James Odell, OMD, ND, L.Ac.
Editorial - The material published in this editorial is intended to foster scholarly inquiry and rich discussion of the controversial topic of bioethics and health policy. The views expressed in this article are solely the authors and do not represent the policy or position of the Bioregulatory Medicine Institute (BRMI), nor any of its Board Advisors or contributors. The views expressed are not intended to malign any religious or ethnic group, organization, company, individual, or any other.Every effort has been made to attribute the sources of this article to the rightful authors
Gain-of-function (GOF) research involves experimentation that aims to (and actually does) increase the transmissibility and/or virulence of pathogenic viruses. GOF research typically involves mutations that confer altered functionality of a protein, molecule, or organism such as a virus. Such research (when safely conducted by responsible scientists) allegedly intends to improve the understanding of disease-causing agents, their interaction with human hosts, and/or even their potential to cause pandemics. But concerns about the safety of GOF studies have been voiced by numerous scientists from their very beginning. No matter how anyone justifies it or spins it, GOF studies manipulate pathogenic, deadly viruses to increase their transmissibility or virulence. Within the field of virology, these studies create ‘chimeric viruses’ defined as a new hybrid microorganism. These are created by joining nucleic acid fragments, from two or more different microorganisms, in which each of at least two of the fragments contains essential genes necessary for replication. This type of research has proven to be historically unsafe. Serious questions arise as to whether GOF research and the development of chimeric viruses are necessary for understanding viruses considering its potential for deadly contamination (pandemics) and bioterrorism.
The term “potential pandemic pathogen (PPP)” was coined for such manufactured viruses. The first suspected experimental effort to create a PPP occurred in 2005 with a laboratory re-creation of a strain of influenza, H1N1 from 1918, by Tumpey and colleagues. This was based on synthesizing nucleic acid
sequences obtained from partially preserved viral RNA in frozen corpses from 1918, and then creating infectious viruses by reverse genetics. The pandemic influenza virus of 1918–1919 killed an estimated 20 to 50 million people worldwide. The question was raised as to whether it was wise to construct a virus that was historically associated with the worst pandemic in modern history and somewhat different from any virus currently circulating. However, the debate seems to have been internal to the US Department of Health and Human Services (HHS), particularly the National Institutes of Health (NIH), and it was judged that the work should proceed.
In the United States, more GOF study controversy occurred in 2011 when two laboratories published reports of mutational screens of H5N1 avian influenza viruses, identifying variants which proved transmissible through the air between ferrets. The Dutch virologist Ron Fouchier, based at Erasmus Medical Center in Rotterdam, and Yoshihiro Kawaoka at the University of Wisconsin-Madison announced that they had successfully mutated H5N1, a strain of bird flu, to pass through the air between ferrets, in two separate experiments. Ferrets are considered one of the best flu models because their respiratory systems react to the flu much like humans. The mutations that gave the virus its ability to be airborne transmissible were gain-of-function mutations. Of course, the concern then became that if their mutated H5N1 ever left the lab it could cause a pandemic.
Around this time more scientists raised concerns about the potential of a laboratory accident that could lead to the release of a pathogen that, by design, combined high virulence and antigenic novelty with high human-to-human transmissibility. These early critiques also questioned whether the scientific and public health value of such research justified the risks involved. One of the first major discussion meetings on this topic, to my knowledge, was held at the Royal Society of London in 2012 (https://royalsociety.org/science-events-and-lectures/2012/viruses/), with mainly UK and North American speakers.
In 2012 and 2013, contamination and safety concerns continued to be published throughout the media and voiced by the international scientists.1 Then in 2014, as many as 75 scientists at the Center of Disease Control and Prevention were exposed to anthrax. A few weeks later, FDA officials discovered 16 forgotten vials of smallpox in storage. Meanwhile, the largest, most severe, and most complex Ebola outbreak in history was raging across West Africa, and the first patient to be diagnosed in the US had just been announced. On October 16, 2014 following these biosafety mishaps involving anthrax, smallpox, and H5N1 in government laboratories, the White House Office of Science and Technology Policy announced the launch of the U.S. Government in implementing a deliberative process to re-evaluate the potential risks and benefits associated with certain GOF experiments. The then Obama administration paused the release of federal funding for GOF studies anticipated to enhance the pathogenicity or transmissibility of respiratory influenza droplets among mammals and, in particular the COVID viruses - SARS and MERS. Thus, there was a moratorium on GOF between 2014 and 2017on the grounds of safety concerns and views of many top scientists who considered this type of viral research ‘unnecessarily dangerous’ – with potential risks of accidental release of pandemic potential viruses.
Following the funding pause, two major discussion meetings were held by the US National Academy of Sciences, and multiple meetings were held by the NSABB. A few ethicists, and others, debated the scientific and public health rationale for GOF or PPP experiments, the risks they posed, and the ethics of performing research that poses potentially major risks to unaware persons not involved in the studies. This process raised awareness of many issues that had not been previously highlighted, notably the lack of a framework for assessing research risks to persons who are not research participants, the very poor availability of data on biosafety in biological laboratories in the US and elsewhere, and the consequent uncertainty in risk-benefit calculations.
GOF Research in Europe
The debate on the risks and merits of GOF research has not been limited to the United States, as the Dutch Court of Appeals recently handed down a verdict concerning Erasmus University Medical Centers (EMC) objection to export license rules regarding the publication of highly pathogenic avian influenza virus GOF research. Export licenses are in place in the European Union to prevent the proliferation of weapons of mass destruction and apply to specific biological agents, chemical agents, and technologies. In 2012, the Dutch government ruled that EMC had to apply for an export license to publish their GOF work, which they had done in order to expedite publication. However, EMC later filed an objection, maintaining that GOF research in this context was for “basic scientific research.” The Dutch Court of Appeals ruled that EMC had no legal standing to contest the export license regulations, but did not address the legality of the export license itself, leaving the issue open for further debate. Currently, all GOF research within the European Union requires an export license for publication.
GOF laboratory contamination mishaps have historically occurred on more than one occasion. In 1975 smallpox, the deadly infectious disease that killed about 30 percent of those who contracted it, finally became eradicated from the world. Around 300 million-plus people died of smallpox in the century before it was annihilated. In 1978, smallpox suddenly appeared again in Birmingham, England when Janet Parker, a photographer at Birmingham Medical School developed a horrifying rash. 2 The doctors initially mistakenly diagnosed it as chickenpox. Parker's condition worsened and she was admitted to the hospital, where testing determined she had smallpox. Unfortunately, she died of the disease a few weeks later. People then questioned how she acquired smallpox that was supposed to have been eradicated. It turned out that the building Parker worked in also contained a research laboratory, one of a handful in the world where smallpox was still studied. Some papers reported the lab was badly mismanaged 3, with important safety precautions being ignored. Interestingly, the doctor who ran the lab died by alleged suicide shortly after Parker was diagnosed. So somehow, smallpox escaped the lab to infect this individual elsewhere in the building. Through sheer luck and a rapid response from health authorities, including quarantine of more than 300 people, the deadly error did not turn into an outright pandemic.
As previously mentioned, in 2014 the FDA did a cleanup for a planned move to a new office. They found hundreds of unclaimed vials of virus samples in a cardboard box in the corner of a cold storage room.4 Six of them, it turned out, were vials of smallpox. No one had been keeping track of them and no one apparently even knew they were there. They may have been there since the 1960s. The surprised and panicked scientists put the materials in a box, sealed it with clear packaging tape, and carried it to a supervisor’s office. This of course is not approved handling of dangerous biological materials. It was later found that the integrity of one vial was compromised, luckily, not one containing a ‘deadly’ virus. Additionally, there is also strong circumstantial evidence that the reintroduction of H1N1 into human circulation in 1977 after its disappearance in 1950 began with the accidental release of a laboratory strain.5, 6
Lab mishaps continue to occur and with GOF studies creating more virulent and pathogenic organisms, it becomes only a matter of time before dangerous organisms escape into the world or are used in bioterrorism. Highly transmissible, highly virulent GOF viruses like the modified H5N1 strains that have been created have the ability to infect millions and potentially kill a large fraction of those afflicted.
Current GOF Risks and Policy
GOF risks fall into two general categories which are separate but related: namely, biosecurity and biosafety. Biosecurity risk is the likelihood that someone would use the products or information obtained regarding a more pathogenic virus from GOF experiments that led to a more pathogenic virus that caused intentional damage in the form of bioterrorism. Biosafety risk is the likelihood of accidental escape that could trigger an outbreak and epidemic.
Here is a more in-depth review of the risk of GOF studies:
• Biosafety—i.e. health dangers associated with laboratory accidents
• Biosecurity—i.e., health dangers associated with crime and terrorism if pathogens are not physically secure and/or if malevolent actors gain access to them.
• Proliferation—i.e., dangers that might grow proportionally with an increased rate of GOF, potentially in different settings with varying biosafety standards.
• Information risk—i.e., if published studies facilitate malevolent action (e.g., by terrorists) or, possibly, breach of intellectual property.
• Agricultural—i.e., risks to agriculturally-relevant animals if enhanced pathogens arising from GOF are accidentally or intentionally released into animal populations, and possible implications for human health.
• Economic risks—i.e., financial implications of (accidental or intentional) pathogen release with resulting stock market collapse, business bankruptcies, job losses with increasing unemployment, starvation increases, suicides, and overall health-care downfall.
• Loss of public confidence—i.e., compromise of trust (in the scientific enterprise) that could result from (accidental or intentional) pathogen release.
Resuming Gain-of Function Studies
On Dec 19, 2017, the US National Institutes of Health (NIH) announced that they would resume funding GOF experiments involving influenza, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus. This ended the safety moratorium.
In review, during the GOF moratorium, a panel called the National Science Advisory Board for Biosecurity spent months designing a new process for determining the risks and benefits of GOF studies that could make pathogens more likely to spread and cause serious disease in humans. That led to a December 2017 HHS review framework for research on what the government now calls enhanced potential pandemic pathogens (enhanced PPPs). The policy stipulates that after a proposed enhanced PPP experiment passes NIH scientific peer review, an HHS panel of federal officials with wide-ranging expertise weighs the risks and benefits. If the committee approves, it can then receive NIH funding.
Then in February 2019, the magazine Science reported that the HHS review panel had approved two H5N1 projects in labs in Wisconsin and the Netherlands.7 These approvals and funding were for the same labs (Kawaoka and Fouchier labs) that created the controversy in 2011. Remembering that in 2011, Fouchier and Kawaoka alarmed the world by revealing they had separately modified the deadly avian H5N1 influenza virus so that it spread between ferrets.8 The news greatly disturbed opponents of such research, and they criticized federal officials for not disclosing the approvals in an op-ed in The Washington Post.9 HHS and NIH soon publicized the two approved projects, but did not release the risk reviews.
Today, much of this GOF research has little to zero transparency, particularly what is funded by the NIH and conducted in China at the Wuhan Institute of Virology. This P4 lab in Wuhan (P4 is an exceedingly high biosafety level designation) is not only the first of its kind in China, but also the first in Asia. When it opened in 2017, U.S. scientists expressed concerns that, considering China’s opaque administrative structure, if one of those killer viruses “escaped” from the lab, it could cause a doomsday disaster.
Wuhan Institute of Virology, a biosafety level 4 laboratory located in Jiangxia District, Wuhan that has engaged in gain-of-function research.
Hector Retamal/AFP/Getty Images
Dr. Marc Lipsitch is Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health. He is an author of more than 100 peer-reviewed publications on antimicrobial resistance, mathematical modeling of infectious disease transmission, bacterial and human population genetics, and immunity to Streptococcus pneumoniae. Dr. Lipsitch was quoted,7 “I still do not believe a compelling argument has been made for why these studies (GOF) are necessary from a public health point-of-view; all we have heard is that there are certain narrow scientific questions that you can ask only with dangerous experiments”, he said. “I would hope that when each HHS review is performed someone will make the case that strains are all different, and we can learn a lot about dangerous strains without making them transmissible.” Lipsitch pointed out that every mutation that has been highlighted as important by a gain-of-function experiment has been previously highlighted by completely safe studies. “There is nothing for the purposes of surveillance that we did not already know”, said Dr. Lipsitch. “Enhancing potential pandemic pathogens in this manner is simply not worth the risk.”10
Gain-of-Function - Chimera Virus Research in China
Since the SARS virus of 2003 China launched extensive virology research programs. These occurred through their military labs (People’s Liberation Army) and other labs such as the P4 virology lab in Wuhan located, apparently, just 280 meters away from the Hunan Seafood Market. The P4 lab in Wuhan was initially started as a joint venture with the French government. Chinese authorities switched the management of the project to a firm with close ties to the Chinese military complex. The Lab is a subsidiary of the Wuhan Institute of Virology managed by the China Academy of Sciences. The Chinese government has been working on GOF coronavirus studies for well over a decade. One of the most renowned Chinese virologists of this field is Shi Zhen-Li (surname Shi 石) who is renowned for her extensive research of SARS-like coronaviruses of bat origin. Since the SARS virus outbreak in 2003, Shi Zhengli and her team have conducted research on coronaviruses. In 2005, Shi and colleagues found that bats are a natural reservoir of SARS-like coronaviruses.11 To further determine the mechanism by which a SARS-associated coronavirus (SARS-CoV) may infect humans, Shi led a research team that studied the binding of spike proteins (s-protein) of both natural and chimeric SARS-like coronaviruses to ACE2 receptors in human, civet, and horseshoe bat cells.12, 13 ACE2's functions include ultimately acting as a vasodilator that influences blood flow. It is located on cells all around the body, but ACE2 receptors also occur in many organs. It is especially common on cells lining air sacs (pneumocytes) in the lungs, which is partly why infection is associated with respiratory symptoms like pneumonia.
From 2010 onwards, Shi and her team have been primarily focused on identifying the capacity for coronavirus transmission across species, specifically putting the emphasis of study on the s-protein, or spike protein, of the coronaviruses. To successfully initiate an infection, viruses need to overcome the cell membrane barrier. Enveloped viruses achieve this by membrane fusion, a process mediated by specialized viral fusion proteins.
For coronaviruses, this fusion occurs through its spike protein. Each spike protein consists of three components that combine to form a 'trimer' structure with two parts or 'subunits', S1, and S2. You can think of the spike as a multistage rocket, with S1 being the boosters and S2 as a space shuttle: once attached to the ACE2 receptor, a spike sheds its S1 subunit and the remaining S2 part changes its shape or 'conformation' to enable the viral envelope to fuse with the outer membrane and drop the virus' genetic material inside the cell.
The spike proteins (shown sticking out from the round virus) have high homology with the SARS virus. These are the proteins that make up the “key” that binds with the ACE2 receptors in humans to enter the cell. This contributes to the organ failure we see with infected persons as it drives the virus into the cells of the lungs and other organs such as the heart and kidneys, which also have ACE2 receptors.
Thus, for SARS-CoV entry into a host cell, its s-protein needs to be cleaved by cellular proteases at 2 sites, termed S protein priming, so the viral and cellular membranes can fuse.14 In other words, Shi and her research team has been dedicated to finding ways that can better allow bat coronavirus to be transmissible to other animals.
In June of 2010, Shi’s team published a paper that describes research to understand the susceptibility of angiotensin-converting enzyme 2 (ACE2) proteins of different bat species to the s-protein of the SARS virus.15 With their chimeric research, they also modified key amino acid components to mutate the bats' ACE2 receptor in order to examine compatibility with the SARS s-protein. This paper demonstrated their awareness of the relationship between the s-protein and the ACE2 receptor.
It is now understood that 2019-nCoV can infect the human respiratory epithelial cells through interaction with the human ACE2 receptor. Indeed, the recombinant spike protein can bind with the recombinant ACE2 protein. Shi and her colleagues' paper also signified that they had discovered the passageway for coronaviruses to infect human bodies.
Angiotensin-converting enzyme 2, a monocarboxylase that degrades angiotensin II to angiotensin 1–7, is also the functional receptor for severe acute respiratory syndrome (SARS) coronavirus (SARS‐CoV) and is highly expressed in the lungs and heart. Patients with SARS also suffered from cardiac disease including arrhythmias, sudden cardiac death, and blood pressure -systolic and diastolic dysfunction.
In 2013, Shi and her team published a paper in the journal Science China Life Sciences in which they isolated and identified numerous bat viruses (bat lyssaviruses, bat paramyxoviruses, bat filoviruses, bat reoviruses, and others).Bats are the only mammals capable of sustained flight and are notorious ‘reservoir hosts’ for some of the world’s most highly pathogenic viruses, including Nipah, Hendra, Ebola, and SARS.16 A reservoir is one or several animal species that are not or not very sensitive to the virus, which will naturally host one or several viruses. The absence of symptoms of the disease is explained by the effectiveness of their immune system, which allows them to fight against too much viral proliferation.
Bats Have Been Linked with Seven Major Epidemics Over the Past Three Decades.
In October 2013 Shi and her team published their findings in the prestigious journal Nature and claimed a breakthrough in coronavirus research.17 They provide evidence that SARS-CoV originated in bats. They concluded, “Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs.” In their research, they isolated three bat viruses, one of which had an s-protein that integrated with human ACE2 receptors. This effectively demonstrated the direct human infection of SARS-like viruses to humans without the need for an intermediate host. Then in 2014, Shi and her team collaborated on additional gain-of-function experiments led by Ralph S. Baric of the University of North Carolina, which showed that two critical mutations that the MERS coronavirus possesses allow it to bind to the human ACE2 receptor.18 In 2015, She and colleagues further showed that SARS had the potential to re-emerge from coronaviruses circulating in bat populations in the wild.19
Then in November 2015, Shi and her team from Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology together with scientists from the Department of Epidemiology at the University of North Carolina at Chapel Hill, published a paper in the journal Nature Medicine describing their joint gain of function coronaviruses research and new chimeric virus creation. According to Ralph Baric, an infectious-disease researcher at the University of North Carolina at Chapel Hill and co-author of the study, this study began before the US moratorium was enacted. So, the US National Institutes of Health (NIH) allowed it to proceed while it was under review by the agency. Baric claims the NIH eventually concluded that the work was not ‘so risky’ as to fall under the moratorium.20
They revealed the formation of a new synthetic virus or self-replicating chimeric virus. This chimeric virus had SARS virus as the framework with the key s-protein replaced by one they had found in a coronavirus, she mentioned in her 2013 paper. They concluded “we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo (mice).” In short, they took genes from a bat coronavirus spike-protein and spliced it to a mouse coronavirus genome, then tested this for its ability to infect human airway cells through their ACE-2 receptors. This chimeric recombinant coronavirus was tested in mice with significant deadly infections occurring. According to their paper, “all mouse studies were performed at the University of North Carolina, prior to the 2014 GOF moratorium involving influenza, MERS and SARS viruses.” This new virus demonstrated a powerful ability for cross species infection. The mice infected with this chimeric virus showed severe lung damage with no cure. Shi Zhengli’s team and her US colleagues’ successful recombinant splicing of the SARS virus was strategically important to the development of cross-species transmission. Their study eerily concluded that there was "a significant risk of a SARS coronavirus re-emergence".
The fact that scientists are deliberately manipulating the genetics of deadly viruses to manufacture chimeric viruses and then test them for their ability to cause human disease should have created an outrage in the scientific community. This event was not even reported in mainstream media. The medium (chimeric coronavirus) from transfected cells was harvested and served as seed stocks for subsequent experiments (to be performed later).
An additional piece of vaccination information emerged from their 2015 study entitled ‘A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence’. They revealed that in order “to evaluate the efficacy of existing vaccines against infection with SHC014-MA15 (chimeric coronavirus), we vaccinated aged mice with double-inactivated whole SARS-CoV (DIV). Previous work showed that DIV could neutralize and protect young mice from challenge with a homologous virus; however, the vaccine failed to protect aged animals in which augmented immune pathology was also observed, indicating the possibility of the animals being harmed because of the vaccination. Here we found that DIV did not provide protection from challenge with SHC014-MA15 with regards to weight loss or viral titer. Consistent with a previous report with other heterologous groups 2b CoVs, serum from DIV-vaccinated, aged mice also failed to neutralize SHC014-MA15. Notably, DIV vaccination resulted in robust immune pathology and eosinophilia). Together, these results confirm that the DIV vaccine would not be protective against infection with SHC014 and could possibly augment disease in the aged vaccinated group.”21 The phenomena that specific viral vaccines can exacerbate an existing viral disease is well documented, particularly with influenza vaccines.22, 23, 24, 25, 26, 27
In summary, the researchers created and examined the disease potential of a synthetic SARS-like virus, SHC014-MA15, which was chimerically created from viruses found in Chinese horseshoe bat populations. Using what they described as "SARS-CoV reverse genetics system", the researchers said that they generated and characterized a "chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone." The mice died a grim death and the experiment was hailed a success by the researchers.
Back in Wuhan, Shi and her team then focused their chimeric viral research on primates. At this stage, some scientists took notice and became genuinely concerned, understanding this development was a dangerous move towards simulating the infection in humans. Academic debates on GOF studies one again began worldwide.
Dr. Wain-Hobson of the Pasture Institute in France expressed his disapproval and concern. In an article, he told Nature, “If the virus escaped, nobody could predict the trajectory.” Richard Ebright, a molecular biologist and biodefence expert at Rutgers University in Piscataway, New Jersey agrees and said, “The only impact of this work is the creation, in a lab, of a new, non-natural risk.”28 Both Drs Ebright and Wain-Hobson are long-standing critics of GOF research.
In October of 2014, the Obama Administration wary of the potential threats to public health and GOF research suspended funding to these research projects. Funding cuts and scientific criticism of GOF studies however did not stop Shi Zhengli’s team research. She and her colleagues continued under the cover and funding of the Chinese Government.
The question then is why would anyone be creating a virulent designer coronavirus that can infect humans? For what purpose is this research? Is it for a bioweapon? Is it so that you can create a vaccine and be the recipient of the profits? The standard pro-gain-of-function narrative is that the ultimate objective of such research is to better inform public health and preparedness efforts and/or development of medical countermeasures. Many scientists disagree. As Dr. Marc Lipsitch pointed out, every mutation that has been highlighted as important by a gain-of-function experiment has been previously brought to light by completely safe studies.
NIH Funding Resumes
On Dec 19, 2017, the NIH announced that they would again resume funding gain-of-function experiments involving influenza, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus ending the safety moratorium.29 This once again opened the door to NIH funding to GOF studies China. As a safety condition, the federal government then began requiring that any National Institutes of Health grant proposals involving gain-of-function research undergoes a review by an expert panel to evaluate the risk of such work against the potential gains. But the names of the expert-panel members are not publicly available, nor are its reviews of study proposals. “We’re not trying to say the policy is wrong, we’re trying to say the policy is ambiguous,” says Dr. Marc Lipsitch, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and one of the researchers calling for greater transparency around such work.
In 2019, the NIH committed $3.7 million over six years for research on bat coronaviruses in China. The program followed a previous $3.7 million, a 5-year project for collecting and studying bat coronaviruses, which ended in 2019, bringing the total to $7.4 million. One primary concern by many scientists is some of this newest additional 3.7 million was directed to the Wuhan Institute of Virology for coronavirus GOF studies. When the NIH was questioned about the grants they responded, “The grant you are referencing is a multi-site, multi-country project supporting research that aims to understand what factors allow coronaviruses, including close relatives to SARS, to evolve and jump into the human population and cause disease. Specifically, the project includes studying viral diversity in animal (bats) reservoirs, surveying people that live in high-risk communities for evidence of bat-coronavirus infection, and conducting laboratory experiments to analyze and predict which newly-discovered viruses pose the greatest threat to human health.”30 The National Institute of Allergy and Infectious Diseases (NIAID), under Anthony Fauci’s leadership, has financially supported six studies of bats and their connection to coronavirus.
SARS-CoV-2 Origin Debate