Why Scientists Tweak Lab Viruses to Make Them More Contagious
Some “gain of function” studies explore how a dangerous pathogen might cross species barriers to start an outbreak. They are not without controversy
The microbiology toolbox includes techniques to induce mutations in viruses that give the microbes new powers. Scientists perform these manipulations for many reasons, including wanting to understand how the microbes evade detection by our immune systems. But adding capability to a pathogen carries obvious risks, especially if this “gain of function” involves enhanced virulence or infectiousness. Escape from a lab, by accident or design, is a possibility. So why do it? Some researchers argue the work can offer a peek at what a virus can do before it goes into the natural world and poses a threat to people.
Controversy over gain-of-function research has generated academic papers, conferences and even a moratorium in 2014, when the U.S. government paused funding for three years until steps could be taken to ensure the safety of the procedure. Debate about gain-of-function experiments continues in the latter phases of the pandemic as thoughts turn to the “next one” or a possible second act for COVID-19. Science policy makers must wrestle with defining the rare instances in which the benefits of experiments that enhance a virus’s capacity to survive and flourish in human hosts outweigh any risks.
Densely technical discussions often bog down over the very definition of gain of function. Recently, semantics were front and center in the debate over whether National Institutes of Health–funded work at the Wuhan Institute of Virology (WIV) in China constituted gain-of-function research, a contention denied by the U.S. agency. The WIV has also been the focus of a revived dispute over whether SARS-CoV-2, the virus that causes COVID-19, escaped from its facility.
Here are a few basic answers to questions about why an obscure technical term now receives so much attention.
What is gain of function research?
Techniques to enhance some aspect of an organism’s functioning are commonplace in research and applied to everything from mice to
measles. One typical application of this approach is tweaking mouse genes to generate more of a protein that
limits fat deposition.
But that is not the kind of
gain-of-function study that raises fears among scientists and regulators. The high-risk practices are those that create mutations to examine whether a pathogen becomes more contagious or lethal as a means of estimating future threats.
Some experts acknowledge the critical differences between the two types of studies. One proposed term to represent the more threatening subset of this research is “potential pandemic pathogens,” says Marc Lipsitch, a professor of epidemiology at the Harvard T. H. Chan School of Public Health. That phrase “singles out the name and reason for being concerned,” he adds. It has not caught on in common usage, however, returning only about 8,500 results in a Google search, compared with 13.4 million for “gain of function.”
Making this distinction is important for a few reasons, Lipsitch says. When the U.S. government placed the 2014 moratorium on “gain of function research,” some of the studies that were
affected carried no obvious risk of setting off a pandemic.
What is the purpose of this research?
Knowing what makes a microbe more dangerous enables preparation of countermeasures, says Lipsitch, who is one of 18 signatories to a May 14 letter, published in
Science, that
calls for the investigation of a SARS-CoV-2 lab spillover as one of several possible explanations for the origins of the COVID-19 pandemic. He points to the difficulties of studying viruses for the development of vaccines and treatments without doing experiments in a mouse or in other nonhuman animals. There is, Lipsitch says, a “direct path from doing that research to gaining public health benefits,” enabling a balancing of risks and potential benefits.
The riskier version of gain-of-function research creates viruses with abilities they do not have in nature. In two separate studies in 2011, scientists famously and controversially did just that with the H5N1 influenza virus, or “bird flu,” resulting in a version capable of airborne transmission among ferrets. The naturally occurring virus does not have this ability. Making mammal-to-mammal transmission easier set off alarm bells and triggered discussion of a U.S. moratorium.
In 2015 researchers engineered a hybrid pathogen that combined features of the original SARS virus (SARS-CoV) that infected humans in the early 2000s with that of a bat coronavirus. Most bat coronaviruses cannot infect the cells lining the human respiratory tract. This experiment was intended to mimic what would happen if a third species served as a mixing vat for the bat and human viruses to exchange genetic material. The result was a pathogen that could enter human cells and also cause disease in mice. Reactions to this work were polarized, as demonstrated by experts quoted in a 2015 article in
Nature: one said that all the research did was create a “new, non-natural risk” among the multitude that already exist, while another contended that it showed the potential for this bat virus to become a “
clear and present danger.”
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