The strain of the monkeypox virus that spread globally this year, causing mostly rash and flulike symptoms, will be given a second strain in a U.S. government lab. They will look at the changes to see if they make the virus more lethal. The researchers hope that by unraveling how certain genes make monkeypox more deadly, they will be able to create better drugs and vaccines.
The planned experiments were first reported by science. If a more potent version of the outbreak strain accidentally escaped the high-containment, high-security lab at the National Institute of Allergy and Infectious Diseases, it could spark an Epidemic with substantially more lethality. He and others argue that the experiments should go through a special review to make sure they are safe.
It is unclear if the rules apply to the study. The panel decided that it was not subject to review. The panel decided that Monkeypox did not meet the definition of a Potential Pandemic Pathogen because it did not spread easily. With monkeypox widespread, the National Institutes of Health is planning to reexamine the work, but it may not qualify as "Enhancing" aPPP. It is not expected that the study will create a monkeypox strain that is more dangerous than the two already known.
The debate over when a study that alters a pathogen is too risky for the US government to fund has been going on for a decade. Over the past 2 years, that wrangling became even more ferocious, as the COVID-19 Pandemic spawned allegations, so far proven, that the disease escaped from a lab in China. In the wake of the Pandemic, the U.S. government is likely to make changes to how it manages GOF studies.
There are significant potential risks to both under- and overregulation.
An expert panel convened by the Department of Health and Human Services and the National Institute of Neurological Disorders and Stroke released a draft report last month that recommends broadening the GOF rules to include pathogens. The monkeypox study could be put under more scrutiny if the recommendation is adopted. New oversight and restrictions could be imposed on other researchers working with viruses.
Scientists are concerned that an expanded definition could make the oversight system worse. They say the rules have caused confusion and delays that have deterred scientists from studying emerging pathogens and finding ways to fight them. The proposed changes could impede research into evolving or emerging Viruses if not implemented carefully. She and others say that expanding the regulations could lead to research being driven overseas or into the private sector where U.S. regulations are less strict.
The changes don't go far enough according to others. They want the U.S. government to create an entirely new independent body to oversee risky research and to give the public more information about proposed experiments that could have dire consequences. The practice of collecting viruses from wild animals and studying them in the lab raises the risk of the viruses jumping to humans, according to some.
The work should be asked if it should continue. James LeDuc retired last year as director of the University of Texas Medical Branch's Galveston National Laboratory. It is one thing to modify them so that you can study them.
The proposed rules represent a potential pivot point in the debate over the funding of high-risk GOF studies. LeDuc is part of a group of scientists who are pushing for changes in the field. He says the goal is to find the right balance.
The controversy over studies that enhance or alter pathogens has been going on for more than 100 years. If you want to make vaccines, you need to transfer a virus between dishes of animal cells or whole animals so that it doesn't harm people but grows better. Since the late 1990s, the use of genetic engineering techniques has made these studies more efficient.
There were twoNIH-funded experiments with H5N1 bird flu in 2011. The University of Wisconsin, Madison, and the University of Tokyo, as well as Ronald Fouchier at the Erasmus University Medical Center, were interested in finding a way to make the bird flu vaccine more effective. The H5N1 could be spread from birds to people and kill a lot of people. They were able to modify the virus so that it could spread between laboratory ferrets.
The work was discussed at a meeting before it was published. The journal editors and government officials called for a review of the National Science Advisory Board for Biosecurity because they were worried that the information could end up in the wrong hands. In the wake of the 2001 anthrax attacks in the United States, the HHS established a dual use research center. Researchers stopped their GOF experiments during the review. The H5N1 papers were published and the work began again.
The White House imposed a second pause on U.S.-funded GOF research after a number of accidents at U.S. labs working with pathogens. It stopped certain studies with the coronaviruses that cause Middle East respiratory syndrome and Severe Acute Respiratory syndrome. 29 potential GOF projects were identified by the National Institute of Health. The agency allowed 18 to resume because they didn't meet the risky GOF definition or were urgent to protect public health A step that can help researchers develop treatments is the adaptation of the Middle East Respiratory Syndrome toinfecting mice. There were 11 studies that had GOF components removed.
U.S. officials promised to come up with a more comprehensive approach to identify and potentially block risky studies before they began. Less-risky approaches for studying altered viruses, such as using weakened virus strains, computer models, or "pseudoviruses" that can't replicate, were advocated by advocates of tighter rules.
Studies with live virus are the only way to see the effect of a change. There is only so much you can learn from alternative techniques. It's best to use intact virus.
Gain-of-function research can give viruses and other pathogens new capabilities. A decade ago, studies that enabled H5N1 avian flu to more easily spread among mammals kicked off a debate that continues today.
The debate culminated in the release of the current HHS policy called Potential Pandemic Pathogens Care and Oversight. An HHS panel must review any study that is funded by the National Institute of Allergy and Infectious Diseases that is expected to create or use an enhanced version of a highly transmissible pathogen. It excludes natural, unmodified viruses and GOF work done to develop vaccines or to assess the risks of a new variant of the flu.
Three projects have been approved by the HHS committee that is charged with implementing the policy. The H5N1 work was continued by two people. The grants are no longer valid. The third involved work with H7N9 bird flu, but the investigator decided to use a nonpathogenic flu strain.
Critics say that other studies have been ignored. The work led by Baric is an example. His team was interested in finding out if bat coronaviruses had the ability to cause disease. The answer has been shown to be absolutely yes. The researchers weren't able to grow the viruses in the lab. The wild bat virus uses a spike to enter a host cell and cause a disease in mice.
The work was allowed to continue during the sabbatical. According to Baric, the researchers did not intend to make the mouse-adapted SARS virus riskier for people. Baric and his team reported in Nature Medicine in 2015 that a bat coronaviruses called SHC014 was to blame for sickening mice. The hybrid virus could not be stopped by any of the available remedies. Critics of the work claim that it created a potential epidemic.
Baric acknowledged that a review panel mightdeem similar studies building chimeric viruses based on circulatingbat coronaviruses too risky to pursue. He has called the chimeric viruses essential to efforts to test the effectiveness of drugs and vaccines against coronaviruses. They argue that Baric's work could have helped the world prepare for the COVID-19 Pandemic if it had been done sooner.
The GOF debate has been spiced up by high-profile allegations that the disease came from a lab in China. One prominent advocate of the lab-leak theory, Senator Rand Paul (R–KY), a senior member of the Senate's health panel, has sparred with NIAID Director Anthony Fauci. The EcoHealth Alliance received a grant from the National Institute of Health to help create chimeras. Baric collaborated with Shi to develop the methods used by the researchers.
The EcoHealth grant was exempt from the P3CO policy by theNIH. The bat coronaviruses were not known to be infectious. If Shi's lab observed a 10-fold increase in the growth of a chimeric virus, it would need a P3CO review.
The documents show that there was an increase in growth in the lungs of mice that had been exposed to the disease. EcoHealth disputes the idea that it failed to report the results quickly. Paul and some proponents of the lab-leak theory claim that the National Institute of Health colluded with Ecohealth to hide the risks of the study.
There is no scientific consensus on whether the experiments crossed a red line. Some scientists argue that they were unacceptably risky. Others don't agree. The hybrid viruses created by Shi's lab were too far away from the disease to have caused the epidemic.
The swine flu made it clear that the GOF rules needed a fresh look. The review board of the P3CO policy was expanded in January 2020 to look at ways to increase transparency. Some White House officials wanted the panel to consider banning funding for some GOF studies.
I worry that people will [fear] accidentally tripping a wire.
The draft report did not go that far. GOF work should not be exempt from P3CO review. Two new categories not covered by the current rules should be included in the definition of a pathogen thattriggers a review.
A category would include potentially highly transmissible pathogens with low or moderate virulence. Studies show that about 1% or less of people are killed by the disease. Tuberculosis, seasonal flu, and the noroviruses that cause stomach bugs may be included.
The pathogens that are less transmissible are included in the second category. The Nipah virus, which is deadly but isn't easily transmitted because it's spread through blood or other body fluids, could be included.
Whether a pathogen or experiment fits into a reviewable category will remain a judgement. It can be hard to predict whether a virus can become highly transmissible. The co-chair of the working group acknowledges that it can be possible to define virulence. Her panel said policymakers should give examples. The final recommendations will be out in December or January of next year.
Researchers worry that subjectivity will deter them from pursuing valuable pathogen science because they will get entangled in red tape. When things are unpredictable, I worry that people will avoid going close to the line because of the risk of tripping a wire.
Some scientists think that even an expanded policy could be too loose. Shi's WIV1 chimeric virus experiments are not likely to be reviewed because the starting viruses weren't known to cause human disease. The monkeypox studies are not creating new genes. It's like changing the machinery of a clock where you have a lot of different pieces. The Icahn School of Medicine at Mount Sinai doesn't know how it will work
To close some gaps, a group of GOF critics organized by Inglesby has urged NSABB to expand the review requirements to include GOF studies of any pathogen. The reviews should be conducted by a new, independent agency rather than HHS, which they argue has been reluctant to aggressively regulate studies it funds through the National Institute of Health.
According to Richard Ebright of Rutgers University, a prominent GOF critic, at least 11 grants that should have gone through P3CO review are funded by theNIH. Full proposals, which are usually not public, would verify his estimate. Most of the institutions involved are in the U.S. and are studying flu. A grant proposal from EcoHealth describes plans for further bat coronaviruses chimera work in Baric's lab.
There is still a small area of research that will be affected by a broader P3CO policy. She doesn't expect another shut down of experiments while they are reviewed.
Privately funded GOF research and what happens in other countries will not be affected by a U.S. ban. In Japan and most of Europe, oversight is limited to rules on bio safety and voluntary self-regulation. They don't know how the 2020 Chinese bio safety law will affect research.
Some researchers think that GOF work is too risky. Since the beginning of the year, labs in China have published at least three papers in journals describing experiments with potential bird flu strains that may have crossed the line because of drug resistance or adaption to mammals. The earlier Fouchier or Kawaoka studies were as alarming as none.
Concerns have been raised about a study described in a June preprint. The bat coronaviruses were passed through human cells and in mice to see if they had a specific change that would help them spread the disease. The finding that the virus didn't do anything sheds light on how the COVID-19 epidemic began. The work may not have been worth the risk according to others.
More and more laboratories are jumping into the field. In an interview with the MIT Technology Review last year, Baric said that only a few labs were engineering bat coronaviruses before the outbreak. Some inexperienced groups could proceed with less respect for the inherent risk posed by this group of pathogens. Baric was not reachable for this story.
Some GOF critics want to start a global discussion about how to regulate high-risk pathogen studies. The Bulletin of the Atomic Scientists created the Pathogens Project in order to warn of threats such as nuclear war. The project will gather international experts, including University of Cambridge microbiologist Ravindra Gupta, who has advised the United Kingdom's COVID-19 response, and George Gao, former director of China's Center for Disease Control and Prevention.
The idea is to reach out and try to find a broad set of interested parties from across the globe. There are some possible actions. There is an appropriate international entity that could take this on. He says that those may be small goals, but they are a start.
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