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
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.
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