no one's talking "grab a stud and impgregnate that mare to keep the racehorse breed going here. You know we're talking gene splicing petri dish shit. Let's use your source against your own arguments, I've highlighted those that contradict your statements saying everyone and their grandma is doing routine "perfectly safe" gain of function research everywhere:
Yet that did little to quell questions about the role Baric’s research may have played in furthering scientists’ ability to modify coronaviruses in potentially dangerous ways.
Yet Baric also pioneered the reverse-genetics techniques that have allowed other researchers, including those at the Wuhan Institute of Virology, to engineer viruses with altered functions. Some scientists fear that the technique, which allow coronaviruses to be recreated from their genetic code, could engender a future pandemic, and other critics, like Senator Paul, imply they might have led to the creation or release of SARS-CoV-2.
So gain-of-function has been used in virology and microbiology for decades as a part of the scientific method. But that classic definition and purpose changed in 2011 and 2012, when researchers in Wisconsin and the Netherlands were funded to do gain-of-function research on avian flu transmissibility.
Those were the experiments that took H5N1, which had a high mortality rate in humans but low transmissibility, and made it highly transmissible through respiratory avenues.
The number-one conclusion was that we needed to understand the genetics and biology of flu emergence and transmission.
In response, the NIH called for proposals. Two researchers responded and were funded, and they discovered genetic changes that regulated H5N1 transmissibility in ferrets.
After that, they were labeled as rogue scientists, and gain-of-function was defined in negative terms. But in fact, they were working within the confines of the global health community’s interests.
Then again, the other side argues that regardless of how safe your BSL-3 or BSL-4 research infrastructure is, human beings are not infallible. [Pathogen labs are assigned a biosafety level rating of 1 to 4, with 4 being the highest.] They make mistakes, even in high-containment facilities. Consequently, the risks may outweigh the benefits of the experiment. Both sides of the argument have justified concerns and points of view.
In addition to concerns over a lab escape, there were also concerns about whether the knowledge of how to do such experiments might fall into the wrong hands.
That’s certainly part of the issue. And there was a fair amount of debate about whether that information [about genetic changes associated with flu transmission] should be made public. There are two or three instances in the virology literature of papers that are a potential concern.
Some consider my 2015 paper in this light, although after consultation with the NIH and the journal, we purposely did not provide the genetic sequence of the chimera in the original publication. Thus, our exact method remained obscure.
[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.]
How did that chimeric work on coronaviruses begin?
Around 2012 or 2013, I heard Dr. Shi 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 her whether she’d be willing to make the sequences to either the SHC014 or the WIV1 spike available after she published.
And she was gracious enough to send us those sequences almost immediately—in fact, before she’d published. That was her major contribution to the paper. And when a colleague gives you sequences beforehand, coauthorship on the paper is appropriate.
That was the basis of that collaboration. We never provided the chimeric virus sequence, clones, or viruses to researchers at the WIV; and Dr. Shi, or members of her research team, never worked in our laboratory at UNC. No one from my group has worked in WIV laboratories.
And you had developed a reverse-genetics technique that allowed you to synthesize those viruses from the genetic sequence alone?
Yes, but at the time, DNA synthesis costs were expensive—around a dollar per base [one letter of DNA]. So synthesizing a coronavirus genome could cost $30,000. And we only had the spike sequence. Synthesizing just the 4,000-nucleotide spike gene cost $4,000. So we introduced the authentic SHC014 spike into a replication-competent backbone: a mouse-adapted strain of SARS. The virus was viable, and we discovered that it could replicate in human cells.
So is that gain-of-function research? Well, the SARS coronavirus parental strain could replicate quite efficiently in primary human cells. The chimera could also program infection of human cells, but not better than the parental virus. So we didn’t gain any function—rather, we retained function. Moreover, the chimera was attenuated in mice as compared to the parental mouse-adapted virus, so this would be considered a loss of function.
Finally, the work also supported federal policy decisions that prioritized basic and applied research on coronaviruses.
So I would argue that anyone saying there was no justification to do the work in 2015 is simply not acknowledging the infrastructure that contributed to therapeutics and vaccines for covid-19 and future coronaviruses.
The work only has value if the benefits outweigh the risks. Are there safety standards that should be applied to minimize those risks?
Certainly. We do everything at BSL-3 plus.
Is all that standard for other facilities in the US and internationally?
No, I don’t think so. Different places have different levels of BSL-3 containment operations, standard operating procedures, and protective gear. Some of it is dependent on how deep your pockets are and the pathogens studied in the facility. An N95 is a lot cheaper than a PAPR.
Internationally, the US has no say over what biological safety conditions are used in China or any other sovereign nation to conduct research on viruses, be they coronaviruses or 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 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. And into that backbone they shuffled in the spike genes of other bat coronaviruses, to learn how well the spike genes of these strains can promote infection in human cells.
By this definition, the Chinese might be doing gain-of-function experiments, depending on how the chimera behaves. Others argue that SARS and WIV1 are different, and as such the experiments would be exempt. Certainly, the CDC considers SARS and WIV1 to be different viruses. Only the SARS coronavirus from 2003 is a select agent. Ultimately, a committee at the NIH is the final arbiter and makes the decision about what is or is not a gain-of-function experiment.
Definitions aside, we know they were doing the work in BSL-2 conditions, which is a much lower safety level than your BSL-3 plus.
Historically, the Chinese have done a lot of their bat coronavirus research under BSL-2 conditions. Obviously, the safety standards of BSL-2 are different than BSL-3, and lab-acquired infections occur much more frequently at BSL-2. There is also much less oversight at BSL-2.
There must be some recognition that a laboratory infection could have occurred under BSL-2 operating conditions. Some unknown viruses pooled from guano or oral swabs might replicate or recombine with others, so you could get new strains with unique and unpredictable biological features.
And if all this research is being performed 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 training records of the staff? What is the history of potential exposure events in the lab, and how were they reviewed and resolved? What are the biosafety procedures designed to prevent potential exposure events?
Should they have been doing such experiments in a BSL-2 lab?
I would not. However, I don’t set the standard for the US or any other country. There’s definitely some risk associated with these and other SARS-like bat viruses that can enter human cells.
This is serious stuff. Global standards need to exist, especially for understudied emerging viruses. If you study hundreds of different bat viruses at BSL-2, your luck may eventually run out.
In addition to the WIV and you, are other groups doing coronavirus engineering?
Before covid-19, there were probably three to four main groups globally. That’s changed dramatically. Now the number of labs doing coronavirus genetics is likely three or four times higher and continuing to increase. That proliferation is unsettling, because it allows many inexperienced groups, globally, to make decisions about building and isolating chimeras or natural zoonotic [viruses].
By “inexperienced,” I mean that they are applying previous discoveries and approaches in the coronavirus field, but perhaps with less respect for the inherent risk posed by this group of pathogens.
People are making chimeras right now for the variants of concern, and each of those variants is providing new insights into human transmissibility and pathogenesis.
