Gain of Function

Scientists Manipulating Virus (AI image)

Gain of Function (GOF) research is used to create new capabilities for a virus/bacteria/cells. The stated goal for this research is to understand how viruses may evolve naturally and develop ways to stop them. Critics say that the product of Gain of Function research could be leaked by a lab or used by terrorists to cause a pandemic.

Gain of Function can be a subset of Dual Use Research of Concern (DURC), or research that has the potential for both beneficial and harmful applications.

Enhanced Potential Pandemic Pathogens

D. Christian Hassell Explains Difference between PPP and ePPP

Potential Pandemic Pathogens", often referred to as "P3" or PPP, exist naturally while "Enhanced Potential Pandemic Pathogens" (eP3 or ePPP) are the product of Gain of Function research. D. Christian Hassell, a National Science Advisory Board for Biosecurity member representing the Department of Defense in 2020, explained that oftentimes "P3" is used as a "euphemism" for "Enhanced Potential Pandemic Pathogens".

Gain of Function in H5N1

Research that enhances the transmissibility of H5N1 influenza viruses (Gain of Function research) raises biosafety concerns, as accidental release or misuse (e.g., for bioterrorism) of these "Enhanced Potential Pandemic Pathogens" (ePPPs) could have devastating consequences.

Gain of Function in Covid-19

The 2019 Covid-19 Pandemic was most likely the result of a leak or misuse of Gain of Function Research.

Gain of Function Timeline

Note: Timeline generated on fully sourced information on this page.

• Late 2011: Two studies funded by the National Institutes of Health (NIH) caused controversy. These studies involved mutations that could make H5N1, a dangerous bird flu strain, transmissible in mammals. Concerns arose about the research, known as "Gain of Function," potentially leading to a lab leak or misuse.

• Early 2012: A voluntary moratorium on Gain of Function research on avian influenza H5N1 was implemented due to safety and security concerns.

• April 2012: The National Science Advisory Board for Biosecurity (NSABB) requested redacting key details from the H5N1 studies due to concerns about potential misuse. The World Health Organization (WHO) disagreed and favored full publication.

• April, 2012: The NSABB reversed course and allowed full publication of the H5N1 studies with the support of the NIH and HHS.

• April 26, 2012: During a hearing titled "Biological Security: The Risk of Dual-Use Research", Anthony Fauci acknowledged concerns but advocated against a moratorium on Gain of Function Research on H5N1. He highlighted the importance of research for pandemic preparedness but also acknowledged the risks of misuse.

• December 17-18, 2012: During a meeting on Gain of Function Research on H5N1 Bird Flu Virus, Anthony Fauci, then director of the National Institute of Allergy and Infectious Diseases (NIAID), showed support for this type of research. He highlighted the importance of research on emerging infectious diseases and mentioned grant recipients were expected to publish their findings.

• October 2014: A moratorium on funding for certain Gain of Function research involving influenza, MERS, and SARS viruses was implemented following two mishaps at government labs, one handling anthrax and one handling avian flu at CDC labs.

• December 19, 2017: The NIH announced the lifting of the funding pause on Gain of Function research. A new framework to guide funding decisions for research involving "Potentially Pandemic Pathogens" was established.

2014 - 2017 Another Moratorium on Gain of Function

In 2014, a moratorium on Gain of Function Research "was imposed a few months after two mishaps at government labs, one handling anthrax and one handling avian flu". The moratorium was lifted in 2017.

From a Scientific American titled "U.S. Lifts Moratorium on Funding Controversial, High-Risk Virus Research" dated December 19, 2017:

"The federal government announced on Tuesday that it is lifting a three-year moratorium on funding controversial research that involves genetically altering viruses in ways that could make them more contagious, more deadly, or both—and that critics say risks triggering a catastrophic pandemic.

Called gain-of-function experiments, the studies aim to understand genetic changes that can make viruses such as bird flu, SARS (severe acute respiratory syndrome), and MERS (Middle East respiratory syndrome) more transmissible from person to person. But if they escaped from the lab, perhaps through human error, the modified viruses could in theory spread quickly or be extremely virulent, increasing the toll of an outbreak.

The moratorium was imposed a few months after two mishaps at government labs, one handling anthrax and one handling avian flu, which together suggested that biosafety and biosecurity at even the most respected labs fell well short of what is needed to protect the public.

• January 2014: An accidental cross contamination which included the highly pathogenic avian influenza (HPAI) A (H5N1) virus occurred at a CDC lab in January 2014 but wasn't identified until May.

• June 5, 2014: During a CDC lab procedure in June 2014, established safety practices were not followed, potentially exposing some employees to live anthrax bacteria.

On December 19, 2017, the NIH released a memo stating that the funding pause for Gain of Function Research was being lifted, citing a new framework that will guide funding decisions for research involving potentially pandemic pathogens (PPPs) and enhanced PPPs, which are modified versions of PPPs with increased transmissibility or virulence. The framework ensures a multi-layered review process for such research proposals.

As an aside, Dr. Samuel Stanley, president of Stony Brook University and chairman of the National Science Advisory Board for Biosecurity made a similar statement to that of Anthony Fauci while endorsing Gain of Function Research: “Evolution guarantees that naturally pathogenically ‘enhanced’ [strains] of influenza and other pathogens will emerge...Nature is the ultimate bioterrorist and we need to do all we can to stay one step ahead” by conducting research “to help us better recognize and countermand these strains.”

Summary of 2011 - 2013 H5N1 Controversy

In 2011, two taxpayer-funded studies sparked debate. These studies described mutations that could make H5N1, a dangerous bird flu strain, transmissible in mammals. Concerns arose about the research, known as "gain-of-function," potentially leading to a lab leak or misuse. This was further fueled by past incidents of lab leaks involving SARS.

Fauci in the Middle of the Debate

Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID) that funded the research, initially supported a moratorium on such research while acknowledging safety concerns. However, he later advocated for its continuation.

Publication Dispute and Resolution

The National Science Advisory Board for Biosecurity (NSABB) requested redacting key details from the H5N1 studies. The World Health Organization (WHO) disagreed, favoring full publication. Ultimately, in April 2012, the NSABB reversed course, allowing full publication with the support of the NIH and HHS.

Deeper Summary

In 2011, two H5N1 studies were submitted for publication. These taxpayer-funded studies described how mutations in H5N1 could be used to become transmissible in mammals. In late December 2011, the National Science Advisory Board for Biosecurity (NSABB) asked the scientists to redact key details from the papers.

Anthony Fauci headed the National Institutes of Health agency National Institute of Allergy and Infectious Diseases (NIAID) that funded the "controversial Dutch experiment" spearheaded by virologist Ron Fouchier (and also a team headed by Yoshihiro Kawaoka at the University of Wisconsin-Madison). Concerned that the research, known as "Gain of Function", could lead to potentially devastating outcomes, such as a lab leak or be accessed by terrorists, scientists called for a moratorium on that category of research in January 2012.

Note that several lab leaks involving Severe Acute Respiratory Syndrome (SARS) occurred in Singapore, Taiwan, and China between 2002 and 2004.

While Anthony Fauci agreed to the moratorium initially, he expressed concerns that while it is important to "be extremely sensitive to safety and security", he "would not want to see...an overreaction." As time went on, however, Anthony Fauci, then a member of the NSABB, was explicit that Gain of Function research should continue. By March, 2012, Anthony Fauci was pushing to stop the moratorium.

The World Health Organization disagreed with the NSABB's request that the H5N1 papers should be redacted. In April, the NSABB changed course. In a statement by then-NIH Director Francis Collins with approval from then-HHS Secretary Kathleen Sebelius agree "with the NSABB’s recommendation that the information in the two manuscripts should be communicated fully and we have conveyed our concurrence to the journals considering publication of the manuscripts."

Council on Foreign Relations Weighs In

In July, 2013, a "working paper" titled "H5N1: A Case Study for Dual-Use Research" by Gigi Kwik Gronvall of the Council on Foreign Relations attempted to justify the use of Gain of Function Research but with global safety norms, using the controversy around H5N1 as a case study.

'a most, most unusual smoldering, pre-pandemic threat'

Gain of Function Research on H5N1 Bird Flu Virus December 17-18, 2012

During a meeting titled "Gain-of-Function Research on HPAI (Highly Pathogenic Avian Influenza A) H5N1 Viruses: Welcome and Introductory Remarks" on December 17-18, 2012, Anthony Fauci showed support for Gain of Function research on H5N1 Bird Flu. In what appeared to be an incentive to continue the Gain of Function research, Anthony Fauci alluded to funding, stating that grant recipients were expected to publish their findings. Anthony Fauci explained that after a voluntary moratorium on gain-of-function research on avian influenza, a workshop was organized to discuss risk-benefit analysis and develop criteria for future funding of such research by taxpayers through the NIH and CDC. This workshop aimed to guide future research decisions while considering scientific, public health, safety, and security aspects.

'We are playing with fire'

On May 14, 2012, CNN reported in an article titled: "Science journal could give recipe for deadly avian flu virus":

"“We need as scientists and health officials to stay one step ahead of the virus as it mutates and changes its capability,” Fauci told CNN Radio recently. “To anticipate that would be important to determine whether the countermeasures we have available, such as antivirals and vaccines, would actually be effective against such a virus that changed in such a way.”

But a number of scientists are stepping forward to say it is not worth it – and that this research could actually bring us closer to that nightmare.

How? By making a lethal virus that spreads like seasonal flu.

“We are playing with fire,” says Dr. Thomas Inglesby and his colleagues at the Center for Biosecurity at the University of Pittsburgh Medical Center.

"If this engineered virus were to escape the laboratory, by accident or by evil, “it could endanger the lives of hundreds of millions of persons,” Inglesby says.

Fauci: 'nature itself is the most dangerous bioterrorist'

During a hearing dated April 26, 2012, titled "Biological Security: The Risk of Dual-Use Research", Anthony Fauci acknowledged concerns but advocated against a moratorium on Gain of Function Research on H5N1. His testimony highlighted what he perceived to be the importance of taxpayer-funded research on emerging infectious diseases like H5N1 influenza. He acknowledged that Gain of Function research can predict and prepare for pandemics, but it can also be misused (dual-use research of concern [DURC]). He assured hearing participants that a new government-wide policy aims to balance public health benefits with biosecurity risks, ensuring research transparency and communication.

Excerpt from Anthony Fauci's statement:

"the issue at hand is the ongoing threat of the emergence of an H5N1 pandemic influenza and the research that was supported by the NIH to address this threat. The publication of the results of such research in the form of the two manuscripts that you mentioned has focused considerable public attention on the issue of dual-use research, namely research that is directed at providing new information critical to the public health, but at the same time has the potential for malevolent applications.

My written testimony is submitted for the record, and in my few minutes of time, I will highlight just a few important aspects of this issue.

First, the public health challenge. Seasonal influenza is an ongoing threat to public health worldwide and is among the leading global causes of death due to infectious diseases. Each year, influenza causes more than 200,000 hospitalizations and up to 49,000 deaths in the United States and up to a half-a-million deaths globally. Yet influenza has animal reservoirs, especially in birds, and these viruses can undergo extensive genetic changes and jump species, resulting in an influenza virus to which humans are highly vulnerable.

Such an event can and historically has led to global disasters, such as the one you mentioned, the prime example being the 1918 global influenza pandemic that killed up to 100 million people worldwide and caused enormous social and economic disruption. There is a clear and present danger that we will have another influenza pandemic, since these viruses continue to circulate in the world and are constantly evolving toward pandemic capability, as we have seen in 1957, 1968, and 2009.

Over the last decade, a highly pathogenic H5N1 influenza has emerged among chickens. Rarely, the virus spreads to humans. Since 2003, approximately 600 confirmed cases have occurred in humans in more than a dozen countries shown in red on this poster. Nearly 60 percent of those reported cases have resulted in death. Should the virus mutate to transmit more efficiently to and among people, a widespread influenza pandemic could ensue.

Indeed, nature itself is the most dangerous bioterrorist, and even as we meet today, H5N1 and other influenza viruses are naturally mutating and changing with the potential of a catastrophic pandemic. This is not a theoretical danger. It is a real danger.

For decades, NIH has supported basic influenza research included on transmissibility, host adaptation, and virulence. The goal is to anticipate what the virus is continually trying to do on its own in the wild and to prepare for it. Such goals were pursued by the NIH-funded scientists Kawaoka and Fouchier and could have important positive implications for pandemic influenza prediction, prevention, diagnosis, and treatment.

Kawaoka and Fouchier constructed variants of H5N1 avian influenza in order to identify which genetic mutations might alter the transmissibility of the virus. In their studies, they employed a standard influenza animal model, namely the ferret...

... I might point out that one of the causes of the public misunderstanding was the widespread belief that the virus that was transmitted by aerosol from one ferret to another actually killed the ferrets when, in fact, that was not the case.

We feel that these studies provide critical information and it was important to determine if H5N1 virus that has this enhanced transmissibility would remain sensitive to existing anti-influenza drugs and vaccines. In addition, and importantly, knowledge of the genetic mutations that facilitate transmission may be critical for global surveillance of emerging influenza viruses.

Yet since transmissibility of a virulent virus was increased, this constitutes dual-use research of concern (DURC), which is shown on this poster. If a particular research experiment is identified as DURC, that designation does not necessarily mean that such research should not be published, nor should it even be prohibited in the first place. However, it does call for us, as you mentioned, to balance carefully the benefit of the research to the public health, the biosafety and biosecurity conditions under which the research is conducted, and the potential risk that the knowledge gained from such research might fall into the hands of those with ill intent.

[...]

Importantly, the public attention and concern generated by this issue has triggered a voluntary moratorium or pause on this type of research on the part of the influenza research community as well as a fresh look at how the U.S. Government handles DURC, as manifested by a formalization of a government-wide policy to address the issue.

This policy, which was released on March 29, strengthens and formalizes ongoing efforts in DURC oversight and is described in my written testimony. The ultimate goal of the NIH in its embrace of this new policy is to ensure that the conduct and communication of research in this area remain transparent and open at the same time as the risk-benefit ratio of such research clearly tips towards benefitting society.

'An Engineered Doomsday'

On Jan. 7, 2012, a New York Times editorial titled "An Engineered Doomsday" explained that scientists created a potentially deadly airborne influenza virus while researching bird flu. This research could be misused by terrorists and the benefits seem minimal. The editorial suggests destroying the virus or strictly controlling it, and argues for stricter oversight of such research in the future.

Verbatim:

"Scientists have long worried that an influenza virus that has ravaged poultry and wild birds in Asia might evolve to pose a threat to humans. Now scientists financed by the National Institutes of Health have shown in a laboratory how that could happen. In the process they created a virus that could kill tens or hundreds of millions of people if it escaped confinement or was stolen by terrorists.

We nearly always champion unfettered scientific research and open publication of the results. In this case it looks like the research should never have been undertaken because the potential harm is so catastrophic and the potential benefits from studying the virus so speculative.

Unless the scientific community and health officials can provide more persuasive justifications than they have so far, the new virus, which is in the Netherlands, ought to be destroyed. Barring that, it should be put in a few government-controlled laboratories with the highest containment rating, known as biosafety level 4. That is how the United States and Russia contain samples of smallpox, which poses nowhere near the same danger of global devastation.

In the future, it is imperative that any such experiments be rigorously analyzed for potential dangers — preferably through an international review mechanism, but also by governmental funding agencies — before they are undertaken, not after the fact as is happening in this case. The most frightening research was done by scientists at the Erasmus Medical Center in Rotterdam, who sought to discover how likely it is that the “bird flu” virus, designated A (H5N1), might mutate from a form that seldom infects or spreads among humans into a form highly transmissible by coughing or sneezing. Thus far the virus has infected close to 600 humans and killed more than half of them, a fatality rate that far exceeds the 2 percent rate in the 1918 influenza pandemic that killed as many as 100 million people. Working with ferrets, the animal that is most like humans in responding to influenza, the researchers found that a mere five genetic mutations allowed the virus to spread through the air from one ferret to another while maintaining its lethality. A separate study at the University of Wisconsin, about which little is known publicly, produced a virus that is thought to be less virulent.

These findings led to an unprecedented request from an American federal advisory board that the researchers and the two scientific journals that plan to publish the studies omit any details that might help terrorists figure out how to unleash a devastating pandemic. That presumably includes details on how the engineered virus was made and details on the precise mutations that allowed it to go airborne.

We doubt that anything at all should be published, but it seems clear that something will be.

The two journals reviewing the papers seem inclined to follow the advisory board’s recommendations that the research be published in a redacted form, provided there is some way for researchers who need the information to gain access to the full details. The Erasmus team believes that more than 100 laboratories and perhaps 1,000 scientists around the world need to know the precise mutations to look for. That would spread the information far too widely. It should suffice to have a few of the most sophisticated laboratories do the analyses.

Defenders of the research in Rotterdam claim it will provide two major benefits for protecting global health. First, they say the findings could prove helpful in monitoring virus samples from infected birds and animals. If genetic analysis found a virus somewhere that was only one or two mutations away from going airborne, public health officials would then know to bear down aggressively in that area to limit human contact with infected poultry and ramp up supplies of vaccines and medicines. But it is highly uncertain, even improbable, that the virus would mutate in nature along the pathways prodded in a laboratory environment, so the benefit of looking for these five mutations seems marginal.

A second postulated benefit is that the engineered virus can be used to test whether existing antiviral drugs and vaccines would be effective against it and, if they come up short, design new drugs and vaccines that can neutralize it. But genetic changes that affect transmissibility do not necessarily change the properties that make a virus susceptible to drugs or to the antibodies produced by a vaccine, so that approach may not yield much useful new information.

We cannot say there would be no benefits at all from studying the virus. We respect the researchers’ desire to protect public health. But the consequences, should the virus escape, are too devastating to risk.

Dangerous Research

On December 20, 2011, the National Institutes of Health published a Press Release addressing controversial H5N1 research, assuring the public that the (Gain of Function) research is necessary and measures are in place to mitigate misuse [by terrorists] of findings.

As summarized by AI:

"The US is concerned about both seasonal influenza and potential pandemics. While avian influenza (H5N1) rarely infects humans now, scientists worry it could mutate and become highly transmissible. Research is crucial to prepare for this possibility, but some details could be misused. A committee reviewed unpublished research on H5N1 transmission and recommended redacting specific methods while allowing publication of the overall findings. The US is working on secure access to such details for qualified researchers and developing a policy to oversee research with potential for misuse."

Excerpt of Press Release:

"Currently, H5N1 avian influenza virus — the strain commonly referred to as "bird flu" — rarely infects humans and does not spread easily from person to person. However, many scientists and public health officials are concerned that the virus could evolve in nature into a form that is transmissible among humans — an event that could potentially make this deadly virus an extremely serious global public health threat. Thus research on factors that can affect the transmissibility of the H5N1 virus is critically important to international efforts to prepare and prevent threats to public health.

While the public health benefits of such research can be important, certain information obtained through such studies has the potential to be misused for harmful purposes. The National Science Advisory Board for Biosecurity (NSABB) — an independent expert committee that advises the Department of Health and Human Services (HHS) and other Federal departments and agencies on matters of biosecurity — completed a review of two unpublished manuscripts describing NIH-funded research on the transmissibility of H5N1. These manuscripts — which describe laboratory experiments that resulted in viruses with enhanced transmissibility in mammals – concluded that the H5N1 virus has greater potential than previously believed to gain a dangerous capacity to be transmitted among mammals, including perhaps humans, and describe some of the genetic changes that appear to correlate with this potential.

Following its review, the NSABB decided to recommend that HHS ask the authors of the reports and the editors of the journals that were considering publishing the reports to make changes in the manuscripts. Due to the importance of the findings to the public health and research communities, the NSABB recommended that the general conclusions highlighting the novel outcome be published, but that the manuscripts not include the methodological and other details that could enable replication of the experiments by those who would seek to do harm.

The NSABB also recommended that language be added to the manuscripts to explain better the goals and potential public health benefits of the research, and to detail the extensive safety and security measures taken to protect laboratory workers and the public.