A Bottom-Up Approach to Biosecurity

Abstract

Introduction

Concern about the safety and security of research undertaken on pathogens has driven new policies and increased governmental oversight. The US National Science Advisory Board for Biosecurity (NSABB), created to help address this concern, has recommended valuable steps to reduce the risks from potentially dangerous experiments. Along with the US Federal Select Agent Program, the NSABB has produced important guidance to define especially risky research and has suggested policies to avoid or mitigate the risk of potentially dangerous studies.¹ Most recently, the NSABB was asked to review the effectiveness of 2 major biosecurity policies: research with enhanced potential pandemic pathogens (ePPP) and oversight of dual-use research of concern (DURC). Their recommendations were published in 2023.² They suggested, among other things, that policies dealing with ePPP and DURC be merged, that the scope of agents of concern be broadened, and that a “bottom-up” approach to review proposed research be considered to enhance the safety and security of the research enterprise. Subsequently, the White House Office of Science and Technology Policy issued a request for information seeking additional input from the research community.³ The COVID-19 pandemic and speculation by some that SARS-CoV-2 may have originated from laboratory research has added urgency to the need for comprehensive biosecurity and biosafety programs for all research facilities to maintain the public trust.

The current system of pathogen research oversight has several weaknesses. It relies heavily on the select agent list of especially dangerous and weaponizable pathogens and toxins⁴ while ignoring more common agents that may have greater pandemic potential. Current policy lacks the capacity to adjust adequately to rapid advances in biotechnology, including those that facilitate the creation of chimeric and mutant agents of unknown pathogenic potential. A major consequence of these issues is that studies identified as potentially dangerous and requiring additional review have languished for months, awaiting an opaque governmental decision, which has delayed important research, impacted scientific morale, and jeopardized the continuity of funding for some academic programs. Finally, science is an international endeavor, but adherence to US government policy can only be required for activities funded by the US government. This leaves foreign researchers unencumbered by US guidance and producing a patchwork of inconsistent international policies.

We share here our experience in successfully implementing a robust program of oversight of research conducted at the University of Texas Medical Branch (UTMB) that is built upon a bottom-up model and has been effectively used for over 20 years. It may serve as an example that could be adapted by others to meet the current NSABB recommendations.

Our program requires that principal investigators (PIs) conduct a comprehensive risk assessment of all their proposed studies with any human pathogen through a formal notification of use (NOU) submission that addresses both recombinant and nonrecombinant materials, as well as agents regulated and unregulated by the US Centers for Disease Control and Prevention and US Department of Agriculture, not just select agents. The NOU is then extensively reviewed by our Institutional Biosafety Committee (IBC), with results usually provided to the applicant within 30 days.

Notification of Use

The NOU is based on the premise that the PI is among the most knowledgeable persons regarding the study to be conducted and is the best prepared to address risks associated with the proposed project. It places the responsibility of risk assessment on the PI, which involves fully considering all aspects of the work, including who, where, what, and why.

Assessment of who will be involved in the study includes consideration of all persons with the potential to encounter the agent as well as documentation of their training in biosafety and biosecurity; their experience with the experimental systems proposed, including animal models; and their enrollment in the employee health program, among other considerations. The PI proposes where the studies will be conducted and addresses the specific biocontainment levels and measures required to safely and securely conduct the work. We are fortunate at UTMB to have access to all levels of biocontainment. Assessment of what and why requires the PI to include a description of the proposed studies and to specifically address the 7 dual-use experiments of greatest concern,⁵ describe any recombinant studies to be conducted, provide a realistic assessment of the potential benefits of the proposed research, and consider alternative approaches that might provide similar findings with reduced risks.

If laboratory animals are to be used, formal institutional animal care and use committee approval is also required. If human subjects are to be involved, institutional review board approval is likewise required. PIs are required in the NOU to identify studies proposing to use arthropod or other vectors, and to detail special precautions to be taken. Any human- or animal-pathogenic agent to be handled in the laboratory should be included (UTMB scientists do not work with plant pathogens or toxins of concern), thereby addressing NSABB recommendation 10.1 that review should include research “that directly involves any human, animal or plant pathogen or toxins.”²

PIs should also consider risks associated with specialized equipment, instrumentation, or procedures, such as those with the potential to produce aerosols, as well as protocols for accidental spills and waste stream management. Details of any special personal protective equipment that may be used should be included in the NOU. Gene editing, DNA synthesis, chimeric pathogens, and any other recombinant studies are fully described, and anticipated results of studies and their associated risks are outlined. This comprehensive NOU holds the added benefit of providing institutional leadership with transparent, formal documentation and situational awareness of work being undertaken. Particular emphasis is placed on evaluating the potential for gain of function. Changes in technology continuously inform updates to the risk assessments performed. For example, UTMB recently revised the process to include the careful review of any work involving CRISPR/Cas9 or similar gene editing technologies of either pathogen or host, along with any gene drive systems, such as those under development for introducing transgenic arthropod vectors into nature.⁶ Although a similar risk assessment is performed at many institutions, some may not have the breadth of expertise to cover the full spectrum of risks.

Institutional Biosafety Committee

The IBC's role is to carefully review the proposed study to ensure that the work can be conducted safely and securely under appropriate biocontainment by fully trained individuals. Our IBC is led by an experienced senior faculty member with an active select agent research program, and includes representatives from the UTMB Department of Biosafety, building containment engineers, an infectious diseases clinician knowledgeable about the human disease potential of the pathogens studied, veterinarians from the UTMB Animal Resources Center, selected faculty members with experience in research methods in biocontainment, 2 community members, and ex officio legal representation. Currently, the committee includes 2 of the 4 alternate select agent-responsible officials. The makeup of the IBC is revisited annually to ensure that relevant new technologies are represented by faculty experts.

The committee carefully reviews each full NOU, paying special attention to the study design and DURC; proposed biocontainment to be used; special safety precautions, such as personal protective equipment; training of individuals involved; institutional animal care and use committee or institutional review board approvals, as appropriate; and anticipated results. The goal is to establish a dialogue between the IBC and the PI, so that should unanticipated results be encountered, the IBC will be promptly informed and safety and security precautions will be adjusted before further work is conducted.

The IBC meets at least monthly, with the goal of providing responses to PIs within 30 days of their NOU submission. When NOUs are received that include experiments with significant risk for gain of function, a special subcommittee performs an in-depth review and recommends a decision to the full IBC. This subcommittee, in addition to added scientific expertise, includes experts in bioethics and communications. Studies identified as requiring further review under the policies for federal oversight of life sciences DURC or potential pandemic pathogen care and oversight³ are forwarded to the US Department of Health and Human Services for final consideration.

Biosafety and Biosecurity Training

Studies involving ePPP are planned on the assumption that individuals involved in the conduct of the studies proposed are fully trained and experienced to work safely and securely under the appropriate level of biocontainment. UTMB is fortunate in that congressional funding was provided when the Galveston National Laboratory was constructed, which allowed us to establish a robust training facility and program. This program, including mockup biosafety level 3 and biosafety level 4 laboratories, prepared our faculty, staff, students, and operations personnel for work at all levels of biocontainment. Over the course of nearly a decade, we offered training not only to our own personnel but also to many others from biocontainment facilities nationally and internationally. Unfortunately, we were unable to continue training external partners due to our inability to access funding to sustain the program; however, we continue to train UTMB staff and students using institutional resources.

Nationally and internationally, access to comprehensive training for research in biocontainment is not consistently available to all entities where potentially risky research may be undertaken. New strategies are needed to ensure that all individuals associated with studies involving ePPP—including PIs, staff, students, and operations personnel—are provided with the opportunity for consistent, comprehensive training in biosafety and biosecurity before their studies commence. Reliable funding sources are needed to sustain this critically important element of pathogen research.

Access to Biocontainment Laboratories

It is essential that work with ePPP be conducted in laboratories with appropriate biocontainment. The US National Institutes of Health, in partnership with several states, has invested nearly US$1 billion to construct a network of regional and national biocontainment laboratories located on academic campuses; UTMB is fortunate to be one of them. These facilities have been in operation for over a decade and many have played key roles in advancing essential research on dangerous emerging pathogens, diagnostics, and countermeasures.

Other entities have independently constructed their own biocontainment laboratories to support their research activities. Additionally, several maximum biocontainment facilities are managed by the federal government, including by the US departments of defense, homeland security, agriculture, and health and human services. These facilities are generally managed by well-trained and experienced scientists. They are supported by engineers well versed in the operations of the containment systems of these complex facilities, which are routinely inspected under the Federal Select Agent Program, other relevant oversight agencies, and collaborators conducting due diligence. They are, in theory, available for collaborative studies to assist investigators who lack access to appropriate biocontainment; however, extensive training is needed to ensure that visiting scientists work safely. This requirement represents a major barrier to short-term collaborations. Nonetheless, it may be possible to make greater use of existing biocontainment laboratories through a focused effort to facilitate collaborations and training.

Can the “Bottom-Up” Approach Be Applied Nationally?

We recognize that UTMB is uniquely qualified to implement the bottom-up approach described here. We are fortunate to have access to all levels of biocontainment, and this has allowed us to attract a diverse and talented faculty of experts in infectious diseases. Our ability to provide comprehensive training in biosafety and biosecurity further distinguishes our program. Clearly, few other entities enjoy these resources, and it is appropriate to ask if it is realistic to consider if our system of bottom-up management of biosecurity might be applied more widely. We suggest that it can be implemented at many other institutions with appropriate policy guidance and support. The following steps can help achieve that goal.

Develop a model NOU that can be adapted for use involving any ePPP, including human, animal, or plant pathogens. Key points to be considered should be clearly identified and could be adapted to meet specific challenges in the relevant field. Such a model could be used both nationally and as a template for international adaptation.

Ensure access to a well-qualified IBC. Not all entities will have sufficiently experienced and comprehensive expertise in modern microbiology research to adequately assess the risks of all proposed work. To supplement the expertise lacking in some institutions, a centralized IBC could be formed, composed of experts who meet virtually or perhaps at established centers of excellence where resident experts are already available. This centralized IBC could be developed following the model already used for institutional review boards. Alternatively, supplemental expertise could be provided to existing IBCs through a panel of expert consultants, who could be drawn upon for the review of particularly challenging NOUs. Supplemental reviewers could be recruited, qualified, and compensated much like a study section member who reviews US National Institutes of Health proposals. A timely response to NOU submissions will be essential, ideally within 30 days of submission. Studies deemed to require governmental review would be forwarded to the appropriate agency for final consideration, and approved studies could proceed. To provide either a centralized IBC or supplemental experts, members would require appropriate compensation as reviews require a major investment of time and effort that takes reviewers away from their own research, teaching responsibilities, and other duties. Funding agencies could offer grants or contracts to establish centers of excellence for review of ePPP proposals or support the costs of review by commercial IBCs. Academic center leadership would need to recognize the service value of faculty participation in the review process when considering reviewers for promotion and tenure decisions.

Facilitate collaborations between existing biocontainment laboratories and investigators who lack access to appropriate containment to help ensure that work with ePPP is done safely and securely in partnership with well-trained individuals working in an environment specifically designed for this purpose.

Train researchers in biosafety and biosecurity to enable the safe conduct of research involving ePPP. Ensuring that appropriate training is available to all individuals involved is critically important, but unfortunately such training is not consistently accessible to all those in need. This is especially concerning among some international laboratories where resources may be limited and experienced leadership may be lacking. Funding agencies should consider ways to ensure that all individuals involved in ePPP research have access to appropriate training based on an agreed-upon set of skills and capabilities. Engaging international partners by offering training in biosafety and biosecurity that is built on US or international standards could be especially beneficial. A network of approved training centers and clear guidance on skills and procedures needed for specific tasks at each level of biocontainment would result in a safer and more secure workforce and research enterprise. The US government should consider options for funding a sustained network of training centers that is accessible to both US investigators and international partners.

Conclusion

It is clear that new approaches are needed to augment existing policies and regulations designed to enhance the safety and security of research involving ePPP. More regulations are not necessarily the answer; we need to make better use of the existing expertise and major investments that have already been made to allow US scientists to be global leaders in biomedical research involving dangerous pathogens.

A formal record can be created and fully reviewed prior to starting research by using a bottom-up approach, which places the responsibility on PIs, laboratory leadership, and institutional officials to conduct a comprehensive risk assessment of their proposed studies using a standardized NOU template that has been carefully constructed to fully address research involving ePPP, DURC, gain of function, and work with any agent or toxin. Technically competent experts, who are themselves working at the cutting edge of their fields, can assess the completeness of the risk assessments and suggest modifications and adjustments to mitigate risks. Studies deemed especially risky would be forwarded for review by government officials.

Such a model has been successfully used at UTMB for many years. We feel confident that it could be scaled to national application with minimal investments by funding agencies. Such a model could form the basis for wider application by the international scientific community and help to restore public trust while ensuring safe laboratory practices and the completion of important research.

References

US Department of Health and Human Services (HHS). Framework for Guiding Funding Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens. Washington, DC: HHS; 2017. Accessed April 16, 2024. https://www.phe.gov/s3/dualuse/documents/P3co.pdf

National Science Advisory Board for Biosecurity. Proposed Biosecurity Oversight Framework for the Future of Science. Bethesda, MD: National Institutes of Health; 2023. Accessed April 16, 2024. https://osp.od.nih.gov/wp-content/uploads/2023/03/NSABB-Final-Report-Proposed-Biosecurity-Oversight-Framework-for-the-Future-of-Science.pdf

Office of Science and Technology Policy. Request for information; potential changes to the policies for oversight of dual use research of concern (DURC) and the potential pandemic pathogen are and oversight (P3CO) policy framework. Fed Regist. 2023; 88(169):60513-60516. https://www.govinfo.gov/content/pkg/FR-2023-09-01/pdf/2023-18906.pdf

US Centers for Disease Control and Prevention, US Department of Agriculture Animal and Plant Health Inspection Service. HHS and USDA Select Agents and Toxins, 7 CFR Part 331, 9 CFR Part 121, and 42 CFR Part 73. Federal Select Agent Program. Published April 17, 2023. Accessed April 16, 2024. https://www.selectagents.gov/sat/docs/HHS-USDA-Select-Agents-and-Toxins-List_508.pdf

National Research Council. Biotechnology Research in an Age of Terrorism. Washington, DC: The National Academies Press; 2004. Accessed April 16, 2024. https://doi.org/10.17226/10827

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