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[Baric is referring to a 2015 collaboration with Zhengli Shi of the Wuhan Institute of Virology, or WIV, in China, which created a so-called chimera by combining the “spike” gene from a new bat virus with the backbone of a second virus. The spike gene determines how well a virus attaches to human cells. A detailed discussion of the research to test novel spike genes appears here.]
However, the sequence was repeatedly requested after the covid-19 pandemic broke out and was therefore discussed with the NIH and the magazine and given to the community. Those who studied these sequences indicated that SARS-CoV-2 was very different.
How did this chimerical work on coronavirus begin?
Around 2012 or 2013, I heard Dr. Shi at a meeting. [Shi’s team had recently discovered two new coronaviruses in a bat cave, which they named SHC014 and WIV1.] We talked after the meeting. After posting I asked if SHC014 or WIV1 would be available to make the sequences available.
And it was nice enough to post these awesome sequences almost immediately, in fact, before he published. That was the main contribution he made on paper. When a colleague gives you sequences in advance, it is appropriate to co-author on paper.
That was the basis of that collaboration. We never gave a sequence of chimeric viruses, clones, or viruses to WIV researchers; and Dr. Shi or members of his research team never worked in our UNC lab. No one on my team has worked in WIV labs.
And did you develop the reverse genetics technique, which allowed these viruses to be synthesized only from the genetic sequence?
Yes, but at the time, the costs of DNA synthesis were expensive, based on about a dollar [one letter of DNA]. So synthesizing a coronavirus genome can cost $ 30,000. And we just had the peak sequence. Synthesizing the 4,000 nucleotide pike gene costs $ 4,000. So we introduced SHC014 into the spine with the ability to replicate the real vertex: the strain adapted to the SARS mouse. The virus was viable, and we found that it could replicate in human cells.
So is it a function gain study? Well, parental strains of SARS coronavirus could be replicated quite effectively in early human cells. Chimera could also program human cell infection, but not better than the parent virus. So we didn’t get any function, it was us attached function. In addition, the chimera was weakened in mice compared to the virus adapted to the parent mouse, so it would be considered a loss of function.
One of the downsides to functional gain research — including this research — is that the work has little practical value. Would you agree?
Well, for 2016, using chimeras and reverse genetics, we identified enough coronaviruses like high-risk SARS to be able to test and identify drugs with broad anti-coronavirus activity. We identified Remdesivir as the first antiviral drug to work against all known coronaviruses and published it in 2017. It was immediately introduced into human trials and became the first drug approved by the FDA to treat kovid-19 infections worldwide. A second drug, called EIDD-2801 or molnupiravir, was shown to be effective against all known coronaviruses prior to the 2020 pandemic, and was later shown to work against SARS-CoV-2 in March 2020.
As a result, I disagree. I would ask critics if they identified a broad-spectrum coronavirus drug before the pandemic. Can the documents in their labs say that the strategic approach to document the development of effective pan-coronavirus drugs was effective against an unknown viral pandemic?
Unfortunately, waiting for remdesivir could only be given by internal injection. We are moving towards an oral delivery formulation, but a covid-19 pandemic ensued. I would really like to have an oral drug at the beginning. That’s a game changer that will help infected people in the developing world and U.S. citizens.
Molnupiravir is an oral medication, and phase 3 trials show rapid control of the virus infection. Emergency permitting has been considered in India.
Finally, the work also supported federal policy decisions that prioritized basic and applied research on coronaviruses.
What about vaccines?
Around 2018 and 2019, the NIH Vaccine Research Center contacted us to begin testing a messaging-RNA-based vaccine against MERS-CoV. [a coronavirus that sometimes spreads from camels to humans]. MERS-CoV has been an ongoing problem since 2012, with a 35% death rate and therefore a real health risk worldwide.
We had tremendous data in early 2020, when we developed that these mRNA vertex vaccines were effective in the mouse model to protect against the deadly MERS-CoV infection. If it was designed against the original SARS strain of 2003, it has also been very effective. So, I think it was not thought for the NIH that mRNA-based vaccines should be a safe and robust platform against SARS-CoV-2 and give high priority going forward.
Recently, we published an article that multiplexed chemical fiber mRNA vaccines protect against all SARS-like virus infections known to mice. Global effort to develop pan-sarbecoronavirus vaccines [sarbecoronavirus is the subgenus to which SARS and SARS-CoV-2 belong] It will ask us to make viruses like the ones described in the 2015 paper.
So I would argue that anyone who said there was no justification for the work in 2015 does not recognize covid-19 and the infrastructure that helped them in future coronavirus therapy and vaccines.
Work has value if the benefits outweigh the risks. Is there a need to apply safety rules to minimize these risks?
Definitely. We do everything in BSL-3 plus. The minimum requirements in the BSL-3 would be an N95 mask, eye protection, gloves and a lab coat, but the truth is that Tyve wears waterproof clothing, aprons and ankle boots and we have double gloves. Our staff wears bells with PAPR [powered air-purifying respirators] workers who supply HEPA filtered air. So not only are we doing all the research in a biosafety cabinet, we are also doing the research in a negative pressure holding facility with a number of redundant features and backups, and each employee is included in their own personal restraint.
Another thing we do is do emergency simulations with local first responders. We also work with a local hospital. With so many laboratory infections, there is no known event that caused this infection. And people get sick, right? You need to have medical care plans in place to quickly quarantine people at home, make sure they have masks, and communicate regularly with a doctor on campus.
Is all this standard for other US and international facilities?
No, I don’t think so. Different locations have different levels of BSL-3 holding operations, standard operating procedures, and protective equipment. Some depend on the depth of the pockets and the pathogens examined at the facility. An N95 is much cheaper than a PAPR.
Internationally, the U.S. has no say in conducting research on viruses used in China or any other sovereign nation for biological safety requirements, be it coronaviruses or Nipah, Hendra or Ebola.
The Wuhan Institute of Virology was making chimeric coronaviruses using techniques similar to yours, right?
Let me be clear that we have never sent any of our molecular clones or chimeric viruses to China. They developed their own molecular clone, based on WIV1, which is a bat coronavirus. And they introduced the spicy genes of other bat coronaviruses into that spine to learn how the gene spikes of these strains can promote infection in human cells.
Would you call that function gain?
An NIH committee makes decisions about the gainful investigation of the function. The rules for functional gain are based on viruses with pandemic potential and experiments intended to improve the transmissibility or pathogenesis of strains of SARS, MERS, and avian influenza in humans. WIV1 is approximately 10% different from SARS. Some say that the definition of “SARS coronavirus” covers anything of the genus sarbecoronavirus. According to this definition, the Chinese would be conducting function gain experiments, depending on the behavior of the chimera. Others say that SARS and WIV1 are different, so experiments would be exempt. There is no doubt that the CDC believes that SARS and WIV1 are different viruses. Only the 2003 SARS coronavirus is the selected agent. In the end, an NIH committee is the final arbiter and decides whether or not to function as a profit experiment.
Aside from the definitions, we know that the work was being done under BSL-2 conditions, which is a much lower level of security than your BSL-3 plus.
Historically, the Chinese have conducted a lot of research on bat coronavirus in BSL-2 conditions. Clearly, the safety standards for BSL-2 are different than those for BSL-3, and laboratory-acquired infections occur much more frequently in BSL-2. There is much less oversight in BSL-2.
This year, a joint commission of the World Health Organization and China said it was very difficult for a laboratory accident to have caused SARS-CoV-2. But you later signed a letter with other scientists asking them to study all possible reasons in depth. Why was that?
One of the reasons I signed the letter in science was that the WHO report did not really discuss how the work was done in the WIV lab, or the panel of experts who analyzed the data, said it was “very unlikely” that the laboratory leaked or infected the pandemic.
Some acknowledgments need to be made that laboratory infection could occur under BSL-2 operating conditions. Some unknown viruses collected from guano or oral sugars can be replicated or recombined with others, so you can get new strains with unique and unpredictable biological properties.
And if all this research is being done in BSL-2, there are questions that need to be answered. What are the standard operating procedures for BSL-2? What are employee training records? What is the history of possible exposure events in the laboratory, and how were they reviewed and resolved? What are the biosafety procedures designed to prevent exposure events?
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