Ralph Baric

Part 2: Gain-Of-Function Research At The Wuhan Lab—What Exactly Was The Wuhan Lab Doing With Coronaviruses?

“I’m just a soul whose intentions are good; Oh Lord, please don’t let me be misunderstood.”  —The Animals

In the first part of this two-part blog series, I described what gain-of-function research entails in order to set the stage for this blog post which describes the coronavirus research that went on in the Wuhan labs. So, was it dangerous and risky? Did it likely lead to the release of SARS-CoV-2 that caused COVID? Let me try to clarify all that now.

Coronavirus research at the Wuhan lab: After the first SARS epidemic in China in 2002, the Wuhan Institute of Virology (WIV) had established itself as a world class coronavirus research lab. It was from their diligent work that the world learned that the first SARS virus came from a horseshoe bat via other animals such as civets and raccoon dogs. That was the result of years of arduous research trudging through bat guano muck in hundreds of caves throughout China to collect samples from thousands of bats. They reported their finding 14 years after SARS appeared and shortly after another strange, lethal flu popped up in the Middle East that was soon attributed to yet another bat-borne coronavirus that came via camel intermediate hosts—MERS.

Before these two coronaviruses that jumped from animals to cause significant disease in humans, the viruses were only known to cause mild human maladies; basically, the common cold. Therefore, when it was learned that the deadly SARS and MERS diseases were caused by coronaviruses, it rattled the cages of health experts around the world. This was brand new!

Hence, even before COVID struck, bat-born coronaviruses were hot on the radars of infectious disease nerds and public health worrywarts. The WIV, as one of the world’s preeminent labs for identifying novel coronaviruses was given international funds to continue their efforts to identify and catalog bat coronaviruses. As they did years earlier when they identified the origin of the SARS virus in horseshoe bats, WIV scientists traveled to far-flung Chinese caves to collect bat guano and biological samples (blood, saliva, fecal) from captured bats. The samples were brought back to the lab in Wuhan for analysis.

Since it is exceedingly difficult and potentially very dangerous to grow wild viruses from such samples (failure is the norm even when many viruses are present in the samples) the lab resorted to their previous tried and true methods of searching the samples for viral genome sequences. They found a LOT of new ones!

Their first and primary order of business in this research was the very mundane task to sequence and catalog all the different coronaviruses they found. They then colligated these genomes into trees of different virus families and posted all the data in a vast database for world scientists to use. They were coronavirus genealogists.

The database is an enormously useful research tool for scientists around the world studying the origins and evolution of coronaviruses in animals and humans. (Coronaviruses also cause significant animal disease, so they also are of great agricultural interest around the world.)

The Wuhan lab also was charged with predicting which of the new virus sequences they found might pose future health threats to humans.

This is where all the controversy begins.

Remember that the Wuhan scientists actually did not have these viruses on hand, just their genome sequences. So, without the actual virus, how could they evaluate the ability of new coronaviruses to infect humans? To do this WIV scientist, Zhengli Shi, used a genetic engineering technique first published in 2015 by Univ. of North Carolina Scientist Ralph Baric to study coronaviruses from their genome sequences (she was a collaborator on Baric’s 2015 paper, so was quite familiar with the approach). It was a technique that also was in use at the time by several labs around the world. It is notable that NIH funded this coronavirus research conducted by Baric at UNC well before COVID appeared and didn’t consider it to be GoF research then.

Using Baric’s genetic engineering technique, Shi’s lab at the WIV used as a tool, a benign coronavirus that they could grow in the lab that was only distantly related to the first SARS virus, but was not known to cause human disease. Its genome sequence was not at all related to SARS-CoV-2 that caused COVID, and which had not yet appeared.

Shi’s lab removed the spike protein gene sequence from the genome of this benign lab virus tool and methodically replaced it with spike protein sequences from each new virus they sequenced. They then grew the lab virus tool carrying the new spike protein and tested its ability to infect human cells in tissue culture.

It is the spike protein that determines whether a coronavirus can infect human cells. Therefore, if the chimeric lab virus carrying the new spike gene infected human cells, it would indicate that the virus the spike protein sequence came from was a likely human pathogen and that virus sequence was then listed on the database as a potential human risk. However, if the chimeric test virus failed to infect the human tissue culture cells, that meant that the spike protein from the new virus genome would not support infection of human cells and the new virus sequence was not categorized as a concern for human infection.

This is how newly identified coronavirus sequences were categorized as potential human health threats without ever having to grow or isolate each virus itself.

In other words, this test simply expressed the spike protein of each novel coronavirus on the backbone of the safe lab virus genome in order to see if it could infect human cells. This completely negated the need to grow and handle the potentially much more dangerous wild-type virus.

It is important to notice that this strategy eliminated all risk of a lab leak of any dangerous virus since it was not necessary to grow or handle potentially dangerous wild-type viruses using this technique.

Is this gain-of-function-research? Strictly speaking, no. Remember, this sort of coronavirus engineering research had been done years earlier in Baric’s UNC lab, and was being done in other labs around the world, and it was never regarded as GoF research then by NIH.

NIH considers GoF research on pathogens to be research that either: 1) increases the pathogenicity of a microbe (that is, makes its disease worse), 2) improves its transmissibility or its ability to infect hosts, or 3) alters the host range of a pathogen. Therefore, in the WIV experiments to assess the ability of novel virus genome sequences to infect human cells, the chimeric test viruses that simply expressed new spike proteins on a laboratory virus backbone either retained the ability of the original lab virus to infect human cells, or they lost the ability to infect human cells.

Therefore, the chimeric viruses gained no new function that was tested. They either retained or lost the ability to infect human cells. The experiments were not at all designed to give the test virus any new functions. Furthermore, these experiments could not have led to the development of SARS-CoV-2 that caused the COVID pandemic, even by accident, since the laboratory test virus used to create the chimeric viruses in the experiments was not at all related to the SARS-CoV-2 virus.

There is a devil in the details: But. Notice that one of the the NIH definitions of GoF research is research that alters a pathogen’s host range. For example, take a flu virus that only passes between birds; avian flu. If you make changes in its genome so that the birds can also pass it to humans that mutation alters its host range and is a GoF change.

In the WIV lab, viruses with new spike protein gene sequences were only tested for their ability to infect human cells in a petri dish. The ability of these chimeric viruses with new spike proteins to also infect other animals was not tested. Theoretically, the chimeric test viruses could feasibly also infect, say a water buffalo, or a wart hog, or some other animal that the original lab virus might not have been able to. That would be a technical gain-of-function. But, that begs the question; in such an experiment, how would you know whether or not the host range of the chimeric virus had changed until you possibly had tested its ability to infect every known animal? A logistical impossibility.

Therefore, based on this theoretical point, it cannot be definitely stated that the experiments were not GoF experiments. In fact, chances are pretty good that some of the novel spike protein sequences attached to the lab test virus in fact altered its host range and, thus, the experiments would technically be GoF research.

Bottom line: Technically speaking, therefore, these experiments carried out at the WIV probably could be called GoF experiments. By a lawyer. Not by a scientist. That picks the proverbial nit and splits a very fine frog hair, to mix metaphors. The same research had been done ten years earlier in Ralph Baric’s UNC lab and was not considered GoF then. What is important is that the research at the UNC or the WIV never set out to create viruses with enhanced virulence, transmissibility, or altered host range. That was never the intent. The aim of the WIV research was solely to predict the human risk posed by novel coronaviruses without actually having to directly work with the potentially dangerous pathogens. Actually working with the dangerous viruses would have posed a very real risk.

Bottom, bottom line: The research conducted at the WIV was the most safe and responsible way to identify new coronaviruses that could potentially pose future human health risks. It is to the detriment of human health that this research has come under heavy criticism and that such future research has been hampered by criticism from people who fail to understand what the research is about and have, therefore, demonized it and want to prevent it.

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