“There are a lot of emerging diseases out there with more to come. Most of them are zoonotic—that is, diseases of animals transmissible to humans, which means they require for their investigation more specific expertise and more containment laboratory research than has been the case with classical diseases transmitted from human-to-human,” says Dr. Frederick Murphy, a professor of pathology at the University of Texas Medical Branch (UTMB) in Galveston. “There are many determinants that lead to the emergence of new diseases. Factors that pertain to the diseases themselves, the host, the ecology, the environment, and human activity, all intertwine in influencing emergence of new human and domestic animal disease problems.

“Much of the research to be done on these diseases will be done in the new high-containment laboratories being planned and built in our country and elsewhere around the world. Further, most of the infectious agents listed as bioterrorism threats are zoonotic and require similar facilities for the practical kind of research that will lead to the development of better diagnostics, better vaccines and drugs, and other means of intervention in the aims of terrorists.”

Factors that can impact the emergence of a disease and the level of its threat include microbial or viral determinants, such as mutation, natural selection, and evolution. Determinants pertaining to the host include natural resistance, as well as innate and acquired immunity, while natural determinants include ecological, environmental, and zoonotic influences. Factors related to human activity are personal behavior, societal, commercial, and iatrogenic influences. The accidental release of a viral threat from a laboratory or the malicious introduction of a disease into an environment can also lead to deadly consequences.

“It is only war and infectious diseases that present mega threats to humanity—that is, situations where truly catastrophic mortality and morbidity can occur,” says Murphy. “The interplay of bioterrorism and naturally emerging diseases involves a teeter-totter in time, where one year we think more about bioterrorism, especially after the anthrax episodes in 2001, and other years our focus turns to emerging diseases, especially after an episode like SARS in 2003 or highly pathogenic avian influenza today. At this time, the teeter-totter seems to favor naturally emerging diseases, a subject that includes all elements of dealing with new infectious agents, including biosafety, biosecurity and biocontainment.”

Proper Design Breeds Safe Practices

A facility that is designed and maintained to the highest standards elicits safe human behavior which, in turn, drives conformance to safe practices and safe operations. The conformance to safe practices and safe operations leads to maximum protection of the scientific staff, the community, and the environment. All this starts with the facility.

“A modern, well-designed and well-built facility makes laboratory staff feel proud and respected, and they know conformance with all safe practice guidelines, regulations, and standards for facility cleanliness is expected,” notes Murphy. “In my experience, old, poorly maintained laboratories often lead to improper shortcuts, inconsistent conformance with guidelines, rules, and standard operating procedures, and an overall sense of laissez faire—a recipe for trouble.”

The most important elements that should be remembered when designing a high-containment laboratory pertain to the overall integration of the best ideas supporting safe practices, the best equipment and devices, and the best facility planning. Murphy believes safe practices are often purposely omitted from the design phase with planners thinking the staff working in the laboratory will compensate for any shortcoming in the design. In designing laboratories today, the design should consider and facilitate safe work practices.

In many cases, safe practices are confused with safe equipment and devices that relate directly to the worker, such as personal protective equipment. Focus must be on all aspects of safe practices and innovations. Although there has been much innovation in this area in recent years, few laboratories have embraced changes in longstanding practices. New biocontainment laboratories can play an important role in moving laboratory workers toward changes in out-of-date practices.

“In too many cases, the subject of safe equipment and devices has been focused only on the biological safety cabinet,” says Murphy. “However, we must also consider the centrifuge, the autoclave, the small equipment, the animal holding and handling equipment, and everything else that adds up to an overall concept of safe equipment and devices. Modern decontamination technology and systems are also worthy of attention in designing new high-containment laboratories.”

Proper Design Requires Understanding of Key Concepts

The concepts of biosafety, biocontainment, biosecurity, and scale must be fully understood in order to protect the scientists, prevent the release of biological agents into the community, and control access to biological agents.

Biosafety: This term is typically used to focus on the protection of the staff and others potentially exposed in the workplace. Biosafety is grounded in safe laboratory practices, engineering devices, personal protective equipment, and safe facility design. Safe laboratory practices and safe engineering devices operate in an endless loop, driven by safe facility design.

Biocontainment: This term is typically used to focus on prevention of the release of biological agents from the laboratory into the surrounding environment. Much of the content in the Fifth Edition of the publication Biosafety in Microbiological and Biomedical Laboratories (BMBL) from the Centers for Disease Control and the National Institute of Allergy and Infectious Diseases deals with the principles of biocontainment. The BMBL states, for example, that “Laboratory management is responsible for providing facilities commensurate with the recommended biosafety level for the agents being manipulated.”

Biosecurity: This term is typically used to focus on controlling access to the biological agents housed in the lab. This is the focal point for dealing with the threat of bioterrorism, where concepts start with the classification of microorganisms as bioterrorism threats, and include biosecurity conditions appropriate for each class of threat agent. There are several lists of Select Agents, and deciding which list is pertinent in any particular circumstance must be understood before considering biosecurity systems. The most common list is the NIAID/CDC Biodefense Category A, B & C Pathogens List.

“However, we must also be ready to focus on future threats stemming from the ability of terrorists to modify microorganisms, making them more virulent and more resistant to host immune defenses. We need to appreciate the limitations of present threat lists and understand how to deal with potential future threats.”

Scale: Murphy expects that larger and newer biocontainment facilities, which can support all the adjunct programs that contribute to research and development programs, will be the most successful in advancing the national and international need for improved diagnostics, new and improved vaccines and new and advanced drugs. However, many small biocontainment laboratories are being designed and built. For example, the NIH/NIAID, working with the American Society for Microbiology, conducted a survey in 2006 that showed there are about 277 BSL-3 facilities in the United States. Meanwhile, another estimation conducted by individuals at the Los Alamos National Laboratory and the Lawrence Livermore National Laboratory suggested that there are more than 1,400 BSL-3 laboratories nationwide.

“If we do not even know how many such laboratories are operating in our country, we are not in a position to know enough about their programs, their facility details or their biosafety systems,” says Murphy. “Certainly, many of these are small BSL-3 laboratories that are isolated and insular, undercapitalized, and are cutting corners in regards to biosafety and biosecurity expenses, and cutting corners in regards to expensive equipment and elements of construction that are essential.”

Murphy is of the opinion that, “The rise of larger laboratories offers an important advance for our country programmatically and in regard to biosafety and biosecurity.”

Who’s In Charge Here?

The most important threat to leaders underwriting the design, construction, operation, and maintenance of high-containment facilities is the human element, according to Murphy.

“There used to be the notion that you could always pass accountability up to the president of the university or the head of the institution,” he recalls. “You can’t do that anymore because every guidance document says it is the principal investigator, or the person in charge of the primary unit, who is accountable. When thinking of what can go wrong, it’s a good idea to know who will be left holding the bag.”

An increasing number of guidelines are clearly defining the words “authority,” “responsibility,” and “accountability.” For example, the BMBL states that it is the laboratory director who is primarily responsible for the safe operation of the lab, the selection of additional safety practices, the assessment of risks and the application of recommended biosafety levels, and for providing appropriate training of personnel. Many laboratories requiring biocontainment have reflected these principles in their own regulations, guidelines and SOPs. Many make it clear who is in charge. For example, the biosafety manual for the University of California, San Francisco states that “the laboratory director/supervisor/manager/principal investigator can delegate or assign his/her responsibility, but cannot delegate or assign his/her accountability. He/she is ultimately accountable.”

Accountability is defined as the obligation to accept responsibility, while responsibility means the obligation to answer for one’s actions.

“These terms are better defined by their usage. When a person is given responsibility, he or she must also be given the necessary authority,” explains Murphy. “When a person is responsible for something, he or she is accountable for the outcome. Accountability flows upward in the organization and is the means by which power is used responsibly.”

The institutional understanding of these three terms answers the question of  “Who is in charge here?” This understanding may also help an organization realize the need for advanced education, technical training, mentorship, and career development of the next generation of leaders and staff members in high-containment facilities.

The concepts surrounding the safe operation of biocontainment facilities are grounded in an ever-expanding plethora of regulations and guidelines, including the BMBL and the World Health Organization’s Biosafety Guidelines to name just a few. The Fifth Edition of the BMBL includes more information about the principles and practices of biosafety, biosecurity, occupational medicine and immunization, decontamination and sterilization, biological toxins, agent summary statements for agricultural pathogens, and especially biological risk assessment.

Importance of Risk Assessment

Risk assessment has assumed a larger role in driving all biosafety considerations, including those pertaining to facilities. Risk assessment is a process used to identify the following:

* The hazardous characteristics of known infectious agents or materials;
* Activities that can result in exposure or infection from the agent;
* The likelihood that such exposure will cause illness;
* The probable consequences of such an infection or illness.

“This information is used to guide the selection of appropriate biosafety levels and microbial practices, safety equipment, and facility safeguards that can prevent infections,” notes Murphy. “The selection of precautions follows upon the assessment of laboratory procedure hazards and agent hazards, such as the route of transmission of the agent, stability of the agent, infectious dose of the agent, concentration of the agent in the material being handled, origin of the specimen/sample containing the agent, availability of data from clinical studies of infection caused by the agent, availability of effective prophylaxis, availability of medical surveillance, and evaluation of the experience and skill level of the laboratory personnel.”

The BMBL describes risk assessment as a five-step process, which starts with the identification of agent hazards and performance of an initial assessment. The next step is to identify laboratory procedure hazards and then determine the appropriate biosafety level and selection of additional precautions. The fourth step is to evaluate the proficiencies of staff regarding safe practices and the integrity of biosafety equipment and devices. The final step is to review the results of the risk assessment with a biosafety professional.

The risk assessment process promises to become an important aspect of the management of high-containment labs, adding some bureaucratic complexity, but also substantially enhancing the ability of leaders to meet their responsibilities. The assessment may also reveal a need to update diagnostic systems and provide more training for personnel.

“Assessment of specific work to be done with a particular infectious agent should determine the appropriate combination of biosafety, biocontainment, and biosecurity,” says Murphy. “However, many local and national regulators are stepping in and offering their own interpretations of just what is safe and what is secure. In every case, this is leading to stricter interpretations and more bureaucratic oversight.”

The Patriot Act, for instance, calls for elaborate facility security plans. It states, in part, that “facilities must develop comprehensive security plans…in regard to physical security, data and information technology system security, security policies for personnel, policies for accessing Select Agent areas, specimen accountability, receipt of Select Agents into the laboratory, transfer and shipping of Select Agents.”

Conclusions

Murphy applauds the fact that architects and engineers have become the dominant players in the design of biocontainment laboratories.

“Years ago, the scientists who would occupy the high-containment facility were the key to good design, and the architects and engineers merely followed the advice of the scientific staff,” he recalls. “Today, the architects and engineers who specialize in high-containment laboratory design and construction know much more than the scientists. There has been much more learning from prior experience and each new laboratory reflects many lessons learned along the way. Biosafety and biosecurity consultants have been playing an important role, too.”

Costs must also be considered when constructing laboratories, especially small-scale BSL-3 facilities. Overcoming the cost inefficiencies inherent in such small laboratories can be a daunting task in light of biosafety requirements. Once cost issues have been addressed, it can be difficult to find a qualified design firm and contractor because the best designers and contractors are busy with larger projects. There is also a shortage of qualified people to properly maintain BSL facilities and an insufficient number of trained, experienced laboratory personnel. Given these realities, Murphy thinks many institutions will centralize their biocontainment facilities.

“We need to not only train scientists, engineers and architects, but we also need to evolve a better career development pattern so they don’t have to worry about a lifetime committed to a field that may not support them 10 years out,” says Murphy. “A national training center is needed in our country to fulfill present staffing shortfalls and to underpin the career development of staff members ready to fulfill future needs. This need pertains not just to scientists and laboratory technologists, but also to on-site engineers, maintenance staff, security staff, and other specialists.”

By Tracy Carbasho

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