Gain of Function Has Never Worked. Did Futile Line of Research Devastate the World…For Nothing?

Prior to the pandemic, the term “gain of function research” was rarely heard outside the confines of a laboratory or a government bureaucrat’s office. 

COVID changed all that and the term, its GOF abbreviation, and the debate over its implications took center stage in the international pandemic discussion. 

Researchers, members of the public health nomenklatura, elected officials, and just regular folks whose lives were upended and freedoms stripped by the overwhelming, overreaching, and over-the-top response to the pandemic all grappled with the idea of GOF as they tried to defend, downplay, question, or just get even the vaguest handle on the cause and meaning of the pandemic. 

What is GOF? Is GOF dangerous? Who is paying for GOF research? Why is GOF research being done? Is GOF responsible for the pandemic or did GOF help fight the pandemic – or both? 

One question – oddly enough – was not often asked: Has gain of function research ever worked? 

And even more oddly – more ominously, as well – the answer is no, it has never worked as advertised to the public. 

And if something that has never worked, something knowingly pointless, as it were, turns out to be the actual cause of the pandemic – that GOF did indeed lead to the creation of COVID - that adds a level of incompetence, intentionality, and infuriating futility to the misery of the past three years that is truly numbing. 

The risk/reward calculation under those circumstances is very clear – zero chance of reward for performing an infinitely risky act. Performing any activity – from crossing the street to breeding superbugs in a lab – with those odds is unconscionable. 

So what exactly is GOF? That in and of itself is difficult to specify as the term has been used to describe a number of different concepts, possibly in order to mystify the public and obfuscate the significant risks inherent in the process as it relates to virus enhancement. 

The general definition offered to the public by officials during the pandemic was essentially this: GOF takes a virus and enhances its lethality to, or transmissibility amongst, humans in order to be able to study the resulting bug to speed the search for a potential treatment if and when the virus evolves in nature to the same danger point. 

In other words, if scientists can work with the possible superbugs now they can get a “head start” and be better prepared to fight them in the future if they should appear naturally (zoonotically) and threaten humans. 

By that definition – a common, descriptive, and precise definition - gain of function has never worked.

Admittedly, it may have “worked” if a different goal was in mind. First, if a more plausible reason for engaging in the practice – the creation of bioweapons – has resulted in a “success” it will obviously never be made known to the public. 

Second, it can be said to have worked if the actual point of GOF is to sell vaccines, etc. in response to a new bug; in fact, in that (admittedly hyper-cynical but far from impossible) scenario, GOF has worked in spades (the recent Senate report that claims China was working on a COVID vaccine even before the rest of the world had heard of the virus may bolster this awful explanation.) 

“Enhanced potential pandemic pathogens (research) has no civilian applications,” said Dr. Richard Ebright, a Board of Governors Professor of Chemistry and Chemical Biology at Rutgers University and Laboratory Director at the Waksman Institute of Microbiology. “In particular, it is not needed for, and has not contributed to, developing any vaccine or drug, preventing any outbreak, or controlling any outbreak.” 

Then why do it? 

Here is where the slippery definition issue raises its ugly head. 

Dr. Ralph Baric is the William R. Kenan, Jr. Distinguished Professor in the Department of Epidemiology and Professor in the Department of Microbiology and Immunology at the University of North Carolina – Chapel Hill and has been a self-described “reluctant spokesman” for GOF for nearly a decade. 

He has a very different opinion on the matter. 

When contacted and asked if GOF has ever worked, Baric, before quickly ending the telephone call, said “Yeah, I don’t think I want to participate in this discussion, but there are examples – look harder.” 

“Looking harder” found, amongst other things, a Technology Review article in which Baric did expand upon the process. First and foremost, he said: 

“Human beings have practiced gain-of-function for the last 2,000 years, mostly in plants, where farmers would always save the largest seeds from the healthiest plants to replant the following year. The reason we can manage to have 7 billion people here on the planet is basically through direct or indirect genetic engineering through gain-of-function research. The simple definition of gain-of-function research is the introduction of a mutation that enhances a gene’s function or property—a process used commonly in genetic, biologic, and microbiologic research.” 

By that definition, breeding dogs for specific traits (lungs and height for sighthounds like Irish wolfhounds, roly-poly skin and coat for guard dogs like Shar-Peis, etc.) is an example of GOF, as is cross-breeding roses to get different colors. 

In the current context, that is disingenuous at best, purposefully obtuse at worst – by that logic, the Earth and Jupiter are the same thing because they are both planets. 

Baric does admit that the “classic” definition of GOF changed somewhat about a dozen years ago when the H5N1 avian flu virus was intentionally modified. H5N1 was already known to be particularly nasty to humans but, thankfully, it had a very tough time making the jump to humans. The virus was modified to make it more easily transmittable in order, it was claimed, to be able to better study and develop defenses against it if and when it did make the jump. 

Citing that as GOF successes, Baric said in the article that two drugs – including remdesivir of COVID fame – emerged from the process. 

Other experts in the field do not see the H5N1 work as qualifying as a “success” for GOF. 

“H5N1’s lethality was already known and it was so close already” said Dr. Jay Bhattacharya, a Stanford professor of medicine and a co-author of the “Great Barrington Declaration” that called for an entirely different, far more targeted approach to dealing with the pandemic. “(Proponents of GOF) cannot take credit for that.” 

Bhattacharya also finds it odd that said proponents of GOF must point to such wobbly “evidence” as the H5N1 episode to support their claims. 

“Given the amount of investment and the attention GOF has gotten, you would think the supporters would be more forceful in telling the world of their success,” Bhattacharya said. “Given that it is so potentially consequential, the public deserves more transparency.” 

Kevin Esvelt, a biology professor at MIT, agrees with Bhattacharya. “The public has never heard about it (working) because virus enhancement has, to my knowledge, never directly contributed to any real-world treatment or intervention,” Esvelt said. 

Esvelt also sees different definitions applying to different concepts and processes. For example, he notes that all bioengineering involves a type of "gain of function" but that it is only concerning, or problematic, when the function gained is the transmissibility or virulence of a pathogen. Instead, he defines the specific process that Baric and Wuhan Institute of Virology engage in as “virus enhancement.” 

Even so, the entire raison d’etre of the “make viruses nastier in the lab so we can be better fight them in the future” concept is inherently, irrevocably, and dangerously flawed. 

“The notion that you'd get the same outcome in the lab as will occur in nature is implausible. Evolution isn't that reproducible even under controlled conditions, and of course nature applies different conditions. So the ‘learn which mutations are dangerous’ argument doesn't hold much water,” Esvelt said. 

In other words, GOF researchers are basically trying to hit the evolutionary lotto - "Hey, look at that - it evolved EXACTLY how we predicted.” Since that has not occurred, that leads to other questions regarding its necessity, including that its usefulness may not at all lay in its publicly-stated purpose. 

The fact that – by default – super viruses have inherent bioweapon possibilities and the military-style response to the pandemic have led many to wonder about its real purpose. 

Remember - Ebright used the word “civilian.” 

As to COVID itself, in 2015, Baric worked with Dr. 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. (A spike gene determines how well a virus attaches to human cells.) 

In that article, Baric stressed that his lab did not cooperate too closely with the WIV – “Let me make it clear that we never sent any of our molecular clones or any chimeric viruses to China,” Baric said. 

Baric said he believes COVID to have emerged zoonotically but does admit the possibility of sloppy lab work and has steadfastly called for hyper-vigilant lab security protocols globally. He did, however, add that “(A)s the pathogenesis of SARS-CoV-2 is so complex, the thought that anybody could engineer it is almost ludicrous.” 

As to the definition of exactly what GOF is, it seems Baric believes it is in the eye-of-the-beholder - or at least the befunder – “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,” Baric said. 

Which brings us back to exactly what the NIH thinks qualifies as GOF. 

According to this 2021 paper by a trio of Johns Hopkins researchers titled “COVID‐19 and the gain of function debates” that imprecision makes any discussion of the true impact of GOF exceedingly difficult. 

“(T)he fuzzy and imprecise nature of the term GOF has led to misunderstandings and has hampered discussions on how to properly assess the benefit of such experiments and biosafety measures,” the paper states. 

While the National Institutes of Health did not reply to repeated emails and telephone messages asking for their current definition or even a comment on the subject, it seems the NIH itself looks at it this way, with GOF acting as possible means to enhance a pathogen (nasty microbe, virus, etc.). From a 2017 report (on the proper future oversight of GOF projects after they had been paused in the United States out of safety concerns for four years): 

“A potential pandemic pathogen (PPP) is one that satisfies both of the following: 

2.2.1. It is likely highly transmissible and likely capable of wide and uncontrollable spread in human populations, and 

2.2.2. It is likely highly virulent and likely to cause significant morbidity and/or mortality in humans. 

2.3. An enhanced PPP is a PPP resulting from the enhancement of a pathogen’s transmissibility and/or virulence. Wild-type pathogens that are circulating in or have been recovered from nature are not enhanced PPPs, regardless of their pandemic potential. “ 

It is the enhancing of pathogens that the NIH now considers a type of GOF research, though this was not always the definition it used, a fact highlighted by Kentucky Sen. Rand Paul in a tense exchange with the inexplicably powerful bureaucrat Dr. Anthony Fauci. Paul noted that shortly before that November, 2021 hearing the definition on the NIH website had been changed; Fauci side-stepped the question of why that was done but did admit the term itself is “nebulous”.  

Here is original definition the senator was referring to: 

The term gain-of-function (GOF) research describes a type of research that modifies a biological agent so that it confers new or enhanced activity to that agent. Some scientists use the term broadly to refer to any such modification. However, not all research described as GOF entails the same level of risk. For example, research that involves the modification of bacteria to allow production of human insulin, or the altering of the genetic program of immune cells in CAR-T cell therapy to treat cancer generally would be considered low risk. The subset of GOF research that is anticipated to enhance the transmissibility and/or virulence of potential pandemic pathogens, which are likely to make them more dangerous to humans, has been the subject of substantial scrutiny and deliberation. Such GOF approaches can sometimes be justified in laboratories with appropriate biosafety and biosecurity controls to help us understand the fundamental nature of human-pathogen interactions, assess the pandemic potential of emerging infectious agents, and inform public health and preparedness efforts, including surveillance and the development of vaccines and medical countermeasures. This research poses biosafety and biosecurity risks, and these risks must be carefully managed. 

Wayback Machine link here - https://web.archive.org/web/20211019065407/https:/www.nih.gov/news-events/gain-function-research-involving-potential-pandemic-pathogens . 

Here is what it was changed to: 

This research can help us understand the fundamental nature of human-pathogen interactions, assess the pandemic potential of emerging infectious agents such as viruses and inform public health and preparedness efforts, including surveillance and the development of vaccines and medical countermeasures. While such research is inherently risky and requires strict oversight, the risk of not doing this type of research and not being prepared for the next pandemic is also high. While ePPP (enhanced potential pandemic pathogen) research is a type of so called “gain-of-function” (GOF) research, the vast majority of GOF research does not involve ePPP and falls outside the scope of oversight required for research involving ePPPs. 

Even with the devastation that was likely caused by GOF, the NIH still appears to be playing fast and loose with the process, the definitions, and the safety regulations. 

Ebright said that “(A)t least approximately two dozen current NIH-funded projects appear to include enhanced potential pandemic pathogens research as defined in the P3CO Framework (approximately a dozen involving enhancement of potential pandemic pathogens other than SARS-CoV-2, and at least approximately another dozen involving enhancement of SARS-CoV-2,)” Ebright said. “None have received the risk-benefit review mandated under the P3CO Framework.” 

For a complete look at the current oversight – i.e. risk reduction - framework, see here: https://www.phe.gov/s3/dualuse/documents/p3co.pdf 

Take monkeypox, for example. Science Magazine reports that “In a U.S. government lab in Bethesda, Maryland, virologists plan to equip the strain of the monkeypox virus that spread globally this year, causing mostly rash and flulike symptoms, with genes from a second monkeypox strain that causes more serious illness. Then they’ll see whether any of the changes make the virus more lethal to mice. The researchers hope that unraveling how specific genes make monkeypox more deadly will lead to better drugs and vaccines.” 

Esvelt also questioned the benefits of the GOF process even if it worked: 

“And even if GOF was predictive, what intervention is going to change as a result? Are we going to develop a vaccine because it might accumulate the remaining mutations and spill over into humans? How are we going to test its efficacy against a presumably lethal, pandemic-capable virus that hasn't yet infected any human and might never do so?" asked Esvelt. 

GOF could be an example of scientific “white whaleism,” the maniacal search for something that carries only personal meaning – Ahab’s Moby Dick – just for the sake of the search, the chance to prove something to others that needs not proving, the doing of something out of a tunnel-vision obsession that will bring no tangible benefit and only the very real risk of catastrophe to others. 

“There are no cost-benefit analyses and no vaccine manufacturers clamoring for the data. It seems to be entirely driven by the all-knowledge-is-worth-having assumption” said Esvelt. 

As with any complicated, insecure, obscure, purposefully obtuse system, a fog-filled gray area exists around GOF and it must never be forgotten that gray areas are very convenient, very deniable places in which to hide questionable conduct. 

Did COVID spring from gain of function research in a Chinese lab? At this point, it seems somewhere between likely and probable that it did, protestations of the Chinese government and those reliant on government – doesn’t matter which government – funding aside. 

Why is GOF being performed? As it has never worked as advertised in the past, a logical possibility is that it could be useful for certain military applications and, of course, it may remain theoretically possible that some remote, ephemeral upside may someday occur…if the researchers get very very very lucky. 

Did the United States help pay for the research? Despite Fauci’s claims – which showed him to be either a liar or an incompetent or both – the answer is yes and the NIH is still funding GOF research, seemingly with questionable oversight (see above.) Overall, hundreds of millions of dollars (a precise figure is unavailable for obvious reasons) have gone into GOF research globally. 

Is GOF dangerous? Though almost all lab-based scientific research and advancements carry at least a tiny element of risk, nothing like the level of terminal, global, and trans-generational risk of GOF has – to the public’s knowledge - been undertaken since the Manhattan Project and the study of radiation. And even that had very specific, very probable, and very real and tangible benefits (useful for “pure” or basic science, ending World War II, power generation, nuclear medicine, etc.) that GOF cannot begin to claim. 

Did GOF create and either/or help end the pandemic? Those are million-dollar questions. 

Speaking of a million dollars, the effort to contact Dr. Peter Daszak’s EcoHealth Alliance – which took its cut of the money it funneled from the NIH to the WIV for gain of function research for comment for this article was unsuccessful. 

But the effort did lead to one of the saddest moments of irony possible, though. When you call the EcoHealth office, this is the message – to this day - you hear: “Our office is currently closed due to the COVID-19 pandemic.”