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From: TSS (
Date: September 24, 2004 at 6:53 am PST

-------- Original Message --------
Date: Fri, 24 Sep 2004 08:58:36 -0500
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy

Science, Vol 305, Issue 5692, 1918-1921 , 24 September 2004
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Five possible sources of BSE in North American cattle. Sheep, deer, and
elk could spread prion diseases (TSEs) to cattle through direct animal
contact or contamination
of pastures. Endemic BSE has not been proven to exist anywhere in the
world, but it is difficult to exclude this possibility because of the
inefficient spread of BSE infectivity
between individual animals (2). BSE caused by spontaneous misfolding of
the prion protein has not been proven.

Science, Vol 305, Issue 5692, 1918-1921 , 24 September 2004
[DOI: 10.1126/science.1103581]

A Fresh Look at BSE

Bruce Chesebro*

Mad cow disease, or bovine spongiform encephalopathy (BSE), is the cattle
form of a family of progressive brain diseases. These
diseases include scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in
humans, and chronic wasting disease (CWD) in deer and elk.
They are also known as either "prion diseases" because of the association
of a misfolded cellular prion protein in pathogenesis or
"transmissible spongiform encephalopathies" (TSEs) because of the
spongelike nature of the damaged brain tissue (1).

The recent discovery of two BSE-infected cows, one in Canada and one in
the United States, has dramatically increased concern in
North America among meat producers and consumers alike over the extent to
which BSE poses a threat to humans as well as to
domestic and wild animals. The European BSE epidemic of the late-1980s
seems to have been initiated a decade earlier in the United
Kingdom by changes in the production of meat and bone meal (MBM) from
rendered livestock, which led to contamination of MBM with
the BSE infectious agent. Furthermore, the fact that UK farmers fed this
rendered MBM to younger animals and that this MBM was
distributed to many countries may have contributed to the ensuing BSE
epidemic in the United Kingdom and internationally (2).

Despite extensive knowledge about the spread of BSE through contaminated
MBM, the source of BSE in Europe remains an unsolved
mystery (2). It has been proposed that BSE could be derived from a
cross-species infection, perhaps through contamination of MBM by
scrapie-infected sheep tissues (see the
figure). Alternatively, BSE may have been an endemic disease in cattle
that went unnoticed because of its low level of horizontal transmission.
Lastly, BSE might have originated
by "spontaneous" misfolding of the normal cellular prion protein into the
disease-associated abnormal isoform (3), which is postulated to be the
infectious agent or "prion."

Five possible sources
of BSE in North American cattle. Sheep, deer, and elk could spread prion
(TSEs) to cattle
through direct animal contact or contamination of pastures. Endemic BSE has
not been proven to
exist anywhere in the
world, but it is difficult to exclude this possibility because of the
inefficient spread of BSE
infectivity between
individual animals (2). BSE caused by spontaneous misfolding of the prion
protein has not been


Spontaneous protein misfolding is not a new phenomenon as proteins are
known to sometimes misfold after synthesis. Cells in turn have devised
ingenious ways to deal with this
problem. These include molecular chaperone proteins that bind to
misfolded proteins and help them to unfold, and organelles called
proteosomes that degrade misfolded or
unwanted proteins. However, although misfolded prion proteins have been
generated in test tubes as well as in cultured cells, it has been difficult
to demonstrate that such
misfolded abnormal prion proteins are infectious (4, 5). Even the most
recent data do not prove conclusively that infectivity has been generated
in vitro because misfolded
synthetic prion proteins were not able to transfer disease directly to
wild-type mice (6). To obtain infectivity and subsequent prion disease, the
misfolded proteins had to be
inoculated and incubated for 1 to 2 years in transgenic mice that
overexpressed a mutant version of the prion protein. Previous data from
this group showed that transgenic mice
expressing high amounts of prion protein developed neurological disease
without inoculation of misfolded prion protein (7). Thus, at the
biochemical level, the critical attributes
of the misfolded prion protein required for infectivity are not known,
and misfolding of prion protein alone may not be sufficient to generate an
infectious agent (8).

Nevertheless, the idea that BSE might originate due to the spontaneous
misfolding of prion proteins has received renewed interest in the wake of
reports suggesting the occurrence
of atypical BSE (9-11). These results imply that new strains of cattle
BSE might have originated separately from the main UK outbreak. Where and
how might such strains have
originated? Although such rare events cannot be studied directly, any
number of sources of the original BSE strain could also explain the
discovery of additional BSE strains in
cattle (see the figure). However, it would be worrisome if spontaneous
BSE were really a valid etiology because such a mechanism would be
impossible to prevent--unlike other
possible scenarios that could be controlled by large-scale eradication of
TSE-positive animals.

Another way to look at this problem is to examine evidence for possible
spontaneous TSE disease in other animals besides cattle. Spontaneous BSE
would be extremely difficult to
detect in cattle, where horizontal spread is minimal. However, in the
case of the sheep TSE disease, scrapie, which spreads from ewes to lambs at
birth as well as between adults,
spontaneous disease should be detectable as new foci of clinical
infection. In the early 1950s scrapie was eradicated in both Australia and
New Zealand, and the mainland of both
these countries has remained scrapie-free ever since. This scrapie-free
status is not the result of selection of sheep resistant to scrapie because
sheep from New Zealand are as
susceptible as their UK counterparts to experimental scrapie infection
(12). These experiments of man and nature appear to indicate that
spontaneous clinical scrapie does not
occur in sheep. Similarly, because CWD is known to spread horizontally,
the lack of CWD in the deer or elk of eastern North America but its
presence in western regions would
also argue against a spontaneous disease mechanism. This is particularly
noteworthy in New Zealand, where there are large numbers of deer and elk
farms and yet no evidence of
spontaneous CWD. If spontaneous scrapie does not occur in sheep or deer,
this would suggest that spontaneous forms of BSE and sporadic
Creutzfeldt-Jakob disease (sCJD) are
unlikely to be found in cattle or humans. The main caveat to this notion
is that spontaneous disease may arise in some animal species but not
others. In humans, sCJD--which is
considered by some researchers to begin by spontaneous misfolding of the
prion protein--usually takes more than 50 years to appear. Thus, in animals
with a shorter life-span,
such as sheep, deer, and cattle, an analogous disease mechanism might not
have time to develop.

What can we conclude so far about BSE in North America? Is the BSE
detected in two North American cows sporadic or spontaneous or both?
"Sporadic" pertains to the rarity of
disease occurrence. "Spontaneous" pertains to a possible mechanism of
origin of the disease. These are not equivalent terms. The rarity of BSE in
North America qualifies it as a
sporadic disease, but this low incidence does not provide information
about cause. For the two reported North American BSE cases, exposure to
contaminated MBM remains the
most likely culprit. However, other mechanisms are still possible,
including cross-infection by sheep with scrapie or cervids with CWD,
horizontal transmission from cattle
with endemic BSE, and spontaneous disease in individual cattle. Based on
our understanding of other TSEs, the spontaneous mechanism is probably the
least likely. Thus,
"idiopathic" BSE--that is, BSE of unknown etiology--might be a better
term to describe the origin of this malady.

What does all this imply about testing cattle for BSE in North America?
Current testing in the United States indicates that BSE is rare (one
positive result in 40,000 cattle
tested). However, additional testing of 200,000 head of slaughtered
cattle over the next 1 to 2 years, as recently proposed by the U.S.
Department of Agriculture (USDA), should
tell us the incidence more precisely. Nevertheless, if any rare cases are
detected, we may still not know their origin. If evidence arises of a focal
occurrence of BSE, we might
gain important insight into unexpected sources of contamination. However,
because current tests do not seem to be able to detect BSE in infected
animals less than 30 months of
age, even more extensive testing will not completely guarantee the
negative status of younger animals in the food chain. Therefore, the
alternative option of testing all slaughtered
cattle, as implemented in some countries such as Japan, would appear to
provide little additional benefit. This fact has been acknowledged as the
basis for a new agreement between
the United States and Japan aimed at reestablishing the beef trade
between the two countries.

One problem with the current U.S. testing program was the announcement a
few months ago of unconfirmed positive BSE tests in two additional North
American animals that were
subsequently found to be negative when tested with the more accurate
method of Western blotting. The public release of information about
unconfirmed positive tests detected by
the rapid test used for mass screening may be a good idea in the interest
of openness, but it has the potential to create unwarranted anxiety. If
unconfirmed positives are a
frequent occurrence, it would seem reasonable to follow a more cautious
approach and wait until confirmatory testing is complete before publicly
announcing the details.

Based on the experience of many European countries, the mainstays of
controlling BSE in cattle and avoiding spread to humans are threefold:
first, eliminate feeding of ruminant
tissues to ruminants; second, remove high-risk cattle tissues from human
food; and third, continue to test for BSE in cattle in order to monitor
progress with the elimination of
the disease on a local and national basis. In the next 12 months, after
extensive USDA test results are available, the extent of any possible BSE
spread in the United States will be
better documented. But, in fact, the United States and Canada have
already instituted the most important steps to prevent the spread of cattle
BSE in advance of the results--that
is, a ban on feeding ruminant MBM to other ruminants and removal of
high-risk tissues from meat for human consumption. It is hoped that the new
data will not deviate enough
from previous predictions to require further measures for management of
this problem. The most important line of defense against any possible
spread of BSE will be to maintain
strict vigilance in the implementation of the current regulations.


1.S. B. Prusiner, Proc. Natl. Acad. Sci. U.S.A 95, 13363 (1998)
2.P. G. Smith, R. Bradley, Br. Med. Bull. 66, 185 (2003) [Medline].
3.C. Weissmann, A. Aguzzi, Curr. Opin. Neurobiol. 7, 695 (1997)
4.A. F. Hill et al., J. Gen. Virol. 80, 11 (1999) [Medline].
5.R. Chiesa et al., J. Virol. 77, 7611 (2003) [Medline].
6.G. Legname et al., Science 305, 673 (2004).
7.D. Westaway et al., Cell 76, 117 (1994) [Medline].
8.B. Chesebro, Science 279, 42 (1998).
9.A. G. Biacabe et al., EMBO Rep. 5, 110 (2004) [Medline].
10.Y. Yamakawa et al., Jpn. J. Infect. Dis. 56, 221 (2003) [Medline].
11.C. Casalone et al., Proc. Natl. Acad. Sci. U.S.A. 101, 3065 (2004)
12.E. F. Houston et al., J. Gen. Virol. 83, 1247 (2002) [Medline].

The author is in the Laboratory of Persistent Virus Diseases, Rocky
Mountain Laboratories, National Institute of Allergy and Infectious
Diseases, Hamilton, MT 59840, USA.
E-mail: 10.1126/science.1103581

Volume 305, Number 5692, Issue of 24 Sep 2004, pp. 1918-1921.
Copyright © 2004 by The American Association for the Advancement of
Science. All rights reserved.

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