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ScienceWeek
MEDICAL BIOLOGY: ON MAD COW DISEASE
The following points are made by Paul Brown (American Scientist 2004 92:334):
1) The Canadian cattle industry has yet to recover from the discovery of bovine spongiform encephalopathy (BSE) ("mad cow disease") in a single cow on an Alberta farm in May of 2003. A 400-kilogram cow that used to fetch 500 Canadian dollars on the open market now sells for as little as 79 Canadian cents -- less than the price of a fast-food burger.
2) The economic fallout is a consequence of the discovery in 1996 that mad-cow disease could cross the species barrier to inflict human beings with variant Creutzfeldt-Jakob disease (vCJD). This disease is characterized by a progression of psychiatric and neurological symptoms that culminate in death, usually a year or two after the onset of the first indications of illness. As of May 2000, a total of 155 cases of vCJD had been identified: 144 in the UK (where the outbreak began), 6 in France, 1 in Ireland, and 1 in Italy. Additional single victims in Hong Kong, Canada and the US were infected in the UK, where they had been residing during the years of peak risk, in the late 1980s or early 1990s.
3) Both BSE and vCJD belong to a family of diseases known as the transmissible spongiform encephalopathies (TSEs). The oldest known TSE is scrapie, which was first described in sheep in the early 18th century. Natural TSE infections have so far been restricted to sheep and goats (scrapie), and to deer and elk ("chronic wasting disease"). However, many mammalian species are susceptible to experimental infections by TSE agents, including primates, various ungulates, felines, and laboratory rodents. Although the disease has different names in different species, each illness is an expression of the same basic pathological process, and they all share many clinical and biological similarities.
4) The disease agents that cause TSE were recognized as being rather special from the start. Although TSEs behave in many ways like a viral illness, they show some peculiar differences -- for example, a long latency period between infection and illness and a correspondingly long duration of illness. The agents also seem to have an astonishing resistance to inactivation and for a very long time could not be linked to any visible structure. For many years the TSE agents were therefore called "slow" or "unconventional" viruses; however, all known biological viruses contain nucleic acids, and 50 years of exhaustive searches for a disease-specific nucleic acid have proved fruitless.
5) While the search was on for suspicious nucleic acids, another line of research was uncovering the crucial role of a protein --called a prion -- that appears to be inseparable from infectivity. Prions are host-encoded proteins, rather than foreign proteins, and more than 30 different mutations in the gene on human chromosome 20 that codes for the prion are associated with inherited forms of TSE. In the infected host, the normal protein (which usually resides on the surfaces of cells, including neurons) is converted into an insoluble form that is resistant to digestion by proteinases. The chain of amino acids that make up the insoluble form is folded differently from the normal protein, and in some ways is similar to the amyloid proteins associated with Alzheimer's disease. Although scientists have begun to think of TSE as one of a group of "misfolded-protein diseases," it is distinct from other amyloid-based diseases in that it alone is transmissible.
6) Many researchers believe that the misfolded protein is the primary cause of the disease -- that is, the prion itself is the transmissible agent of TSE. Healthy laboratory animals inoculated with tissues from infected animals develop the disease, and the misfolded protein that accumulates in their brains is readily detectable by various immunological methods. But there are still some fundamental questions that have yet to be answered. How, for example, does infection trigger the accumulation of the abnormal prion protein that clutters the diseased brain? In other words, how does the protein replicate? And how can it confer the information required to produce different strains of the infectious agent, both within and between species? One theory suggests that the misfolded protein acts as a seed molecule, a kind of template, that imposes the abnormal conformation on the normal protein. This notion has generated considerable interest in the scientific community, and a number of laboratories are working on the problem. Whatever the final judgment on prions as the sole cause of TSE, it is clear that the protein plays a crucial role in the infectious process and is a valuable marker of infectivity.(1-5)
References (abridged):
1. Brown, P. 2003. Transmissible Spongiform Encephalopathy as a Zoonotic Disease. ILSI Europe Report Series. Brussels: International Life Sciences Institute
2. Brown, P., and R. Bradley. 1998. 1755 and all that: A historical primer of transmissible spongiform encephalopathy. British Medical Journal 317:1688-1692
3. Brown, P., R. G. Will, R. Bradley, D. L. Asher and L. Detwiler. 2001. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: Background, evolution, and current concerns. Emerging Infectious Diseases 7:6-16
4. Hadlow, W. J., R. C. Kennedy and R. E. Race. 1982. Natural infection of Suffolk sheep with scrapie virus. Journal of Infectious Diseases 146:657-664
5. Prusiner, S. B. 2001. Shattuck Lecture--Neuro-degenerative diseases and prions. New England Journal of Medicine 334:1516-1526
American Scientist http://www.americanscientist.org
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MEDICAL BIOLOGY: ON THE EPIDEMIOLOGY OF MAD COW DISEASE
The following points are made by Christl A. Donnelly (New Engl. J. Med. 2004 350:539):
1) On December 9, 2003, a nonambulatory ("downer") dairy cow was slaughtered in Washington State, and because the animal's condition was attributed to complications from calving, the animal was judged to be fit for human consumption (designated as "inspected and passed" by the U.S. Department of Agriculture [USDA]). Samples taken from this animal tested positive for bovine spongiform encephalopathy (BSE, also known as "mad cow disease") on December 22; the USDA diagnosis was subsequently confirmed by the British world reference laboratory. The international response to the announcement of this result on December 23 was strong and swift, with bans being imposed immediately on U.S. beef and cattle by Japan, Mexico, South Korea, and other countries. Although it has now been confirmed that the infected cow was imported from Alberta, Canada, in 2001, the bans have remained in place.
2) A rational interpretation of the potential risks posed by BSE in North America must be grounded in the findings of long-term studies of the epidemics of BSE and new-variant Creutzfeldt-Jakob disease in Europe; these studies have focused particularly on Britain -- the country that has been the most affected, with more than 179,000 confirmed clinical cases of BSE.(1,2) The disease was first identified in England in 1986, and the recycling of infection through the inclusion of bovine protein in cattle feed was soon identified as the process driving the epidemic. The key measure that brought the British BSE epidemic under control was the ban, introduced in 1988, on feeding tissues from one ruminant animal to other ruminant animals. However, because of the long delay between infection and the onset of clinical signs of disease (five years, on average), the annual incidence of clinical cases did not peak until 1992. This ban targeted ruminant animals in general, rather than cattle in particular, because scrapie, a BSE-like disease that affects sheep, has long been endemic in Britain.
3) The identification in 1996 of a new variant of Creutzfeldt-Jakob disease in humans in association with BSE prompted authorities to strengthen many existing BSE-control measures (for example, the British ban on ruminant feed was extended to feed including any mammalian meat or bone meal) and to introduce new measures (for example, a British ban on the consumption of cattle older than 30 months of age). Although most of the estimated 4 million cattle that were infected over the course of the BSE epidemic in Britain(3) were slaughtered for consumption, to date only 145 (definite or probable) cases of new-variant Creutzfeldt-Jakob disease have been identified in British patients, only 6 of whom remain alive. The decrease in the incidence of new-variant Creutzfeldt-Jakob disease in Britain since the peak of the epidemic in 2000 (when there were 28 cases) has dramatically decreased the uncertainty surrounding the likely size of the primary epidemic involving the known susceptible genotype (with homozygosity for methionine at codon 129 of the prion protein gene).(4) A small number of additional cases have been reported in other countries (Ireland, France, Italy, Canada, and the US). The only affected US resident, whose probable case of new-variant Creutzfeldt-Jakob disease was identified in 2002, was a 22-year-old woman who had moved from the United Kingdom to Florida in 1992.
4) Although a ban on ruminant feed was introduced in the US in 1997 as a precaution in response to the identification of new-variant Creutzfeldt-Jakob disease, there is still a risk of cross-contamination from other livestock feed. Specifically, materials from deer and elk may be used in feed for nonruminant animals in the US, unless the deer or elk are known to be positive for chronic wasting disease, a BSE-like disease in cervids. Although the Food and Drug Administration (FDA) recommended in September 2003 that deer and elk from areas where chronic wasting disease is endemic no longer be used for any animal feed, the nonbinding nature of this recommendation would allow materials from animals with unidentified chronic wasting disease to be included in feed for nonruminant animals, resulting in a potential risk of cross-contamination of cattle. Similar risks were minimized in Britain in 1996 with the extension of the feed ban to include the feeding of mammalian meat or bone meal to any farmed livestock, including fish and horses.
5) The author concludes: The available evidence suggests that if the current control measures are well enforced, then the risk, if any, from US cattle, is very low, although further regulation to limit exposure to material from cervids infected with chronic wasting disease would further reduce the potential risk of cervid-to-cattle transmission. Consumers need not be overly anxious about the risks they may have incurred by consuming beef, but they should press authorities to test more cattle, to strengthen the regulations on feed production, and to extend the ban on brain and spinal cord in food for human consumption to include cattle younger than 30 months of age.
References:
1. BSE: homepage. London: Department for Environment, Food and Rural Affairs (DEFRA), 2003. Accessed January 16, 2004, at http://www.defra.gov.uk/animalh/bse/index.html
2. Anderson RM, Donnelly CA, Ferguson NM, et al. Transmission dynamics and epidemiology of BSE in British cattle. Nature 1996;382:779-788. [Erratum, Nature 1997;384:302.]
3. Ferguson NM, Donnelly CA. Assessment of risk posed by bovine spongiform encephalopathy in Cattle in Great Britain and the impact of potential changes to current control measures. Proc R Soc Lond B Biol Sci 2003;270:1579-1584
4. Monthly Creutzfeldt-Jakob disease statistics. London: Department of Health, 2004. Accessed January 16, 2004, at http://www.doh.gov.uk/cjd/index.htm
New Engl. J. Med. http://www.nejm.org
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MEDICAL BIOLOGY: ON MAD COW DISEASE IN THE US
The following points are made by US Centers for Disease Control and Prevention (Morb. Mort. Weekly Rep. 2004;52:1280-1285):
1) On December 23, 2003, the U.S. Department of Agriculture (USDA) made a preliminary diagnosis of bovine spongiform encephalopathy (BSE) in a single "downer" (i.e., nonambulatory disabled) dairy cow in Washington state. On December 25, this diagnosis was confirmed by the BSE international reference laboratory in Weybridge, England. The occurrence of BSE in the United States reinforces the need for physicians to be aware of the clinical features of variant Creutzfeldt-Jakob disease (vCJD) and to arrange for brain autopsies in all decedents with suspected or probable CJD to assess the neuropathology of these patients.
2) The BSE-positive cow was aged 6.5 years when it was slaughtered on December 9. Before slaughter, the cow was nonambulatory; its condition was attributed to complications from calving. The animal was examined by a USDA Food Safety and Inspection Service (FSIS) veterinary medical officer both before and after slaughter. After examination, the carcass was released for use as food for human consumption. Tissues (e.g., brain, spinal cord, and small intestine) considered to be at high risk for the transmission of the BSE agent were removed from the cow during slaughter and sent for inedible rendering (often used for nonruminant animal feed). Because the cow was nonambulatory at slaughter, brain tissue samples were taken by USDA's Animal and Plant Health Inspection Service (APHIS) as part of its targeted surveillance for BSE. On December 23, a presumptive diagnosis of BSE was made, and the herd to which this cow belonged was placed under a state hold order. USDA, in collaboration with state and other federal animal and public health agencies, industry representatives, and the Canadian Food Inspection Agency (CFIA), initiated investigations of potentially exposed cattle and regulated products.
3) On December 24, FSIS recalled beef from cattle slaughtered in the same plant on the same day as the BSE-positive cow. Some of the beef subject to the recall had been shipped to several establishments, which processed it further. Meat products manufactured from the recalled meat were distributed primarily to locations in Oregon and Washington, with smaller quantities distributed to locations in California, Idaho, Montana, and Nevada.
4) The U.S. Food and Drug Administration (FDA) and inspectors from Oregon and Washington have located all known potentially infectious rendered products from the BSE-positive cow. The rendering plants that processed this material have placed a voluntary hold on all known potentially infectious products, none of which had left the control of the companies or entered commercial distribution as of January 7, 2004. FDA continues its investigation of all regulated products related to the BSE-positive cow.
5) APHIS, in collaboration with CFIA, traced the birth of the BSE-positive cow to a farm in Alberta, Canada. On January 6, USDA and CFIA announced that DNA evidence had confirmed this traceback to Canada with a high degree of certainty. This line of investigation indicates that the BSE-positive cow was one of 82 animals from a Canadian herd cleared for shipment to the United States; 81 of the cattle listed on the Canadian animal health certificate entered the United States on September 4, 2001, through Oroville, Washington. These cattle are being traced to determine their disposition or current location. The BSE-positive cow gave birth to two live calves while in the United States. The first is a yearling heifer on the same farm as the BSE-positive cow. The second, a bull calf, was in a group of calves at another location, a calf-feeding operation that also was under a state hold order. Because the bull calf could not be identified definitively, APHIS completed the elimination of all calves at this site on January 6. Since the epidemiologic investigation began, APHIS has developed criteria for determining additional cattle at risk for BSE that should be eliminated.
6) BSE is a progressive, fatal neurologic disorder of cattle and is classified as one of the transmissible spongiform encephalopathies, a group of diseases of animals and humans believed to be caused by abnormally folded proteins called prions. BSE was first identified in 1986 in the United Kingdom (UK), where it caused a large outbreak among cattle. Although the source of the BSE epizootic agent is uncertain, feeding cattle BSE-contaminated meat-and-bone meal is the major contributory factor to the amplification of BSE among cattle. Since 1986, BSE cases have been identified in 20 European countries, Japan, Israel, and Canada. Since BSE surveillance was initiated in the United States in 1990, USDA has tested brain tissue from approximately 57,000 cattle, targeting those at high risk for BSE (e.g., downer cattle and cattle with neurologic signs); the case described in this report represents the first identification of BSE in the US. Whether an epidemiologic link exists between this BSE case traced to Canada and the previous case reported in Canada is not known.
7) Epidemiologic and laboratory evidence suggests that the BSE agent has been transmitted to humans via consumption of BSE-contaminated cattle products, causing vCJD. However, the risk for acquiring vCJD from consumption of BSE-contaminated product is low, presumably because of a "species barrier" that provides substantial but incomplete protection against development of vCJD. In the UK, where an estimated one million or more cattle probably were infected with BSE, cases of vCJD continue to be reported. However, the number of cases of vCJD remains small, with 148 probable and confirmed vCJD cases identified as of January 7, 2004, including those of three persons residing in Ireland, Canada, and the US who are believed to have been exposed to BSE in the UK. Seven additional cases not directly linked to the BSE outbreak in the UK also have been reported (six in France and one in Italy).
8) In the US, the feeding of rendered cattle products to other cattle has been prohibited since 1997, and the importation of cattle and cattle products from countries with BSE or considered to be at high risk for BSE has been prohibited since 1989; these measures have minimized the potential exposure of animals and humans to the BSE agent.
9) Substantial clinical and epidemiologic differences exist between vCJD and the more commonly occurring classic form of CJD recognized in the United States for decades before the emergence of BSE. Although strong epidemiologic and laboratory evidence indicates that vCJD is linked causally with BSE, no exogenous source of infection has been identified for approximately 85% of classic CJD cases. The median age at death of classic CJD patients in the United States is 68 years, compared with 28 years for vCJD patients. The age distribution of these deaths illustrates that most vCJD occurs in age groups in which classic CJD is rare. In addition, the median duration of illness before death for classic CJD patients in the United States is 4-5 months, compared with 13-14 months for vCJD patients.
Centers for Disease Control and Prevention http://www.cdc.gov
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