Did Gain-of-Function Research Create Covid-19? We asked Ralph Baric.

[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 footage was requested several times after the emergence of the covid-19 pandemic, and therefore after discussion with the NIH and the newspaper, it was provided to the community. Those who analyzed these sequences said it was very different from SARS-CoV-2.

How did this chimerical work on coronaviruses start?

Around 2012 or 2013, I overheard Dr Shi attending a meeting. [Shi’s team had recently discovered two new coronaviruses in a bat cave, which they named SHC014 and WIV1.] We spoke after the meeting. I asked her if she would be willing to make the SHC014 or WIV1 footage available after it was released.

And she was kind enough to send us these footage almost immediately – in fact, before she had published. This was his main contribution to the article. And when a colleague gives you sequences beforehand, the co-author on paper is in order.

It was the basis of this collaboration. We never provided the chimeric viral sequence, clones or viruses to WIV researchers; and Dr. Shi, or members of his research team, have never worked in our lab at UNC. No one in my group has worked in the WIV labs.

And you had developed a reverse genetics technique that allowed you to synthesize these viruses from the genetic sequence alone?

Yes, but at the time, DNA synthesis costs were expensive – about a dollar per base [one letter of DNA]. Thus, the synthesis of a coronavirus genome could cost $ 30,000. And we only had the spike sequence. It cost $ 4000 to synthesize the single peak gene of 4000 nucleotides. We have therefore introduced the authentic SHC014 tip into a replication competent backbone: a strain of SARS adapted to mice. The virus was viable and we found that it could replicate in human cells.

So, is this gain of function research? Well, the parental strain of the SARS coronavirus could replicate quite efficiently in primary human cells. The chimera could also program the infection of human cells, but no better than the parental virus. We therefore did not acquire any function – on the contrary, we retained a function. In addition, the chimera was attenuated in mice compared to the parental mouse-adapted virus, which would therefore be considered a loss of function.

One of the disadvantages of gain-of-office research – including this research – is that the work has little practical value. Would you accept?

Well, by 2016, using chimeras and reverse genetics, we identified enough high-risk SARS-like coronaviruses to be able to test and identify drugs that have broad activity against coronaviruses. We identified remdesivir as the first broad-based antiviral drug that worked against all known coronaviruses, and published about it in 2017. It immediately went into human trials and became the first drug approved by the FDA to treat covid-19 infections worldwide. A second drug, called EIDD-2801, or molnupiravir, was also found to be effective against all known coronaviruses before the 2020 pandemic, and then to be effective against SARS-CoV-2 by March 2020.

Therefore, I do not agree. I would ask critics if they had identified broad spectrum coronavirus drugs before the pandemic. Can they cite papers from their labs documenting a strategic approach to develop effective anti-pan-coronavirus drugs that have been shown to be effective against an unknown emerging pandemic virus?

Unfortunately, remdesivir could only be given by intravenous injection. We were moving towards an oral delivery formulation, but the covid-19 pandemic has emerged. I really wish we had had oral medication early on. It is the game changer that is said to help infected people in the developing world, as well as the citizens of the United States.

Molnupiravir is an oral drug, and phase 3 trials demonstrate rapid control of viral infection. It has been considered for emergency use authorization in India.

Finally, the work also supported federal policy decisions that prioritized basic and applied research on coronaviruses.

What about vaccines?

Around 2018 to 2019, the NIH Vaccine Research Center contacted us to begin testing a messenger RNA vaccine against MERS-CoV. [a coronavirus that sometimes spreads from camels to humans]. MERS-CoV has been a persistent problem since 2012, with a mortality rate of 35%, so it has a real potential to threaten global health.

At the start of 2020, we had a huge amount of data showing that in the mouse model we had developed, these mRNA-spiked vaccines were really effective in protecting against fatal MERS-CoV infection. While it was designed against the original strain of SARS from 2003, it was also very effective. So I think it was a no-brainer for the NIH to view mRNA-based vaccines as a safe and robust platform against SARS-CoV-2 and to give them a high priority moving forward.

More recently, we published an article showing that multiplexed chimeric spike mRNA vaccines protect against all known SARS-like viral infections in mice. Global efforts to develop pan-sarbecoronavirus vaccines [sarbecoronavirus is the subgenus to which SARS and SARS-CoV-2 belong] will force us to create viruses like the ones described in the 2015 article.

So I would say that anyone who says there was no justification for doing the job in 2015 is simply not acknowledging the infrastructure that has contributed to therapeutics and vaccines against covid-19 and future coronaviruses.

Work has no value unless the benefits outweigh the risks. Are there safety standards to apply to minimize these risks?

Certainly. We do everything at BSL-3 plus. The minimum requirements at BSL-3 would be an N95 mask, goggles, gloves and a lab coat, but we actually wear waterproof Tyvek coveralls, aprons and slippers and we wear double gloves. Our staff wear balaclavas with PAPR [powered air-purifying respirators] that provide HEPA filtered air to the worker. So not only do we do all the research in a biological safety cabinet, but we also do the research in a negative pressure containment facility, which has lots of redundant features and safeguards, and each worker is locked in their own combination of personal containment.

Another thing we do is organize emergency drills with local first responders. We are also working with the local hospital. With many lab infections, there is actually no known event that caused this infection. And people get sick, right? Health surveillance plans need to be in place to quickly quarantine people at home, ensure they have masks, and communicate regularly with a doctor on campus.

Is all of this standard for other installations in the US and around the world?

No, I do not think so. Different locations have different levels of BSL-3 containment operations, standard operating procedures, and protective equipment. Part of it depends on the depth of your pockets and the pathogens studied in the facility. An N95 is much cheaper than a PAPR.

Internationally, the United States has no say in the biosecurity conditions used in China or any other sovereign country to conduct research on viruses, whether it is coronavirus or from Nipah, Hendra or Ebola.

The Wuhan Institute of Virology was making chimeric coronaviruses, using techniques similar to yours, right?

Let me clarify that we never sent any of our molecular clones or any chimeric viruses to China. They have developed their own molecular clone, based on WIV1, which is a bat coronavirus. And in that backbone, they mixed spike genes from other bat coronaviruses, to learn how spike genes from those strains can promote infection in human cells.

Do you call it a gain in function?

NIH committee determines research on gain-of-office. The gain-of-function rules focus on viruses with pandemic potential and experiments aimed at improving the transmissibility or pathogenesis of strains of SARS, MERS and avian influenza in humans. WIV1 is about 10% different from SARS. Some argue that the “SARS coronavirus” by definition covers everything that belongs to the sarbecoronavirus genus. According to this definition, the Chinese could do gain-of-function experiments, depending on the behavior of the chimera. Others argue that SARS and WIV1 are different and as such experiments would be exempt. Granted, the CDC considers SARS and WIV1 to be different viruses. Only the 2003 SARS coronavirus is a selective agent. Ultimately, an NIH committee is the final arbiter and makes the decision on what is and is not a job gain experience.

Definitions aside, we know they performed the job under BSL-2 conditions which is a much lower level of safety than your BSL-3 plus.

Historically, the Chinese have done much of their research on bat coronaviruses under BSL-2 conditions. Obviously, the safety standards of BSL-2 are different from those of BSL-3, and laboratory-acquired infections occur much more frequently with BSL-2. There is also much less surveillance at BSL-2.

This year, a joint commission from the World Health Organization and China said it was extremely unlikely that a lab accident caused SARS-CoV-2. But later you signed a letter with other scientists calling for a full investigation into all possible causes. Why was that?

One of the reasons I signed the letter in Science was that the WHO report didn’t really talk about how the work was done in the WIV lab, or what data the expert group had. examined to come to the conclusion that it was “very unlikely” that a laboratory leak or infection was the cause of the pandemic.

There must be some recognition that a laboratory infection may have occurred under BSL-2 operating conditions. Some unknown viruses grouped together from guano or oral swabs can replicate or recombine with others, so you might get new strains with unique and unpredictable biological characteristics.

And if all of this research is done at BSL-2, then there are questions that need to be addressed. What are the standard operating procedures in the BSL-2? What are the personnel training records? What is the history of potential laboratory exposure events, and how were they investigated and resolved? What are the biosafety procedures designed to prevent potential exposure events?

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