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.]

But the series has been requested multiple times after the covid-19 pandemic unfolded and was therefore made available to the community after discussion with the NIH and the journal. Those who analyzed these sequences noted that it was very different from SARS-CoV-2.

How did this chimerical work on coronaviruses begin?

Around 2012 or 2013, Dr. I heard that Shi was present 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. I asked him if he would like to make the SHC014 or WIV1 spike sequences available after they aired.

And he was kind enough to send us these sequences almost instantly – in fact, before had published. It was his greatest contribution to the newspaper. And when a colleague has given you the sequences in advance, co-authoring on paper is appropriate.

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

And have you developed a reverse-genetic technique that allows you to synthesize these viruses only from genetic sequencing?

Yes, but DNA synthesis costs were expensive back then – around a dollar per base. [one letter of DNA]. So synthesizing a coronavirus genome could cost $30,000. And we only had a spike array. The 4,000-nucleotide spike gene costs $4,000 to synthesize. That’s why we added the original SHC014 spike to a replication-competent backbone: a mouse-adapted SARS strain. The virus was viable, and we discovered that it could replicate in human cells.

So this is gain-of-function research? Well, the SARS coronavirus parent strain can reproduce quite efficiently in primary human cells. Chimera can also program the infection of human cells, but no better than the main virus. So we did not gain any function – rather held function. Also, the chimera was attenuated in mice compared to the parent mouse-adapted virus, so this would be considered a loss of function.

One of the blows against gain-of-function research, including this research, is that the study has little practical value. Do you agree?

By 2016, using chimeras and reverse genetics, we had identified enough high-risk SARS-like coronaviruses to be able to test and identify drugs with broad-based activity against coronaviruses. We identified Remdesivir as the first broad-based antiviral drug that works against all known coronaviruses and published on it in 2017. It immediately entered human trials and became the first FDA-approved drug to treat covid-19 infections globally. A second drug, called EIDD-2801 or molnupiravir, was also shown to be effective against all known coronaviruses before the 2020 pandemic, and then to work against SARS-CoV-2 until March 2020.

In conclusion, I disagree. I would ask critics if they had detected any broad-spectrum coronavirus drugs prior to the pandemic. Can they point to articles from their lab documenting a strategic approach to develop effective pan-coronavirus drugs that turn out to be effective against an unknown emerging pandemic virus?

Unfortunately, remdesivir can only be given by intravenous injection. We were moving towards oral delivery formulation but the covid-19 pandemic has emerged. I wish we had an oral-based drug before. This is the game changer that will help infected people in developing countries and citizens in the US.

Molnupiravir is an oral drug and phase 3 trials demonstrate rapid control of viral infection. Accepted for emergency use clearance in India.

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

What about vaccines?

Between 2018 and 2019, the Vaccine Research Center at the NIH contacted us to begin testing a messenger-RNA-based vaccine against MERS-CoV. [a coronavirus that sometimes spreads from camels to humans]. MERS-CoV is an ongoing problem with a death rate of 35% since 2012, so it has the potential to be a real global health threat.

In early 2020, we had an enormous amount of data showing that these mRNA spike vaccines are indeed effective in protecting against deadly MERS-CoV infection in the mouse model we have developed. If designed against the original 2003 SARS strain, it was also very effective. Therefore, I think it is easy for the NIH to view mRNA-based vaccines as a safe and robust platform against SARS-CoV-2 and give them a high priority to move forward.

We recently published a paper showing that multiplexed, chimeric spike mRNA vaccines protect against all known SARS-like virus infections in mice. Global efforts to develop pan-sarbecoronavirus vaccines [sarbecoronavirus is the subgenus to which SARS and SARS-CoV-2 belong] It will require us to make viruses like the ones described in the 2015 article.

So I would argue that someone who said there was no justification for doing this work in 2015 does not acknowledge the infrastructure that contributes to therapeutics and vaccines for covid-19 and future coronaviruses.

The value of the work only if the benefits outweigh the risks. Are there safety standards that must be implemented to minimize these risks?

Absolutely. We do everything in BSL-3 plus. The minimum requirements at BSL-3 would be an N95 mask, eye protection, gloves and lab coat, but we actually wear waterproof Tyvek suits, aprons and booties, and we’re double gloved. Our staff wear caps with PAPR [powered air-purifying respirators] providing the worker with HEPA filtered air. Therefore, we do not only do all the research in a biological safety cabinet, we also conduct the research in a negative pressure containment facility with many redundant features and redundancy, and each worker is enclosed in their own special personal containment suit.

Another thing we do is conduct emergency drills with local first responders. We also work with the local hospital. In many laboratory infections, there is no known event that actually causes this infection. And people get sick, right? You should have medical surveillance 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 do not think so. Different locations have different levels of BSL-3 containment procedures, standard operating procedures and protective gear. Some depends on how deep your pockets are and the pathogens being studied at the facility. N95 is much cheaper than PAPR.

Internationally, the US has no say in what biological safety conditions are used to conduct research on viruses in China or any other sovereign country, be it coronaviruses, Nipah, Hendra or Ebola.

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

Let me make it clear that we never send our molecular clones or chimeric viruses to China. They developed their own molecular clone based on WIV1, a bat coronavirus. And they scrambled the spike genes of other bat coronaviruses into this backbone to find out how well the spike genes of this species could support infection in human cells.

Can you call this gain of function?

A committee at the NIH makes the determinations of gain-of-function research. Gain-of-function rules focus on viruses with pandemic potential and experiments aimed at improving the infectivity or pathogenesis of SARS, MERS, and avian influenza strains in humans. WIV1 differs from SARS by about 10%. Some argue that by definition, the “SARS coronavirus” covers everything in the sarbecoronavirus genus. According to this definition, the Chinese may be experimenting with gain-of-function depending on how the chimera behaves. Others argue that SARS and WIV1 are different and therefore experiments would be exempted. Of course, the CDC considers SARS and WIV1 to be different viruses. Only the SARS coronavirus in 2003 is a selected agent. Ultimately, a committee at the NIH is the final arbiter and decides what is and is not an acquisition-of-function experiment.

Definitions aside, we know they do the job in BSL-2 conditions, which is a much lower security level than your BSL-3 plus.

Historically, the Chinese have done most of their bat coronavirus research under BSL-2 conditions. Obviously, BSL-2’s safety standards are different from BSL-3, and laboratory-acquired infections occur much more frequently in BSL-2. There is also much less oversight in BSL-2.

This year, a joint commission by the World Health Organization and China said it was extremely unlikely that a laboratory accident caused SARS-CoV-2. But then you signed a letter with other scientists asking for a thorough investigation of all possible causes. Why was it?

One of the reasons I signed the letter in Science was that the WHO report didn’t really discuss how the work was done in the WIV lab, or what data the expert panel had reviewed to conclude that it was “very unlikely”. The cause of the pandemic was laboratory escape or infection.

There should be some understanding that a laboratory infection may have occurred under BSL-2 operating conditions. Some unknown viruses collected from guano or oral swabs can replicate or recombine with others, resulting in new strains with unique and unpredictable biological properties.

And if all this research is being done at BSL-2, there are questions that need to be addressed. What are the standard operating procedures in BSL-2? What are the training records of the personnel? 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 potential exposure events?


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