The term ‘gain of function’ is perhaps one of the most misunderstood in the scientific lexicon. I would like to explain what the phrase means from the perspective of a scientist who has done gain of function research for the past 40 years.
Gain of function (GoF) research gives an organism a new property or enhances an existing one. The organism can be a virus, bacterium, fungus, rodent, bird, fish or anything that can be experimentally manipulated (technically whales and elephants could be included in the definition but it would be very difficult to to GoF research on them).
Many have the impression that GoF research involves making an organism more deadly – for example, increasing the capacity of a virus to cause disease. That impression is incorrect. Certainly GoF research might lead to a more dangerous organism, but most of the time that is not the goal.
There are two broad approaches to GoF research. I’ll illustrate them with viruses but the principles could apply to any organism. In one approach, a virus is passaged in a host until a virus with different properties is obtained. An example is the adaptation of a strain of poliovirus – the type 2 Lansing strain – to replicate in mice and paralyze them. The Lansing strain does not infect mice, but an investigator passed the virus 99 times from mouse to mouse and ended up with a new strain that could now paralyze the mice. The new version of the virus had a new property – it could now infect mice. This experiment was GoF research.
Another way to do GoF research is to use recombinant DNA technology to engineer changes in the genome of the organism. In experiments done in my laboratory, we took a small piece of the genome of the mouse-adapted Lansing strain of poliovirus – coding for just eight amino acids – and spliced it into the genome of another poliovirus that is unable to infect mice. The recombinant virus from this experiment had a new property – the ability to infect mice. This experiment would also be classified as GoF.
An illustration of how GoF can be done on mice is our creation of transgenic mice susceptible to poliovirus. Mice cannot be infected with the virus because they do not produce the cell receptor for poliovirus. We introduced the human poliovirus receptor gene into the mouse germline, leading to mice that produce poliovirus receptor. After infection, these poliovirus receptor transgenic mice can be infected with poliovirus and develop paralysis. The mice have a new property – susceptibility to poliovirus infection. The mice are a product of a GoF experiment.
GoF research may have a myriad of useful outcomes. Do you want to make a different tasting beer? Modify an enzyme in the yeast used for fermentation. But in the past 30 years GoF research has received a bad name. The catalyst was a series of experiments on highly pathogenic avian H5N1 influenza viruses. These viruses rarely infect humans and do not transmit well among people. In experiments to understand what limited transmission, the virus was genetically modified and passaged among ferrets. The result was a virus that could transmit among ferrets by respiratory droplets. These GoF experiments were met with criticism, entirely unwarranted as the passaged viruses had lost their virulence for ferrets! Nevertheless since then a dark cloud has unjustifiably hung over all GoF research.
GoF research has been in the press again recently as a consequence of the COVID-19 pandemic. After the SARS-CoV pandemic of 2003, wildlife sampling efforts in China revealed many SARS-like coronaviruses in bats. To assess the potential of these viruses for infecting humans, their spike protein encoding genes were substituted into the SARS-like CoV WIV1. These recombinant viruses reproduced in human airway cells – no different from WIV1 – but at least one caused more severe disease in mice. Consequently these are GoF experiments. Some have suggested that such GoF work gave rise to SARS-CoV-2 in a lab, but this notion is impossible, as none of these viruses are close enough to be a precursor of the current pandemic virus.
The production of recombinant coronaviruses to assess pandemic potential was carried out in several laboratories, all funded by the NIH. Recently Dr. Anthony Fauci told Congress that the NIH did not fund GoF coronavirus research. The press has suggested that he lied, but the truth is that his definition of GoF research is that it only involves passaged of organisms in animals. This interpretation is not correct but being wrong does not mean you are lying.
I want readers to understand that the goals of GoF research are laudable, and only a small subset has the potential to harm humans. Consequently these experiments are highly regulated and carried out under high levels of biological containment. GoF is not a dirty word.
14 thoughts on “Gain of function research explained”
For a while after I heard the term GoF, I thought I did not understand it. And when I had some idea I thought it only applied to viruses. But no. Now I understand that in an effort to be specific I should have been more generalized. Generalizations are something we’re all cautioned not to do. This article set me straight.
So SARS2 Cov2 did indeed come from from the many viruses collected from wild bats and was not the product of GoF experiments? Or is it impossible tor virologists o tell?
You are as big a fraud as Fauci. He has a duty of candor when testifying. Picking a definition which gives a false impression doesn’t make you wrong it makes you a liar. Or are you saying Fauci is too stupid to know the full and complete definition of GOF? Stop being an apologist for this liar.
As for lab origination of SARS-2, it is now a fact. Again, you engage in the same practice as Fauci. Skewing the conclusion by using a limiting predicate.
â€œ lab origination of SARS-2 it is now a factâ€-
Then do you mind directing us to the pub stating that ?
It is the opinion of Committee Minority Staff, based on the preponderance of available
information; the documented efforts to obfuscate, hide, and destroy evidence; and the lack of physical evidence to the contrary; that SARS-CoV-2 was accidentally released from a Wuhan Institute of Virology laboratory sometime prior to September 12, 2019. The virus, which may be natural in origin or the result of genetic manipulation, was likely collected in the identified cave in Yunnan province, PRC, sometime between 2012 and 2015. Its release was due to poor lab safety standards and practices, exacerbated by dangerous gain-of-function research being conducted at inadequate biosafety levels, including BSL-2. The virus was then spread throughout central Wuhan, likely via the Wuhan Metro, in the weeks prior to the Military World Games. Those games became an international vector, spreading the virus to multiple continents around the world.
David I will leave it at the following : RaTG13 ( the one you are referring to) the coronavirus detected in horseshoe bats in southwest China’s Yunnan Province in 2013, differ from SARS-CoV-2 in about 1,100 nucleotide positions.
All most recent papers point to a natural virus- a similar emergence to the one caused by SARS-CoV.
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What was the benefit of doing the research to infect mice with the polio virus and the ferrets with H1N5?
Nothing you have said shows that the virus didn’t come from a lab and none of the papers can legitimately say that either. Whether it was man or nature made is not the point, and only a red-herring. The odds of it not coming from the lab are infinitely astronomical and the only acceptable proof it did not come from the lab is a showing it is not technically feasible for any scientist to create the virus, the lab did not have the expertise to create the virus or the original host of the virus has been found. The fact that there was destruction of lab notes or data confirms that the virus came from a lab.
David I disagree – this is not the place for a dissertation on the natural reservoirs of corona viruses that share the same furin (RRAR) cleavage site that so many indicate as proof of a man made virus – the evidence in the document you linked is mostly circumstantial but with very little scientific back up if any.
Unless a true scientific investigation is launched into the matter then the outcome will only be speculative in nature.
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Max, there are more arguments for GoF origin of SARS-CoV-2 than just the presence of the furin cleavage site. Besides, Shi Zhengli and her team successfully inserted this very site into the spike protein several times in the past. There is now also evidence about Daszak wanted to further modify the coronavirus spike protein to find potential, what’s called furin cleavage sites, and even introduce human specific cleavage sites. (https://gallagher.house.gov/media/press-releases/gallagher-addresses-new-documents-supporting-lab-leak-hypothesis)
Regarding RaTG13, there are reasons to believe it is not and never was present in nature.
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