Chimeric Viruses Containing Select Agents: The Biology Behind Their Creation, Attenuation, and Exclusion From Regulation.

The US Centers for Disease Control and Prevention (CDC), as part of the Federal Select Agent Program, and under the purview of 42 CFR §73.3, has the ability to regulate chimeric viruses that contain portions of pathogens that are part of the select agents and toxins list. In addition, the CDC is responsible for excluding pathogens from regulation, including chimeric viruses, that are sufficiently attenuated. Since 2003, the CDC has excluded over 20 chimeric viruses that contain portions of select agents. But in late 2021, the CDC proposed a regulatory first-the addition of a chimeric virus to the select agents and toxins list. To better understand the importance and applicability of this action, we surveyed the landscape of previous exclusions from select agent regulation. First, we reviewed the exclusion criteria used by the Intragovernmental Select Agents and Toxins Technical Advisory Committee in their advisement of the Federal Select Agent Program. We then reviewed the literature on chimeric viruses that contain portions of select agents and that have been excluded from regulation due to sufficient attenuation, focusing on chimeric alphaviruses and chimeric avian influenza viruses. By analyzing biological commonalities and patterns in the structure and methodology of the development of previously excluded chimeric viruses, we provide insight into how the CDC has used exclusion criteria in the past to regulate chimeric viruses. We conclude by contrasting previous exclusions with the recent addition of SARS-CoV-1/SARS-CoV-2 chimeric viruses to the select agents and toxins list, demonstrating that this addition strays from established, effective regulatory processes, and is thus a regulatory misstep.

Regulating Select Agent Chimeras: Defining the Problem(s) Through the Lens of SARS-CoV-1/SARS-CoV-2 Chimeric Viruses.

In late 2021, the US Centers for Disease Control and Prevention (CDC) posted an interim final rule (86 FR 64075) to the federal register regulating the possession, use, and transfer of SARS-CoV-1/SARS-CoV-2 chimeric viruses. In doing so, the CDC provided the reasoning that viral chimeras combining the transmissibility of SARS-CoV-2 with the pathogenicity and lethality of SARS-CoV-1 pose a significant risk to public health and should thus be placed on the select agents and toxins list. However, 86 FR 64075 lacked clarity in its definitions and scope, some of which the CDC addressed in response to public comments in the final rule, 88 FR 13322, in early 2023. To evaluate these regulatory actions, we reviewed the existing select agent regulations to understand the landscape of chimeric virus regulation. Based on our findings, we first present clear definitions for the terms "chimeric virus," "viral chimera," and "virulence factor" and provide a list of SARS-CoV-1 virulence factors in an effort to aid researchers and federal rulemaking for these agents moving forward. We then provide suggestions for a combination of similarity and functional characteristic cutoffs that the government could use to enable researchers to distinguish between regulated and nonregulated chimeras. Finally, we discuss current select agent regulations and their overlaps with 86 FR 64075 and 88 FR 13322 and make suggestions for how to address chimera concerns within and/or without these regulations. Collectively, we believe that our findings fill important gaps in current federal regulations and provide forward-looking philosophical and practical analysis that can guide future decisionmaking.

Motivating Proactive Biorisk Management.

Scholars and practitioners of biosafety and biosecurity (collectively, biorisk management or BRM) have argued that life scientists should play a more proactive role in monitoring their work for potential risks, mitigating harm, and seeking help as necessary. However, most efforts to promote proactive BRM have focused on training life scientists in technical skills and have largely ignored the extent to which life scientists wish to use them (ie, their motivation). In this article, we argue that efforts to promote proactive BRM would benefit from a greater focus on life scientists' motivation. We review relevant literature on life scientists' motivation to practice BRM, offer examples of successful interventions from adjacent fields, and outline ideas for possible interventions to promote proactive BRM, along with strategies for iterative development, testing, and scaling.

Understanding Biosafety and Biosecurity in Ukraine.

The Russian invasion of Ukraine in February 2022 was accompanied by unfounded Russian allegations of bioweapon activities in Ukraine conducted by the United States and its allies. While false, such allegations can cause substantial damage to disarmament efforts and international cooperation for strengthening disease surveillance and global health security. The purpose of this article is to describe Ukraine's biosafety, biosecurity, and dual-use policies and to provide important context for understanding the unwarranted Russian allegations. Moreover, the analysis of Ukraine's biorisk management system highlights some of the international efforts underway to ensure that life sciences research across the world is conducted safely, securely, and responsibly. With the help of international partners, Ukraine has strengthened its biorisk management governance, as well as identified areas for improvement that it is working to address.

The Promise of Emergent Nanobiotechnologies for In Vivo Applications and Implications for Safety and Security.

Nanotechnology, the multidisciplinary field based on the exploitation of the unique physicochemical properties of nanoparticles (NPs) and nanoscale materials, has opened a new realm of possibilities for biological research and biomedical applications. The development and deployment of mRNA-NP vaccines for COVID-19, for example, may revolutionize vaccines and therapeutics. However, regulatory and ethical frameworks that protect the health and safety of the global community and environment are lagging, particularly for nanotechnology geared toward biological applications (ie, bionanotechnology). In this article, while not comprehensive, we attempt to illustrate the breadth and promise of bionanotechnology developments, and how they may present future safety and security challenges. Specifically, we address current advancements to streamline the development of engineered NPs for in vivo applications and provide discussion on nano-bio interactions, NP in vivo delivery, nanoenhancement of human performance, nanomedicine, and the impacts of NPs on human health and the environment.

The Dual-Use Education Gap: Awareness and Education of Life Science Researchers on Nonpathogen-Related Dual-Use Research.

With the rise of synthetic biology, dual-use research risks are not confined to pathogen-related research. However, existing measures to mitigate the risks of dual-use research, such as export control, are still designed to hinder access to pathogens and do not address the risks of nonpathogen-related dual-use research. The current self-regulatory approach requires scientists to be aware of their responsibility and know how to assess risks and establish countermeasures. The purpose of this study was to examine the state of knowledge about dual-use research among life science students and to test an alternative teaching approach on the importance of considering biosecurity risks for teams participating in the International Genetically Engineered Machine (iGEM) competition. We conducted an international survey from July 18 to September 13, 2018, which was completed by 192 respondents from 29 countries and 74 universities. Based on the results of the survey, we designed and tested a learning workshop on dual-use research within the iGEM community. Results from the workshop and the survey show that educational machinery so far have failed to integrate teaching about dual-use research issues.

Improving Biosecurity in Pakistan: Current Efforts, Challenges, and Recommendations on a Multidimensional Management Strategy.

Rapidly advancing biotechnological research and easy access to biological information have created challenges for preventing their intentional misuse. Because of the dedicated efforts of science and policy leaders in Pakistan, the country is on the road to becoming a regional role model in ensuring biosafety and capacity for biosecurity. Although Pakistan has made remarkable efforts promoting a culture of biosafety and biosecurity, several constraints persist related to sustainable development and the expansion of the biosecurity capacity in Pakistan. Studies suggest there is little understanding of dual-use research of concern among the majority of life scientists in Pakistan. Further, Pakistan has yet to fully develop and implement approaches for risk assessment, frameworks for oversight and regulation, or tools and procedures for monitoring and reporting situations in which misuse of biological materials might occur. More data are needed to answer questions about key biosecurity hazards specific to the country or region and the procedures that may be required for periodic risk assessments. Integrating biosecurity into the existing infrastructure with limited resources is key challenge in implementation. More coordination is required among various stakeholders to develop an effective biosecurity framework. This article focuses on Pakistan's strides toward biosecurity preparedness in terms of protecting pathogens, toxins, or biological technologies with dual-use risks to prevent their malevolent use. We propose a multidimensional biosecurity management model at the national level to strengthen the biosecurity enterprise in Pakistan.

Deployment of Engineered Microbes: Contributions to the Bioeconomy and Considerations for Biosecurity.

Engineering at microscopic scales has an immense effect on the modern bioeconomy. Microbes contribute to such disparate markets as chemical manufacturing, fuel production, crop optimization, and pharmaceutical synthesis, to name a few. Due to new and emerging synthetic biology technologies, and the sophistication and control afforded by them, we are on the brink of deploying engineered microbes to not only enhance traditional applications but also to introduce these microbes to sectors, contexts, and formats not previously attempted. In microbially managed medicine, microbial engineering holds promise for increasing efficacy, improving tissue penetration, and sustaining treatment. In the environment, the most effective areas for deployment are in the management of crops and protection of ecosystems. However, caution is warranted before introducing engineered organisms to new environments where they may proliferate without control and could cause unforeseen effects. We summarize ideas and data that can inform identification and assessment of the risks that these tools present to ensure that realistic hazards are described and unrealistic ones do not hinder advancement. Further, because modes of containment are crucial complements to deployment, we describe the state of the art in microbial biocontainment strategies, current gaps, and how these gaps might be addressed through technological advances in synthetic engineering. Collectively, this work highlights engineered microbes as a foundational and expanding facet of the bioeconomy, projects their utility in upcoming deployments outside the laboratory, and identifies knowns and unknowns that will be necessary considerations and points of focus in this endeavor.

The Emerging Neurobioeconomy: Implications for National Security.

Neuroscience and neurotechnology (neuroS/T) are techniques and tools used to assess or affect the nervous system. Current and near-future developments are enabling an expanding palette of capabilities to understand and influence brain functions that can foster wellbeing and economic growth. This "neurobioeconomy" is rapidly growing, attributable in large part to the global dissemination of knowledge that fosters and contributes to scientific innovation, invention, and commercialization. As a result, several countries have initiated programs in brain research and innovation. Not all brain sciences engender security concerns, but a predominance in global biomedical, bioengineering, wellness/lifestyle, and defense markets enables considerable power. Such power can be leveraged in nonkinetic or kinetic domains, and several countries have identified neuroS/T as viable and of growing value for use in warfare, intelligence, and national security operations. In addition to the current focus on biotechnology, the United States and its allies must acknowledge the significance of brain science and its projected impact on the economy, national security, and lifestyles. In this article, we examine growth of the neuroS/T market, discuss how the neurobioeconomy poses distinct ethical and security issues for the broader bioeconomy, provide examples of such issues that arise from specific nation-state activity and technological commercialization, and propose a risk assessment and mitigation approach that can be engaged by the economic, scientific, and security communities.

COVID-19, SARS-CoV-2, and Export Controls.

Export controls are intended to prevent the proliferation of materials that could be misused to make biological weapons. They are not intended to stifle critical research and development in the midst of a pandemic. This article explores how and why export controls might apply to severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019. It outlines the taxonomic and genetic factors associated with the current approach to export control lists and discusses how they lead to unnecessary ambiguity. The authors describe ways in which the current export control systems might be revised in the short, medium, and long term, including sequence, disease, and function-based approaches.

Strengthening Security for Gene Synthesis: Recommendations for Governance.

Since the inception of gene synthesis technologies, there have been concerns about possible misuse. Using gene synthesis, pathogens-particularly small viruses-may be assembled "from scratch" in the laboratory, evading the regulatory regimes many nations have in place to control unauthorized access to dangerous pathogens. Progress has been made to reduce these risks. In 2010, the US Department of Health and Human Services (HHS) published guidance for commercial gene synthesis providers that included sequence screening of the orders and customer screening. The industry-led International Gene Synthesis Consortium (IGSC) was formed in 2009 to share sequence and customer screening methods, and it now includes the major international gene synthesis providers among its members. Since the 2010 HHS Guidance was released, however, there have been changes in gene synthesis technologies and market conditions that have reduced the efficacy of these biosecurity protections, leading to questions about whether the 2010 HHS Guidance should be updated, what changes could make it more effective, and what other international governance efforts could be undertaken to reduce the risks of misuse of gene synthesis products. This article describes these conditions and recommends actions that governments should take to reduce these risks and engage other nations involved in gene synthesis research.

Trends in Synthetic Biology Applications, Tools, Industry, and Oversight and Their Security Implications.

Recent developments in synthetic biology tools and techniques are driving commercialization of a wide range of products for human health, agriculture, environmental stewardship, and other purposes. This article reviews some of the trends in synthetic biology applications as well as some of the tools enabling these and future advances. These tools and capabilities are being developed in the context of a rapidly changing industry, which may have an impact on the rate and direction of progress. Final products are subject to a regulatory framework that is being challenged by the pace, scale, and novelty of this new era of biotechnology. This article includes discussion of these factors and how they may affect product design and the types of applications that are most likely to be supported and pursued commercially. The final section provides perspective on the security implications of these advances, with a focus on US interests.

The Threat of Synthetic Smallpox: European Perspectives.

This article explores how advances in synthetic biology, and the potential threat of deliberately recreating and spreading smallpox, are affecting the multilateral debate on the remaining variola virus stocks. It draws on in-depth, semi-structured interviews with 10 high-profile, European-based experts in biosecurity and synthetic biology. Four overarching themes affecting the retention or destruction debate are discussed, relating to biosecurity, dangerous knowledge, accidental releases, and eradication. We conclude that while synthetic biology seems to affect all the main discourses in the variola stocks debate, a range of views is present and it is not apparent that advances in synthetic biology are causing a shift toward either retention or destruction of the stocks.

Defining the Synthetic Biology Supply Chain.

Several recent articles have described risks posed by synthetic biology and spurred vigorous discussion in the scientific, commercial, and government communities about how to best detect, prevent, regulate, and respond to these risks. The Pacific Northwest National Laboratory's (PNNL) deep experience working with dual-use technologies for the nuclear industry has shown that analysis of supply chains can reveal security vulnerabilities and ways to mitigate security risk without hindering beneficial research and commerce. In this article, a team of experts in synthetic biology, data analytics, and national security describe the overall supply chain surrounding synthetic biology to illustrate new insights about the effectiveness of current regulations, the possible need for different screening approaches, and new technical solutions that could help identify or mitigate risks in the synthetic biology supply chain.