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Gain-of-function research
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Gain-of-function research
Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host range, i.e., the types of hosts that a microorganism can infect. This research is intended to reveal targets to better predict emerging infectious diseases and to develop vaccines and therapeutics. For example, influenza B can infect only humans and harbor seals. Introducing a mutation that would allow influenza B to infect rabbits in a controlled laboratory situation would be considered a gain-of-function experiment, as the virus did not previously have that function. That type of experiment could then help reveal which parts of the virus's genome correspond to the species that it can infect, enabling the creation of antiviral medicines which block this function.
In virology, gain-of-function research is usually employed with the intention of better understanding current and future pandemics. In vaccine development, gain-of-function research is conducted in the hope of gaining a head start on a virus and being able to develop a vaccine or therapeutic before it emerges. The term "gain of function" is sometimes applied more narrowly to refer to "research which could enable a pandemic-potential pathogen to replicate more quickly or cause more harm in humans or other closely-related mammals."
Some forms of gain-of-function research (specifically work which involves certain select agent pathogens) carry inherent biosafety and biosecurity risks, and are thus also referred to as dual use research of concern (DURC). To mitigate these risks while allowing the benefits of such research, various governments have mandated that DURC experiments be regulated under additional oversight by institutions (so-called institutional "DURC" committees) and government agencies (such as the NIH's recombinant DNA advisory committee). A mirrored approach can be seen in the European Union's Dual Use Coordination Group (DUCG).
Importantly, regulations in the United States and European Union both mandate that at least one unaffiliated member of the public should be an active participant in the oversight process. Significant debate has taken place in the scientific community on how to assess the risks and benefit of gain-of-function research, how to publish such research responsibly, and how to engage the public in an open and honest review. In January 2020, the National Science Advisory Board for Biosecurity convened an expert panel to revisit the rules for gain-of-function research and provide more clarity in how such experiments are approved, and when they should be disclosed to the public.
In early 2011, two groups were investigating how flu viruses specific to birds could possibly cross over and create pandemics in humans: one led by Yoshihiro Kawaoka at the University of Wisconsin–Madison in Madison, Wisconsin, and another led by Ron Fouchier at Erasmus University Medical Center in the Netherlands. Both groups had serially passaged the H5N1 avian influenza in ferrets, manually taking the virus from one ferret to another, until it was capable of spreading via respiratory droplets. The normally bird-specific virus, through replication over time in the ferrets' lungs, had adopted several amino acid changes that enabled it to replicate in the mammalian lungs, which are notably colder than those found in birds. This small change also allowed the virus to transmit via droplets in the air made when the ferrets coughed or sneezed.
Proponents of the Kawaoka and Fouchier experiments cited several benefits: these answered the question of how a virus like H5N1 could possibly become airborne in humans, allowed other researchers to develop vaccines and therapeutics which specifically targeted these amino acid changes, and also demonstrated that there was a linkage in avian viruses between transmissibility and lethality: while the virus had become more transmissible, it had also become significantly less deadly. Various critics of the research (including members of Congress) responded to the publications with alarm. Others called the experiments an "engineered doomsday". Questions were raised by other scientists including Marc Lipsitch of the T. H. Chan School of Public Health at Harvard University about the relative risks and benefits of this research.
At an international technical consultation convened by the WHO, it was concluded that this work was an important contribution to public health surveillance of H5N1 viruses and to a better understanding of the properties of these viruses, but that broader global discussions were needed. The European Academies of Science Advisory Council (EASAC) concluded that all required laws, rules, regulations, and codes of conduct are in place in several EU countries to continue this type of work responsibly. In the US, where regulations were previously less strict than in the EU, a new governmental policy and review mechanism was launched for "Potential Pandemic Pathogen Care and Oversight" (P3CO).
In May 2013, a group led by Hualan Chen, director of China's National Avian Influenza Reference Laboratory, published several experiments they had conducted at the BSL3+ laboratory of the Harbin Veterinary Research Institute, investigating what would happen if a 2009 H1N1 circulating in humans infected the same cell as an avian influenza H5N1. Importantly, the experiments had been conducted before a research pause on H5N1 experiments had been agreed upon by the broader virologist community. They used these experiments to determine that certain genes, if reassorted in such a dual-infection scenario in the wild, would allow transmission of the H5N1 virus more easily in mammals (notably guinea pigs as a model organism for rodent species), proving that certain agricultural scenarios carry the risk of allowing H5N1 to cross over into mammals. As in the Fouchier and Kawaoka experiments above, the viruses in this study were also significantly less lethal after the modification.
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Gain-of-function research
Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host range, i.e., the types of hosts that a microorganism can infect. This research is intended to reveal targets to better predict emerging infectious diseases and to develop vaccines and therapeutics. For example, influenza B can infect only humans and harbor seals. Introducing a mutation that would allow influenza B to infect rabbits in a controlled laboratory situation would be considered a gain-of-function experiment, as the virus did not previously have that function. That type of experiment could then help reveal which parts of the virus's genome correspond to the species that it can infect, enabling the creation of antiviral medicines which block this function.
In virology, gain-of-function research is usually employed with the intention of better understanding current and future pandemics. In vaccine development, gain-of-function research is conducted in the hope of gaining a head start on a virus and being able to develop a vaccine or therapeutic before it emerges. The term "gain of function" is sometimes applied more narrowly to refer to "research which could enable a pandemic-potential pathogen to replicate more quickly or cause more harm in humans or other closely-related mammals."
Some forms of gain-of-function research (specifically work which involves certain select agent pathogens) carry inherent biosafety and biosecurity risks, and are thus also referred to as dual use research of concern (DURC). To mitigate these risks while allowing the benefits of such research, various governments have mandated that DURC experiments be regulated under additional oversight by institutions (so-called institutional "DURC" committees) and government agencies (such as the NIH's recombinant DNA advisory committee). A mirrored approach can be seen in the European Union's Dual Use Coordination Group (DUCG).
Importantly, regulations in the United States and European Union both mandate that at least one unaffiliated member of the public should be an active participant in the oversight process. Significant debate has taken place in the scientific community on how to assess the risks and benefit of gain-of-function research, how to publish such research responsibly, and how to engage the public in an open and honest review. In January 2020, the National Science Advisory Board for Biosecurity convened an expert panel to revisit the rules for gain-of-function research and provide more clarity in how such experiments are approved, and when they should be disclosed to the public.
In early 2011, two groups were investigating how flu viruses specific to birds could possibly cross over and create pandemics in humans: one led by Yoshihiro Kawaoka at the University of Wisconsin–Madison in Madison, Wisconsin, and another led by Ron Fouchier at Erasmus University Medical Center in the Netherlands. Both groups had serially passaged the H5N1 avian influenza in ferrets, manually taking the virus from one ferret to another, until it was capable of spreading via respiratory droplets. The normally bird-specific virus, through replication over time in the ferrets' lungs, had adopted several amino acid changes that enabled it to replicate in the mammalian lungs, which are notably colder than those found in birds. This small change also allowed the virus to transmit via droplets in the air made when the ferrets coughed or sneezed.
Proponents of the Kawaoka and Fouchier experiments cited several benefits: these answered the question of how a virus like H5N1 could possibly become airborne in humans, allowed other researchers to develop vaccines and therapeutics which specifically targeted these amino acid changes, and also demonstrated that there was a linkage in avian viruses between transmissibility and lethality: while the virus had become more transmissible, it had also become significantly less deadly. Various critics of the research (including members of Congress) responded to the publications with alarm. Others called the experiments an "engineered doomsday". Questions were raised by other scientists including Marc Lipsitch of the T. H. Chan School of Public Health at Harvard University about the relative risks and benefits of this research.
At an international technical consultation convened by the WHO, it was concluded that this work was an important contribution to public health surveillance of H5N1 viruses and to a better understanding of the properties of these viruses, but that broader global discussions were needed. The European Academies of Science Advisory Council (EASAC) concluded that all required laws, rules, regulations, and codes of conduct are in place in several EU countries to continue this type of work responsibly. In the US, where regulations were previously less strict than in the EU, a new governmental policy and review mechanism was launched for "Potential Pandemic Pathogen Care and Oversight" (P3CO).
In May 2013, a group led by Hualan Chen, director of China's National Avian Influenza Reference Laboratory, published several experiments they had conducted at the BSL3+ laboratory of the Harbin Veterinary Research Institute, investigating what would happen if a 2009 H1N1 circulating in humans infected the same cell as an avian influenza H5N1. Importantly, the experiments had been conducted before a research pause on H5N1 experiments had been agreed upon by the broader virologist community. They used these experiments to determine that certain genes, if reassorted in such a dual-infection scenario in the wild, would allow transmission of the H5N1 virus more easily in mammals (notably guinea pigs as a model organism for rodent species), proving that certain agricultural scenarios carry the risk of allowing H5N1 to cross over into mammals. As in the Fouchier and Kawaoka experiments above, the viruses in this study were also significantly less lethal after the modification.