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. This is performed in a research context to understand the way in which a pathogen adapts to environmental pressures, allowing disease control measures to be better planned, and potential vaccines and therapies to be explored. Gene editing technology such as CRISPR may be utilized in combination with selective serial passaging to investigate the role of specific genes on protein expression and ultimate organism function.
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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.
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The swine flu scare of 1976 and the H1N1 human influenza pandemic of 1977. Human H1N1 influenza virus appeared with the 1918 global pandemic and persisted, slowly accumulating small genetic changes, until 1957, when it appeared to go extinct after the H2N2 pandemic virus appeared. In 1976, H1N1 swine influenza virus struck Fort Dix, N.J., causing 13 hospitalizations and one death. The specter of a reprise of the deadly 1918 pandemic triggered an unprecedented effort to immunize all Americans. No swine H1N1 pandemic materialized, however, and complications of immunization truncated the program after 48 million immunizations, which eventually caused 25 deaths.
Human H1N1 virus reappeared in 1977, in the Soviet Union and China. Virologists, using serologic and early genetic tests, soon began to suggest the cause of the reappearance was a laboratory escape of a 1949-50 virus, and as genomic techniques advanced, it became clear that this was true. By 2010, researchers published it as fact: “The most famous case of a released laboratory strain is the re-emergent H1N1 influenza-A virus which was first observed in China in May of 1977 and in Russia shortly thereafter.” The virus may have escaped from a lab attempting to prepare an attenuated H1N1 vaccine in response to the U.S. swine flu pandemic alert.
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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.
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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.
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In the year 2005 genetic research was being conducted on the 1918 'Spanish Flu', the flu virus responsible for the last significant global pandemic before Covid-19; killing tens of millions of people. Scientists, Tumpey and colleagues, found different phenotypes of the Spanish Flu, most notably a high-virulence phenotype.
How long have we been blaming Russia for everything and France for being vulnerable push overs?
Abstract
The pandemic influenza virus of 1918-1919 killed an estimated 20 to 50 million people worldwide. With the recent availability of the complete 1918 influenza virus coding sequence, we used reverse genetics to generate an influenza virus bearing all eight gene segments of the pandemic virus to study the properties associated with its extraordinary virulence. In stark contrast to contemporary human influenza H1N1 viruses, the 1918 pandemic virus had the ability to replicate in the absence of trypsin, caused death in mice and embryonated chicken eggs, and displayed a high-growth phenotype in human bronchial epithelial cells. Moreover, the coordinated expression of the 1918 virus genes most certainly confers the unique high-virulence phenotype observed with this pandemic virus.
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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.
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In 2011, Dutch researcher Ron Fouchier and American virologist Yoshihiro Kawaoka sparked a major controversy when, separately, they submitted manuscripts to Science and Nature in which they described how to generate strains of H5N1 avian influenza that were transmissible between mammals. This research on mammalian airborne transmissible H5N1, or matH5N1, was published only after the National Science Advisory Board on Biosecurity and the World Health Organization engaged in lengthy and contentious review processes that focused on whether the research should be made public.
The experiments—which not only demonstrated that mammalian transmission of the virus was possible but also provided information on how to construct such a virus—triggered broad concern about the safety and security of so-called “gain-of-function” experiments.
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It can be argued that these experiments were simply the workings of two brilliant analytical minds truly trying to improve the world. Unfortunately, for them the United States Government was not impressed and was quick to make sure their works were not published on any level.
Researchers in the Netherlands have created a mutated, highly contagious form of the deadly H5N1 bird flu strain that some fear could kill millions if it were unleashed on the general public...
Virologist Ron Fouchier, who carried out his research at the Erasmus Medical Center in Rotterdam, said in a statement that he hoped his research would assist in developing better vaccines and treatments for influenza in the future.
"We know which mutation to watch for in the case of an outbreak, and we can then stop the outbreak before it is too late," Fouchier said in a statement on the medical center's website. "Furthermore, the finding will help in the timely development of vaccinations and medication."...
The study results were to be published in the U.S. journal Science, but the National Science Advisory Board for Biosecurity, an independent committee that advises the U.S. Department of Health and Human Services and other federal agencies, reviewed it Tuesday and warned that bioterrorists could potentially misuse the published research "for harmful purposes."
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In October 2014, the United States officials announced a pause in funding of gain-of-function (GOF) studies related to influenza MERS and SARS. However, according to ScienceInsider, in 2018, the U.S health committee quietly approved funding for Fouchier’s studies related to the H5N1 virus that caused furor 8 years ago.
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In 2012, an Egyptian Virologist, Dr. Ali Mohamed Zaki who was working in a Saudi Arabian hospital; found a new type of Virus in a deceased patient and needed help identifying it. After several failed attempts to get help identifying this new virus, he sent it Ron Fouchier. Which only caused more controversy to surround Ron Fouchier.
Frustrated with the lack of information about the virus, Dr. Zaki sent the virus sample to Fouchier in the Netherlands. It turned out to be a new type of coronavirus, previously unknown to the scientific community....
Saudi Arabia – the country where the virus originated – was unhappy with Fouchier’s conduct. The coronavirus was smuggled out of Saudi Arabia without the approval of the Saudi authorities...
Ziad Memish, Saudi Arabia’s deputy minister of health, asserted that national procedures for reporting potential new pathogens “were either intentionally or inadvertently circumvented.”
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Fouchier was the one who sent Coronavirus to the Canadian scientist Frank Plummer at the National Microbiology Laboratory in Winnipeg. It was under Plummer, Chinese biowarfare spy Xiangguo Qiu and her team smuggled deadly coronaviruses from the Canadian lab to Wuhan Institute of Virology... Like Fouchier and the Chinese agent Charles Lieber who created virus-transmitters, Plummer was the key to the COVID-19 investigation and co-incidentally ended up dead a week after the publication of our report.(February 2020)... Although, the moot question is – is it a coincidence that the way the Saudi SARS Coronavirus was smuggled out of Saudi Arabia, in an exact similar fashion the virus was also smuggled out by Chinese spies from the Canadian lab to Wuhan Institute of Virology – which is now under investigation for the COVID-19 outbreak?
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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. 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. 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. 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.
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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.
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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.
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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
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Funding for this US/China joint chimeric research was supported by grants from the National Institute of Allergy & Infectious Disease, the National Institute of Aging of the US National Institutes of Health (NIH), the National Natural Science Foundation of China, and by USAID-EPT-PREDICT funding from EcoHealth Alliance.
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https://www.nature.com/articles/nm.3985/
...we built a chimeric virus encoding a novel, zoonotic CoV spike protein—from the RsSHC014-CoV sequence that was isolated from Chinese horseshoe bats1 —in the context of the SARS-CoV mouse-adapted backbone. The hybrid virus allowed us to evaluate the ability of the novel spike protein to cause disease independently of other necessary adaptive mutations in its natural backbone. Using this approach, we characterized CoV infection mediated by the SHC014 spike protein in primary human airway cells and in vivo, and tested the efficacy of available immune therapeutics against SHC014-CoV.
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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
https://web.archive.org/web/20200128222519/https://www.nature.com/articles/nm.3985
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".
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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.
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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.
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https://www.nature.com/articles/nature.2015.18787
Studies testing hybrid viruses in human cell culture and animal models are limited in what they can say about the threat posed by a wild virus, Daszak agrees. But he argues that they can help indicate which pathogens should be prioritized for further research attention.
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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.
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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...
...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.
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