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F:' ~ Infrastructure for Research on Transmissible ~ Soonsiform Encepha/opathies The chief goals of research on transmissible spongiform encephalopa- thies (TSEs) in the United States are to prevent an outbreak of bo- vine spongiform encephalopathy in this country; to prevent the fur- ther spread of chronic wasting disease; to eradicate scrapie; to reduce the incidence of Creutzfel~t-Takob disease; and to develop better diagnostic tools, chemoprophylactic agents, and treatments for prion diseases. A1- though these goals may be easy to defend, they will not be easy to achieve. This chapter begins by reviewing the present U.S. infrastructure for research on TSEs. It next addresses the need for consistent, science-based standards for biological safety levels in laboratories conducting such research. The need for standard reagents and materials is then discussed. The final section examines opportunities for international collaboration in TSE research. PRESENT U.S. INFRASTRUCTURE The infrastructure for TSE research in the United States is small, aging, and funded at a level below that needed to achieve the research goals cited above expeditiously. At present fewer than 20 principal investigators con- duct TSE research funded by the National Institutes of Health (NIH), the largest sponsor of TSE research in the United States. In fiscal year 2002, NIH spent $27.2 million dollars on TSE research from the total NIH bud- get of $23.2 billion (personal communication, Robert Zalutsky, NIH, June 20031. Approximately 75 percent of the funds provided for TSE research goes to two laboratories (personal communication, R.T. Johnson, The Johns 214

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INFRASTRUCTURE FOR RESEARCH ON TSEs 215 Hopkins University, 20021. In addition to the funds provided by NIH, the Agriculture Research Service of the U.S. Department of Agriculture (USDA) spent approximately $6.6 million dollars on TSE research in fiscal year 2002 (Rexroad, 20031. This level of effort is quite different from that supported by the Euro- pean Commission (EC). One recent EC report listed 58 delegations of re- searchers conducting TSE research (European Commission, 20011. It is esti- mated that the countries of the European Union invest manyfold greater amounts of money in TSE research annually. Moreover, few U.S. scientists are involved in TSE research for a num- ber of reasons, including but not limited to the paucity of available funds. First, the small number of TSE research laboratories in the United States limits the number of opportunities to obtain training, experience, and ex- pertise especially for new investigators. Second, the costs of conducting prior-related research are generally higher than those of conducting other kinds of infectious-disease research. The animals needed for prion bioas- says are expensive to maintain, and the long incubation periods associated with prion diseases necessitate relatively long time frames for a single ex- periment. Furthermore, laboratory equipment used in this research must be dedicated solely to TSE research and cannot readily be shared for other research purposes because of decontamination difficulties (see Chapter 71. The biohazardous nature of prions also leads to delays, frustration, and extra costs associated with adherence to safety regulations and compliance requirements. TSE research laboratories are extremely expensive to build or expand because special safeguards are required to protect both investiga- tors and the public. USDA and institutional policies require TSE laborato- ries to meet the biological safety standards at biological safety level (BSL) 2 or 3. These additional costs and the lengthy periods of time required for prion research can discourage young investigators who are in relatively short doctoral or postdoctoral training programs. Moreover, investigators who have just completed their training and wish to start up their own laborato- ries must weigh the high initial costs, and the long-term investment involved, as well as the uncertain availability of funds for TSE research as compared with those for other types of research. Efforts to reestablish an intramural NIH laboratory on human prion diseases should be encouraged. Research conducted by such a laboratory would complement the animal prion research work at NIH's Rocky Moun- tain Laboratories. The new laboratory also could become a center for train- ing new investigators. Moreover it could better handle issues of infrastruc- ture investment, sustained funding, and investigator security than . . . . . . . extramural . programs In unlversltles ant . private Institutes.

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216 ADVANCING PRION SCIENCE Recommendation 8.1: Provide funds to attract and train more in- vestigators in prion disease research. In addition, for investigators conducting prion bioassay research, provide grants for 5- to 7-year periods. [Priority 11i Recommendation 8.2: Provide funds to boost the capacity of the U.S. infrastructure for research on transmissible spongiform en- cephalopathies by expanding or upgrading existing laboratories, animal facilities, and containment laboratories (biological safety levels 2 and 3), and by building new ones. [Priority 11 NEED FOR CONSISTENT, SCIENCE-BASED STANDARDS FOR BIOLOGICAL SAFETY LEVELS IN TSE LABORATORIES At present, neither USDA nor the Department of Health and Human Services (DHHS) has published regulations specifying the BSLs required for laboratories conducting various types of prion research. USDA provides non-regulatory guidance to TSE investigators on laboratory BSL require- ments and regulates the movement of prior-contaminated specimens of ani- mal origin across state lines. DHHS has published guidance for appropriate BSLs in laboratories conducting prion research (CDC and NIH, 1999), but the manual has no regulatory authority. The BSL research requirements for USDA-funded projects may differ from those for projects funded by agencies of DHHS (primarily NIH and the Centers for Disease Control and Prevention ECDC]~. This lack of consis- tent and regulatory guidance from USDA and DHHS creates confusion within the prion research community. As a result, it is unclear when re- search involving TSE agents must take place within a BSL 2 laboratory versus a BSL 3 laboratory. The difference is significant because the costs of building, upgrading, and maintaining the two types of laboratories differ notably. In addition, there are far fewer BSL 3 facilities than BSL 2 facilities in the United States. This limits the amount of TSE research requiring BSL 3 conditions that can take place in this country. Recommendation 8.3: Provide funds to develop scientifically based biological safety level standards for laboratories conducting re- search that involves infectious agents known to cause transmissible spongiform encephalopathies. [Priority 21 iThe committee denotes each recommendation as priority level 1, 2, or 3 based on the criteria and process described in the Introduction.

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INFRASTRUCTURE FOR RESEARCH ON TSEs 217 If embraced by the community of organizations that fund TSE research, such BSL standards could serve as a common, consistent framework for regulations governing laboratory biosafety for the full spectrum of TSE research. NEED FOR STANDARDIZED REAGENTS AND MATERIALS Few of the basic materials used in prion research have been standard- ized or commercialized, a fact that creates additional challenges for TSE investigators. The reagents used to conduct individual studies are often made by the laboratory conducting the study or borrowed from a fellow investigator's laboratory. The consequent lack of standardization has ham- pered the ability of one laboratory to replicate the results of another, thus delaying opportunities to validate key discoveries. The same lack of standardization characterizes the animals used in TSE research. Many of these animals are specially inbred or are genetically al- tered to have specific mutations, have the genes of other species embedded in their chromosomes (transgenic animals), or have specific genetic coding areas deleted (knockout mice). The processes and level of quality control required to produce these engineered animals are not well established. The issue of standardized materials is also a concern for researchers in Europe and elsewhere. In September 1999, the World Health Organization (WHO) held a consultation meeting and recommended that a working group be established to address this problem (WHO, 20001. The working group is organizing a systematic collection of animal and human reference materials for TSE research from a variety of prion research centers (WHO, 20011. That effort is laudable, but progress has been slow. In addition, barriers relating to the importation of potentially infectious materials into the United States would preclude, delay, or complicate the retrieval of ma- terial from this WHO reference center. Therefore, there needs to be a mecha- nism in the United States for giving investigators access to research refer- ence standards. Reference Repositories NIH sponsored a meeting in February 2002 to establish a TSE reagent repository. At that meeting, various mechanisms to improve the availability of reagents for TSE research were discussed, including the establishment of a centrally run NIH repository. A good mode! for this is the AIDS reagent repository at NIH. A government-commercial partnership involving one or more private companies could also establish a repository. Or a government contract for establishing a repository could be awarded to a central organi- zation, which could subcontract requirements of the contract to other orga-

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218 ADVANCING PRION SCIENCE nizations. This mechanism has worked well with the Vaccine Development Program at the National Institute of Allergy and Infectious Diseases (per- sonal communication, R.T. Johnson, The Johns Hopkins University, 20021. The TSE research community in the United States needs not only stan- dard reference materials but also reference centers. These centers do not necessarily need to be stand-alone facilities, nor does any one center need to contain all the various types of required reference materials. For example, one repository might contain diagnostic assay reference material, one might contain different reference strains of priors, and another might contain transgenic or specially engineered animals. The preferred mode! is to use existing repositories (for example, the Jackson Laboratory, an animal pro- duction repository) and add prior-related materials to their collections. The preexisting building, equipment, personnel, and database infrastructure as- sociated with this approach would make the marginal costs far less than those associated with building new repositories. The funding required to start up such repositories may initially need to come from government research funds or scientific foundations. Once the repositories had been established, the fees paid by investigators using the materials would cover the general operating costs. New NIH-Based TSE Reagent Repository On July 9, 2003, NIH announced its intent to establish a TSE reagent repository (Beise! and Nunn, 2003), satisfying a goal of the DHHS TSE Action Plan (DHHS, 20011. The reagents will be available free of charge to scientists around the world. The committee applauds NIH for establishing this international resource for advanced TSE research. The repository will be a collaborative project of the National Center for Allergy and Infectious Diseases (NIAID) and the National Institute of Neurological Disorders and Stroke (NINDS). The collection will include nonhuman materials containing TSE agents; noninfectious materials, such as antibodies, plasmids, and cell lines; and live animals, such as transgenic mice. It is anticipated that TSE investigators will have relatively easy access to the contents of the new repository, since that has been the case with the AIDS Research and Reference Reagent Program at NIH. More than 2,000 investigators from 63 countries are registered with the AIDS Reagent Pro- gram (Beise! and Nunn, 20031. The announcement encourages TSE investigators to register with the repository and to donate reagents. Investigators will be expected to assume liability for the reagents they borrow, to abide by the safety standards that are established, and to agree to a donor-assigned release for discoveries that are made using the reagents and later commercialized. Donors will receive

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INFRASTRUCTURE FOR RESEARCH ON TSEs 219 semiannual reports of how their reagents are used and acknowledged in relevant publications, on the repository's Web site, and in the repository's annual catalog (NIH, 20031. Recommendation 8.4: Provide funds to support new or established transmissible spongiform encephalopathy (TSE) repositories that contain a collection of reference materials and genetically engi- neered animals (including transgenic mice), as well as reagents use- ful for developing TSE diagnostics and for other TSE research. All registered investigators involved in prion research should have ac- cess to these collections. [Priority 11 Standardized Reagents for Validating TSE Diagnostic Tests The Food and Drug Administration (FDA) can play an important role in assisting the TSE research community, as well as the commercial sector, by maintaining panels of reference reagents for validating the performance characteristics, such as sensitivity and specificity, of new tests for the detec- tion of both PrPSc and infectivity. These panels would consist of reagents known to contain TSE-related material (positive controls), as well as re- agents known to be free of TSE-related material (negative controls). FDA has developed such panels in the past for validating antibody-screening tests for HIV and hepatitis C virus. Recommendation 8.5: Provide funds to support the U.S. Food and Drug Administration's development of panels of reference reagents needed to evaluate the performance characteristics of tests designed to detect the prion protein and TSE infectivity. These panels would be used to confirm the performance characteristics of test kits be- fore they are approved for public use, as well as to perform quality control on test kit lots before their release to the market. [Priority 31 The pace of progress in research on prion diseases will be determined not only by what is studied, but also by the capacity to pursue scientific inquiry. A small, albeit dedicated, effort is proceeding in the United States, and that effort will continue to make contributions, but at a pace that ulti- mately may not accomplish the nation's goals in a timely manner. To ac- complish the broad goals cited at the beginning in this chapter, the capacity to conduct TSE research must be enhanced significantly. Doing this will require more laboratories that can serve as training platforms, more re- searchers who can enter the field of study, a larger and more reliable fund- ing environment, and better scientific tools. It is noteworthy that the secretary of Health and Human Services ap-

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220 ADVANCING PRION SCIENCE proved an action plan on August 23,2001, to increase the infrastructure for TSE research (DHHS, 2001~. Achieving the laudable goals set forth in that plan will require sustained attention, effort, and funding. OPPORTUNITIES FOR INTERNATIONAL COLLABORATION A quick remedy for the shortage of U.S. laboratory space for prion investigators is unlikely. However, several large European laboratories con- ducting prion research may represent opportunities for collaboration with U.S. investigators and might even allow U.S. investigators to use their labo- ratory space. Many TSE investigators have been engaged in international collaborative research efforts for years. These efforts should continue and be expanded. There is a significant TSE infrastructure research base in Eu- rope and other sites around the world. This base should be leveraged not only to conduct collaborative studies, but also to provide training opportu- nities. The French government has already established 35 fellowships for foreign TSE researchers and is actively seeking U.S. applicants (personal communication, R. T. Johnson, The Johns Hopkins University, 2002~. France has a BSL 3 facility that can house 60 macaques, and the govern- ment is building a dedicated prion research facility that will house 120 monkeys and provide laboratories for visiting scientists (personal commu- nication, R.T. Johnson, The Johns Hopkins University, 2002~. At a meeting of this committee, a scientist from a large Swiss TSE research facility indi- cated that a great deal of collaborative TSE research is occurring on both a national and an international scale (Racber, 2002~. The EC maintains an online database of TSE research that is being funded by the the European Union and includes project descriptions and contact information (CORDIS Project Database, 2002~. Also, in 2001 the EC published a reference document assembled by a group of TSE experts that lists all the European laboratories conducting TSE research at that time, as well as points of contact and descriptions of the research projects (European Commission, 2001~. These contacts may be able to provide information to interested investigators about present opportunities for collaboration with their research groups or with other groups in their countries. Another resource for TSE investigators seeking funding and the oppor- tunity to collaborate with colleagues abroad is the Human Frontier Science Program (HFSP). Based in Strasbourg, France, this organization promotes collaborative international research by requiring that proposed projects in- clude investigators from different scientific disciplines and different coun- tries (HFSP, 2003~. The principal applicant must be from an eligible mem- ber country: Austria, Belgium, Canada, Denmark, Finland, France, Germany, Greece, Italy, Japan, Luxembourg, the Netherlands, Portugal,

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INFRASTRUCTURE FOR RESEARCH ON TSEs 22 the Republic of Ireland, Spain, Sweden, Switzerland, the United Kingdom, or the United States. HFSP supports novel, interdisciplinary, basic research involving complex biological systems, including TSE-related studies. The organization awards grants to project teams and provides fellowships to individual scientists so they can work in foreign laboratories. The fellow- ships are aimed at young investigators seeking experience in a field outside their specialty. Further opportunities for U.S. scientists to conduct TSE research with foreign investigators outside Europe are offered by the University of Melbourne (personal communication, C. Masters, University of Melbourne, May 4, 20031. The United States could foster international collaboration by sponsor- ing one or a series of international conferences on advancements in prion science. Investigators from around the world would be invited to attend and present their research findings. This would facilitate both the timely dissemination of emerging scientific information and the face-to-face inter- actions among scientists that could foster new collaborative research initia- tives. Funds from the National Prion Research Project might be able to provide some or all of the support for such conferences. Recommendation S.6: Provide funds to enable U.S.-based investi- gators of transmissible Spongiform encephalopathies (TSEs) to col- laborate or train with TSE investigators internationally and to use TSE research facilities abroad. Exploiting such opportunities will expand the range of TSE research that U.S. scientists can conduct. [Priority 31 REFERENCES Beisel C. and Nunn M. 2003, July 9. NIH TSE Reagent Repository. [E-mail from cbeisel@nih.gov] . CDC and NIH (Centers for Disease Control and Prevention and National Institutes of Health). 1999. Biosafety in Microbiological and Biomedical Laboratories (4th ed). Washington, DC: U.S. Government Printing Office. CORDIS Project Database. 2002. EU-Funded TSE Projects. [Online]. Available: http:// europa.eu.int/comm/research/quality-of-life/tse/projects_en.html [accessed May 8, 2003]. DHHS (U.S. Department of Health and Human Services). 2001. Bovine Spongiform Encepha- lopathy/Transmissible Spongiform Encephalopathy (BSE/TSE): Action Plan. Washing- ton, DC: DHHS. EC (European Commission). 2001. Inventory of National Research Activities in Transmissible Spongiform Encephalopathies (TSEs) in Europe. Brussels: EC, Research Directorate Gen- eral, Quality of Life and Management of Living Resources Programme. HFSP (Human Frontier Science Program). 2003. Human. [Online]. Available: http:// www.hisp.org/home.php [accessed May 8, 2003].

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222 ADVANCING PRION SCIENCE Raeber A. 2002. Is BSE a Worldwide Problem? Commercial Diagnostic Testing for TSEs in Europe. Presentation to the IOM Committee on Transmissible Spongiform Encephalopa- thies: Assessment of Relevant Science, Meeting I. Washington, DC. Rexroad C. 2003. Researching Transmissible Spongiform Encephalopathies at the Agricul- tural Research Service. Presentation to the IOM Committee on Transmissible Spongiform Encephalopathies, Assessment of Relevant Science, Meeting 5. Washington, DC. WHO (World Health Organization). 2000. WHO Consultation on Public Health and Animal Transmissible Spongiform Encephalopathies: Epidemiology, Risk and Research Require- ments. Geneva: World Health Organization Communicable Disease Surveillance Control and Office International des Epizooties. WHO. 2001. Blood Safety and Clinical Technology. Working Group on International Refer- ence Materials for Diagnosis and Study of Transmissible Spongiform Encephalopathies (TSEs): Third Meeting. Geneva.