Gain-of-Function Research: when does the end justify the means?

In all living things lies a set of instructions – from mushrooms and mosquitoes to algae and avocados, each cell contains a script it follows to function as required. These instructions, known as the genome, define what an organism is, distinguishing it from other species and amongst members of its own kind. On a cellular level, the genome is a user manual which, when read properly, allows each individual to thrive throughout every stage of their life.

In this way, genetic material can be compared to a computer code. Just as your body uses its genetic programming to repair and rest itself while you sleep, your phone interprets a code to trigger your morning alarm clock. Both sets of code run in the background, meaning we often end up taking them for granted. It’s only when your phone malfunctions and you find yourself late for work, or when your genome experiences a glitch and you get sick, that we realize just how precious and delicate this code really is. Such is the case for a viral attack.

The computer-code-genome metaphor can easily be extended to the concept of viruses. Essentially, a virus is a rogue bit of code that takes control of its host by interrupting the normal set of instructions. This code is varied and complex, and viruses are constantly rewriting their genome to be able to be more infectious, more transmissible, and more sinister. A digital virus that began with unusually slow computer performance after having visited a questionable website can quickly lead to the devastating ‘blue screen of death’. Similarly, a virus of the living world that originated as a mild illness in a bird can learn how to jump between species, going on to trigger a deadly response in humans. Viruses are powerful and sneaky, constantly changing and adapting to their environments. Cleverly, they rewrite their code to be able to wreak greater havoc.

In order to predict the behavior of viruses, researchers can alter their genome in a lab setting. This type of research, known as gain-of-function research, allows scientists to investigate the different properties that may make viruses so dangerous, either by applying different environmental pressures to a virus or rewriting a line of code themselves. Through these strategies, a virus’s transmissibility (potential to become more infectious), its method of transmission, its potential to jump between species, the symptoms it causes, its lethality, and more can be manipulated artificially to learn about changes that may occur naturally. At face value, knowing more about viruses is obviously a good idea. After all, this can help develop prevention and treatment strategies for new viruses before they even exist. But when this knowledge comes at the expense of potentially creating more dangerous pathogens, it’s understandable how some gain-of-function experiments can be so controversial, equally within the scientific community and amongst the general public.

Following the lab-creation of a more transmissible bird flu virus and a series of lab accidents in the early 2010s, the United States pressed pause on American gain-of-function research. In particular, experiments that “may be reasonably anticipated to” make viruses more transmissible or pathogenic (cause more severe symptoms) in mammals were targeted by a 2014 White House report. After an evaluation of biosafety concerns, detailed risk-benefit analysis, and a call for more transparency and broader community consultation, gain-of-function research in the United States resumed in 2017. By 2019, the controversial bird flu projects were, once again, up and running. And by early 2020, gain-of-function research was already back under the microscope, as the world truly began to realize the devastating consequences of viruses.

When the US government lifted their three-year moratorium on funding virus-targeted gain-of-function research, the decision was not taken lightly. The conclusion came after a 1,000-page risk-benefit assessment and an ethical review had been carried out by a team of experts in the field. Even so, the director of the National Institute of Health, Francis Collins, MD, PhD, emphasized a need to “consider the potential biosafety and biosecurity risks associated with such research”. To this end, for gain-of-function research to be approved, researchers need to show that there are no other equally effective but less risky strategies for answering their questions, prove that they can do the work safely, and have careful strategies in place to quickly react to any potential accidents. These are three of the highlights of an eight-point framework that now guides American gain-of-function studies.

Still, history proves that biosecurity accidents do happen. The ‘Russian Flu’ of 1977, which reportedly killed over 700,000 people, is generally believed to have originated from a lab, although no scientific paper has conclusively proved this theory. In 1978, a deadly case of smallpox – which was eradicated a year earlier – was linked to the mismanagement of a research lab in Birmingham, England. Skipping forward several decades, in 2014, the American Food and Drug Administration stumbled upon hundreds of vials of forgotten virus samples in a storage room. Six of these contained smallpox. The same year, as many as 75 scientists at the Centers for Disease Control and Prevention were exposed to anthrax. Although not necessarily viral in nature or linked to gain-of-function research, these are just a few examples that prove that wherever there are pathogens, there is a chance of infection and illness. Even with rigid security protocol in place, accidents can occur. Hence the hesitancy towards purposefully creating more dangerous viruses.

Gain-of-function researchers, especially when working with viruses, understand the delicate nature of their work. Ultimately, their primary goal is to help, not hinder, and their research isn’t strictly creating mutant pathogens. “It’s all about staying one step ahead of the virus,” says Michael Beard, PhD, head of the Viral Pathogenesis Research Laboratory at The University of Adelaide. “If we fully understand what the virus can do, then we can maybe develop better therapeutics, we can maybe develop better antiviral therapies, maybe even perhaps inform vaccine design.” In reality, we have already seen benefits from this kind of experimentation, such as a vaccine against yellow fever and a novel herpes virus-based treatment for melanoma. Many other experiments that don’t involve viruses have led to better understanding of other cancers and genetic disorders, so that better treatments can be developed, or served to determine the genome of plants for better agricultural practices. In the best scenario, gain-of-function research will continue to contribute to other helpful discoveries, saving many lives. In the worst, human error leads to a catastrophic and deadly situation. For the researchers, who understand the weight of this responsibility, it comes down to a careful assessment between risk and reward, and incredible attention to detail in their work.

So, in light of current events, what’s the verdict on the future of gain-of-function research? For now, the jury’s still out. What is clear, however, is that the increasing politicization of the topic and the lab-leak theory are doing more harm than good. Misconceptions on gain-of-function research, a lack of transparency, a lack of nuance – a battle of egos is currently playing out in the public arena, in lieu of a level-headed science-based discussion. And in the words of Dr. Marc Lipsitch, a Harvard-based epidemiologist, “it’s just going to make it harder to get back to a serious debate”.

Note: To be very clear, the origins of the SARS-CoV-2 virus responsible for the current global situation are still unknown. It may take years of careful investigation to pinpoint exactly how the Covid-19 pandemic came to be, or it may always remain a mystery. For now, most experts agree that the most likely scenario is that SARS-CoV-2 jumped from animals to humans, as is often the case with coronaviruses. This article’s sole purpose is to define and explore some of the nuance surrounding gain-of-function research.