In the March/April 2010 issue of GeneWatch, Beth Willis of Frederick Maryland stated:
We also know that high containment biodefense lab proliferation is a national policy problem that has to be addressed in Washington.
As the director of a Biosafety Level Three (BSL3) laboratory at a large academic medical center, I thought it might be useful to GeneWatch readers to hear some comments from the inside of one of those laboratories. I will describe our efforts to build a safe and collaborative environment in our containment laboratory, and the impact of increased regulations following the anthrax attacks and PATRIOT Act on our procedures.
Our respiratory infectious agent program was begun in 1999 with the construction of new Biosafety Level three containment space within existing laboratory space in our research building as part of the Center for Emerging and Re-emerging Pathogens (CERP) at UMDNJ-NJMS. The laboratory was designed for the study of the causative agents of tuberculosis and HIV-AIDS. The initial application was submitted before the year 2001, which was followed by unprecedented regulatory oversight. However, we had formed close ties and collaborations with the Emergency Response and Biosafety personnel at the university during the process of designing the lab.
Soon after opening in 1999, we received additional funding for work with bacterial and viral agents, some of which were considered potential biological weapons agents; such microbes are now termed "Select Agents." Consulting with our colleagues in safety and security, we instituted new procedures in the form of training programs and safety procedures. For example, we felt it was essential for safety reasons that two people be present at all times during work with dangerous pathogens such as Bacillus anthracis (anthrax) and Yersinia pestis (plague): we recognized that people can be tired, be distracted, make mistakes, and that having two people carrying out the experiments would serve as a internal check for errors and to prevent accidents. This "two-person rule" was later required to ensure security of the reagents, discussed below.
During the months immediately following the 2001 anthrax attacks, the scientific community saw a gradual increase in regulations and oversight for Select Agent work, mostly in the form of increased security and access control. The impact of these new rules was discussed in Dias et al, 2010, and also reviewed by Andrew Thibedeau in the March/April 2010 issue of GeneWatch. Further debate of the impact and efficacy of these regulations is outside the scope of this article. Note however that there are few differences in procedures between working with TB and anthrax in our laboratory.
Traditional lab safety and bloodborne pathogen training, mandated by the Occupational Safety and Health Association (OSHA), is provided to all laboratory workers. OSHA has identified within its array of standards for general industry those with specific application to laboratories, such as chemical safety/"right-to-know", hazardous waste and regulated medical waste handling, fire safety, personal protective equipment, and emergency procedures. The formats for trainings in many institutions are slides and lectures with a short quiz, but we wanted a more hands-on approach for our BSL3 safety training.
However, following the model of emergency responder training methods and with the involvement of our first responder colleagues, in 2002 we began to develop a series of exercises to test the efficacy of our training modules. These exercises range from tabletop format to full-scale scenario exercises involving representatives of departments and agencies at the level of the institution, the city, the county, and the State. We have as many as 100 people attending our exercises, both players and observers.
Experienced first responders are well seasoned in carrying out training exercises. We found that scientists and laboratory workers were unfamiliar with the format and purpose of an emergency response training exercise. The scientists felt anxious about the possibility of error. Many scientists are perfectionists and they struggled with the stress of thinking that everything had to go exactly right. They were often defensive and sometimes critical of their colleagues. They were also unfamiliar with the incident command system procedures that drive emergency response to incidents such as those that might be experienced at our laboratories. So we learned to prepare them beforehand for how these exercises work, pointing out that they are designed to instruct us in what we do not yet know, and to discover what might not work. Our BSL3 staff are now required to complete awareness level incident command training (FEMA course ICS 100). The exercises are followed by long discussions that analyze in detail where the problems lie and what the solutions might be. After the first full-scale exercise, a real emergency occurred. A pressurized water pipe burst due to extremely cold temperatures on a Saturday evening, resulting in at least 6 inches of water in the BSL3 and throughout the CEP. The previous exercises helped staff to respond calmly to this crisis, without panic or confusion, allowing them effectively to carry out emergency procedures in this off-hours emergency. Similarly, we experienced a regional blackout, and the response to this crisis also went fairly smoothly.
We hold frequent "refresher" trainings to review protocols and introduce modifications that might be required by changes in CDC regulations. For our twice-yearly reviews, we have changed the format of the quizzes, created games and asked participants to lead discussions. All members of the laboratories, from staff workers to the Principal Investigators, are involved. We held a hands-on demonstration for aerosol creation using fluorescent marker dyes so users could analyze their own technique. We have recently instituted an entirely new format: initially and once per year thereafter, the BSL3 manager and institutional biosafety officer will follow and observe each user as s/he carries out a protocol, including entry and exit procedures.
Finally, and perhaps most importantly, we strive to create a supportive atmosphere that leads to a secure and collaborative environment. In a punitive environment, there is the chance that an accident will go unreported; this is a most dangerous situation. It is essential to create an environment where if a mistake is an honest one, people trust that they will not be punished, be restricted from access to their experiments, lose their jobs or worse.
It was in the wake of the World Trade Center attacks and the anthrax letter mailings that security became an enormous issue in academic laboratories such as ours. All workers must comply with the terms of the USA PATRIOT ACT (Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism Act of 2002) and other legislation (Public Health Security and Bio-terrorism Preparedness and Response Act of 2002). "Personnel reliability", as regulated by this and other legislation, has had an ever-widening effect on the process of science. The early and close relationship between law enforcement and our facility meant that in an operational sense, many security procedures were incorporated into the procedures in our laboratory from the very opening of the program. First and foremost, researchers must now be fingerprinted and submit to a background check by the Department of Justice before handling or accessing select agents. All refrigerators and incubators have locks and pin numbers, with two-person access. Most importantly, there are inventory requirements for Select Agents, so that samples are tracked from seed stocks and working stocks, accounting for every microliter of culture. Lab notebooks are always vital for researchers, but tracking agents and tubes is important to be sure there has not been a theft of an agent. If an inventory status cannot be resolved, and does not match the laboratory notebook, then that incident is treated as a theft, which requires reporting to the FBI and CDC. This type of reporting was new to scientists, and in the beginning there was no guidance as to the best way to record all this data. Inventories can add in a layer of anxiety in order to be sure that things are logged properly, since the repercussions can be severe. Now, several years after the introduction of inventory requirements, guidance has been given as to the preferred method of data recording, and many laboratories, including ours, have developed a system to reduce the time burden of this regulation. Note that this kind of oversight and tracking is modeling on the tracking of radiological material and its utility for replicating organisms has been questioned by many scientists (Casadevall and Imperiale, 2010).
Ethics, dual use and responsible conduct
Massive increases in funding over the past decade— over $50 billion between 2001 and 2009—have been directed towards civilian biodefense (Franco, 2009). An enormous amount of federal effort and capacity is now directed towards select agent research in particular and infectious disease research in general. The global proliferation of BSL3 containment laboratories has sparked safety and security concerns and is reflected in increased oversight of laboratory operations, as discussed above. Additionally, the concept of dual use research is receiving increasing attention around the world (Selgelid, 2009). Dual use research of concern is research that is conceived for the purpose of healing or helping human kind but which can be used in the development of dangerous technologies for malevolent purposes. Our research program focuses on bacterial Select Agents, and the experiments we perform with these organisms are intrinsically dual use, in view of their potential—and in some cases, historical—development as bioweapons.
Over the past fifteen years at our institution, we have developed a number of avenues for introducing the concept of dual use research to the university community (Connell and McCluskey, 2010). The first is through the federally mandated "Responsible Conduct of Research" education of National Institute of Health (NIH)-sponsored trainees . The second route is through the Institutional Biosafety Committee, originally mandated by the NIH in the 1970's to review experiments involving recombinant DNA and since expanded to include infectious agents. The third avenue is the laboratory safety training mandated by the Occupational Safety and Health Association for all laboratory workers. The fourth route is through a robust biodefense "certificate" academic curriculum, open to all students at the university regardless of program (PhD, MS, MD, nursing, etc). We are in the process of designing and implementing a fifth approach using an institutionally based "train-the-trainer" system of intercalating dual use awareness into individual academic departments through periodic seminars and discussion groups. Of course, there is some apprehension in the scientific and security communities that identifying inherently or potentially dangerous research will have the negative effect of directing attention to possible "recipes." In other words, increasing awareness of potential dangers might lead, paradoxically, to the actual creation of such perils. These and other debates in the field of dual use ethics (Rappert, 2007; Segelid, 2009) are beyond the scope of this discussion, but most would agree that scientific inquiry and its dissemination must be allowed to continue.
The transition from basic microbiology laboratory to biocontainment laboratory is a complex process of learning new regulations, increased training and responsibility, and incorporation of new practices and procedures. Maintaining a containment laboratory is an ongoing process: regulations change and security requirements differ among funding agencies, but most importantly, we recognize continuous monitoring in emergency response and safety training in an emotionally safe environment. As the biomedical research enterprise becomes increasingly complex with regard to policy and regulation, the Biosafety Officer plays a pivotal role, coordinating the needs of the workers, the requirements of the regulatory agencies and the needs of the institution. In turn, the cooperation of the PI with the biosafety officer is also vital; the PI can set the atmosphere for the laboratory and can also foster in post doctoral fellows, technicians, and students an appreciation of the delicate balance of conducting good scientific experiments in as safely as possible. This balance between the scientists and the regulatory personnel is instrumental in developing a successful and safe Select Agent research program.
Nancy Connell is Professor in the Department of Medicine at New Jersey Medical School, Director of the Biosafety Level Three Facility of the university’s Center for the Study of Emerging and Re-emerging Pathogens, and chair of the university’s Institutional Biosafety Committee.
Bhattacharjee Y. 2009. Biosecurity. The danger within. Science. 6(323):1282-1283.
Casadevall A, Imperiale MJ. 2010. Destruction of microbial collections in response to select agent and toxin list regulations. Biosecur Bioterror. 8(2):151-4.
Connell, N. and B. McCluskey. 2010. Bringing Biosecurity-related Concepts into the Curriculum: A US View. In Education and Ethics in the Life Sciences: Strengthening the Prohibition of Biological Weapons. (B. Rappert, ed.). The Australian National University Press. Canberra ACT 0200, Australia.
Dias MB, Reyes-Gonzalez L, Veloso FM, Casman EA. 2010. Effects of the USA PATRIOT Act and the 2002 Bioterrorism Preparedness Act on select agent research in the United States. Proc Natl Acad Sci USA. 107: 9556-61
Environmental Protection Agency (1986). Emergency Planning and Community Right-to-Know Act of 1986. Available at: http://frwebgate.access.gpo.gov/cgi-bin/usc.cgi?ACTION=BROWSE&TITLE=42USCC116
Federal Emergency Management Agency-Emergency Management Institute. (2009). Introduction to Incident Command System, ICS-100. Available at: http://training.fema.gov/EMIWeb/IS/IS100a.asp
Federal Register Chapter 1 Part 73 Select Agents and Toxins Sec.19 Notification of theft, loss, or release. Available at: http://www.gpoaccess.gov/cfr/
Franco C. 2009. Billions for biodefense: federal agency biodefense funding, FY2009-FY2010. Biosecur Bioterror 7 (3): 291-309.
Franco C and TK Sell. 2010. Federal agency biodefense funding, FY2010-FY2011. Biosecur Bioterror 8(2):129-149.
Jaax, J. (2005) Administrative issues related to infectious disease research in the age of bioterrorism. Institute of Laboratory Animal Resources Journal 46: pp.8-14.
Kwik G, Fitzgerald J, Inglesby TV, O'Toole T. 2003. Biosecurity: responsible stewardship of bioscience in an age of catastrophic terrorism. Biosecur Bioterror. 1(1):27-35.
Office of Biotechnology Activities.(2002) NIH Guidelines for Research Involving Recombinant DNA Molecules. Available at: oba.od.nih.gov/rdna/nih_guidelines_oba.html
Rappert B. 2007. Codes of conduct and biological weapons: an in-process assessment.Biosecur Bioterror. 2007 Jun;5(2):145-54.
Selgelid MJ. Governance of dual-use research: an ethical dilemma. Bull World Health Organ. 2009 Sep;87(9):720-3.
The White House, Office of the Press Secretary, Fact Sheet: Combating Terrorism: Presidential Decision Directive 626, Annapolis, Md. (May 22, 1998).