Techniques for inducing mutations in viruses that give microorganisms new abilities are included in the microbiology toolbox. Scientists do these experiments for a variety of purposes, including to learn how bacteria avoid detection by our immune systems. However, enhancing a pathogen’s capabilities comes with apparent hazards, especially if this “gain of function” implies increased virulence or infectiousness. It’s possible to get out of a lab by accident or design. So, why are you doing it? Some researchers believe the research can provide a glimpse into what a virus can accomplish before it enters the natural world and becomes a threat to humans.
Gain-of-function research has sparked scholarly articles, conferences, and even a three-year moratorium in 2014 when the US government halted funding until steps could be done to ensure the procedure’s safety. The debate over gain-of-function trials rages on in the final stages of the pandemic, as thoughts turn to the “next one” or a possible COVID-19 sequel. Science policymakers must define the rare cases in which the benefits of research that improve a virus’s ability to live and thrive in human hosts outweigh the risks.
The definition of gain of function is a topic that frequently bogs down densely technical talks. Recently, semantics were at the forefront of a discussion about whether studies financed by the National Institutes of Health at China’s Wuhan Institute of Virology (WIV) constituted gain-of-function research, a claim contested by the US agency. The WIV is also at the center of a resurgent debate over whether SARS-CoV-2, the virus that causes COVID-19, escaped from its confines.
Here are some basic explanations for why an obscure technical word is getting so much attention lately.
What are the benefits of function research?
In research, techniques to improve some aspect of an organism’s functioning are frequent, and they’ve been used on everything from mice to measles. Changing mice genes to produce more of a protein that prevents fat deposition is a common application of this method.
However, this is not the type of gain-of-function study that scientists and regulators are concerned about. High-risk procedures include creating mutations to see if a pathogen becomes more contagious or fatal to predict future threats.
Some professionals recognize the important distinctions between the two types of investigations. According to Marc Lipsitch, a professor of epidemiology at Harvard T. H. Chan School of Public Health, one proposed name to reflect the more dangerous portion of this research is “possible pandemic pathogens.” He says that this sentence “singles out the name and reason for concern.” However, the term has yet to catch on in popular usage, with a Google search yielding just roughly 8,500 results compared to 13.4 million for “gain of function.”
Lipsitch believes that distinguishing between the two is critical for several reasons. When the US government imposed a ban on “gain of function research” in 2014, some of the experiments that were halted had no evident risk of causing a pandemic.
What is the goal of this investigation?
According to Lipsitch, who is one of 18 signatories to a letter published in Science on May 14 calling for the investigation of a SARS-CoV-2 lab spillover as one of several possible explanations for the origins of the COVID-19 pandemic, knowing what makes a microbe more dangerous allows for the preparation of countermeasures. He emphasizes the limitations of studying viruses for the development of vaccines and therapies without using mice or other nonhuman animals as test subjects. There is a “direct road from completing that study to getting public health advantages,” according to Lipsitch, allowing for a balance of risks and potential gains.
Gain-of-function research is more dangerous since it gives viruses powers they don’t have in nature. Scientists famously and controversially accomplished just that with the H5N1 influenza virus, or “bird flu,” in two separate trials in 2011, resulting in a form capable of airborne transmission among ferrets. This ability does not exist in naturally occurring viruses. Making mammalian-to-mammal transmission simpler rang off alarm bells, prompting calls for a moratorium in the United States.
Researchers created a hybrid pathogen in 2015 that merged characteristics of the original SARS virus (SARS-CoV), which infected people in the early 2000s, with those of a bat coronavirus. The majority of bat coronaviruses are incapable of infecting the cells that line the human respiratory tract. The goal of this experiment was to see what would happen if a third species acted as a mixing vat for bat and human viruses to swap genetic material.
The result was a pathogen capable of infecting human cells as well as mice. As experts quoted in a 2015 article in Nature demonstrated, reactions to this work were polarised: one claimed that all the research did was create a “new, non-natural risk” among the many that already exist, while another claimed that it demonstrated the potential for this bat virus to become a “clear and present danger.”
Gain-of-function viral studies, according to experts in the latter group, can predict what will happen in nature. Researchers can get firsthand proof of how a virus evolves by speeding things up in the lab. To keep one step ahead of these viruses, such knowledge could be used to make predictions regarding the future viral activity.
According to Lipsitch, this computation must be done on a case-by-case basis. “There isn’t a one-size-fits-all solution,” he adds. But the most important issue to answer in this complicated calculation is: “Is this work so valuable for public health that the risk of conducting it outweighs the benefit?”
Lipsitch was “extremely vociferous” about the influenza-ferret study, as he puts it, and he spearheaded the charge for a 2014 embargo on comparable gain-of-function research. He explains, “I did that because I thought we needed a real accounting of the rewards and hazards.” “I used to believe that the benefits were insignificant, and I still believe that.”
In 2017, the moratorium was removed. Later, a federal review panel in the United States approved the continuation of funding for more lab investigations employing gain-of-function alterations of bird flu viruses in ferrets. Enhanced safety procedures and reporting requirements were among the conditions of the approvals, according to reports.
The NIH and its National Institute of Allergy and Infectious Diseases have “never approved any grant that would have supported ‘gain-of-function research on coronaviruses that would have increased their transmissibility or lethality for humans,” according to a statement released on May 19 about SARS-CoV-2, the virus that is currently causing the most concern.
What are the potential dangers?
Gain-of-function research may be hypothetical, but lab breaches in the United States are not. Serious infractions are rare, and pathogens are nearly never released into the population as a result of them. However, 2014 demonstrated why human error could be the largest unknown when it comes to organizing these tests.
Several lab mishaps that year put researchers in jeopardy and sparked widespread anxiety. These were not gain-of-function mishaps, but they did show the dangers that a biosafety lab might offer, whether due to negligence or malfeasance. After safety procedures were disregarded, some 75 Atlanta-based employees of the US Centers for Disease Control and Prevention found in 2014 that they could have been exposed to anthrax. During a cold-storage cleanout at the NIH that year, several long-forgotten vials of freeze-dried smallpox—a virus long considered to be held in only two sites, one in Russia and one in the United States—were discovered. After sending out vials of a relatively innocuous influenza virus tainted with the considerably more dangerous H5N1 avian flu virus a month later, the CDC made headlines once more. According to Science, one plausible reason was that a researcher was “overworked and racing to make a lab meeting.”
In a 2020 editorial about gain-of-function studies, Michael Imperiale, a professor of microbiology and immunology and associate vice president for research and compliance at the University of Michigan, said that the key to planning them is to have proper mechanisms to ward off the threats of accidental or intentional harm. “The hazards can be significantly decreased if suitable biosafety measures are in place and proper containment is used,” he says. The strongest containment procedures are in place in biosafety level 4 (BSL-4) labs, and the United States currently has 13 or more such facilities planned or in operation. The new coronavirus is being studied in labs a notch lower: BSL-3
Imperiale and his co-author, mBIO editor in chief Arturo Casadevall, said in their editorial that even forecasting the threat level of an accidental release is challenging. Two groups attempted to estimate what would have happened if the modified H5N1 virus had escaped into the human population after the studies of ferret-to-ferret transmission were published. Imperiale and Casadevall noted that one group projected “extremely high levels” of transmission. The other, from one of the labs engaged in the ferret-influenza research, came to the opposite conclusion.
The writers of the editorial noted that the source of a pathogen—whether from nature or a lab—does not impact how the world should prepare to respond to it in the context of the COVID-19 pandemic. Gain-of-function studies, on the other hand, should be guided by transparency in research planning, a “rededication” to biosafety, and a robust surveillance mechanism to detect violations.
What other options are there for testing a potential viral threat?
Imperiale believes that gain-of-function research may be superfluous if a virus has already spread from an animal host to humans. According to him, “in some circumstances, animal models may serve as valuable surrogates for humans” when studying the virus’s effects.
Researchers can also assess the ability of viral proteins to interact with various cell types. The software can forecast how these proteins will interact with different cell types and how their genetic sequences will be linked to distinct virus characteristics. The viruses may also be programmed not to proliferate if the researchers employ cells in a lab dish.
Loss-of-function research is another approach. Another technique to unlock the secrets of a microbe is to use virus variants with lower pathogenic potential. However, highly pathogenic forms can differ significantly from their less dangerous relatives, such as in how frequently they reproduce, thereby limiting the use of such investigations.
