Gain-of-function research refers to the serial passage of microorganisms to increase their transmissibility, virulence, immunogenicity, and host tropism by applying selective pressure to a culture.
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This is done in the context of research to understand how a pathogen adapts to environmental pressures, allowing for better planning of disease control measures and exploring potential vaccines and therapies. Gene editing technology such as CRISPR can be used in combination with selective serial passages to study the role of specific genes on protein expression and ultimate function of the organism.
Applications of the gain of function search
Gain-of-function studies are most often applied in virology and have revealed many details concerning the biological mechanisms responsible for transmission and replication of the virus.
The high rate of replication and mutation of viruses generally leads to escaped mutants, lines which have acquired changes in their genome which reduce or eliminate the affinity of natural or vaccine-induced antibodies to the virus, without significantly reducing the survival.
Most of the mutations that a virus can acquire are deleterious to viral function, although in some cases the mutation can both increase virulence and allow better immune evasion. For example, the first studies of the E484K mutation of the spike protein of severe acute resSARS-CoV-2 suggest that the affinity towards the ACE2 receptor, the target of the virus, is enhanced, while neutralization by serum antibodies from of patients having recovered from the type SARS-CoV-2 are avoided more effectively.
The FDA requires animal testing for vaccines before human trials can take place. However, since the viral tropism towards the model species is unlikely to already exist, in cases where human viruses are being studied strains capable of infecting the model species must be generated. This can be done using gain-of-function research where the virus has passed through the animal, which allows molecular determinants of transmissibility to be identified and the vaccines under study to be tested.
Controversy around research on gain of office
In 2012, an article was published in Science by Herfst et al., titled: Airborne transmission of the influenza A / H5N1 virus between ferrets. The group had genetically modified the A / H5N1 virus by site-directed mutagenesis and serial passage in ferrets, creating an airborne strain in ferrets.
This demonstrated that it was possible for the bird flu virus to spread through the air and that the strain was sensitive to certain antiviral drugs, but raised many concerns about the ethics and safety of the creation of such a virus. The possibility of an accidental or intentional malicious release of such a virus prompted Barack Obama’s US administration to suspend funding for gain-of-function research related to influenza, SARS or MERS in 2014, although that this decision has since been overturned.
The use of low pathogenic strains for gain-of-function research, or specifically loss-of-function research, where the function of genes is studied through their elimination, has been proposed due to the safety concerns associated with generation. pathogens with increased virulence. However, replication kinetics and tropism are not necessarily well reproduced in low pathogenic strains, while research on loss of function alone often does not provide sufficient data.
More distant alternatives such as single protein virus or replication incompetent in vitro studies, in silico the modeling or comparison of long-term genetic sequences of samples taken from patients is the subject of increasingly intense investigations to replace research on gain of function
As noted, gain-of-function research may highlight possible mutations that can occur in currently known viruses and allow for better community surveillance, identifying when such mutations occur and allowing vaccines to be prepared before such. epidemic.
However, the mutations that a virus can acquire naturally are very varied and are not guaranteed to appear the same as those developed by serial passages in the laboratory. Likewise, the cost and time associated with vaccine development and storage means that preparatory vaccine storage is unlikely to become a real benefit of gain-of-function research.
In addition, intertropical research such as the aforementioned work on ferrets may not be applicable to viruses in humans, because the way in which a mutation alters the interaction of a virus with its environment may differ from host to host. the other. On the other hand, this type of research provided the only way to conclusively demonstrate the possibility that H5N1 has the ability to transfer between mammals and become airborne.
The scientific community is asking for transparency and safety accreditation for any laboratory carrying out research into gain of function on highly pathogenic organisms. This is especially important when it comes to public relations and opinion in the aftermath of the COVID-19 pandemic, where public distrust of science has been highlighted around unfounded conspiracy theories regarding the origin of SARS-CoV-2.
Regardless of the true origin of SARS-CoV-2, the pandemic has demonstrated that the world’s infrastructure is largely unprepared for such an outbreak, and many scientists argue that research into gain of function could have predict and enable the world to better prepare for the epidemic.