Pushing the Envelope on Cost/Benefit Analysis

Today, whether we like it or not, there is a constant need to justify funding for cutting-edge research. Grant money is scarce, and thanks to the internet, journalists are reporting the latest discoveries faster than ever before, raising questions among the general public about the possible impact of these studies. It is with this in mind that I think we are reaching a crossroads in public perception—with research on the avian influenza virus H7N9 likely to take center stage.

H7N9 has caused more than 130 human infections in China. Although the virus is not currently transmissible among humans, a team of researchers is suggesting that creating mutant viruses with different degrees of transmissibility in mammals will help us understand the potential for human-to-human transmission.

In a letter published this August in both Science and Nature, 22 researchers from 12 universities in the the US, Europe, and Asia present a case for performing gain-of-function [GOF] experiments in H7N9 to examine immunogenicity, adaptation, drug resistance, transmission, and pathogenicity (1,2). The authors argue that “classical epidemiological tracking does not give public health authorities the time they need to mount an effective response to mitigate the effects of a pandemic virus. To provide information that can assist surveillance activities—thus enabling appropriate public health preparations to be initiated before a pandemic—experiments that may result in GOF are critical.”

Such experiments could provide new insights into virus function and possible paths of future evolution resulting in increased transmissibility to humans. The challenge, though, is to monitor and report that progress as a growing range of mutations are engineered in the lab. Prior work by the same researchers examined the H5N1 virus and its capacity for airborne transmission between ferrets in the lab (3). This work was controversial, leading to several public discussions amongst government officials, researchers, and journal editors before that work was finally published.

The rationale behind new GOF studies in H7N9 is curious. While planning ahead for a potential pandemic is important, are vaccine developers willing to design vaccines against “hypothetical” viruses based on GOF mutations? Actually, work has already begun on an H7N9 vaccine, so it is not clear what impact new GOF studies would have.

While surveillance should be done, are GOF experiments really necessary given our current knowledge of the potential mechanisms by which viruses can acquire the ability to broaden their host range? Next-generation sequencing can decode a whole genome in a day, and airborne transmission can be determined quickly based on information from patients. Sequencing might not be a viable option in the developing world, so does the knowledge gained through GOF studies improve surveillance options? I'm not suggesting these questions could not be answered, rather I am echoing the need for greater transparency, as many have suggested.

Fears about scientific experiments should not be used as a tool to get an experiment done or to stop such research altogether.

Researchers must go to extra lengths to accurately explain the rationale behind experiments that might create more transmissible viruses and how they will be safely conducted. A nice article in Nature Biotechnology suggesting a new safeguard mechanism for GOF studies was recently published (3). Here, the authors took advantage of endogenous miRNAs in human cells to prevent transmission of viruses. The technique appears effective and provides a degree of possible containment when working with GOF viruses. Such techniques and approaches need to be highlighted as widely as the letters suggesting these experiments in the first place.

Hyperbole aside, this is a moment where scientists need to consider the psychological impact of their work on the general public. Fears about scientific experiments should not be used as a tool to get an experiment done or to stop such research altogether. There should not be any perception that scientists are simply creating a series of “monster viruses” that will be locked away in labs around the world; this only feeds public fears and future Hollywood movies. Providing clear explanations for the potential of such research, as well as the safeguards built into these studies, will help to reduce concerns and provide a stronger framework for experimental success.

The H5N1 studies led to lengthy discussions on the cost/benefits of engineering influenza viruses. In the end, it was decided that the benefits outweighed the potential risks. Now, as researchers push the envelope once again, it is important to revisit that cost/benefit question. Share your thoughts with us at [email protected].