FEATURE ARTICLE
Mad-Cow Disease in Cattle and Human Beings
Bovine spongiform encephalopathy provides a case study in how to manage risks while still learning the facts
Paul Brown
BSE Origins
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 mad-cow 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.
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