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
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 public-health 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.
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.
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 immunologic
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.
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