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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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