|
Items in cart [0] |
Questions? Call 888-624-8373 |
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 214
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
OCR for page 215
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.
OCR for page 216
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.
OCR for page 217
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-
OCR for page 218
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
OCR for page 219
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-
OCR for page 220
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,
OCR for page 221
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].
OCR for page 222
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.
Representative terms from entire chapter:
transmissible spongiform
