The Gain-of-Function Deliberative Process

In biomedical research, scientists commonly perform experiments that involve enhancing or diminishing the function of a gene, which may change the observable characteristics of a model organism.  Such gain- and loss-of-function studies are a cornerstone of many fields of experimental biology and are routinely performed to help understand genetic pathways, infer the function of genes and proteins, and more.

Key to our understanding of what causes infectious disease, whether it’s influenza, HIV/AIDS, or the common cold, is figuring out the characteristics of what makes microorganisms cause disease. When applied to the study of infectious diseases, loss- and gain-of-function experiments can help identify determinants of virulence, pathogenesis, or other pathogen (disease-causing agents) characteristics.  These types of experiments aid in the discovery of potential targets or strategies for the development of vaccines or other medical countermeasures or inform disease surveillance efforts.

In recent years, there has been a lot of attention paid to certain types of gain-of-function studies resulting in pathogens with enhanced pathogenicity (ability to cause disease) or transmissibility (ability to be passed from one individual to another), especially in mammals.  These are what the popular press sometimes calls “superbugs,” and concerns have been raised about whether they might be intentionally or accidentally released.  Gain-of-function studies also present “dual use” concerns—that is, although the experiments are performed to provide insight into disease or to develop treatments, they may also generate research products or information that could be misused to harm public health or national security.  These biosafety and biosecurity issues are particularly acute with studies involving viruses, like influenza, that have a history of causing pandemics in humans. Indeed, some people have argued that certain gain-of-function studies should not be undertaken at all.

The U.S. government (USG) launched a deliberative process in October 2014 to re-evaluate the potential risks and benefits associated with gain-of-function research involving certain pathogens with the potential to cause a pandemic.  This process involves both the National Science Advisory Board for Biosecurity (NSABB), which will develop formal recommendations to the USG, and the National Academies, which in December 2014 hosted the first of two meetings to foster broad stakeholder discussions.  In addition, a risk-benefit assessment is being conducted by a private company, Gryphon Scientific, to inform the deliberations.  During this process, the USG has paused the release of new funding for gain-of-function studies that could enhance the pathogenicity or transmissibility of influenza, Middle East Respiratory Syndrome (MERS), or Severe Acute Respiratory Syndrome (SARS) viruses.

The initial task of the NSABB was to advise on the design and conduct of the risk-benefit assessment.  In May, the Board approved its Framework for Guiding Risk and Benefit Assessments of Gain-of-Function Studies.  This framework outlines principles that should guide the risk-benefit assessment, describes the types of risks and benefits that should be analyzed, and makes recommendations on the types of pathogens, pathogen characteristics, and types of gain-of-function studies that should be analyzed.  The National Institutes of Health (NIH) and Gryphon Scientific are using this framework to guide the analysis of the risks and benefits.

The NSABB’s second task is to develop recommendations to the USG on a conceptual framework for evaluating research proposals involving gain-of-function studies that raise concerns.  The Board will convene on September 28th at the NIH campus in Bethesda, Maryland to discuss its progress and continue its deliberations.  This meeting will also include an update on the risk-benefit assessment and a panel discussion of the ethical, legal, and policy issues associated with the gain-of-function issue.  The meeting is open to the public and will also be webcast live.  Additional information, including links to the pre-registration website and meeting agenda, can be found on the NSABB meeting webpage.

The results of the risk-benefit assessment are anticipated this fall and the Board’s draft recommendations are anticipated in early 2016.  These draft recommendations will then be discussed at a second National Academies meeting next spring before being finalized. The USG will consider the Board’s recommendations as it develops policy for the funding and oversight of gain-of-function studies and expects to revisit the funding pause at that time as well.

Public input is key to this process.  NSABB meetings, as well as those hosted by the National Academies, are free and open to the public.  Public participation is encouraged and all NSABB meetings include time for members of the public to provide comments.  Written comments can be submitted to the Board at any time at [email protected].

The debate about gain-of-function studies involving pathogens with pandemic potential are related to broader ongoing discussions about laboratory safety and security.  However, even more broadly, the gain-of-function debate is about public trust in the scientific enterprise.  The life sciences are rapidly evolving and we have the ability to manipulate biological systems in ways that were not possible, even 10 years ago.  New discoveries and emerging technologies hold immense promise but they will also continue to test our policy frameworks.  It is an exciting time, but also a sobering one for those in science policy.  It is our job to help ensure that science can advance rapidly as well as safely, ethically, and responsibly.

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