Infection, Genetics and Evolution 29 (2015) 26–34

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Infection, Genetics and Evolution journal homepage: www.elsevier.com/locate/meegid

Discussion

The hidden face of academic researches on classified highly pathogenic microorganisms q Christian A. Devaux Centre d’Etudes d’agents Pathogènes et Biotechnologies pour la Santé-CPBS, UMR5236 CNRS-UM1-UM2, 1919 route de Mende, F-34293 Montpellier cedex 5, Montpellier, France

a r t i c l e

i n f o

Article history: Received 19 September 2014 Received in revised form 27 October 2014 Accepted 29 October 2014 Available online 7 November 2014 Keywords: Highly pathogenic microorganisms Biosafety and biosecurity concerns Biological weapons and bioterrorism threats Psychosis Prohibited experiments Regulation and criminal sanctions

q

a b s t r a c t Highly pathogenic microorganisms and toxins are manipulated in academic laboratories for fundamental research purposes, diagnostics, drugs and vaccines development. Obviously, these infectious pathogens represent a potential risk for human and/or animal health and their accidental or intentional release (biosafety and biosecurity, respectively) is a major concern of governments. In the past decade, several incidents have occurred in laboratories and reported by media causing fear and raising a sense of suspicion against biologists. Some scientists have been ordered by US government to leave their laboratory for long periods of time following the occurrence of an incident involving infectious pathogens; in other cases laboratories have been shut down and universities have been forced to pay fines and incur a long-term ban on funding after gross negligence of biosafety/biosecurity procedures. Measures of criminal sanctions have also been taken to minimize the risk that such incidents can reoccur. As United States and many other countries, France has recently strengthened its legal measures for laboratories’ protection. During the past two decades, France has adopted a series of specific restriction measures to better protect scientific discoveries with a potential economic/social impact and prevent their misuse by ill-intentioned people without affecting the progress of science through fundamental research. French legal regulations concerning scientific discoveries have progressively strengthened since 2001, until the publication in November 2011 of a decree concerning the ‘‘PPST’’ (for ‘‘Protection du Potentiel Scientifique et Technique de la nation’’, the protection of sensitive scientific data). Following the same logic of protection of sensitive scientific researches, regulations were also adopted in an order published in April 2012 concerning the biology and health field. The aim was to define the legal framework that precise the conditions for authorizing microorganisms and toxins experimentation in France; these regulations apply for any operation of production, manufacturing, transportation, import, export, possession, supply, transfer, acquisition and use of highly pathogenic microorganisms and toxins, referred to as ‘‘MOT’’ (for ‘‘MicroOrganismes et Toxines hautement pathogènes’’) by the French law. Finally, laboratories conducting researches on such infectious pathogens are henceforth classified restricted area or ZRR (for ‘‘Zone à Régime Restrictif’’), according an order of July 2012. In terms of economic protection, biosafety and biosecurity, these regulations represent an undeniable progress as compared to the previous condition. However, the competitiveness of research laboratories handling MOTs is likely to suffer the side effects of these severe constraints. For example research teams working on MOTs can be drastically affected both by (i) the indirect costs generated by the security measure to be applied; (ii) the working time devoted to samples recording; (iii) the establishment of traceability and reporting to national security agency ANSM, (iv) the latency period required for staff members being officially authorized to conduct experiments on MOTs; (v) the consequent reduced attractiveness for recruiting new trainees whose work would be significantly hampered by theses administrative constraints; and (vi) the limitations in the exchange of material with external laboratories and collaborators. Importantly, there is a risk that French academic researchers gradually abandon research on MOTs in favor of other projects that are less subject to legal restrictions. This would reduce the acquisition of knowledge in the field of MOTs which, in the long term, could be highly detrimental to the country by increasing its vulnerability to natural epidemics due to pathogenic microorganisms that are classified as MOTs and, by reducing its preparedness against possible bioterrorist attacks that would use such microorganisms. Ó 2014 Elsevier B.V. All rights reserved.

Supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), and the University of Montpellier. E-mail address: [email protected]

http://dx.doi.org/10.1016/j.meegid.2014.10.028 1567-1348/Ó 2014 Elsevier B.V. All rights reserved.

C.A. Devaux / Infection, Genetics and Evolution 29 (2015) 26–34

1. Introduction Scientific progress is required for economic development and improvement of quality of life and health worldwide (Declaration on Science and the use of Scientific knowledge, 1999; Devaux, 2005). In the field of infectious diseases, a better knowledge of re-emerging pathogens, discovery of emerging pathogens and the identification of targets for the development of innovative drugs and vaccines is also a guarantee for improving health in a globalized world where infectious pathogens ignore frontiers (Devaux, 2012). Faced with the globalization of health concerns (i.e., epidemics), it is not surprising that the international community wishes to share information in an open space for scientific exchanges, to improve its reactivity. It is the concept of ‘‘One world one health’’. The ‘‘One Health’’ initiative (News. www.onehealthinitiative.com), is a worldwide strategy for expanding interdisciplinary collaboration and communication in all aspects of health care for humans, animals, and the environment. Biology is certainly the scientific domain where knowledge is evolving the most rapidly. The last two decades have seen a revolution in the fields of genetics and molecular biology. Advances in genomics and proteomics have also opened major perspectives for applications in the field of health. Whole genome sequencing of infectious pathogens has never been so rapidly achieved as today, creating an infinite source of knowledge to fight against epidemics. However, it is conceivable that this new knowledge, easily accessible, also opens up new opportunities for ill-intentioned people (European Commission, 2004, 2007). If examples of misuse or misconduct remain extremely rare, the fears associated with the progresses of scientific knowledge, its applications and its hazardous or dual use are a significant source of concern, anxiety and skepticism among our societies. Whatever the scientific field of research, threats and abuses that could emerge from the use of advanced technologies is clearly expressed by the public and through the media. This also applies to biology and health and in a more acute way to infectious pathogens affecting humans because of their potential use for bioterrorism. Every single week debates are held on the consequences of potential adverse effects of biology, the use of genetically modified organisms, the threat of pandemic infectious diseases, the construction and use of biological weapons by military units or by terrorists (Weiss, 2002; Betti-Cusso, 2003; Bricaire, 2011). Of note, this is also an unlimited source of inspiration for filmmakers with movies such as ‘‘Alert’’ by Wolfgang Petersen in 1995 or ‘‘Contagion’’ by Steven Soderbergh in 2011, which may contribute to spread fear among masses. Sometimes, scientific work evoke a sense of supernatural and the fear of death such as the work of a French and Russian team of scientists whose identified in 2012 several archeological sites in northeastern Siberia and successfully amplified fragments of the virus-causing Variola by performing polymerase-chain-reaction (PCR) on a sample from a 300-year-old mummy (Biagini et al., 2012); this results probably influence our emotions recalling the famous legend of the curse of tutankhamun’s tomb, but do they really represent threat for humanity? The perception related to more or less rational threats, sometimes prevails in political circles and even in the scientific community itself, leading to protective measures that can severely restrict the implementation of research. Indeed, we are currently facing two diametrically opposed points of view: one is to allow the researchers to freely decide which experiments should be performed and to share all the information on infectious pathogens as soon as they are available to facilitate the development of drugs and vaccines; the other is to control laboratories, to prohibit risky experiments and to hold back information in order to avoid any possible dual use. In democratic societies, there are legitimate

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questions about handling highly pathogenic microorganisms which cannot remain unanswered even if scientific knowledge sometimes involves considerations such as the concept of doubts: What risk must be taken to study infectious pathogens and be prepared to prevent future outbreaks? At which stage should experiments be prohibited because considered too risky? How to be prepared against malicious action when you are in charge of a laboratory handling highly pathogenic microorganisms? At which level do security measures and controls become so heavy, that it turns out impossible to work efficiently? And, more importantly, who decides whether a given pathogen represents a real threat to society? This article revisits some incidents that led to the accidental or deliberate release of highly pathogenic microorganisms, the societal demand for strongly limiting the risks that such serious events can reoccur, the biosafety and biosecurity measures that have been taken at the international level – and particularly in France – to avoid spread of infectious agents or release of sensitive scientific information that might aid bioterrorists, and the impact of such measures on the research activity of laboratories working on highly pathogenic microorganisms. 2. Societal perception of biological research since September 11th 2001 After the terrorist attacks of September 11th 2001 in New York and Washington DC by Al-Qaida and the mailing of Bacillus anthracis (anthrax)-containing letters via the US Postal Service, the fear of dual use of pathogens for bioterrorism purposes has further increased the mistrust against the laboratories handling pathogens on a daily basis for research. This is certainly due to deficiencies and dysfunctions that affect communication between scientists and the media, but also involves politicians and citizens. In June 2002, US President George W. Bush signed a law which defined a list of agents considered as severe bioterrorism threats and promoted the BioShield project on July 21, 2004 whose aim was to prepare countermeasures against bioterrorist attacks (BioShield project, 2004). Finally, in December 2006, the US congress created the Biomedical Advanced Research and Development Authority (BARDA) (BARDA, 2006). Besides the reactions of the security authorities of all democratic nations which decided to implement countermeasures to avoid, as much as possible, the recurrence of such terrorist acts, it is important to note that on January 9, 2003, during the plenary meeting of the National Academy of Sciences, the chairman Ronald Atlas addressed the issue of responsibility of the scientist faced with the question of bioterrorism and censorship of certain articles on pathogens (Atlas, 2003). This was of course a necessary and reasonable initiative. However, it was mainly dictated by the consequences of the September 11 terrorist attack and the worldwide fear of bioterrorism. Moreover, this was mainly a means to expose to the media the known problem of possible dual use of research on pathogens; indeed, the international Convention on Biological Weapons submitted by the British government was opened for signature on April 10, 1972, and was enforced on March 26, 1975 (UNOADA, 1975). Examples of deliberate use of pathogens on civilian populations during war or accidental spread of a pathogen well before 1972 are countless! As historic example of bio warfare is the use of corpses of animals and humans who died of plague catapulted over the walls of the town of Caffa (a Genoese possession at the time, currently in Ukraine) during the siege of 1346 by an army of Mongol warriors; in contrast, the misconduct of a ship captain who, for economic reasons, voluntarily ignored the health recommendations of quarantine resulted in the plague of Marseille in 1720 (Devaux, 2013).

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When we compare infectious outbreaks occurring nowadays to what happened during several centuries of history, there is not much difference. The only new important factor since the early 2000 is the extraordinary recent advances in genetics, molecular biology, genomics, proteomics and biotechnologies that could change biologists’ capacities to manipulate and control pathogens. Today, pathogens can be identified and their genome fully sequenced quite rapidly. Once characterized and published, the sequence of infectious pathogens are immediately deposited in an international DNA/RNA database and may be freely used for research purposes by any scientist who wants to compare sequences, or define sequences of interest (i.e., a virulence gene). Since there are virtually no limits on the ability of researchers to reconstruct pathogens from available genome sequencing data, obvious concerns arise about the possible misuse of these data by ill-intentioned people trained in biology. However, it is more conceivable that a terrorist group would steal, or obtain with complicity, a highly pathogenic strain rather than trying to reconstruct the pathogen. 3. Increased societal demand for limiting spread of scientific information After the attacks of September 11, 2001, the strong societal demand for increased security against bioterrorism could not be ignored. Concomitantly, risky laboratory experiments performed on Poxviruses contributed to increase fear among the scientific community (Jackson et al., 2001). Similarly, a researcher team in Pittsburg reported the identification of key proteins in smallpox which contribute to the virulence of the virus. These results opened the possibility to genetically modify virulence of smallpox (Rosengard et al., 2002). During the same period, several other papers were published, reporting sensitive data on viruses such as HIV and Ebola. A team at the University of Pennsylvania developed a hybrid virus between HIV and Ebola; this new virus carrying the surface proteins of Ebola was capable of infecting lung tissue, potentially enabling aerosol delivery (Kobinger et al., 2001). A group in Europe reported creation of a DNA-based system allowing performing reverse genetics on Ebola virus with the possibility of reconstructing replicative Ebola virus from DNA in the absence of viral source (Volchkov et al., 2001). Publication of such papers, considered as valuable information that might aid bioterrorists, raised questions about openly publishing sensitive information (Müllbacher and Lobigs, 2001; Boyce, 2002; Singh and Singer, 2002; Malakoff, 2003). Editors of international journals debated about the possibility of prohibiting sensitive publications to prevent misuse of information by ill-intentioned people. By the voice of John Marburger, head of the Control Office of Science and Technology (OSTP office depending of the White House), the US administration stated that research should primarily remain ‘‘unclassified’’, even though the official position of the Department of Homeland security headed by Tom Ridge stated that: ‘‘scientists were clearly encouraged to pay more attention to the concept of security in the context of peer review of scientific articles’’. Questioned by BIOTECH.INFO on the subject as part of my duties at the direction of the CNRS life science department, I responded that if there had to be a control, it should occur by a legal framework of measures aimed at controlling the laboratories working on highly pathogenic microorganisms, but not by acting on the dissemination of knowledge (Devaux, 2003a). By saying that, I was taking into account both the ability of anticipation and the self-censorship of scientists whom I was responsible. I was also afraid that access to basic US databases such as GenBank (GenBank. www.ncbi.nlm.nih.gov/genbank/), could be denied to the international community for security reasons. It is worth noting that during the year 2003, of the 6000–8000 papers

published in microbiology journals, only 2% concerned highly pathogenic microorganisms. However, I had clearly been too naïve about my evaluation of the self-censorship ability of some researchers worldwide who wanted to make the audience ratings. If it was ever necessary to add psychosis to an already complex debate, Craig Venter announced in 2003 (Smith et al., 2003), that his team had managed to recreate a synthetic virus (a bacteriophage) from synthetic oligonucleotides in 14 days only. For this purpose he was inspired by a method published earlier in Science by Eckard Wimmer’s team at Stony Brook University, NY, who created infectious Poliovirus from artificially engineered sequences (Cello et al., 2002). A few months later, an American team expert in influenza viruses, transferred several genes of the Spanish flu virus (H1N1 influenza virus), including the H1 hemagglutinin and the N1 neuraminidase, into the genome of a virus affecting mice (Tumpey et al., 2004). The recombinant virus thus obtained turned to be lethal for rodents. According to the authors of this work, the ability of the recombinant virus to cause lethal disease in mice without prior adaptation to this new host was quite remarkable, given that the genes of the Spanish flu virus derives directly from sequences of human origin. Next, a consortium of Japanese, Americans and Canadians researchers conducted the same kind of experiment by engineering a human influenza virus that contained the genes for hemagglutinin and neuraminidase of the Spanish flu virus (Kobassa et al., 2004). While the original human influenza virus was mild in mice, the hybrid virus was highly virulent. These papers triggered global discussion regarding the benefits and risks of conducting such studies. Obviously these studies should be restricted to laboratories that have the appropriate biosafety conditions for conducting such experiments, and should be run under specific policies of biosafety and biosecurity. The question of publishing crucial scientific information that could be used by bioterrorists to produce highly pathogenic strains was also addressed. In 2011, two studies (Herfts et al., 2012; Imai et al., 2012) funded by the National Institutes of Health (NIH, USA) examined mammalian transmissibility of highly pathogenic avian influenza H5N1, and identified viruses mutations enabling H5N1 to spread efficiently among mammals and possibly humans. The generation of these strains raised biosafety and biosecurity concerns. As a result, members of the influenza research community initiated a one year voluntary moratorium on gain-of-function studies (Patterson et al., 2013). 4. How to control laboratories and prevent the risk of accidental or intentional release of highly infectious pathogens Controlling the risk of inadvertent or deliberate spread of infectious pathogens from academic laboratories obviously requires control of these laboratories but the safest way of globally controlling the risks resides in more rapid outbreak detection and reporting (Teich et al., 2002; Lober et al., 2002). Many structures have been created that address this issue, such as the World Health Organization (WHO, Geneva), the Center for Diseases Control and prevention (CDC, Atlanta), the European CDC, among others. An integrated global alert and response system for emerging infectious disease (EID) has been set up by WHO (Russel et al., 2011). Another aspect of the problem concerned the storage and transportation of dual goods related to infectious pathogens. Since 1984, an agreement between several states led to the creation of the Australia Group whose aim was to reduce the risk of promoting chemical and biological weapon proliferation (Australia Group. www.australiagroup.net). Fifteen states were involved in 1985, 33 states in 2006. The main objective of the Australia Group is to ensure that, through the imposition of control regimes on precursor of chemical-weapons and many biological agents, the exports do not contribute to the proliferation without harming normal trade. When

C.A. Devaux / Infection, Genetics and Evolution 29 (2015) 26–34

strong suspicion hangs over an export of goods not listed, it is still possible to refuse it on the basis of a clause called ‘‘catch-all’’. Coming back to 2001, the debate was focused on one side on the fact that some biology laboratories were engaged in high risk experiments involving infectious pathogens (a form of sorcerer’s apprentice researcher), and on the other side on the fact that terrorists might acquire weapons of mass destruction simply by consulting publications from scientists irresponsible enough to provide, with free access, all the details necessary for an average biologist to produce a bio-weapon (fear of forming a trainee directly or indirectly linked to a terrorist organization). In this context, simple measures of good laboratory practice may contribute to limit the risk of misuse (Fig. 1). To express my point of view as responsible for biological research at the French CNRS, I wrote an editorial in 2003 in the ‘‘Journal du CNRS’’ (Devaux, 2003b). My first remark was to avoid giving into the psychosis that was largely fueled by media and politicians: (i) civil researchers are not, a priori, bio-terrorists nor activists; (ii) civil researchers have an ethical conduct and are generally capable of self-censorship; (iii) the civil researchers who work on pathogens have not in mind the development of biological weapons; usually their objective is to improve health worldwide by studying infectious pathogens; (iv) civil researchers working on genetically modified organisms must declare their projects to a national classification committee in charge of assessing the potential associated risks and allow (or not) experimentation; and (v) contrary to experts in the field of defense, the academic researchers should reasonably be able to work and publish their work (because it is on these bases that their work is evaluated and ranked). My second remark was that if censorship must exist, it cannot meet a unilateral position of some publishers (even if the most powerful editors in terms of worldwide distribution of articles were present), because scientists will always find an editor willing to publish their work, if they do not anticipate risks by self-censorship. Indeed, the issue becomes political and policy is to define the rules. In my opinion, the question of biosafety was probably more a problem of organization at the international level for setting-up a control on laboratories listed as allowed to handle such infectious pathogens, trying to control staff, trainees and visitors, and to avoid clandestine experiments (as this has been practiced for a long time by committees in charge of controlling nuclear research). I was suggesting that the different

Absence of dual use risk

Project using infecous pathogens concept and design by PI Dual use potenal

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states, under recommendations of experts in the field, should define a list of ‘‘allowed’’ and ‘‘forbidden’’ infectious pathogens, and evaluate the risk that, even under such ‘‘secure’’ conditions, a terrorist organization could divert products or information in order to have a dangerous pathogen at its disposal. During the past few years, international biosecurity measures have been set-up by most countries hosting BSL-3 and BSL-4 facilities (biosafety laboratories-levels 3 and 4). Working groups have also classified infectious pathogens by risk level. Yet, the international lack of consensus on classified pathogens remains surprising. 5. How to work with infectious pathogens in France today Once a laboratory chooses to work with BSL-3 microorganisms, the laboratory director needs to obtain a license for the contained use of genetically modified organisms. This license is obtained following an evaluation by the French High Council of Biotechnologies. In addition, the application must be registered by the police and it is valid for a period of 5 years. To the best of their possibilities, French laboratories working with infectious pathogens should make sure that they are not training scientists who could use this experience in connection with terrorist movements. Before 2011, French biology laboratories working with infectious pathogens were called ERR (for ‘‘Etablissement à Régime Restrictif’’, establishment under restrictive measures) the principle of which was to protect the laboratories under biosecurity measures however the regulation did not protect the knowledge and know-how. This has recently changed. Indeed, since 2011, newly established safety rules are aiming at avoiding that important scientific knowledge may be released to the public without discrimination (Decree number 1425-2011 of November 2, 2011) (French Decree of November 2, 2011). If on one hand it is fairly easy to protect sensitive or classified information from trainees who originate from countries at risk for terrorism, it is much less obvious to ensure full protection of the data. For example, today a French laboratory cannot work without the financial support of national research agencies such as the ANR (‘‘Agence Nationale de Recherche’’) and/or European funds. Yet, in both cases, the funding agencies require that all data (including sensitive ones), originating from the funding project, must be sent to international referees for evaluation. More importantly, when laboratories are evaluated by

Funding applicaon and award process. Instuonal approval

Work conducted in accordance with biosafety

Public disseminaon (publicaons; other research products)

Periodic reassessement of dual use potenal Inial evaluaon for dual use according to the Fink’ categories

Risk assessment (instuonal review)

Progression of dual use research ( risk management: biosafety and biosecurity)

Work conducted in accordance with risk management

Responsible communicaon

Fig. 1. Good laboratory practice to limit the risk of misuse of result/product derived from a research project in the field of infectious pathogens. This cartoon suggests how to screen project using an initial evaluation of dual use. Depending on the evaluation the project enters a normal procedure of work or a specific procedure adapted to dual use potential.

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the AERES (Agence d’Evaluation de la Recherche et de l’Enseignement Supérieur) every 4 or 5 years, the most important results of the laboratory should be presented to a committee of international experts. All discussions leading to the evaluation of data, strengths and weakness of a research team are published in a public report that everyone, including ill-intentioned persons, can access on the website of the agency. Finally, laboratories themselves provide very sensitive information about their skills and equipment in order to attract top international researchers in their teams. But how to do differently if the objective is to obtain financial support for running experiments, be well evaluated at the national and international levels, and attract top international researchers in his/her laboratory? The French law establishes a series of measures related to dualuse technologies (Fig. 2). Dual-use goods (EC 428/2009; May 5th, 2009) (European Union, 2009) are not prohibited products and represent technologies normally used for civilian purposes which may have potential military or terrorism applications. The rule that apply to dual use goods is to ensure protection of workers and the environment from a technical biohazard, and prevent risks of facing a threat of diversion for malicious use. Consequently, the law requires secure possession and handling of pathogens, controlled premises, and traceability of samples (Transport; arrival; sampling; storage; experimentation; destination; etc.) (Decree n 1192/2001 of December 13, 2001) (French Decree of December 13, 2001). Experiments that aim at: (i) increasing the pathogenicity or virulence of an infectious pathogens; (ii) provide a means of pathogen resistance to treatment; (iii) increase the stability of the pathogen in the environment or improve its dispersion; (iv) construction of an infectious agent with unknown properties; (v) the bypass of diagnostic means; (vi) the construction of an agent reducing immunity, are all forbidden by the law on dual-use. These restrictions meet the recommendation of the Fink report (National Research Council, 2004) which defines seven classes of experiments that, accordingly, would require the ‘‘review and discussion by informed members of the scientific and medical community before they are undertaken or, if carried out, before they are published in full detail.’’ These consist of experiments that: (i) would demonstrate how to render a vaccine ineffective; (ii) would

Funconing of the French State

French Constuon

Parliament (Naonal Assembly + Senate)

Law

confer resistance to therapeutically useful antibiotics or antiviral agents; (iii) would enhance the virulence of a pathogen or render a non-pathogen virulent; (iv) would increase transmissibility of a pathogen; (v) would alter the host range of a pathogen; (vi) would enable the evasion from diagnostic/detection modalities; and (vii) would enable the weaponization of a biological agent or toxin.

6. The specific problem of handling infectious pathogens classified ‘‘MOTs’’ Pathogens classified as MOTs (Decree 736-2010 of June 30, 2010) (French Decree of June 30, 2010), are subject to more drastic measures concerning their acquisition and handling. These measures were enforced in French academic laboratories from February 2012; they are related to the import, export, storage, transfer, acquisition and transport of certain microorganisms and toxins. These measures are established under the control of ANSM (for ‘‘Agence Nationale de Sécurité du Médicament et des produits de santé’’, the French equivalent of the American Food and Drug Administration) The list of pathogens classified as MOT was updated in the order of April 30, 2012 (French Order of April 30, 2012). Better practices on biosafety and biosecurity related to MOT were announced on January 23, 2013 and amended on June 11, 2013. Instructions concern the head of the laboratory, the holder of the authorization, the persons authorized to handle the MOT. The holder of the authorization and persons authorized to handle the MOT are registered. Non-compliance with the law can be punished by an important fine and three years of incarceration. The rules controlling the use of MOT samples are extremely time-consuming with a potential associated risk of impacting, in the long term, the competitiveness and efficiency of research teams working on such pathogens. Every year, the ANSM demands to report on the inventory and traceability of samples. A precise description of the containment measures must be submitted to ANSM and to the police and the inventory of available sample is performed under the police control (Order of June 30, 2010) (French Order of June 30, 2010). Research teams must also comply

Decree #2001-1192 (December 13, 2001) Decree #2010-292 (March 18, 2010) about the concept of Dual Use Researches Decree #2010-736 (June 30, 2010) about « MOT» classified microorganisms Decree #2011-1425 (November 2, 2011) about «PPST» protecon of scienfic data

Law n°2008-595 (June 25, 2008) about genecally modified microorganisms

Decree

Implementaon of the law

Order

Administrave decision from a Ministry Order of July 16, 2007, about biosafety measures Order of July 3, 2012 about the ZRR classificaon

Circular

Laboratory Management (field of health and infecous diseases)

Service instrucon Circular #3415 of November 7, 2012, about protecon of scienfic data

Fig. 2. Structuration of the French legal norms and their impact on laboratories working in the field of health and infectious diseases and handling infectious pathogens. On the left, is shown a cartoon of the structuration of the French legal norms. Examples of law, decree, order, and circular that have a direct impact on the laboratory management for laboratories handling infectious pathogens are given on the right part of the figure.

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with frequent monitoring of ANSM inspectors and these can stop the research activities of the laboratory staff for several days in order to double check the experimental laboratory procedures. At the end of every inspection, the inspectors compiles a report which can include, if applicable, ‘‘corrective measures’’ that may require several days or weeks of work to comply with. It is likely that in line with international rules on biosecurity and the European norm CEN CWA 15793-2008 of February 2008 on ‘‘Laboratory bio-risk management standard’’ (European Union, 2008), the designation of a biosafety officer and a biosecurity officer becomes mandatory for laboratories handling MOT. Of course, this will again affect academic laboratories in terms of wage costs and operating constraints. To date, the French regulations already impose the appointment of a biosafety officer called ‘‘manager du risque’’ (Order of January 23, 2013) (French Order of January 23, 2013).

7. Working into a French ZRR laboratory French laboratories currently conducting researches on MOT pathogens are subject to ZRR (for ‘‘Zone à Régime Restrictif; restricted access area) classification (Fig. 3). The decision to classify (or not) a laboratory as a ZRR (Order of July 3, 2012) (French Order of July 3, 2012), is taken after a risk analysis based on a risk scale ranking from R1 to R4 which takes into account: (i) the risk of violation of economic interests (R1); (ii) the risk of abuses of defense capabilities (R2); (iii) the risk of proliferation (R3); and, (iv) the risk of terrorism (R4). Under institutional supervision, the director of such ZRR laboratories (which may be subject to criminal sanction for not complying with the law and instructions), must set up the monitoring of any person who wishes to join a research team and therefore work inside his/her research unit. Any person expected to work in a ZRR-ranked laboratory is subjected to police investigation requiring an average time of investigation of one week to one month until approval and is recorded using the software ASSAV (for ‘‘Application de suivi des stages, accueils et Scienfic sector without risk according to decree #2011-1425 R=0 (i.e, Humanies and social sciences)

visites’’ a follow-up of approved staff members, trainees and visitors) (Fig. 4). Authorized persons receive a badge set which defines access to certain areas of the laboratory. This significantly complicates the movement of people within the laboratory, reduces scientific exchanges with neighboring laboratories, requires duplication of equipment, and, eventually, reduces the attractiveness for national and international researchers more likely to join laboratories that are not subject to these rules. In terms of biosecurity these regulations provide undeniable progress, but in terms of competitiveness and attractiveness which are important indicators of the international visibility of a laboratory, the effect is quite negative. In addition, these constraints generate indirect costs for the related security measures (card readers on access; video surveillance; fingerprint recognition for access to BSL-3 facilities; salary of staff members who spend time for controlling that such measures are appropriately used; etc.). These security constraints do not only apply to scientific staff, they affect all persons who are linked to the laboratory for various reasons. All staff in charge of maintaining premises and equipment must also undergo the same morality investigation screening before being allowed to work in the laboratory. Visiting scientists and collaborators, which are temporarily involved in the laboratory activities, must be constantly accompanied by authorized staff members. Consequently, it mobilizes staff on activities other than research work. In addition, the supplementary capacities required to supply the computer services in a ZRR laboratory, are also well above that of conventional biology laboratory, due to the obligation for the staff to ensure the information systems security. The repository which governs the protection of information systems contains no less than 66 different points for which the director of a ZRR laboratory must comply with the French Law.

8. Discussion Remarkable advances in biology are foresting the hope of eradicating a number of infectious diseases in the near future. Differen-

Scienfic sector with risk according to decree #2011-1425 R>0 (i.e., Biology and Health)

R=1 risk of violaon of economical interest R=2; R=3; R=4: risk of abuses of defense capabilies; risk of proliferaon; risk of terrorism (i.e; infecous diseases laboratory)

Risks evaluaon

ZRR

Controled access

No restricon

Restricted access (i.e., BSL3 facility for MOT)

Restricted access

Staff members:

Registered

Registered/requires authorizaon by FSD/HFSD

Trainees:

Registered

Registered/requires authorizaon by FSD/HFSD

Visitors:

Registered

Registered/ requires authorizaon by the Laboratory director

Fig. 3. The French classification (unprotected/protected) of researches. Humanities and Social Sciences are not classified researches. Biology, medicine and health belong to protected area with respect to decree of June 30, 2010. Laboratory of this field are eligible as ‘‘ZRR’’ restricted access area if risk R > 0, and it is mandatory if R = 3 or R = 4. Within ZRR, some area can receive a reinforced protection is necessary (i.e., Biology Safety Laboratory Level 3, BSL3). Laboratory handling classified MOT (microorganisms and toxins), fall under the ZRR category.

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Decision within 2 months

Ministry level

Last level validaon

Validaon by the HFSD security advisor Accepted/Refused

2nd level validaon Decision within 2 weeks

Instuonal level Validaon by the FSD security advisor

Laboratory level

Decision within 1 week

Validaon by the director

New staff member

A S S A V

Accepted/Refused

1st level validaon Authorizaon requested

Registraon of personal informaon

Visitor

Trainee Fig. 4. Selection process designed at authorizing staff members, trainees and visitors to enter a ZRR restricted research area. The request for authorization is made using the ASSAV computer system and requires several steps of approval before validation of candidates to permanent access to ‘‘ZRR’’ restricted access area can occur. The validation process requires the advice of the security advisor of the institution (the ‘‘FSD’’, for ‘‘Fonctionnaire de sécurité et defense’’, Officer of security and defense) and the security advisor of the Ministry of research (the ‘‘HFSD’’ ‘‘Haut Fonctionnaire de sécurité et defense’’), Approval for visitors only requires registration into ASSAV followed by a decision of the laboratory director.

tially from what happens in nuclear physics for example, biologists had to grow accustomed to work with national security agencies. Yet, recent events such as the publication of sensitive data, bioterrorist attacks, and incidents in laboratories, have alerted the scientific community on the need of new regulations for controlling access to dangerous pathogens, for guarding against the inadvertent or deliberate production of new infectious agents, and for controlling the divulgation of sensitive information subject to dualuse. If on one hand these regulations are clearly required, it is worth noting that for decades, before the enforcement of new regulations, all specialists in the field of infectious diseases have applied procedures aiming at insuring traceability of samples, securing handling, and avoiding any contamination of staff and environment. All scientists handling infectious pathogens are aware that experiments involving infectious pathogens are subject to more constraints with respect to other biological models and duly apply all the biosafety and biosecurity measures required. This, however, has an impact on the efficiency and visibility of research teams handling pathogens, which is even more evident in the case of MOTs. It is obvious that the main objective of academic scientists is discovery. In the same way to their colleagues in other field of biology, virologists and bacteriologists should discover ways to fight diseases (infectious diseases). Similar to other scientists they need to publish quickly and at the highest level possible. If handling of unclassified infectious pathogens is much less difficult than manipulating classified pathogens, this reason might sometimes prevail over the interests of studying MOT. Unless special incentives are taken, a drastic reduction in the number of academic laboratories interested in studies of MOTs and a shift to other microbiological models of unclassified pathogens is to be expected. On the long term this can become a real problem in terms of loss of knowledge in the field of infectious diseases. Yet, where is the boundary between rational and irrational approaches for handling classified pathogens? It is worth noting that sometimes a pathogen classified MOT in France can be studied without any biosecurity constraints in another European country as it is the case for the bacterium Brucella; MOT classification yields additional difficulties when animal experiments are planned with these pathogens, as the corresponding A-3-facility (for ‘‘Animal facility-level 3’’) and the people using

it, are then subject to the same legal MOT obligations as for BSL-3 laboratories. The debate on biomedical research at age of terrorism is far from being closed. Examples from the US are quite instructive on this subject. Screening of biologists by the FBI is required in the US as it is in France by the national security services. The US government intrusion in laboratory is currently so strong that it has conducted researchers to prefer to destroy their stocks of infectious agents rather than to comply with the screening procedures of the security services. In 2005, the US government fined Boston University in Massachusetts $8100 after workers there contracted tularemia, an infectious disease caused by a pathogen considered as potential bioweapon (Callaway, 2007). In February 2006, a researcher working at the Texas A&M University biodefense laboratory was infected with Brucella after aerosol chamber mishap and the school did not immediately notify the CDC as required by federal law (under the US federal law, such incidents are supposed to be reported within seven days to the CDC). Other researchers from the same laboratory were exposed to Coxiella burnetti. Representatives from the CDC’s Select Agents and Toxins Division inspected the laboratory and, ordered the research team to stop its work on all pathogens until further notice. Texas A&M University could face fines of up to $750,000, and a long-term ban on funding for similar research (News. www.cidrap.umn.edu). In 2010, researchers at University of Wisconsin conducted what was considered unauthorized research on a bioterrorism agent; the scientists developed antibiotic-resistant variants of Brucella and tested them on mice; the University of Wisconsin was fined $40,000 by the National Institutes of Health, and the principal investigator was ordered to stay out of the laboratory for five years (News. Homeland security agency. www.homelandsecuritynewswire.com). Of course, everyone has to admit that stringent measures of biosafety and biosecurity must exist to minimize the risks of pathogen release/spread, even if they will never totally avoid human error or accident. This can also be illustrated by the incredible lost by the Galveston National Laboratory BSL-4 facility (University of Texas), of five vials containing Guanarito virus. This incident which occurred in March 2013, was revealed by media (News. http://abcnews.go.com). Guanarito is a deadly Venezuelan virus which can causes hemorrhagic fever in infected patients. In

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June 2014, almost 80 scientists and staff members at the CDC Atlanta were accidentally exposed to live anthrax (News. http:// articles.mercola.com). Another incident occurred in July 2014 at the NIH, Bethesda; where six freeze-dried vials of the virus that causes smallpox were found in a NIH building that was unequipped and unapproved to handle BSL-4 pathogen (News. http://abcnews.go.com). Smallpox virus is only permitted in two laboratories in the world: the CDC Atlanta (USA) and the Vector Institute in Novosibirsk (Russia). Recently, the US CDC’s bioterrorism and flu laboratory was shut down after having shipped by mistake to another laboratory a deadly H5N1 flu strain, with a double risk during transportation and for other scientists which received the strain (News. Sawyer, 2014. ABC World News). Obviously, there is not only in the USA that incidents with infectious pathogens are revealed. For example, in 1979, 94 Russians were exposed to anthrax through an accidental atmospheric release in Sverdlovsk (Siberia), and 64 of them died (Wilkening, 2006). Recently, after a routine full inventory, the Pasteur Institute in Paris (France) announced in April 2014 the lost over the last 6 months of hundreds of vials containing fragments of the SRAS virus (News. http://ekladata.com). This incident triggered a thorough investigation by the ANSM in the laboratories that were supposed to securely store the samples. If the numerous international examples of known incidents that have occurred in recent years are proof that biosafety and biosecurity controls are necessary, the fact that American scientists have decided to destroy their stocks of infectious agents – material which sometimes represents decades of work –, to avoid problems with the security services, also demonstrate that it remains quite difficult to work in such a context of permanent suspicion and the risk to be considered as a criminal. Last August, a former researcher from the Canadian Food Inspection Agency (CFIA) has decided of pleading guilty for fraudulently attempting to export dangerous pathogens to China. Indeed, this researcher had been arrested at the Ottawa airport two years ago while he was in possession of several vials containing Brucella; he was immediately charged by the federal police and risks up to ten years of imprisonment (News. http://french.ruvr.ru). Rather than filling burdensome administrative declarations and even being at risk for criminal sanctions if not complying with the law, some French researchers are beginning to think of infectious pathogen stockpile destruction. However, the destruction of sensitive strains is a significant loss of possible source of knowledge for the future. Altogether, these constraints could lead to the fact that we do no longer prepare the next generation of young infectiologists trained to the study of such pathogens (and this might represent a risk to public health), and that academic laboratories will strongly reduce their stocks of infectious pathogens or even abandon their objective to work on sensitive infectious pathogens. Another possibility will be that MOTs will become a model of research only for scientific staff in military laboratories, because these researchers are not under the pressure of ‘‘publish or perish’’ and could keep their data confidential. However, as a consequence of economic difficulties that impact spending in all sectors funded by the French government, the military research is submitted to funding restrictions; military laboratories’ leaders should only consider the health of soldiers as their research priority. Since infectious diseases affecting sick soldiers are rarely related to MOTs, it is very likely that research on MOTs will remain neglected with respect to other pathogenic microorganism causing epidemics among the troops. In absence of additional funding and incentives, the legal constraints applied to laboratories handling MOTs, could result in a lack of preparedness for the country once facing clinical cases and a decrease of people protection. . .indeed the contrary of the objective of the law. Recently, some French research labor unions called for the withdrawal of the ZRR device (French Labor union news, 2014a,b.

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SNPREES-FO; SNCS-FSU). As often, ideological reactions are disproportionate and not really adapted to the situation. Indeed, we must find a balance between the need to protect the staff against human errors, to protect research facilities against misuse by persons potentially linked to terrorist activities, and the ability to conduct experiments in the framework of regulations that can realistically be applied to academic laboratories. This requires to set-up protection rules that avoid the creation of barriers preventing the academic research on MOT to remain competitive. Currently, most French laboratories involved in infectious diseases research complain about the administrative constraints that are imposed as part of their duty on infectious pathogens specially if there are handling MOT. It is difficult to predict whether it will be possible to find the right balance between the need to control the work performed in the laboratories handling infectious pathogens and the ability to maintain the competitiveness of these academic laboratories at an acceptable level preventing them from abandoning this field of research. Generalized restriction of research with potential applications in bioterrorism and on re-emerging infectious diseases, could greatly hinder efforts to develop medical countermeasures to bioterrorism, including therapeutics and vaccines. Availability of such treatments could also be lacking in the event of the re-emergence of an infectious pathogen strictly for environmental reasons.

Author contributions Christian A. Devaux solely contributed to this paper.

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The hidden face of academic researches on classified highly pathogenic microorganisms.

Highly pathogenic microorganisms and toxins are manipulated in academic laboratories for fundamental research purposes, diagnostics, drugs and vaccine...
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