MAD COW DISEASE
The BSE Epidemic in Great Britain
An Interview with Dr.
Frederick A. Murphy
Dean of the
School of Veterinary Medicine, University of California
Davis
by
Sean Henahan, Access Excellence
The announcement by British health authorities that bovine
spongiform encephalopathy (BSE, pictured in medulla of cow,
left), also known as mad cow disease, may have been
transmitted to humans has led to a chaotic situation in the UK
with ripple effects occurring throughout Europe and the rest of
the world. What is BSE and what is its relation to scrapie in
sheep and Creutzfeldt-Jakob disease (CJD) in humans? How did
the current epidemic begin? I asked Frederick A. Murphy,
DVM,
PhD, Dean of the School of Veterinary Medicine at the
University of California, Davis these and other questions in an
attempt to sort out the science from the media hysteria
surrounding the announcement from the UK on March 21, 1996 that
10 people may have become infected with the BSE agent through
exposure to beef.
Let's start at the beginning. What exactly is
BSE?
BSE, that is bovine spongiform
encephalopathy, also known in Britain as the mad cow disease,
is a progressive, lethal central nervous system disease of
cattle. It is characterized by the appearance in neurons in the
brain of affected cattle of vacuoles, clear holes, that give the
brain the appearance of a sponge -- this is where the term
spongiform came from.
What is the reason for the current panic?
What is the link, if any, between BSE in cattle, scrapie in
sheep and CJD in humans?
BSE was initially recognized in cattle in
the UK in 1986; there is good information that it had not
occurred before then. Epidemiological research led to the
conclusion that the bovine agent had originated from the scrapie
agent, which had been present in sheep in the United Kingdom for
at least 200 years. It is presumed, but will likely never be
proven, that the scrapie agent jumped species and moved into
cattle when sheep offal (the leftover parts of butchered
animals) was included in protein supplements fed to cattle.
After cattle started to die, cattle carcasses and offal were
included in the same protein supplements -- this seems to have
amplified the epidemic.
The epidemic in cattle in Britain reached incredible
proportions; by 1993 more than 1,000 cases per week were being
reported. More than 160,000 infected cows have now been
identified, involving more than 50% of the dairy herds in the
UK. Protein supplements containing sheep and cattle offal were
banned in the UK in 1988, but it was not until 1991-1992 that
the ban was strictly enforced. Given the long incubation of
BSE, the epidemic curve (number of new cases reported per week)
didn't start downward until late 1993. It is now down to about
250 cases per week..
Even by 1990 when the epidemic curve was on the upswing,
questions were raised in many quarters in the UK, "...does BSE
pose a risk to human health?" British government officials at
the time said don't worry, there is nothing to worry about.
This of course only led the public to become more skeptical.
Even then, in 1990, the editors of the British journal Nature
reacted, saying: "...Never say there is no danger {risk}.
Instead, say that there is always a danger {risk), and that the
problem is to calculate what it is. Never say that the risk is
negligible unless you are sure that your listeners share your
own philosophy of life..." I think this advice has come back to
haunt British officials again, six years later.
The next chapter started with the announcement on March 21, 1996
of 10 cases of CJD in people not otherwise considered at high
risk. These individuals were much younger than the usual cases
of CJD that occur sporadically everywhere in the world at an
incidence of about one per million population per year. This
sporadic incidence of CJD is the same even in countries, like
Australia, where there is no scrapie. Also, there have been
statements in the press, but no details, that the pathologic
changes in the brains of these 10 patients are different from
those in usual CJD cases. In any case, it is the
age-distribution of these 10 cases (average age 27 vs. 63 for
sporadic CJD cases) that led the British expert committee to
make its startling announcement.
So, the problem in the UK can be traced to
feed supplements containing infected cow and sheep parts?
In the early 1980s in England the rendering
process (by which livestock carcasses are converted to various
products, including protein supplements for livestock feed) was
changed. Earlier, a solvent extraction step had been used to
extract fats (tallow); this step was stopped when the price of
the petroleum-based solvents used to extract fats went up. The
infectious agent is solvent-sensitive. Otherwise, the
infectious agent is extremely hardy -- it can survive boiling
and many disinfectants, but is readily destroyed by extremely
high temperature (such as in an autoclave), or by oxidizing
agents, or by solvents.
Of course, this change in the rendering process was only part of
the story -- in tracing the source of the problem other
practices employed in the livestock industries of the UK have
to be assessed -- and the still mysterious events that likely
led to the species jump of the scrapie agent into cattle must
be assessed too.
Our knowledge of CJD goes back to earlier
studies of kuru, the so called headhunter disease seen in Papua
New Guinea, where people became infected after eating the
brains of their foes and preparing their dead relatives for
burial. How are these diseases related?
Kuru and CJD should be thought of as two
different spongiform encephalopathies. Kuru studies were
instructive since they showed for the first time that a slowly
progressive neurological disease of humans can be infectious,
that is transmitted from one person to another. For this
discovery Carleton Gajdusek was awarded the Nobel Prize.
Recently, as the power of molecular biology has been applied to
the spongiform encephalopathies, it has become clear that each
disease (scrapie, BSE, and others in animals, and CJD, kuru and
Gerstmann-Straussler-Scheinker disease in humans) is caused by a
distinct variant prion.
You've mentioned prions. What are they? How
are they associated with the pathogenesis of these diseases?
Prions are the most bizarre infectious
agents ever imagined. It was Stanley Prusiner of the University
of California, San Francisco, who first discovered the nature
of prions and suggested they are the causative agents of the
spongiform encephalopathies. For this he won the prestigious
Lasker Prize two years ago. Prions (pronounced pree-ons ) are
proteins, rogue proteins, and nothing else. They contain no
nucleic acid (DNA or RNA). They consist of a single molecule
containing about 250 amino acids, termed the PrP protein. They
are abnormal variants of proteins that occur normally in cells,
such as human brain cells. Amazingly, abnormal PrP proteins,
when they enter the body, are able to convert their normal
counterparts into more of the abnormal forms. The difference
between the normal and abnormal proteins does not lie in their
primary structure (the sequence of their amino acids), but
rather in their folding -the abnormal PrP proteins are folded
in a way that allows them to resist normal protease degradation
so that over time this leads to the build up of aggregates of
PrP, especially in neurons in the brain. These aggregates
resemble the tangles of abnormal protein found in neurons in
Alzheimer s disease patients, but as in Alzheimer s disease, we
do not know how the presence of these tangles causes neurologic
disease.
Prions are the only "life forms" that break the great "central
dogma" of biology. That is, we have come to expect that all
life forms from viruses to bacteria to plants to humans to
hand down the blueprints for all their progeny via their DNA
(except for some viruses which carry their blueprints as an RNA
genome), and we expect that the process for converting the
blueprints into building blocks must involve replication of DNA,
transcription of the message into RNA, and translation of the
RNA s message to form proteins, the building blocks of cells,
tissues, organs and whole organisms. Here we have life forms
where abnormal proteins, the PrP proteins, direct the refolding
of normal proteins just by direct contact.
PrPs from the various spongiform encephalopathies have been
sequenced and found to differ, in some cases by very little, in
some cases by quite a bit. For example, recent research has
shown that the scrapie PrP protein differs from the BSE PrP
protein at only seven amino acid loci, whereas the BSE PrP
protein differs from the human CJD PrP at more than 30 loci.
These differences explain the concept of strains and help
explain why prions from one species might jump more easily into
another species than another. It is difficult to find the terms
to discuss prions -- for example, can we talk about mutants
when there is no DNA? What would Watson and Crick think of all
this?
Are there factors that may predispose an
animal or human to infection? After all, it would seem that
many more people are exposed to prions than actually get
disease?
In a nutshell, the answer to this question
is, we don t know. It s true in every disease that there are
more exposures than infections. And it s true that in most
cases we don't know why one person or animal gets infected and
another doesn't. With the prion diseases, we don't know much
about a dose effect -- beyond a minimum infectious dose, does
a big dose of prions lead to a higher probability of infection
or a faster progression to clinical disease? In the real-world
setting, what do we know about how easy it was for prions
contained in feed supplements to enter a cow's body? The answer
is, not much.
How is a prion different from a virus? What
does a virus have that a prion does not?
As President of the International Committee
on the Taxonomy of Viruses, I've had to wrestle with this
question -- in our most recent report, we have a chapter on
prions, contributed by a study group chaired by Stanley
Prusiner. This chapter is included in a section entitled
sub-viral agents. This title has allowed us to avoid the
question, to keep our definition of virus intact, to hold to a
sense that a virus should have a nucleic acid (DNA or RNA)
genome, and still keep the prions under the wing of virologists
around the world. After all, it is virologists who care most
about prions, and it is virology meetings and virology journals
where scientific progress on prions and prion diseases is
reported.
What about the hypothesis that prions are
not infectious themselves, but serve only as a kind of virus
activator?
People who still believe that there has to
be some nucleic acid somewhere in the picture have been caught
out in the cold by all the recent progress in our understanding
of the nature of prions. Perhaps these people have to
rationalize some direct role of a nucleic acid in the infectious
moiety and so they envision some kind of activator role for the
prion, acting in concert with a yet-to-be-found traditional
virus. As the nature of prions becomes better known, I think
this idea will fade away.
Is there any evidence that CJD can appear as
a genetic disease?
Yes, there is a familial form of CJD,
accounting for about 10% of cases. In the familial disease
there is are mutations in the gene encoding the normal protein
such that the protein tends to fold in the abnormal way and
tends to pile up into aggregates in brain cells with lethal
consequences.
How do we know that these new cases of
so-called BSE disease in humans are not CJD? How can we tell if
someone got CJD from a cow, or if they got it from their
grandfather?
We can tell by genetic analysis. This has
been well studied in the familial form of CJD. The prion
protein in familial cases is the same in each family member
that has it, and different in all other families. Sometimes the
difference is as small as one amino acid, but these differences
can be used to determine the pedigree of the prion. I'm sure
such analyses are being applied to the 10 cases just reported in
the UK.
The British announcement has raised
questions not only about the safety of British beef, but
British milk and dairy products as well. What is known about
this?
There has never been any evidence of any
prion being transmitted through milk. Although, we don't know
if prions can occur in the milk of a cow with BSE, there is
very good epidemiologic evidence that this is not a route of
transmission. For example, if the BSE prion was transmitted in
cow s milk, wouldn't we expect to see BSE in calves fed on such
milk? There are solid data from the UK that such calves have
not become infected.
There is a report that the French are
worried about infection via cosmetics containing animal
products? Is this far fetched?
It seems far fetched to me. Cosmetics are
full of lipid-solvent-based chemicals which would be very
destructive to prions.
What about the political impact of the BSE
epidemic?
The global political impact has been
incredible. We're now reading that this might be the ultimate
crisis for Prime Minister Major's Tory government, and could
lead to its downfall. There are also huge economic costs. Some
estimates go as high as $50 billion, with 300,000 jobs at risk.
At the recent Turin (Italy) meeting of the leaders of the
European Community, representatives of European countries even
brought up questions concerning the pace of the unification of
Europe. Even though it has now been decided that quite a bit of
the cost of eliminating BSE from British cattle will be shared
among other European governments, I don t think we ve heard the
last of these tensions at the highest levels of governments.
What are public health authorities doing in
the US?
There was just a big meeting in Washington
with people from the American agricultural sector, veterinary
medicine, USDA, and cattlemen groups. Ruminant (cattle and
sheep) -based feeds are already excluded in the US on a
voluntary basis, but this will soon become an FDA regulation.
There is no indication of BSE infection in US cattle. APHIS, the
Animal and Plant Health Inspection Service of the USDA, will be
increasing its surveillance measures. In my personal opinion,
this kind of direct surveillance based upon histopathological
examination of brains of selected cattle, has been modest in
scope and scale until now -- I suspect that the level of such
surveillance will increase. Another kind of surveillance is
also ticking up: trained APHIS inspectors working in cattle
sales yards and slaughter house yards are on the lookout for
animals with clinical signs of BSE. Education is also being
improved for practicing veterinarians and farmers. The USDA has
also announced that it will increase its research in this area.
So, do you feel confident eating US beef?
Absolutely -- I m a beef eater, always will
be. Last year the concern in this country was over E. coli
0:157 in hamburgers. As you will recall, cooking
temperatures were raised to kill the bug in ground beef. We
survived that scare, and now we eat fast-food hamburgers
without a second thought. In regard to BSE, the American public
should feel confident in eating American-grown beef -- the BSE
prion has never been found in our country.
Similar encephalopathy has been reported in
cats in England. Is there a risk of pet-to-owner
transmission?
Other animals in the UK exposed to the same
protein supplements as cows, such as some zoo animals, did get
infected. Indeed, cats began to get the disease about the same
time as the BSE epidemic began in cattle in Britain. Whether
these cats got infected from the same feed products (such as
bone meal as well as protein supplements) that cows were
eating, or whether they got infected by being fed infected meat
products is not likely ever to be known. In any case, I cannot
imagine any circumstance whereby humans might be at risk from
their cats.
What about the gardener who just put bone
meal on his gladiolus bulbs. Could he be inhaling prions?
If the gardener is in America, the bone meal
would have come from American livestock. Since there is no
evidence that BSE occurs in this country, that risk would seem
vanishingly small. We don't know what the risk to a British
gardener might be because we don't know enough about the
transmission of the BSE agent. All in all, I call this a
...what if...? question -one can go on and on asking such
question, never pausing for answers, never getting anywhere.
Is the US government responding adequately?
I would say, yes. As I mentioned, our
agricultural sector, our USDA, has taken this matter very
seriously and is doing many things to minimize risk. Our health
sector, our CDC and State health departments, are on top of the
matter as well. I would like to see a better interaction between
surveillance, research and public education between the health
sector and agricultural sector. In my view, veterinary medicine
is right in the middle of all this -- serving as a health
science and as an agricultural science -- communicating with
people across all turf boundaries. I expect that my colleagues
in veterinary medicine in our country will play a major role in
our national response over the coming months. My colleagues in
veterinary medicine in the UK have done a fine job -- their
sound scientific recommendations have, however, been caught up
in the mega-political mess that would overwhelm any
scientifically based activities.
What are the research priorities now?
At the heart of the matter we're dealing
with the abnormal folding of a native bovine protein. This
protein, the abnormal PrP protein, is not immunogenic and
doesn't seem like a reasonable target for vaccine development.
The number one need is for a diagnostic test that could be used
for early diagnosis in cattle and humans. We keep hearing that
such tests are forthcoming immediately, but I've heard that for
several years now and we still do not have such tests. Whenever
such a test comes along, it will then be along time before it
could be validated and proof tested in the field. I think this
development should be a national priority.
What would such a test be like? It can't be a DNA or RNA probe
since the gene encoding the PrP protein is a normal constituent
of the body. It may have to be an immunological test, one that
is specific for the abnormally folded shape of the PrP protein.
What do you think could form the basis for
treatment of these prion-related encephalopathies?
For cattle with BSE there will not likely
ever be a treatment -slaughter will continue to be the
end-game. Stanley Prusiner thinks that for humans with CJD one
tack should involve designing drugs that would stabilize the
normal protein throughout the body, preventing its refolding
into the abnormal PrP protein. Prusiner also thinks that
antisense technology may prove useful. This might involve
delivering into human brains engineered genes that would block
those genes that give rise to unwanted proteins. Of course,
this would require that the normal protein from which abnormal
PrP proteins derive are not essential-- so far we do not know
what the function of the normal protein may be. Progress in
this area could spin off and provide keys for Alzheimer's
research as well. All this would seem to represent years of
research.
Related information on the
Internet
UK-Institute for Animal Health
UK- Institute for Food
Health and Technology
The Official Mad Cow Disease Home Page (Many Links)
Mad Cow: The Science and the Story
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