Diane DiEuliis

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 Parkinsons 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, α‐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.

Opinion: Specimen collections should have a much bigger role in infectious disease research and response

When public health officials become aware of the first signs of a disease outbreak, they need to determine a few critical things as quickly as possible. What’s the disease agent? How did it get here? How does it spread and how can it be contained? Has it been seen before? If so, what was the approach and how well did it work?

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 Parkinsons 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 Parkinsons 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 Parkinsons Disease Rating Scale and Movement Disorder Society Unified Parkinsons 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.

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. ABSTRACT 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.

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. ABSTRACT 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.

Erratum for DiEuliis and Gronvall, “A Holistic Assessment of the Risks and Benefits of the Synthesis of Horsepox Virus”

Volume 3, no. 2, e00074-18, 2018, [https://doi.org/10.1128/mSphere.00074-18][1]. Page 6 of the PDF, third full paragraph, line 4: “smallpox” should be “horsepox.” The corrected sentence should read “Given much of this information already exists in the literature, the publication of the

Gene editing using CRISPR/Cas9: implications for dual-use and biosecurity

We have read with interest the recent paper by Kang, et al (2017), addressing clinical and ethical issues related to the safe and responsible use of CRISPR/Cas. The authors provide a number of important considerations about the current capabilities offered by this novel gene-editing tool, including germ line editing in embryos, and potential diverse uses in adult human applications. The authors posit that the tool in of itself does not represent a threat, and that periodic assessment will ensure its responsible use. We agree, but with caveat: namely, that any tool that imparts great capability also involves at least some risk, if not threat, that the power conferred by such capacity can be used to leverage or evoke a variety of ends. This deviation of intent is a principal concern of dual-use research and its applications. Apropos such potential, we provide a complementary view that considers capricious, if not nefarious use of CRISPR to modify biological entities (e.g., microbes, plants, animals, and humans) and/or produce bioagents that pose risk and/or threat to public safety (DiEuliis and Giordano, 2017). We view this as a real, present and certainly near-term future concern, and propose a set of additional considerations that we feel are important security components that will be essential to assessing the use of CRISPR/ Cas. We propose that agreed-upon international, ethical “norms” for human modification for therapeutic purposes are relevant and applicable to any such use of this technique. Kang et al (2017) advocate international standards of ethics, and note efforts made to date by the National Academies (2017) in this regard. We concur with the need for international ethical standards and guidelines, and also note the need for more engaged discourse to define the needs, values and ethical system(s) and principles to be employed (Palchik, Chen, and Giordano, 2017; Lanzilao, Shook, Benedikter, and Giordano, 2013) Furthermore, in recognition of the potential risk/threat posed by genetic modification, we strongly endorse involvement of the Biological Toxins and Weapons Convention (BTWC), in order to ensure inclusion of biosafety and biosecurity communities in any such deliberation and determination of standards. Templates may exist and could be consulted for the development of international norms and best practices through engagement of expertise in technical aspects of emergent technology and security fields (Talinn Manual, NATO, Carnegie Endowment 2017). Expanding the scope and platform of international dialogue can be instrumental to ensuring that all aspects of emerging biotechnological tools and methods are evaluated for their potential to be weaponized or used in other ways that threaten public safety (Gerstein and Giordano, 2017). Importantly, many of the agents modified or designed for therapeutics will have dual uses of concern. A particularly good example are those that are able to modify human biological, cognitive and/or behavioral function(s). A recent study of US public attitudes toward genetic enhancement showed that while the use of CRISPR for therapeutics was viewed as being appropriate, its use for bio-enhancement was regarded as far less acceptable (Scheufele et al., 2017). But public attitudes often do not reflect the needs and values desiderata of the military, and CRISPR and related techniques offer considerable potential to both create novel weaponizable entities, and to modify aspects of human performance in ways that are relevant and meaningful to warfare operations. In considering implications on a global scale, countries could embed these genetic modification programs within academic and/or commercial research and development infrastructures to make dual-use applications difficult to detect (Giordano, 2016). As well, the relative availability of this technique enable increasing use by public research and do-it-yourself (i.e., biohacking) communities which could foster risk incurred by both inadvertent misuse and/or intentional development of products that threaten public safety (Giordano, 2017). These dual use aspects should be included in critical discussions.

Biodata Risks and Synthetic Biology: A Critical Juncture

The tools of synthetic biology and the life sciences are rapidly advancing, as the ability to apply classical engineering to biological systems creates increasing possibilities for innovations in health and medicine, materials science, energy and agriculture. Intrinsic to these capabilities is the mounting ‘digitization of biology’, as the genetic code and its related metadata (including translated proteins, associated functions, herein referred to as “biodata”) are amassed in order to engineer biology for specific purposes. The full spectrum of risks associated with the compilation and use of a wide range of biodata has not been fully identified or comprehensively understood. Further, divergences in traditional attitudes about security among disciplines, namely, biological sciences, engineering, information technology, and data science, complicate discussions on approaches to risk mitigation. To provide a more unified perspective and clarity, we propose that there are unique risks associated with the digitization of biology, represented by overlapping concerns of biosecurity and privacy. We discuss these in three categories of risk: 1) pathogen risks; 2) manufacturing risks, and 3) risks to individual privacy that can allow human harms. Further, we note that there is insufficient address or treatment of these risks in the formulation of ethics, policy and governance. Mitigation of risks will require characterization of all three spheres of risk, acknowledgement that they may require different solutions, and engagement of divergent disciplines and stakeholders to design solutions.

The Role of Scientific Collections in Scientific Preparedness.

Building on the findings and recommendations of the Interagency Working Group on Scientific Collections, Scientific Collections International (SciColl) aims to improve the rapid access to science collections across disciplines within the federal government and globally, between government agencies and private research institutions. SciColl offered a novel opportunity for the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, to explore the value of scientific research collections under the science preparedness initiative and integrate it as a research resource at each stage in the emergence of the infectious diseases cycle. Under the leadership of SciColl’s executive secretariat at the Smithsonian Institution, and with multiple federal and international partners, a workshop during October 2014 fully explored the intersections of the infectious disease cycle and the role scientific collections could play as an evidentiary scientific resource to mitigate risks associated with emerging infectious diseases.