The shifting sands of ‘gain-of-function’ research

The mystery of COVID’s origins has reignited a contentious debate about potentially risky studies and the fuzzy terminology that describes them.

Nature.com

Selected excerpts- read the entire piece at the link above

In Greek mythology, the Chimaera was a fire-breathing monster, a horrifying mishmash of lion, goat and snake that laid waste to the countryside. In 2015, virologists led by Ralph Baric at the University of North Carolina in Chapel Hill reported the creation of their own chimaera. They took a version of the coronavirus responsible for the deadly outbreak of severe acute respiratory syndrome (SARS) in the early 2000s — now known as SARS-CoV — and adorned it with surface proteins from a different coronavirus taken from Chinese horseshoe bats. In the laboratory, this particular mash-up was able to break into human cells and also make mice ill¹.

The 2015 study did raise broad interest for another reason: some wondered whether such an experiment should ever have been attempted. The work was considered by some an example of ‘gain-of-function’ virology, in which scientists bestow new abilities on pathogens to study them.

The term first gained a wide public audience in 2012, (could have been 2011?) after two groups revealed that they had tweaked an avian influenza virus, using genetic engineering and directed evolution, until it could be transmitted between ferrets^2,3. Many people were concerned that publishing the work would be tantamount to providing a recipe for a devastating pandemic, and in the years that followed, research funders, politicians and scientists debated whether such work required stricter oversight, lest someone accidentally or intentionally release a lab-created plague. Researchers around the world voluntarily paused some work, but the issue became particularly politicized in the United States.

US funding agencies, which also support research abroad, later imposed a moratorium on gain-of-function research with pathogens while they worked out new protocols to assess the risks and benefits. But many of the regulatory discussions have taken place out of the public eye.

In 2012 (2011?)- this ‘tweaking’ of an avian influenza virus was a topic covered at my now defunct google blog. When gain of function issues were raised around this latest incarnation of the conrona virus we reviewed the avian flu manipulation. Which was intended to make the virus spread easier and increase it’s lethality. And additional information related to this most recent virus. I’m going to dig that out and repost the report here. As soon as possible.

Now, gain-of-function research is once again centre stage, thanks to SARS-CoV-2 and a divisive debate about where it came from. Most virologists say that the coronavirus probably emerged from repeated contact between humans and animals, potentially in connection with wet markets in Wuhan, China, where the virus was first reported. But a group of scientists and politicians argues that a laboratory origin has not been ruled out.

It’s no surprise that politicians and scientists would disagree on GOF’s meaning, because it can mean different things in different contexts. At its most innocuous, GOF is a classic genetics term to describe mutations that give a gene, RNA or protein new abilities or expression patterns. Gain of function might result in bacteria that are extra sensitive to potassium ions⁵, for example, or an Arabidopsis plant with short stems and curly leaves⁶. A complementary approach — loss-of-function — involves disabling a gene to see what happens to organisms that lack it.

The meaning of Gain of Function is quite clear it’s a methodology that creates some form of mutation to gain a function in whatever is being manipulated- A virus can be made more deadly. Made to spread easier. What ever the desired gain of function is. I don’t buy the depending on context- that sophistry.

The term GOF didn’t have much to do with virology until the past decade. Then, the ferret influenza studies came along. In trying to advise the federal government on the nature of such research, the US National Science Advisory Board for Biosecurity (NSABB) borrowed the term — and it stuck, says Gigi Gronvall,a biosecurity specialist at the Bloomberg School of Public Health at Johns Hopkins University in Baltimore, Maryland. From that usage, it came to mean any research that improves a pathogen’s abilities to cause disease or spread from host to host.

Virologists do regularly fiddle with viral genes to change them, sometimes enhancing virulence or transmissibility, although usually just in animal or cell-culture models. “People do all of these experiments all the time,” says Juliet Morrison, a virologist at the University of California, Riverside. For example, her lab has made mouse viruses that are more harmful to mice than the originals. If only mice are at risk, should it be deemed GOF? And would it be worrying?

Ignoring the intentional tactic of downplaying the risks through the nonsensical claim of “if only mice are at risk should it be deemed GOF?” If mice are at risk is there some reason we should assume people are not?

GOF research starts to ring alarm bells when it involves dangerous human pathogens, such as those on the US government’s ‘select agents’ list, which includes Ebola virus and the bacteria responsible for anthrax and botulism. Other major concerns are ‘pathogens of pandemic potential’ (PPP) such as influenza viruses and coronaviruses. “For the most part, we’re worried about respiratory viruses because those are the ones that transmit the best,” says Michael Imperiale, a virologist at the University of Michigan Medical School. GOF studies with those viruses are “a really tiny part” of virology, he adds.

But this little slice of the field became the focus when the NSABB talked about regulating or monitoring GOF research (see ‘Evolving terminology’). After the ferret flu studies were eventually published, researchers and regulators struggled to determine what sorts of experiment should receive extra scrutiny as a potential biosecurity risk.

Last week, leaders at the US National Institutes of Health (NIH) told the US Congress that EcoHealth Alliance had not informed the agency about experiments in Wuhan in 2018 that enhanced the virulence of WIV1 in mice, and that immediately reporting such findings was a condition of the funding. A representative for EcoHealth Alliance says that the data were reported in 2018 and that the organization is working to “promptly address what we believe to be a misconception about the grant’s reporting requirements and what the data from our research showed”. Both EcoHealth Alliance and the NIH have stated that the viruses in question had no role in the emergence of SARS-CoV-2 and that the research doesn’t constitute GOF. But the continued controversy has set off more questions as to whether such research is warranted — and prompted more calls for transparency in how it is reviewed and approved.

Notice that the research with mice, done by Eco Health Alliance, was gain of function research and should have been reported as such. Contradicts the previous spin from the author of this piece. Pay particular attention to the fact that Eco Health Alliance and it’s financial backer the NIH (Fauci led) both claim their GoF research had no role in the emergence of Sars-CoV-2. Should we take their word for that?

Notably, the committee at the HHS charged with reviewing potential GOFROC work has not publicly released any of its deliberations (although details of grant review are typically kept private).

Only a handful of countries even have national policies on oversight for potentially risky biomedical research. And although China has long been a participant in international treaties and conventions on biosecurity, the nation didn’t pass sweeping legislation until 2020. Its law, which took effect this April, requires approvals for research with highly pathogenic microbes by provincial departments of health or rural affairs. But the law does not specifically address GOF studies, and some experts say the rules are vague⁸.

The big questions about GOF

The initial set of experiments that made GOF a household name revolved around avian influenza, a type known as H5N1. People sometimes catch it from poultry, and it can be fatal, but humans don’t typically transmit the virus to one another. Scientists wanted to know, however, what it would take to make that happen. “That’s the kind of question you can only answer with a gain-of-function experiment,” says Angela Rasmussen, a virologist at the University of Saskatchewan Vaccine and Infectious Disease Organization in Saskatoon, Canada.

(The corresponding authors of these two studies did not respond to, or declined, interview requests from Nature.)

Again the author of the Nature piece downplays this GoF experimentation. However, at the time this research was done a large batch of vaccines was immediately created. Information that I’m familiar with through my older research.

Baric’s studies, and the similar ones carried out by researchers in Wuhan that Rand Paul was concerned about⁵, did predict that a coronavirus could jump to humans and cause a pandemic, years before they were proved right. But the benefits go beyond that, says Rasmussen. “The irony is, these experiments and the work that was done at the Wuhan Institute of Virology, I think, really gave us a lot more information about SARS-CoV-2 than we would have had.”

Predicted it? Or gained of functioned it?

With all the challenges inherent in GOF studies, why do them? Because, some virologists say, the viruses are constantly mutating on their own, effectively doing GOF experiments at a rate that scientists could never match. “We can either wait for something to arise, and then fight it, or we can anticipate that certain things will arise, and instead we can preemptively build our arsenals,” says Morrison. “That’s where gain-of-function research can come in handy.”

You can’t anticipate certain things will arise because they may never happen. I guess wild speculation might be a better way to describe this process? Or something else entirely different will occur. The only reason, in my opinion, for GoF research is to manipulate a virus in order to create a ‘vaccine’ against it. And that’s questionable anyway. Once a virus is released in the wild. All bets are off the table. However, profits can be made and the media is there to sell the agenda. As we’ve all borne witness to.