GoF (pt2)

Before I revisit GoF (which I guess is admittedly, something of a hobbyhorse of mine), I must plug the BDG’s recent podcast on Euthanasia. Many thanks to the large (14+?)  group that gathered to eat my doughnuts and then discuss a difficult topic.

Anyway … on to a topic which I think  in some ways just as important but sadly, one that frankly, I don’t see is being discussed particularly rationally. Why is GoF so important an issue for me? I think it indicates a growing divide between scientists who do science, scientists who now no longer do science but earn a dollar commenting on science and politicians who have never done science but control the purse strings.

OK, GoF stands for Gain of Function and research using this technique has become increasingly controversial and something of a scientific football. Essentially, molecular biologists tinker with a pathogen’s genes and enable that pathogen to do “more”. That could include a wider host range (a non-human to human virus), different transmissibility (non-airborne to airborne) and so on.

Why are these experiments performed? Current medical countermeasures are often insufficient largely because of resistance mechanisms. There is, therefore, a continual need to develop new antiviral drugs and additional options, such as immunotherapy. GoF studies, which enhance viral yield and immunogenicity, are clearly going to aid the development of vaccines and other antivirals. How do we begin to study pathogens that only infect humans and have no animal models?

A recent PNAS paper (Menachery et al) describe a methodology involving a number of approaches to assess the ability of SARS-CoV–like viruses to infect human cells and cause disease in mouse models. The authors’ results suggest that a bat SARS-like virus, WIV1-CoV, can infect human cells but is attenuated in mice. Moreover, they indicate that additional changes in the WIV1-CoV genome would be required to increase the pathogenesis of the virus for mice. Vincent Racaniello (Professor in Microbiology at Columbia and one of the hosts of the fabulous TWiV podcast) was asked to write a commentary on the paper (see below) and again, criticised the current pause on GoF experiments. Essentially, Racaniello (and many others) want these studies to go ahead but more importantly want a balanced and informed debate to decide on the future of these experiments. Ideally, out of a series of debates and what would undoubtedly be some heated exchanges, a set of criteria would be agreed such that a panel could approve (or not) each and every GoF based on merit and potential risk. I won’t try and summarise Racaniello’s commentary, it is one I whole heartedly agree with. My worry is that large swathes of what might be considered “pure research” are already difficult to get funded because of a sometimes rather uninformed group of politicians who control the purse-strings. GoF undoubtedly has risks but surely the most prudent course of action would be to debate, discuss and then reach a decision. Pausing potentially valuable research without any plan to evaluate its benefits is surely rather reactionary?

Sadly, Wain-Hobson and others who stress some rather apocalyptic scenarios, currently have the upper hand. The sometimes angry exchanges between various camps may well be exciting but ultimately, given no international/multidisciplinary meeting is on the cards, it’s all rather sad.

Anyway, Racaniello’s commentary:

“The current government pause on these gain-of-function experiments was brought about in part by several vocal critics who feel that the risks of this work outweigh potential benefits. On multiple occasions these individuals have indicated that some of the SARS-CoV work discussed in the Menachery et al. article is of no merit. … These findings provide clear experimental paths for developing monoclonal antibodies and vaccines that could be used should another CoV begin to infect humans. The critics of gain-of-function experiments frequently cite apocalyptic scenarios involving the release of altered viruses and subsequent catastrophic effects on humans. Such statements represent personal opinions that are simply meant to scare the public and push us toward unneeded regulation. Virologists have been manipulating viruses for years—this author was the first to produce, 35 y ago, an infectious DNA clone of an animal virus—and no altered virus has gone on to cause an epidemic in humans. Although there have been recent lapses in high-containment biological facilities, none have resulted in harm, and work has gone on for years in many other facilities without incident. I understand that none of these arguments tell us what will happen in the future, but these are the data that we have to calculate risk, and it appears to be very low. As shown by Menacherry et al. in PNAS, the benefits are considerable.

A major goal of life science research is to improve human health, and prohibiting experiments because they may have some risk is contrary to this goal. Being overly cautious is not without its own risks, as we may not develop the advances needed to not only identify future pandemic viruses and develop methods to prevent and control disease, but to develop a basic understanding of pathogenesis that guides prevention. These are just some of the beneficial outcomes that we can predict. There are many examples of how science has progressed in areas that were never anticipated, the so-called serendipity of science. Examples abound, including the discovery of restriction enzymes that helped fuel the biotechnology revolution, and the development of the powerful CRISPR/Cas9 gene-editing technology from its obscure origins as a bacterial defense system.

Banning certain types of potentially risky experiments is short sighted and impedes the potential of science to improve human health. Rather than banning experiments, such as those described by Menachery et al., measures should be put in place to allow their safe conduct. In this way science’s full benefits for society can be realized, unfettered by artificial boundaries.”

Casadevall.A., 2014 mBio 5(4) “Risks and benefits of gain-of-function experiments with pathogens of pandemic potential, such as influenza virus: a call for a science-based discussion.”

Menachery.V.D., Yount Jr. B.L., Sims.A.C., Debbink.K., Agnihothram.S.S., Gralinski.L.E., Graham.R.L., Scobey.T., Plante. J.A., Royal.S.R., Swanstrom.J., Sheahan.T.P., Pickles.R.J., Corti.D., Randell.S.H., Lanzavechia.A., Marasco.W.A., & Baris.R.S. 2016 PNAS “SARS-like WIV1-CoV poised for human emergence.”

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