The University of Missouri Regional Biocontainment Laboratory – What It Is and the Emphasis on Regional

George Stewart McKee Professor of Microbial Pathogenesis and Chairman, Department of Veterinary Pathology, University of Missouri

f you build it, he will come W. P. Kinsella (Shoeless Joe, Houghton Mifflin, 1982) I Concerns over bioterrorism, emerging infectious diseases, and food safety and security led to the creation of a regional network of biosafety level 3 facilities in the United States. These facilities provide safe environments for conducting research on high consequence bacterial and viral pathogens. The facilities were expensive to build and will be expensive to operate. They do, however, provide unique opportunities for researchers throughout the country to conduct research programs that are not possible without the specialized containment laboratories. To be economically viable, the biocontainment labs must be maximally utilized. This necessitates that Universities that host these facilities create an environment that encourages and facilitates collaborative and cooperative research agreements with regional research institutions.

Introduction that researchers who can exploit the Contemporary scientific research resources will be identified. Some may often involves the use of expensive be recruited to the University, other equipment and facilities. When users as collaborators or users of the universities make a commitment to facilities on a fee-for-service basis. provide these facilities, the decision not This model has been quite only involves an up-front expenditure of successfully applied in certain scientific often scarce resources, but disciplines, most notably physics, where programmatically commits the the costs of particle colliders, cyclotrons, university to very specific research and nuclear reactors are beyond the directions. Prior to having the scope of most university budgets. specialized facilities, it is unlikely that a Physicists at Universities lacking these critical mass of faculty will exist who facilities book time on these instruments work in that research arena, because of and then spend the bulk of the year the very lack of those facilities. The analyzing the data back at their home newly constructed facilities, or institution. Biologists, as a general rule, expensive equipment, thus become the tend not to think regionally when it “Field of Dreams” with the expectation comes to their individual research

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programs. For example, Midwestern created in this program (Figure 1). NIH schools lack research programs in provided 75% of the construction costs marine biology, despite being ideally for the RBLs and the remainder of the situated equidistant from the Pacific and construction costs was provided by the Atlantic Oceans. We do not seek out host institution or state. The grantees in time-sharing options with institutions turn agreed to operate the which have the ships and equipment to biocontainment labs for a period of conduct this type of research (i.e. Scripts twenty years. The two NBLs, with the and Woods Hole Oceanographic highest level of biocontainment (BSL-4), Institutions). Modern research in receive operation support through the molecular biology is increasingly NIH awards and are facilities that can dependent on the use of expensive handle exceedingly dangerous equipment and specialized facilities. pathogens for which there is no vaccine Will biologists follow the lead of our or therapy available. The RBLs, are BSL- physicist colleagues and make use of 3 facilities which are designed for work regional or national resources? This will on pathogens that are transmitted by the soon be put to the test with the aerosol route, have significant mortality construction of the national network of rates, but for which vaccines or Regional Biocontainment Laboratories. treatments are available. The NIH The RBL Network provided construction costs for the The anthrax postal (Amerithrax) RBLs, but made it clear that operating bioterrorism events in the fall of 2001 costs for them was not to be part of this raised bioterror concerns in the US and program. The Biosecurity Research worldwide1. In February 2002, Institute (BRI) at Kansas State University consultations between the National was not part of the NIH program, but is Institute of Allergy and Infectious included in this discussion because of its Diseases (NIAID) and its Blue Ribbon unique attributes relative to the other Panel on Bioterrorism produced several containment facilities. recommendations for NIAID to better Microbial pathogens that are of protect the American public from the concern as agents of bioterrorism, are threat of bioterrorism. One part of the federal government’s Select recommendation was to create more Agent program, and research on these laboratory space for work with agents require BSL-3 containment dangerous pathogens. A request for facilities3. The select agent pathogens proposals was issued to create a regional include a variety of bacterial, viral network of biosafety level 3 laboratories pathogens that share the property of (Regional Biocontainment Laboratories being transmissible by the aerosol route. [RBLs]) and biosafety level 4 facilities Examples include the agent of anthrax (National Biocontainment Laboratories (Bacillus anthracis), plague (Yersinia [NBLs]2. Two NBLs were ultimately pestis), tularemia (Francisella tularensis), created, one in Boston, MA and the other and St. Louis Encephalitis Virus. Prior to in Galveston, TX. Thirteen RBLs were 2001, research on virulent strains of B.

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BSL-3 Facility Location Approximate Gross Estimated Cost Square Footage Colorado State University RBL Ft. Collins, CO 33,850 $30 million George Mason University Fairfax, VA 53,000 $48 million Biomedical Research Laboratory Howard T. Ricketts RBL Chicago, IL 35,000 $31 million (University of Chicago) Kansas State University Manhattan, KS 113,000 $54 million Biosecurity Research Institute New England Regional Biosafety Boston, MA 41,000 $33.7 million Laboratory (Tufts University) Pacific RBL Honolulu, HI 25,000 $47.5 million University of Hawaii RBL at Duke University Durham, NC 33,145 $22.4 million Southeast Biosafety Laboratory Birmingham, AL 43,500 $32 million (Univ. Alabama at Birmingham) Tulane University RBL Covington, LA 38,000 $27.5 million University of Medicine & Dentistry Newark, NJ 34,700 $39 million Of New Jersey RBL University of Louisville Center for Louisville, KY 37,000 $34.6 million Preventive Medicine University of Missouri Columbia, MO 32,500 $18.5 million University of Pittsburgh RBL Pittsburgh, PA 20,000 $28.8 million University of Tennessee Health Memphis, TN 30,315 $25 million Science Center RBL anthracis could be conducted at the research on this pathogen requires the lower biocontainment level, BSL-2, more specialized and expensive BSL-3 which is more typical of the level of containment. Thus reclassification of typical University medical microbiology biosafety conditions, in addition to an laboratories. However, with inclusion of increased emphasis on biodefense- B. anthracis on the select agent list, related research, created the increased

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demand for biocontainment research new space were already largely laboratories. identified. The RBLs support NIAID-funded At the other end of the spectrum biodefense and emerging infectious were Kansas State University, the diseases research and are members of University of Louisville and the the NIAID Biodefense Network. University of Missouri that at the time of Additionally, the RBLs serve as regional the awarding of the RBL grants, had resources for research institutions in the either no biosafety level 3 laboratory area, and would be available and space or had small individual prepared to assist national, state, and laboratories. Existing faculty with need local public health efforts in the event of for these facilities were not present at a bioterrorism emergency. At the same these universities at the time of the RBL time as the RBL construction grant grant submissions or were present in too program, NIAID held a competition to small a number to utilized the newly establish a network of Regional Centers constructed research space. Without the of Excellence for Research in Biodefense specialized facilities, no existing projects and Emerging Infectious Diseases were in place in these institutions. Thus (RCEs)4. Although the RBL construction the RBLs were built with the intention grant program was distinct form the that biocontainment-requiring programs RCE program, the RBLs have in many would have to be established de novo. cases formed an alliance with the RCEs The Kansas State University and provide an important source of Biosecurity Research Institute is unique biocontainment research space for the among the biocontainment laboratories RCE research projects. in that it is a BSL-3Ag facility, The RBLs are intended to be specifically designed to permit research regional resources, although the on larger animals, specifically food majority of them are concentrated in the animals. It is the only facility listed eastern half of the United States. The above which can study zoonotic Universities hosting the RBLs fall into a infections involving cattle, sheep, goats, spectrum of experience in research and swine. It is a remarkable facility that programs related to high containment can contribute substantially to our pathogens. At one end of the spectrum understanding of zoonotic diseases and was Colorado State University, which food safety. Although Kansas State had had large established biosafety level 3 strong research programs in food safety programs in tuberculosis and arthropod- and security, at the time the University borne viruses. Construction of the RBL completed construction of the BRI, it had permitted them to expand their heavily no active BSL-3 or BSL-3Ag research utilized facilities and further build these programs. However, the facility has research programs. The existing already paid dividends for the programs at Colorado State meant that University as the presence of the BRI has at the time of the RBL construction, been cited as one factor in the selection investigators and projects going into the of the Manhattan, KS site for the Department of Homeland Security’s

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National Agro- and Biodefense Facility recruit faculty specifically to the (NBAF), a biosafety level 3 and 4 facility facilities. These faculty could be for research on foreign animal diseases recruited to different departments at the and zoonoses to replace the aging Plum University (such as Biology, Island Animal Disease Center. Biochemistry, Microbiology, etc). Construction of NBAF will create a However, usually it is a specific group 500,000 sq ft. facility dedicated to the or department that was the driving force study of zoonotic and foreign animal in the development of the proposal for diseases and will provide an influx of the RBL, and other departments did not infectious disease expertise to the necessarily buy in to this specific Midwest. However, Kansas State, like research direction for the University. the other Universities hosting RBLs, Because of chronically tight budgets, must internally build up its research new faculty hires are limited at the programs in infectious diseases to make Universities. Many departments opt not optimal use of their new facilities. to recruit with the RBL in mind. This Challenges to internally building may be due to specific programmatic or biocontainment research programs teaching needs for the individual Biocontainment facilities are department. Another potential concern, expensive to build, especially with the however, is economic. With universities requirement for redundant safety committed to operating the RBLs or the features. They are additionally BRI, funding sources to operate these expensive to operate. Their energy costs facilities will have to come from overly are greater than conventional laboratory stretched budgets. Adding a faculty buildings. They require a special work member who utilizes the facility might force of highly trained individuals to target that department for providing provide for the increased security and funds for operational costs. At least that maintenance aspects of the building. The is the fear shared by heads of the need for a larger and more highly departments. As a consequence, for trained work force for biocontainment many of the RBLs and the BRI, very few facilities drives up personnel costs. faculty researchers have actually been Many of these expenses are fixed, and recruited to staff the biocontainment thus operating the facility at 50% laboratories and to write grants to capacity is not significantly less support operation of the facilities. Most expensive than operating it at full of these facilities will be markedly capacity. Thus the only way that these under-utilized at the time they acquire facilities will not be an economic drain the requisite certifications to begin BSL-3 on the Universities is to have them and Select Agent Program operations. operating at capacity and the research The addition of faculty after the projects bringing in revenue in the form facilities become operational, improves of grants and contracts to the host the situation but takes time before the institutions. It is critical that newly hired researchers can contribute. Universities, once they commit to The faculty, and whatever postdoctoral, operating biocontainment facilities, student, and technical staff they hire,

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must undergo Department of Justice scheduling space in over-subscribed background checks and extensive small individual biocontainment labs. training before they can begin working One path for this activity would be to under biosafety level 3 conditions. establish a formal collaboration with a Research projects must be approved by faculty member at the RBL host University Compliance committees (the institution. The limited number of Institutional Biosafety Committee [IBC] biocontainment-related investigators and the Animal Care and Use initially at the RBL host institution, Committee [ACUC]) as well as obtaining however, limits this approach. A more CDC or USDA authorization for select fruitful initial approach would be for the agent-related activities. These are time- RBL host institutions to contract out the consuming processes that can delay the use of its biocontainment facilities and initiation of research projects by many technical expertise to regional months. Only after all of the compliance universities and biotech or approvals are in place and all of the pharmaceutical companies. The RBL biosafety and agent-specific training would not only provide the facilities and have been conducted, will the research specialized equipment necessary to projects be initiated. Only then can the conduct the studies, but would provide preliminary data be generated to a trained technical staff as well. The support research grant applications to advantages to this approach to the federal agencies. The development of a outside investigator would be not funding stream to the RBL based on having to provide the federal regulatory research grants is a very slow and clearances for lab workers, not having to laborious process. train lab personnel in techniques which Putting the “regional” in regional may not be totally familiar to the biocontainment laboratories investigator, and not having to secure Construction of the BRI is housing for the researchers during the finished and that of the RBLs is largely duration of the experiments. accomplished (although many have not The biocontainment facility host yet initiated operations until the institutions will have to develop appropriate federals approvals [i.e. CDC business plans to facilitate these contract Select Agent]) are in place. It is obvious services. Fee for service rates would that as these facilities begin operations, have to be established. Marketing space will be available for researchers approaches would have to be outside the host university to conduct established and web sites developed to infectious disease research. University effectively inform researchers from both researchers, as well as those in the academic institutions and the private private sector, will have opportunities to sector about the capabilities of the conduct research or evaluate biocontainment facility and the types of therapeutics or vaccines that would be expertise resident in the facility. either impossible in their home Development of effective business and institutions owing to a lack of marketing strategies is beyond the biocontainment space or difficulties in expertise of the scientists conducting

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infectious disease research, so it is institutions would accept the compliance imperative that the Universities mobilize approvals from the other university the requisite expertise from other sectors would greatly streamline this approval of the university. It is also important that process. Institutions lacking containment university officials of the RBL host facilities may not have the requisite institution maintain open lines of biosafety expertise on their research communication with the other regional compliance committees. In these cases, a research universities so that when full review by the RBL host university opportunities for research interactions would be necessary. arise, the institutions involved will be Another issue which could slow able to respond quickly to these. down the agreement process, especially Impediments to regional when dealing with private sector cooperation companies, is the handling of intellectual Time is the biggest concern when property issues. This is especially establishing cooperative research important when research involving agreements involving biocontainment potential therapeutic agents or vaccines facilities. Once an agreement between is conducted. Again it is imperative that institutions is reached, a long list of the RBL host university have in place approvals at both the federal and local personnel and procedures to act on these levels is required. If select agent issues in a timely manner. organisms are involved, approval by the Summary CDC and/or the USDA is required. The The RBL network can become a RBL would have to gain approval for major resource to universities and working with the specific agent, if provide the necessary research approval for that particular organism is environment to advance our knowledge not in place. Agent-specific standard of biothreat and emerging infectious operating procedures would have to be disease agents. With the large number of developed and agent-specific training of diseases arising naturally in the past the RBL personnel instituted. At the host twenty years (Mother Nature being the university level, project applications to ultimate bioterrorist), these facilities will the research compliance committees, the play a vital role in protecting American IBC and ACUC committees. Getting public health in the years to come. proposals approved by these federal and However, to effectively utilize these university committees can take months facilities, researchers must learn to to achieve. University research establish research ties with these compliance committees will be placed in specialized facilities and the RBL host a relatively unique position of university must establish effective lines evaluating proposals for projects of communication with regional originating from outside the university. universities and private sector University Research Offices will have to companies to facilitate cooperative develop policies to effectively handle research agreements. Regional these occurrences. The establishment of biocontainment laboratories should be inter-university agreements whereby the truly regional and universities must

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learn to be less territorial in dealing with References their sister institutions. The 1. Atlas, R.M. 2002. Bioterrorism: from threat to reality. Ann. Rev. Microbiol. biocontainment facilities should be a 56:167-185. source of new opportunities and if 2. http://grants.nih.gov/grants/guide/rfa- managed correctly, not a fiscal drain on files/RFA-AI-04-032.html 3. http://www.cdc.gov/selectagent/index.ht the host university. ml 4. http://www3.niaid.nih.gov/LabsAndRes ources/resources/rce

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