Beyond gain of function: strengthening oversight of research with potential pandemic pathogens.

In 2017, the Department of Health and Human Services adopted a policy, known as the P3CO Framework, to govern proposed research that could enhance the lethality or transmissibility of a potential pandemic pathogen. The prospect of a human-made virus with artificially enhanced lethality and transmissibility has raised serious biosafety and biosecurity concerns. The COVID-19 pandemic has generated new concerns about the risks posed by such research. Even if the origins of the pandemic are presumed or proven to be the result of a natural zoonotic spillover event, the pandemic has placed greater scrutiny on research that could generate pandemic-capable viruses and dramatically illustrated the consequences if such a virus were released from a laboratory. This article assesses the strengths and weaknesses of the P3CO Framework and provides recommendations for strengthening oversight of research with potential pandemic pathogens. The P3CO Framework should be replaced by a national policy that would apply to all relevant research, regardless of the source of funding and be implemented by a new national agency for biorisk management. This new policy would need to be accompanied by a comprehensive analysis of potential pandemic pathogen risks, clear guidance on how to identify research that falls within the scope of the policy, a rigorous process for reviewing the risks and benefits of such research, and criteria for determining the appropriate measures needed to conduct such research safely, securely, and responsibly.

Improved understanding of biorisk for research involving microbial modification using annotated sequences of concern.

Regulation of research on microbes that cause disease in humans has historically been focused on taxonomic lists of 'bad bugs'. However, given our increased knowledge of these pathogens through inexpensive genome sequencing, 5 decades of research in microbial pathogenesis, and the burgeoning capacity of synthetic biologists, the limitations of this approach are apparent. With heightened scientific and public attention focused on biosafety and biosecurity, and an ongoing review by US authorities of dual-use research oversight, this article proposes the incorporation of sequences of concern (SoCs) into the biorisk management regime governing genetic engineering of pathogens. SoCs enable pathogenesis in all microbes infecting hosts that are 'of concern' to human civilization. Here we review the functions of SoCs (FunSoCs) and discuss how they might bring clarity to potentially problematic research outcomes involving infectious agents. We believe that annotation of SoCs with FunSoCs has the potential to improve the likelihood that dual use research of concern is recognized by both scientists and regulators before it occurs.

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.

Insidious Insights: Implications of viral vector engineering for pathogen enhancement.

Optimizing viral vectors and their properties will be important for improving the effectiveness and safety of clinical gene therapy. However, such research may generate dual-use insights relevant to the enhancement of pandemic pathogens. In particular, reliable and generalizable methods of immune evasion could increase viral fitness sufficient to cause a new pandemic. High potential for misuse is associated with (1) the development of universal genetic elements for immune modulation, (2) specific insights on capsid engineering for antibody evasion applicable to viruses with pandemic potential, and (3) the development of computational methods to inform capsid engineering. These risks may be mitigated by prioritizing non-viral delivery systems, pharmacological immune modulation methods, non-genetic vector surface modifications, and engineering methods specific to AAV and other viruses incapable of unassisted human-to-human transmission. We recommend that computational vector engineering and the publication of associated code and data be limited to AAV until a technical solution for preventing malicious access to viral engineering tools has been established.

Computational modeling of first responders' willingness to accept radiation exposure during radiological or nuclear events.

Since the events of 9/11, a concerted interagency effort has been undertaken to create comprehensive emergency planning and preparedness strategies for the management of a radiological or nuclear event in the US. These planning guides include protective action guidelines, medical countermeasure recommendations, and systems for diagnosing and triaging radiation injury. Yet, key areas such as perception of risk from radiation exposure by first responders have not been addressed. In this study, we identify the need to model and develop new strategies for medical management of large-scale population exposures to radiation and examine the phenomena of radiation dread and its role in emergency response using an agent-based modeling approach. Using the computational modeling platform NetLogo, we developed a series of models examining factors affecting first responders' willingness to work (WTW) in the context of entering areas where radioactive contamination is present or triaging individuals potentially contaminated with radioactive materials. In these models, the presence of radiation subject matter experts (SMEs) was found to increase WTW. Degree of communication was found to be a dynamic variable with either positive or negative effects on WTW dependent on the initial WTW demographics of the test population. Our findings illustrate that radiation dread is a significant confounder for emergency response to radiological or nuclear events and that increasing the presence of radiation SME in the field and communication among first responders when such radiation SMEs are present will help mitigate the effect of radiation dread and improve first responder WTW during future radiological or nuclear events.

Biosecurity risks associated with vaccine platform technologies.

Vaccine platforms have been critical for accelerating the timeline of COVID-19 vaccine development. Faster vaccine timelines demand further development of these technologies. Currently investigated platform approaches include virally vectored and RNA-based vaccines, as well as DNA vaccines and recombinant protein expression system platforms, each featuring different advantages and challenges. Viral vector-based and DNA vaccines in particular have received a large share of research funding to date. Platform vaccine technologies may feature dual-use potential through informing or enabling pathogen engineering, which may raise the risk for the occurrence of deliberate, anthropogenic biological events. Research on virally vectored vaccines exhibits relatively high dual-use potential for two reasons. First, development of virally vectored vaccines may generate insights of particular dual-use concern such as techniques for circumventing pre-existing anti-vector immunity. Second, while the amount of work on viral vectors for gene therapy exceeds that for vaccine research, work on virally vectored vaccines may increase the number of individuals capable of engineering viruses of particular concern, such as ones closely related to smallpox. Other platform vaccine approaches, such as RNA vaccines, feature relatively little dual-use potential. The biosecurity risk associated with platform advancement may be minimised by focusing preferentially on circumventing anti-vector immunity with non-genetic rather than genetic modifications, using vectors that are not based on viruses pathogenic to humans, or preferential investment into promising RNA-based vaccine approaches. To reduce the risk of anthropogenic pandemics, structures for the governance of biotechnology and life science research with dual-use potential need to be reworked. Scientists outside of the pathogen research community, for instance those who work on viral vectors or oncolytic viruses, need to become more aware of the dual-use risks associated with their research. Both public and private research-funding bodies need to prioritise the evaluation and reduction of biosecurity risks.

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.

The impact of radiation dread on mass casualty medical management during a radiological or nuclear event.

Since the events of 9/11, a concerted interagency effort has been undertaken to create comprehensive emergency planning and preparedness strategies for management of a radiological or nuclear event in the US. These planning guides include protective action guidelines, medical countermeasure recommendations, and systems for diagnosing and triaging radiation injury. Yet, key areas such as perception of risk from radiation exposure by first responders have not been addressed. In this article, we identify the need to model and develop new strategies for the medical manage-ment of large-scale population exposures to radiation, examine the phenomena of radiation dread and its role in emergency response, and review recent findings on the willingness to work of first responders and other personnel involved in mass casualty medical management during a radiological or nuclear event.

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.

The biosecurity benefits of genetic engineering attribution.

Biology can be misused, and the risk of this causing widespread harm increases in step with the rapid march of technological progress. A key security challenge involves attribution: determining, in the wake of a human-caused biological event, who was responsible. Recent scientific developments have demonstrated a capability for detecting whether an organism involved in such an event has been genetically modified and, if modified, to infer from its genetic sequence its likely lab of origin. We believe this technique could be developed into powerful forensic tools to aid the attribution of outbreaks caused by genetically engineered pathogens, and thus protect against the potential misuse of synthetic biology.

Lists of Chemical Warfare Agents and Precursors from International Nonproliferation Frameworks: Structural Annotation and Chemical Fingerprint Analysis.

To support efforts to stem the proliferation of chemical weapons (CWs), we have curated and structurally annotated CW-control lists from three key international nonproliferation frameworks: the Chemical Weapons Convention (CWC), the Australia Group (AG), and the Wassenaar Arrangement. The curated lists are available as web tables at the Costanzi Research website (https://costanziresearch.com/cw-control-lists/). The annotations include manually curated 2D structural images, which provide a means to appreciate at a glance the similarities and differences between different entries, as well as downloadable 2D structures, in two different formats and three different structural identifiers, namely, simplified molecular-input line-entry system, standard InChI, and standard InChIKey, which are intended to provide a platform for cheminformatics analyses. The tables also include links to National Center for Biotechnology Information's PubChem and National Institute of Standards and Technology's Chemistry WebBook cards, hence providing prompt access to a wealth of physicochemical, analytical chemistry, and toxicological information. To showcase the importance of structural annotations, we discuss a discrepancy in a CW-control list covering the defoliant Agent Orange, which we identified through our curation process, and propose a solution to address it. Moreover, we present the results of chemical fingerprinting analyses, through which we clustered the entries of the three CW-control lists under study into structurally related groups and studied the overlaps between the three lists. As an application of this study, we examine the recent updates of CWC Schedule 1 and the AG precursors list, highlighting the relationships between the two amendments and proposing the possible addition of further chemicals. Our research is intended to facilitate the communication between scientific advisors and policymakers as well as the work of chemists and cheminformaticians involved in the CW nonproliferation field. Ultimately, we seek to provide tools to bolster the control of CWs and support the global efforts to rid the world of this category of weapons.

A Critical Analysis of the Scientific and Commercial Rationales for the De Novo Synthesis of Horsepox Virus.

This article evaluates the scientific and commercial rationales for the synthesis of horsepox virus. I find that the claimed benefits of using horsepox virus as a smallpox vaccine rest on a weak scientific foundation and an even weaker business case that this project will lead to a licensed medical countermeasure. The combination of questionable benefits and known risks of this dual use research raises serious questions about the wisdom of undertaking research that could be used to recreate variola virus. This analysis also raises important questions about the propriety of a private company sponsoring such dual use research without appropriate oversight and highlights an important gap in United States dual use research regulations.

Biodosimetry: A Future Tool for Medical Management of Radiological Emergencies.

With the threat of future radiological or nuclear events, there is a need to model and develop new medical countermeasures for managing large-scale population exposures to radiation. The field of radiation biodosimetry has advanced far beyond its original objectives to identify new methodologies to quantitate unknown levels of radiation exposure that may be applied in a mass screening setting. New research in the areas of genomics, proteomics, metabolomics, transcriptomics, and electron paramagnetic resonance (EPR) applications have identified novel biological indicators of radiation injury from a diverse array of biological sample materials, and studies continue to develop more advanced models of radiation exposure and injury. In this article, we identify the urgent need for new biodosimetry assessment technologies, describe how biodosimetry diagnostics work in the context of a broad range of radiation exposure types and scenarios, review the current state of the science, and assess how well integrated biodosimetry resources are in the national radiological emergency response framework.

The De Novo Synthesis of Horsepox Virus: Implications for Biosecurity and Recommendations for Preventing the Reemergence of Smallpox.

In March 2017, the American biotech company Tonix announced that a Canadian scientist had synthesized horsepox virus as part of a project to develop a safer vaccine against smallpox. The first de novo synthesis of an orthopoxvirus, a closely related group of viruses that includes horsepox and the variola virus that causes smallpox, crosses an important Rubicon in the field of biosecurity. The synthesis of horsepox virus takes the world one step closer to the reemergence of smallpox as a threat to global health security. That threat has been held at bay for the past 40 years by the extreme difficulty of obtaining variola virus and the availability of effective medical countermeasures. The techniques demonstrated by the synthesis of horsepox have the potential to erase both of these barriers. The primary risk posed by this research is that it will open the door to the routine and widespread synthesis of other orthopoxviruses, such as vaccinia, for use in research, public health, and medicine. The normalization and globalization of orthopoxvirus synthesis for these beneficial applications will create a cadre of laboratories and scientists that will also have the capability and expertise to create infectious variola virus from synthetic DNA. Unless the safeguards against the synthesis of variola virus are strengthened, the capability to reintroduce smallpox into the human population will be globally distributed and either loosely or completely unregulated, providing the foundation for a disgruntled or radicalized scientist, sophisticated terrorist group, unscrupulous company, or rogue state to recreate one of humanity's most feared microbial enemies. The reemergence of smallpox-because of a laboratory accident or an intentional release-would be a global health disaster. International organizations, national governments, the DNA synthesis industry, and the synthetic biology community all have a role to play in devising new approaches to preventing the reemergence of smallpox.

Strengthening Biosecurity in Iraq: Development of a National Biorisk Management System.

Since 2004, the Republic of Iraq has undertaken a concerted effort to comply with all of its international obligations to prevent the proliferation and the use of chemical, biological, radiological, and nuclear (CBRN) weapons. A centerpiece of this effort is Iraq's development of a National Biorisk Management System. The Iraqi National Monitoring Authority (INMA), which is responsible for CBRN security and non-proliferation in Iraq, has played a key role in establishing this system. This article provides an overview of Iraq's international non-proliferation commitments, describes the legal and organizational steps it has taken to implement these commitments, and examines current initiatives to strengthen Iraq's biosecurity.

From biodefence to biosecurity: the Obama administration's strategy for countering biological threats.

The Seventh Review Conference of the Biological Weapons Convention (BWC), the first international treaty to outlaw an entire class of weapons, was held in Geneva in December 2011. On 7 December, Secretary of State Hillary Clinton became the highest-ranking US government official to address a BWC meeting. Secretary Clinton told the assembled delegation that 'we view the risk of bioweapons attack as both a serious national security challenge and a foreign policy priority'. At the same time, she warned that a large-scale disease outbreak 'could cripple an already fragile global economy'. Secretary Clinton's speech reflected a new understanding that the range of biological threats to international security has expanded from state-sponsored biological warfare programmes to include biological terrorism, dual-use research and naturally occurring infectious diseases such as pandemics. Recognizing these changes, President Barack Obama released a new national strategy for countering biological threats in 2009. This strategy represents a shift in thinking away from the George W. Bush administration's focus on biodefence, which emphasized preparing for and responding to biological weapon attacks, to the concept of biosecurity, which includes measures to prevent, prepare for and respond to naturally occurring and man-made biological threats. The Obama administration's biosecurity strategy seeks to reduce the global risk of naturally occurring and deliberate disease outbreaks through prevention, international cooperation, and maximizing synergies between health and security. The biosecurity strategy is closely aligned with the Obama administration's broader approach to foreign policy, which emphasizes the pragmatic use of smart power, multilateralism and engagement to further the national interest. This article describes the Obama administration's biosecurity strategy; highlights elements of continuity and change from the policies of the Bush administration; discusses how it fits into Obama's broader foreign policy agenda; and analyses critical issues that will have to be addressed in order to implement the strategy successfully.

Modernizing confidence-building measures for the Biological Weapons Convention.

The Seventh Review Conference of the Biological Weapons Convention in December 2011 provides an opportunity to modernize the treaty to better address the challenges of the 21st century. The key to this modernization is to redesign the treaty's Confidence-Building Measures (CBMs), the only formal mechanism for increasing transparency and demonstrating compliance with the treaty, to address changes in the global scientific, health, and security environments since the end of the Cold War. The scope of the CBMs should be expanded beyond state-run biological warfare programs to encompass a broader array of threats to global security, such as biological terrorism, laboratory accidents, dual-use research, and disease pandemics. Modernizing the CBM mechanism to take into account these new risks would extend the transparency-enhancing benefits of CBMs to a range of new and important topics, such as biosafety, laboratory biosecurity, and dual-use research oversight; make the CBMs and the treaty itself more relevant to the concerns and priorities of more states; and build on progress made during the recent series of intersessional meetings. To accomplish this, the CBMs need to be revised to shift their focus from hardware, the dual-use capabilities relevant to the treaty, to software, the political and legal institutions that govern the development and use of these capabilities. A more modern CBM mechanism should encourage greater participation in the confidence-building process, improve international cooperation against the full spectrum of biological risks, and promote the goal of universal membership in the treaty.

The four faces of microbial forensics.

The emerging field of microbial forensics played a major role in the investigation of the 2001 anthrax mailings and has been closely associated with the process of attribution, or identifying the perpetrator of a biological attack for purposes of criminal prosecution or military retaliation. Nevertheless, microbial forensics has other potential applications in intelligence, nonproliferation, and verification. This article describes the relevance of microbial forensics for a variety of law enforcement and national security missions, examines the obstacles to its broader use, and concludes with some policy recommendations.