Did gain-of-function research create covid-19? We asked Ralph Barrick.


[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, after the outbreak of the covid-19 pandemic, the sequence was repeatedly requested, so it was provided to the community after discussions with NIH and journals. Those analyzing these sequences stated that it is very different from SARS-CoV-2.

How did the work on the chimerism of the coronavirus begin?

Around 2012 or 2013, I heard Dr. Shi attend a conference. [Shi’s team had recently discovered two new coronaviruses in a bat cave, which they named SHC014 and WIV1.] We will talk after the meeting. I asked her if she would provide the sequence of the SHC014 or WIV1 spike after her publication.

She sent us these sequences very kindly and almost immediately-in fact, forward She published. This is her main contribution to this paper. When a colleague gives you the sequence in advance, the co-author of the paper is appropriate.

This is the basis of this cooperation. We have never provided chimeric virus sequences, clones or viruses to WIV researchers; Dr. Shi or her research team members have never worked in our laboratory at the University of North Carolina. No one in my group has worked in the WIV laboratory.

You developed a reverse genetic technology that allows you to synthesize these viruses from genetic sequences alone?

Yes, but the cost of DNA synthesis was very high at the time-about $1 per base [one letter of DNA]Therefore, it may cost US$30,000 to synthesize the coronavirus genome. We only have spike sequences. It costs $4,000 to synthesize a spike gene of only 4,000 nucleotides. Therefore, we introduced the true SHC014 spike into the backbone with replication ability: a SARS strain adapted to mice. The virus is alive and we found that it can replicate in human cells.

So is this a gain-of-function study? Well, the SARS coronavirus parent strain can replicate very efficiently in primary human cells. Chimeras can also be programmed to infect human cells, but they are no better than parental viruses.So we don’t get any functionality—on the contrary, we Reserve Function. In addition, the chimera is attenuated in mice compared to the parental mouse-adapted virus, so this will be considered a loss of function.

One of the blows to the acquisition of function research (including this research) is that this work has little practical value. Would you agree?

Well, by 2016, using chimerism and reverse genetics, we have identified enough high-risk SARS-like coronaviruses to be able to test and identify drugs with broad activity against coronaviruses. We identified Remdesivir as the first broad-spectrum antiviral drug against all known coronaviruses and published it in 2017. It immediately entered human trials and became the first drug approved by the FDA to treat global COVID-19 infection. The second drug, called EIDD-2801 or molnupiravir, was also proven effective against all known coronaviruses before the 2020 pandemic, and then proved effective against SARS-CoV-2 by March 2020.

Therefore, I disagree. I will ask critics if they found any broad-spectrum coronavirus drugs before the pandemic. Can they point out the papers in their laboratory that document a strategic approach to the development of effective pan-coronavirus drugs that have been shown to be effective against an unknown emerging pandemic virus?

Unfortunately, Remdesivir can only be administered intravenously. We are moving to oral-based delivery formulations, but there is a covid-19 pandemic. I really hope we have an oral medication sooner. This will change the rules of the game and will help people living in developing countries as well as American citizens.

Molnupiravir is an oral drug. Phase 3 trials have proven that it can quickly control viral infections. It has been considered for emergency use authorization in India.

Finally, this work also supports federal policy decisions that prioritize basic and applied research on the coronavirus.

What about the vaccine?

From 2018 to 2019 or so, the NIH Vaccine Research Center contacted us to start testing a messenger RNA-based vaccine against MERS-CoV [a coronavirus that sometimes spreads from camels to humans]Since 2012, MERS-CoV has been an ongoing problem with a mortality rate of 35%, so it has a real global health threat potential.

By the beginning of 2020, we have a large amount of data showing that these mRNA spike vaccines are indeed effective in preventing the lethal MERS-CoV infection in the mouse model we have developed. It is also very effective if it is designed for the original 2003 SARS strain. Therefore, I think NIH takes mRNA-based vaccines for granted as a safe and powerful platform for SARS-CoV-2 and gives them a high priority for development.

Recently, we published a paper showing that multiple chimeric spike mRNA vaccines can prevent all known SARS-like virus infections in mice.Global efforts to develop pan-sarbecoronavirus vaccine [sarbecoronavirus is the subgenus to which SARS and SARS-CoV-2 belong] We will be asked to create the virus described in the 2015 paper.

Therefore, I believe that anyone who says that there is no reason for this work in 2015 will not recognize the infrastructure that contributes to COVID-19 and future coronavirus treatments and vaccines.

Only when the benefits outweigh the risks can work be valuable. Should safety standards be adopted to minimize these risks?

certainly. We do everything in BSL-3 plus. The minimum requirements for BSL-3 are N95 masks, goggles, gloves and lab coats, but we actually wear impermeable Tyvek protective clothing, aprons and boots, and wear double gloves.Our staff wear hoods with PAPR [powered air-purifying respirators] Provide workers with HEPA filtered air. Therefore, we not only conduct all the research in the biological safety cabinet, but also conduct the research in the negative pressure containment facility, which has many redundant functions and backups, and each worker is wrapped in his own personal protective clothing.

Another thing we did was to conduct emergency drills with local first responders. We also cooperate with local hospitals. For many laboratory infections, there is actually no known event that caused this infection to occur. People get sick, right? You must develop a medical monitoring plan to quickly isolate people at home, ensure that they wear masks and communicate with doctors on campus regularly.

Are all of these standards for other facilities in the United States and internationally?

No, I don’t think so. Different places have different levels of BSL-3 containment operations, standard operating procedures, and protective equipment. Some of these depend on how deep your pocket is and the pathogen being studied in the facility. N95 is much cheaper than PAPR.

Internationally, the United States has no say in what kind of biosafety conditions are used in China or any other sovereign country to conduct virus research, whether it is coronavirus or Nipah virus, Hendra virus or Ebola virus.

Wuhan Institute of Virology is making chimeric coronaviruses, and the technology used is similar to yours, right?

Let me make it clear that we have never sent any of our molecular clones or any chimeric viruses to China. They developed their own molecular clone, based on WIV1, which is a bat coronavirus. They shuffled the spike genes of other bat coronaviruses into this trunk to understand how the spike genes of these strains promote infection of human cells.

Would you call it functional gain?

A committee of the NIH makes a decision on the acquisition of functionality research. The function acquisition rules focus on viruses with pandemic potential and experiments aimed at enhancing the infectivity or pathogenesis of SARS, MERS, and avian influenza virus strains in humans. There is about 10% difference between WIV1 and SARS. Some people believe that, by definition, “SARS coronavirus” covers anything in the genus sarbecoronavirus. According to this definition, the Chinese may be experimenting with gains of function, depending on the behavior of the chimera. Others think that SARS and WIV1 are different, so the experiment will be exempted. Of course, the CDC believes that SARS and WIV1 are different viruses. Only the 2003 SARS coronavirus is a selective pathogen. Ultimately, a committee of the NIH is the ultimate arbiter and decides what an gain-of-function experiment is.

Regardless of the definition, we know that they are working under BSL-2 conditions, which is much lower than the security level of BSL-3 plus.

Historically, the Chinese have conducted a large number of bat coronavirus studies under BSL-2 conditions. Obviously, the safety standards of BSL-2 are different from BSL-3, and laboratory-acquired infections occur more frequently in BSL-2. BSL-2 also has much less supervision.

This year, a joint committee of the World Health Organization and China stated that a laboratory accident is extremely unlikely to cause SARS-CoV-2. But you later signed a letter with other scientists requesting a thorough investigation of all possible causes. why?

One of the reasons why I signed this letter in the journal Science is that the WHO report does not really discuss how the work of the WIV laboratory is carried out, or what data the expert panel reviewed to conclude that it is “very unlikely “Laboratory escape or infection is the cause of the pandemic.

It must be recognized that laboratory infections may occur under BSL-2 operating conditions. Some unknown viruses collected from bird droppings or oral swabs may replicate or recombine with other viruses, so you can obtain new strains with unique and unpredictable biological characteristics.

If all these studies are conducted on BSL-2, then there are still some issues that need to be resolved. What are the standard operating procedures in BSL-2? What is the employee’s training record? What is the history of potential exposure events in the laboratory, and how are they reviewed and resolved? What are the biosafety procedures designed to prevent potential exposure incidents?


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