Paul Brown. American Scientist. Volume 92, Issue 4. Jul/Aug 2004.
In December 2003, the U.S. Department of Agriculture discovered a case of bovine spongiform encephalopathy (BSE), often called mad-cow disease, in a dairy cow from Washington state. The news was more than a little disturbing to the American cattle industry. The mad-cow scare had previously devastated the cattle business in the few countries where BSE had been reported, especially Great Britain and Canada. The Canadian cattle industry has yet to recover from the discovery of BSE in a single cow on an Alberta farm in May of last year. 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.
The economic fallout is, of course, 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 Great Britain (where the outbreak began), 6 in France, 1 in Ireland, and 1 in Italy. Additional single victims in Hong Kong, Canada and the U.S. were infected in the U.K., where they had been residing during the years of peak risk, in the late 1980s or early 1990s. The extraordinary commercial and publichealth consequences of BSE, as well as the near-global distribution of products derived from cattle, have generated a considerable amount of attention from industry, government and the general public. As a result, there is a daunting volume of information-not all of it reliable-surrounding the nature of mad-cow disease. I will here attempt to distill the essence of what we know about the disease, especially with respect to its consequences for human and animal welfare in North America.
The Nature of the Disease
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.
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.
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.
Many scientists 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.
Whether it is a lone protein or not, the itinerary of the infectious agent within the body depends on how the infection is initiated. When the agent is experimentally introduced into rodents by inoculation, the abnormal protein replicates in the spleen and the lymph nodes and then travels along the splanchnic nerves (which supply sympathetic innervation in the abdomen) to the spinal cord and then to the brain. If the agent is ingested, it can bypass the spleen and proceed directly from the gut to the brain stem by way of the vagus nerve. Experiments suggest that the optic and olfactory tracts are also potential portals of entry.
The role of circulating blood in naturally occurring TSE remains uncertain. Blood has been shown to be infectious in experimental models of TSE and naturally occurring scrapie infections, and a highly probable case of transmission by means of a “packed” red-cell transfusion from a patient with vCJD was recently reported in Great Britain. During the 1990s, many countries, including the U.S., imposed restrictions on blood donations from persons who lived for three months or more in the United Kingdom between 1980 and 1996, and in March 2004, Great Britain instituted a ban on blood donations from any of its residents who had received a blood transfusion since January 1980.
The origin of BSE may never be known with certainty, but any satisfactory explanation must answer two fundamental questions. Why did BSE begin in the mid 1980s? And why did it begin in Great Britain?
It is generally believed that cattle were infected by eating contaminated dietary supplements made from the carcasses of infected animals. The timing of the madcow outbreak seems to coincide with two changes made in the system of rendering livestock carcasses into animal feed during the late 1970s. First, the process of liquefying separate batches of carcasses into greaves (a water-soluble proteinaceous slurry) and tallow (a water-insoluble fat) was largely replaced by a process in which carcasses moved continuously through the rendering equipment, which could have resulted in uneven or incomplete exposure to heat. second, a terminal extraction of greaves with hydrocarbon solvents under steam to extract a small amount of residual tallow was eliminated.
Although experiments suggest that neither change by itself had a great effect, their combination may well have contributed to survival of the infectious agent. If the level of infectivity was near the threshold of transmission, even small changes in the agent’s survival rate could have made the difference. Supporting evidence comes from the fact that the prohibition of meat-and-bone-meal dietary supplements in 1987 was followed 5 years later by a downturn in BSE cases. This is what would be expected if the supplements were the source of the infection, since 5 years is the average incubation period between BSE infection and manifest illness.
The use of dietary supplements made from cattle and sheep was widespread in the 1980s. Livestock species (sheep, pigs and chickens), several kinds of zoo animals, laboratory animals and pets also received feed that was supplemented with meat-and-bone meal. Fortunately, not all of these animals are susceptible to TSE. However, TSE does appear to have been transmitted by feed to ungulates (including bison and some zoo exotics, such as gemsbok, eland and kudu), felines (including lions, tigers, cheetahs and pet cats) and primates (lemurs and rhesus monkeys). Pigs are not at risk for oral BSE infection, and chickens and dogs appear to be resistant to infection by any route.
It is still not certain whether the infected feed was made from the remains of sheep or cattle. A species-crossing infection from sheep with scrapie is the leading hypothesis. Accurate figures for the international prevalence of scrapie are not available (farmers are generally reluctant to report it), but the disease is certainly widespread in Britain, which has a relatively large ratio of sheep to cattle. Thus a pervasive potential source of infection had already existed in Britain, whereas BSE was unknown until the epidemic began in 1986. Moreover, the argument that an unrecognized spontaneous case of BSE served as the founder of the BSE outbreak has a formidable obstacle. Sporadic cases of BSE could not have been occurring only in Britain, and yet no coincident epidemics occurred in other countries (such as the U.S.) that changed their rendering processes at about the same time. Moreover, the distribution of early BSE cases in Britain (and other countries that unwittingly imported BSE from Britain) is consistent with multiple initiation sites rather than a single-point source of infection. This favors sheep as the source of the infection because scrapie was prevalent and could easily have entered several rendering plants throughout Britain, whereas the spontaneous BSE cases would have had to arise almost simultaneously throughout the country.
To be fair, it should be mentioned that the sporadic-BSE hypothesis more easily explains two curious features of the disease. Like most infectious pathogens, the scrapie agent has many distinguishable strains, but BSE seems to be caused by a single strain. Although there is precedence for strain selection when a pathogen crosses from one species to another, a bovine origin for BSE eliminates the need for this kind of selection process. The other distinguishing feature of BSE is that it is transmissible to human beings, whereas all evidence to date suggests that scrapie is not. Why should the passage of scrapie through a bovine species change its pathogenicity for human beings? As a matter of fact, an analogous phenomenon has been experimentally documented: BSE can infect mice directly but is unable to infect hamsters unless first passed through mice. However, because this kind of interspecies behavior is exceptional, most scientists believe that the balance of evidence points to scrapie as the source of BSE.
If scrapie were the infectious source of the disease in cattle, it raises the possibility that the BSE agent could complete the circle by going back to sheep in infected feed. This would be especially disturbing because in the process of “back-crossing” to sheep, the agent might carry its newly acquired ability to infect humans. It is presently impossible to detect such back-crossing because the clinical, pathological and molecular biological manifestations of the disease in experimentally infected sheep are indistinguishable from native versions of scrapie.
Variant CJD is the fourth member of the CJD family-sporadic and inherited forms of CJD were first described in the 1920s, and iatrogenic CJD (caused by medical procedures) was recognized in the 1970s. The first clue that something new was happening was the appearance of a distinctive form of spongiform encephalopathy in adolescents and young adults in a country still recovering from a vast epidemic of spongiform encephalopathy in cattle. A connection between BSE and the human cases was strongly suggested, and has since been experimentally confirmed by the molecular similarity of their misfolded proteins, which are distinct from those of all other TSEs. The clinical and pathological features of vCJD also differ from those of sporadic CJD. Instead of the usual onset of memory loss and incoordination that characterize sporadic CJD, patients with vCJD present with psychiatric problems and complain of sensory symptoms such as pain, numbness or “pins and needles.” Their illness lasts longer (on average, about 14 months, instead of 4 months for the sporadic disease), and at autopsy their brains contain myriad “daisy plaques”-deposits of misfolded amyloid protein surrounded by “petals” of spongy tissue that are not seen in the sporadic disease.
Human infections most probably resulted from the ingestion of beef products that were contaminated with central nervous system tissue; however, this hypothesis still lacks the kind of laboratory evidence that clinched the identification of BSE as the source of infection. Furthermore, epidemiological studies have not uncovered any convincing disease clusters or pointed to any regional peculiarities that might link contact with BSE-infected cattle to human cases of the disease. Investigations of supposed high-risk groups, such as farmers, slaughterhouse workers and butchers, have not found any cases of vCJD.
Because physical contact with infected cattle could not be implicated, the next logical possibility was exposure to cattle products. This has proved to be difficult to assess because in one way or another virtually the entire British population is exposed to a large number of bovine-derived products. Consumption of meat and dairy products and exposure to products containing either tallow or gelatin (or their derivatives) is nearly universal. No correlation has been established between vCJD and exposure to any particular product.
The most plausible hypothesis points to slaughterhouse practices and meat preparation-about which the scientific community was completely naive-as the key to the transmission of the disease. Before the appearance of BSE, vertebral columns were routinely included in the remains of carcasses from which as much meat as possible had been removed. Spinal cords were usually removed, but cord fragments and spinal ganglia were certainly present. These truncated carcasses were then subjected to a process of compression to yield a paste of “mechanically recovered meat.” This paste was often added to a variety of packaged meat products-hot dogs, sausages, beef patties, luncheon meats and beef stews-in proportions as high as 30 percent, but usually in the range of 5 to 10 percent. It is now abundantly clear that central nervous system tissues were entering the human food chain through this “unadvertised” paste, and that this was the most likely vehicle of infection.
That said, two very curious phenomena remain unexplained. The most puzzling is the relatively young age at which the disease appears: The great majority of vCJD cases have been in people under the age of 30, which is in stark contrast to sporadic CJD, which typically affects the 50-to-70-year-old age group. Two explanations have been proposed. The first calls into play the normal aging process of the immune system. As children mature, some elements of the immune system undergo atrophy, inducing lymphatic tissue elements scattered throughout the small intestine (called Peyer’s patches). These tissues are known to be involved at a very early stage of oral BSE infections, and their atrophy in adulthood could provide a degree of comparative resistance. The second possibility concerns dietary differences between age groups. Children and adolescents are probably more likely than adults to eat comparatively inexpensive products (including school cafeteria offerings) that contain mechanically recovered meat. However, information about the distribution and consumption of commercial foods, which might provide the best clues, is unreliable, and the dietary histories of patients with vCJD obtained from their relatives are similarly suspect.
The other puzzle concerns the relatively small number of cases. Presumably, the potentially contaminated beef products were distributed throughout the British population of 60 million, yet fewer than 150 cases have been identified over a period of nearly 10 years of active surveillance, and only a handful of cases have appeared in countries where BSE was exported. Although genetic susceptibility may play a role, the most reasonable explanation is that infectivity was very unevenly distributed among the meat products and only rarely achieved a transmissible level. Transmission would have been made even more difficult by the comparative inefficiency of oral infections.
BSE in North America
Were it not for the international trade in cattle and cattle feed, BSE would probably have been confined to Great Britain. But cattle and feed continued to be exported from Britain to countries all over the globe for several years throughout the late 1980s and early ’90s-after the cause of BSE had been identified. From the mid-1990s onwards, cases of the disease began to appear in Europe and in countries as far afield as Oman and Japan.
Ironically, the discovery of BSE in the United States at the end of 2003 recapitulated what had occurred with scrapie nearly 60 years before, when infected sheep were imported from Canada, which had earlier imported infected sheep from Great Britain. This time, at least one BSE-infected cow (and probably more) was imported to Canada from Great Britain during the high-risk 1980s. At some point these cows were probably rendered into feed that infected some “next generation” cows. The BSE cow that was discovered in Washington state in December 2003 had been imported to the U.S. in September 2001 from the same province of Canada (Alberta) in which the Canadian BSE cow had earlier been identified. Both cows were born in 1997, just before the ruminant-to-ruminant feed ban was implemented, and it is now a matter of record that some leftover feed continued to be used to supplement the diets of newborn calves.
When the two cows were slaughtered in 2003, neither was suspected of having BSE, so their carcasses were sent to rendering plants for use in feed supplements. The cows were only discovered to have BSE when their brains were later tested as part of a routine surveillance program of “downer” (nonambulatory or disabled) cows, and beef products from the cow in Washington state had already entered the human food supply.
Regulatory agencies in Canada and the U.S., primed by the mad-cow scare in Great Britain and continental Europe, reacted quickly in response to the discovery of the infected cows. All living cows that could be traced from both farms, as well as products made from their tissues, were destroyed. A host of new regulations were also either implemented or proposed, of which the most important were these: prohibition of tissues known to be infectious in BSE cows (cranium, vertebral column, distal ileum, lymphoreticular tissues) for use by either animals or human beings; elimination of mechanically recovered meat unless it could be shown by sensitive immunologie tests to be free of nervous tissue; initiation of a much-increased BSE immunological testing program for downer cows (which are henceforth not to be used for food or other products for either animals or human beings); and a “beefed-up” program of onsite inspections of rendering plants, feed mills and slaughterhouses. Along with a strictly enforced ruminant-to-ruminant feed ban, these measures should prevent the future spread of BSE to other animals and human beings-even if the disease is eventually found to occur as a rare spontaneous event.
Given the absence of indigenously infected cattle and the expanded BSE testing program, the U.S. has both the motivation and resources to answer, once and for all, the vexing question of whether or not BSE occurs spontaneously. If it occurs at the same rate as sporadic CJD in human beings (one case per million per year), several years of testing hundreds of thousands of cattle will be required to obtain a statistically significant result. Because other equally motivated countries are disqualified by the occurrence of cattle with foodborne BSE, only in the U.S. do we still have this unique, one-time only opportunity to confirm or refute the thesis that the BSE outbreak could have resulted from a spontaneous occurrence.
When BSE and its human counterpart, vCJD, pass into history-which they undoubtedly will-some may believe that a quarter century of scientific knowledge was gained at the expense of veterinary and public health. This would be neither fair nor accurate. Great Britain and indeed the world owe an immense debt of gratitude to the few key investigators who correctly identified the basic issues with extraordinary rapidity. The problem was in translating the evolving scientific knowledge into government policy, because until public concern forces the issue, governments are almost always loathe to take a proactive stance in the face of purely hypothetical risks. This is due in great measure to the fact that regulations designed to protect public health from imagined dangers invariably cause real damage to the commercial sectors involved, and unless the data are undeniable, these interests will understandably argue against restrictive measures. It is thus not at all clear that any so-called “lessons” will inform future situations, because risk-benefit analyses that are based on incomplete knowledge depend on both scientific and political considerations and will continue to frustrate scientists and policy makers alike.