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Two years later,
in the summer of 1963, TME appeared again, almost simultaneously,
on 2 more mink farms. Suspecting a possible feed-based source of
contamination, based on the 1961 outbreak, the scientists went through
the two farms' feed records.
A striking finding
was that, from July through October 1962, meat "from beef carcasses
unfit for human consumption (so-called 'downer' cows)" that
came from Farm A was fed to minks on both Farms A and B. As the
scientists noted, "Since mink on both farms developed the disease
almost simultaneously, we believe this feed component has to be
incriminated" (Hartsough and Burger, 1966a: 389). Although
the authors could not completely rule out the possibility of sheep
parts being part of the suspect meat shipment, this was the first
suggestion that "downer" cows may be connected to TME.
("Downer" cow is a term that refers to cattle that are
killed because they no longer can stand up or have collapsed or
died for any of a number of reasons. There are an estimated 100,000
downer cows in the U.S. each year.)
The evidence
was convincing enough that, at an NIH-sponsored meeting on TSEs
in 1964, Drs. Burger and Hartsough hypothesized that sporadic cases
of a bovine TSE occurred in the US under the clinical picture of
downer cow (Burger and Hartsough, 1965).
The next recorded
outbreak of TME in the U.S. occurred 22 years later, in 1985, on
a mink ranch in Stetsonville, Wisconsin. Dr. Richard Marsh and his
colleagues (Marsh et al., 1991) studied this outbreak and produced
a number of lines of evidence that linked "downer" cows
to TME. First, the mink's diet consisted of 95% "downer"
cow and 5% horse meat. The minks received no sheep meat, so scrapie
can be ruled out as the infectious agent.
Dr. Marsh also
performed a number of experiments that further supported the notion
that cows were the source of the infectious agent. Dr. Marsh injected
brains from Stetsonville mink with TME into the brains of 2 Holstein
calves. Within 19 months, both calves had developed a fatal spongiform
encephalopathy. They did not act like "mad cows" in Britain;
rather they just got a bit lethargic and fell over, i.e. they exhibited
symptoms of "downer cow." Furthermore, when brains of
these cattle were either injected into mink or simply fed to them,
the mink developed TME. The authors concluded that "these results
suggest the presence of a previously unrecognized scrapie-like infection
in cattle in the United States" (Marsh et al., 1991: 589).
The evidence
is not solely linked to the Stetsonville outbreak. Dr. Marsh's cattle
inoculation experiments have been repeated using mink brain isolate
from the early 1960s outbreak of TME in Hayward, WI and in Blackfoot,
ID. The results of those studies mirror what Dr. Marsh found: the
inoculated cattle die of a TSE within two years (Robinson et al.,
199?). Furthermore, the cows inoculated with TME do not behave like
"mad cows," but exhibit behaviors consistent with "downer
cows."
Some scientists
have tried to argue that TME is caused by feeding scrapie-infested
sheep to the ranch mink. To test this possibility, Dr. Marsh has
tried feeding brains from scrapie-infested sheep to mink. Since
there are believed to be at least 20 different strains of scrapie,
Dr. Marsh tried feeding brains from a number of different strains
of scrapie-infested sheep. In none of these cases was he able to
infect mink with TME (Marsh et al., 1991). Indeed, we know of no
studies in the scientific literature which demonstrate that mink
fed scrapie-infested sheep develop TME.
A second problem
with the hypothesis that scrapie is the cause of TME is that the
first outbreak of TME in the US could not have involved feeding
of scrapie-infested sheep. The first recorded case of scrapie in
the US occurred on a ranch in Michigan in 1947, the year of the
first TME outbreak in Wisconsin. The infected sheep was a Suffolk
that could be traced back to Britain (where scrapie was rampant
among the sheep). Indeed, in the first few years after scrapie was
identified in the US, virtually all the infested sheep could be
shown to have come from Britain (Detwiler, 1992). Thus, when the
first case of TME occurred on a farm in Wisconsin in 1947, there
were no known scrapie-infested sheep in the state at the time, unless
one hypothesizes the existence of a native scrapie that had gone
completely undetected.
Scrapie-infested
cattle studies
Drs. Marsh,
Hartsough and Burger's work suggested that TME may result from consumption
of "downer cows." This raises the question of where a
TSE which causes "downer cow" behavior might come from.
One obvious possibility is scrapie. Thus, in 1979, at the USDA field
station in Mission, Texas, researchers inoculated cattle with scrapie
to see if cattle were susceptible to it: "It had earlier been
observed that the carcasses of 'downer' (paralyzed) cows had been
used as food for mink in which transmissible mink encephalopathy
developed. Since natural scrapie had never been described in cattle,
the study was designed to determine the susceptibility to experimental
transmission of this spongiform encephalopathy" (Gibbs et al.,
1990: pg. 1275).
Ten animals
were injected with scrapie-infested brain homogenates in the brain,
muscles and under the skin, as well as fed it. Three of the injected
animals developed neurologic symptoms some 2-4 years after inoculation.
The clinical symptoms were not those seen in cows with British-style
BSE (i.e. the cows did not act "mad"); rather, the symptoms
were more similar to those seen in "downer cow" syndrome:
"neurological signs 27-48 months after inoculation, consisting
of progressive difficulty in rising, a stiff-legged gait, incoordination,
abnormal tail position, disorientation, and terminal recumbency"
(Gibbs et al., 1990: pg. 1275).
More interesting
than the clinical symptoms was the fact that Dr. Hadlow's histopathological
analysis of the brains of the three affected cows revealed only
diffuse gliosis with little or no vacuolization of the neurons.
At the time, this was not considered sufficient evidence to conclude
that the animals had a TSE: "Histopathological examination
of the brains of affected animals revealed mild diffuse gliosis
and few vacuoles, changes which were reported as being insufficient
to confirm a clinical diagnosis of scrapie. Attempts to transmit
the disease by inoculating homogenates of brain from affected cattle
to mice were unsuccessful" (Gibbs et al., 1990: pg. 1275).
However, Dr.
Gibbs believed at the time that the three cows had died of a TSE,
in large part due to the animals' behavior (Gibbs, pers. com., March
28, 1997).
Ten years later,
an immunohistochemical test became available that could detect the
supposed infectious agent in scrapie (i.e. PrP27-30). Dr. Gibbs
arranged to have the brains of the cattle reexamined using the new
probe and found that the three cows with clinical symptoms tested
positive while the other cows were negative. Dr. Gibbs et al. published
the results of their work in an article entitled "Experimental
transmission of scrapie to cattle" in The Lancet (Gibbs et
al., 1990). Since publication of the article, another series of
mouse inoculation studies using brains from the suspect cows has
been done and resulted in passage of disease (Gibbs, pers. com.,
March 28, 1997).
Dr. Gibbs ended
the article by stating that the evidence suggested that a bovine
TSE was present at a low level in US cattle and that "downer
cows" should be tested: "Susceptibility of cattle to scrapie
further suggests the possibility that sporadic cases of BSE may
have occurred in the United States under the clinical picture of
the downer cow syndrome, as suggested by the work of Burger and
Hartsough and Marsh. A search for PrP27-30 in the brains of downer
cattle should provide useful information for this hypothesis"
italics added (Gibbs et al., 1990: 1275).
After Gibbs
et al. were able to show conclusively in 1990 that the Mission cattle
Texas had indeed been infected with scrapie, the USDA repeated the
experiment at an ARS (Agricultural Research Service) facility in
Ames, Iowa under the direction of Randall Cutlip. Dr. Cutlip's results
mirrored those found in the earlier study: some of the cows inoculated
with scrapie did die of a TSE, but they did not exhibit behaviors
associated with "mad cow" disease in Britain (i.e. British
BSE). Rather, the behavior is more subtle and could be mistaken
as "downer cow." As Cutlip et al. concluded, "Thus,
undiagnosed scrapie infection could contribute to the 'downer-cow'
syndrome [in the U.S.]" (Cutlip et al., 1994: 814).
BSE Surveillance
Program
In sum, the
indirect evidence from the TME studies, as well as from the scrapie-inoculated
cattle studies, points to the existence of a native bovine TSE in
downer cows in the U.S.
This native
BSE could arise spontaneously in cattle; it seems unlikely that
all cases are linked to scrapie. But USDA's Surveillance has only
recently started looking at downer cows. In 1965, Drs. Burger and
Hartsough were hypothesizing the existence of a native BSE strain
in the US that could be hiding in the downer cow population. In
1987, Dr. Marsh began hypothesizing the same thing and calling on
USDA to look at downer cows for potential TSEs. By 1990, even NIH
(in the person of Dr. Clarence Gibbs) was calling for testing of
downer cows for the presence of the mutant prion using an immunohistochemical
probe (Gibbs et al., 1990). The same year, USDA set up an advisory
committee called the Scrapie/BSE consultants committee. Dr. Richard
Marsh was one of the members. This committee designed and began
the BSE monitoring program done by the USDA.
At the start,
the BSE Monitoring program did not look at brains from downer cows.
There were two selection criteria for animals to be chosen for testing.
First were rabies-suspect but rabies negative cattle. Second were
animals that had gotten at least two years worth of animal protein
(energy-dense feeds) in the diet and had died of obvious neurologic
symptoms. Dr. Marsh argued that the CNS symptomology exhibited by
"downer cows" would go unrecognized by these two selection
screens and therefore argued that downer cows be added to the selection
criteria. For at least two years, 1991 and 1992, the committee declined
to follow Dr. Marsh's suggestion. At approximately the same time,
Dr. Marsh was trying to secure funding to sample downer cows and
test them, both pathologically and imuunohistologically, for evidence
of a TSE. In the early 1990s, Dr. Marsh submitted grant proposals
for two years in a row to USDA; both proposals were turned down.
The net result
has been that very few downer cows have been included in the BSE
Surveillance program. They were first included in the program in
1996. As of January 23, 1997, some 5,342 cattle brains had been
tested. Yet only a couple hundred of the brains came from downer
cows. While we applaud USDA for finally deciding to include downer
cows in their surveillance, USDA needs to focus more strongly on
the downer cows.
Given that the
USDA tested only 1,000 cows for BSE in 1999 and 2,000 cows in 2000
-- this is a miniscule number. Also, the number of downer cows examined
out of the 2,000 test is even smaller. Remember that it's commonly
expected that 100,000 U.S. cows are "downer cows" each
year, meaning the U.S. is testing a fraction of a percent of this
population.
Since the USDA
has not publicly admitted that we could have a native bovine TSE
already present in the US, the BSE Surveillance program has focused
on looking for British-style BSE.
The USDA must
admit that there is a strong likelihood that a native TSE exists
in US cattle. Once the USDA makes this admission, the other changes
needed in the Surveillance program will logically follow. First,
the veterinarians and pathologists who are looking at the brain
samples have been trained with slides and materials from British
cattle with BSE, so that they are looking for the characteristics
of the British strain of BSE. The brain damage characterisitic of
British style BSE is easily seen as there is lots of vacuolization
of the nerves.
However, the
work of the USDA and ARS on transmission of US scrapie to cattle
suggest that a US strain of a TSE in cattle probably could show
only subtle changes in brain morphology with very little, if any,
vacuolization of nerves. Thus, the U.S. vets may not may not be
looking for the right brain characteristics. Consequently, vets
should be trained using materials that show TSEs with subtle characteristics,
such as the pathology slides from the three affected cattle from
the original Mission, Texas studies or from the affected cattle
in Dr. Cutlip et al.'s repeat study. Furthermore, USDA should make
greater use of the immunohistochemical probe. Indeed, all suspect
brains should be examined using the probe.
In addition,
the USDA needs to focus more heavily on the downer cow population.
At present, only a few of hundred downer cows have been examined.
This is completely inadequate. If the disease were occuring at a
rate of one in 1,000 animals, it might not show up at all in this
sample. Yet this is a rate that would be of great public health
concern. Likewise, there are approximately 100,000 downer cows each
year in the US (Marsh, 1992). If just one-half of one percent (0.5%)
of these cows had a TSE, that would mean 500 infected cows. One
would have to look at 5,000 cows just to see 25 cases.
Consequently,
we believe that USDA should expand the BSE Surveillance Program,
modify the selection criteria and focus far more heavily on downer
cows. In fact, the major selection criterion should be downer cows.
For example, USDA could try to sample at least 500-1,000 downer
cows every year. Furthermore, among downer cows, USDA should focus
on those that exhibit CNS symptoms and not downer cows that have
broken legs, milk fever, etc. The USDA could also focus on states
which make the largest use of rendered ruminant protein in their
cattle feed and that have some of the oldest cows. This would mean
focusing on the larger dairy states such as Wisconsin, California
and New York.
Adapted from
Michael K. Hansen, Ph.D., Research Associate Consumer's
Union letter to USDA.
References
Bobowick, A.R., Brody, J.A., Matthews, M.R., Roos,
R. and D.C. Gajdusek. 1973. Creutzfeldt-Jakob disease: A case-control
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Boller, F., Lopez, O.L. and J. Moossy. 1989. Diagnosis
of dementia: Clinicopathologic correlations. Neurology, 39: 76-79.
Davanipour, Z., Alter, M., Sobel, E., Asher, D.M.
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Detwiler, L.A. 1992. Scrapie, Revue Scientifique
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Gibbs, C.J., Safar, J., Ceroni, M., Di Martino,
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of scrapie to cattle. Lancet, 335: 1275.
-------------- 1997. Statement to the Committee
on Government Reform and Oversight, Subcommittee on Human Resources
and Intergovernmental Relations, U.S. House of Representatives.
January 29, 1997.
Hadlow, W.J. 1996. Letter to Patrick McCaskey, USDA/FSIS/Eastern
Lab, dated November 10, 1996.
--------------------1997. Letter to Patrick McCaskey,
USDA/FSIS/Eastern Lab, dated April 10, 1997.
Hartsough, G.R. and D. Burger. 1966a. Encephalopathy
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----------------------------------------------------b.
Encephalopathy of mink. II. Experimental and natural transmission.
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Manuelidis, E.F. and L. Manuelidis. 1989. Suggested
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Alzheimer disease, and rteroviral CNS infections. Alzheimer Disease
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Marsh, R.F. 1992. Transmissible mink encephalopathy,
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Bethesda, Maryland, December 9-10, 1992. 7 pp.
----------------, Bessen, R.A., Lehmann, S. and
G.R. Hartsough. 1991. Epidemiological and experimental studies on
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