Gain of Function Research. Have We Opened Pandora’s Box?

Examining Gain of Function research from both sides of the spectrum.

Gain of Function Research (GOF) is one of the most controversial aspects to rise up out of the ashes of our almost post-pandemic society. For most of the West, unfettered access to vaccines has seen the covid pandemic beaten back, while in third world countries and Asia, SARS-CoV2 continues its unchecked transmission through unvaccinated populations, laying waste to countries like India.

What role has GOF played in all of this? Therein lies the crux of the debate, it either had everything to do with the virus or nothing or has perhaps contributed to it. There is evidence in favor of each of these scenarios, both for and against. Even science and its practitioners are divided on the topic and laypeople around the globe interpret a rambling cohort of random and often incorrect “facts” to arrive at their own conclusions. 

This discussion doesn’t relate to the SARS-CoV2 virus or its origins. It is solely about Gain of Function research. Are there risks associated with it, what are those risks, and is the scientific community justified in continuing to do the research? Is there sufficient evidence to suggest a global ban on this type of research?

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We thought we’d play devil’s advocate, posing both sides of the argument for and against the discontinuation of GOF research. To start us off, let’s establish exactly what Gain of Function research entails.

What is Gain of Function research, exactly?

Gain-of-function research refers to the serial passaging of microorganisms to increase their transmissibility, virulence, immunogenicity, and host tropism by applying selective pressure to a culture. So in other words, in layman’s terms, it’s about creating something nastier, tougher, and more deadly than the original by manipulating it in a laboratory.

Why would we want to do this? Aside from the obvious answer of weaponizing disease, there are a number of very valid scientific reasons for this research.

Also, to be clear, associating Gain of Function research as being mutually exclusive to influenza or coronaviruses is patently wrong. The field is immense and it is totally imprecise to equate GOF studies only with influenza transmission experiments. Virology is founded on adaptation approaches, and these have broad utility because they provide phenotypic evidence of a genotypic change when combined with a discriminatory biological assay.

Gain of Function studies are mostly applied in virology (to viruses) and have revealed many details regarding the biological mechanisms behind virus transmission and replication. Obviously, everything we can learn about the enemy is useful. How a virus evolves is a key part of our strategy to defeating it, developing vaccines, and knowing where to watch out for potential vectors. Gain of Function allows us a window into this world.

The high replication and mutation rate of viruses commonly leads to escape mutants, lineages that have acquired changes to their genome that lessen or eliminate the affinity of natural or vaccine-induced antibodies towards the virus, while not notably lowering survival. Most people now associate these words and terms with SARS-COV2 and its mutations and discussions about its origin.

Most mutations a virus acquires aren’t helpful to virus function, but in some cases mutation can both enhance virulence and allow better immune escape. For example, early studies regarding the E484K mutation of the spike protein of severe acute resSARS-CoV-2 suggest that affinity towards the ACE2 receptor, the target of the virus, is enhanced, while neutralization by serum antibodies sourced from patients having recovered from wild type SARS-CoV-2 are evaded more effectively.

In simple terms, the virus evades our natural immunity by developing new ways of attacking us and these include “hiding” by not triggering signals our immune system has trained itself to look out for. Influenza is an excellent example, returning year after year with a new book of tricks, and boom, you’re down with the flu again.

Gain of Function allows scientists to encourage these mutations in a laboratory setting where they can study the process and figure out ways of keeping our medicines and vaccines one step ahead of the curve. The potential for unearthing an as yet unknown key to controlling viruses may very well lie in the pursuit of this research.

So before we plow ahead let’s clear the air. 

This article refers only to Gain of Function research in terms of its applicability to enhancing dangerous pathogens. 

Sounds really cool, where’s the problem?

And Gain of Function really is. One of the reasons we’ve been able to develop vaccines so rapidly for Covid, Moderna had a working model ready to go in a month, is thanks in no small part to GOF research. So there are clear and easily defined benefits to the research. There are, however, also very distinct dangers involved that we cannot afford to ignore. 

Without being dramatic, pursuing this line of research without properly ensuring its safety, could lead to an extinction-level event. Us being the species we wipe out. It’s an unlikely, but not impossible consequence.

In 2012 a paper was published in Science by Herfst et al., titled: Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets. The group had genetically modified the A/H5N1 virus (Avian influenza) by site-directed mutagenesis and serial passages in ferrets, creating a strain that was airborne transmissible in ferrets.

This demonstrated that it was possible for the avian influenza virus to become airborne and that the strain was sensitive to certain antiviral drugs. The paper raised many concerns regarding the ethics and safety of creating such a virus. The risks of accidental or intentional malicious release caused the USA administration under Barack Obama to halt funding for gain-of-function research relating to influenza, SARS, or MERS in 2014. 

In 2016, under questionable advice from the National Science Advisory Board for Biosecurity (NSABB), the NIH overturned the moratorium on GOF research and resumed funding research, including projects run in Wuhan 

The dangers of Gain of Function lie on a number of fronts and it is these we will explore in-depth in this article. Our aim is to provide as balanced a discussion as possible on the topic. Here then a quick overview of what we will look at.

Laboratory Safety: Can we ensure that research and viruses and other organisms used in Gain of Function research stay where they are supposed to stay. In the confines of a laboratory? History tends to suggest no. How do we secure these facilities, keeping in mind they are global and subject to various different regulatory bodies, to ensure lab leaks do not occur? Can we human-proof them?

Military Engagement: Discover something deadly or set about building it and every single military complex on the face of the planet perks up its ears. Biological weapons are the most deadly, untraceable, and easily dispersed weapons on the planet. When every single human can act as a potential vector for spreading a virus, you can simply build it (or steal it), release it and sit back and watch.

Corporate Agendas: There’s a thin line here between conspiracy and corporate greed, but this is still a hugely valid concern, particularly now that we have the basic parameters for a global pandemic established, thanks to SARS-CoV2. As companies like Microsoft, Amazon, Google, The Gates Foundation and other large corporates dip their toes into Healthcare, we’d be well-served to remember these organizations serve their shareholders and the gods of capitalism. Our well-being is not on their checklist for global domination.

Laboratory Safety and Gain of Function Research

This is, on a personal level, where my largest concerns lie. These concerns are motivated by the following factors, all of which can and may contribute to the potential leaking of a deadly pathogen from a laboratory, and I am not alone. In 2014 scientists calling themselves the Cambridge Working Group urged caution on creating new viruses. In what may have been prescient words, they specified the risk of creating a dangerous virus.

“Accident risks with newly created ‘potential pandemic pathogens’ raise grave new concerns,” they wrote. “Laboratory creation of highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza, poses substantially increased risks. An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control.”

The human element

The most secure systems in the world are all subject to this one, flawed cog. The human one. Whether by intention (disgruntled or “bought” researchers) or accidental (overworked, momentary lapses of concentration) this risk can only be removed by isolating and automating processes completely. 

This could potentially be achieved by robotic automation, where robotic arms and machines can perform experiments in total isolation, without the need for a human to breach the working environment. Obvious drawbacks still exist to this system, including the need to physically introduce cultures into the secured environment, prohibitive costs for many facilities, and extending the time required for processing research. 

Automation still doesn’t overcome the major problem associated with this kind of research, that of human involvement. Smuggling out a pathogen remains a constant possibility, with many people within a facility having access to Biosafety Level 4 laboratories. The accidental infection of laboratory technicians also remains a very real risk.

The slow and painful dismantling of accepted dogma also poses a huge risk. We have only now, in the last few months accepted a massive body of evidence supporting the fact that coronaviruses can move about freely in the air, like the measles virus. They become aerosolized and don’t require water droplets. Six feet isn’t an obstacle, neither are walls and doors, so our so-called secured facilities may very well have been built on flawed science.

What we thought was sufficient protection for certain viruses simply wasn’t. It’s a simple mistake, but a fatal one based on 80-year-old research, and our inability to freely question accepted scientific dogma poses a very real risk in fields that deal with potential pandemic-capable pathogens.

How often do pathogens escape their laboratory confines? This is a question we can attempt to answer by looking back at the incidents listed over the last few decades. It is of course entirely possible that many have been covered up, particularly those originating from off-grid laboratories run by the military and other government agencies.

The paper referenced above makes for interesting reading and has this to say on the 1977 H1N1 virus that mysteriously resurfaced after a 20-year absence.

Public awareness of the 1977 H1N1 pandemic and its likely laboratory origins has been virtually absent. Virologists and public health officials with the appropriate sophistication were quickly aware that a laboratory release was the most likely origin, but they were content not to publicize this, aware that such embarrassing allegations would likely end the then nascent cooperation of Russian and Chinese virologists, which was vital to worldwide influenza surveillance.

The most plausible reason for a Chinese or Russian laboratory to thaw out and begin growing a c1950 H1N1 virus in 1976–77 was as a response to the US 1976 “swine flu” program, which resulted in a program to immunize the entire US population against H1N1 influenza virus. It was clearly a rational response for other countries with virology capabilities to explore making their own H1N1 vaccines. Thawing available frozen stocks of the virus was necessary because H1N1 was no longer circulating. 

Modern commentators have begun to articulate this connection between the 1976 Swine flu immunization program and the 1977 H1N1 re-emergence:

“Perhaps an even more serious consequence [of the 1976 swine flu episode] was the accidental release of human-adapted influenza A (H1N1) virus from a research study, with subsequent resurrection and global spread of this previously extinct virus, leading to what could be regarded as a ‘self-fulfilling prophecy’ epidemic.”(Zimmer 2009)

SARS, the laboratory escape artist 

SARS has not naturally recurred since 2003, but there have been six separate “escapes” from virology labs studying it: one each in Singapore and Taiwan, and in four distinct events at the same laboratory in Beijing.

  • The first escape was in Singapore in August 2003, in a 27-year-old virology graduate student at the National University of Singapore. He had not worked directly with SARS, but SARS was present in the virology laboratory where he worked with West Nile Virus (WNV). Investigation showed that his preparation of WNV was contaminated with the SARS virus and that this was the likely origin of his infection.
  • The second escape was in Taiwan in December 2003, when a SARS research scientist fell ill on a return air flight after attending a medical meeting in Singapore Dec 7- 10.
  • On April 22, 2004 China reported a suspected case of SARS in a 20-year-old nurse who fell ill April 5 in Beijing. The next day it reported she had nursed a 26-year old female laboratory researcher who had fallen ill on March 25. Still ill, the researcher had traveled by train to her home in Anhui province where she was nursed by her mother, a physician, who fell ill on April 8 and died April 19. The researcher had worked at the Chinese National Institute of Virology (NIV) in Beijing.
  • Several Chinese and international groups investigated the outbreak at the NIV and identified in retrospect two additional SARS laboratory infections at the NIV that had previously gone unrecognized and had begun in February 2004.

Foot and Mouth Disease, Pirbright, England 2007

Foot and Mouth Disease (FMD) is a veterinary disease that affects primarily cloven-hoofed domestic animals (pigs, sheep and cattle). It has been eradicated in North America and most of Europe. It is highly transmissible, capable of spreading through direct contact and even through some prepared meats (sausages, airline food), on boots of farmworkers (or tourists’ shoes: that’s why there’s that question “have you visited a farm” on the re-entry customs checklist coming into the USA), and even by aerosol spread.

Two separate instances were recorded in 2007 of the virus escaping a facility in Pirbright tasked with producing vaccines against FMD for the veterinary industry. The outbreaks cost the UK an estimated 200 million pounds and the damage to the livestock and meat industry was substantial.

As an aside, in the US, previous law had banned it on the continental US, so FMD virus was only held in the USDA Plum Island facility off of Long Island (in a facility originally built in the 1950s for anti-animal BW work). Currently, a replacement facility under the Department of Homeland Security (DHS), the National Bio and Agro-Defense Facility (NBAF) is under construction in Manhattan, KS and will become the new home of this incredibly infectious and highly transmissible virus. It seems we don’t learn our lessons.

It is clear that accidents occur in laboratories. To suggest they don’t is both dishonest and disingenuous. The question we need to be asking now is given the current chaos on the heels of the Covid Pandemic, can we afford any new accidents? Although there is no concrete evidence to support the laboratory leak in Wuhan, it cannot completely be dismissed yet either.

Can scientists and science assure us there will be no future mishaps? The answer to that has to be no. So there remains a risk, a global risk. The question we then need to ask is this. Do the benefits we are afforded by GOF research justify the potential risks?

The Military and Weaponizing Diseases

GOF serves two purposes in this setting. It allows for the creation of more deadly pathogens and it allows scientists to study the way in which these pathogens can be combated. This is where the lines of ethical arguments, safety, and practical enforcement become blurred.

This technology is comparable to the nuclear capability of a country. If we stop all GOF research, how are we then able to protect ourselves against rogue states that do not comply with a global ban on GOF research? Biological agents are undoubtedly the new preferred weapon of choice for many countries for very obvious reasons.

  • Biological agents can decimate a targetted population whilst leaving all infrastructure unharmed.
  • The cost of developing these agents is minimal in comparison to say for instance a nuclear arsenal, or an ICBM platform.
  • The nature of the weapon makes its covert development far simpler to achieve.
  • Countermeasures or vaccines can readily be introduced to protect a local population.
  • Militant groups can seek to secure these agents through financial incentives, or simple theft from laboratories that do not engage sufficient security protocols.

Clearly, if you have no compunction about wiping out millions of innocent lives, a biological agent is your weapon of first choice. This is not lost on governments across the globe, and each government engages in its own clandestine efforts to stay up to speed in the virus wars. Their tool of choice is Gain of Function.

By restricting GOF research to military laboratories, you restrict the potential risks of theft. You cannot remove this risk completely, as again, we are dealing with human beings, but you can ensure the risk is dramatically reduced. The flipside of this coin isn’t that great though. The military is not renowned for transparency and the regulation and safety monitoring of these facilities by impartial external agencies would prove nigh on impossible.

Additionally, the focus of military financed research will lean heavily toward the weaponization of the viruses it studies. To sanction this is comparable with strapping a load of dynamite to your back and tossing lit matches over your shoulder. 

It’s a catch 22 and irrelevant of what the global scientific community decides about GOF research, you can rest assured that military agencies across the globe will continue irrespective. The genie is out of the bottle and we cannot put it back. Many find themselves uncertain as to whether we should even try and from a military perspective, the argument of preparedness holds water.

Corporate greed and that thin line in the sand

Welcome, all our conspiratorial compatriots, to the juicy bits. Supposition and wild conjecture based on rumor, possibility, and the public whipping post, to which we have all bound ourselves with the unbreakable bonds of capitalism. Our scrambled financial history of Keynesian economics and Friedman has bred financial behemoths, monsters controlled by individuals rather than governments, and therein lies our problem.

These companies, owned by individuals like Bezos, Gates, Zuckerberg, and others are driven by one singular purpose. He who dies with the most wins. While there are considerable donations made and charitable organizations founded, the motives and ambitions of these individuals remain the subject of intense debate. Covid has presented and highlighted the next frontier. Healthcare. And the respective owners of the monsters are falling over each other to get to the front of the queue.

If you think large corporations would be discouraged by killing off a few million people to conquer a single global market, think again. If you had to remove all the unhealthy, disease-causing, potentially toxic and carcinogenic items from your local supermarket chain’s shelves, you’d probably be left with a single shelf of produce. American consumers are being fattened and slaughtered by large businesses. It’s been happening for decades, and most consumers never realize it.

So the question here boils down to this. Who is the more evil? Your local Costco or a large corporate who decides to “manage” a future pandemic? If you’re killing your customer over two decades using fat-laden poisons or in two months with a designer virus, there really isn’t any difference, is there.

The Gates Foundation has already spread its reach into the WHO, vaccine trials, and development, and yes, Gain of Function research. Bill Gates, without a single shred of medical or scientific training relating to these fields, is dictating global health policy or attempting to. He is not alone. The fortunes to be made from global vaccines are not to be sneezed at and arguably, all you need is a product that caters to a demand. 

How you set about creating that demand is where the issues arise. 

Before you dismiss this as a flight of fancy, remember the world you are I now live in. One that in January of 2020 would have seemed like a dystopian fairytale, had you described it. We have to assume the worst of manipulative corporations that have ALL profited hugely from the pandemic. Allowing them potential access to gain of function research is in my humble opinion, a terrible idea.

Back to reality and today

Where does all this leave us? It’s an almost foregone conclusion that the term Gain of Function will become a household name over the next few months as we ramp up our (what I believe to be futile) efforts to track the origin of SARS-CoV2. The virus may or may not present its origin when it and science meet in a mutually agreeable place at a date of its choosing.

The role played by GOF research will remain at the forefront of the discussion and its very presence in the discussion, whether it is eventually shown to be complicit or not, should sound a warning call to both science and those that seek to protect our societies. Laboratories across the globe are currently engaged in GOF research. Even now as I write this, many will be rushing ahead on projects and multi-tasking, all too aware of the ax that now dangles above the neck of GOF.

This in itself presents additional opportunities for laboratory breaches. 

We’ve been having this discussion for a while now. This 2015 article in Nature entitled “Gain-of-function experiments: time for a real debate” highlights just how long we’ve been debating the benefits of GOF research and also provides an excellent defense for the technology. In the article the author frames the problem as follows; (PPP refers to Potentially Pandemic Pathogens)

Creating PPPs — a subset of GOF experiments involving creation of novel, virulent, transmissible viruses — is one of these approaches. Unlike other GOF experiments, the creation of PPPs entails a unique risk that a laboratory accident could spark a pandemic killing millions. The question is not whether to carry out research on PPPs or to do nothing; it is whether to have a portfolio of approaches to defeat viruses without creating a pandemic risk, or whether to include PPP experiments in that portfolio. For example, we should decide whether devoting our limited resources for flu research towards PPP creation experiments — which are expensive, often underpowered, low-throughput and often poorly generalizable5, and which create pandemic risk — is better than using those resources to enhance the rest of the portfolio for flu preparedness.

We need to sit down as a global community and address Gain of Function now. Scientists need to produce a foolproof design, perhaps an enhanced version of BSL4, for future experimentation that all but eliminates the risk of escape and we need to ensure that any changes are implemented and rigorously policed. Organizations like the National Science Advisory Board for Biosecurity (NSABB) have proven themselves hopelessly unsuited to either determining risk or monitoring facilities.

An independent body, divorced from the role of science, needs to be established to monitor global GOF research involving PPP. The question now is who that would be and the World Health Organization is clearly not a candidate. They have proven themselves, over the duration of the pandemic, to be woefully ill-equipped to either address the demands of new emergent science or to cope with the dynamics of imminent threat. To date, they’ve been hugely non-commital on what they refer to as dual use research of concern (DURC).

All in all, it’s a series of events that will require a level of cooperation beyond anything we’ve been able to achieve over the course of the pandemic and that may prove to be its undoing. We may just simply resort to bans or moratoriums on a country-by-country basis that restrict GOF research on anything that could remotely be considered an end-of-days pathogen.

The research scientists rushing about their laboratories trying to force five years of research into an ever-narrowing window may already have seen the writing on the wall.

I’ll leave you with a quote from David A. Relman, from the 2015 Nature article referenced above. Do click on the referenced article in the quote.

More than twice a week in US laboratories, there is a ‘possible release event’ or a ‘possible loss event’, even if we look only at select agents — some of the most dangerous pathogens. For every 1,000 lab-years of work in BSL-3 laboratories in the United States with select agents, there are at least 2 accidental infections.

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This article lives here: The Quack ScaleGain of Function Research. Have We Opened Pandora's Box?
Dr Robert Turnerhttps://cre8tive.media
Robert is a Founder of Medika Life. He is a published author and owner of Cre8tive Digital Media. He lives between the Philippines and the UK. and is an outspoken advocate for human rights. Access to basic healthcare and eradicating racial and gender bias in medicine are key motivators behind the Medika website and reflect Robert's passion for accessible medical care globally.

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