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 NSABB@od.nih.gov.

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.

Staying Ahead of the Curve on Chimeras

One of the truisms of science policy is that developments are often reactive, in response to external events or breakthrough leaps forward in science and technology.  Thoughtful, deliberative policymaking on emerging fields of science and biotechnologies is challenging, particularly since unpredictability is inherent in the very nature of scientific discover.  Simply put, the wheels of science often turn faster than the wheels of policy.

Today, NIH published a notice in the NIH Guide for Grants and Contracts announcing the agency would “not fund research in which human pluripotent cells are introduced into non-human vertebrate animal pre-gastrulation stage embryos” while we consider a possible policy revision in this area.   As described in the Guide notice, this is an exciting area of science that is rapidly progressing, but in which ethical and animal welfare considerations might merit additional guidance to move forward.  This is a unique opportunity to take a deep breath, look at the state of the science, and think about current policies and consider whether any additional policies are needed to promote the responsible conduct of this promising science.

Of course, thinking about the ethical considerations related to the formation of these types of animal-human chimeras is not new.   In 2005, the National Academies Guidelines for Research on Human Embryonic Stem Cells urged caution for experiments in which human embryonic stem cells were introduced into non-human embryos, suggesting both restrictions and additional consideration might be necessary.  NIH adopted several of those provisions in the 2009 NIH Guidelines for Human Stem Cell Research. While the Academies report pre-dated the discovery of the ability to create induced pluripotent stem cells, the ethical considerations raised remain resonant.   Advances in cellular technologies and gene editing present opportunities to address interesting scientific questions and propel progress in regenerative medicine.  They also illustrate that the time is ripe to proactively consider whether additional ethical considerations should be put into place to guide the science moving forward.

Moving forward, NIH will bring together experts in the field to discuss the state of the science: what are the aims of research involving early stage chimeras and what are the advances on the horizon?  This discussion will help serve as a foundation to consider policy needs going forward.  In other words, thoughtful, deliberative policymaking at its best.

Genomic Data Sharing: Part II – Playing by the Rules

The discussions surrounding the Precision Medicine Initiative (PMI) have highlighted some of the policy challenges inherent in balancing the sharing of valuable research data with the protection of participants whose data is being shared. How do you ensure that researchers, and even participants themselves, have appropriate access to data while making sure that the data is not inadvertently or deliberately released or misused in a way that might present a risk to participants?

As mentioned in the last blog post: Part I – Enhancing Consent through the NIH Genomic Data Sharing Policy, the NIH is not new to this, of course, and has had success in developing policies that support the sharing of data that also harbors information about the disease status of research participants.  The NIH Genomic Data Sharing (GDS) Policy, which became effective on January 25, 2015, and its predecessor, the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS) have enabled the sharing of potentially sensitive genomic and phenotypic data from NIH-funded studies.  The ethical principles and privacy safeguards incorporated in the GDS Policy enable secondary use of NIH genomic data while respecting participant autonomy and protecting privacy.

These protections have been built into both the submission and access stages of the genomic data sharing process.  When investigators submit data, their institution must assure, through submission of an Institutional Certification, the appropriateness of the data submission as well as the secondary use of the data, based on the consent of the participants.  When qualified investigators seek access to the  data, they must describe how they intend to use the data through a Data Access Request (DAR) in the database of Genotypes and Phenotypes (dbGaP) and promise, through a  Data Use Certification (DUC) Agreement, to adhere to the GDS Policy’s ethical principles, terms of data access, and privacy safeguards.  Before access is granted, each request is reviewed by an NIH Data Access Committee (DAC) for consistency with the appropriate data uses, as outlines by the data submitters, and Policy expectations.

Since 2007, and under the GWAS Policy, approximately 3,700 datasets have been submitted and made available in dbGaP for secondary research, and nearly 21,000 access requests from over 3,300 investigators from 46 countries, have been approved by NIH.  Of the large number of approved requests, we can say that approved users of the data have adhered to the terms of Policy most of the time, and that only 27 violations of the Policy (out of the 21,000 approved requests) have been reported.  The figure below provides a schematic of this, as well as the general categories that these violations fall under.  Policy compliance violations, also known as data management incidents, have occurred in both the submission and access processes as well as in data security.  For example, in one case, an investigator accidentally reversed the labels for two datasets in a data submission, such that a dataset meant only for disease-specific secondary research was made available for general secondary research use and vice versa.  Fortunately, the mistake was discovered before the data were improperly used.  The datasets were then reconfigured with the appropriate use categories and made available again to the research community.  NIH has also made a similar mistake in handling the data once it was received.

In all Policy compliance violation cases, NIH has worked cooperatively with the violator to remedy the situation.  Most importantly, however, and to the best of our knowledge, none of the 27 Policy compliance violations have resulted in harm to the research participants from which the data were generated.  Additional information on Policy compliance violations and specific cases, as well as other statistics on data submission, access, and use, are available on the Facts & Figures section of the GDS Policy website.

In order to advance our understanding of how the myriad of genetic, environmental, and behavioral factors interact to play a role in human health and disease, we must continue to enable the responsible sharing of genomic and associated data broadly within biomedical research community, while at the same time respecting the wishes of study participants.    NIH’s policies for sharing of genomic data have led the way and set a precedent for culture changes in sharing all types of data, including sharing of data though groundbreaking initiatives such as PMI.

For more information on the GDS Policy please visit the GDS website.