Does Biotechnology Pose New Catastrophic Risks?

Advances in biotechnology in the twenty-first century, fueled in large part by the field of synthetic biology, have greatly accelerated capabilities to manipulate and re-program bacteria, viruses, and other organisms. These genetic engineering capabilities are driving innovation and progress in drug manufacturing, bioremediation, and tissue engineering, as well as biosecurity preparedness. However, biotechnology is largely dual use, holding the potential of misuse for deliberate harm along with positive applications; defenses against those threats need to be anticipated and prepared. This chapter describes the challenges of managing dual-use capabilities enabled by modern biotechnology and synthetic biology and highlights a framework tool developed by a National Academies committee to aid analysis of the security effects of new scientific discoveries and prioritization of concerns. The positive aspects of synthetic biology in preparedness are also detailed, and policy directions are highlighted for taking advantage of the positive aspects of these emerging technologies while minimizing risks.

A practical approach to remote longitudinal follow-up of Parkinson's disease: the FOUND study.

The objective of this study was to examine a remote method for maintaining long-term contact with Parkinson's disease (PD) patients participating in clinical studies. Long-term follow-up of PD patients is needed to fill critical information gaps on progression, biomarkers, and treatment. Prospective in-person assessment can be costly and may be impossible for some patients. Remote assessment using mail and telephone contact may be a practical follow-up method. Patients enrolled in the multi-center Longitudinal and Biomarker Study in Parkinson's Disease (LABS-PD) in-person follow-up study in 2006 were invited to enroll in Follow-up of Persons With Neurologic Diseases (FOUND), which is overseen by a single center under a separate, central institutional review board protocol. FOUND uses mailed questionnaires and telephone interviews to assess PD status. FOUND follow-up continued when LABS-PD in-person visits ended in 2011. Retention and agreement between remote and in-person assessments were determined. In total, 422 of 499 (84.5%) of eligible patients volunteered, AND 96% of participants were retained. Of 60 patients who withdrew consent from LABS-PD, 51 were retained in FOUND. Of 341 patients who were active in LABS-PD, 340 were retained in FOUND (99.7%) when the in-person visits ceased. Exact agreement between remote and in-person assessments was ≥ 80% for diagnosis, disease features (eg, dyskinesias), and PD medication. Correlation between expert-rated and self-reported Unified Parkinson's Disease Rating Scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale, which were examined at times separated by several months, was moderate or substantial for most items. Retention was excellent using remote follow-up of research participants with PD, providing a safety net when combined with in-person visits, and also is effective as a stand-alone assessment method, providing a useful alternative when in-person evaluation is not feasible.

Safely balancing a double-edged blade: identifying and mitigating emerging biosecurity risks in precision medicine.

Tools and methods of precision medicine are developing rapidly, through both iterative discoveries enabled by innovations in biomedical research (e.g., genome editing, synthetic biology, bioengineered devices). These are strengthened by advancements in information technology and the increasing body of data-as assimilated, analyzed, and made accessible-and affectable-through current and emerging cyber-and systems- technologies. Taken together, these approaches afford ever greater volume and availability of individual and collective human data. Machine learning and/or artificial intelligence approaches are broadening this dual use risk; and in the aftermath of COVID-19, there is growing incentive and impetus to gather more biological data from individuals and their environments on a routine basis. By engaging these data-and the interventions that are based upon them, precision medicine offer promise of highly individualized treatments for disease and injury, optimization of structure and function, and concomitantly, the potential for (mis) using data to incur harm. This double-edged blade of benefit and risk obligates the need to safeguard human data from purloinment, through systems, guidelines and policies of a novel discipline, cyberbiosecurity, which, as coupled to ethical precepts, aims to protect human privacy, agency, and safety in ways that remain apace with scientific and technological advances in biomedicine. Herein, current capabilities and trajectories precision medicine are described as relevant to their dual use potential, and approaches to biodata security (viz.- cyberbiosecurity) are proposed and discussed.

Perspective: The Rapidly Expanding Need for Biosecurity by Design.

Advancing biotechnologies are revolutionizing not only health and medicine, but also many different sectors such as agriculture, energy, chemistry, and textiles. As synthetic biology is leveraged as a programmable platform for the creation and biodesign of high-value biological medicines, foods, and commodities, the world is facing new territory in terms of ensuring the safety and security of both novel and engineered biological organisms, as well as the biological and digital platforms in which they are designed. Biosecurity practices and policies have traditionally revolved around preventing the misuse of biological pathogens, primarily through controlling access to pathogens. The advent of biodesign capabilities, such as gene editors, gene synthesis capabilities, and genetic engineering, requires a reevaluation of traditional biosecurity policies to mitigate risks associated with such engineering of biological entities. Here, features of "Biosecurity by Design" approaches are described, including the application of risk/benefit analysis and risk mitigation, post-COVID opportunities, and ethical global norms in the progression of biodesign and growing bioeconomies.

The Need for Modernization of Biosecurity in the Post-COVID World.

At present, there are two hypotheses about the emergence of SARS-CoV-2; the first is that it was due to a naturally occurring zoonotic jump, and the second contends that it spread due to an accidental dispersion of a laboratory-acquired infection in Wuhan, China. While the pandemic's actual origins remain occluded, it is useful to examine the latter possibility as a paradigm for evaluating biosecurity policy in the post-COVID world. While the pandemic may not have emerged from a research lab, this is possible with research on dangerous pathogens and prompts questions for biosecurity. How might biosecurity protections for such research be modernized while still enabling important, necessary public health research that utilizes dual-use or gain-of-function capabilities? As the world takes urgent action to mitigate shortcomings in the response to COVID-19, such questions and their potential solutions are vital to inform and direct future life science and technology endeavors.

Proceedings of the Ninth Annual Deep Brain Stimulation Think Tank: Advances in Cutting Edge Technologies, Artificial Intelligence, Neuromodulation, Neuroethics, Pain, Interventional Psychiatry, Epilepsy, and Traumatic Brain Injury.

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury.

Balancing Act: Precision Medicine and National Security.

Developments in genetics, pharmacology, biomarker identification, imaging, and interventional biotechnology are enabling medicine to become increasingly more precise in "personalized" approaches to assessing and treating individual patients. Here we describe current scientific and technological developments in precision medicine and elucidate the dual-use risks of employing these tools and capabilities to exert disruptive influence upon human health, economics, social structure, military capabilities, and global dimensions of power. We advocate continued enterprise toward more completely addressing nuances in the ethical systems and approaches that can-and should-be implemented (and communicated) to more effectively inform policy to guide and govern the biosecurity and use of current and emerging bioscience and technology on the rapidly shifting global stage.

Breaching the Department of Defense's Biotech Bottleneck.

The global biotechnology revolution offers a profusion of promising innovations for the US Department of Defense (DoD). As with other emerging technologies, the commercial market, rather than defense, is driving the evolution of biotechnology products, and the ability to harness biotechnology for defense benefits has been hampered by strategic confusion in DoD. Here we describe a set of high-level challenges and a set of potential solutions that could bring innovative biotechnology closer to reality for the warfighter and DoD writ large.

A longitudinal program for biomarker development in Parkinson's disease: a feasibility study.

Long-term follow up is necessary to understand the natural history of treated Parkinson's disease (PD). The Longitudinal and Biomarker Study in PD (LABS-PD) is an observational study designed to prospectively measure the evolution of motor and non-motor features of PD and sample promising biomarkers from early to late stage illness. LABS-PD is organized on the premise that cohorts from completed clinical trials can be re-recruited for long-term follow up. LABS-PD will eventually contain multiple cohorts, but to test the feasibility of the strategy, we examined enrollment and biomarker sampling in the initial cohorts. The first PD cohort (PostCEPT) comes from the de novo clinical trial of a mixed lineage kinase inhibitor (PRECEPT). We assessed the recruitment from PRECEPT to PostCEPT, the ability to link data from the two studies, and sample collection for a variety of biomarkers. A total of 537 of 709 eligible PRECEPT subjects (76%) enrolled in PostCEPT; 509 (95%) had repeat dopamine transporter imaging. PRECEPT clinical and imaging data were successfully linked to PostCEPT, to provide 3 to 4 year follow-up. A biomarker sub-study enrolled over 100 PD cases from PostCEPT and 100 controls to measure olfaction and blood markers of gene expression, alpha-synuclein, and proteomic profiles. We were also successful in linking clinical and biomarker data to DNA samples that have been collected in the publicly accessible Coriell repository. The PostCEPT cohort and associated studies strongly support the feasibility of the LABS-PD approach of retaining and repurposing clinical trial cohorts to collect longitudinal clinical and biomarker data.

Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification.

Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein alpha-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking alpha-synuclein to mitochondria has been reported. Here, we show that the distribution of alpha-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of alpha-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for alpha-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link alpha-synuclein to other PD genes in regulating mitochondrial homeostasis.

Biodefense Policy Analysis-A Systems-based Approach.

Understanding the overall biosecurity and biodefense policy landscape, the relationships between policies and their effects on each other, and the mechanisms for leveraging advances in science and technology to enhance defensive capabilities is crucial for ensuring that policy strategies address long-standing gaps and challenges. To date, policy analyses have been conducted primarily on single issues, which limits analyses of broader effects of policies, particularly after implementation. Here we describe the first-ever systems-based analysis of the US biosecurity and biodefense policy landscape to analyze functional relationships between policies, including examination of the unintended positive or negative consequences of policy actions. This analysis revealed a striking bifurcation of the US policy landscape for countering biological threats, with one grouping of policies focused on prevention of theft, diversion, or deliberate malicious use of biological sciences knowledge, skills, materials, and technologies (ie, biosecurity) and a second grouping on development of capabilities and knowledge to assess, detect, monitor, respond to, and attribute biological threats (ie, biodefense). An analysis of indirect effects demonstrated that policies within groups may result in mutual benefit, but policies in different groups may counteract each other, limiting achievement of the policy objectives in either group. The current policy landscape predominantly focuses on pathogens and toxins, having limited focus on rapidly changing biotechnologies with potential to positively contribute to biodefense capabilities or introduce unknown and/or unacceptable security risk. Based on our analyses, we present actions for implementing biosecurity and biodefense policy in the United States that intends to harness the benefits of science and technology while also minimizing potential risks. This article synthesizes and highlights the major findings and conclusions from the detailed analyses, which can be found in the full report ( http://www.gryphonscientific.com/biosecurity-policy/ ).

A Holistic Assessment of the Risks and Benefits of the Synthesis of Horsepox Virus.

The re-creation of horsepox virus, an extinct orthopoxvirus with similarity to smallpox virus, has caused concerns in the biosecurity and biodefense communities that the technical capabilities achieved could advance the re-creation of smallpox virus by nefarious actors. The work is now published. While the authors went through due biosecurity diligence at their research institution and with the proper Canadian federal authorities, now that the experiments have been published, there is an opportunity to discuss the dual use risks and benefits of the research itself, as well as those associated with publication of such research-all of which challenge current policies. Here, an analytical framework is used to assess the risks and benefits of such dual use research, and relevant components of biosecurity policy and the biodefense enterprise (including the acquisition of medical countermeasures) in the United States are discussed. The authors emphasize the need to use such risk/benefit assessments at the onset of research and throughout its development, followed by an assessment for its responsible communication.

Why Gene Editors Like CRISPR/Cas May Be a Game-Changer for Neuroweapons.

This year marks the Eighth Review Conference (RevCon) of the Biological Toxins and Weapons Convention (BWC). At the same time, ongoing international efforts to further and more deeply investigate the brain's complex neuronal circuitry are creating unprecedented capabilities to both understand and control neurological processes of thought, emotion, and behavior. These advances have tremendous promise for human health, but the potential for their misuse has also been noted, with most discussions centering on research and development of agents that are addressed by existing BWC and Chemical Weapons Convention (CWC) proscriptions. In this article, we discuss the dual-use possibilities fostered by employing emergent biotechnologic techniques and tools-specifically, novel gene editors like clustered regular interspaced short palindromic repeats (CRISPR)-to produce neuroweapons. Based on our analyses, we posit the strong likelihood that development of genetically modified or created neurotropic substances will advance apace with other gene-based therapeutics, and we assert that this represents a novel-and realizable-path to creating potential neuroweapons. In light of this, we propose that it will be important to re-address current categorizations of weaponizable tools and substances, so as to better inform and generate tractable policy to enable improved surveillance and governance of novel neuroweapons.

Biosecurity Implications for the Synthesis of Horsepox, an Orthopoxvirus.

This article examines the biosecurity and biodefense implications resulting from the recent creation of horsepox virus, a noncirculating (extinct) species of orthopoxvirus. Here we examine the technical aspects of the horsepox virus synthesis and conclude that orthopox synthesis experiments currently remain technically challenging-and will continue to be so, even once this work is published in the scientific literature. This limits potential misuse by some types of nefarious actors. We also examine the implications of one stated purpose for the recreation of horsepox virus: the development of a smallpox vaccine. If the development is successful, it could take advantage of US government incentives for the priority FDA review of medical countermeasures (MCMs) against biosecurity threats. However, if this case leads to the determination that this incentive is counterproductive for security, the newly created priority review voucher program should be more clearly defined or limited based on need. Limiting the program could have costs that require further consideration, however, as general incentives for biodefense medical countermeasure development are required for MCMs to be available. Finally, while the recreation of horsepox virus was not technically trivial, nor was it cell-free, this experiment was a de facto demonstration of already-assumed scientific capabilities. The ability to recreate horsepox, or smallpox, will remain no matter what policy controls are put into place. It will be impossible to close off all avenues for nefarious misuse of gene synthesis, or misuse of biological materials more broadly. As a result, we advocate for the implementation of policy, regulations, and guidance that will make illicit recreation harder, more burdensome, more detectable, and, thus, more preventable without having sweeping negative consequences for the research enterprise. As part of our biosecurity efforts, we must also encourage and enable scientists to participate actively and to do all they can to safeguard their technical fields from irresponsible or illicit actions.

Options for Synthetic DNA Order Screening, Revisited.

Gene synthesis providers affiliated with the International Gene Synthesis Consortium (IGSC) voluntarily screen double-stranded DNA (dsDNA) synthesis orders over 200 bp to check for matches to regulated pathogens and to screen customers. Questions have been raised, however, about the continuing feasibility and effectiveness of screening. There are technical challenges (e.g., oligonucleotides and tracts of DNA less than 200 bp are not screened) and corporate challenges (e.g., the costs of screening are high, but other costs are dropping, so screening is an increasing portion of operating costs). In this article, we describe tangible actions that should be taken to (i) preserve the effectiveness of DNA order screening as a security tool and (ii) develop additional mechanisms to increase the safety and security of DNA synthesis technologies. Screening is not a perfect solution to DNA synthesis security challenges, but we believe it is still a valuable addition to security, and it can remain effective for some time.

The Department of Defense Chemical and Biological Defense Program: An Enabler of the Third Offset Strategy.

The US Department of Defense (DOD) established programs to defend against chemical and biological weapons 100 years ago because military leaders understood that the operational capability of the US military is diminished when service member health is compromised. These threats to operational readiness can be from an overt attack using chemical and biological threats but may also arise from natural exposures. In the current era of rapidly emerging technologies, adversaries are not only rediscovering chemical and biological weapons; they are also displaying an increased propensity to employ them to cause strategic instability among deployed forces or nations undergoing conflict. The United States's investments in its Chemical and Biological Defense Program (CBDP) can be a critical enabler of the third offset strategy, which is a DOD initiative that seeks to maximize force capability to offset emerging threats. To realize this vision, the CBDP must make fundamental changes in acquiring and employing effective technologies so that enemy use of chemical and biological agents against US assets is no longer a viable option. Maximization of US force health status will provide a strategic advantage over theater opponents more vulnerable to operational degradation from chemical and biological threats.