Monthly Archives: December 2015

Genetically Modified Emerging Viruses: Debate over Gain-of-Function Research

Scientists generally loathe restrictions on their freedom to conduct research. Nonetheless, many virologists recognize the need to regulate studies that involve live, potentially pandemic, deadly pathogens, especially when those investigations involve modifying and even creating such pathogens.

We encountered this issue in an earlier posting (1), which told how in 2012 Yoshihiro Kawaoka and Ron Fouchier independently created variants of the H5N1 avian influenza virus that could be transmitted between ferrets (2, 3). They did so by using site-specific mutagenesis to modify the HA protein of the avian virus. Ferrets were used because they are a good model for influenza transmission between humans.

Important to our story, avian influenza viruses are spread in bird populations by the fecal-oral route. And, while H5N1 avian influenza viruses can be extremely pathogenic in humans, they have not yet naturally acquired the ability to be transmissible through the air—an ability that is necessary for influenza viruses to be pandemic in humans. So, to ascertain whether H5N1 avian influenza viruses could adapt to become transmissible via aerosols under natural conditions, both Kawaoka and Fouchier passaged their genetically modified H5N1 avian viruses in ferrets. The genetically modified H5N1 viruses indeed acquired additional mutations during passage in ferrets, which enabled them to become transmissible via the respiratory route. Moreover, each research group reported that the airborne-adapted mutant H5N1 viruses caused lung pathology in the recipient ferrets, none of which died.

The NIH supports studies like the above because of their potential to shed light on the interactions between emerging deadly pathogens and humans, and because they might help to clarify just how threatening these emerging viruses actually are. But regardless of those considerations, the White House Office of Science and Technology Policy (OSTP) and the Department of Health and Human Services were concerned by the potential risks of the avian flu experiments. Consequently, in October 2014 those governmental agencies initiated an assessment of gain-of-function research—that is, studies in which pathogens are manipulated to alter their virulence and transmissibility. Biosafety and biosecurity were the government’s key concerns. Possible risks included the prospects of a potentially pandemic modified virus either escaping from the laboratory, or being stolen from the laboratory and being misused to threaten public health and national security.

With those concerns in mind, the government imposed a temporary suspension of funding of new gain-of-function projects. The OSTP announced that effected studies would include those which “may be reasonably anticipated to confer attributes to influenza, MERS, or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route.” In addition, the government requested that researchers already carrying out gain-of-function projects should “voluntarily” postpone their studies until the risks might be evaluated by the National Science Advisory Board for Biosecurity (NSABB) and the National Research Council (NRC) of the National Academies.

As expected, these government-imposed restrictions caused quite a bit of controversy in the research community. Some scientists expressed concern that a ban on gain-of-function experiments might be applied too broadly, to include less dangerous types of work, such as development of seasonal influenza vaccines. [In that instance, gain-of-function research might be useful to evaluate the transmissibility of particular influenza strains, and to asses how those strains might mutate to evade candidate vaccines.] The government responded to this concern by modifying its review protocols in order to take public health considerations into account. Yet some researchers still feared that valuable research time could be lost while waiting for an exemption.

But what of experiments such as those of Fouchier and Kawaoka, which do entail a clear and present risk to public safety? The key question in those instances is whether the knowledge gained from the experiments might afford a benefit that is significant enough to justify the danger. Unfortunately, the answer is not always clear, as thoughtful individuals on each side of the debate make valid arguments. And, even if there were a consensus on the merit of a project, the delay in funding imposed by the review process might again cause valuable research time to be lost, or perhaps even destroy the research program, or cause outstanding young scientists to turn to other areas of inquiry, or even end their research careers.

The debate over government imposed restrictions on gain-of-function research waned somewhat after they were first announced. However, it was reignited last month by the announcement by Ralph Baric and co-workers at the University of North Carolina that they had created a chimeric SARS-like virus, which expresses the spike (attachment protein) of a bat coronavirus in a mouse-adapted SARS-CoV backbone (4). As in the cases of the genetically modified H5N1 avian influenza viruses, the newly generated SARS-like virus is potentially an extremely dangerous, possibly pandemic pathogen.

Coronaviruses, showing their characteristic spikes, which give them their characteristic “crown-like” (coronal) appearance
Coronaviruses, showing their characteristic spikes, which give them their characteristic “crown-like” (coronal) appearance

Baric’s team generated the chimeric SARS-like virus using the SARS-CoV reverse genetics system. The justification for the project was to evaluate the risk of SARS coronaviruses emerging from coronaviruses currently circulating in bats. Apropos that, the origin of the SARS coronavirus is not known for certain. However, the genetic diversity of coronaviruses in bats, in which they are avirulent, is consistent with the possibility that bats are a reservoir for SARS-coronaviruses.

The North Carolina group reported that their hybrid SARS-like virus could indeed bind to, and replicate efficiently in human airway cells in vitro. In fact, the chimeric virus replicated as well as epidemic strains of SARS-CoV in the human cells. Moreover, the chimeric virus replicated in, and caused severe pathogenesis in mouse lung in vivo.

Baric and co-workers began their project before the government announced the moratorium. Yet the work was allowed to continue because it was judged not risky enough to be bound by the restrictions; a decision that has since provoked quite a bit of controversy. Moreover, the North Carolina researchers themselves acknowledged the risk of their studies, noting, “Scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue…(4)”

Still, the key question is whether Baric’s experimental findings are important enough to justify their risk. At least some in the science community contend that they do not meet that test. In any case, Baric intends to study his new SARS-like virus in non-human primates, for the purpose of better understanding the potential threat of bat coronaviruses to humans.

References:

1. Opening Pandora’s Box: Resurrecting the 1918 Influenza Pandemic Virus and Transmissible H5N1 Bird Flu, posted on the blog April 15, 2014.

2. Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, Zhong G, Hanson A, Katsura H, Watanabe S, Li C, Kawakami E, Yamada S, Kiso M, Suzuki Y, Maher EA, Neumann G, Kawaoka Y. 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486:420-428.

3. Herfst S, Schrauwen EJ, Linster M, Chutinimitkul S, de Wit E, Munster VJ, Sorrell EM, Bestebroer TM, Burke DF, Smith DJ, Rimmelzwaan GF, Osterhaus AD, Fouchier RA. 2012. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336:1534-1541.

4. Menachery VD, Yount Jr BL, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Sh ZL, Baric RS. 2015. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nature Medicine doi:10.1038/nm.3985

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