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[The early history of transmissible spongiform encephalopathies exemplified by scrapie].

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Transmissible spongiform encephalopathies (TSE) are unique diseases in that they are sporadic, hereditary, and infectious. The transmissible pathogen--the prion--stands out from all other pathogens in being devoid of nucleic acids. Instead its most important and possibly only constituent is a host-encoded protein, the prion protein (PrP), in an alternative conformation induced by post-translational modifications. Thus TSEs belong to and are so far the only transmissible member of the continuously growing group of disorders collectively referred to as protein conformational disorders. During elucidation of these disorders, many different--and contradictory--theories have been put forward. Early researchers, mostly driven by the economic effect of these diseases upon sheep farming, engaged in heavy disputes concerning the heredity vs infectivity of scrapie. After the experimental demonstration of scrapie's infectivity during the twentieth century, research focused on elucidating the nature of the transmissible agent. The current work comprehensively summarizes the early literature available on TSE research.
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Brain Research Bulletin 77 (2008) 343–355
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Brain Research Bulletin
journal homepage: www.elsevier.com/locate/brainresbull
Research report
The early history of the transmissible spongiform encephalopathies
exemplified by scrapie
Kurt Schneidera,, Heiner Fangeraub, Britta Michaelsen c, Wolfgang H.-M. Raaba
aDepartment of Operative and Preventive Dentistry, Heinrich-Heine-University/Westdeutsche Kieferklinik, Moorenstrasse 5, Building 18.13, D-40225 Düsseldorf, Germany
bInstitute for the History of Medicine, Heinrich-Heine-University, Universitätsstrasse 1, Building 23.12.04, D-40225 Düsseldorf, Germany
cMedical Faculty, University Giessen, Germany
article info
Article history:
Received 7 January 2008
Received in revised form 27 May 2008
Accepted 18 September 2008
Available online 23 October 2008
Keywords:
Transmissible spongiform encephalopathy
Slow virus disease
Prion disease
Scrapie
History
abstract
Transmissible spongiform encephalopathies (TSE) is a group of diseases that is unique in comprising
disorders that can occur sporadically, are hereditary and/or infectious. The transmissible pathogen – the
prion – is distinct from all other pathogens in being devoid of nucleic acids.
During the elucidation of these disorders, many different – and contradictory – theories have been
put forward. Early researchers, mostly driven by the economic impact of these diseases on sheep farm-
ing, engaged in heavy disputes concerning heredity vs. infectivity of scrapie. Following the experimental
demonstration of scrapie’s infectivity during the 20th century, research focused on the characterization
of the nature of the transmissible agent.
The current work comprehensively summarizes the available early literature on TSE research. A review
of the historical literature is presented, describing the efforts in breeding, transmission experiments, and
theories about the nature of the infectious agent.
© 2008 Elsevier Inc. All rights reserved.
1. Introduction
The term “transmissible spongiform encephalopathy (TSE)”
is used to denote a group of inevitably fatal neurodegener-
ative disorders affecting mammals and man. TSEs affecting
man include Creutzfeldt-Jakob-disease [43,98,99], Gerstmann-
Sträussler-Scheinker-syndrome (GSS) [73,74], Kuru [72,204], fatal
familial insomnia (FFI) [121] and sporadic fatal insomnia (sFI)
[122,124]. TSEs affecting mammals are scrapie in sheep and goats,
transmissible mink encephalopathy in mink (TME) [30,86], chronic
wasting disease in elk, mule deer and white-tailed deer (CWD)
[198], bovine spongiform encephalopathy in cattle (BSE, mad cow
disease) [194], exotic ungulate encephalopathy in exotic ungulates
(EUE) [100,102] and feline spongiform encephalopathy in cats (FSE)
[115,201].
In earlier times, people most interested in scrapie were the
sheep farmers who were directly affected by its economic impact.
Since then, the interest in TSEs has broadened to the research com-
munity and – caused by BSE’s pathogenic potential for humans – to
Corresponding author. Tel.: +49 172 93 93 027.
E-mail addresses: Kurt.Schneider@uni-duesseldorf.de (K. Schneider),
Heiner.Fangerau@uni-duesseldorf.de (H. Fangerau), raabdent@uni-duesseldorf.de
(W.H.-M. Raab).
the general public, which can be recognized by scrapie’s mention
even in fiction [177,178].
During the 20th century, different theories on the nature of the
causative agent of TSEs were put forward. In the course of time,
most of these turned out to be unfounded. The TSE agent was pro-
posed to be (in chronological order of publication):
sarcosporidia (1914) [128];
a filterable virus (1938) [45];
a slow virus (1954) [170];
a replicating polysaccharide (1966) [8,61];
a protein (1967) [81,140];
a replicating membrane (fragment) (1967) [75,94];
a DNA-polysaccharide complex (1968) [3];
a viroid (1972) [52];
a lipid (1978) [10];
aSpiroplasma sp. (1979) [18–20,78];
a virino (1979) [51];
a prion (1982) [146];
a virus (1984) [123,157–159];
mitochondria(l nucleic acid(s)) (1989) [5,6];
a holoprion, consisting of PrPSc(PrP in the scrapie specific con-
formation, the apoprion) and a (dispensible) nucleic acid (the
coprion) (1991) [193].
0361-9230/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.brainresbull.2008.09.012
344 K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355
Fig. 1. Publications on transmissible spongiform encephalopathies (literature anal-
ysis with Index Medicus and cross citations; results are comparable to an analysis
concerning CJD (1966–1985) [27].
The most popular propositions put forward for the causative
agent were a virus and a pathogenic protein (the prion). Unusually
long incubation periods militated against viruses as cause. These
long incubation periods gave rise to the term ‘slowvirus’. Infectious
proteins, on the other hand, seemed to contradict a biochemical
dogma stating that information coding the structure of proteins is
exclusively derived from nucleic acids while proteins never code
for amino acid sequences.
A chronological analysis of the published literature and the
increase in the number of publications on TSEs reflect a progres-
sive increase in interest in these disorders. Reasons for this increase
are both findings and theories that were regarded as especially
important as well as the economic impact [28] of the disease. The
upsurge in the number of publications after the middle of the 20th
century coincides with an idea stated by Hadlow [84] in 1959:
two diseases so far considered unrelated might have a common
cause — scrapie in sheep and kuru, which was described in 1957
for the first time, in the Fore (aborigines in Papua New Guinea).
This idea launched a still continuing research boom. The increase
in publications was accelerated in 1985 by the advent of the bovine
spongiform encephalopathy which, originating in UK, necessitated
the culling of hundreds of thousands of cattle. The paramount eco-
nomic impact of this disease is reflected in the funding mobilized
primarily for the elucidation of its cause as well as for its prevention
(74 projects funded in Germany as of December 2007,155 projects
funded by the EU,235 projects funded by the U. S. Department of
Agriculture3). The amount of research results is directly recogniz-
able in the number of publications. As far back as 160 years, there
was – for former circumstances – a comparable rise in publica-
tions, driven by enormous losses caused by an increased number
of scrapie cases in many areas of East Germany (see Fig. 1). The
decline in publications (in the last few years), visible in the fig-
ure, is caused by the way the literature was collected — by tracking
citations.
1http://www.tse-forum.de/tse forum/index eng.htm.
2http://cordis.europa.eu/search/index.cfm?fuseaction=proj.resultslist&CFID=1950907&CFTOKEN=40896272.
3http://cris.csrees.usda.gov/.
The uncertainty concerning the origin of TSEs that was prevalent
until the 1990s and the still persisting uncertainty concerning the
mode of transmission of some naturally occurring TSEs has a long
history that dates back to the first descriptions of scrapie more than
250 years ago.
Considering the popularity that TSEs have achieved in recent
years, there are remarkably few publications focussing on the his-
torical development of TSE research [28,85]. Most of them are
introductory chapters of books [4,91,137,196].
This paper presents an analysis of publications on scrapie dur-
ing the period from 1750 until 1936. This period starts with the first
publication describing scrapie [118](see Fig. 2) that is still reliably
trackable. The end of this period is the year in which Cuillé and
Chelle [44] demonstrated without any doubt scrapie to be trans-
missible.
After a short quantitative and qualitative literature review, the
article concentrates on historical attemptsto transmit scrapie. After
discussing the impact of breeding on scrapie, it focuses on the
pitfalls of transmission experiments and finally presents different
theories about the character of the transmissible agent of scrapie.
2. Historical literature
Scrapie is the disease with the longest history of publications
and the prototype of TSEs. The analyzed publications compriseorig-
inal articles, reviews and contributions to periodicals. Almost all
authors were devoted to the search for the cause of the disease.
The multitude of proposed causes is by all means comparable to
the number of suggested pathogens put forward during the 20th
century.
Some publications refer to a paper dating back to the year 1732
as the first description of scrapie. However, this is considered to
be a misconception because a publication from this year cannot be
found. At the same time, in 1772, scrapie was reported to be known
for some 40 years — a point in time dating back to the year 1732:
This Distemper is generally said to be of about forty Years stand-
ing in England ...[40]
There are several other references pointing to years before 1750.
Gajdusek claims that the first citations are from the 17th century
[69].Brown[26] mentions first reports dating back to the 15th cen-
tury. Gaiger [68] presumably and May [126] explicitly refer to Kuers
[111] who mentions a reference by an agricultural writer at the time
of the Romans. All of these authors unfortunately failed to supply
the corresponding citation.
The analyzed literature (predominantly German — reflecting the
geographical focus of the disease as well as the availability of the
literature) was mostly written by “Ökonomen” (economists). These
“Ökonomen” were shepherds, farmers, or their — often aristocratic
or governmental — employers.Reports written by veterinarians and
natural scientists are scarce, in part because the disease was not
known to them:
Scrapie has been known for a long time, being put on record by
several agricultural authors. Moreover, old shepherds know it.
Only veterinarians missed this disease [180].4
This remarkable situation is explainable by the attempt of many
shepherds to keep the breakout of scrapie in their herds secret
[188]:
4[Scrapie] ist ... längst bekannt gewesen, — nur nicht den Thierärzten — ihrer
ist von verschiedenen ökonomischen Schriftstellern erwähnt, auch kennen sie alte
Schäfer [180].
K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355 345
Fig. 2. First mention of scrapie.
Every single beauty of the body, every exceptional feature of the
wool of the sires will be stressed as much as possible. All abnor-
malities of the herd will be hidden from the eye of the buyer.
Individuals only raising the vague suspicion of being affected by
scrapie will never ever be showcased to the scrutinizing inspec-
tion of the knowledgeable [1].5
M’Gowan characterized this behaviour of the shepherds as “sup-
pressio at least, if not a perversio veri[128].
The lack of awarenessof scrapie by veterinarians may be one rea-
son why neither genetics (around 1860), nor bacteriology (around
1880) had any impact on the elucidation of scrapie’s causes. It
took until the end of the 1930s that scrapie’s transmissibility was
demonstrated beyond any doubt [44–47]. Moreover, although the
earliest available description of scrapie [118] clearly states that
the disease is infectious, during the 19th century there was a
widespread conviction that the disease is transmitted by sexual
intercourse (this view is found in more than half of the articles
that were analyzed) and might have hampered the consideration
of, and thus also the conduction of experiments analyzing any other
mode of transmission (less than one fifth of the analyzed articles
propose infection by mere coexistence of animals or spontaneous
appearance of scrapie as a cause).
5Jede Körperschönheit, jede vorzügliche Woll-Eigenschaft der Stähre wird nach
Würden herausgestrichen, alle Abnormitäten der Heerde werden dem Auge des
Käufers möglichst entrückt, und Individuen, die die Traberkrankheit nur ahnden
lassen, dem prüfenden Blicke des Kenners bestimmt nicht und am allerwenigsten
dargestellt [1].
The literature can be subdivided into two groups:
retrospective case and/or autopsy reports;
contributions criticizing and comparing these case reports with
each other (reviews).
There are lengthy discussions about the causes and the modes
of transmission of scrapie. Many authors were convinced that the
disease can develop spontaneously, an opinion partially substan-
tiated by a reference to flawless biblical circumstances [164]. This
idea, proposed in 1826,resembles the degeneration concept formu-
lated shortly thereafter by Augustin Morel (1809–1875). Morel, too,
assumed a biblical “type primitif”, which was modified somatically,
morally and psychically from generation to generation by external
circumstances resulting in disease [165].
According to the medical concepts prevalent at the time, early
reports about this disease discussed miasmata [147,190], thun-
der [156] or other exceptional atmospheric events [148–150],
intoxication [25], worm infections [66], poor quality or insuf-
ficient amounts of food [126,162,163], too nourishing a pasture
[65,66,88] or feedstuff [55,57,88,126,148,152,154], too humid a
pasture [111 ] or too much humidity in the sheep pen [154],
nutritional deficiencies in sodium or potassium salts [57], tail
docking [126], too young [56] or too old [57,162,163] dams,
too early [29,55,57,88,126,154,174,181], too late [88,164], too lit-
tle [65,66,152,154,182] or too much [55,57,126,138,154,174] sexual
activity of the rams, cross-breeding [55,154] or inbreeding [126] as
possible causes of scrapie.
346 K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355
Causal research wasdone using correlations, comparing affected
with unaffected sheep farms. Different methods of care taking,
atmospheric or other conditions prevalent in one but not in the
other sheep farm were proposed as causative.
Despite some authors doubting scrapie’s heredity [110],itwas
common sense by the end of the 18th [40] and in the beginning of
the 19th[181,188,191] century that scrapie was a hereditary disease.
Thaer, in 1826, describe d scrapie’s mode of hereditary transmission
as ‘greater or less predisposition to acquirethis disease in one or the
other state of development if some additional circumstance would
happen’ [182].6
At that time, many authors held mostly the rams responsi-
ble for propagation of the disease during copulation [1], resulting
in suggestions to control the spread of disease by mating only
healthy rams with the ewes [138]. However, Thaer, in a com-
ment to Rudolphi [161], as well as von Richthofen [189], conceded
that scrapie can also show up without a hereditary predisposi-
tion, thereby affecting animals in hitherto healthy flocks. Beyond
this, once the disease had developed spontaneously, it was con-
sidered to be henceforth hereditary, a proposition resembling
Lamarck’s ideas about the origin of hereditary traits formulated in
1809.
There were sporadic reports [129,162,163] referring to scrapie by
one of its customary names and describing the symptoms correctly,
but nevertheless suggesting that the affected animals recovered
mostly with or without treatment.
Despite these dubious descriptions, the prevalent advice given
to shepherds who noticed this disease among their sheep was to
cull the entire flock [186] and to move the sheep to a different pad-
dock. It might be supposed that the idea of breeding animals for
resistance against scrapie by selecting supposedly less susceptible
animals as a way to combat this torment gained additional impact
with Darwin’s ideas about evolution and Weissmann’s germ plasm
theory that neglected any Lamarckian concepts of the hereditabil-
ity of acquired characteristics. This idea of breeding sheep against
susceptibility to scrapie is still up-to-date, given the correlation
between genotype and susceptibility.
As early as 1821, when Richthofen called scrapie a hereditary
malady (“Erbübel”) [155], Albrecht Daniel Thaer [181] described
a hereditary predisposition and a transmission of this disease
by asymptomatic animals. The same author suspected a heredi-
tary and a non-hereditary variant of scrapie to exist [188], which,
admittedly, were found not to be discriminable by their symp-
toms. Further ancient references to the knowledge of a hereditary
predisposition for scrapie, dating back to the years 1826 and
1827, respectively, can be found by Thaer [182] and by von
Richthofen [188,191]. Von Richthofen calls scrapie a ‘hereditary
malady intended to distribute perpetually’7and states ‘that the
ailment is not restricted locally, but shows up only if heredity or
contagion were causally involved’8[191].
Despite the early knowledge of infectivity, there were several
unsuccessful attempts to transmit scrapie, leading to doubts as to
whether scrapie is indeed infectious. Dammann [48], in 1869, tried
to transmit the disease from sheep to sheep by keeping healthy
and diseased animals together in the same herd. After an observa-
tional period of up to 22 months, this experiment turned out to be
6Jeder, der einen verständigen Begriff von Krankheit hatte, bezog das Erbliche
nur auf eine größere oder geringere Disposition, diese Krankheit in einer gewis-
sen Entwicklungsperiode zu bekommen, wenn irgend eine veranlassende Ursach
hinzukäme, wie das bei vielen thierischen und menschlichen Krankheiten der Fall
ist [182].
7...immer weiter sich verbreiten wollendes Erbübel” [191].
8...daß diese Krankheit keinesweges örtlich, sondern blos alsdenn entstanden
sei, wenn die Erblichkeit oder Ansteckung dabei zum Grunde lag ...[191].
unsuccessful. Thereafter, he transferred blood of diseased animals
to mucous membranes of healthy ones. Once again, transmission
of scrapie was not achieved (no observation period was given). This
led the author to speculate about a route of transmission through
fly larvae, an experiment that succeeded only more than 130 years
later [142]. Dammann consequently considered scrapie to be non-
infectious.
Cassirer [32] adopted Dammann’s view that scrapie is not
an infectious disease. In 1898, he reported the examination
of five sheep, one of them only post mortem, that had suc-
cumbed to scrapie. After having excluded insects found in the
frontal sinus at necropsy, as well as cocci used in transmission
experiments, as vectors of scrapie, he analyzed the central ner-
vous system. Following gross anatomical as well as microscopic
examinations, he concluded that, within the limitations of the
methods available at his time, the nervous system shows no mod-
ifications in scrapie diseased animals (our italics). This is in clear
contrast to Besnoit’s [25] observations, who, in the same year,
detected profound injuries of the nervous system and periph-
eral nerves, as well as obvious vacuolation. He proposed an
intoxication of sheep, acquired from food, as the reason for dis-
ease.
Among the majority of authors, there was widespread agree-
ment that changes in the spine of patients could be found [126],
which were claimed to have been observed during necropsies. This
might be explainable with the observed problems in locomotion.
Many authors reported sheep in the late states of disease having
difficulty following their flock.
Starting with an initial affection caused by one or the other
agent, the authors described the transmission from patient to
hitherto healthy flock fellows. During the discussions of possi-
ble transmission routes, a clear distinction between genetically
transmitted and infectious disease was lacking. While there were
reports about an infection of the mating partner or of the
embryo during copulation, a distinction between genetically trans-
mitted and sexually transmitted disease was not being made.
Both, a transmission from ram to dam and from dam to ram
was considered possible. However, the probability of contracting
scrapie was reported to depend on gender (ram >ewe >wether)
[126,152]. This confusion is recognizable in the following cita-
tion:
However, what is most important from the author’s point of
view for the persistance and distribution of scrapie is infection:
plain infection as well as infection during copulation ...[151]9
This passage is equally suited to describe an infectious as well as
a sexually or genetically transmitted disease. Another citation from
the same year but by another author highlights this intermingling:
There are two ways for this disease to spread. First, by copu-
lation, in fact with greater probability by the male than by the
female participant. Second, it is contagious by gregariousness
of diseased and healthy animals in flocks, in sheep-pans and on
the paddock. ...First of all, the shepherd who is eager to rid his
herd of the disease is advised to remove all sires — except those
which have been proven not to be affected — and replace them
with animals which are completely free of hereditary diseases
[1].10
9Dasjenige aber, worauf nach der Meinung des Herrn Verfassers das Bleiben und
Verbreiten der Traberseuche am vorzüglichstenberuhet, ist die Ansteckung, sowohl
an und für sich, als auch das Anstecken durch die Begattung ...[151].
10 Ansteckend ist die Krankheit auf zwei Wegen. Erstlich durch die Begattung
und zwar mehr durch den männlichen als durch den weiblichen Antheil. Zweit-
ens wird sie ansteckend durch das Zusammenleben kranker und gesunder Thiere
K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355 347
Today, it is hard to conceive how to justify the requirement of
absence of any hereditary disease in order to prevent an ailment
that is supposed to spread by cohabitation.
The lacking distinction between the different modes of trans-
mission, which was prevalent in the 19th century, was recognized
by the beginning of the 20th century [173]. However, the dep-
recation of the idea of a disease that can be transmitted by
infection as well as by genetic transmission was justified by the
lack of any other disorder that unites both ways of transmis-
sion:
These observations I think justify the conclusion that the dis-
ease spreads by contagion. It has been stated by a considerable
number of farmers that the disease is hereditary, and some have
stated their belief that it is both hereditary and contagious. I
may point out, however, that no disease is known which is both
hereditary and contagious, although the mistake is not unnat-
ural in a lay mind, which does not always distinguish between
hereditary transmission and congenital infection [173].
The analysis of scrapie was complicated by the fact that in for-
mer times many other diseases affecting sheep (Drehkrankheit,
Kreuzdrehe and Gnubberkrankheit) were confused with scrapie.
Different authors considered one or more of them to be iden-
tical with or different from scrapie. Contemporary authors tried
to discriminate “Drehkrankheit”, “Gnubberkrankheit”, “Kreuz-
drehe” and “Traberkrankheit”. While many of them differentiated
between “Drehkrankheit” and “Kreuzdrehe” on the one hand and
“Traberkrankheit” on the other [57,66,88,111,126,153,161,180,191],
there were other authors who considered “Kreuzdrehe” and
“Traberkrankheit” to be the same, but to be different from
“Gnubberkrankheit” [192]. Spinola [171], however, used the terms
“Gnubberkrankheit” and “Kreuzdrehe” synonymously. This confu-
sion of terms, as well as the vague and ambiguous description of the
symptoms of scrapie and of the other diseases, hamper the attempt
to extend scrapie’s documentedhistory beyond the year 1750. What
makes things worse are the many different names that were used
to refer to scrapie (see Table 1).
3. Breeding
Since their domestication about 11,000 years ago [141], sheep
have served different purposes as farm animals. They were and are
used as suppliers of food (mutton and milk), clothing (fur and wool)
and fertilizer. Strings of instruments can be made out of sheep gut,
while percussion instruments can be manufactured using sheep
skin. In recent times sheep are (together with goats) employed
in landscape conservation. Complete man-made landscapes as the
Lüneburger Heide (in Northern Germany) or the Rhön (low moun-
tain range in the border triangle of Hesse, Thuringia and Bavaria
(Germany)), are indeed inconceivable without sheep [166].
For millennia, man tried (and succeeded) to improve the qual-
ity of meat and wool as well as the amount of milk produced by
sheep by selective breeding. During the middle ages, sheep of good
wool quality were considered an asset worthy of protection. Aris-
tocratic sheep owners, the Mesta, forbade exportation of Merino
sheep from Spain on penalty of death [12]. This demonstrates the
efforts invested in and the value of breeding sheep with desirable
phenotypes.
in einem Haufen, in einem Stalle und auf einer Weide. ... Der Schaafzüchter,
welcher seine Heerde von der Traberkrankheit ganz reinigen will, muß fürs erste
alle gebrauchten Sprungböcke, wenn nicht Individuen darunter sind, deren Tra-
berfreiheit unbezweifelt erwiesen ist, fortschaffen, und muß ganz von erblichen
Krankheiten freie sich zu verschaffen suchen [1].
Table 1
Historical/locally customary names of scrapie (in alphabetical order).
Name of scrapie Used in Citations
Basqvilla Disease Spain [190]
Cuddie Trot Scotland [87,120,128]
Drab(en) Germany [111,113,191]
Dreb/Deeb Germany [65,66]
Drehkrankheit aGermany [82]
Gaubber/G(n)aup(p)er bGermany [29,66,110,111,113,191]
Gnubberkrankheit c/Gnub(b)ern Germany [32,111,126,182,183,205]
Goggles England [13,34,39,120,128,186]
Knopper/Knubber(n)/(K)nupper Germany [65,111,113,161]
Khujali Tons (India) [101,207]
Kreu(t)zdrehe(n) aGermany [11,65,66,191,192]
Kreutzschlagen Germany [7,113]
La maladie convulsive France [120]
La maladie foll(i)e France [21,24,87,120]
La maladie trotteurs France [24]
La prurigo lombaire France [21,120]
La Tremblante France [21,24,70,87,128,135]
Mukoo Gangotri (India) [101,207]
Petermännchen Germany [57]
Prurigo lombaire France [24]
Prurigo lumbar Spain [202]
Reiberkrankheit Germany [21,126,189,191]
Reiber-Uebel Germany [29,191]
Rickets England [21,40,196]
Rida Iceland [50,133,170]
Rub/Rubbers England [21,90,120,173,203]
Rubbing disease England [136]
Ruppe Germany [66]
Scabies dorsalis Germany [191]
Schrucken/Schru(c)kigsein Germany [66,126,143,161,182,191]
Scratchie Scotland [120]
Shakings England [21,120,128]
Shrewcroft England [120,128]
Shrugginess England [136]
Spruckigkeit Germany [111,113 ]
Tempermänner Germany [57]
Trab(en)/Traberkrankheit Germany [21,87,118,135,161,205]
Trotting disease England [50,132,136]
Trz ˛
esawka Poland [120]
Wetzkrankheit Germany [126,143]
Yeukie pine Scotland [87]
Zitterkrankheit Germany [21,120,126]
aMany authors consider this nomenclature to be a misnomer based on a mistake
[57,66,88,111,126,153,161,171,180,191].
bThis disease, too, was presumed to be different from scrapie [110].
cWagenfeld[192] consideres Gnubberkrankheit to be different from ‘Kreuzdrehe’
and ‘Traberkrankheit’.
Whichever trait sheep were selected, it is reasonable to consider
resistance against scrapie not to be one of these qualities at that
time. In fact, it is conceivable that breeding for good wool quality
involved inadvertant breeding for susceptibility for scrapie. How-
ever, as detailed records of the animals used for breeding during
the middle ages are hard and information about their genotype is
impossible to come by, this is an eventuality that is impractical to
prove or disprove in hindsight.
Today, there are additional reasons for genetic selection. One
of them is conservation of species and their genepool. E.g., the
Rhönschaf11 was supposed to be close to extinction during the sec-
ond half of the 20th century. In 1957, only 300 Rhön sheep were
known in West-Germany [89](down from 13,855 in 1948 [22,166]).
This reduction was mostly due to a general reduction in the num-
ber of sheep, and partly due to the exclusion of Rhön sheep living
in Thuringia from breeding on account of the border separating
East- and West-Germany until 1989 (300 ewes were reported to
live in the former German Democratic Republic in 1990 [166]).
11 http://www.aid.de/landwirtschaft/tierspecial/schafrassen/rhoensch.htm.
348 K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355
Table 2
Polymorphisms in the prion protein sequence in sheep.
Codon Amino acids
136 A V Ala Val
154 H R His Arg
171 H QR His Gln Arg
According to Refs. [96,185,200].
Efforts were undertaken to increase the size of the remaining herds.
Today, the Rhönschaf is ubiquitious again in the Rhön with about
3000 ewes [89]. A second reason for today’s genetic selection is the
utilization of knowledge about the genetic layout of individuals,
which can be used to select for resistance or against susceptibility
to specific diseases.
Only recently, Commission Regulation 999/2001 [58],
1492/2004 [59] and 1428/2007 [60] of the European Commu-
nity were released aimed at eradicating TSEs. The last two of
these regulations proposed the preference of animals carrying
the genotype A136 R154 R17 1 (or ARR, for short) for breeding. There
are 12 different combinations of codons at position 136, 154 and
171 in ovine PrP (Table 2), none of which are pathogenic. Instead,
some of these polymorphisms raise the susceptibility for scrapie,
while others lower it, a conception that was already formulated
in 1826 [182], self-evidently without any knowledge about the
molecular genetic fundamentals. One of these polymorphisms
(ARR) is considered to provide sheep with the lowest susceptibility
to scrapie.
Clearly, this technique was only available after the sequence of
PrP was discovered and epidemiological studies could correlate the
genotype of sheep with the susceptibility for scrapie.
4. Transmission experiments
Most publications contain statements for or against the dis-
cussed modes of transmission. Many authors were convinced that
scrapie was transmitted by sexual intercourse [1,2,11,13,32,40,55,
56,66,67,88,126,151,152,154,155,160,162,163,171,174,181,188,190,191,
206]. However, this opinion was not shared by others
[110,161,173,182,183]. Even infection without sexual contact was
considered possible [1,118,119,127,129,150,151,155,173] or impos-
sible [13,48,55,66,111,113,126,148,154,171,174,175,181–183,206].
There was another group of authors who favoured the idea of a
spontaneous origin of scrapie [57,111,113,154,164,171,182,183,188],
one that was refuted by others [127]. Proponents of one cause did
not necessarily reject other causes. Some authors changed their
mind in the course of time. Thaer, for instance, was a proponent
of sexual transmission in 1821 [181], but turned down this idea in
1826 and suggested a spontaneous origin [182,183]. Other authors
considered multiple ways of origin and transmission possible (see
Fig. 3).
Most authors reported the main season for contraction to be
autumn and the prevalent age of the sheep to be one to three
years [111,113,128]. Single authors mentioned lambs and yearlings
as vulnerable [155].
M’Fadyean [127] succeeded in demonstrating that lambs housed
together with infected ewes for only a few days contracted scrapie
29 months later. However, the diseased sheep were lambs of the
infected ewes. Thus, these experiments wereunable to differentiate
between hereditary and infectious transmission. This complication
was acknowledged and advocated against by Gaiger [68] 6 years
later, in 1924.
Experiments by M’Fadyean included subcutaneous and intra-
venous injection of intestinal contents, water containing skin
scrapings, up to 25 cm3of blood, 3 cm3annantois and foetalcotyle-
Fig. 3. Number of citations suggesting different ways of transmission.
dons and up to 7 cm3of cerebrospinal fluid derived from diseased
animals [127]. None of these experiments was capable of transmit-
ting scrapie.
The same author also reported an involuntary experiment con-
ducted by two tenants of farms who had almost exactly the same
story to tell [127]. Both of them had scrapie-free flocks of sheep.
Both of them bought ewe lambs in the autumn of 1907 from the
same breeder. In the spring of 1909, the first cases of scrapie
appeared in the flocks, exclusively affecting the animals bought in
1907. All these animals bought in 1907, including their offspring,
were sold in autumn 1909, whereupon the farms were scrapie-
free for one and a half-year. In spring 1911, the disease reappeared,
this time affecting animals that had been bred on the farms before
the purchase in 1907, thus demonstrating that an infectious pro-
cess must have taken place between the formerly existing animals
and the purchased ones. Based on these and other observations,
Gaiger [68] suggested sexual intercourse as the most likely mode
of transmission.
Only in 1936, Cuillé and Chelle succeeded in demonstrating
scrapie’s transmissibility beyond any doubt. After an observation
period of 1 1/2 years before the inoculations to demonstrate the
absence of scrapie, the authors inoculated their experimental ani-
mals intraocularly, epidurally, subcutaneously and intracerebrally
using suspensions from brain and spinal cord. Many of their exper-
imental animals died after inoculation from unrelated diseases
(mostly inflammations). From the surviving animals, both sheep
[44–46] and goats [47], as recipients, could be infected. However,
while the incubation periods for sheep were between 11 and 22
months, goats stayed apparently healthy for a duration of 25–26
months. The authors found no differences in the presentation of
natural and experimentally infected animals [45].
Former experimenters expected comparatively short incuba-
tion periods and therefore abandoned their experiments after
this period of time if no symptoms were visible. Others used
animals originating from flocks (or even descending from ewes)
which were infected with scrapie. After being unsuccessful in their
attempts to transmit scrapie, the recipient animals were sold to
the butcher [127]. Cuillé and Chelle were the first to adhere to
two important circumstances in combination in their experimental
design:
K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355 349
1. they expected an exceptionally long incubation period of years
instead of days or weeks as it was observed in other infectious
diseases;
2. they used recipient animals that originated from scrapie-free
flocks which had been observed for 18 months before the inoc-
ulation to confirm their health.
Greig, in 1940 [79] and in 1950 [80], reported an experiment
that started in 1932 to demonstrate the natural transmission of
scrapie. Two flocks of sheep, one scrapie infected, the other not,
were grazed alternating on the same paddock. Care was taken that
during exchange of the sheep, which was twice a week, no immedi-
ate contact between the members of the two flocks was possible. 39
months later, seven (and possibly three more, which were doubt-
ful) animals of the flock that had been free of scrapie developed
scrapie symptoms, thus demonstrating that a transmission of the
disease was also possible without artificial inoculation.
In 1946, Gordon [76] described another accidental experiment
concerning the infectivity of scrapie. Between 1931 and 1934, trials
to test a vaccine against looping-ill were conducted. Sheep were
infected with looping-ill virus by intracerebral inoculation. Three
batches of 10% saline suspension were made from the brains, spinal
cords and spleens of 140, 114 and 44 treated sheep, respectively,
sufficient to immunize more than 44,000 sheep against the dis-
ease. 0.35% formalin was added to these suspensions to inactivate
the looping-ill virus. During 1935 and 1936 the vaccine proved its
effectiveness against looping-ill. In autumn 1937, the first cases of
scrapie appeared in a group of vaccinated animals where scrapie
had not been observed before. By reconstructing the vaccination
schedule, batch number two could be identified as the one that
must have transmitted this unexpected disease. Several lessons
were learned from this accident:
1. scrapie is definitely transmissible (which was still not demon-
strated at the time of vaccination as Cuillé and Chelle’s [44–47]
experiments describing successful transmission were yet to be
published);
2. the scrapie agent is found in the brain, the spinal cord and/or
the spleen of diseased animals (from which the vaccine was
produced);
3. the scrapie agent is resistant to treatment with formalin. Gordon
[77] reported values of 10% formalin for at least 28 months that
the agent can withstand without inactivation;
4. subcutaneous inoculation is a possible way of transmission;
5. the incubation period is 2 years or longer.
The influence exerted by the inactivated looping-ill virus was
analyzed by Stamp et al. [172]. They inoculated twenty sheep
intracerebrally with 1ml scrapie sheep brain pool (SSBP) each, an
inoculum developed to standardize experimentswith scrapie infec-
tion. Half of these sheep were additionally infected with looping-ill
virus 4 months later. The brains and spleens of the double infected
animals were made to looping-ill vaccine which was treated with
0.3% formaldehyde for 2 weeks at 4 C. From the brains and spleens
of the sheep infected with scrapie only a control inoculum was
prepared. The vaccine and the control inoculum were injected sub-
cutaneously into 30 sheep each. Two of the sheep receiving the
looping-ill vaccine and five of the sheep receiving the controlinocu-
lum contracted scrapie after incubation periods as short as 5 and
8 months, demonstrating that the addition of looping-ill virus did
not assist in transmission of scrapie.
While in Gordon’s vaccinations, the way of transmission could
be reconstructed unambiguously, there are many reports about
scrapie infections where the route of infection is equivocal.
One conceivable way of infection, which was rejected by some
researchers [32,160], but was suggested once again in 1954 by Sig-
urdsson [170], is through vectors. While Wisniewski et al. [199]
and Carp et al. [31] described mites as vectors, Post et al. [142]
were unable to reproduce these results. Instead, they demonstrated
transmission of scrapie through fly larvae and pupae.
Clouscard et al. [35] transmitted scrapie to sheep by feeding
them third-stage nematode larvae. The authors supposed that the
infectivity present in the ground for several years was insufficient
to promote disease. However, upon infection with large numbers
of larvae introduced into the ovine gastrointestinal tract, lesions
created by these larvae facilitated penetration of the agent.
The accident during looping-ill vaccination was not the only
iatrogenic transmission of TSEs. From 1974 on, reports started
to appear that described transmission of CJD to humans dur-
ing corneal transplantation [54], with stereotactic electrodes [23],
through pituitary gonadotrophins [36,114], through pituitary-
derived human growth hormone [63,114], through dura mater
grafts [14–17,179] and during liver transplant [42]. Finally, the
transmissibility of scrapie through blood transfusion was demon-
strated in sheep [93,95,97], raising concerns for human blood
recipients.
5. Theories about the nature of the infectious agent
Despite the different propositions for the nature of the infec-
tious agent, it should never be forgotten what Gajdusek and Gibbs
[71] had to say about the conception of a ‘virus’. They considered it
a ‘semantic problem’ if an ‘agent that transmits disease and turns
on its own synthesis’ should be called a virus or not. Finally, Gaj-
dusek [70] defended his notion of a ‘virus’ with the comparison to
computer viruses which are known not to contain any nucleic acid
either, but, nevertheless, are infectious and self-sufficient enough
to support their own replication and subsequent propagation using
machinery of the host.
In the following table, a timeline summary of the most impor-
tant theories about the infectious agent, including arguments for
and/or against the individual opinions, is presented.
1914: Based on observations made by others, M’Gowan [128] sug-
gested an association between sarcocysts and emaciation. Other
symptoms associated with scrapie, such as itching and paralysis
were believed not tob e observable‘in the riot of a slaughter-house’.
Another explanation for the missing absence of record of scrapie
specific symptoms was the fact that inspectors in abattoirs most
often only saw carcasses which obviously could not demonstrate
any suspicious behaviours. The author claimed to have found a
correlation between the presence of sarcocysts and scrapie: ‘The
sarcocyst is always present in the skeletal muscle of scrapie sheep
in large numbers; and the more advanced the case the larger is the
number of the sacrocyst present’. While this might have been pure
coincidence, the author failed to present a causative correlation
between sarcocysts and scrapie.
1938: After demonstrating scrapie’s transmissibility [44], Cuillé
and Chelle [45] set out to estimate the agent’s size. Therefore, they
homogenized 15cm of spinal cord of an affected sheep in 50 cm3
of physiological serum. This solution was filtered and inoculated.
The recipient sheep fell ill 16 months later, prompting the authors
to speculate that the infectious agent was a ‘filterable virus’.
195 4: Sigurdsson [170] speculated whether rida (a chronic
encephalitis of sheep) and scrapie could be identical. Unsuccess-
ful attempts to cultivate bacteria causing rida led the author to
suspect viruses to be the culprit. In order to abandon the use of
the phrase ‘chronic’ with its connotation of ‘irregular and unpre-
dictable course’ to characterize rida, Sigurdsson suggested the
350 K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355
term slow infection, in summary giving rise to the notion of a “slow
virus” as the causative agent.
196 6 : Alper et al. [9] irradiated extracts of brains from infected
mice with an electron beam and with ultraviolet radiation of 253.7
nm, which was known to be preferably absorbed by nucleic acids.
After finding inactivation by ionizing radiation only at unusu-
ally high doses and finding virtually no inactivation by ultraviolet
light, the authors concluded that if the infectious agent indeed
contained nucleic acid, its length had to be in the range of 800
bases (1.5×105Da), due to the exceptionally small target size
observed in the irradiation experiments. Instead, they suggested
that the infectious agent ‘is likely to be of an unusual nature’.
Discussing these experimental results from Alper et al. as well
as the fact that no virus had been observed in scrapie, Field [61]
speculated that ‘some new class of particle—perhaps a replicating
polysaccharide—might be involvedin certain slow ...“virus” infec-
tions’. In a follow-up paper, Alper et al. [8] picked up and endorsed
Field’s idea, as ‘some polysaccharides may confertemplate activity’
for replication of the particle.
196 7: Pattison and Jones [140] performed extraction and electro-
dialysis experiments with the scrapie agent. Their findings led
them to conclude ‘that the transmissible agent of scrapie may be,
or may be associated with, a small basic protein’.
One of the first to formulate a “protein only” theory of scrapie
pathogenesis was the mathematician J. S. Griffith [81].Hepre-
sented three ideas to explain the observed modes of transmission,
all of which expected the prion protein to be host encoded. The
first idea suggested the prion protein to be silenced by an active
repressor. As soon as the infectious prion protein invades the cell,
it disables its repressor, thereby activating the transcription of
its own gene. This idea is invalidated today by the demonstra-
tion that the prion protein is almost ubiquitiously expressed [37].
The second idea was nearly identical to what today is thought
to be the mode of transmission. By introducing a seed of modi-
fied prion protein, the native cellular prion protein molecules are
prompted to attach to this seed. Eventually, this grown seed is
split into two new seeds, thereby giving rise to its exponential
propagation. The third idea, which Griffith rejected based on what
was known in 1967, referred specifically to the missing immune
response. According to this idea, the prion protein would be identi-
cal to, and thereby indiscernible from, an antibody directed against
itself. Griffith pointed out that this is not what immunologists call
an auto-immune response.
196 7: Gibbons and Hunter [75] pondered on the pros and cons
of the scrapie agent being a virus, a protein, a carbohydrate or
a membrane. Based on the inability to isolate or visualize the
scrapie agent, and especially based on the results of radiation
experiments, the authors considered the virus theory unlikely, but
not entirely dismissible. While the authors acknowledged that the
results of many inactivation experiments were compatible with
the protein hypothesis,they wondered how a protein could exhibit
such exceptional resistance against heat and formalin. Further-
more, treatment with proteolytic enzymes was expected by the
authors ‘to produce more marked effects than have been observed
if the agent were a simple protein’. The carbohydrate hypothesis
was discounted based on the scrapie agent’s sensitivity to ‘treat-
ment with phenol and strong urea—reagents widely used in the
isolation of polysaccharides’. Finally, based on results of extrac-
tion experiments, which were demonstrated to contain infectious
activity ‘even after fifty such “extractions”’, the authors suggested
cell membranes to be the infectious agent, which also ‘could
well account for conflicting observations of the size of the agent’.
Hunter et al. [94] presented a model trying to explain the mem-
brane hypothesis by the assumption of a molecule binding to the
membrane and thus modifying its structure. This modified struc-
ture was believed to spread throughout the hitherto unaffected
membrane fractions, thus explaining the replication of the agent.
196 8 : Incorporation (of [3H]thymidine and uridine diphosphate
[14 C]glucose (UDPG)) and centrifugation experiments led Adams
and Caspary [3] to conclude that there might be ‘a new DNA-
polysaccharide complex in scrapie brain’.
1972 : Based on the finding that the potato spindle tuber disease is
not caused by a virus, but by ‘a replicating RNA with a molecular
weight of about 50,000’, Diener [52] suggested that viroids (as he
called them) might also be causative for scrapie. He arrived at this
conclusion by comparing features of the scrapie agent with those
of the potato spindle tuber viroid (PTSV) and finding several sim-
ilarities: long incubation periods, absense of virus-like particles
in electron microscopy, comparable calculated molecular weight
based upon irradiation experiments, extraordinary heat resistance
and ‘neglibile amounts of detectable infectivity ...in soluble form
in tissue homogenates’. Ten years later, Diener et al. [53] compared
viroids and prions and found that some of their features were after
all dissimilar. While prions are resistant to RNase, PSTV is sensitive
to it. On the other hand, ‘proteinase K and trypsin greatly reduce
the titer of the [scrapie] agent’, while PSTV proved to be unaffected
by proteases.
1978: Alper et al. [10] extended their irradiation experiments to
wavelengths between 237 and 280 nm and to electrons and pro-
vided for a way to differentiate between results with and without
oxygen in order to account for the effects of radiolysis. Based on
the finding that the scrapie agent was more readily deactivated in
the presence of oxygen, which the authors described to resemble
the behaviour of membraneous systems, they concluded ‘that the
component essential for replication contains a lipid fraction’.
1979: Following the detection of spiral-formed inclusions resem-
bling those of Spiroplasma sp. in the brain of a CJD victim, Bastian
[18] posed the question whether ‘Spiroplasma and the transmis-
sible agent of CJD [might] be one and the same’. This proposition
was underpinned by the propensity of Spiroplasma to infect mice,
and the impossibility to detect the CJD agent and Spiroplasma
serologically. Gray et al. [78] reported similar findings in electron
microscopical sections.
1979: Discussing the time course and the temporal behaviour of
different scrapie strains, Dickinson and Outram [51] coined the
term virino for the scrapie agent. It was meant to describe ‘(by
analogy with neutrinos)’ their properties: ‘small, immunologically
neutral particles with high penetration properties but needing
special criteria to detect their presence’.
1982: Based on the resistance of the pathogen, the protein hypoth-
esis was revived by the introduction of the new term “prion”,
which was (and is) meant to denote ‘proteinaceous infectious
particle’, by Prusiner [146]. This nomenclature was chosen to
‘underscore the requirement of a protein for infection’. However,
at this time, it was not sure whether this particle contains nucleic
acid or not, a question that was only answered by the prepara-
tion of synthetic mammalian prions [116,117]. The author offered
two possibilities for the nature of the agent: ‘(i) a small nucleic
acid surrounded by a tightly packed protein coat or (ii) a pro-
tein devoid of nucleic acid, that is, an infectious protein’. The
author admitted that the second alternative ‘is clearly heretical’.
While none of these alternatives was preferred by the author, the
emphasis on “protein” was meant to exclude many other theories
popular up to this time. However, the belief that there must be
some de novo synthesis of the pathogen was not abandoned. The
author offered two different ways of prion replication for the case
that the prion was devoid of nucleic acid: 1. ‘activate transcrip-
tion of host genes coding for prion protein’ or 2. ‘code for their
own replication by reverse translation (protein-directed protein
synthesis)’. The time for Griffith’s idea [81] (replication by induc-
K. Schneider et al. / Brain Research Bulletin 77 (2008) 343–355 351
ing a conformational change of pre-existing protein) to become
conceivable was still to come. However, it was admittedly not
known at this time that the prion protein is indeed host encoded
[131].
198 4: Heat inactivation experiments and comparisons with the
behaviour of viruses led Rohwer [158,159] to the conclusion that
the scrapie agent could be a virus, a conception that was shared
by others [123].
1989: While screening two cDNA libraries constructed from brain
membrane and cytoskeletal preparations from scrapie-infected
hamster brains, Aiken et al. [6] detected that scrapie ‘infectivity is
associated with the inner membranes or matrix [of mitochondria]
or copurifies with mitochondria and mitoplasts’.
1991: To account for the different strains as well as ‘the apparent
mutability of the agent’, Weissmann [193] suggested the infec-
tious agent to ‘consist of two components which together form
the holoprion. One component is PrPSc (the apoprion) which, even
when devoid of nucleic acid, can cause transmissible disease ...;
the other is a nucleic acid (the coprion), of which many variants can
exist and which ...determines its strain-specific characteristics’.
6. Conclusion
Scrapie has been documented since the year 1750, initially in
the form of retrospective case reports written by shepherds or
their employers. For fear of economic harm, shepherds attempted
to keep outbreaks of scrapie secret, resulting in the disease being
— especially in the 18th and 19th century — largely unknown
to veterinarians. In trying to come up with a meaningful the-
ory about scrapie’s transmission, early authors formulated ideas
which intermingled characteristics of hereditary, sexually trans-
missible and infectious diseases. After the demonstration of scrapie
to be a transmissible disease in 1936, it took 70 more years
until the infectious agent — the prion — could be identified
[116,117].
Insufficient importance was given tofinding out whether scrapie
was curable. Many authors argued against a curability, others
claimed to have cured animals [29,113,129,152,155,163,188,190].A
multitude of tested, suggested or rejected cures were described:
flushing the patients with cold water [67,171,205], application of
sulphuric acid [152,205], injections of lead salt solutions [160] or
turpentine oil [88,183], feeding or rubbing the animals with herbal
extracts [181,205], application of mercury ointments [88], and
burning their spines with red-hot irons [29,64,66,171,181,205,206].
A faster way to get rid of the problem was suggested by several
authors, who advised shepherds to slaughter the affected animals
and use them for human consumption as soon as they notice this
ailment in their herds [1,29,57,88,110,113,118,119,126,128,155,174],
since even cured animals were expected to retain damaged genetic
material.
While wethers were not considered worthy enough to be cured,
attempts to cure breeding animals were discouraged by the pre-
vailing danger of transmission of the disease to the progeny:
A wether wouldn’t be worth the effort, but should be culled
as soon as the first symptoms are obvious. It is, however, not
advisable to cure a breeding animal, because the predisposition
for the disease is heritable [181]12
If those remedies indeed succeed to cure the patient, I still
believe that even cured animals — especially female lambs and
12 Ein Hammel wäre der Mühe nicht werth, sondern ist gleich zu schlachten,wenn
die Voranzeigen deutlich genug erscheinen. Ein Zuchtthier aber möchte ich nicht
curiren, ..., weil ... die Anlage zur Krankheit sich vererbt [181].
dams —, but also rams that were used as sires in an affected
flock, contribute to the disease’s further spread [155]13
Even now, some 250 years on, a cure for scrapie or any other
member of the transmissible spongiform encephalopathies, is not
in sight. Now, as then, for scrapie, the only advice that can be given
to farmers is to cull all affected animals.
Possibly, in days to come, the current concept of the prion might
be ambiguous, too. Prusiner suggested prions to be the pathogenic
agents of TSEs in 1982 [146]. Twelve years later, Wickner [195]
found similar mechanisms of alternative protein folding to be
responsible for traits that were inherited in a non-mendelian fash-
ion in yeast. These prions (in a wider sense) were not associated
with disease and widened the concept of the prion. More recently,
papers suggest alternative foldings of proteins to be much more
common than was expected so far. This might some day open up
the door for a revolutionary new concept of long-term memory
[49,134,167–169,184], leaving the original concept of the prion –
pathogenic agent of TSEs – as a reminiscence of the first important
discoveries in prion research.
Acknowledgements
The assistance of Mrs. Marianne Hesse-Dornscheidt of the ULB
Düsseldorf in finding ancient articles is greatly appreciated. Many
thanks go to Ms. Katy Jordan, Hon. Librarian of the Royal Bath &
West of England Society Library at the University of Bath, U.K., for
making us aware of and supplying us with articles from the Letters
and Papers on Agriculture, Planting &c, addressed to the Bath and
West of England Society.
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... Here we give an overview of historical observations linking a variety of diseases in mammals, leading to the formulation of the prion hypothesis by Griffith [4], subsequent experimental validation by Prusiner [5] and discovery of prions in fungi. (For a more complete history of prion diseases refer to any of these reviews [6][7][8][9][10].) Scrapie is likely the first prion disease to be observed with reports dating back to the 1500s [7,11]. ...
... (For a more complete history of prion diseases refer to any of these reviews [6][7][8][9][10].) Scrapie is likely the first prion disease to be observed with reports dating back to the 1500s [7,11]. The first publication describing scrapie appeared in 1759 [12] and because scrapie was reported to be an infectious "distemper" from which sheep could never recover, shepherds of the time were advised to separate any animal observing symptoms from the rest of the flock. ...
... Publications at this time discussed and debated possible modes of transmission for this disease; ideas were wide ranging from inbreeding [13], humidity of the sheep pen [14] and even atmospheric events [15]. By the late nineteenth century, it was strongly believed that scrapie was a hereditary disease, but some reports noted spontaneous occurrences leading some to believe there was two forms of scrapie: hereditary and non-hereditary [7]. ...
Chapter
As described above, a combination of mathematical and experimental studies over the past few decades have led to the formulation of a protein‐only form of inheritance associated with prion phenotypes. We first summarize our present knowledge and then remark on present day studies and challenges that remain in modeling prion disease. Today we believe that prion phenotypes are established through two distinct phases, nucleation and amplification. Once an initial nucleus—prion aggregate above a critical size—is introduced to a host, four steps are required for successful in vivo propagation of prion phenotypes (see Figure 4). First, normal folded protein must be continuously created. Second, aggregates of the misfolded form of the protein act as templates by converting normally folded protein to the same misfolded state. Third, the total number of templates increases through fragmentation where a single aggregate is split into two (or more) smaller aggregates. Finally, misfolded protein must spread through other cells. For yeast, this transfer of misfolded protein occurs through cell division where for mammals this likely involves extracellular diffusion [33].
... Sheep and goats affected with the neurological pathology of scrapie had been the subject of scientific investigation for centuries, with the first verified report published in Germany in 1750 (Leopoldt, 1750), although cases were cited in other reports going back to 1732 in Spain and in England. Leopoldt's initial report postulates an infectious cause for scrapie, although other scientists would debate whether hereditary or other causes were more likely for many years to come (reviewed in Schneider et al., 2008). Experiments to prove transmissibility were undertaken many times but had various deficiencies leading to continued disagreement. ...
... p0200 Scrapie modes of transmission have been debated for many years. Although experimental transmission can take several forms, the natural transmission of scrapie horizontally between individuals occurs through direct contact between animals and through contact with environmental contamination (reviewed in Schneider et al., 2008). Scrapie is predominantly acquired through the oral route, and the placenta and amniotic fluid are the most common sources of oral infection, although fetal parts, feces, and milk have all shown infectivity (see Schneider et al., 2008). ...
... Although experimental transmission can take several forms, the natural transmission of scrapie horizontally between individuals occurs through direct contact between animals and through contact with environmental contamination (reviewed in Schneider et al., 2008). Scrapie is predominantly acquired through the oral route, and the placenta and amniotic fluid are the most common sources of oral infection, although fetal parts, feces, and milk have all shown infectivity (see Schneider et al., 2008). ...
Chapter
While philosophers in ancient times had many ideas for the cause of contagion, the modern study of infective agents began with Fracastoro's 1546 proposal that invisible “spores” spread infectious disease. However, firm categorization of the pathogens of the natural world would need to await a mature germ theory that would not arise for 300 years. In the 19th century, the earliest pathogens described were bacteria and other cellular microbes. By the close of that century, the work of Ivanovsky and Beijerinck introduced the concept of a virus, an infective particle smaller than any known cell. Extending into the early–mid-20th century there was an explosive growth in pathogenic microbiology, with a cellular or viral cause identified for nearly every transmissible disease. A few occult pathogens remained to be discovered, including the infectious proteins (prions) proposed by Prusiner in 1982. This review discusses the prions identified in mammals, yeasts, and other organisms, focusing on the amyloid-based prions. I discuss the essential biochemical properties of these agents and the application of this knowledge to diseases of protein misfolding and aggregation, as well as the utility of yeast as a model organism to study prion and amyloid proteins that affect human and animal health. Further, I summarize the ideas emerging out of these studies that the prion concept may go beyond proteinaceous infectious particles and that prions may be a subset of proteins having general nucleating or seeding functions involved in noninfectious as well as infectious pathogenic protein aggregation.
... Transmissible spongiform encephalopathies are a complex group of diseases that are still poorly understood. There are at least six different theories that have been used to explain their cause and transmission (MacKenzie 2007; Manuelidis et al. 2007;Schneider et al. 2008). Contributing to the difficulty in understanding the disease is the long incubation period (up to 8 years for cattle). ...
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A wide range of raw materials are now used routinely in aquaculture feeds throughout the world, primarily to supply protein and energy in the form of lipid from edible oils. Protein meals and oils used can generally be divided into those of plant or animal origin and many have considerable potential to supply the required dietary nutrients required by aquaculture species. However, the use of any raw material introduces a suite of risks that need to be considered to enable the production of safe, sustainable and functional feeds to underpin this sector. A lack of understanding of some of those risks can result in failure of dietary specifications being met and/or negative nutritional elements being introduced (e.g. antinutritional factors). Importantly, it is this feed that when fed to food‐producing animals is such an important element of food safety, and as such any undesirable aspects relating to feed production can also have a negative impact on the rest of the food chain. However, there is some disparity internationally among raw materials that are used and the perceptions surrounding the risk of their use. It is the scientific assessment of these risks that is the basis of this review.
... Classical scrapie was first described centuries ago (Schneider et al., 2008). Its spread is global, with the exception of Australia and New Zealand (OIE, 2016b), and it is quite common in European countries (EFSA, 2016). ...
Article
Full-text available
Background. Transmissible spongiform encephalopathies (TSEs) or prion diseases are a unique group of neurodegenerative diseases of animals and humans, which always have a fatal outcome and are transmissible among animals of the same or different species. Scope and Approach. The aim of this work is to review some recent data about animal TSEs, with the emphasis on their causative agents and zoonotic potential, and to discuss why the surveillance and control measures over animal TSEs should remain in force. Key Findings and Conclusions. We still have incomplete knowledge of prions and prion diseases. Scrapie has been present for a very long time and controlled with varied success. Bovine spongiform encephalopathy (BSE) emerged unnoticed, and spread within a few years to epidemic proportions, entailing enormous economic consequences and public concerns. Currently, the classical BSE epidemic is under control, but atypical cases do, and probably will, persist in bovine populations. The Chronic Wasting Disease (CWD) of the cervids has been spreading in North America and has recently been detected in Europe. Preventive measures for the control of classical BSE remain in force, including the feed ban and removal of specified risk materials. However, active BSE surveillance has considerably decreased. In the absence of such preventive and control measures, atypical BSE cases in healthy slaughtered bovines might persist in the human food chain, and BSE prions might resurface. Moreover, other prion strains might emerge and spread undetected if the appropriate preventive and surveillance measures were to cease, leaving behind inestimable consequences.
... Classical scrapie is a naturally occurring transmissible spongiform encephalopathy (TSE) of sheep and goats. Though it has been recognized in some regions of the world for over 250 years (reviewed by Schneider et al., 2008), classical scrapie (herein just 'scrapie') was first diagnosed in the USA in 1947 following the import of an infected sheep. In contrast, chronic wasting disease (CWD) is a naturally occurring TSE of cervids (elk, deer and moose) which was first observed in the 1960s in deer held captive in several wildlife facilities in the USA ( Williams & Young, 1980;reviewed by Haley & Hoover, 2015). ...
Article
Full-text available
Development of mice expressing either ovine (Tg338) or cervid (TgElk) prion protein (PrP) have aided in characterization of scrapie and chronic wasting disease (CWD), respectively. Experimental inoculation of sheep with CWD prions has demonstrated the potential for interspecies transmission but, infection with CWD versus classical scrapie prions may be difficult to differentiate using validated diagnostic platforms. In this study, mouse bioassay in Tg338 and TgElk was utilized to evaluate transmission of CWD versus scrapie prions from small ruminants. Mice (>5/homogenate) were inoculated with brain homogenates from clinically affected sheep or goats with naturally-acquired classical scrapie, white-tailed deer with naturally-acquired CWD (WTD-CWD), or sheep with experimentally-acquired CWD derived from elk (sheep-passaged-CWD). Survival time (time to clinical disease) and attack rates (brain accumulation of protease resistant PrP, PrPres) were determined. Inoculation with classical scrapie prions resulted in clinical disease and 100% attack rates in Tg338, but no clinical disease at endpoint (>300 days post inoculation, dpi) and low attack rates (6.8%) in TgElk. Inoculation with WTD-CWD prions yielded no clinical disease or brain PrPres accumulation in Tg338 at endpoint (>500dpi) but rapid onset of clinical disease (~121dpi) and 100% attack rate in TgElk. Sheep-passaged-CWD resulted in transmission to both mouse lines with 100% attack rates at endpoint in Tg338 and an attack rate of ~73% in TgElk with some culled due to clinical disease. These primary transmission observations demonstrate the potential of bioassay in Tg338 and TgElk to help differentiate possible infection with CWD versus classical scrapie prions in sheep and goats.
... Although for over 250 years there were no reported cases of transmission of classical scrapie to humans (Schneider et al., 2008), uncertainties related to the species barrier (Bruce et al., 1994) led many countries to develop policies to eliminate all animals infected with TSEs from the food chain (Heaton et al., 2011). ...
Article
Full-text available
Scrapie is a neurodegenerative prion disease of sheep, goats and mouflons, belonging to the group of transmissible spongiform encephalopathies (TSEs), which affects humans as well. Even though classical scrapie has been known for over 250 years, the 1985 BSE crisis related to the advent of new forms of the Creutzfeldt-Jakob disease (vCJD) in humans imposed the implementation of rapid coercive legal measures of prevention, control and eradication of TSEs. According to the prion hypothesis, the transmissible agent is the pathological isoform (PrP Sc) of cellular prion protein (PrP C). Specific polymorphisms of the gene that encodes cell prion protein (PrnP) in sheep have been associated with resistance / natural susceptibility to the development and progression of the disease. Combinations of alleles at three adjacent codons (136 [A/V], 154 [H/R], 171 [H/Q/R]) underpin the classification of 15 possible genotypes in risk classes, applicable in selection schemes where the maximum resistance is conferred by ARR allele, and the minimum by the VRQ allele. Although, after applying these programmes, the genetic structure of sheep populations has changed favourably, genotype association studies showed that no genotype is completely resistant to the infection, including homozygote ARR / ARR. With the discovery of atypical scrapie (Nor98), it became evident that the connection between the genetics of prion protein gene polymorphisms and susceptibility to the disease must be re-evaluated individually for each breed. In scrapie monitoring and control programmes, three diagnostic categories of the disease are observed: classical scrapie, atypical scrapie and BSE scrapie in small ruminant. This review shows the chronology of progress in the fight for the eradication of TSEs in sheep, 30 years after the BSE epidemic outburst, focusing especially on the link between the molecular diagnostic forms and the genetics of the disease.
... Although for over 250 years there were no reported cases of transmission of classical scrapie to humans (Schneider et al., 2008), uncertainties related to the species barrier (Bruce et al., 1994) led many countries to develop policies to eliminate all animals infected with TSEs from the food chain (Heaton et al., 2011). ...
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Scrapie is a neurodegenerative prion disease of sheep, goats and mouflons, belonging to the group of transmissible spongiform encephalopathies (TSEs), which affects humans as well. Even though classical scrapie has been known for over 250 years, the 1985 BSE crisis related to the advent of new forms of the Creutzfeldt-Jakob disease (vCJD) in humans imposed the implementation of rapid coercive legal measures of prevention, control and eradication of TSEs. According to the prion hypothesis, the transmissible agent is the pathological isoform (PrP Sc) of cellular prion protein (PrP C). Specific polymorphisms of the gene that encodes cell prion protein (PrnP) in sheep have been associated with resistance / natural susceptibility to the development and progression of the disease. Combinations of alleles at three adjacent codons (136 [A/V], 154 [H/R], 171 [H/Q/R]) underpin the classification of 15 possible genotypes in risk classes, applicable in selection schemes where the maximum resistance is conferred by ARR allele, and the minimum by the VRQ allele. Although, after applying these programmes, the genetic structure of sheep populations has changed favourably, genotype association studies showed that no genotype is completely resistant to the infection, including homozygote ARR / ARR. With the discovery of atypical scrapie (Nor98), it became evident that the connection between the genetics of prion protein gene polymorphisms and susceptibility to the disease must be re-evaluated individually for each breed. In scrapie monitoring and control programmes, three diagnostic categories of the disease are observed: classical scrapie, atypical scrapie and BSE scrapie in small ruminant. This review shows the chronology of progress in the fight for the eradication of TSEs in sheep, 30 years after the BSE epidemic outburst, focusing especially on the link between the molecular diagnostic forms and the genetics of the disease.
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Observations on strain behaviour and direct demonstrations of natural selection establish that the scrapie agent and prions in general are able to evolve. Accordingly, it is conceivable that atypical non-contagious scrapie in sheep and goats can transform to classical contagious scrapie under particular circumstances. In consequence, atypical scrapie can be regarded as a latent hazard that warrants comprehensive risk assessment and biosecurity preparedness planning. Evidence for this proposition comes from differences in the expression of atypical and classical scrapie that may make scrapie contagious, historical records of scrapie in Western Europe, and contemporary accounts of the epidemiology of atypical scrapie. Biosecurity preparedness can be based on current knowledge of pathophysiology and epidemiology and can be built around a three-stage model for the endogenous emergence of a propagating epidemic of scrapie. The first stage concerns the occurrence of atypical scrapie. The second stage concerns the acquisition of communicability in prion populations provided by atypical scrapie and the third stage concerns circumstances allowing disease transmission and the initiation of a propagating epidemic. The range of component causes envisaged for possible outbreaks of endogenous classical scrapie is broad. However, exposure of sheep and goats to cyanobacterial toxins qualifies for special attention.
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