"MAD COWS", ENGLISHMEN AND THE PRION HYPOTHESIS
by Dorothy B. Preslar, Director AHEAD/ILIAD programs
The Prion Hypothesis
According to information published by the World Health Organization in
March 1999, there had been 39 cases of the new variant CJD disease
diagnosed since 1994. Information from other sources indicate
approximately 75 cases through March 2000, with fatalities in at least 90%
of the cases.
In March 1996 the public was startled by a statement made to the
British Parliament that ten recent cases of a rare brain disease in the UK
might be linked to a similar disease in cattle. The human disease found in
the cases is a variant form of Creutzfeldt-Jakob Disease (CJD), which was
recognized before the turn of the 20th Century and kills one person out
of a million world wide per year. The cattle disease is Bovine Spongiform
Encephalopathy (BSE), which was first diagnosed in the UK in 1986 and
subsequently in other countries. It was initially believed to have
resulted from feeding healthy cattle the remains of sheep killed by a
related disease called Scrapie.
For at least a decade, the UK and other countries have taken a number
of actions to reduce the incidence, or prevent the occurrence, of BSE.
Notwithstanding the similarities of the disease in animals and humans,
the possibility that it could be transmitted from cow or sheep to man, by
any means, was generally accepted as close to zero; the principal reason
being the natural barrier to such cross-infectivity between animals and man.
However, an article by evolutionary biologist David Krakauer and others,
hypothesizes that the barrier may be less than total (Nature, 25
April, 1996, p. 675). Proof that BSE has crossed the barrier would,
according to a 1996 communication from Dr. Tom Pringle, involve a
demonstration "by immunofluorescence that traces of rogue cow protein
is present in human victims." Such a demonstration has not yet been
In animals other than cattle, sheep and goats, the disease is usually r
eferred to as Transmissible Spongiform Encephalopathy (TSE) and includes
Chronic Wasting Disease that affects mule deer and elk, and is present in
the US. The feline type (FSE) affects domestic cats and TME (transmissible
mink encephalopathy) affects...mink, of course. TSE has been found
in zoological specimens: in Great Britain, for example, confirmed cases
include six kudus, five eland, a nyala and a gemsbok, one Arabian oryx, one
puma, one scimitar-horned onyx, one ocelot and four cheetah; in Germany t
here were 3 ostriches. Infection in all cases is believed to have
resulted from feed containing the remains of animals infected
by some form of TSE.
There are five known human forms of the disease -- CJD, nvCJD (the
newly recognized varient of CJD (NV-CJD), kuru, Gerstmann-Straussler
Syndrome (GSS) and Fatal familial insomnia. There are three forms of
Classic CJD -- sporadic, inherited and infective. Sporadic CJD is the most
prevalent. Until the appearance in the UK of a CJD-type disease in
persons whose average age is 26.5, it was considered a disease of men and
women dying over the age of 45 and was, thus, thought to be a result of
genetics or ageing, or both. The inherited form, Gertsmann-Straussler,
represents 10-15 percent of confirmed cases; 100 families have thus far been identified. The
infective form is rare -- about 80 cases. Fatal familial insomnia (FFI)
is likewise considered to be caused by a mutated gene in about 9
Kuru (from a Pacific Islander word meaning "tremble") was, about a
quarter of a century ago, initially ascribed to a tribal custom of eating
the brains of a deceased relative, although in-depth analysis of the
cases showed more cases in females who prepared the brains than in males
who ate them. Since 1957 about 2,600 cases have been identified, but less
than 10 cases in 1995. The newly recognized form, nvCJD, resembles kuru,
both pathologically and clinically, more than it does Creutzfeldt-Jakob.
Common to all types of the disease -- both human and animal -- is the
progressive deterioration of the brain. The overt symptoms are loss of
coordination (insomnia in FFI) followed by dementia, although in some
CJD cases the sequence is reversed. Under the microscope, tissue specimens
appear as if holes have been randomly drilled through on a horizontal plane
-- like Swiss cheese or, in a more subtle analogy, like a sponge. Hence
the name spongiform encephalopathy. Once the disease is overt, the
patient can expect to live about one year; the span is one month to more
than 10 years.
Until recently, it was not thought that human CJD could be diagnosed
before death. Tonsil biopsy samples have recently been used in
investigation. And there have been claims for a test using cerebrospinal
fluid that not only diagnoses CJD but also distinguishes it from
Alzheimers, which has similar symptoms. However, validating such tests
requires carrying it out in a substantial number of clinically suspected
CJD cases and comparing the results with those of subsequent postmortem
histopathological examination of brains, and finding a very high
degree of correlation.
As to what is the immediate cause of spongiform encephalopathy, in the
past three decades research has focused on the "prion hypothesis" -- that
a naturally occurring protein has "gone bad", changing a normally
harmless "prion protein" into a dangerous, protease-resistant form.
Probably the best explanation of prions for laypersons appeared in the
January 1995 issue of Scientific American in an article written by
Stanley B. Prusiner, the leading proponent of, and winner of a Nobel Prize
in 1997 for, the prion hypothesis.
[Note: This is an attempt at an explanation intended to be
understandable by non-scientists as well as scientists. The latter
will recognize that some of the matters briefly described are more complex
than it is possible to indicate here, and that
research is continually bringing new knowledge in this field.]
Increasingly, research is confirming the hypothesis of Stanley Prusiner
and his colleagues, that in transmissible spongiform encephalopathies (such
as BSE in cattle and CJD in humans) the infective agents are abnormal,
distorted PRIONS. A prion (PrP) is a small protein molecule found in the
brain cell membrane. It is not "live" -- it has no associated DNA.
"Prion" is a generic term. Different species have brain cell proteins
of different compositions. For example, the human prion differs by 30
different amino acids from the cattle prion.
Protein molecules have three-dimensional folded shapes. An infective
prion (PrPsc) is one whose shape has become distorted (misshapen). [The
PrPsc designation originally referred to sheep scrapie prions, but is
now used as a generic designation for
all kinds of infective prions.] The distorted shape is protease-resistant,
i.e. it is not broken down into amino acids in the digestive system. It is
also highly resistant to normal heating and to normal sterilants.
When a distorted prion molecule reaches (by whatever route) the prions
in the brain cell membrane of a "host" individual, that molecule is able
to act as a three-dimensional "template" to cause a normal prion molecule
to adopt a similar distorted
shape; and that in turn is able to act as a template to do the same to
another normal prion molecule; and so on.
One familiar example of a template is the three-dimensional Jello (or
jelly) mold, which causes the surface of the jelly in contact with the
mold to "set up" in
exactly the same shape as the mold. Another, but only two-dimensional,
example is the dressmaker's paper patterns
that enable the cloth to be cut to their exact sizes and shapes.
Distorted and infective BSE prions probably first arose from the
inclusion of scrapie-infected sheep offals in feed for cattle, and probably
also from inclusion of offals from cattle suffering from previously
unrecorded cases of BSE at low incidence
level, amplified by subsequent "re-cycling" of infected cattle offals in
cattle feed. There is currently no conclusive evidence of vertical
transmission in animals, as in mother to offspring transmission.
CJD prions are likewise misshapen human brain prions. They may arise
from a genetic predisposition of an individual
by transfer from a person with (or incubating) CJD, via instruments used in
nerosurgery, opthalmological prodecures, dental work or caesarian birth
deliveries not sufficiently autoclaved after prior use
from injection of human pituitary gland extract from corpse pituitary
glands from persons who had died from CJD (used as growth stimulants, as
happened before synthetic material became available); or
possibly from transfusion of CJD-infected blood or entry through cuts
and abrasions on those who handle infected animal carcasses.
There is no scientific evidence that CJD prions can be caused by
BSE prions; i.e. no scientific evidence that BSE-infective prions can act
as a shape template to cause distortion in normal human prions. Thus,
there is no evidence that eating red meat increases the chance of
contracting nvCJD. There are, however, representations in folklore that
eating too much beef can "addle" the brain. Such a belief was popular at
the end of the 16th Century. In Shakespeare's "Twelfth Night" (Act One,
Scene Two), Sir Andrew says "Methinks sometimes I have no more wit than a
Christian or an ordinary man has, but I am a great eater of beef, and I
believe that does harms to my wit." "No question." replies Sir Toby.