This week, the National Science Advisory Board for Biosecurity (NSABB) returned to its ongoing deliberation over the scope and form of oversight of gain of function (GOF) research on viruses and other pathogens. Since a moratorium on federal funding was declared in 2014, the NSABB has been working on establishing guidelines both for funding and oversight of this specific research area. The concerns over GOF research are that experiments could produce particularly dangerous pathogens which pose public health risks (see earlier post for background). In this review, the NSABB actually focused its attention on a subset of GOF research, defined as Gain of Function Research of Concern (GOFROC):
[T]he working group identified the attributes of GOFROC, which is research that could generate a pathogen that is: 1) highly transmissible and likely capable of wide and uncontrollable spread in human populations; and 2) highly virulent and likely to cause significant morbidity and/or mortality in humans.
In its public meeting this week, the NSABB adopted recommendations from a report by its own internal working group; they are as follows (underlined for emphasis):
1: Research proposals involving GOF research of concern entail significant potential risks and should receive an additional, multidisciplinary review, prior to determining whether they are acceptable for funding. If funded, such projects should be subject to ongoing oversight at the Federal and institutional level.
2: An external advisory body that is designed for transparency and public engagement should be utilized as part of the U.S. government’s ongoing evaluation of oversight policies for GOF research of concern.
3: The U.S. government should pursue an adaptive policy approach to help ensure that oversight remains commensurate with the risks associated with the GOF research of concern.
4: In general, oversight mechanisms for GOF research of concern should be incorporated into existing policy frameworks when possible.
5: The U.S. government should consider ways to ensure that all GOF research of concern conducted within the U.S. or by U.S. companies be subject to oversight, regardless of funding source.
6: The U.S. government should undertake broad efforts to strengthen laboratory biosafety and biosecurity and, as part of these efforts, seek to raise awareness about the specific issues associated with GOF research of concern.
7: The U.S. government should engage the international community in a dialogue about the oversight and responsible conduct of GOF research of concern.
This completes the current NSABB review of federal policies pertaining to GOF/GOFROC research. However, the report does recommend an ongoing institutional apparatus to review policies, not individual experiments. It also recommends that privately-funded experiments involving GOFROC receive additional oversight, although that could require Congressional action. Finally, against a backdrop of reported safety lapses at federal laboratories (see here and here), the NSABB locates improved biosafety and biosecurity measures as an equally important concern in establishing how GOFROC can be managed.
In 2016, the National Science Advisory Board for Biosecurity (NSABB) has returned to reconsider the issues regarding the approval, funding and oversight of experiments on pathogens that are engineered to contain mutations conferring elevated transmissibility in mammals and/or enhanced pathogenicity (virulence). This line of research has been called gain-of-function research (GOF). Such pathogens are studied to determine which genetic changes in a virus or bacterium confer attributes which create a more dangerous pathogen. Knowledge that a specific genetic mutation could confer a higher risk profile could theoretically allow more precise and knowledgeable public health surveillance of naturally occurring mutations. In addition, therapeutic countermeasures could be developed in advance of an actual strain appearing in the population. Nonetheless, these experiments could produce what have been called potentially pandemic pathogens (PPP) and are therefore controversial because of the possible release of a dangerous microbe, either by accident (biosafety) or design (biosecurity). The NSABB is charged with advising the federal government on bioterrorism-related scientific matters, the panel being created post-9/11. In the wake of controversial experiments published in 2011 and 2012 describing the creation of GOF H5N1 influenza viruses with enhanced transmissibility in humans, the NSABB has been working on formalizing a risk-benefit framework for determining whether certain experiments should be restricted or their funding limited. In 2014, a federal moratorium on the funding of GOF studies was imposed following a series of biosafety incidents at federal laboratories (some GOF studies have been allowed to resume, involving Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza). The NSABB is now conducting public meetings as the next stage in the deliberative process it outlined in 2015. The NSABB commissioned a formal risk and benefit assessment (RBA) from an outside contractor to provide the board with qualitative and quantitative information about the risks and benefits of conducting certain scientific studies. The NSABB also commissioned a formal study of the ethical frameworks that could be relevant to the formulation of official policy. In addition, a working group of the NSABB has published their review of the current issues. Their findings are as follows:
Key Finding 1: There are many types of GOF studies and not all of them have the same level of risks. Only a small subset of GOF studies - GOF studies of concern - entail risks that are potentially significant enough to warrant additional oversight.
Key Finding 2. The U.S. government has effective policy frameworks in place for managing risks associated with life sciences research. There are several points throughout the research life cycle where, if the policies are implemented effectively, risks can be managed and oversight of GOF studies could be applied.
Key Finding 3. Oversight policies vary in scope and applicability, therefore, current oversight is not sufficient for all GOF studies that raise concern.
Key Finding 4. There are life sciences research studies that should not be conducted on ethical or public health grounds if the potential risks associated with the study are not justified by the potential benefits. Decisions about whether GOF studies of concern should be permitted will entail an assessment of the potential risks and anticipated benefits associated with the individual experiment in question. The scientific merit of a study is a central consideration during the review of proposed studies but other considerations and values are also important.
Key Finding 5. The biosafety and biosecurity issues associated with GOF studies are similar to those issues associated with all high containment research, but a small subset of GOF studies have the potential to generate strains with high and potentially unknown risks (emphasis added). Managing risks associated with all high containment research requires Federal-level oversight, institutional awareness and compliance, and a commitment by all stakeholders to safety and security. Biosafety and biosecurity are international issues requiring global engagement.
Last month, the NSABB held an public committee meeting to review all of these recently commissioned reports, with the purpose of making progress in developing a formal roadmap for the federal government to use in deciding whether and/or how to support GOF experiments. The NSABB also invited public comments on the studies cited above. Criticism from other scientists include critiques of the GOF definition itself, objections to the comparatives used in the RBA assessment (e.g., 1918 pandemic influenza virus), a call for more clinician involvement in the process, as well as general objections to a lack of avenues for more public participation in the debate. As this deliberative process plays out over the next several months, the fate of the government-imposed moratorium will also be a consequence of the NSABB conclusions. The deliberative process continues: the second public National Academies of Sciences Symposium on GOF research will be held on March 10 & 11, 2016 and will include a discussion of the RBA study as well as NSABB’s preliminary findings and draft recommendations (the first symposium was held in 2014, see here). There will be an opportunity for the public to participate in the event as well as to submit questions online.
Over the last year, reports of biosafety lapses in federal laboratories conducting research on anthrax, smallpox and Ebola virus elicited strong reactions in the scientific community and generated official responses to reduce the likelihood of similar events (see here for overview of CDC, NIH and FDA incidents). As the nation's signature public health agency, the incidents at the CDC laboratories were especially troublesome. In general, laboratories conducting microbiological research are designed to accommodate the safety requirements attendant to the threat of the pathogen itself. The safety evaluation will mandate the appropriate facilities, procedures and trained personnel based on the level of risk Laboratories are classified in a tier of biosafety levels (BSL1-4), with a BSL-4 designation describing the highest level containment environment:
Biosafety Level 4 is required for work with dangerous and exotic agents that pose a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no vaccines or treatments, or a related agent with unknown risk of transmission. Agents with a close or identical antigenic relationship to agents requiring BSL-4 containment must be handled at this level until sufficient data are obtained either to confirm continued work at this level, or re-designate the level. Laboratory staff must have specific and thorough training in handling extremely hazardous infectious agents. Laboratory staff must understand the primary and secondary containment functions of standard and special practices, containment equipment, and laboratory design characteristics. All laboratory staff and supervisors must be competent in handling agents and procedures requiring BSL-4 containment.
Now, the CDC has issued its internal report on the December, 2014 Ebola incident in which a lab worker was possibly exposed to live Ebola virus. The report is detailed,
and it is clear that human error explains the incident where Ebola virus may have been unintentionally transferred from a BSL-4 lab to a BSL-2 lab, which would lack the same degree of protection for potentially exposed workers. An earlier internal CDC report on the June, 2014 anthrax incident, involving transfer of a biological sample from a BSL-3 to a BSL-2 lab also identified personnel errors, as well as gaps in the overall containment protocols. In August, 2014, as a result of the pattern of safety lapses, the White House ordered a stand-down for federal laboratories to pause and review their biocontainment policies and practices, as well as perform an audit of pathogens and select agents. Reports now issued by the CDC and NIH detail the result of the stand-down,
detailing the scale and site of research with the most dangerous pathogens, and identifying instances where undocumented biological samples have been left behind from earlier investigations. Overall, the stand-down produced a real-time status report on pathogen storage and handling in the leading federal labs; it is clear from the specific incidents reports, however, that human error can still override the most carefully planned containment measures.
