The Culture of Biosafety, Biosecurity, and Responsible Conduct in the Life Sciences: A Comprehensive Literature Review.

Introduction: Managing biological risks requires an organizational culture that holistically ensures the biosafety, biosecurity, and biocontainment of infectious disease agents and toxins, in addition to conducting science in a responsible manner, complying with relevant laws, regulations, guidelines, and policies, as well as emphasizing norms, values, and beliefs of the entire life sciences profession. Methods: Drawing upon the Federal Experts Security Advisory Panel's (FESAP's) 2014 recommendation to "strengthen a culture that emphasizes biosafety, laboratory biosecurity, and responsible conduct in the life sciences," we undertook a comprehensive literature review of the culture of biosafety, biosecurity, and responsible conduct in the life sciences, including metrics by which to evaluate interventions at the organizational level. Results: We identified 4031 unique citations published from January 2001 to January 2017 by searching the MEDLINE/PubMed, Scopus, Web of Science, and Global Health databases. In addition, a subset of 326 articles was reviewed in full. Discussion: We found that while there were discussions in the literature about specific elements of culture (management systems, leadership and/or personnel behavior, beliefs and attitudes, or principles for guiding decisions and behaviors), there was a general lack of integration of these concepts, as well as limited information about specific indicators or metrics and the effectiveness of training or similar interventions. Conclusion: We concluded that life scientists seeking to foster a culture of biosafety and biosecurity should learn from the substantial literature in analogous areas such as nuclear safety and security culture, high-reliability organizations, and the responsible conduct of research, among others.

Evolution of different dual-use concepts in international and national law and its implications on research ethics and governance.

This paper provides an overview of the various dual-use concepts applied in national and international non-proliferation and anti-terrorism legislation, such as the Biological and Toxin Weapons Convention, the Chemical Weapons Convention and United Nations Security Council Resolution 1540, and national export control legislation and in relevant codes of conduct. While there is a vast literature covering dual-use concepts in particular with regard to life sciences, this is the first paper that incorporates into such discussion the United Nations Security Council Resolution 1540. In addition, recent developments such as the extension of dual-use export control legislation in the area of human rights protection are also identified and reviewed. The discussion of dual-use concepts is hereby undertaken in the context of human- and/or national-security-based approaches to security. This paper discusses four main concepts of dual use as applied today in international and national law: civilian versus military, peaceful versus non-peaceful, legitimate versus illegitimate and benevolent versus malevolent. In addition, the usage of the term to describe positive technology spin-offs between civilian and military applications is also briefly addressed. Attention is also given to the roles civil society and research ethics may play in the governance of dual-use sciences and technologies.

Biosafety, biosecurity and internationally mandated regulatory regimes: compliance mechanisms for education and global health security.

This paper highlights the biosafety and biosecurity training obligations that three international regulatory regimes place upon states parties. The duty to report upon the existence of such provisions as evidence of compliance is discussed in relation to each regime. We argue that such mechanisms can be regarded as building blocks for the development and delivery of complementary biosafety and biosecurity teaching and training materials. We show that such building blocks represent foundations upon which life and associated scientists--through greater awareness of biosecurity concerns--can better fulfil their responsibilities to guard their work from misuse in the future.

Biosafety and biosecurity as essential pillars of international health security and cross-cutting elements of biological nonproliferation.

The critical aspects of biosafety, biosecurity, and biocontainment have been in the spotlight in recent years. There have also been increased international efforts to improve awareness of modern practices and concerns with regard to the safe pursuit of life sciences research, and to optimize current oversight frameworks, thereby resulting in decreased risk of terrorist/malevolent acquisition of deadly pathogens or accidental release of a biological agent, and increased safety of laboratory workers. Our purpose is to highlight how the World Health Organization's (WHO) revised International Health Regulations (IHR[2005]), the Biological Weapons Convention (BWC), and the United Nations Security Council Resolution (UNSCR) 1540 overlap in their requirements with regard to biosafety and biosecurity in order to improve the understanding of practitioners and policymakers and maximize the use of national resources employed to comply with internationally-mandated requirements. The broad range of goals of these international instruments, which are linked by the common thread of biosafety and biosecurity, highlight their significance as essential pillars of international health security and cross-cutting elements of biological nonproliferation. The current efforts of the Republic of Georgia to enhance biosafety and biosecurity in accordance with these international instruments are summarized.

Protecting the health of U.S. military forces in Romania: endemic disease threat considerations.

In 2005 the United States and Romania signed a historic access agreement establishing the first U.S. military bases in the former Soviet bloc country of Romania. The bases will host joint exercises aimed at developing regional military cooperation with forces throughout the entire 92-country USEUCOM area of responsibility (AOR). These forward operating bases (FOBs) or "lily pads" will include the Smârdan Training Range, Babadag Training Range, Mihail Kogalniceanu (MK) Air Base, and Cincu Training Range. They will be under the command of Joint Task Force East (JTF-East), headquartered at the MK Air Base. Here described are the naturally occurring pathogens of clinical significance that exist in the region, including those of known biowarfare/bioterrorism (BW/BT) potential. Notwithstanding the length of deployment for training, proactive clinical and environmental surveillance should be linked to the implementation of adequate Force Health Protection (FHP) measures to minimize the impact these medical threats may have on JTF-East operations.

Mupirocin resistance screening of methicillin-resistant Staphylococcus aureus isolates at Madigan Army Medical Center.

Mupirocin is an antibiotic used for eradication and infection control of methicillin-resistant Staphylococcus aureus (MRSA). Mupirocin binds to the bacterial isoleucyl tRNA synthetase, thus disrupting bacterial protein synthesis. Four hundred nine MRSA clinical isolates collected in 2006 and 2007 at Madigan Army Medical Center were screened for mupirocin resistance by E test and polymerase chain reaction; 7 MRSA isolates (1.7%) were found to be fully resistant to mupirocin (minimum inhibitory concentration [MIC] by E test: > 1,024 microg/mL), 10 isolates (2.4%) had MIC values of 1 to 32 microg/mL, while 392 MRSA isolates (95.9%) had MIC values of < 1 microg/mL. No trend of increased mupirocin resistance was found when compared with subsequent years. These results show that mupirocin remains a valid infection control measure due to its unique mechanism of action and the high susceptibility rate of MRSA isolates. In addition, rapid screening by polymerase chain reaction of MRSA shows promise in assessing the fully resistant mupirocin phenotype.

Genital co-infection with herpes simplex viruses type 1 and 2: comparison of real-time PCR assay and traditional viral isolation methods.

We report the clinical case of a genital outbreak with both Herpes Simplex Type 1 (HSV-1) and Herpes Simplex Type 2 (HSV-2) during pregnancy. Herpes was presumptively identified by clinical presentation of lesion and Tzanck smear while serotypes were identified by cell culture and polymerase chain reaction (PCR). This case report highlights the need for increased surveillance of both serotypes in genital infection of pregnant women for effective disease management and reduced risk of transmission. Increasing rates of genital infection with HSV-1, the possibility of genital co-infection with HSV-1 and HSV-2 and the non-specificity and lack of sensitivity of traditional viral isolation methods may lead to under-diagnosis of genital HSV-1 infections unless molecular diagnostic methods, such as polymerase chain reaction (PCR) are routinely deployed in the clinical setting.

Virus signaling and apoptosis in the central nervous system infection.

Viruses target the central nervous system (CNS) incidentally, due to complications of systemic infection, or specifically, by ascending via the axons of peripheral and cranial nerves. In the CNS, viruses cause acute disease (viz. encephalitis), latent infections or neurodegenerative pathology. Causation of acute disease or immune-mediated pathology, and virus involvement in the etiology of chronic neurodegenerative diseases depends, at least in part, on the ability to commander signaling pathways. Better understanding of these virus-host cell interactions will help identify molecular targets for the development of improved therapeutic strategies.

Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase.

Herpes simplex virus type 1 (HSV-1) triggered apoptosis in hippocampal cultures, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry with antibody specific for the large fragment of activated caspase 3. The levels of phosphorylated (activated) c-Jun N-terminal kinase (JNK) were also increased in HSV-1-infected hippocampal cultures as were the levels of activated c-Jun, its target. JNK activation was involved in HSV-1-induced apoptosis as evidenced by apoptosis inhibition with the JNK inhibitor SP600125. HSV-2 activated the mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) survival pathway and did not trigger apoptosis in hippocampal cultures. The MEK specific inhibitor U0126 inhibited ERK activation and caused a significant increase in the percent TUNEL(+) cells in HSV-2-infected cultures, indicating that the failure of HSV-2 to trigger apoptosis is due to its ability to activate the MEK/ERK survival pathway. JNK was also activated in brain tissues from patients with HSV-associated acute focal encephalitis (HSE) that were positive for HSV-1 antigen. JNK activation correlated with apoptosis, as determined by immunohistochemistry with antibody to activated caspase 3 or cleaved poly (ADP-ribose) polymerase (PARP). The data suggest that HSE has an apoptotic component that may contribute to disease pathogenesis.

Targeting apoptosis in neurological disease using the herpes simplex virus.

Herpes Simplex Viruses type 1 (HSV-1) and 2 (HSV-2) cause central nervous system (CNS) disease ranging from benign aseptic meningitis to fatal encephalitis. In adults, CNS infection with HSV-2 is most often associated with aseptic meningitis while HSV-1 frequently produces severe, focal encephalitis associated with high mortality and morbidity. Recent studies suggested that the distinct neurological outcome of CNS infection with the two viruses may be due to their distinct modulation of apoptotic cell death: HSV-1 triggers neuronal apoptosis, while HSV-2 is neuroprotective. Apoptosis also occurs in the etiology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Down's syndrome, and determines the loss of specific neuronal populations and the decline in cognitive functions. Notwithstanding, the therapy of these disorders may rely on the use of replication-defective HSV-1 vectors to deliver anti-apoptotic transgenes to the CNS. However, the recent discovery of a neuroprotective activity innate to the HSV-2 genome (the ICP10 PK gene) suggests that: i) ICP10 PK may constitute a novel therapeutic approach by targeting both the apoptotic cell death and the cognitive decline, and ii) HSV-2 may be more suitable than HSV-1 as a vector for targeting neuronal disease.

Expression of herpes simplex virus type 2 protein ICP10 PK rescues neurons from apoptosis due to serum deprivation or genetic defects.

Previous studies have shown that the herpes simplex virus type 2 protein kinase ICP10 PK activates the Ras/MEK/MAPK pathway in nonneuronal cells. Here we report that ectopically expressed ICP10 PK has anti-apoptotic activity in various paradigms of neuronal cell death. Neuronally differentiated PC12 cells and primary murine hippocampal cultures transfected with an expression vector for ICP10 PK were protected from cell death resulting from growth factor withdrawal. Protection from apoptosis was also seen in ICP10 PK-transfected hippocampal neurons from the trisomy 16 mouse, a naturally occurring genetic abnormality the human analog of which is Down syndrome. Cells transfected with an expression vector for a mutant that lacks kinase activity were not protected, although it was expressed as well as ICP10 PK. The data indicate that ICP10 PK has a broad anti-apoptotic activity in neuronal cells which depends on a functional PK.