What is gain of function research in genetics?

It’s the rumour that won’t go away – that SARS-CoV-2 was accidentally 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 the 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.

A function is simply a property of an organism, such as plants that are more tolerant to drought or disease, or enzymes that evolved to make our bodies work.

The language about GOF has become loaded with negative connotations that associate this work with dangerous or risky research. But like rhetoric about genetic modification, these connections don’t represent the diversity of the field or the security precautions that regulate the research. At its core, though, the research does exactly what the name suggests.

GOF research observes these mutations and sees how certain stimuli might affect evolutionary changes and properties of a virus or organism.

However, in our current climate it’s often spoken about in a much narrower context, as though it’s specifically about how a virus changes to move more easily between humans, or how viruses become more lethal. This just doesn’t represent the full picture of GOF research.

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.

Beyond the benefit to fundamental biology research about the nature of viruses and evolution, GOF contributes to three clear areas: pandemic preparedness, vaccine development, and identification of new or potential pathogens.

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, which is information that is fed into epidemiological modelling.

This GOF information helps predict things such as how likely a virus is to become a nasty variant in a certain population size or density, during a certain season, or within a particular period or time. This informs how we react to a pandemic. Beyond this, it also informs how quickly a virus might mutate to overcome vaccines, and provides genetic information that may be useful in vaccine development. Specifically, GOF research can accumulate potential vaccine candidates in a database that can be accessed if an outbreak occurs because of natural evolution.

In turn, this means vaccine development can be sped up exponentially because candidates are already available.

For instance, a report from a 2015 GOF risk-assessment workshop for expert organisations revealed the genomics information from GOF research. This showed that bat-borne, SARS-like coronaviruses had many strains and mutations that had “pandemic potential against which countermeasures need to be developed”.

This information led to current pandemic responses and vaccine development – the pandemic was already predicted because of a thorough understanding of the evolution of coronaviruses.

In another example, GOF experiments about influenza showed that the virus had the potential to be transmitted between different mammals with only a few changes to the genetic code, and has contributed to seasonal flu vaccines.

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 a bit every generation. This happens because, to reproduce, the DNA of the parent must be replicated. The mechanisms that do this aren’t perfect, so little mistakes can be made when the DNA is copied.

Most of the time, the changes are tiny – just a single unit of DNA (called a nucleotide) could be changed, and it may have no effect on the proteins made. At other times, the tiny change of a single nucleotide can make a gene gain a whole new function, which could be beneficial to an organism.

Natural mutations that occur during reproduction are one example of evolution in action.

These changes happen every generation, so organisms that can 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 they still accumulate mutations, but the major difference is that they can reproduce very, very fast – they can start reproducing within hours of ‘being born’ –and evolve at an exceptionally rapid rate.

This is why we have identified so many new variants of SARS-CoV-2 since the beginning of 2020. Every time the virus enters a new host, it reproduces rapidly, and mutations occur. Over time these mutations change the properties of the virus itself.

For example, new mutations may end up making the virus more virulent or cause worse symptoms because the proteins have changed their properties.

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?

The viruses in a lab don’t have a human host in which to grow, so researchers grow them in Petri dishes or animals instead.

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 without intervention or aid.

This video is an example of GOF research with bacteria (not a virus, but the method is similar). The researchers put bacteria onto a giant petri dish with different concentrations of antibiotics. They leave the bacteria and watch how it naturally evolves to overcome the antibiotic.

The new strains of bacteria were able to be 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.

Read more: What happens in a virology lab?

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.

After these have been identified, a single or small nucleotide change will be made to the virus to confirm the predictions gained from genomic research. The modified virus will then be 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.

This type of research is done in specialised laboratories that are tightly controlled and heavily regulated under biosecurity laws that involve containment and decontamination processes.

Read more: How are dangerous viruses contained in Australia?

Concerns about gain of function research.

While the benefits of virus GOF research centre around pandemic preparedness, concerns have been raised about whether the research is ethical or safe.

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, as influenza still circulates, but the controversial study sparked heavy debate about whether it should be acceptable.

The two major concerns are about whether this poses any threat to public health if a virus escapes the lab, or whether the techniques could be used for nefarious purposes.

In the past year, 16 years after the H1N1 study, there has been debate about whether SARS-CoV-2 had spontaneous zoonotic origins, or whether it was ‘created’ in a lab in GOF experiments, and then escaped.

So now, 16 years after the first controversial H1N1 study, this speculation has pushed GOF research back into the public eye and led to many criticisms of the research field, and regulation of laboratories that use this technique.

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, however, the rules surrounding GOF research, risk assessments and disclosure of experiments are now under review again, in order to clarify policy.

Read more: The COVID lab-leak hypothesis: what scientists do and don’t know

Beyond this, the speculation has sparked further inquiries into the origin of SARS-CoV-2, although the World Health Organization concluded that viral escape from a laboratory was very unlikely.

Regardless, it’s never a bad thing to review biosafety, biosecurity and transparency policy as new evidence becomes available, and they have been frequently reviewed throughout history.

As for the concern that a government or private entity might abuse scientific techniques for malevolent purposes, scientists can, and do, support bans on research they deem ethically irresponsible, such as the controversial ‘CRISPR babies’.

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.

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