The gain-of-function controversy: can benefits outweigh risks?

Veronica Rezelj (PhD student in the Elliott lab) explores the current ‘Gain of function’  debate surrounding the virology community and asks: “Is it in the public interest to support gain of function experiments?” Feel free to have your say in in this poll: http://doodle.com/3hmck4iwwne4d828

World-leading biologists, including David Baltimore, a world-renowned virologist and Nobel Prize laureate, have recently called for a moratorium on the use of CRISPR-Cas9 genome-editing technology. While this relatively new technique has revolutionized biological laboratory research, practical (and moral) issues preclude its clinical use, which could have vast therapeutic potential. In fact, this week saw the publishing of the first paper describing editing the genome of a human embryo. But this is not the first time that a call for a pause in research has been made when newly available techniques with the potential to explore new areas of nature have become available.

An example of this is the call for a moratorium on recombinant DNA technology followed by the famous 1975 Asilomar conference. With rising concerns over ‘gain-of-function’ (GoF) experiments involving viruses with “pandemic potential”, and the ability to manipulate these viruses genetically, the field of Virology is no different than other biological sciences, but how has this happened?

In the beginning

In 2012 two controversial research papers were published, which proved to be contentious and probably significantly altered  the landscape of modern virology for years to come. Both papers described the genetic changes necessary for an exemplary highly pathogenic avian Influenza A/H5N1 strain to become transmissible in ferrets, one lab model used for research into influenza biology. These viruses, now capable of ferret transmission under lab conditions, lost their ability to make the animals sick. In spite of this, a media furore started and pressure mounted on the scientists to hold back on future experiments and allow for a pause for thought to stop any experiments in the future that may prove unsafe.

Following these events, the influenza research community, including the authors of the published research, agreed on “a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals”. Shortly thereafter, the National Institutes of Health and the Centers for Disease Control and Prevention abided by this moratorium.

This pause was meant as an opportunity for discussion and debate over issues stemming from this work, and to assess the risks and benefits of experiments that lead to a “gain-of-function” in ‘pathogens with pandemic potential’. While the 2012 moratorium was adopted voluntarily, on October 17th of last year the White House Office of Science and Technology Policy (OSTP) announced a mandatory moratorium on funding research involving gain-of-function experiments on influenza, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) viruses that could enhance their pathogenicity or transmissibility, due to biosafety issues. The National Science Advisory Board for Biosecurity is currently leading a formal review of risk-benefit assessments of such experiments to develop a new Federal policy regarding funding of this research, which is expected to be completed within a 1 year plan.

The moratorium came as a shock to many researchers working on said viruses. Although some studies have been excepted from the pause, such as studies involving the development of a MERS mouse model, the scientific community is eagerly waiting to hear about the NSABB review and the new Federal policy later this year. Below I describe why this debate requires careful attention and some factors that come into play in risk-benefit analyses.

The risk-benefit assessment dilemma

One aspect that needs to be considered and assessed in GoF experiments is the risk-benefit trade-off. How is the knowledge gained from the study going to benefit the field? What are the risks associated with the study? The value and benefits of a GoF experiment on potential pandemic pathogens has to be powerful enough to outweigh the risks that the study could pose. Importantly, there is an element of serendipity that cannot be predicted in science. Often the results in research are unexpected, making risk-benefit analyses difficult to assess.

“If we expect to continue to improve our understanding of how microorganisms cause disease we cannot avoid working with potentially dangerous pathogens.”

Risks involved in GoF are those belonging to biosecurity and biosafety. A group called The Cambridge Working Group (CWG) issued a statement where they emphasized that there is an urgent need for a thorough reassessment of biosafety. Only last year three major safety lapses were reported at the CDC: a forgotten cardboard box containing smallpox vials in a refrigerator, anthrax exposure due to inappropriate inactivation of spores and the unintentional shipment of H5N1 influenza virus to other laboratory. Because of the potential of accidents like these happening, the CWG claim that experiments involving potential pandemic pathogens should be carefully assessed, as an accidental infection “could trigger outbreaks that would be difficult or impossible to control”.

On the other side of the argument, a group called Scientists for Science claimed that: “if we expect to continue to improve our understanding of how microorganisms cause disease we cannot avoid working with potentially dangerous pathogens”. They state that research can be performed safely under modern biosafety practices. Clearly, gain- and loss- of function experiments have a beneficial value in microbiology, because they can give direct information of cause and effect relationships. These types of experiments have helped push the virology field forward in basic research, and improved our understanding of the basis of disease and host responses.

Nonetheless, we need to understand that viruses recovered under laboratory conditions have different selective pressures compared to hosts in nature. Therefore, we cannot be certain how pathogenic such viruses would be in nature, as they can be more or less pathogenic than we expect.

The findings of the controversial influenza studies are just an example of mutations (or similar mutations) that could arise naturally in the environment in the future and cause a human H5N1 pandemic. Hence, it is argued, further studies are required in order for us to be prepared for the eventuality of such a pandemic. Additionally, GoF research has been used for vaccine development and to identify novel antiviral targets. In some cases, GoF experiments have been essential to these findings with no alternative scientific approaches available which could be capable of providing clear insights to cause and effect relationships. An additional level of complexity is added to this topic when we ask ourselves what are the risks of not doing certain experiments.

The “gain-of-function” label is too broad and vague

One very important point to address is the meaning of the GoF term. GoF experiments in the field of virology include those in which a virus acquires a new function or phenotype. While this meaning might characterize such experiments as dangerous to some, the term does not define what the consequences of the acquired function or altered phenotype are. In the same way some acquired functions can result in a more virulent, pathogenic or transmissible virus, other functions can also result in viral attenuation.

For instance: virus passage in a non-native host cell line is a typical example of a powerful GoF experiment that can lead to the generation of attenuated vaccines. This has been achieved for many viruses, including poliovirus, measles virus and yellow fever virus. In such cases, the function gained is replication in a non-native host cell driven by evolutionary adaptation, which may come at the expense of replication in the native host. What can result is an attenuated virus, beneficial for vaccine development.

“Hopefully the outcomes of this debate will lead to better experimental design and to the adoption of measures aimed at minimising future risks”

Therefore, the term “gain-of-function” but also “loss-of-function” are somewhat vague, and marred by a lack of definitional clarity that can lead to to misunderstandings, as recently pointed out in an article by Paul Duprex and Arturo Casadevall. The alternative term these authors suggest is “aTRIP” – to describe experiments that alter (a) transmission (T), range and resistance (R), infectivity/immunity (I), and pathogenesis (P).

In sum

The GoF controversy, which initially involved scientists working on avian influenza, later became a concern for those working on MERS and SARS and researchers working on other pathogenic viruses are taking note. Nonetheless, GoF studies have helped the progression of basic virology research in general, and the debate is relevant to the field of virology and microbiology as a whole.  It has stimulated an open and constructive discussion about GoF experiments and experiments that may  be designed disregarding the possible risks that might not be predicted, letting us reflect on issues relating to ethics, risk-benefit trade-off, biosafety and biosecurity. As scientists, we have the responsibility of understanding the risks and biosafety issues involved with our experiments, so as to prevent safety lapses that have previously occurred,  in order for the general public not to be afraid of our research.

Hopefully the outcomes of this debate will lead to better experimental design and to the adoption of measures aimed at minimising future risks. Furthermore, we hope the results of the GoF and of the CRISPR-Cas9 genome-editing moratorium would lead to the adoption of pragmatic and prudent decisions enabling further developments in scientific research to be made, along the lines of what happened in the past with recombinant DNA technology.

If you found this post interesting and want to found out more about the GoF debate, here is a link to a YouTube playlist with recordings of sessions of a GoF symposium. Scientists for Science can be found here where you can sign up to become a supporting scientist. Already quite a few CVR staff are members.

By Veronica Rezelj, Ph.D student. @verorezelj

With thanks to the rest of the blog contributors for reading critically.

The Society for General Microbiology  held a debate in their 2015 Annual Conference titled: “Is it in the public interest to support gain of function experiments in the UK?”. 90% of the answers were “Yes” after the debate. We would now like to ask the general public and other scientists that have not attended this debate the same question:  Is it in the public interest to support gain of function experiments? Please give us your opinion in this poll (http://doodle.com/3hmck4iwwne4d828) and we will let you know the result in a future post.