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It’s the rumour that won’t go away – that SARS-CoV-2 was leaked from a high biosecurity lab in Wuhan, China. The allegation is that the laboratory was conducting gain of function (GOF) research, and that this produced a potent version of coronavirus that led to the pandemic.
This has led to some scepticism and distrust of this field of research and whether it is necessary to conduct experiments using GOF techniques.
What is gain of function research?
Essentially, GOF research is used to learn how viruses gain new functions through mutation and evolution.
GOF research observes these mutations and sees how certain stimuli might affect evolutionary changes and properties of a virus or organism.
At the moment, it’s often spoken about in a much narrower context – specifically how a virus changes to move more easily between humans, or how viruses become more lethal.
What’s the point of GOF research?
Viruses evolve rapidly – that’s why there are so many new SARS-CoV-2 variants. GOF seeks to understand why and how these changes occur, and what environmental factors might influence the process.
In a sense, this is a know-your-enemy approach.
GOF research can help us understand the rate at which mutations occur, and how many generations may be needed for a virus to change in a way that will require extra precautions in the community.
This is one of the streams of data used in epidemiological modelling. It helps predict things such as how likely a virus is to become a nasty variant in a certain population density, or within a particular period of time. It also informs how quickly a virus might mutate to overcome vaccines, and provides genetic information that may be useful in vaccine development.
What is the science behind gain-of-function research?
GOF research is based on observed evolution and changes to DNA or RNA.
The genome is the sum of all the genetic information in an organism. Some of this DNA or RNA is made up of genes, which often hold information on how to make a protein. These proteins perform functions in our body to make everything work.
These genes can naturally change with every generation. The changes are often tiny – just a single unit of DNA (called a nucleotide). They may have no effect on the proteins made, or they can make a gene gain a whole new function.
Natural mutations that occur during reproduction are one example of evolution in action: organisms that breed quickly, such as flies, can also evolve quickly as a species.
This process happens in essentially the same way with viruses, except that viruses have RNA instead of DNA and reproduce asexually. They still make proteins and accumulate mutations, but they can reproduce very, very fast – within hours – and evolve at an exceptionally rapid rate.
This is why we’ve identified so many new variants of SARS-CoV-2. Every time the virus enters a new host, it reproduces rapidly, and mutations occur. Over time these mutations change the properties of the virus.
In these cases, we would say that the mutant strain has gained a function, and this is what GOF research aims to understand.
What happens in a virology lab?
There are two ways of using GOF in a lab: you can observe the virus mutate on its own (without intervention), or you can control small changes through genetic modification.
The first type of use involves putting the virus in different situations to see how it will evolve.
A video on Youtube from Harvard Medical School’s Kishony Lab shows the GOF process with bacteria. The researchers put bacteria onto a giant petri dish with different concentrations of antibiotics, then watch how it naturally evolves to overcome the antibiotic.
The new strains of bacteria were then genetically sequenced to see what genetic changes had caused them to become antibiotic-resistant. This experiment can show how quickly the bacteria evolve, which can inform when or how often antibiotics are given, and whether there is a high-enough concentration of antibiotic that can halt the speed at which the antibiotic is overcome by resistance.
Similar experiments can be conducted with viruses to see how they might change to overcome human antibodies and other immune system protections.
The second type of use is through small changes using genetic modification. This type of experiment occurs after a lot of other genetic information has already been gathered, to identify which nucleotides in virus RNA might particularly contribute to a new function.
A small nucleotide change is made to the virus, which is then placed on a petri dish or inserted into an animal, such as a rabbit or a mouse, to see how the change affects the properties of the virus.
Concerns about gain of function research
In 2005, researchers used this technique for viruses when they reconstructed influenza (H1N1) from samples taken in 1918. The aim was to learn more about the properties of influenza and future pandemics, but study sparked heavy debate.
In 2017, the US government lifted bans on GOF pathogen research after the National Institute of Health concluded that the risks of research into influenza and MERS were outweighed by the benefits, and that few posed significant threats to public health.
Following concerns about the origins of SARS-CoV-2, the rules surrounding GOF research, risk assessments and disclosure of experiments are under review again.
Ultimately, the parameters around how scientific techniques like GOF are used and by whom is not a scientific question, but one that must be answered by ethicists.