Lawrence Broxmeyer, M.D.

Med-America Research

Abstracts
Heart disease: The greatest 'risk' factor of them all.
SARS: just another viral acronym?
Killing of Mycobacterium avium and Mycobacterium tuberculosis
Parkinson's: another look

Is mad cow disease caused by a bacteria?

L. Broxmeyer,

Med-America Research, Whitestone, USA

Received 29 March 2004; accepted 20 April 2004


Abstract

Summary Transmissible spongioform enchephalopathies (TSE’s), include bovine spongiform encephalopathy (also
called BSE or “mad cow disease”), Creutzfeldt–Jakob disease (CJD) in humans, and scrapie in sheep. They remain a
mystery, their cause hotly debated. But between 1994 and 1996, 12 people in England came down with CJD, the human
form of mad cow, and all had eaten beef from suspect cows. Current mad cow diagnosis lies solely in the detection of
late appearing “prions”, an acronym for hypothesized, gene-less, misfolded proteins, somehow claimed to cause the
disease. Yet laboratory preparations of prions contain other things, which could include unidentified bacteria or
viruses. Furthermore, the rigors of prion purification alone, might, in and of themselves, have killed the causative virus
or bacteria. Therefore, even if samples appear to infect animals, it is impossible to prove that prions are causative.
Manuelidis found viral-like particles, which even when separated from prions, were responsible for spongiform STE’s.
Subsequently, Lasmezas’s study showed that 55% of mice injected with cattle BSE, and who came down with disease,
had no detectable prions. Still, incredibly, prions, are held as existing TSE dogma and Heino Dringer, who did pioneer
work on their nature, candidly predicts “it will turn out that the prion concept is wrong.” Many animals that die of
spongiform TSE’s never show evidence of misfolded proteins, and Dr. Frank Bastian, of Tulane, an authority, thinks the
disorder is caused by the bacterial DNA he found in this group of diseases. Recently, Roels and Walravens isolated
Mycobacterium bovis it from the brain of a cow with the clinical and histopathological signs of mad cow. Moreover,
epidemiologic maps of the origins and peak incidence of BSE in the UK, suggestively match those of England’s areas of
highest bovine tuberculosis, the Southwest, where Britain’s mad cow epidemic began. The neurotaxic potential for cow
tuberculosis was shown in pre-1960 England, where one quarter of all tuberculous meningitis victims suffered from
Mycobacterium bovis infection. And Harley’s study showed pathology identical to “mad cow” from systemic M. bovis in
cattle, causing a tuberculous spongiform encephalitis. In addition to M. bovis, Mycobacterium avium subspecies
paratuberculosis (fowl tuberculosis) causes Johne’s disease, a problem known and neglected in cattle and sheep for
almost a century, and rapidly emerging as the disease of the new millennium. Not only has M. paratuberculosis been
found in human Crohn’s disease, but both Crohn’s and Johne’s both cross-react with the antigens of cattle
paratuberculosis. Furthermore, central neurologic manifestations of Crohn’s disease are not unknown. There is no
known disease which better fits into what is occurring in Mad Cow and the spongiform enchephalopathies than bovine
tuberculosis and its blood–brain barrier penetrating, virus-like, cell-wall-deficient forms. It is for these reasons that
future research needs to be aimed in this direction.

c 2004 Elsevier Ltd. All rights reserved

The origin of the existing theory

The theory surrounding neurologist Stanley Prusiner’s
“prions”, coined for proteins that were infectious, was under a rightful cloud of suspicion
from its onset. Working on obscure diseases
thought to be caused by slow viruses, he would in
effect rename them, and by April, 1982 had announced
that the real culprit behind such diseases
as scrapie in sheep, kuru in cannibals, Creutzfeldt–
Jakob disease (CJD) in humans, and chronic
wasting disease in deer and elk was either a virus,
not yet isolated, or some rogue infectious proteinonly
“prion”, which unlike anything yet known
could multiply, and infect, without genes.
Biologists in the 1930s had incorrectly said that
viruses were only proteins and that ‘slow viruses’
might be gene-less had been proposed by and discarded
in Britain as early as 1967. Prion advocates,
salvaging from the experience, put forth that prions
were way smaller than other viruses without
the capacity to carry genes. The biology of scrapie,
however, because of its many strains alone, called
for an agent with genes [75].
By 1984, National Institute of Health’s Rohwer
showed that prions were the size of small viruses,
with plenty of room for genetic material [2]. In the
same study Rohwer attacked the prion supposition
that prions were immortal, citing agents of potential
damage (ibid).
Early prion workers used a test called the incubation-
time assay to judge purification, utilized
cautiously in England since the 1960s. A modification
cut the time to score this assay from a year to
a couple of months. Rohwer commented that this
test was enormously less accurate than traditional
methods and that purifications using it could be off
by a factor of from 100 to 1000. Such knowledge
kept the viral or virus-like bacterial theories alive.
The finding that prions were proteins normally
found in the body, including the brain of healthy
controls, seemed to contradict the best evidence
that they were infectious. The theory survived by
finding a difference. Prions from healthy animals
were “cellular” protein, those from scrapie were
“scrapie” protein. Scrapie protein aggregated into
rods while cellular protein did not. Another “critical
clue” [76]: scrapie protein survived proteinase
while “cellular” did not. This still did not mean
however that some virus or bacteria did not cause
the change to begin with M. bovis, for example,
both by virtue of its cell-wall-deficient, virus-like
forms, and that it shares methyllysines with other
mycobacteria is also protease-resistant [77]. The
amyloid proteins in Alzheimer’s, not currently
linked to prions, are also protease resistant [78].
Healthy “cellular” prions remain a mystery, but
they need not be. Prions are amyloid and it was
common knowledge before prions that there is a
soluble serum protein component (SAP) of amyloid
in healthy blood, its purpose also unknown [74].
What is clear is that the role of deposited amyloid
fibrils, once formed, is to disrupt, destroy, and
compromise, whether in mad cow, JCD, Scrapie,
Alzheimer’s or any of the other degenerative
disorder.
Prion theorists further elaborated that although
proteins normally fold into three-dimensional
states, protein prions sometimes ‘misfolded’, assuming
an incorrect, infectious state, which subsequently
changed cellular protein into itself,
setting off an infectious chain reaction. And since
the damage done by prion protein seemed similar
to the malfunctioning proteins of Alzheimer’s disease,
and even Parkinson’s, these too might be
caused by prions.
Critics point out that despite the vast expenditure
[3] on research geared to verify that prions
caused spongiform encephalopathies, to this point
prions have not been established fully as the cause
of any disease. Furthermore, it remained unclear
how prions destroy brain tissue. In the meanwhile,
experts pointed out that investigators have not
proven that protein-only prions, even amplified
over 100-fold and from infected brain – have increased
infectivity, perhaps the best kept secret of
prion researchers [4,5].
Both CJD and scrapie can be transmitted without
prions [6]. Also, Brain material from which the
prion and its antibodies have been removed can
still infect animals. Prions have been found in
completely unrelated disease processes, such as
Kawsaski syndrome and inclusion body myositis.
Finally, there were many strains of “prion” diseases,
and no credible theory as to how these
strains exist without genetic material. Aguzzi
points out that abnormal prions have exactly the
same amino acid structure as nonpathogenic prions,
found in everyone. How could prion proteins,
then be claimed to do what they are claimed to do?
[7].
By all logical estimates, the death-knell to the
prion hypothesis should have occurred with
Lasmezas’s 1997 interspecies transmission of bovine
spongiform encephalopathy (BSE) in which
more than half of injected mice had no detectable
prions [6]. If this was not enough, then there was
Manuelidis’s 2002 [8] study on infectious neurons
(microglia) with low prion levels in otherwise highly
infectious material, which supported the concept
that pathologic prions were the result of infection
rather than being the actual infectious agent. To
Manuelidis this was likely to be a virus, although
she admitted the fundamental mystery remained.
In fact, to many dissenters, some other, not as yet
identified pathogen such as a virus or bacteria caused “prions” to misfold thus damaging the
brain.

Virus or a viral-like bacteria

The initial slow virus concept for the causal agent
of TSE arose simply because the agent was filterable.
By the mid-1990s, Manuelidis found viral-like
particles which even when separated from proteinacious
prions were responsible for transmitting
infection [9].
In 1928, Eleanor Alexander-Jackson, discovering
unusual and to that point unrecognized forms of
the human and bovine TB bacillus, marveled at
their many forms, including the tiny particles
which the German Hans Much saw in 1908 and soon
became known as Much’s granules [10]. In 1910
Fontes proved Much’s granules, as a sub-classifi-
cation of Kleinberger’s cell-wall-deficient “L-forms”
were filterable and therefore also often
mistaken for viruses. In fact, in certain circles, the
variable acid-fast granules were called ‘the TB
virus’ [11].
Much, for almost 30 years. studied the typical
and atypical forms of tuberculosis watching the
tiny nonacid-fast granules named after him convert
thru a diptheroid stage into classic acid fast rods
and fibrils [10].
L-forms, the connecting link between viruses
and bacteria, where first described by Klieneberger-
Nobel [12] at England’s Lister Institute for
which they were named. L-Forms were “cell-wall
deficient” because they either had a disruption of
or lack of a rigid bacterial cell wall. This allowed
them the plasticity to assume many forms (pleomorphic)
– some of them viral-like, but all of them
different from their classical parent and poorly
demonstrated by ordinary staining [12]. Of all the
bacteria, L-forms predominate and are crucial to
the survival of tuberculosis and the mycobacterium,
whose cell-wall deficient forms escape destruction
by the body’s immune system. Because of
their small size and configuration bacterial L-forms
have, at different times, been called ‘viruses’,
‘retroviruses’ or ‘C-particles’.
Mellon and Fisher warned that filterable forms of
M. avium, M. bovis and M. tuberculosis could easily
be mistaken for viruses. Mellon stated that the
granular, prion-like forms of TB, found in its bovine
and avian strains, prevalent in the very animals
susceptible to BSE, including cattle and
sheep, all originated from Much’s granules [13].
Such viral forms of mycobacteria like M. bovis
could by themselves produce disease. And since
they were filterable, they could easily penetrate
the blood–brain barrier [14]. Filterable, viral form
of TB or TB in cattle have been recovered as an
ultra virus in all body fluids, including urine and in
the spinal fluid in central nervous system infection.
This is similar to the granules Gabizon found in
“prions” in the urine [15].
Xalabarder of Barcelona noted L-forms of bovine
tuberculosis even in the blood of people simply
vaccinated against TB with BCG, a diluted M. bovis
vaccine [16]. He emphasized that L-Forms of the
mycobacteria were remarkably different from Lforms
of other species in their resistance to physical
and chemical agents [17]. Similar to prions,
mycobacterial CWD forms escape destruction by
the body’s immune system, and are seemingly imperishable
(ibid). Xalabarder noted that these Lforms
contain proteins, both RNA and DNA but do
not stain well by ordinary mycobacteria dyes. Klieneberger-
Nobel adds that L-forms consists of the
formation of very small forms, poor in ribonucleic
acid (ibid). Yet no matter how small and enucleated,
some of these L-forms will revert back to
virulent mycobacteria. In the case of cattle this has
led to a 10,000–15,000 year history of sometimes
fatal interaction between M. bovis, the cow, and
man.
Like Klieneberger, Dr. Virginia Livingston compared
the filterable forms of her tuberculosis-like
germ to ‘L-mycoplasma’ or ‘mycoplasmic-like
forms’, because without intact cell walls they were
often mistaken for the bacteria mycoplasma, which
has no cell wall [18]. The differentiation between
Mycoplasma and cell wall deficient bacteria, in
general, is difficult at best [19], and L-forms of TBlike
bacteria are already on record as having been
mistaken for mycoplasma-like forms [20]. One of
these bacteria is Spiroplasma.
To Dr. Frank Bastian, professor of neuropathology
at Tulane University, morphological and immunologic
evidence all pointed to a bacterial cause
for TSE. His finding DNA in TSE tissues clearly indicated
the association of a bacteria with the disease
[21].
Bastian collected evidence suggesting that a
cell-wall-deficient, spiral-shaped bacteria (can also
occur as a coccoid or filamentous form), called
Spiroplasma, a mycoplasma, picked-up by both its
DNA and on electron microscopy is involved in
brains infected with Creutzfeldt–Jakob but not in
controls [21]. Bastion also found this particular
mycoplasma, only discovered in 1976, in another
spongiform encephalopathy, scrapie in sheep. The
Spiroplasma implied, however, Spiroplasma mirium,
is for the most part hosted in rabbit ticks and
before his research caused cataract and disease in
733 Is mad cow disease caused by a bacteria?
suckling mice only. And Spiroplasmas, in their
short, less than 30 year history, had always been
associated with an insect host at some point,
though several primary isolations have been made
from plants.
Whether Spiroplasma causes the abnormal proteins
in TSE or is a consequence of TSE itself requires
further experimentation [21,72].

An unnoticed epidemiologic finding

While various theories continued to swarm around
the cause of TSE’s, the best epidemiologic maps of
the peak incidence and prevalence of BSE or mad
cow disease, done in the UK, it turns out, suggestively
matched those of the highest prevalence of
England’s bovine tuberculosis in cattle, with a
predominant distribution in the Southwest (see
Figs. 1 and 2) extending to counties further north
[22,23], the very area where BSE in the UK began.
An idea of the prevalence of cow tuberculosis in
England during the nineteenth century can be
gained by the following: in 1890, Queen Victoria
ordered that the dairy cows at the Home Farm at
Winsor be tuberculin tested. Thirty-five of forty
were found tuberculin positive and tuberculous
lesions were found in all of these positive reactors.
And yet the premises “in which these cows were
kept were probably the best in the kingdom. . .”
[24]. It is claimed that in England, supposedly next
to BSE, bovine TB is the most serious animal disease
that its Ministry of Agriculture has to cope with and
in 1934 at least 40% of British cows were infected
with TB [25], accounting for 6% English deaths from tuberculosis in the 1930s and 1940s. Despite the
fact that mandatory cow tuberculin skin testing
was introduced in 1960, data for the year 2000 in
Great Britain show a national herd incidence of
2.8%, with an exponential increase in cases in the
southwest of England over the past 10 years [26].
Furthermore, there is small but significant reservoir
of humans who ate beef and milk products
prior to 1960 and can reactivate previous M. bovis
infection, sometimes with CNS manifestations [27].

In his 1932 historical overview, Webb speculates
that man was first introduced to tuberculosis when
he began domesticating cattle around 5000 B.C.
[28]. Thus one could surmise that human tuberculosis
originated by transfer of M. bovis, which has
the potential to infect humans, into the human
body, where it adapted as the tubercle bacillus
(ibid).
Garnier though, using deletion analysis, recently
questioned this, placing human M. tuberculosis as
having come first, and, having infected cows at the
time of cattle domestication 10,000–15,000 years
ago [26]. At any rate, prior to that, the tuberculous
bacilli, always soil born, first infested and then
infected an assortment of mammals, both ruminants
and primates.
Modern genetics has verified that DNA between
human (M. tuberculosis) and cow (M. bovis) tuberculosis
are almost identical, indicating they are Figure 1 Bovine tuberculosis in UK 1999.
Figure 2 BSE-positive cattle in UK 1997.
734 Broxmeyer
virtually the same species [29]. Even in culture
plates their appearance is similar.


The mycobacteria emerge in mad cow
disease

By 1975, a new problem had arisen in the wildlife of
southwest England, the cradle of BSE. Bovine
strains of mycobacterium were isolated from the
badger Meles meles. An entirely new development
in a country where the bovine form of the disease
had been supposedly eradicated since 1960, it was
viewed with grave concern by public health authorities.
Not only was it not clear how the badgers
of southwest England, in intimate contact with the
cattle their, had acquired bovine tuberculosis but
it was then found that not a single badger from
other areas harbored the disease [81].
Furthermore, it soon became obvious that the
cattle found to harbor TB, either M. bovis or M.
avium (fowl TB) were consistently and markedly
underestimated, with many “healthy” animals
harboring the disease [30–34]. There were many
reasons for this. TB lesions, were virtually to be
found in any organ or body cavity of diseased animals
yet traditionally only a handful of organ systems
were checked before slaughter. Also in the
early stages of the disease, lesions were hard to
find, even during post-mortem examination.
Therefore Francis’s observation that “the possibility
of danger to public health from the flesh of
tuberculous cattle, although very small, can never
be absolutely denied” is only partially correct [35].
Carnivores may acquire M. bovis through the alimentary
tract by eating infected meat [36,73]. Man
is no exception. Adding to the problem is that despite
clear FDA recommendations for cooking meat
[37], certain consumers prefer to eat their meat
rare to medium-rare.
The power of oral consumption of virulent mycobacteria
into the alimentary tract was unfortunately
shown in the German Lubeck tragedy, in
which inadvertent mycobacterial contamination of
otherwise watered-down bovine tuberculosis was
protectively administered for infant immunization.
Out of 251 newborns, 72 died and 100% had alimentary
lesions, primarily in the small intestine
[38].
That tuberculosis and the mycobacterium can
cause the progressive ataxia found in Mad Cow
‘downers’ has been adequately cited, in both man
and cattle [39–41]. Moreover, that M. bovis, cow
tuberculosis, can cause the clinical signs and histopathology
of “mad cow” in cattle is also on record
[42]. Otter [40] studied ataxia and weight loss
secondary to M. bovis in deer. No other TB organism
has as great a host range as bovine TB, which
can infect all warm-blooded vertebrates (animals
with a backbone).
Mycobacterium bovis, a relatively common
cause of TB meningitis in pre-pasteurization times,
cannot only cause meningitis and encephalitis in
humans [27,43,44] but in cattle as well [45]. The US
Department of Agriculture’s fact sheet on bovine
tuberculosis clearly and specifically states that in
diagnosing the disease, lesions must be looked for
in the nervous system of cattle. Hartley’s study
showed pathology identical to “mad cow” from
systemic M. bovis in cattle, causing a tuberculous
spongiform necrotizing encephalitis without recovery
from the CNS of classical forms of TB (ibid).
The neurotaxic potential for cow tuberculosis is
best attested to by that, in England, prior to 1960,
one quarter of all tuberculous meningitis victims
suffered from M. bovis infection [46]. Wilkins, doing
an epidemiological survey found bovine tuberculosis
associated with lifelong residency in the UK
and attributed its low incidence among tuberculosis
isolates to a low tendency for M. bovis to
reactivate [71].
Once the most prevalent infectious disease of
cattle in the US, bovine TB caused more losses
among US farm animals in the early part of this
century than all other infectious diseases combined
[47]. And M. bovis still causes worldwide annual
losses to agriculture of $3 billion dollars. In his
Nobel Prize address of 1901 Von Behring stated “As
you know, tuberculosis in cattle is one of the most
damaging infectious diseases to affect agriculture”
[26]. But the problem was more extensive than
even Von Behring realized. Enter Mycobacterium
avium complex or MAC.

Fowl tuberculosis: a major plight in the
cattle industry

Mycobacterium avium causes tuberculosis in
chickens and other fowls but can also infect an
extensive range of different animal species including
cattle, sheep, deer and man. The M. avium
complex (MAC) includes closely related M. avium,
M. intracellular and M. avium subsp. paratuberculosis
or paratuberculosis. Paratuberculosis, extremely
slow growing, causes Johne’s disease in
domestic and wild ruminants, a problem known and
neglected in cattle and sheep for almost a century.
Johne’s disease caused by M. paratuberculosis is
rapidly emerging as the disease of the new
735 Is mad cow disease caused by a bacteria?
millennium. Recent European epidemiological
studies indicate an alarming increase of paratuberculosis
in cattle and sheep, and the USDA reports
that between 20% and 40% of US dairy herds
are infected [48]. This, as well as its role in Crohn’s
disease in humans has shifted attention front and
forward [49].The evidence to support M. paratuberculosis
infection as a cause of Crohn’s disease is
mounting rapidly [50].
Not only has M. paratuberculosis been found in
Crohn’s disease by five investigative groups in different
countries, but Crohn’s patients and Johne’s
diseased cattle have antibodies which cross-react
with the antigens of paratuberculosis [19]. All
paratuberculosis isolated from Crohn’s have been
of the bovine subtype, found in cattle [51]. Cattle
and sheep can infect one another with paratuberculosis
[52]. Deer are also susceptible.
Since paratuberculosis is not classified as a human
pathogen, the beef from cattle infected with
it is not prevented from entering the food chain
[53]. Paratuberculosis causes a disease in cattle
that is similar to Crohn’s in humans in that both
attack the terminal illium. Crohn’s disease is no
small problem, and the number of Americans suffering
from it is between 400,000 and 1,000,000
(Scientific facts about Mycobacterium paratuberculosis
and Crohn’s disease Source: http://members.
aol.com/ParaTBweb/crohn.htm).
Paratuberculosis is highly heat resistant [54],
and may not be killed by standard techniques for
cooking beef [55], even more so than M. bovis.
It is estimated that from 5% to 20% of all cattle
in the US alone, are infected with paratuberculosis,
bringing estimated losses to $1.5 billion
annually, [56], but the problem is worldwide.
And Rosisiter found it in up to 34% of dairy cows
[57], the very same cattle frequently used for
the production of the ground beef that enters
the food chain [58].


Amyloid: the common denominator in all
spongioform encephalopathies

“It is an astounding finding, because we never
would have dreamed that amyloid and prions are
the same”, proclaimed Stanley Prusiner [1].
In the past amyloid was usually the deposition
that took place due in the course of chronic in-
flammatory disease, mainly tuberculosis, the usual
precipitating cause. The very term “amyloidosis”,
coined by Virchow, was a misnomer, assuming that
the infiltrative material had chemical similarities
to the starch (or amylum) of plants, which it did
not. Nevertheless, by force of use and habit, the
word stuck.
Hass’s study proved a direct correlation between
amyloid deposition and the mycobacteria by
injecting M. bovis into rabbits and following M.
tuberculosis in humans. He concluded that the only
infectious disease which served as an apparent
cause of amyloidosis was tuberculosis [59]. All
21 human subjects with amyloid in Hass’s investigation
had chronic pulmonary tuberculosis. In a
50-year study based upon autopsy, Schwartz saw
amyloidosis, primary and secondary, in the brain
and elsewhere as a by-product of underlying infectious
tuberculosis, either reactivating itself or
being reactivated by a host of traumatic, chemical,
biologic or physical insults [60]. Microscopically, in
the brain, Schwartz found plaques and amyloid
degeneration of nerve fibrils.
When Schwartz injected 22 guinea pigs with
M. tuberculosis, all but four came down with
amyloidosis. His uninfected controls, with the exception
of one showed no amyloid. He thereby
confirmed Hass, who’s large series of rabbits
showed that three out of four inoculated with
bovine tuberculosis had amyloid disease within 15
months [59]. Hass’s amyloid uniformly showed a
principal protein fraction as well as a minor fraction
whose physical behavior also implied another
protein.
The amyloid issue had surfaced previously
when in 1978, Researcher Pat Merz, in breakthrough
work, identified tiny fibrils in the brains
of scrapie infected mice not present in well
controls. Prion purists refused to admit that their
prion rods were related to Merz’s find, citing her
entities as longer fibrils and claiming that Merz
stated plainly that her scrapie associated fibrils
(or SAF) were not amyloid and therefore could
not be prion rods, the term Prusiner used for
amyloid fibrils. Actually Merz said that her Scrapie
associated filaments were amyloid-like on
more than one occasion and workers in the field
suggested that the two entities in Merz and
Prusiner’s papers were identical [1]. Delgado saw
such fibrils in either case as typical features of
amyloid [62].
Meanwhile, by 1994, de Beer, studying the relationship
between a major rise of serum amyloid
and having tuberculosis, saw a rapid descent in
amyloid in patients treated with anti-tubercular
drugs [63].
As an offshoot of de Beer’s work, Tomiyama
dissolved b-amyloid plaque with rifampin, a first
line drug in the treatment of TB, and one of the
few agents, to this day, that is able to dissolve
amyloid plaque [64].
736 Broxmeyer


Conclusion

The TSE’s are chronic wasting diseases and virtually
every aspect and finding of the currently
held “prion” theory for TSE’s, and then some can
be found in the literature of Bovine tuberculosis,
a known disease going back 10,000–15,000 years.
M. bovis extracts have long been known to
shorten the incubation period of scrapie, purportedly
as an immune “stimulator” [72]. In addition
bovine TB’s blood–brain penetrating Lforms
can simulate viral elements found in the
TSE’s [9] and have, on at least one occasion been
mistaken for mycoplasmic-like forms [20], such as
Spirolemma. In addition prions [74] protease resistance
is shared by both bovine tuberculosis
cell-wall deficient forms [17] and the fact that it
produces protease-resistant methyllysines [77]. In
the UK, the highest area of bovine TB, the
Southwest, was the very area which both
spawned and contained the highest rate of BSE in
cattle [22,23]. M. bovis causes the clinical and
histopathology of “mad cow” in cattle [42]. And
tuberculosis and the mycobacterium can cause
the progressive ataxia found in mad cow “downers”
both in man and cattle [39–41]. Although no
other form of TB has a greater host range than
bovine TB, which includes man and all the other
warm-blooded vertebrates subject to the TSE’s,
it is extremely hard to isolate and Hartley’s study
of mad cow from systemic M. bovis showed a
tuberculous spongioform encephalitis without recovery
of classical CNS mycobacteria [45]. That
bovine tuberculosis can be transmitted thru ingesting
contaminated meat cannot be denied
[35], and its neurotaxic potential showed clearly
in an England prior to 1960, where 25% of all
tuberculous meningitis victims suffered from M.
bovis [46]. And that both forms of bovine tuberculosis,
M. bovis and M. avium subsp. paratuberculosis
(also referred to as paratuberculosis)
are consistently and markedly underestimated in
the meat that we eat has been extensively
brought up [30–34,53]. Paratuberculosis, extremely
slow growing, causes Johne’s disease, a
rapidly emerging, known and neglected, malady
in cattle and sheep for almost a century. The
evidence to support cattle paratuberculosis as
the cause of human Crohn’s disease is mounting
rapidly [19,50,51], and Rossiter found in up to
34% of dairy cows, the very same cattle frequently
used to produce the ground beef that
enters the food [57]. Central neurologic manifestations
of Crohn’s disease are not unknown
[79].
The detection of 14-3-3 protein, in the cerebrospinal
fluid, originally thought to be a highly
reliable indicator for “prion” diseases, also appears
in CNS tuberculosis [69] and the very fabric of the
TSE’s and prion diseases, amyloid has been implicated
and re-implicated as being caused by bovine
and human tuberculosis [59,60]. The well-known
resistance of the edible muscle tissue, favored by
man, in cattle to tuberculosis once even brought up
the possibility of using muscle grafts for surgical
salvage in pulmonary tuberculosis [70].
Creutzfeldt–Jakob only kills somewhat over 200
Americans per year, though this number is questionable
after a study in which Alzheimer’s was
misdiagnosed in up to 13% of patients actually
suffering from Creutzfeldt–Jakob disease [61].
This relatively low incidence fits in with evidence
that man is less susceptible to bovine tuberculosis
then other animal species. In guinea pigs, a single
bovine bacillus may suffice to establish progressive
infection [65]. And Villemin documented that none
of his rabbits inoculated with human tuberculosis
presented a disease so “rapidly and completely
generalized as that obtained by inoculation with
the tubercle of the cow. . ...” [66]. Rich, however,
argued that there was no satisfactory evidence that
humans possess a higher native resistance to bovine
rather then human tubercle bacilli [67]. In
1917, 5% of US cattle were infected with M. bovis,
and approximately 25% of human TB fatalities
originated from cattle [68].
Virginia Livingston [80] quotes Ellen G White’s
1905 Ministry of Healing regarding the topic. Incredibly,
White, almost 100 years ago:
“Flesh was never the best food; but its use is now doubly
objectionable since disease in animals is so rapidly increasing.
Those who use flesh foods little know what they
are eating. Often if they could see the animals when living
and know the quality of the meat they eat, they would
turn from it with loathing. People are continually eating
flesh that is filled with tuberculosis and cancerous germs.
Tuberculosis, cancer and other fatal diseases are thus
communicated.”
Today the greatest hindrance to finding a cure
for TSE’s lies in the very theory they have become
embedded in. Santana’s oft quoted “he who does
not remember the past is condemned to relive it in
the future” seems clear here. Early twentieth
century recognition of the spread of cow tuberculosis
was obvious and at one time American milk
contained the words: “tuberculin tested,” an epitaph
to the up to 30% of human cases of pre-pasteurization
tuberculosis. It is almost certain that
Crohn’s disease is a form of bovine tuberculosis.
How long will it then take before the transmissible
737 Is mad cow disease caused by a bacteria?
spongioform encephalopathies are also recognized
as being the result of this disease?

References

[1] Taubes G. The game of the name is fame. But is it science?
Discover 1986;7(12):28–52.
[2] Rohwer RG. Scrapie infectious agent is virus-like in size and
susceptibility to inactivation. Nature 1984;308(5960):
658–62.
[3] Mitchell S. Mad cow: prion research misguided. Medline Plus
2003;(Dec 29).
[4] Manuelidis L. Transmissible encephalopathies: speculations
and realiaties. Viral Immunol 2003;10(2):123–39.
[5] Saborio G, Permanne B. Sensitive detection of pathological
prion protein by cyclic amplification of protein misfolding.
Nature 2001;411:810–3.
[6] Lasmezas CI, Deslys JP. Transmission of the BSE agent to
mice in the absence of detectable abnormal prion protein.
Science 1997;275(5298):402–5.
[7] Aguzzi A. Prion diseases, blood and the immune system:
concerns and reality. Haematologica 2000;85(1):3–10.
[8] Baker CA. Microglia from Creutzfeld–Jakob disease-infected
brains are infectious and show specific mRNA
activation profiles. J Virol 2002;76(21):10905–15.
[9] Manuelidis L, Sklavidis T. Viral particles are required for
infection in neurodegenerative Creutzfeldt–Jakob disease.
Proc Natl Acad Sci USA 1995;92:5124–8.
[10] Much H. Die Variation des tuberkelbacillus in form und
wirkung. Beitr Klin Tuberk 1931;7:60–71.
[11] Fontes A. Bemerkungen ueber die Tuberculoese Infection
und ihr virus. Mem Instit Oswaldo Crus 1910;2:141–6.
[12] Klieneberger-Nobel E. Origin, development and significance
of L-forms in bacterial cultures. J Gen Microbiol
1949;3:434–42.
[13] Mellon RR, Fisher LW. New studies on the filterability of
pure cultures of the tubercle group of micro-organisms. J
Infect Dis 1932;51:117–28.
[14] Biron MG, Soloveva IP. Acute hematogenic generalization of
tuberculous caused by L-forms of Mycobacteria. Probl
Tuberk 1989;8:75–6.
[15] Shaked GM, Shaked Y. A protease-resistant prion protein
isoform is present in urine of animals and humans affected
with prion diseases. J Biol Chem 2001;276(34):31479–82.
[16] Xalabarder C. Electron microscopy of tubercle bacilli.
Excerpta Med Sect XV Chest Dis 1958;11:467–73.
[17] Xalabarder C. Formas L de mycobacteria y nefritis cronicas.
Publ Inst Antitubercul Suppl 1970;7:1–83.
[18] Livingston V. A specific type of organism culturerd from
malignancy: bacteriologic and proposed classification. Ann
NY Acad Sci 1970;174:636–54.
[19] Mattman L. Cell-wall-deficient forms – Stealth pathogens.
Boca Raton: CRC Press; 2001.
[20] Pachas WN, Schor M. Evidence for the bacterial origin of
Acholeplasma landladies A. Diagn Microbiol Infect Dis
1985;3(4):295–309.
[21] Bastion FO, Foster FW. Spiroplasma sp. 165 rDNA in
Creutzfeldt–Jakob disease and scrapie as shown by PCR
and DNA sequence analyses. Neuropathol Exp Neurol
2001;60(6):613–20.
[22] MSIA Mapping Mad Cow Disease, Extent of BSE-positive
occurrences (BSE occurrences/100 farms/km squared) The
map cabinet Mapping Sciences Institute, Australia New
South Wales Division; 2003.
[23] Bourne J, Donnelly C. An epidemiological investigation into
bovine tuberculosis third report of the independent scientific
group on cattle TB; 2001.
[24] Francis J. Bovine tuberculosis. Staples Press: London;
1947.
[25] Turnbull A. Disease control division of MAFF speaking at the
All Party Parliamentary Group for Animal Welfare meeting;
1996.
[26] Garnier T, Eiglmeier K. The complete genome sequence of
Mycobacterium bovis. Proc Natl Acad Sci USA 2003;100(13):
7877–82.
[27] Norton RE, Lumb R. Mycobacterium bovis meningitis. Med J
Austral 1995;162(5):276–7.
[28] Webb GB. Tuberculosis. New York: Hoeber; 1936.
[29] Wayne LG. Am Rev Respir Dis 1982;125(Suppl.):31–41.
[30] Wilson TM, Howes M. An epizootic of bovine tuberculosis
in Barbados, West Indies. Can J Comp Med 1979;43(2):
151–7.
[31] Cassidy JP, Bryson DG. Tonsillar lesions in cattle naturally
infected with Myobacterium bovis. Vet Rec 1999;144(6):
139–42.
[32] Rogers RJ, Donald BA. The distribution of Mycobacterium
bovis in Queensland cattle herds with observations on the
laboratory diagnosis of tuberculosis. Aust Vet J 1980;
56(11):542–6.
[33] Thoen CO, Himes EM. Bovine tuberculosis in the United
States and Puerto Rico: a laboratory summary. Am J Vet Res
1979;40(1):118–20.
[34] Whipple DL, Bolin CA. Distribution of lesions in cattle
infected with Mycobacterium bovis. J Vet Diagn Invest
1996;8(3):351–4.
[35] Francis J. Very small public health risk from flesh of
tuberculosis cattle. Aust Vet J 1973;49:496–7.
[36] Lantos A, Niemann S. Pulmonary tuberculosis due to Mycobacterium
bovis subsp. caprae in captive Siberian tiger.
Emerg Infect Dis (serial online) 2003;(Nov.). Available from:
http://www.cdc.gov/ncidod/EID/vol9no11/03-0297.html.
[37] USDA-FSIS Technical information-Kitchen Thermometers
Food Safety and Inspection Service; 1998.
[38] Schurmann P. Beobachtungen bei den Lubecker Sauglingstuberkulosen.
Beit Klin Tuberk 1932;81:294.
[39] Hoheisel G, Chan KM. Involvement of the central nervous
system in disseminated tuberculosis. Deut Med Wochensch
1991;116(33):1228–33.
[40] Otter A, Munro R. Mycobacterial meningitis as a cause
of ataxia and weight loss in a deer. Vet Rec 1995;136(7):
180.
[41] Gray F, Gherardi R. Lesions of the spinal cord and spinal
roots in human immunodeficiency virus infection. Rev
Neurol (Paris) 1990;146(11):655–64.
[42] Roels S, Walravens C. Mycobacterium bovis meningitis in a
cow with clinical signs of BSE. Vet Rec 2003;152(26):807–8.
[43] Jones PG, Silva J. Mycobacterium bovis meningitis. J Am
Med Assoc 1982;247:2270.
[44] Wilkins EGL, Griffiths RJ. Tuberculous meningitis due to
Mycobacterium bovis: a report of two cases. Postgrad Med J
1986;62:653–5.
[45] Hartley WJ. A focal narcotizing encephalitis in cattle
associated with tuberculosis. Acta Neuropathol 1974;
29(3):263–8.
[46] Griffiths AS. Bacillus tuberculosis. In: A system of bacteriology
in relation to medicine. London: HMSO; 1930.
[47] USDA Factsheet: Bovine Tuberculosis Animal and Plant
Health Inspection Service Maryland; August 2002.
[48] USDA report Johne’s Disease on US Dairy Operations; 1997.
[49] Bakker D, Willemsen PT. Paratuberculosis recognized as a
problem at last: a review. Vet Q 2000;22(4):200–24.
738 Broxmeyer
[50] Chamberlin W, Graham DY. Review article: Mycobacterium
avium subsp. paratuberculosis as one cause of Crohn’s
disease. Aliment Pharmacol Ther 2001;15(3):337–46.
[51] Pavlik I, Bejckova L. Characterization by restriction end
nuclease analysis and DNA hybridization using IS900 of
bovine, ovine, caprine and human dependent strains of
Mycobacterium paratuberculosis isolatedin various localities.
Vet Microbiol 1995;45:311–8.
[52] Muskens J. Paratuberculosis in sheep: its possible role in
the epidemiology of paratuberculosis in cattle. Vet Microbiol
2001;78(2):101–9.
[53] Barnes N, Clarke C. Mycobacterium paratuberculosis cervical
lymphadenitis followed five years later by terminal
ileitis similar to Crohn’s disease. Br Med J 1998;(7).
[54] Sung N, Collins MT. Thermal tolerance of Mycobacterium
paratuberculosis. Appl Environ Microbiol 1998;64(3):
999–1005.
[55] Merkal RS, Crawford JA. Heat inactivation of Mycobacterium
avium–Mycobacterium intracellular complex organisms
in meat products. Appl Environ Microbiol
1979;38(5):831–5.
[56] Theon CO, Baum KH. Current knowledge on paratuberculosis.
J Am Vet Med Assoc 1988;192:1609–11.
[57] Rossiter CA, Henning WR. Isolation of Mycobacterium
paratuberculosis (M. ptb) from thin market cows at
slaughter. Dairy Sci 2001;84(Suppl):1.
[58] McDowell RM, McElvaine MD. Long-term sequelae to foodborne
disease. Rev Sci Tech Off Int Epiz 1997;16(2):337–
41.
[59] Hass G, Huntington R. Amyloid. III The properties of
amyloid deposits occurring in several species under diverse
conditions. Arch Pathol 1943;35:226.
[60] Schwartz P. Amyloid degeneration and tuberculosis in the
aged. Gerontologia 1972;18(5–6):321–62.
[61] Manuelidis L, Manuelidis EE. Creutzfeldt–Jakob disease and
dementias. Microb Pathog 1989;7(3):157–64.
[62] Delgado WA. Amyloid deposits in labial salivary glands
identified by electron microscopy. J Oral Pathol Med
1997;26(1):51–2.
[63] de Beer FC, Nel AE. Serum amyloid A protein and C-reactive
protein levels in pulmonary tuberculosis: relationship to
amyloidosis. Thorax 1984;39(3):196–200.
[64] Tomiyama T, Satoshi A. Rifampicin prevents the
aggredgation and neurotoxicity of amyloid B protein in vitro.
Biochem Biophys Res Commun 1994;204(1):
76–83.
[65] Levinthal W. Tuberkuloseinfektion von Meerschweinchen
mit kleinsten Bazillenmengen. Z Hyg 1927;107:387.
[66] Cummins S.L. Tuberculosis in History Bailliere, Tindall, Cox
z;pmfpm; 1949.
[67] Rich AR. The pathogenesis of tuberculosis. Springfield, IL:
Charles C. Thomas; 1946.
[68] YoumansGP.Tuberculosis. Philadelphia:W.B. Saunders; 1979.
[69] Satoh J, Kurohara K. The 14-3-3 protein detectable in the
cerebrospinal fluid of patients with prion-unrelated neurological
diseases is expressed constitutively in neurons and
glial cells in culture. Eur Neurol 1999;41(4):216–25.
[70] Delarue NC, Pearson FG. Experience with surgical salvage in
pulmonary tuberculosis: application to general thoracic
surgery. Can J Surg 1975;18(6):519–29.
[71] Wilkins EG, Griffiths RJ. Bovine variants of Mycobacterium
tuberculosis isolated in Liverpool during the period 1969 to
1983: an epidemiological survey. Q J Med 1986;59(230):
627–35.
[72] Bastion FO. Bovine spongiform encephalopathy: relationship
to human disease and nature of the agent. ASM News
1993;59(5):235–40.
[73] Gutierrez M, Sampler S. Identification by spoligotyping of a
caprine genotype in Mycobacterium bovis strains from
cattle and other animals, a tool for studying epidemiology
of tuberculosis. J Clin Microbiol 1997;35:3328–30.
[74] Wyngaarden JB, Smith LH. Cecil textbook of medicine. 19th
ed. Philadelphia: W.B. Saunders; 1992.
[75] Dickenson AG, Frasor H. Extraneural competition between
different scrapie agents, leading to loss of infectivity.
Nature 1975;253(5492):556.
[76] Prusiner SB. The prion diseases scientific American
1995;272(1):48–51, 54–57.
[77] Pethe K. Bifani pablo mycobacterial heparin-binding hem
agglutinin and laminin-binding protein share antigenic
methyllysines that confer resistance to proteolysis. Proc
Natl Acad Sci USA 2002;99(16):10759–64.
[78] Tsubuki S, Takaki Y. Dutch, Flemish, Italian and Arctic
mutations of App and resistance of Abeta to physiologically
relevant proteolytic degradation. Lancet 2003;361(9373):
1957–8.
[79] Jaussaud R, Deville JF. Central neurologic manifestations of
Crohn’s disease. Rev Med Int 1999;20(6):527–30.
[80] Wheeler VL, Wheeler OW. The microbiology of cancer
compendium. Craftsman Graphics San Diego 1977.
[81] McDiarmid A. Some diseases of free-living wildlife. Adv Vet
Sci Comp Med 1975;19:97–126.

Corresponding author. Correspondence to: Dr. Lawrence Broxmeyer MD Med-America Research, 148-14A Eleventh Avenue, Whitestone, NY 11357, USA

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