news/ralph-baric-on-the-front-lines-of-coronavirus-for-three-decades/

I didn’t expect too much here. Apparently they had an afternoon Classified Section where all the good stuff was discussed, but there were a few golden nuggets

Dr. Baric testified that the DARPA PREEMPT solicitation — which called on researchers to learn what makes a virus jump between species “down to the nucleotide level” — could be answered only one way: “That’s a gain-of-function experiment. There’s no other way to think about it.”

Duh. In other words this was not a nefarious proposal cooked up by Daszak, Baric and WIV but a response to a request by DoD’s research arm. The only part they didn’t like was vaccinating bats in bat caves with vaccines, not that China would have allowed this

One of the main scientific papers arguing COVID arose naturally, “The proximal origin of SARS-CoV-2,” leaned on a simple assumption: if someone had engineered the virus, they would have built it to latch onto human cells as tightly as possible. Because the real virus doesn’t grip in that “ideal” way, the paper treated that as a sign no one designed it. But years earlier, Dr. Baric had actually run an experiment and found the assumption was wrong. When a virus grips too tightly, it gets stuck and can’t spread as well. So, a knowledgeable designer would deliberately avoid the “ideal” grip the paper assumed they’d use — meaning the very feature the Proximal Origin paper called proof of natural origin is something an engineer might choose on purpose.Dr. Baric said he reported the experiment to NIH and destroyed the materials.

Now for some excerpts

February 2020 Presentation-Origins

MS. SALAZAR: Biological Science Expert Group. And this isn’t on you, but there’s this secrecy about this group that has caused a lot of confusion and frustration probably among you, as well. But this isn’t classified, and I am fine to hold back our questions, generally, on that until later, even ones that aren’t classified, just so everyone feels comfortable. But we will be going through a classification review of that transcript, and it’s not classified, so I just want to flag that. But I think we have made it public, sir. Are you at least comfortable talking about the presentation here, the presentation that was given? It was public.

MR. ERVIN: I think it would be better to discuss it in the classified session, since there’s going to be a classified session anyway

MS. SALAZAR: Okay.

MR. ERVIN: We have 4 1/2 hours --

MS. SALAZAR: Can I just ask, that presentation, did you present three different potential origin options?

DR. BARIC: Yes.

MS. SALAZAR: And what were they?

DR. BARIC: Natural origins, laboratory escape, and genetic engineering.

MS. SALAZAR: Okay. And then was that your position - when you presented it, was it these are all of the possible options? Was it these are the likely options? This is one I think is more likely than not?

DR. BARIC: Oh --

MS. SALAZAR: At that time did you have a position?

DR. BARIC: Yes. I put it in that order. Most likely natural origin, I couldn’t rule out laboratory escape. Genetic engineering was unlikely, but it needed to be reviewed by evolutionary biologists.

DR. BARIC: There was an hour discussion, and certainly in part of that discussion is going to be discussion about whether or not it could be engineered. And the answer is, from a technical point of view, yes, it could be engineered. There are some key things that you have to have. The first and most important is a full- length molecular clone of that virus.

MS. SALAZAR: Both ends?

DR. BARIC: What?

MS. SALAZAR: Is it --

DR. BARIC: You have to have a full-length molecular clone of SARS coronavirus. If you have that and it doesn’t have a furin cleavage site, you could drop in a cleavage site, using that clone. So technically, it could be engineered, and it should be discussed.

MS. SALAZAR: Do you have any reason to believe that they don’t have that capability?

DR. BARIC: There is no evidence that they had a molecular clone of that virus. They only had one molecular clone. They weren’t very good at reverse genetics. And the molecular clone they had WIV1. And WIV1, they would take spike genes of other sarbecos and drop it into that clone because they had a difficult time making more clones. The problem with coronavirus is part of the genome sequence is really toxic in bacteria, so you have to come up with ways around that. And so best example of this is a virus emerged in southern China called SADS coronavirus, 2016 or so. It caused 100 percent or 99 percent mortality in piglets. It’s related to a virus called HKU2. They were trying to make a molecular clone for that virus for three or four years. We started around 2019, made a clone, published it before them.

MS. SALAZAR: And why were they trying to do that?

DR. BARIC: I mean, they had a virus that caused 99 percent mortality in piglets that could destroy their swine industry, so obviously it was important for them to develop the reagents that they could use to develop countermeasures and vaccinate swine. The other issue, just to go on on that, you know, it’s hard to imagine a better reservoir species for emerging virus than a swine. And the swine population, they have billions of swine in China, so you have this massive reservoir. And you have a virus that drops into those, and that virus can use, although not very well, it can use the human receptor for entry.

MS. SALAZAR: So I’ve seen SADS come up a lot when people are talking about pan-corona vaccines.

DR. BARIC: I wouldn’t include it in a pan-corona vaccine because --

MS. SALAZAR: Am I mistaking it with PEDV?

DR. BARIC: It’s a lower probability virus. Okay. So for a pan-coronavirus vaccine you have pan-coronavirus beta coronavirus vaccines and alpha coronavirus vaccines. So this is an alpha coronavirus. So the only thing that people have really worked on extensively are pan-beta coronavirus vaccines, focused heavily on SARS coronavirus and MERS coronavirus. So I don’t imagine that that would be included in any pan-beta coronavirus vaccine.

Now, for pan-alpha coronavirus vaccines, the classic human coronaviruses are 229E and LN63. SADS would be something that you might want to consider. But the fact of the matter is that those viruses, in general, in Clade 1, in alpha-coronavirus group have been much less well studied. And so the threat potential and where that exists really is a guess.

DARPA PREEMPT/FCS

DR. BARIC: Yeah. So from my perspective, let’s talk about the grant for a minute. Let’s make sure we put it in perspective. So DARPA was interested in addressing a problem about the warfighter. And I think there’s, what, about 250,000 troops and their families across the globe. Many of those soldiers go into wild areas of the world where they come in contact with pathogens. So they can then infect members of their group, they can take the virus back to the base, and they can bring it back to the United States. So this is a real threat, potential threat to the public of the United States, because of where they go. So DARPA came up with a proposal that they wanted to know, down to the nucleotide level, what regulates a virus jumping between species and then develop countermeasures for it. Now, if you want to know, down to the nucleotide level, what drives a cross-species jumping event, you are talking gain-of-function experiments.

MS. SALAZAR: So is that what DARPA was -- I mean --

DR. BARIC: Yes.

MS. SALAZAR: -- they explicitly --

DR. BARIC: The part one was they wanted to know what the threat potential was in certain wild areas of the world, so you did surveillance.

MS. SALAZAR: So are you talking about what the DARPA PREEMPT program --

DR. BARIC: Yes.

MS. SALAZAR: -- that they specifically said “we want you to do gain-of-function research.”

DR. BARIC: They said they want you to know, down to the nucleotide level what drives cross-species jumping events.

MS. SALAZAR: And that’s gain-of-function research.

DR. BARIC: That’s a gain-of-function experiment. There’s no other way to think about it. You can do loss- of-function, but it doesn’t prove that it’s jumping across there. All you say is you knock that mutation out, it loses the ability. Gain-of-function proves it, and it’s causal. So in my opinion, when I read that, that’s exactly what they’re asking for. They mention in there that this could involve gain-of-function research in their announcement. So part one of that grant was to do surveillance in China, looking in that case for viruses.

As part of the thought process, there were two questions. There were two ideas that came forward. One was why don’t sarbecoviruses have furin cleavage sites. And I’ve studied coronaviruses all my life. I know sarbecoviruses. I’ve seen zoonotic strains. They don’t have furin cleavage sites. MERS strains do. Human coronaviruses do. Feline coronaviruses do. Why don’t sarbecos? There should be sarbecos out there that have furin cleavage sites, so they were going to look for them.

Once they found them and they sequenced it they were going to work on it with pseudotypes. They were going to drop those spike genes into pseudotypes and ask what’s -- we were also going to look at the receptor binding domain, obviously, and I think we hypothesized in there that there should be strains with 25 percent variation in spike that could still use the ACE2 receptor. And those are obviously of interest because if you’re interested in developing pan- sarbecovirus vaccines or drugs you want, in essence, the bookends of the heterogeneity that exists in the virus subgenus, right. You want strains that you know and strains that are very different, because you have no idea what would emerge in the future. So if you have breadth then you have a better chance of developing something that could be used immediately. So those are two major features. The first part would be then to find sarbecoviruses. If we found the sarbecovirus with a furin cleavage site it would be dropped into a pseudovirus, and its biological characteristics evaluated by the Chinese. They would remove the furin cleavage site. They would introduce changes into the receptor binding domain and look in the context of those pseudotypes, which is the safe system, to ask questions about what the role of those mutations were in tropism and entry of viruses in receptor usage.

Following gleaning that data, we would then use a zoonotic sarbecovirus as a receptacle to drop the spike genes of some of these viruses, and if we found one with a full-on furin site we would put it in there and evaluate its biology. We would also remove that furin cleavage site and ask what the effect was on pathogenesis in replication. So it’s a loss-of-function first.

At the end of that there was speculation that if the furin cleavage site looked like it was having effect on replication of pathogenesis we would consider putting it into a gain-of-function scenario where we would drop it into a null backbone. So that’s how the experiment was written.

MS. SALAZAR: And who was going to be doing that work?

DR. BARIC: That part would be done by me.

MS. SALAZAR: Okay.

DR. BARIC: Well, at least that’s the way the grant was written initially. Whether that would have functionally happened is a fair question, because if the Chinese discovered the virus, the question always exists whether they would share it with me to do that work or not.

MS. SALAZAR: If you were on the proposal, you would have expected that they would?

DR. BARIC: I would have, but I would also be uncertain that they would do that.

MS. SALAZAR: And so you said that it would be -- this was gain-of-function. This proposal -- because this is the first time I’m hearing that -- because, I mean, PREEMPT, there were grants that were funded. So DEFUSE wasn’t. But this is the first time I’m hearing that the actual call, the BAA was asking for --

DR. BARIC: It was asking to understand cross-species movement of viruses down to the nucleotide level. And my interpretation of that was gain-of-function, and they discuss gain-of-function. Now, I found it very interesting that the letter that they provided shortly thereafter said that the experiments were DURC. DURC is Dual-Use Research of Concern. involving 15 pathogens, none of which is a coronavirus. So I never saw that letter in the review.

Now, Peter Daszak may have gotten that letter, but we were told the main reason the grant was rejected was that we proposed to do intervention studies in the bat caves, and they had said they wanted to do this in a more controlled setting.

MS. SALAZAR: In the laboratory?

DR. BARIC: In a laboratory setting.

MS. SALAZAR: So when you say in a bat cave, what does that mean?

DR. BARIC: It means one approach was to take double- stranded RNA and spray it in the bat cave and then induce innate immune responses in bats, so that those innate immune responses would control virus infection and virus titers would go down. So the idea would be the soldiers, before they went into a cave, they may spray the cave to lower the titer of the virus in the cave so it’s less likely that they’d be infected. DARPA has kind of wild experiments.

MS. SALAZAR: But where was that portion? So I think

DR. BARIC: Well, that would’ve had to have been done in China because it was based on the strains that would be found in the cave complex that they were doing their discovery work.

MS. SALAZAR: I recall that there was some Michigan --

DR. BARIC: Yeah. There was a Michigan group that had these kind of sprayers --

MS. SALAZAR: But that was part --

DR. BARIC: Yeah, that was part of it, but the Michigan group also had a vaccine vector where we would put in viral antigens to try to immunize the bats.

MS. SALAZAR: And I think that there was, in the actual proposal, there was discussion about going to caves in Michigan. So to me that sounds like we might have been doing this in the United States as opposed to China.

DR. BARIC: If they were doing it in Michigan, what they were doing were pilot experiments to see if the approach, especially the double-stranded RNA approach, reduced virus titers for North American strains. And there’s no sarbecoviruses in North America at this time.

MS. SALAZAR: So what they would be spraying in the caves would not be the gain-of-function?

DR. BARIC: No.

MS. SALAZAR: Okay. Why is that?

DR. BARIC: So gain-of-function, you’re talking about a live virus.

MS. SALAZAR: What would they be spraying?

DR. BARIC: They’re spraying a small, double-stranded RNA molecule that induces host innate immune responses.

That’s host defense molecules that prevent virus infection, or limit virus replication.

MS. SALAZAR: Why are they trying to do these two different tasks? So they’re doing something to gain function and they’re doing something to spread --

DR. BARIC: No. So you’re confounding experiments. The first aim, again, is to sort of walk through this process of what makes a threat virus, how do you identify it, and how do you then try to counter that threat approach.

MS. SALAZAR: With, so --

DR. BARIC: So there were two approaches that were discussed, that were presented in that grant. One was the use of small molecule, double-stranded RNA to induce, let’s call it innate immunity. These involve proteins that are induced in every one of our cells that regulate the replication and pathogen assists of viruses, and bacteria for that matter. So most people in the scientific community feel that what determines whether you live or die following a virus infection is the efficiency of inducing these innate immune molecules that regulate virus replication efficiency. And there’s about 1,000 different genes that host cells make that target key steps in virus replication to knock it down. And it all starts with interferon signaling. Okay, that’s the basis for it.

MS. SALAZAR: But this is all under one proposal. You’re saying that these were separate technical aims.

DR. BARIC: That’s correct.

MS. SALAZAR: So when you have a separate technical aim you just have two completely separate experiments that are never going to meet, that have zero connectivity? That, to me, I don’t know, but that doesn’t make logical sense to me that you would have -- why wouldn’t you have separate --

DR. BARIC: I think you’re making an incorrect intuitive leap. I was trying to describe the two approaches that were being used to control viruses in a cave setting. The other approach was that having identified strains of viruses that had spike genes that could infect human cells and potentially cause human disease, those spike genes would be isolated and placed in virus vaccine vectors that would then be delivered to the bats in the cave, is the second approach. The first approach is immediate innate immune knockdown so that the virus burden in the cave goes down and it’s less likely that a soldier will be infected. The second approach is to immunize the bats in that cave so that a virus burden would be very, very low, and it would be long-term protection so the cave could be used for a much longer period of time. So they are linked but they’re different approaches to abrogate virus replication.

MS. SALAZAR: Okay. Would this have been subject to the gain-of-function pause in 2017?

DR. BARIC: So the short answer is no, up to a point, okay.

MS. SALAZAR: What’s the point?

DR. BARIC: I’m going to get to that. So if you go back to the NSABB P3CO regulations, the regulations state that viruses, like flu, SARS, and MERS coronavirus, are highly pathogenic viruses, and highly transmissible viruses are covered by this program. And if you do anything on these particular viruses that are highly pathogenic or highly transmissible, and you do any manipulation to increase that, then that’s considered gain-of-function and regulated by those documents, based on my read of them.

There are exemptions to that gain-of-function regulation framework. The first is that if you work with zoonotic viruses, like WIV1, which has never been show to infect a human being, that has never shown to be transmissible in humans, it is not subject to the gain-of- function regulatory framework. It has to be reviewed, but the review process would require that it be -- the review process would, based on the regulations, say it’s not subject to those gain --

MS. SALAZAR: But how do you know what you don’t know?

DR. BARIC: Secondly, if you’re doing work that’s related to the development of vaccines or serology, it’s also except from the gain-of-function policy.

MS. SALAZAR: Or national security. That was also an exemption.

DR. BARIC: I don’t know what you mean by that.

MS. SALAZAR: Yeah. I’m just saying it was. I wasn’t

DR. BARIC: So anyway, all the work with pseudotypes was not subject to gain, right. These are single-hit vectors that can’t cause disease. As soon as we made full molecular clones, or chimeras, they were done in a WIV backbone, which meant that they’re putting a zoonotic spike into a zoonotic strain, to eventually identify vaccine formulations that would be used in the cave, that’s not subject to gain-of-function.

Now, if I remember correctly there is one sentence in there somewhere that says that we will consider potentially moving spike gene, or furin cleavage site into SARS coronavirus. That is definitely gain-of-function and would have to be reviewed before anything else was done. But that occurred boom, boom, boom, boom. You know, we’re talking about eight steps down the line, where you gain a significant amount of data about the role of each spike, its ability to use different receptors, and the role of the furin cleavage site in the ability of that virus to replicate and cause disease, before you do anything about moving it into another strain.

So there was a huge amount of data that would be available to say this could be safe or we shouldn’t do this.

Snip

DR. BARIC: So the idea that just the virus receptor interaction and entry is the whole key to driving a virus to become a pandemic is just nonsense, and it’s always been nonsense. In the case of coronaviruses, there are 49 genes in each of our bodies that regulate disease severity, and the person who gets really sick has a very common loci on chromosome three, with five genes on it, that we inherited from Neanderthals, according to the reports, based on people that do the sequence comparisons. And if you have that loci you’re going to get really sick with sarbecoviruses.

A good example of this is there are strains that use the ACE2 receptor of SARS coronavirus, and you put them in K18 mice that over-express that ACE2 molecule, you can find genome equivalents but no live virus. In other words, the virus gets in, it makes a bunch of those progeny RNA molecules, but it doesn’t make any progeny viruses so it can’t spread.

MS. SALAZAR: But so --

DR. BARIC: And it’s nothing to do with entry. You can have scenarios where the virus grows to the exact same titer, and one person dies and the next person doesn’t even know they’re sick.

MS. SALAZAR: But so the actual moving, the cleavage site --

DR. BARIC: Yes.

MS. SALAZAR: -- into WIV1 --

DR. BARIC: Yes.

MS. SALAZAR: -- is that gain-of-function?

DR. BARIC: Um --

MS. SALAZAR: Because do you know what is --

DR. BARIC: It would depend on the outcomes of all the earlier experiments, right. So remember, one of those experiments was to take the virus that had the furin cleavage site in it, resurrect that virus, put it in animals, see what the effect was. Remove the furin cleavage site, see what the effect was. If the furin cleavage site is driving a massive disease phenotype, then that results in a judgment question about whether you would do the next experiment. And it also would then demand the importance of having it reviewed before you proceeded.

MS. SALAZAR: Okay.

DR. BARIC: Before you proceed.

MS. SALAZAR: So are you saying that we can never say whether a grant proposal was proposing to do gain-of- function until we get all the way up to the point where you actually almost do it?

DR. BARIC: No. I’m saying in the context of a grant proposal where the agency asks you specifically to learn, down to the nucleotide level, what causes the phenotype, yes, you do all those experiments.

MS. SALAZAR: Okay. So are you saying that all of the other entities that were awarded grants --

DR. BARIC: I have no idea what they were awarded. All that I know is that we were not awarded.

MS. SALAZAR: Okay. I mean, you were not awarded, but there was discussion post the denial about doing a smaller proposal, separating it out.

DR. BARIC: I mean, that’s pretty routine. But I don’t believe that, at least from the U.S. side, I don’t believe there was any grant written, that I’m on, where we proposed to do experiments of furin cleavage sites. Yet, the reason why I became less interested in it was we discovered that if you add trypsin exogenously to the cultures, viruses that you couldn’t culture could now be cultured. And that’s because cleavage of S1/S2 boundary, cleavage of the spike, is essential for the virus to get into the cell. And if it can’t be cleaved, the virus replicates exceptionally poorly, if at all. But if you add trypsin, which is a protease, into the media, you could take viruses that you couldn’t culture and now you could culture them.

[Me :Ralph seems to be trying to change the subject here. Why would trypsin and the ease of culturing novel viruses impact his interest in knowing if FCS would affect virus pathogenicity. But its interesting to note he published his Trypsin paper in 2019 and voila, Sars-Cov-2 and a bunch of other similar viruses get isolated over the next 2 years]

So to some extent I was more interested in being able to have a range of coronaviruses. So, for example, remdisivir was tested in about 12 or 13 coronaviruses, including many different sarbecos, from Clade 1 and Clade

So we had a really good idea that it would work against an unknown, and it turned out to be effective against SARS- coronavirus-2 when used appropriately.

[Me: the more viruses you have the more pieces you have to create a consensus virus. This is one thing missing in the interview, perhaps reserved for the afternoon discussion, the most interesting part of Defuse was this

“We will compile sequence/RNAseq data from a panel of closely related strains and compare full length genomes, scanning for unique SNPs representing sequencing errors…..Consensus candidate genomes will be synthesised commercially using established techniques and genome-length RNA and electroporation to recover recombinant viruses]”

Snip

DR. BARIC: Kristian Andersen, in the Proximity [sic] Origins paper, made a pretty articulate argument why he thought it was not engineered. And it’s based on, one, you have to have a molecular clone that would be identical or nearly identical to SARS2, which did not exist. It certainly did not exist in my lab. The second thing you needed to do is to explain its weird insertion into the spike of the S1/S2 boundary. And it’s an out-of-frame insertion that puts in four residues, when in reality there’s only three residues that need to be introduced into it if you wanted to make a furin cleavage site there. And so why are there four residues there? Why is it out of frame? That doesn’t make sense. So why is there a proline residue? Prolines cause kinks in proteins, so that can be very disruptive.

MS. SALAZAR: So you thought that the Proximal Origins argument was well articulated?

DR. BARIC: In terms of the furin cleavage site, yes. And they argued that the most likely event was a recombination event, I think with a virus called HKU9, that had identical region.

Snip

DR. BARIC: No. We’ve never dropped a furin cleavage site into a coronavirus like that.

MR. HENDERSON: Were you aware of any of the other applicants having done the work prior to?

DR. BARIC: Yeah, I think maybe we should take a second and review the furin cleavage site, because you seem to think it is the critical event that drove SARS-2 to be pathogenic. So in the coronavirus literature, furin cleavage sites have a mixed history. So in feline enteric coronavirus, if that virus has a furin cleavage site it’s asymptomatic. It’s an enteric disease. It’s when you lose the furin cleavage site that it becomes a fulminant, deadly disease that is 100 percent fatal in cats. So loss-of- function of that furin cleavage site kills you dead, the cat.

In mouse hepatitis virus, a couple of researchers had removed the furin cleavage site and said what happens to the pathogenesis? There was no change. Another group, taking pseudoviruses, had introduced furin sites into the SARS-coronavirus 2003 strain, and the only thing they found was slightly increased infectivity. Nothing big. Nothing that said “eureka.”

So now let’s compare SARS from 2003 and SARS-2, and let’s ask the question, what experiments were done to prove

that the furin cleavage site drove severe disease in SAR-2 pathogenesis. What they did was a loss-of-function experiment. They deleted those four residues that were introduced by whatever means, and they asked what happened to the virus. It was less pathogenic, and it was less transmissible. Eureka. Furin cleavage site causes that phenotype. Except when you look at the other figures in-the paper, where it shows that it also knocked down the ability of other proteases to cleave at that S1/S2 boundary. So it wasn’t a furin cleavage site-specific knockout.

It was a global protease knockout. And that’s what a loss-of-function experiment does. The only way to really prove it is to take a virus that doesn’t have a furin cleavage site and stick it in. That’s gain-of-function. It’s causality. You know for a fact.

I can make the argument in this room, and I can argue it in front of scientists, that the introduction of the furin cleavage site in SARS-2 attenuated its pathogenesis and increased its transmissibility, and that was to its benefit. And that’s not what you hear.

[Me:I’d like to know how he can be so sure😉]

I’ve looked at a bunch of these different protease studies that people did, where they knocked out the sequence. They were making global proteolytic cleavage knockouts on the spike. And if you don’t cleave S1/S2 efficiently, you knock down replication and pathogenesis.

I also say that SARS-coronavirus-2 had the same R rate 0 that SARS coronavirus 2003 had, early in the pandemic. They both transmitted efficiently. The difference was one transmitted very late only, after severe disease occurred -- that was 2003 -- and in 2019, that strain transmitted before you got disease. And that’s why it’s a pandemic and the other one was not.

Sorry, I know that went long. You’re probably mad at me.

Prophecy

MS. SALAZAR: And was that in -- that was early 2013? Is that the Prophecy program?

DR. BARIC: Prophecy program?

MS. SALAZAR: Prophecy program, or the P3 program?

DR. BARIC: Can I see that?

MS. SALAZAR: No, you can’t, because it’s my notes. The Prophecy program was exploring the evolution of viruses in the hope of predicting viral mutations and ultimately developing drugs and vaccines in advance of need. So that was around 2013.

DR. BARIC: Was that a -- I think that was a different grant that didn’t get funded, if I remember correctly.

MS. SALAZAR: And it looks like we have an email that shows that --

DR. BARIC: Who’s on it?

MS. SALAZAR: It’s to you. It’s someone from DARPA. DARPA researcher John Julius emailed you and Amy Sims on March 14, 2013, and wanted to speak to you for that program, about your experience in modeling host pathogen interactions and the ability to predict genetic variations within a viral population, particularly with coronavirus model systems.

DR. BARIC: Yeah, okay, I remember that. No, it’s a different thing.

MS. SALAZAR: So you didn’t end up --

DR. BARIC: That was never funded. Yeah, we discussed it with them, and I actually think a proposal was written, and they were thinking about funding it, and then the program officer left, and the next program officer said they weren’t interested in it, and that was the end of it.

Note: Prophecy was started up by Michael Callahan in 2009, the same year USAID PREDICT program began. At the same time Callahan was working on a related DARPA program named ADEPT which was created in 2010. The ADEPT program at DARPA supported work on mRNA vaccines and gave Moderna 25 million to start.

Dr Michael Callahan, was in China in January 2020 as reports of a new virus broke. Dr Robert Malone, says Callahan rang him from China on January 4, 2020. It is unclear when he first arrived or the details of the call. Some reports said he told Malone he had been treating hundreds of patients.

ATI/RML

MS. SALAZAR: ATI, the company Autonomous Therapeutics International? Someone say yes or tell me if that’s the correct name. Have you ever done any work with them?

DR. BARIC: I don’t know. You’re going to have to give me more context. I can’t remember it off the top of my head.

MS. SALAZAR: Did you have a UBMTA with NIH-RML? What’s the date on this? It’s from 2023, on pangolin beta coronaviruses, where it looks like you would be providing original material to Vincent Munster from RML. Pangolin coronavirus was the original material, and the transmittal fee to reimburse the provider for preparation and distribution costs amount is zero. Is that something that was executed?

DR. BARIC: I recall sending them WIV1 and SHSC014 for studies in bats. It’s possible that we sent them the pangolin coronavirus. I’d have to check the MTA agreements.

MS. SALAZAR: I guess, is that something that’s published, the pangolin beta coronavirus? What is that?

DR. BARIC: I had mentioned it previously. It’s called pangolin coronavirus GD strain, and it was published in Nature Microbiology.

MS. SALAZAR: And do you know what RML was doing with that?

DR. BARIC: RML, again, I’d have to look at the MTA agreement that would tell me what was in it. We would have to pull it from the MTA. I can tell you that during the pandemic we did hundreds of MTA agreements with research institutions in the United States. If you ask me if I can remember this one directly, I can’t, because if I had a person in my lab who I would say, “Take care of this MTA agreement,” and they would do it.

MS. SALAZAR: Is it typical that the transmittal fee would be zero? I just don’t know.

DR. BARIC: It depends on how much money I would have.

MS. SALAZAR: Okay. Like what does that range sometimes look like?

DR. BARIC: Whatever the shipping cost are.

MS. SALAZAR: Okay. I want to go back to the DARPA question on PREEMPT. I’ll show you this email, and I don’t have another copy of it right now. But it is dated March 7, 2019. It’s from Vineet Menarchery, and you have a couple of other folks on here from Autonomous Therapeutics.

MS. SALAZAR: It says, “Ralph, I’v been working on a DARPA proposal with Autonomous Therapeutics on MERS-CoV with a quick turnaround. They’re funded for another DARPA project to generate therapeutic interfering particles, and are looking to apply their approach for MERS on this specific supplement call. We have been chatting for a few weeks, and they are interested in both in vitro and in vivo experiments with their MERS-CoV targeted TIPs. I am currently planning to work with them on the in vitro side, but suggest they talk directly to you about the DPPR 288/330 model.”

DR. BARIC: Okay.

MS. SALAZAR: Do you recognize this?

DR. BARIC: Within the contest of Vineet, yes.

MS. SALAZAR: Did you end up doing work with --

DR. BARIC: I don’t know. I don’t believe that I ever had -- I mean, this is an easy thing for us to test, to see if we had money from them. But I’m 99 percent sure that we never received any money from this group. The other possibility would be that Vineet asked me to send him the mouse model. The 288/330 is the mouse model that I talked about for MERS earlier. And so if he had that agreement with them and he wanted it, he’s a former postdoc, would’ve sent it to him in a second.

MS. SALAZAR: Because I believe this is a PREEMPT-funded.

DR. BARIC: It might be, but I’m not funded on it.

MS. SALAZAR: Okay.

SNIP

MR. LAMBETH: Just one thing before we go off the record. We did check UNC’s records and there is no record of Autonomous Therapeutics funding the Baric Lab.

Note: Autonomous Therapeutics, Inc was a one of Preempt award winners, under principal investigator Dr. Ariel Weinberger, leads a team made up of CSIRO Australian Animal Health Laboratory; Navy Medical Research Unit-2, funded directly by DARPA; University of California, Los Angeles; University of Chicago Medical School; and University of Texas Medical Branch. The team will study air-borne highly pathogenic avian influenza virus in birds and small mammals, and tick-borne Crimean-Congo hemorrhagic fever virus

Navy Medical Research Unit-2 was the same outfit involved (with Pasteur Institute) in the sampling expedition in 2017 in Laos at the exact site where the BANAL viruses were found

According to Dr Weinberger, around June 2019, Autonomous Therapeutics began a project to find a generic treatment for coronaviruses

A project which presumably requires a generic coronavirus to evaluate against, surely?

“Autonomous is developing what may be the 1st pan-genus antivirals to provide resistance-proof protection against any coronavirus (including future viral mutants that may evade vaccines)

The company is backed by DARPA & BARDA”

Yes, 6 months before the pandemic..

“We then started doing the same thing for coronaviruses (well before the COVID-19 pandemic)”

The Method

“We developed a single biologic with prophylactic efficacy against any Influenza A strain...Armed with the influenza data, we started working on coronaviruses six months before COVID-19 hit...

Random Beta-Coronaviruses?

“The question was whether we could develop a single antiviral for both MERS and SARS, and by extension, for whatever random beta-coronavirus would emerge next.”

So to prove your concept you have to show it works on MERS and SARS and then show it works on a random beta-coronavirus

Did someone say “How Banal”?

You can’t do that using pseudotyped viruses, even in cell culture experiments, you need a live full-length virus, a live full-length random beta-coronavirus.

https://threadreaderapp.com/thread/1603376375309946881.html

Unpublished Works

DR. BARIC: If you’re asking the broader question, do I have unpublished sequences for sarbecoviruses -- unpublished. Unpublished means that --

MS. SALAZAR: Not publicly available.

DR. BARIC: Yeah, right. So the answer is no. I have sequences for sarbecoviruses that we’ve recovered that we have not published yet, but we got those sequences from the published literature.

DR. BARIC: I have chosen not to publish some work.

MS. SALAZAR: Have you chosen to not at the urging of another?

DR. BARIC: No.

MS. SALAZAR: Okay. So I guess what is the work that you’ve chosen not to, and can you tell me why?

DR. BARIC: I’d prefer to talk about that this afternoon.

MS. SALAZAR: Is it classified?

DR. BARIC: No.

MS. SALAZAR: Can you tell me why? I mean, there’s no difference. If it’s not classified -- I don’t want you to have a false sense of security that if we talk about that, it’s not classified, it’s not. You know what I mean? It’s the same as saying it in here.

MR. LAMBETH: I know it’s fine for you to talk about it.

DR. BARIC: Do you know what I’m going to talk about?

MR. LAMBETH: Maybe we should confer, but I think I do.

DR. BARIC: Maybe we should confer. The reason -- I don’t know how to say this.

MS. SALAZAR: Would you like to confer?

MR. LAMBETH: Yeah.

DR. BARIC: Let’s confer, yeah.

MR. LAMBETH: Sorry. Before Dr. Baric begins his answer I just wanted to say that one of the examples he will give he believes could implicate national security. It’s not classified, but we will ask that it be redacted, and are happy to confer about that later.

DR. BARIC: Okay. So I’ll give the straightforward ones first. When we published the 2015 paper, we did not include the full-length sequence of the chimera. And the reason we did not do that is that I initiated a conversation with NIH program and their research journal to request that that sequence not be provided so that no other person would have an exact template for how to build chimeric viruses. I never shared with the Chinese how we did it. I never provided them with the sequence. I never trained anyone from their job in coronavirus reverse genetics. So that’s one example of where we specifically did not provide a sequence until after the pandemic started, when several researchers wrote Nature Medicine and said, “We want to look at the sequence to determine whether it’s the cause of the pandemic.”

MS. SALAZAR: And what was the sequence?

DR. BARIC: The sequence of the SHC014 chimera. So we provided that, and we also put the WIV1 sequence up in PubMed and they analyzed that sequence and agreed that it was not the cause of the pandemic.

MS. SALAZAR: And that was your decision, solely. No one encourage you or suggested?

DR. BARIC: Nobody encouraged me or suggested it. In this case I approached the journal because, again, going back to the transmissible flu studies, it was not just the creation of the transmissible flu virus that was considered sensitive information. It was the details of the technology which also was dual-use. So it’s not necessarily just the creation of the entity or the pathogen that’s gain-or-function or dual-use. The methodology can be sensitive, and I felt that it was best that we did not provide that information. So that’s one example.

MS. SALAZAR: Okay.

DR. BARIC: The second example, which is the reason why I’m reluctant to talk about it here, because I do not want to be responsible as the one who releases it to the public. If you all choose to do that then you can accept the responsibility of that. Sometimes in science you come across findings that are potentially concerning. And so in this case, Fang Li had been doing studies using biochemical approaches to identify the most optimal receptor binding domain possible to grab either the human ACE2 receptor or the mouse ACE2 receptor. The thought in the field from him, as a biochemist, was that would be the most optimal and most dangerous form of virus. I disagreed with him, because in reality, biochemical interactions are, in essence, a bell-shaped curve. If they can’t interact very well, the virus can’t get in. If they react too well, that interaction can’t come apart. So the virus can’t get in, and the virus, as it tries to release, gets caught up in what’s called a dominant negative effect, and it will prevent virus replication. And the reason I knew this is I had over expressed receptors before, with mouse hepatitis virus. And because there was so much receptor there, the virus, as it got in, it replicated fine, but when it came out all the spikes were stripped off of the particle. So if the interaction is too great it kills the virus.

Anyone who might want to do nefarious work in science, wanted to create something, is going to think that the most efficient interaction is where you want to go. So I tested that hypothesis and showed that I was right, that the super-binding things were just as deleterious as the really poor-binding ones. I subsequently told NIH and destroyed those viruses. I have never told anyone, and I would I recommend that this committee not release that, because then you will be responsible for telling terrorists what to do.

National Bioforensic Analysis Center, NBFAC?

MS. SALAZAR: Okay. Have you ever done any work with the National Bioforensic Analysis Center, NBFAC?

DR. BARIC: I’ve been there.

MS. SALAZAR: When were you there?

DR. BARIC: Soon after they started that facility I was there. I can’t remember exactly why I was there. I remember having a tour.

MS. SALAZAR: Have you ever done any work --

DR. BARIC: Uh --

MS. SALAZAR: So you did --

DR. BARIC: Yeah, if you have an email that suggested I did, I’d appreciate it, because I don’t want to be put in the scenario where you’re asking me to recall an event from 13 years back, and then I state it incorrectly.

MS. SALAZAR: Did you consult on a report that NBFAC, or NBACC, as they call it, National Biodefense Analysis and Countermeasures Center of DHS did on a final report for severe acute respiratory syndrome, coronavirus-2 genomic analysis on June 11, 2020?

DR. BARIC: I think this is an afternoon discussion.

MS. SALAZAR: It’s not classified.

DR. BARIC: But it may have been associated with --

MS. SALAZAR: I can tell you it’s definitely not classified.

DR. BARIC: Yeah, but my answer might be.

MS. SALAZAR: Okay. Fair enough.

DR. BARIC: I’m uncertain.

MS. SALAZAR: I don’t want you to say anything --

DR. BARIC: Here’s the problem, is I’m uncertain, an if I answer it and I’m wrong, then I have violated something.

MS. SALAZAR: For just me, I just want everyone to have on the record that the document that I am looking at is unclassified. But I don’t want you to tell us anything that you’re not sure about, so we’ll save it.

MR. HENDERSON: Well, the email, as you said, is unclassified, but whatever you ask about whatever the answer --

MS. SALAZAR: I know. But I’m saying I have document that --

MR. HENDERSON: Yes, that’s unclassified.

DR. BARIC: Will you let me look at the details of that?

MS. SALAZAR: I mean, if you’re not going to be able to answer it right now I don’t want to waste our time.

DR. BARIC: I’m talking about this afternoon. Yeah, please.

Note: In 2018 the Federal Bureau of Investigation (FBI) assumed management of the. National Bioforensics Analysis Center (NBFAC). It was previously run by the DHS.  NBFAC conducts technical analyses in support of federal law enforcement investigations and attempts to coordinate multi-agency biological forensic efforts.

 DHS and the FBI signed a memorandum of agreement that transferred NBFAC management to the FBI.

Interesting timing.

RaTG13-WIV CAPABILITIES

MS. SALAZAR: Did you have a copy of RaTG, the genome before 2020?

DR. BARIC: No. Yeah, so that was first published in 2013 as a sequence fragment, that I didn’t notice. And then they came out with a sequence, I think, in, what 2017, 2018, somewhere around there. It did not catch my notice. I mean, oftentimes, every once in a while we do searches on sequences, to see if there’s anything interesting out there that we might want to work on. But it didn’t catch our attention. So it didn’t come to my attention fully until they published their paper in January of 2020. And so I agree with people like Elaine Chen and others that have looked at the sequence information around that virus and say that I don’t know. Like she has reported, we could not recreate the full-length sequence that they provided, based on the sequence information that they provided. There were gaps, in other words. It was not complete. Some of it was very good, where they had good coverage, so they had a lot of coverage of that particular chromosome and then they cloned out a specific plasma DNA of that region and sequenced it. So there are regions that are really good and the spike is really good. Polymerase has gaps in it. We can’t close those gaps based on their sequence, using all kinds of different program to try to do it. Now, they may have an in-house program that they used, but personally I think they used a reference sequence and they guessed, to fill the gaps.

That’s my gut feeling.

DR. BARIC: Just to let you know, we have ordered a molecular clone for RaTG13. That genome is heavily debilitated. We eventually isolated it. We have not finished submitting the paper.

MS. SALAZAR: Okay. And when did you isolate it?

DR. BARIC: Maybe two and a half years ago.

MS. SALAZAR: Okay. Do you think that Dr. Shi and WIV had the technical capability of doing the work proposed in

DEFUSE on their own?

DR. BARIC: With WIV1, absolutely.

MS. SALAZAR: Okay.

DR. BARIC: I mean, they had the molecular clone.

DR. BARIC: They may not have published them. But the important thing for the U.S. government to realize is they are as good as us in recombinant DNA technology. It is no longer the U.S. is massively in the lead. So their deep sequencing capability is second to none. Their capacity to sequence at least some of those viruses from those patients should have been done.

Now, they claimed that it’s a fungal infection. Fungal infections can occur after acute infection. The virus has cleared and then you get a fungal infection. Okay. So they didn’t lie. They just didn’t tell the whole truth.

MS. SALAZAR: Probably.

DR. BARIC: So they may have sequences of those viruses, and then you might say, eureka, those are the SARS-2 strains, but they didn’t transmit. They were super virulent, and they did not transmit.

End