Testimony Before the Committee on Appropriations United States Senate
The National Institutes of Health Research Agenda for the Transmissible Spongiform Encephalopathies
Statement of Anthony S. Fauci, M.D. Director National Institute of Allergy and Infectious Diseases National Institutes of Health U.S. Department of Health and Human Services Introduction
Mr. Chairman and Members of the Committee, thank you for the opportunity to discuss the role of the National Institutes of Health (NIH) in conducting research to combat the transmissible spongiform encephalopathies (TSEs), a family of neurodegenerative disorders that affect many mammals, including humans. These diseases include scrapie, which primarily affects sheep, bovine spongiform encephalopathy (BSE) or “mad cow disease,” which affects cattle, chronic wasting disease (CWD), which is currently spreading among deer and elk populations in the United States, and Creutzfeldt-Jakob disease (CJD), which affects humans.
The National Institute of Allergy and Infectious Diseases (NIAID) is the lead federal agency for research on emerging, re-emerging, and deliberately emerging infectious diseases, the latter related to acts of bioterrorism. In the context of emerging infectious diseases, NIAID also carries out significant research on TSEs. Other NIH institutes, including the National Institute for Neurological Disorders and Stroke (NINDS), the National Institute of Aging (NIA), and the National Heart, Lung, and Blood Institute (NHLBI), also support substantial and vigorous TSE research programs. Today I will provide some scientific background about TSEs, and describe the NIH research program directed at these unusual diseases, which is designed to allow us to develop new methods to prevent and treat them.
Scientific Background
TSEs are untreatable and invariably fatal diseases of the brain. Although TSEs differ in clinical presentation, they have many characteristics in common, including a similar pattern of pathology characterized by the development of multiple holes in the brain, giving it a spongy appearance at autopsy. The neurological symptoms generally involve behavioral changes, memory loss, and movement disorders, progressing to total incapacitation and death. In most circumstances, TSEs have incubation periods measured in years between the time of infection and the onset of symptoms. Although they are transmissible, infection provokes no discernable response from the immune system.
Incidence. Although CJD is the most common TSE that occurs in humans, it is nonetheless rare, occurring sporadically throughout the world at the stable rate of about one case per million people per year, mostly among people aged 50 to 70 years. About 90 percent of CJD cases are sporadic, with no discernable transmission source or pattern of inheritance; in a small number of cases, a specific source of transmission is known. A familial form of the disease also occurs due to specific, inheritable genetic mutations, and accounts for the remaining CJD cases.
A widespread epidemic of BSE among cattle in Great Britain began in the late 1980s, and was followed several years later by the appearance of CJD in unusually young individuals in the United Kingdom. Furthermore, in these cases, certain clinical and pathological features were slightly different from classic CJD. In 1996, this was recognized as a new form of the disease, called variant CJD (vCJD). It is thought to be the human form of BSE, caused by the consumption of meat contaminated with nervous system tissue from BSE-affected cattle. A total of 156 cases of vCJD have been reported (as of February 2, 2004), almost all of which occurred among people who had multi-year exposures in the United Kingdom during the BSE outbreak there. Changes in feeding practices and widespread testing and culling of infected animals have greatly reduced the incidence of BSE among cattle in the United Kingdom and Europe.
In the United States, only one case of BSE has been identified, in a cow in Washington State, and only a single case of what appeared to be vCJD has been reported, in a British woman living in Florida, believed to have been infected during her stay in Great Britain. There is, however, a TSE that is endemic among wild and farmed populations of deer and elk in the western part of the United States—chronic wasting disease—that is the focus of a great deal of interest because its potential to transmit to humans is unknown.
Transmission. TSEs are transmitted by exposure to material from an infected animal; they vary, however, in the relative ease with which transmission occurs. Known cases of CJD transmission, for example, have been linked to the transplantation of eye and nervous system tissue from donors with undiagnosed CJD, the use of brain-derived hormone extracts pooled from large groups of donors, and the use of neurosurgical instruments that had been previously used on someone with CJD and were not subsequently sterilized with both high heat and chemical treatment. CJD is not spread by routine contact between people. Similarly, BSE is transmitted by contaminated feed, and has not otherwise been observed to spread laterally within a herd. Scrapie and chronic wasting disease spread more readily, however, including within herds. The scrapie agent seems to be able to persist in the environment, as scrapie-free sheep can become infected by grazing on a field that had been occupied by scrapie-infected sheep as much as three years earlier. Moreover, CWD has spread among captive and dispersed populations of herbivorous deer and elk, perhaps through ingestion of contaminated plant material.
The agents that transmit TSEs appear to be very different from those that cause all other known infectious diseases. These agents have not been shown to contain nucleic acids that encode genetic information. This and other evidence led to the hypothesis that disease-causing prions consist solely of an abnormal form of a normal host protein; the term “prion,” in fact, was derived from “proteinaceous infectious particle.” Although many, if not most scientists in the field accept this hypothesis, some believe that other factors may also be involved in disease transmission, such as an unknown virus. Whatever the composition of the transmissible agents, it is clear that they are unusually resistant to heat and chemical treatments that would destroy most other pathogens.
Disease Mechanisms. Whether or not the mis-folded prion protein is the sole agent of transmission, it clearly accumulates in the brains of animals and humans with TSE diseases, and is essential to the pathogenesis of the disease. The function of the normal prion protein, which is located on the surface of cells from many tissues including the brain, is not yet known. When prion proteins adopt an abnormal shape, however, the molecules aggregate to form long, insoluble chains that cells cannot clear by normal maintenance mechanisms. The resulting buildup of the abnormal protein chains causes cell damage and the destruction of brain tissue. Similar chains of abnormally shaped brain proteins are also observed in people with Alzheimer’s disease, Huntington’s disease, and some other neurodegenerative disorders; these other diseases, however, are not transmissible.
NIH Research on TSEs
The NIH has long been a pioneer in research on TSEs worldwide. This is reflected in the award of two Nobel Prizes in physiology and medicine: in 1976, to D. Carleton Gajdusek, an NIH intramural researcher, for work begun in the 1960's that established the transmissibility of these diseases; and in 1997, to Stanley Prusiner for NIH-funded studies that led to the theory that prions are the sole agent of transmission of TSEs. In FY 2004, the NIH will spend an estimated $33.2 million on research on TSEs.
In 2001, HHS Secretary Tommy Thompson approved an Action Plan for TSEs, which delineated specific tasks to be accomplished by different federal agencies. NIH was assigned the primary research responsibility, to be focused on four areas: 1) understanding the infectious agents of TSEs; 2) defining how TSEs are transmitted among animal species and across species barriers; 3) developing diagnostic tests for animals and humans using tissues and blood; and 4) developing drug therapies. The NIH is currently engaged in carrying out this agenda.
Prion Characteristics and Pathogenic Mechanisms. Isolation and characterization of all components of prions, including a complete description of their molecular and chemical properties, is an urgent research priority, as is attaining a better understanding of how the infection spreads within a host. Although the precise nature of TSE infectious agents remains unclear, NIH scientists demonstrated that the abnormal form of the prion protein can convert normal prion protein molecules to the abnormal form, and thus has the potential to be the infectious agent. Experiments using genetically modified mice and studies of infected deer have provided new models for studying mechanisms of prion diseases.
Transmission. In light of the epidemiology of vCJD as well as the prevalence of CWD in deer and elk herds in the western United States, studies to elucidate species barriers as well as the mechanisms of cross-species transmission of TSE disease are a high priority. Recent NIH studies have shown that species once thought to be resistant to certain TSE strains can serve as carriers of the infection without ever displaying symptoms. The implication is that humans exposed to agents that cause mad cow disease or chronic wasting disease might harbor infectious agents that may be able to adapt over many years to become dangerous to other humans exposed to them, even in the absence of clinical signs.
Diagnostics. The development of methods to detect TSE diseases before symptoms appear is critical for the success of both therapeutic strategies and prevention programs. Current tests can diagnose TSE disease based on detection of abnormal prion protein in samples of brain tissue, but because of the very low levels of abnormal prion protein in blood, these tests are not sensitive enough for routine blood screening. NIH is supporting research to stimulate TSE diagnostic test development.
Therapeutics. No effective drug therapies for TSEs currently exist. NIH scientists, however, have recently developed a high-throughput screening test for inhibitors of TSE-associated prion accumulation. After testing more than 2000 FDA-approved drugs and natural products, they have discovered 15 inhibitors of abnormal prion formation representing several different classes of compounds. Most of these are known or likely to be able to enter the brain and have been administered to humans for other purposes, and therefore have promise as either prophylactic or therapeutic anti-TSE agents. Further testing against scrapie in rodents is under way. Studies of the potential use of antibodies and vaccine-based therapies for TSEs also are ongoing.
Conclusion
Mr. Chairman, thank you again for inviting me to discuss NIH’s efforts to address this highly unusual class of infectious diseases. There is much to learn about TSEs, and NIH scientists are working diligently to frame the research questions properly, and to eventually provide answers. I would be pleased to answer any questions.
