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.

Strengthen oversight of risky research on pathogens.

Policy reset and convergence on governance are needed.

Making Security Viral: Shifting Engineering Biology Culture and Publishing.

The ability to construct, synthesize, and edit genes and genomes at scale and with speed enables, in synergy with other tools of engineering biology, breakthrough applications with far-reaching implications for society. As SARS-CoV-2 spread around the world in early spring of 2020, researchers rapidly mobilized, using these tools in the development of diagnostics, therapeutics, and vaccines for COVID-19. The sharing of knowledge was crucial to making rapid progress. Several publications described the use of reverse genetics for the de novo construction of SARS-CoV-2 in the laboratory, one in the form of a protocol. Given the demonstrable harm caused by the virus, the unequal distribution of mitigating vaccines and therapeutics, their unknown efficacy against variants, and the interest in this research by laboratories unaccustomed to working with highly transmissible pandemic pathogens, there are risks associated with such publications, particularly as protocols. We describe considerations and offer suggestions for enhancing security in the publication of synthetic biology research and techniques. We recommend: (1) that protocol manuscripts for the de novo synthesis of certain pathogenic viruses undergo a mandatory safety and security review; (2) that if published, such papers include descriptions of the discussions or review processes that occurred regarding security considerations in the main text; and (3) the development of a governance framework for the inclusion of basic security screening during the publication process of engineering biology/synthetic biology manuscripts to build and support a safe and secure research enterprise that is able to maximize its positive impacts and minimize any negative outcomes.

iGEM and Gene Drives: A Case Study for Governance.

Gene drives have already challenged governance systems. In this case study, we explore the International Genetically Engineered Machine (iGEM) competition's experiences in gene drive-related research and lessons in developing, revising, and implementing a governance system. iGEM's experiences and lessons are distilled into 6 key insights for future gene drive policy development in the United States: (1) gene drives deserve special attention because of their potential for widescale impact and remaining uncertainty about how to evaluate intergenerational and transboundary risks; (2) an adaptive risk management approach is logical for gene drives because of the rapidly changing technical environment; (3) review by individual technical experts is limited and may fail to incorporate other forms of expertise and, therefore, must be complemented with a range of alternative governance methods; (4) current laboratory biosafety and biosecurity review processes may not capture gene drive research or its components in practice even if they are covered theoretically; (5) risk management for research and development must incorporate discussions of values and broader implications of the work; and (6) a regular technology horizon scanning capacity is needed for the early identification of advances that could pose governance system challenges.

Rapid Proliferation of Pandemic Research: Implications for Dual-Use Risks.

The COVID-19 pandemic has demonstrated the world's vulnerability to biological catastrophe and elicited unprecedented scientific efforts. Some of this work and its derivatives, however, present dual-use risks (i.e., potential harm from misapplication of beneficial research) that have largely gone unaddressed. For instance, gain-of-function studies and reverse genetics protocols may facilitate the engineering of concerning SARS-CoV-2 variants and other pathogens. The risk of accidental or deliberate release of dangerous pathogens may be increased by large-scale collection and characterization of zoonotic viruses undertaken in an effort to understand what enables animal-to-human transmission. These concerns are exacerbated by the rise of preprint publishing that circumvents a late-stage opportunity for dual-use oversight. To prevent the next global health emergency, we must avoid inadvertently increasing the threat of future biological events. This requires a nuanced and proactive approach to dual-use evaluation throughout the research life cycle, including the conception, funding, conduct, and dissemination of research.

Guiding Ethical Principles in Engineering Biology Research.

Engineering biology is being applied toward solving or mitigating some of the greatest challenges facing society. As with many other rapidly advancing technologies, the development of these powerful tools must be considered in the context of ethical uses for personal, societal, and/or environmental advancement. Researchers have a responsibility to consider the diverse outcomes that may result from the knowledge and innovation they contribute to the field. Together, we developed a Statement of Ethics in Engineering Biology Research to guide researchers as they incorporate the consideration of long-term ethical implications of their work into every phase of the research lifecycle. Herein, we present and contextualize this Statement of Ethics and its six guiding principles. Our goal is to facilitate ongoing reflection and collaboration among technical researchers, social scientists, policy makers, and other stakeholders to support best outcomes in engineering biology innovation and development.

The CRISPR revolution and its potential impact on global health security.

Global health security is constantly under threat from infectious diseases. Despite advances in biotechnology that have improved diagnosis and treatment of such diseases, delays in detecting outbreaks and the lack of countermeasures for some biological agents continue to pose severe challenges to global health security. In this review, we describe some of the challenges facing global health security and how genome editing technologies can help overcome them. We provide specific examples of how the genome-editing tool CRISPR is being used to develop new tools to characterize pathogenic agents, diagnose infectious disease, and develop vaccines and therapeutics to mitigate the effects of an outbreak. The article also discusses some of the challenges associated with genome-editing technologies and the efforts that scientists are undertaking to mitigate them. Overall, CRISPR and genome-editing technologies are poised to have a significant positive influence on global health security over the years to come.

Multi-cellular engineered living systems: building a community around responsible research on emergence.

Ranging from miniaturized biological robots to organoids, multi-cellular engineered living systems (M-CELS) pose complex ethical and societal challenges. Some of these challenges, such as how to best distribute risks and benefits, are likely to arise in the development of any new technology. Other challenges arise specifically because of the particular characteristics of M-CELS. For example, as an engineered living system becomes increasingly complex, it may provoke societal debate about its moral considerability, perhaps necessitating protection from harm or recognition of positive moral and legal rights, particularly if derived from cells of human origin. The use of emergence-based principles in M-CELS development may also create unique challenges, making the technology difficult to fully control or predict in the laboratory as well as in applied medical or environmental settings. In response to these challenges, we argue that the M-CELS community has an obligation to systematically address the ethical and societal aspects of research and to seek input from and accountability to a broad range of stakeholders and publics. As a newly developing field, M-CELS has a significant opportunity to integrate ethically responsible norms and standards into its research and development practices from the start. With the aim of seizing this opportunity, we identify two general kinds of salient ethical issues arising from M-CELS research, and then present a set of commitments to and strategies for addressing these issues. If adopted, these commitments and strategies would help define M-CELS as not only an innovative field, but also as a model for responsible research and engineering.

Developing a Comprehensive, Adaptive, and International Biosafety and Biosecurity Program for Advanced Biotechnology: The iGEM Experience.

Introduction: The international synthetic biology competition iGEM (formally known as the international Genetically Engineered Machines competition) has a dedicated biosafety and biosecurity program. Method: A review of specific elements of the program and a series of concrete examples illustrate how experiences in implementing the program have helped improved policy, including an increasing diversity of sources for genetic parts and organisms, keeping pace with technical developments, considering pathways toward future environmental release, addressing antimicrobial resistance, and testing the efficacy of current biosecurity arrangements. Results: iGEM's program is forward-leaning, in that it addresses both traditional (pathogen-based) and emerging risks both in terms of new technologies and new risks. It is integrated into the technical work of the competition-with clearly described roles and responsibilities for all members of the community. It operates throughout the life cycle of projects-from project design to future application. It makes use of specific tools to gather and review biosafety and biosecurity information, making it easier for those planning and conducting science and engineering to recognize potential risks and match them with appropriate risk management approaches, as well as for specialists to review this information to identify gaps and strengthen plans. Discussion: Integrating an increasingly adaptive risk management approach has allowed iGEM's biosafety and biosecurity program to become comprehensive, be cross-cutting, and cover the competition's life cycle.

Considerations for the governance of gene drive organisms.

Governance is a broader and more flexible concept than statute-driven regulations as it incorporates components outside the latter's remit. Considerations of governance are critical in the development of emerging biotechnologies such as gene drive organisms. These have been proposed or are being developed to address public and environmental health issues not addressed easily by conventional means. Here, we consider how the concept of governance differs from statute-driven regulation with reference to the role each may play in the development of gene drive organisms. First, we discuss existing statute-based regulatory systems. Second, we consider whether novel risks or different concerns derive from gene drive organisms, concentrating on characteristics that contribute to public health or environmental risk and uncertainties that may affect risk perceptions. Third, we consider public engagement, outlining how existing statute-driven regulatory systems and other governance mechanisms may provide opportunities for constructive interactions. Finally, we provide some observations that may help address science- and values-based concerns in a governance space larger than that of statute-driven regulatory systems.

Enabling a next generation of synthetic biology community organization and leadership.

Synthetic biology seeks to make engineering of complex biological functions more efficient, reliable, and predictable. Advancing the process of engineering biology requires community organization and leadership. As synthetic biology matures into a globally significant enterprise, the community needs to enable a next generation of leaders to organize the field's responsible advancement. We discuss key points raised at a community meeting on these issues at SB6.0--the Sixth International Meeting on Synthetic Biology--and highlight opportunities to carry forward the conversation.

Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naïve CD8(+) T cells.

Variable sensitivity to T-cell-receptor (TCR)- and IL-7-receptor (IL-7R)-mediated homeostatic signals among naïve T cells has thus far been largely attributed to differences in TCR specificity. We show here that even when withdrawn from self-peptide-induced TCR stimulation, CD8(+) T cells exhibit heterogeneous responses to interleukin-7 (IL-7) that are mechanistically associated with IL-7R expression differences that correlate with relative CD5 expression. Whereas CD5(hi) and CD5(lo) T cells survive equivalently in the presence of saturating IL-7 levels in vitro, CD5(hi) T cells proliferate more robustly. Conversely, CD5(lo) T cells exhibit prolonged survival when withdrawn from homeostatic stimuli. Through quantitative experimental analysis of signaling downstream of IL-7R, we find that the enhanced IL-7 responsiveness of CD5(hi) T cells is directly related to their greater surface IL-7R expression. Further, we identify a quantitative threshold in IL-7R-mediated signaling capacity required for proliferation that lies well above an analogous threshold requirement for survival. These distinct thresholds allow subtle differences in IL-7R expression between CD5(lo) and CD5(hi) T cells to give rise to significant variations in their respective IL-7-induced proliferation, without altering survival. Heterogeneous IL-7 responsiveness is observed similarly in vivo, with CD5(hi) naïve T cells proliferating preferentially in lymphopenic mice or lymphoreplete mice administered with exogenous IL-7. However, IL-7 in lymphoreplete mice appears to be maintained at an effective level for preserving homeostasis, such that neither CD5(hi) IL-7R(hi) nor CD5(lo) IL-7R(lo) T cells proliferate or survive preferentially. Our findings indicate that IL-7R-mediated signaling not only maintains the size but also impacts the diversity of the naïve T-cell repertoire.

Interleukin-7 receptor signaling network: an integrated systems perspective.

Interleukin-7 (IL-7) is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor (IL-7R), activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7 receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology.