6
Reporting Foodborne Threats: The Case of Bovine Spongiform Encephalopathy (BSE)

OVERVIEW

The rapid reporting of foodborne threats is essential to reducing the burden of foodborne illness, but it also carries direct and indirect costs to individuals, communities, industries, and national economies. The balance of costs and benefits associated with reporting foodborne threats is clearly illustrated by the world’s recent and ongoing experience with bovine spongiform encephalopathy (BSE, or mad cow disease). A series of workshop presentations by contributors to this chapter explored the biology of BSE and its implications for food safety, international perspectives on BSE surveillance and prevention, and public health lessons learned from this disease and its consequences.

A member of the family of diseases known as transmissible spongiform encephalopathies (TSEs; also known as prion diseases), BSE was first identified in 1986 in the United Kingdom and has since been detected in 26 countries (GAO, 2005). In the early 1980s, Stanley Prusiner, the author of this chapter’s first paper, proposed that the pathogens that cause two TSEs—Creutzfeldt-Jakob disease (CJD) and scrapie, a disease of sheep—consist entirely of an infectious form of protein that he termed the prion; in 1997, he was awarded the Nobel Prize in Physiology and Medicine for his work on prion biology. Researchers have since learned that in addition to scrapie and CJD, prions cause BSE and its human variant, vCJD, as well as chronic wasting disease in deer and elk.

Prusiner presents experimental evidence for the prion model of TSE and describes the etiology and diagnosis of vCJD and other human prion diseases. He emphasizes the differences between prion and viral illnesses—most notably, that prions can arise spontaneously—and observes that the mistaken equation of the



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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary 6 Reporting Foodborne Threats: The Case of Bovine Spongiform Encephalopathy (BSE) OVERVIEW The rapid reporting of foodborne threats is essential to reducing the burden of foodborne illness, but it also carries direct and indirect costs to individuals, communities, industries, and national economies. The balance of costs and benefits associated with reporting foodborne threats is clearly illustrated by the world’s recent and ongoing experience with bovine spongiform encephalopathy (BSE, or mad cow disease). A series of workshop presentations by contributors to this chapter explored the biology of BSE and its implications for food safety, international perspectives on BSE surveillance and prevention, and public health lessons learned from this disease and its consequences. A member of the family of diseases known as transmissible spongiform encephalopathies (TSEs; also known as prion diseases), BSE was first identified in 1986 in the United Kingdom and has since been detected in 26 countries (GAO, 2005). In the early 1980s, Stanley Prusiner, the author of this chapter’s first paper, proposed that the pathogens that cause two TSEs—Creutzfeldt-Jakob disease (CJD) and scrapie, a disease of sheep—consist entirely of an infectious form of protein that he termed the prion; in 1997, he was awarded the Nobel Prize in Physiology and Medicine for his work on prion biology. Researchers have since learned that in addition to scrapie and CJD, prions cause BSE and its human variant, vCJD, as well as chronic wasting disease in deer and elk. Prusiner presents experimental evidence for the prion model of TSE and describes the etiology and diagnosis of vCJD and other human prion diseases. He emphasizes the differences between prion and viral illnesses—most notably, that prions can arise spontaneously—and observes that the mistaken equation of the

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary two can impede the development of effective preventions against invariably fatal prion diseases. “The only rational strategy is to test all cattle for prions and eliminate those harboring prions from the food supply,” Prusiner concludes. The second paper, by Steven Collins, codirector of the Australian National CJD Registry, describes his country’s approach to TSE surveillance in both animals and humans. The vast majority of CJD cases in the Australian Registry are sporadic; no cases of vCJD or endogenous cases of either BSE or scrapie have been reported to date in the country. Collins recounts the range of measures Australia has adopted to protect commercial livestock from BSE and scrapie, which include bans on the importation of meat and bone meal and of live cattle from any country reporting BSE, as well as the prohibition of ruminant-to-ruminant feeding of meat and bone meal. Maura Ricketts, who has directed prion disease surveillance and research for Health Canada and the World Health Organization (WHO), discusses BSE and vCJD from a public health perspective in the chapter’s third paper. After defining and applying relevant core principles of public health, Ricketts identifies and explores key issues that underlie the development and implementation of health policy to address BSE and vCJD. She concludes with an overview of possible public health actions that reflect the importance of controlling the risk of BSE exposure. In the chapter’s final contribution, Wil Hueston of the Center for Animal Health and Food Safety at the University of Minnesota shares insights gained from 16 years of involvement with BSE and the interface between animal and human health. He distills this experience into seven lessons that lead to a series of key actions that could be taken to address key issues raised by BSE and, more generally, to improve the response to infectious disease. PRIONS AND THE SAFETY OF THE FOOD SUPPLY Stanley B. Prusiner, M.D.1 University of California San Francisco In December 2003, mad cow disease made its U.S. debut when federal officials announced that a Holstein cow from Mabton, Washington, had been stricken with bovine spongiform encephalopathy (BSE). Although the U.S. government acted surprised by the finding, they should have expected such cattle based on the biology of the prion diseases. Perhaps the novel principles of disease that have emerged over the past two decades from investigations of prions (Prusiner, 2004b) are still too new and different for many people to grasp easily the implications of this discovery. Prions are unprecedented infectious pathogens that are composed 1 Institute for Neurodegenerative Diseases, Departments of Neurology and of Biochemistry and Biophysics.

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary solely of protein; they are devoid of nucleic acid—DNA and RNA. The absence of a nucleic genome sets prions apart from all other infectious pathogens including viruses, viroids, bacteria, fungi, and parasites. Because prions multiply and cause disease in the host, scientists thought for many years that prions must be slow-acting viruses. Moreover, the identification of varieties or strains of prions made the argument that prions must be viruses even more appealing. Because so many attempts to detect a prion-specific nucleic acid genome failed (Alper et al., 1967; Bellinger-Kawahara et al., 1987a,b; Safar et al., 2005b), some scientists argued that the nucleic acid must be quite small (Bruce and Dickinson, 1987; Chesebro, 2004; Kimberlin, 1982; Weissmann, 1991). Although the identification of micro RNAs has given new life to such arguments in recent years, the production of synthetic prions from recombinant prion protein (PrP) is likely to end the quest for an auxiliary molecule within the prion (Legname et al., 2004, 2005). Based on a wealth of data including the production of synthetic prions in mammals and fungi, it is reasonable to define prions as infectious proteins. Prions multiply by forcing the precursor protein to acquire a second conformation. Different conformations of proteins in the prion state encipher distinct strains and are prone to aggregation. In mammals, prions accumulate to high levels in the nervous system where they cause dysfunction and fatal degeneration. Both mammalian and fungal prions have been produced in cell-free systems (Brachmann et al., 2005; Maddelein et al., 2002; Sparrer et al., 2000; Tanaka et al., 2004). Synthetic PrP peptides and recombinant PrP fragments have been used to form mammalian prions, and N-terminal regions, called prion domains, that are rich in glutamine and asparagine have been used to form fungal prions. In mammals, prions cause a group of invariably fatal, neurodegenerative diseases. No human or animal has ever recovered from a prion disease once neurologic dysfunction has manifested. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of normal, cellular PrP, designated PrPC. The tertiary structure of PrP is profoundly altered as prions are formed, and as such, prion diseases represent disorders of protein conformation. In the sporadic and genetic forms of prion disease, prions arise spontaneously. In contrast, infectious prion diseases result from exposure to an exogenous source of prions. Although the incidence of sporadic prion disease in humans is low (1–5 cases per 106 people), it is the most common form, accounting for approximately 90 percent of all cases. The genetic, or inherited, forms of prion disease account for approximately 10 percent of all human cases and the infectious forms for less than 1 percent. Whether or not the infectious forms of human prion disease are underestimated and low levels of animal prions in the food supply are responsible for 10–20 percent of the sporadic cases is unknown. The prion diseases in humans include CJD, which generally presents as a progressive dementia, as well as kuru and Gerstmann-Sträussler-Scheinker disease (GSS), both of which frequently present as ataxic maladies. Like kuru and

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary GSS of humans, scrapie of sheep and BSE of cattle usually manifest as ataxic illnesses. Deer, elk, and moose with chronic wasting disease (CWD) appear emaciated and ataxic. In these diseases, mammalian PrPC is recruited and converted into the disease-causing isoform (PrPSc). PrPC has a high -helical content and little -sheet structure, whereas PrPSc has less -helical structure and a high -sheet content. Comparisons of secondary structures of PrPC and PrPSc were performed on proteins purified from Syrian hamster (SHa) brains (Pan et al., 1993). Limited proteolysis of PrPSc produces a protease-resistant core, designated PrP 27–30, which retains prion infectivity; under these conditions, PrPC is completely hydrolyzed. Prion Disease Paradigm Despite some similarities between prion and viral illnesses, these disorders are very different. Viral diseases are infectious illnesses that begin with infection by exogenous virions. In contrast, the vast majority of prion diseases are initiated from within the host, in which prions arise spontaneously. Often the term prion infection is used synonymously with prion disease because once prions are formed spontaneously they can be transferred to another host and thus, are infectious. Unlike viral infections, no host defenses are mounted in response to prion infection: no humoral immunity, no cellular immunity, and no interferons are elicited to the replicating prion. Molecular genetic studies have been crucial in deciphering the novel features of the prion disease paradigm. In the sporadic form of prion disease, the sequence of the PrP gene is wild-type (wt); whereas, in the inherited prion diseases, the sequence of the PrP gene harbors a nonconservative substitution or insertion. Generally, the PrP genes of humans and animals with infectious prion disease are wt. Before the discovery of mutations in the PrP gene as the cause of familial prion disease, geographic clusters of prion disease were thought to be due to common source exposures to exogenous prions. For example, Libyan Jews with a very high incidence of CJD were thought to have contracted the disease by eating lightly cooked sheep brains (Alter and Kahana, 1976). Molecular genetic investigations showed that every Libyan Jew developing prion disease carried a PrP gene mutation resulting in an EK substitution at position 200 (Goldfarb et al., 1991; Hsiao et al., 1991). Risk analysis studies revealed that every Libyan Jew carrying the E200K mutation would eventually develop prion disease if he or she did not die of some other illness (Chapman et al., 1994; Spudich et al., 1995). Synthetic Prions and Spontaneous Disease Investigations of humans with PrP gene mutations were extended to transgenic (Tg) mice harboring the analogous mutation causing GSS in humans. Tg

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary mice expressing high levels of MoPrP(P101L) developed neurodegeneration spontaneously (Hsiao et al., 1990; Telling et al., 1996). Extracts prepared from the brains of these mice transmitted disease after approximately 250 days to other Tg mice (designated Tg196) expressing low levels of MoPrP(P101L) (Hsiao, 1994). Subsequently, a synthetic PrP peptide of 55 residues carrying the P101L mutation, designated MoPrP(89–143,P101L), was produced and inoculated into the Tg196 mice (Kaneko et al., 2000). The Tg196 mice developed central nervous system (CNS) dysfunction approximately one year after inoculation, and brain extracts from the ill mice were found to produce disease on serial passage (Tremblay et al., 2004). The MoPrP(89–143, P101L) peptide produced disease in the Tg196 mice only if it was folded into a -rich conformation (Kaneko et al., 2000). An approach similar to the one used in the studies with MoPrP(89– 143,P101L) peptide was employed with wt PrP. In those studies, wt MoPrP(89– 230) was produced in E. coli, purified by chromatography, and polymerized into amyloid fibrils (Legname et al., 2004). The amyloid fibrils were injected into Tg mice expressing MoPrP(89–231) and produced neurodegeneration after approximately 500 days. Brain extracts from the ill Tg mice contained protease-resistant PrPSc and produced disease on subsequent passage into both wt and Tg mice (Legname et al., 2005). These studies demonstrated that only PrP is required to generate prion infectivity, and as such, spontaneous forms of prion disease can occur in any mammal as PrPC seems to be ubiquitous among this class of vertebrates. Spontaneous prion disease contrasts with viral disorders, for which exogenous infection is required except in the case of latent retroviral genomes. For example, after infection with exogenous HIV, the virus may disappear but often its RNA genome has been reverse-transcribed into DNA, and the DNA copies may remain dormant for years. The dramatically different principles that govern prion biology from those underpinning the viral diseases are frequently misunderstood. This lack of understanding has led to some regrettable decisions of great economic, political, and possibly public health importance. For example, scrapie and BSE have different names, yet they are the same disease in two different species. Scrapie and BSE differ in only two respects: first, the PrP sequence in sheep differs from that of cattle at seven or eight positions of 270 amino acids (Goldmann et al., 1990, 1991), which results in different PrPSc molecules. Second, most scrapie strains of prions seem to be different from the BSE strains. The Mad Cow Epidemic The world awoke to the dangers of prion disease in cows after the BSE outbreak began ravaging the British beef industry in the mid-1980s. The truly novel concepts emerging from prion science forced researchers and society to think in

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary unusual ways and made coping with the epidemic difficult. Investigators eventually learned that prions were being transmitted to cattle through meat-and-bone meal (MBM), a dietary supplement prepared from the parts of sheep, cattle, pigs and chickens that are processed, or rendered, for industrial use. High heat eliminated conventional pathogens, but PrPSc survived and went on to infect cattle. As infected cattle became food for other cattle, BSE began appearing throughout the UK cattle population, reaching a high of 37,280 confirmed fied cases in 1992 (Phillips, 2000). The British authorities instituted some feed bans beginning in 1989, but it was not until 1996 that a strict ban on cannibalistic feeding finally brought BSE under control in the United Kingdom; the country saw 612 cases in 2004. Overall, the United Kingdom has identified approximately 180,000 mad cows, and epidemiologic models suggest that another 1.9 million were infected but went undetected (Anderson et al., 1996). For many people, the regulations came too late. Despite the British government’s early assurances to the contrary, mad cow disease proved transmissible to humans. In March 1996, Robert Will and his colleagues reported that 11 British teenagers and young adults had died of a variant of Creutzfeldt-Jakob disease (vCJD) (Will et al., 2004, 1996). In these young patients, the patterns of PrPSc deposition in the brain differed markedly from that found in typical CJD patients. Many scientists, including myself, were initially dubious of the presumed link between BSE and vCJD. I eventually changed my mind, under the weight of many studies. The most compelling of these studies used Tg mice genetically engineered to resemble cattle, at least from a PrP point of view. These mice became ill approximately 250 days after receiving injections of prions either from cattle with BSE or people with vCJD, and the resulting disease looked the same whether the prions originated from diseased cows or vCJD patients (Scott et al., 1999). Since the detection of mad cow disease in the United Kingdom, two dozen other nations have uncovered cases. Canada and the United States are the latest entrants to the list of countries affected. On May 20, 2003, Canadian officials reported BSE in an eight-year-old cow that had spent its life in Alberta and Saskatchewan. (The country’s only previous mad cow had arrived as a UK import 10 years earlier.) Although the animal had been slaughtered in January 2003, slow processing meant that officials did not test the cow remains until April. By then, the carcass had been turned into pet food and exported to the United States. Seven months later, on December 23, 2003, the U.S. Department of Agriculture (USDA) announced the country’s first case of BSE in Washington state. The six-year-old dairy cow had entered the United States at the age of four. The discovery meant that U.S. officials could no longer labor under the misconception that the nation is free of BSE. Like Canada, U.S. agricultural interests want the BSE problem to disappear. Financial woes stem primarily from reduced beef exports: 58 other countries are keeping their borders shut, and a $3 billion export

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary market has largely evaporated. At the time of writing, six more cases of BSE in Canada and two additional cases in the United States have been reported. Infectious Human Prion Diseases Prions from different sources have infected humans. Human prions have been transmitted to others both by ritualistic cannibalism and iatrogenic means. Kuru in the highlands of New Guinea was transmitted by ritualistic cannibalism, as people in the region attempted to immortalize their dead relatives by eating their brains (Alpers, 1968; Gajdusek, 1977; Glasse, 1967). Iatrogenic transmissions include prion-tainted human growth hormone (HGH) and gonadotropin, dura mater grafts, and corneal transplants from people who died of CJD. In addition, CJD cases have been recorded after neurosurgical procedures in which ineffectively sterilized depth electrodes or instruments were used. Variant Creutzfeldt–Jakob Disease (vCJD) The first cases of vCJD in teenagers and young adults were identified in Great Britain in 1994 (Will et al., 1996). More than 170 teenagers and young adults have died of vCJD in Britain, France, Ireland, Italy, Japan, Portugal, and the United States. Although the average age of vCJD patients is 26 years of age, the youngest patient was 12 years old and the oldest was 74 years of age (Spencer et al., 2002). The median duration of the illness is 13 months, with the range from 6 to 69 months. In addition to the young age of these patients (Bateman et al.,1995; Britton et al., 1995), vCJD is characterized by numerous PrP amyloid plaques surrounded by a halo of intense spongiform degeneration in the brain (Ironside, 1997). These unusual neuropathologic changes have not been seen in CJD cases in the United States, Australia, or Japan (CDC, 1996; Ironside, 1997). Both macaque monkeys and marmosets developed neurologic disease several years after inoculation with bovine prions (Baker et al., 1993), but only the macaques exhibited numerous PrP plaques similar to those found in vCJD (Lasmézas et al., 1996). The majority of vCJD patients present with psychiatric symptoms, including dysphoria, withdrawal, anxiety, insomnia, and loss of interest (Spencer et al., 2002; Will et al., 2004). Generally, neurologic deficits do not appear until at least four months later; these neurologic changes consist of memory loss, paresthesias, sensory deficits, gait disturbances, and dysarthria. Most vCJD cases have been reported from Britain, and 10 have been found in France. The one U.S. case was a 23-year-old woman, who is thought to have been exposed to bovine prions while living in Britain during the first 12 years of her life. From both epidemiologic and experimental studies, the evidence is quite compelling that vCJD is the result of prions being transmitted from cattle with BSE to humans through consumption of prion-contaminated beef products.

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary Transmission of vCJD Prions by Blood Transfusion vCJD has been identified in two patients who received blood transfusions from donors that later died of vCJD. In one case, the recipient was a 69-year-old male who was transfused 6.5 years before the onset of neurologic dysfunction (Llewelyn et al., 2004). Many details of the second case are not published, but the patient is known to have died of a nonneurologic disease (Peden et al., 2004). Although vCJD prions were found in the spleen and cervical lymph nodes of this patient, none were found in the brain. A glimpse of future vCJD cases caused by prion-tainted transfused blood may come from a survey of tissues collected during appendectomies and tonsillectomies. Such a survey from the United Kingdom reports that of the 12,674 appendectomy specimens examined, three were positive for PrPSc by immunohistochemistry (IHC) (Hilton et al., 2004). This finding argues that as many as 3,800 people in the United Kingdom may be replicating vCJD prions in their lymphoid tissues. Considering that immunohistochemistry (IHC) is considerably less sensitive than the conformation-dependent immunoassay (CDI), the number of Britons harboring vCJD prions in their lymphoid tissues may approach 20,000 (Safar, 2005a). Approaches to Prion Diseases Because prion diseases have aspects that resemble illnesses caused by viruses as noted above, many people use analogies to viruses when thinking about prions. But these analogies can sow confusion. One example is the presumed origin of the mad cows in Canada and the United States. Although it is true that BSE first appeared in the United Kingdom and then spread elsewhere through exported prion-contaminated feed, approaches from a traditional bacterial or viral epidemic are only partly helpful. In such situations, quarantines or bans can curb the spread of disease. But prions can arise spontaneously, which is an extremely important characteristic that distinguishes prions from viruses. In fact, any mammal is capable of producing prions spontaneously. Spontaneous prion disease is thought to have triggered the epidemic of kuru, which decimated a group called the Fore in New Guinea in the past century. According to one theory, sporadic (s) CJD occurred in an individual whose brain was then consumed by his or her fellow Fore in a funerary rite involving cannibalism. The continued practice created a kuru epidemic. Ceasing the practice of this funerary rite also resulted in the decreased incidence of kuru. Similarly, a feed ban that prevents cattle from eating the remains of other animals is crucial in containing BSE. But such bans will not eliminate the presence of mad cows when pathogenic prions arise spontaneously. If every year, 1– 5 people per million spontaneously develop prion disease, why not the same incidence for cows? Indeed, I suspect that the North American BSE cases are likely to have arisen spontaneously and that afflicted animals have occasionally ap-

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary peared unrecognized in herds ever since humans started cattle ranching. We have been extraordinarily lucky that a spontaneous case did not trigger an American BSE epidemic. Or perhaps small epidemics did occur but were undetected. Still, many prefer the idea that the mad cows in North America acquired prions from their feed. Such reasoning allows people to equate prions with viruses—that is, to think of prions only as infectious agents (even though most of time, they arise spontaneously)—and to offer a seemingly plausible plan to eradicate BSE by quarantining herds. But ignoring the revolutionary concepts that govern prion biology can only hamper efforts at developing an effective program to protect the American public from exposure to these deadly agents. We must think beyond quarantine and bans, and test for prions even in the absence of an epidemic. Diagnosis of Prion Diseases The clinical diagnosis of human prion disease is often difficult until the patient shows profound signs of neurologic dysfunction (Roos et al., 1973; Will et al., 2004). In humans with sCJD, the most common clinical presentation is a progressive dementia. Approximately 10 percent of sCJD patients present with a progressive ataxia. It is widely accepted that the clinical diagnosis must be provisional until a tissue diagnosis either confirms or rules out the clinical assessment. Prior to the availability of antibodies to PrP, a tissue diagnosis was generally made by histologic evaluation of neuropil vacuolation. IHC using anti-glial fibrillary acidic protein antibodies in combination with hematoxylin and eosin (H&E) staining preceded the use of anti-PrP antibody staining. Postmortem Tissue Detection of Prions The role of IHC in the diagnosis of scrapie was challenged after a study of the brains from eight clinically affected goats inoculated with the SSBP1 prion isolate (Foster et al., 2001). Thalamic samples taken from seven of eight goats with scrapie were positive for PrPSc by Western blotting but negative by IHC. The eighth goat was negative by both Western blotting and IHC. Consistent with these findings in goats are the results of a study of humans who died of sCJD or familial (f) CJD. In this study, IHC of formalin-fixed, paraffin-embedded human brain samples was substantially less sensitive than the conformation-dependent immunoassay (CDI) (Safar, 2005a). The CDI detected PrPSc in all regions of the brain that were examined in 24 sCJD and 3 fCJD(E200K) cases. Comparative analyses demonstrated that the CDI was vastly superior to both histology and IHC. When 18 regions of 8 sCJD and 2 fCJD(E200K) brains were compared, it was discovered that both histology and IHC were unreliable diagnostic tools except for samples from a few brain

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary regions. In contrast, the CDI was a superb diagnostic procedure as it detected PrPSc in all 18 regions in 8 of 8 sCJD and 2 of 2 fCJD(E200K) cases (Safar, 2005a). Concerned that limited digestion with proteinase K (PK) was hydrolyzing some or even most of the PrPSc, the CDI was developed so as not to require PK digestion to detect PrPSc. The CDI revealed that as much as 95 percent of PrPSc is protease sensitive (sPrPSc) and thus was being destroyed during limited proteolysis used to hydrolyze PrPC. sPrPSc comprises 80–95 percent of the PrPSc found in the frontal lobe and in the white matter of CJD patients (Safar, 2005a). The CDI detected HuPrPSc with a sensitivity comparable to the bioassay for prion infectivity in Tg mice expressing chimeric human-mouse PrP. The high sensitivity achieved by the CDI is due to several factors including the use of phosphotungstic acid (PTA) that specifically precipitates sPrPSc and rPrPSc (Lee et al., 2005; Safar et al., 1998, 2005a). PTA has also been employed to increase the sensitivity of Western blots, enabling the detection of rPrPSc in human muscle and other peripheral tissues (Glatzel et al., 2003; Wadsworth et al., 2001). A comparison between the CDI and Western blotting on brain samples from sCJD and vCJD patients showed that the CDI is 50- to 100-fold more sensitive (Minor et al., 2004). The CDI has also been used to study GSS caused by the P102L mutation. In mice expressing the GSS mutant PrP transgene, the CDI detected high levels of sPrPSc(P101L) as well as low levels of rPrPSc(P101L) long before neurodegeneration and clinical symptoms occurred (Tremblay, 2004). sPrPSc(P101L) as well as low concentrations of rPrPSc(P101L) previously escaped detection (Hsiao et al., 1994). BSE Testing The transmission of kuru prions to more than 2,500 Fore people in the highlands of New Guinea and the transmission of BSE prions to more than 170 teenagers and young adults who died of vCJD argues that oral prion infection can occur. The recognition that patients with vCJD were infected with BSE prions from cattle (Bruce et al., 1997; Collinge et al., 1996; Scott et al., 1997, 2005) prompted the European Union to institute testing of all cattle over 30 months of age at the time of slaughter. Currently, both Western blotting and ELISA tests for rPrPSc are being used on brainstems from cattle (Grassi et al., 2001; Kübler et al., 2003). The CDI test, which measures both protease-sensitive and protease-resistant PrPSc, has been adapted for bovine brainstems and is available for testing cattle. The recent identification of BSE-positive cattle in Canada and the United States has prompted increased surveillance in these countries, but the number of cattle tested remains less than 2 percent of the annual slaughter (Prusiner, 2004a). Despite the small number of cattle being tested, new cases of BSE are being found. These new cases are attributed to tainted feed by agriculture authorities,

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary who continue to think of prion diseases as being similar to infectious illnesses caused by viruses or bacteria. These officials want to believe that BSE will disappear once the consumption of ruminant-derived feed ceases. They refuse to entertain the idea that most cases of prion disease are likely to be sporadic once contaminated feed is eliminated from the food supply. In Japan, 4 million cattle have been tested over the last four years, and close to 20 cases of BSE have been identified. One Japanese cow was 21 months old and another 23 months old (Yamakawa et al., 2003), younger than the animals tested in the European Union. It seems likely that most or all of these young animals developed sporadic BSE. Determining how early in the incubation period BSE prions can be detected by bioassay is now possible due to the construction of Tg mice expressing bovine PrP, designated Tg(BoPrP)Prnp0/0 mice (Buschmann et al., 2000; Scott et al., 1997, 1999). Prior to the production of Tg(BoPrP)Prnp0/0 mice, cattle were used for bioassays of bovine prions. In a limited study using cattle bioassays, bovine prions were undetectable in the obex of the bovine brainstem until 26 months after oral inoculation (Wells, 2002). In these studies, prion infectivity was detected much earlier in the lymphoid tissue of the distal ileum. Prions in Muscle Animal meat products consumed by humans are predominantly muscle tissue. For many years, muscle tissue was thought to be devoid of prions. In studies of the hind limb muscles of mice, prions were found at a level of 5 percent of that in brain (Bosque et al., 2002); other muscle groups also had prions but at lower levels. PrPSc was found in virtually all muscles after prions were fed to hamsters (Thomzig et al., 2003). Investigations of prions in the tongue have shown high levels of both PrPSc and prion infectivity (Bartz et al., 2003). PrPSc was identified in the muscles of 25 percent of the sCJD patients analyzed (Glatzel et al., 2003). In livestock, PrPSc was found in myocytes of the fore and hind limbs of sheep with both natural and experimental scrapie (Andreoletti et al., 2004), and prion infectivity was reported recently in extracts prepared from the muscle of BSE-infected cattle. In the latter studies, prions were detected by transmission to Tg mice expressing bovine PrP (Buschmann and Groschup, 2005). The Only Rational Strategy The only rational strategy is to test all cattle for prions and eliminate those harboring prions from the food supply. No reasonable human would knowingly expose himself or herself to prions as prion diseases are invariably fatal. In Europe, a policy was instituted four years ago of prion testing for all cattle destined for human consumption that are over 30 months of age. The 30-month cutoff point was chosen for surveillance by the Office International des Epizooties (OIE; also known as the World Organization for Animal Health), but it was never intended for food safety. Some European countries have arbitrarily adopted a 24-

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary Collaborate for intersectoral and community action, recognizing that the entire community is affected; Enforce laws and regulations, notably in feed and food safety; Reorient and assure the quality of health services, particularly recognizing that there will be confusion between other forms of human TSEs and vCJD. Additionally, given the experience in the United Kingdom, recognition that those who develop the disease are young; Create supportive environments for all stakeholders; and Evaluate the impact of interventions. Many lessons were learned as a result of the outbreak of BSE in the United Kingdom and Europe. It is important to control the risk of BSE exposure; countries that have focused on the rate of BSE have been unable to prevent its importation and spread. As in a commonly used homily, a chain is only as strong as its weakest link. The key link for public health practitioners is that BSE and vCJD are the same agent. Simply put, if there were no further infections of cattle with BSE, there would be no further cases of vCJD. INCENTIVES AND DISINCENTIVES FOR DISEASE SURVEILLANCE AND REPORTING: THE BSE CASE STUDY Will Hueston, D.V.M., Ph.D.4 University of Minnesota My contribution to this workshop comes in the form of seven lessons that I have learned from 16 years of involvement with bovine spongiform encephalopathy (BSE), followed by a brief list of recommendations derived from these lessons. The lessons and recommendations are drawn from my experience working as a private practice veterinarian, a resident veterinarian for an agribusiness enterprise, a university faculty member, a government animal health official, and an adviser and consultant to national and state government, national and international organizations, and food system companies from production to retail and food service. Lesson 1: Detecting a New Animal Disease Is Extremely Difficult Most individual animal diseases are treated on the farm following clinical diagnosis by the animal owner, farm manager, or in difficult cases, a private-practice veterinarian. If that clinical diagnosis is incorrect, and/or the animal does not recover, the animal is usually sold (culled), eaten, or buried. Most animal 4 Professor and Director, Center for Animal Health and Food Safety.

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary diagnostic services accessible in such situations are provided on a fee-for-service basis. Only foreign animal disease investigations and diagnostics are provided free of charge by government veterinarians, as they are seen as a public good. Even then, however, the diagnostic workup is generally limited to ruling out a specific foreign animal disease (e.g., foot-and-mouth disease or BSE); there is no follow-up to determine the exact cause of illness if foreign animal diseases are ruled out. Consequently, it is very difficult to detect the signals of the emergence of a new animal disease. Limited national monitoring and surveillance does occur, such as the National Animal Health Monitoring system and more recently the National Animal Health Laboratory Network. Creating inclusive national animal disease databases has been hampered by the lack of widely accepted standardized nomenclature for animal diseases and presenting signs. Unfortunately, most animal diagnostic laboratory and veterinary hospital record-keeping systems are designed to facilitate financial accounting and billing, not epidemiologic analysis. By comparison with Europe, Canada, New Zealand, and Australia, the U.S. federal animal health laboratory system is quite limited. The federal government supports two national laboratories, one operated by the Department of Homeland Security on Plum Island, New York, and the other is operated by the USDA Animal and Plant Health Inspection Services Veterinary Services in Ames, Iowa. Research and diagnostics at these facilities focus on diseases for which there is a specific programmatic target, such as foreign animal diseases at Plum Island, and domestic program diseases such as brucellosis, tuberculosis, and BSE at Ames. These two laboratories provide reference services for state and private laboratories (confirmation of specific program diseases). The U.S. government does not have a national laboratory focused specifically on the detection or description of emerging animal diseases. Animal disease diagnostics in the United States are performed by state, university, and private laboratories that vary greatly in terms of their quality and capacity. About 12 of the 50 state animal diagnostic laboratories are linked in a pilot version of a national animal health laboratory network. Limited funding has been provided to these laboratories to allow them to cooperate with the federal laboratories for foreign animal disease diagnostics but not for the identification and characterization of emerging diseases. Lesson 2: Recognizing BSE in a Low-Incidence Country Is Difficult Even Under the Best Circumstances BSE has no unique presenting clinical signs. Therefore, the disease can only be detected through specialized diagnostic testing of brain samples; it cannot be diagnosed by clinical evaluation of the live animal or by gross necropsy such as that carried out on a dead animal on the farm.

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary Most countries conduct passive surveillance for BSE and other animal diseases, providing diagnostic services for those animals voluntarily presented to the laboratory rather than actively searching for cattle demonstrating clinical signs compatible with BSE or dying of unknown causes. This focus on passive surveillance leads to confusion between the absence of evidence for a disease and the evidence of its absence. Countries with no “BSE suspects” presented for diagnostic workup claim that no BSE exists, even though the clinical signs associated with BSE (changes in mentation, sensation, and locomotion) are found in a number of commonly occurring cattle diseases that can only be differentiated from BSE by extensive diagnostic workup. In addition, adherence to the “disease present or absent” paradigm further reduces the effectiveness of passive surveillance by establishing a bias against detecting the disease so that a country can continue to represent themselves as “BSE-free.” There are huge disincentives for expanding national surveillance for BSE. BSE surveillance is expensive, with the total costs for collecting and testing each sample usually in excess of US$20. Furthermore, it is not in the national interest to discover BSE unless there is a plan in place for addressing it. Reporting BSE can have devastating economic and political consequences; whereas, historically a country’s failure to detect the disease, or its lack of an adequate surveillance system, has been rewarded by continued trade. Lesson 3: Most Farmers Are Honest, but Disincentives for Reporting BSE Greatly Outweigh the Incentives Animal production has historically been measured by the number of animals produced, not the quantity and quality of food generated. Therefore, many producers see themselves as raising animals rather than as part of the food system. We are continuing to work to change that paradigm in order to foster a shared responsibility for the food system, from producer to consumer. For years most countries in the world have pursued a cheap food policy, where the price of food has assumed paramount importance. Consequently, food producers throughout the food system (from the farm to the consumer’s table) strive to keep costs as low as possible. Although animal diseases impose costs on farmers, they recognize that absence of disease (100 percent prevention and control) is not always the optimal economic strategy. Producers weigh the costs of disease diagnostics, prevention, and control against the potential benefits they may ensure. They seek diagnostic support if they believe that understanding and preventing economically important diseases can reduce the cost of production more than the marginal cost of the diagnostics and prevention strategies, or if their products can be accorded a higher health status and, hence, a higher value, as a result of negative results on diagnostic tests where the risk of positive tests is low.

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary One is hard pressed to find individual producer incentives for reporting suspected cases of BSE in the United States. There is no treatment for BSE, and government-mandated controls increase production costs. Feed is the single greatest contributor to cost of production, and government feed regulations have removed a low-cost protein supplement. Removal and destruction of specified risk materials (those tissues where BSE agent accumulates in affected cows) has increased the costs of processing and reduced the value of each animal slaughtered. Additionally, the government certifies the nation’s BSE status, but not that of individual herds. Thus the individual producer gains no benefit from conscientious submission of suspect cattle where all the test results are negative. At the same time, there are numerous disincentives for reporting BSE. Producers on whose farm a BSE cow is identified are ostracized by the rest of the industry, and their products are shunned by consumers and wholesale buyers. Their business (and personal life) is disrupted by the government, industry and media response. Finally, disposal of affected or suspect animals is difficult and often expensive, and government response to BSE diagnosis in a herd has all too often involved destruction of many more animals than epidemiologically necessary to control the disease. Considering all the disincentives, a phrase uttered by the Prime Minister of Alberta was taken out of context as a new mantra for some cattle producers: “Shoot, shovel, and shut up” rather than report BSE suspects. Lesson 4: Testing Can Become an End Unto Itself Before implementing a widespread testing regime for disease surveillance or health monitoring, the purpose of the testing must be clarified. The purpose will change over the course of an epidemic, so it must always be clear why it is done, in order that appropriate sample size can be determined and the test results interpreted appropriately. Testing alone cannot afford safety (defined by dictionaries as the “absence of risk”), and it is meaningless without the concurrent implementation of animal and public health measures. Testing the wrong populations can create a false sense of security that, while politically expedient, does not constitute a public health measure. For instance, controlled BSE challenge studies and accumulated BSE surveillance results demonstrate that young animals will test negative to all of our currently available tests even if exposed to BSE; this is because the disease takes years to create discernible damage to the central nervous system and for the disease agent, the prion protein, to accumulate to detectable levels. Consequently, testing only young cattle assures that all tests are negative but says nothing about the BSE status of a country. Similarly, testing all cattle in a country with BSE decreases the apparent prevalence of the disease because of all the young cattle testing negative regardless of the extent of BSE in the adult population.

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary Lesson 5: Focus on Risk, Not the Presence or Absence of Disease The key for human and animal health protection is effective risk management, not the disease status of the country. Most countries have focused disproportionately on the reported presence or absence of disease rather than on the effectiveness of the risk management. Internally, the lack of positive diagnostic tests has propelled officials to proclaim disease freedom, thereby creating a false sense of security and reducing the imperative of prevention and control. Outside their borders, countries have tended toward implementation of total trade bans when a trading partner identifies BSE, a policy that ignores the fact that a variety of risk management measures exist that allow for the safe trade of animals and animal products from countries regardless of their disease status. Infectious diseases do not respect national borders, and yet we frequently hear the statement “we have sealed our borders,” all too often followed by the false reassurance that the disease of concern will “never” occur here. Not only are these statements factually inaccurate, but also they represent the ultimate risk communication error—providing absolute guarantees. Above all else, we usually fail to consider most zoonoses in the context of ecosystem risk management, and we develop national public policy rather than a regional or global approach. Lesson 6: Take Opportunity Costs into Account Every dollar spent on BSE testing, prevention, or control is unavailable to address a different risk or challenge. The cost of BSE testing may be disproportionate to the resulting public health benefit, as compared with addressing other pressing issues in protecting the global food system. Similarly, taking a zero-risk approach forecasts ever increasing costs as the precautionary principle tends toward taking preemptive actions on every identified hazard, no matter how small the risk. Developing animal health and public health priorities must be conducting from a holistic perspective in which all hazards are considered and the opportunity costs of various initiatives weighed. Similarly, surveillance priorities should be established through broad-based considerations of risk management, not simply from a desire to impress the public or trading partners by more tests. I was struck by the concern voiced by one of my international colleagues caught in a massive (and expensive) government response to a few BSE cases. “What will we tell our grandchildren,” he asked, “when we have spent all this money for a rare cattle disease with a relatively small human health impact, while at the same time we fail to take basic, proven public health measures for other diseases and conditions that impact the lives of millions because ‘we have no money.’” Lesson 7: High Health Status Is a Curse Once high health status is attained, the impetus for maintaining an animal health and public health infrastructure fades. We celebrate the successful eradica-

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary tion of a whole string of animal diseases and successful risk management of zoonoses that plagued our grandparents such as bovine tuberculosis and undulant fever. Having achieved this unique high health status for the entire nation, then we turn around and ask why we are maintaining an infrastructure for something that no longer exists. Anchoring our animal and public health infrastructure on a limited number of “program” diseases undercuts the overall system as successes are celebrated. As a result of the resulting budget cuts and retrenchment, we have few resources to commit to investigating emerging disease threats and little surge capacity when a significant infectious disease outbreak occurs. Replacing experienced professionals with unseasoned new recruits saves money in the short run but costs the nation (and world) in the long term. That is where we find ourselves today as we struggle to manage emerging issues with limited resources. Cutting both physical and human resources provides a rapid means for decreasing budgets, but rebuilding an effective animal and public health infrastructure is a monumental undertaking in terms of resources and time. Strategies for Managing This Dilemma Reframe surveillance discussions to focus on the purpose and the scientific basis for surveillance rather than the number of tests conducted; Consider the entire farm-to-table food system when designing surveillance systems to support effective risk management for the end consumer and the nation; Recognize that no one surveillance system fits all situations; the sampling design, sample size, and testing protocol must be adapted to the needs of each country in order to support optimal risk management; Create more incentives for reporting disease to pull in more samples, rather than simply demanding testing through regulatory initiatives and penalties; Develop a national animal identification system to support rapid response to disease outbreaks and long-term support for emerging disease detection; Strengthen the national animal health laboratory system and increase its capacity, perhaps by providing federal resources to states tied to performance requirements and reporting so that all states can meet a minimum level of proficiency and quality; Foster increased collaboration between biologic, medical, and social sciences in order to better understand the sociology and psychology of disease reporting and compliance. Biologic and medical sciences alone are not enough; Focus on risk management rather than disease eradication or “zero risk”; Adopt and implement science-based regulations for BSE and other emerging diseases building on international standards; Build public-private partnerships to address emerging diseases on a global, rather than a national, scale; Recognize that all animal health issues are public health issues because of

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Addressing Foodborne Threats to Health: Policies, Practices, and Global Coordination - Workshop Summary their direct effects on human heath and their indirect effects on human well-being through their psychologic, economic, and ecologic consequences; and Break down the silos that separate various professions and different stages of the food system (agriculture, processing, distribution, retail, wholesale, and the consumer) in order to aggressively promote transdisciplinary approaches to animal and public health. REFERENCES Alper T, Cramp WA, Haig DA, Clarke MC. 1967. Does the agent of scrapie replicate without nucleic acid? Nature 214(90):764–766. Alpers MP. 1968. Kuru: Implications of its transmissibility for the interpretation of its changing epidemiological pattern. In: Bailey OT, Smith DE, Eds. The Central Nervous System: Some Experimental Models of Neurological Diseases. Baltimore, MD: Williams and Wilkins Company. Pp. 234–251. Alter M, Kahana E. 1976. Creutzfeldt-Jakob disease among Lybian Jews in Israel. Science 192 (4238):428. Anderson RM, Donnelly CA, Ferguson NM, Woolhouse ME, Watt CJ, Udy HJ, MaWhinney S, Dunstan SP, Southwood TR, Wilesmith JW, Ryan JB, Hoinville LJ, Hillerton JE, Austin AR, Wells GA. 1996. Transmission dynamics and epidemiology of BSE in British cattle. Nature 382(6594):779–788. Andreoletti O, Simon S, Lacroux C, Morel N, Tabouret G, Chabert A, Lugan S, Corbiere F, Ferre P, Foucras G, Laude H, Eychenne F, Grassi J, Schlecher F. 2004. PrPSc accumulation in myocytes from sheep incubating natural scrapie. Nature Medicine 10(6):591–593. Baker HF, Ridley RM, Wells GAH. 1993. Experimental transmission of BSE and scrapie to the common marmoset. Veterinary Record 132(16):403–406. Bartz JC, Kincaid AE, Bessen RA. 2003. Rapid prion neuroinvasion following tongue infection. Journal of Virology 77(1):583–591. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. 1995. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK [Letter]. Lancet 346(8983):1155–1156. Bellinger-Kawahara C, Cleaver JE, Diener TO, Prusiner SB. 1987a. Purified scrapie prions resist inactivation by UV irradiation. Journal of Virology 61(1):159–166. Bellinger-Kawahara C, Diener TO, McKinley MP, Groth DF, Smith DR, Prusiner SB. 1987b. Purified scrapie prions resist inactivation by procedures that hydrolyze, modify, or shear nucleic acids. Virology 160(1):271–274. Bosque PJ, Ryou C, Telling G, Peretz D, Legname G, DeArmond SJ, Prusiner SB. 2002. Prions in skeletal muscle. Proceedings of the National Academy of Sciences 99(6):3812–3817. Brachmann A, Baxa U, Wickner RB. 2005. Prion generation in vitro: Amyloid of Ure2p is infectious. EMBO Journal 24(17):3082–3092. Britton TC, Al-Sarraj S, Shaw C, Campbell T, Collinge J. 1995. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK [Letter]. Lancet 346(8983):1155. Bruce ME, Dickinson AG. 1987. Biological evidence that the scrapie agent has an independent genome. Journal of General Virology 68(Pt. 1):79–89. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ. 1997. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389(6650):498–501. Buschmann A, Groschup MH. 2005. Highly bovine spongiform encephalopathy-sensitive transgenic mice confirm the essential restriction of infectivity to the nervous system in clinically diseased cattle. Journal of Infectious Diseases 192(5):934–942.

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