5
Prion Research Infrastructure

The goals of research on transmissible spongiform encephalopathy (TSE) in the United States are broadly aimed at preventing a bovine spongiform encephalopathy outbreak in the United States; preventing further the spread of chronic wasting disease; reducing the incidence of Creutzfeldt-Jakob disease; and developing better diagnostic tools, chemoprophylactic agents, and treatments for prion diseases. Although these goals may be easy to defend, they will not be easy to achieve.

THE PRESENT U.S. INFRASTRUCTURE

The prion research infrastructure in the United States is small, aging, and inadequately funded. At present fewer than 20 principal investigators conduct prion research funded by the National Institutes of Health (NIH), the largest sponsor of TSE research in the United States. The funding for TSE research is miniscule compared to the amount directed at other diseases. In fiscal year 2000, NIH spent $14.69 billion on research, but only $23.86 million-0.16 percent of the institute's research budget-was directed toward TSE research (Johnson, 2002). Furthermore, 75 percent of the funds provided for TSE research go to only two laboratories (Personal communication, R.T.Johnson, Johns Hopkins University, 2002).

This level of effort and funding is quite different from that supported by the European Commission. One recent Commission report listed 58 delegations of researchers conducting TSE research



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5 Prion Research Infrastructure The goals of research on transmissible spongiform encephalopathy (TSE) in the United States are broadly aimed at preventing a bovine spongiform encephalopathy outbreak in the United States; preventing further the spread of chronic wasting disease; reducing the incidence of Creutzfeldt-Jakob disease; and developing better diagnostic tools, chemoprophylactic agents, and treatments for prion diseases. Although these goals may be easy to defend, they will not be easy to achieve. THE PRESENT U.S. INFRASTRUCTURE The prion research infrastructure in the United States is small, aging, and inadequately funded. At present fewer than 20 principal investigators conduct prion research funded by the National Institutes of Health (NIH), the largest sponsor of TSE research in the United States. The funding for TSE research is miniscule compared to the amount directed at other diseases. In fiscal year 2000, NIH spent $14.69 billion on research, but only $23.86 million-0.16 percent of the institute's research budget-was directed toward TSE research (Johnson, 2002). Furthermore, 75 percent of the funds provided for TSE research go to only two laboratories (Personal communication, R.T.Johnson, Johns Hopkins University, 2002). This level of effort and funding is quite different from that supported by the European Commission. One recent Commission report listed 58 delegations of researchers conducting TSE research

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(European Commission, 2001). It is estimated that the countries of the European Union annually invest manyfold larger amounts of money in TSE research. The paucity of funding dedicated to prion research is not the only reason why so few investigators are involved in this field. First, the small number of prion laboratories in the United States limits the number of opportunities to obtain training, experience, and expertise- especially for new investigators. Second, the costs of conducting prion research are generally higher than those of conducting other kinds of infectious-disease research. The animals needed for prion bioassays are expensive to maintain, and the long incubation periods associated with prion diseases require relatively long time frames for a single experiment. Furthermore, prion laboratory equipment must be dedicated solely to TSE research and cannot readily be shared for other research purposes because of decontamination difficulties. The biohazardous nature of prions also leads to delays, frustrations, and extra costs related to adherence to safety regulations and compliance requirements. Prion research laboratories are extremely expensive to build or to expand because special safeguards are required to protect both the investigator and the public. U.S. Department of Agriculture and institutional rules require TSE laboratories to meet the biological safety standards at biosafety level 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 are just out of training and who want to start up their own laboratories must weigh the high financial start-up costs, the long-term investment, and the uncertain availability of funds for prion research compared with those for other types of research. Recommendation: Support programs that attract and train more investigators in prion disease research. In addition, for investigators conducting prion bioassay research, provide grants for 5- to 7-year periods. Recommendation: Provide funds to increase the capacities of animal facilities and containment laboratories (biosafety levels 2 and 3) to conduct prion research.

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INTERNATIONAL COLLABORATION A quick remedy for the shortage of U.S. laboratory space for prion investigators is unlikely. However, several large European laboratories conducting prion research might offer opportunities for collaboration with U.S. investigators and might even allow U.S. investigators to use their laboratory space. The French government already has set up 35 fellowships for foreign TSE researchers and is actively seeking U.S. applicants (Personal communication, R.T.Johnson, Johns Hopkins University, 2002). France has a biosafety level 3 facility with housing for 60 macaques, and the government is building a dedicated prion research facility that will house 120 monkeys and provide laboratories for visiting scientists (Johnson, personal communicaton, 2002). At a recent Institute of Medicine committee meeting, a scientist from a large Swiss TSE research facility indicated that a great deal of collaborative TSE research is occurring on both a national and an international scale (Raeber, 2002). Recommendation: Provide funding for collaborative research and training with European investigators and facilities that provide unique opportunities for prion research. STANDARDIZED REAGENTS AND MATERIALS Few of the basic materials used in prion research have been standardized or commercialized, increasing the number of challenges for TSE investigators. The reagents used to conduct individual studies are often made by the laboratory conducting the study or are borrowed from a fellow investigator's laboratory. The consequent lack of standardization has hampered the ability to replicate the results of one laboratory by another laboratory, delaying opportunities to validate key discoveries. This lack of standardization is also true of the animals used in prion research. Many of these animals are specially inbred or are genetically altered to have specific mutations, have the genes of other species embedded in their chromosomes (transgenic animals), or have deletions of specific genetic coding areas (knockout mice). The processes and the level of quality control required to produce these engineered animals are not well established. This issue regarding standardized materials is also a concern for researchers in Europe and elsewhere. In September 1999, the World

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Health Organization (WHO) held a special consultation meeting to address this problem. The group at the meeting recommended that a working group be established (WHO, 2000). 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, 2001). 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 material from this WHO reference center. Therefore, there needs to be a mechanism in the United States for investigators to have access to research reference 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 model 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 organization, and then other organizations could be subcontracted to carry out the requirements of the contract. This mechanism has worked well with the Vaccine Development Program at the National Institute of Allergy and Infectious Disease (Personal communication, R.T.Johnson, Johns Hopkins University, 2002). The TSE research community in the United States needs not only standard 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 prions, and another might contain transgenic or specially engineered animals. The preferred model is to use existing repositories (for example, the Jackson Laboratory, which is an animal production repository) and add prion-related materials to their collections. The preexisting building, equipment, personnel, and database infrastructure associated 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

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foundations. Later, after the repositories have been established, the fees paid by investigators using the materials would cover the general operating costs. Recommendation: Establish a collection of reference materials and genetically engineered animals (including transgenic mice), as well as reference repositories, useful for the development of TSE diagnostics and for TSE research. All investigators involved in prion research must have access to this collection. It would be reasonable to include the collection in existing, high-quality repositories with similar standardized reagents. 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 detection of both PrPSc and infectivity. The panels would consist of reagents known to contain TSE-related material (positive controls) as well as reagents known to be free of TSE-related material (negative controls). These panels would be used to confirm the performance characteristics of test kits before they are approved for public use, as well as to perform quality control on test kit lots before their release to the market. FDA has developed such panels in the past for validating antibody-screening tests for human immunodeficiency virus and hepatitis C virus. Recommendation: The Food and Drug Administration should have panels of reference reagents available to evaluate the performance characteristics of tests to detect the prion protein and infectivity. The pace of progress in prion disease research 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 ultimately may not accomplish the nation's goals in a timely manner. To accomplish the broad goals mentioned earlier in this chapter, the research capacity to conduct TSE research must be enhanced significantly. That will require more laboratories that can

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serve as training platforms, more researchers who can enter the field of study, a larger and more reliable funding environment, and better scientific tools. It is noteworthy that the Secretary of Health and Human Services approved 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 take sustained attention, effort, and funding. REFERENCES DHHS (U.S. Department of Health and Human Services). 2001. Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathy (BSE/TSE): Action Plan. Washington, D.C.: U.S. Department of Health and Human Services. European Commission (Research Directorate General, Quality of Life and Management of Living Resources Programme). 2001. Inventory of National Research Activities in Transmissible Spongiform Encephalopathies (TSEs) in Europe. Brussels: European Commission. Johnson RT. 2002. Summary of NIH Intramural and Extramural TSE Research Efforts. Presentation to the National Prion Research Program Stakeholders Meeting. Alexandria, VA. Raeber A. 2002. Is BSE a Worldwide Problem? Commercial Diagnostic Testing for TSEs in Europe. Presentation to The IOM Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science, Meeting I. The National Academies, Washington, D.C. WHO (World Health Organization). 2000. WHO Consultation on Public Health and Animal Transmissible Spongiform Encephalopathies: Epidemiology, Risk and Research Requirements. Geneva: World Health Organization Communicable Disease Surveillance Control and Office International des Epizootics. WHO. 2001. Working Group on International Reference Materials for Diagnosis and Study of Transmissible Spongiform Encephalopathies (TSEs): Third Meeting. Blood Safety and Clinical Technology. Geneva.