Inside this test tube there is enough purified BSE to kill ten million cows (picture of Jim Hope's hand). It now seems certain that it can kill humans too. The scientific community that failed to predict that we would be susceptible has been baffled by this agent of disease.
(Paul Brown in his garden) The infectious agent is almost immortal and it maybe impossible to destroy. These agents seem to be resistant to all that we can throw at them. They resist alcohol boiling, glutaraldehyde...
David Taylor at his lab at the Neuropathogenesis Unit in Edinburgh)....ultraviolet, gamma, potassium permanganate, chlorine dioxide, ultraviolet irradiation, ionising radiation... We have here a hot air oven that runs at the same temperature as a home oven when you cook these agent even for a long period you just cant kill them.
Paul Brown. We thought it would be interesting to find out what would happen if we buried some of these agents. We ground up some scrapie brain and put them in some soil, and used my own garden as a burial site and what we found was to a large degree still present after three years. We exposed it to temperatures that turned it to ash and found that these did not entirely destroy the agent. So every known pathogen of man would have been destroyed. But this was not.
Over to Edinburgh.
Narrator.. This extraordinary organism was studied for a long time before BSE appeared because BSE is just a new form of an ancient group of brain disorders called the transmissible spongiform encephalopathies. All SEs are caused by the same infective agent. Many species of animals are vulnerable to it but the disease has always baffled scientists. We know that the infectious agent accumulates in the brain over many years. The damage is slow but irreparable. It always ends in death. Under the microscope the brains of all animals have the same distinctive holes that turn the brain to sponge. In humans the disease is called CJD.
We dont know why but every person on the planet from Af to Am, black or white, vegetarian or carnivore is at risk of getting CJD that has been known for decades. But CJD can infect humans in different ways.
(John Collinge sitting in his lab at St. Mary's Medical School, part of Imperial College in North London). CJD comes in three forms. The majority of CJD is what we called sporadic CJD. Sporadic CJD it is present in similar prevalence all over the world. The lifetime likelihood of getting CJD is one in 50,000. Where ever you look around the world. Then there are these cases that have arisen from tragic medical accidents where people have been exposed to CJD. Children that have been treated for growth deficiency with growth hormone. These are also very rare cases of CJD. There are the inherited forms these run in families they are extremely rare. None of these forms as far as we are aware has anything to do with BSE.
Narrator. (pictures of PNG) . But there is one other form of the disease and it could throw some more light on BSE, because it caused the first and up till now the only case of SE in human history. Early this century a strange new disease appeared in the highlands of Papua New Guinea. Kuru means to tremble with fear. Within a few years it had wiped out hundreds of people in a particular tribe. It was unknown elsewhere in the world. In 1957 scientists went to the highlands to try to find a cause for the disease.
PB.. They found a population that was dying. Equally affecting young women and children. the first symptoms were a little incoordination. The people would stagger a bit when they walked. Once this came sufficiently severe that they became unable to walk unaided. In time the people were unable to even stand and hence became helpless. They would die within 9 months . Because this disease had such a peculiar distribution of age and sex one of the things you think of is endocrine, genetics, toxic causes, malnutrition,. All of these were considered and were studied in detail and non of them were found to be correct. The answer turned out to be simple These people were cannibals. It was clearly being transmitted from person to person by cannibalism. The tribe ate their dead relatives as a mark of respect during funeral rites. This was not warfare cannibalism. This was loving cannibalism. In the course of cannibalistic ritual feasting the body was cut up into parts and the best parts were reserved for men. Muscle. the remaining parts; brain, pancreas, intestines were fed to the women and the children.
Narrator.. The disease was passed on when the women and children ate infected brains When these people died they were eaten and so the epidemic survived. An epidemic of human SE. The cycle was broken when cannibalism was topped on the island. But the incubation period was so long that cases are still dying today.
PB. . The solution was that kuru was passed form human to human and the answers to some laboratory experiments that have taken place by today have led us to believe that without question that the infection can be transmitted by feeding.
Narrator.. In 1986 a new form of the disease struck British cattle. It had never been seen in cattle before. Brain slides from infected cattle showed the same changes as all SEs The two key questions revolved around 'what is the infective agent' and secondarily 'can the disease transmit to humans' and are we going to have an epidemic following exposure to BSE But scientists working in the field had no answers. So little was known about these diseases that researchers could only guess.
(Adriano Aguzzi in his lab in Zurich).. The idea that BSE might be contagious and might provoke a disease in humans and every serious scientist had pointed it out that there is a possibility. But it was unlikely and I still maintain that it was reasonable to assume that it would be very unlikely. The reason is sheep scrapie. It has been with us a long time and yet there is no link between eating sheeps brain and CJD
Narrator.. Scrapie is the sheep form of SE. It exists all over the world. We have had scrapie in Britain. It is fatal in sheep but seems to be harmless in us. We are confident that even eating scrapie infected brains would not cause disease in use. But government scientists believe that cows were susceptible to eating scrapie and it cause the BSE epidemic. Cows were fed a cheap protein supplement to increase their milk yield that supplement contained the rendered carcasses of scrapie containing sheep. The theory is that through this feed the disease crossed the species barrier between sheep and cows. The infected cows were then rendered down and fed to more cows. It was like a cattle cannibalism, chillingly reminiscent of kuru.
For the first two years of the epidemic cows dying of BSE could be slaughtered and sent for human consumption. Their brains ended up in burgers and sausages, meat pies and pates. In 1988 the Govt called on the scientific community for advice. An eminent group of scientists was asked to study all the research on SEs and decide whether BSE was a risk to humans
The committee was headed by the zoologist Professor Richard Southwood
(Richard Southwood, in his office in Park Road, Oxford).. Back in 1988 it was very different. The amount of information that we had about SEs was very small. We knew there was this disease in sheep, scrapie, that had been around for 200 yrs and did not seem to be causing any problem of disease. So we based out recommendations that the chance of transmission was remote on the long experience with scrapie. But we said that the consequences, if we were wrong were grave and so said that steps should be taken in case that was true.
Narrator.. Prof Southwood advised that cattle dying of BSE should not be fed to humans and destroyed. But cattle can be infected with BSE for years without showing any sign of disease. Babies were, however banned from eating the brain tissue from cattle.
RS. . there could be a relationship between the size of the body and the size of the dose that is necessary. That is the reason why we picked on baby food rather than on adult food.
(Hugh Fraser sitting on a farm gate).. This was an inappropriate thing to do, to confine the risk to baby food. We knew from our work in animals and in particular laboratory rodents that young animals are oddly less susceptible to TSEs and the older animals are actually more susceptible than the new-born or neonate.
Narrator.. 9 months after the report of the Southwood Committee the Government introduced an offals ban to protect all humans. But some abattoirs did not fully enforce the ban. We now know that infective material was still getting into food in 1995.
RS.. I have a feeling that we wrote our report in too a reassuring way and in some way this dimmed the urgency.
Narrator. . This reassurance was soon picked up by the Government and the meat industry who used it as their scientific guide and justification.
McLean (junior minister for agriculture, 1989) . 'We rely on the scientific advice of Professor Southwood and his committee who say that the theoretical risk was remote.'
Keith Meldrum (Chief Veterinary Officer throughout BSE epidemic) .'We have to base our ideas of the disease on scrapie' 'We are fairly sure there is no risk to human health' 'The public is not at risk from BSE.'
RS. . You may want to know why we were not more alarmist in our report. But you must remember that at that time we were dealing with a very rare disease in cattle. You must remember that the human form of the disease was and still is very rare. Almost no people had ever heard of it. And if we had been too alarmist we were in danger of upsetting the whole of the meat industry in England and in Europe.
Narrator.. But research carried out since the 1970s should have rung alarm bells at his reassurance with the risk from scrapie. This research showed that scrapie and all SEs changed when they cross into a new species.
Hugh Frazer .. It has certainly been known since the mid 1970s that when scrapie infection is passed within a new species the disease characteristics can change and a phenomenon similar to mutation can occur and because of that a strain can be produced with altered neuropathology and even with an altered host range.
PB.Lets assume that BSE is the result of rendered recycled scrapie in a food change of cattle there is not a shred of evidence that scrapie has ever caused CJD in humans. But scrapie passaged or going into cattle may change the host range of their infection and therefore we cannot predict whether BSE would be or would not be infectious to humans.
Narrator..The Southwood Committee did recognise this possibility when he wrote his report.
RS.. We had no way at that time to recognise whether the BSE agent was exactly the same as the scrapie agent. Work carried out since then has shown that it does perform in a slightly different way.
Narrator . The first clue came in 1990 when domestic cats died of BSE. Cats like humans had never been susceptible to scrapie.
JC. . It was certainly concerning when domestic cats developed an SE and we now know that it was BSE that was now been passed by quite a few wild cats that have been kept in zoos and a few other wild animals that were kept in zoological gardens. That really indicated that BSE had a quite different host range from scrapie that it was infecting species that had not gone down with scrapie in the past. That was certainly a cause of concern for me. Of course that does not tell use that humans are open to BSE but it does tell us that BSE is rather different from scrapie.
Narrator.. Over the years the list of susceptible species grew longer. Scientists grew more worried. BSE crossed into almost every species exposed to it. This was extremely unusual.
AA.. BSE has a lot of very special features that we have not seen in any other types of SE. First of all it is very promiscuous. Meaning that it is not choosy in the type of host that it decides to infect. It can infect basically all species that it basically tries. It will go into mice, it will go into cats it will go into monkeys. So, we are witnessing a very special disease that has different features from the other TSEs we knew before. And so we need to deal with a problem that may even infect humans
JC. . People eating potentially BSE infected were eating a new disease. They weren't eating scrapie anymore. No the new scrapie that may have triggered off the epidemic was long gone.
Narrator.. From the beginning many scientists had been reassured by the link with scrapie. and thought it unlikely that BSE would cross the species barrier into humans. But with the scrapie link gone they faced the reality that we knew little about this new disease and had not clue whether it would infect humans.
JC. . The species barrier between cows and humans was unknown. We cant just cant measure it because that involved injecting humans with BSE, which clearly we couldn't do.
Moira Bruce at her lab in the Neuropathogenesis Unit in Edinburgh.. Its difficult to see however we would have that information as we could not do experiments on humans.
Narrator. .But a human experiment has been done. We have been part of a vast experiment for the last ten years.
JC.. With BSE we are looking at the emergence of a disease which may infect significant numbers of people. And I think we must work out the precise molecular nature of this infectious agent and work out how to kill it.
David Taylor.. These agents seem to disobey the basic rules of biology. It does against everything that we have been taught. PB. The infectious agent is certainly unique.
AA. . The first question that interests everybody is 'what is the nature of the infectious agent'. What is the agent that causes scrapie BSE CJD. and it has been very enigmatic. This question as to what is the infectious agent is clearly the Nobel price question, this what every body is trying to answer and there is a lot of competition.
Narrator. .They mystery of this infectious agent made it difficult to predict if BSE would be a risk to humans. But for decades before BSE had arrived, humans had been searching in vain for the agent of SE.
MB. Scientists had been working on this disease for around 50 years. Thats a very difficult disease to work with. One of the main reasons is that we are not sure what the agent is. So we dont have a direct way of identifying it.
Narrator.. Most infections are caused by bacteria or viruses, which replicate and spread disease. They can be seen under the microscope. And the way they work is well understood. For years scientists searched for a virus as the cause of SEs. But the agent that causes this disease remained invisible. It could not be seen nor even detected by any conventional method. And it had an even stranger quality. One that proved crucial to understanding its true identity.
In 1967 Professor Tikvar Alper tried to find out what would kill the agent. She took a solution of infected brain tissue and placed it in front of a source of radiation. She bombarded it with a dose large enough to destroy any virus or bacteria. IN fact large enough to destroy any infectious organism. But this lethal radiation had little effect. The mysterious agent was still active. (pictures of the radiation source and the experiment being carried out)
'The results of Dr. Tikvar Alper were so remarkable, that we tired to repeat them. And I should say that we repeated them twice with absolutely identical experimental results.' (male researcher, ?Dickinson)
DT. . The extreme resistance of the agent to all manner of inactivation procedures does tell us that they are quite unlike other conventional bacteria and viruses and that they are some novel type of living organism.
Narrator.. Scientists tried to identify this novel organism by taking a solution of infected brain material and studying it under and EM so powerful that it can magnify objects 100,000 times. Even the smalles virus can be seen using this machine. After years of scanning brain samples scientists in 1981 finally had their first glimpse of the killer. But these fibrils had millions of particles of the infectious agent. Even with this powerful EM it was still impossible to identify a tiny individual particle or to know what these fibrils were made of. The only way to identify the nature of the agent without actually seeing it was to analyse it chemically. The lab in the fore front of purifying infective brain sample was Stan Prusiners in San Francisco. In 1982 there was one scientist there who's job was to discover chemical clues about the agent.
(David Bolton sitting in a library in front of his personal research notes from the past).. When I came to SF what I wanted to look for was what was unique about a sample from a diseased brain that was not in a normal brain. What component, what molecule would be in that diseased brain that was never in the normal brain. And so I did some experiments with proteins and separated these proteins using a gel electrophoresis to separate them by their size and make little different bands on the gel. And when I did that I didn't really expect to find anything right off the bat and after one of the experiments I went into the dark room to develop the film and I was very surprised when I saw this. And I knew when I saw this gel. that this had to be it. There was a fuzzy band that was here in the gel that was in each of the 3 samples from the diseased brain, and its not in the samples from the normal brain. And this is exactly what we had been looking for. We and everybody else had been looking for some sort of key some sort of a molecule that we could say was in the diseased brain and not in the normal brain. And that really forced us to conclude that this protein was part of the agent and might be the only component of the agent.
Narrator.. In discovering this protein the lab thought they had finally cornered the elusive infective agent. The scientists called it the PrP protein but it became known as prion. But finding the prion didn't solve the mystery. It deepened it. This key molecule was not the fragment of a virus or bacteria, the normal agents of disease. It was simply a protein. And proteins cant be infectious
Weissman. . In 1982 I was in Australia at a lecture by Stan Prusiner. It was the first time I heard him speak and he was talking about his so called prion diseases scrapie in particular. And he proposed that a protein was the infectious agent. That seemed very odd and very novel. And I was not really quite sure that it could be true.
Narrator.. For a protein to be an infectious agent was a scientific heresy. Apart form water our bodies are mainly made up of proteins. They are tiny. Far smaller than the smallest virus. There are literally thousands of protein and each has a unique role. Some digest our food, some absorb our oxygen and some form our neurotransmitters in the brain that allow us to think. But proteins cant cause an infectious disease. That's because they contain no DNA, no nucleic acid, and therefore they cant replicate. Nothing on the planet replicates without NA. By dividing and forming a second copy NA provides the only mechanism by which all life multiplies. It is the nucleic acid inside every bacterium and virus that allows it to replicate and cause disease. How could this mysterious protein cause disease without any means of copying itself.
PB. . To the best of my knowledge all infectious agents require the participation of NA in order to multiply, replicate, The idea therefore that replication could occur without NA is heresy.
DB. . We could not figure out how a protein could replicate when it does not have NA.
Narrator.. This puzzled scientists for years but tantalisingly an answer had already been worked out 30 years ago. The theory had remained buried in the literature almost forgotten because at the time that it was written in 1967 it was dismissed as being too outlandish.
DB . I started thinking about this several years before when I had been doing some literature review, I had been looking at the journals in the library at a paper. I was looking at one paper at one paper on the nature of the scrapie agent. And when I went to photocopy it, there was another paper and it was by a mathematician called JS Griffiths and in this paper he talks about self-replication in scrapie which is one of these diseases. He outlines 3 ways in which a protein alone could replicate and cause disease. Now he came up with the idea that you could have two different forms of protein. One was abnormal, disease forming, a rogue protein if you will. And the other was a normal protein that was in the cell, in the brain of a normal person. And the essential part of the theory is that the abnormal form of the protein binds of the normal form and converts it to form an abnormal or disease forming protein. And now you can see that if one molecule binds to another molecule and converts it then now we have two molecules of abnormal protein and two bind to two more and have four and so on and so on until you have thousands and millions of abnormal proteins in the brain and pretty soon then you have disease. You have so much abnormal protein that it would cause disease and cause neurones to die.
The most amazing thing that the paper was published in 1967 He was a mathematician wrote this one paper. He never published anything again in scrapie. The insight was really very astounding. Someone back then with so little information could see a way that a protein could be an infectious agent.
Narrator.. What Griffiths proposed was an abstract theory. And it was completely ignored by the scientific community. But over the years clues have been found to indicate that he may have had the answer all along. In 1985 it was discovered that there were two forms of the PrP protein just as Griffiths had predicted. One was a normal protein genetically manufactured by every animal and found throughout the healthy body. Like all other proteins it seems to have some valuable function. Certainly it never caused disease but something could trigger it to mutate; to change form into a prion. This form of the protein, the prion, is identical down to the last amino-acid but abnormal. This new shape makes it so chemically stable that it resists heat and disinfectants and because it is simply a protein, without NA, it can survive huge doses of radiation, because radiation kills by destroying NA. Once in its abnormal form it seems to have the unique ability to corrupt any healthy PrP proteins that it comes into contact with and turn them into prions too. This is not replication, it is conversion.
JC.. It is a strange observation that you have these two quite different forms of the same protein with quite different properties. One of them is a killer if this protein is present in your brain. then you are in serious trouble. The other is a normal constituent of all our brains. Obviously understanding how one converts into the other and in the longer term how to stop it is a tremendous puzzle.
Narrator.. Although there are still puzzles we do know that once converted prions link together in long indestructible chains that accumulate in the brain and somehow cause the devastating holes that kill. If this theory is confirmed it will be a revolution in biology. But so far it remains unproven. So far no one has found a convincing explanation for how prions corrupt normal proteins and so the protein only hypothesis remains controversial.
AA.. The protein only hypothesis is beautiful.
DB.. I very strongly believe in the protein-only hypothesis
AA. .It is intellectually very appealing
Weissman.. I became largely convinced that largely the protein only hypothesis was true.
AA.. It should not go and mention is in its current incarnation does not explain everything
Hugh Fraser.. The idea that it is an infectious protein is an exciting and curious idea but it is one that I do not accept.
MB.. It may be that the agent is just a protein but if it is it is quite an extraordinary protein and it behaves in an extraordinary way.
JC . This has been an extremely controversial area of science. There has been a very rapid evolution of ideas. And I think that BSE has arrived on the scene in the midst of this scientific controversy and of course that has added to the complexities of making these sort of risk assessments. Narrator.. In the late 1980s while people were eating infected food. Scientists were still trying to unravel the mysteries of the infectious agent. The prion controversy had split the scientific community and this division only made the search for answers more difficult. If the prion hypothesis was right it was crucial to understand whether the cow prion in BSE could infect humans. To do meant deciphering the strange rules of the species barrier. All animals make slightly different forms of PrP protein. The more closely related the species the more similar their PrP is. The key to the species barriers between all these barriers depends on how easily the prions from one type of animals can lock onto the proteins of another and turn them into prions too. This is what determines how easily one species can infect another. But it doesnt always depend on how similar their proteins are. JC. .It really is quite an unpredictable phenomenon. By and large we tend to think that animals that are more closely related in evolutionary terms are going to be easier to transmit the disease to. But it is not always like that at all. For instance it can be extremely difficult to transmit the disease between mice and hamsters which are quite closely related. but it seems quite easy to transmit BSE from cows and mice, which are quite distantly related species. So you know there are some strange rules operating here and so the only way to find out is to do the experiment. You can just sit down and work out how easy it can go from one species to another. It is something you have to determine experimentally.
Narrator.. First of all scientists tried infecting primates who's PrP protein was close to humans. But when the marmosets and macaques died of BSE it still was not proof that humans were susceptible to BSE. These animals PrP although similar were still too different from ours to be a realistic human model. A closer primate to humans is the chimpanzee. They were never tested.
PB.. Had the experiment been done ten years ago we would have that answer today. As it is the experiment to the best of my knowledge still has not been done. It is being discussed and I'm afraid when he answer comes, which will probably be positive, it wont have any significance at all because we will already know the answer.
Narrator.. In the early 90s scientists in America decided to try to different approach to determine the rules of the species barrier on a molecular level. In the test tube.
(Kath Priola at the Rocky Mountain Labs in Montana).. Evidence from other labs have suggested that the type of PrP protein that an animal makes can determine whether that animal is susceptible to infection with an agent from a different species. So what we know is that this protein, this PrP protein is composed of a sequence of what we call amino acids that are linked in a long chain. And that the amino acid sequence of the PrP from a sheep is different from the sequence from animal such as a cow and what we are interested is determining if it is those differences between those types of PrP that can affect whether or not the species barrier is broken and infection can occur.
Narrator . Dr. Priola was intrigued by the puzzle of the species barrier between mice and hamsters. Although closely related and with similar PrP proteins, the hamster disease does not infect mice but the mouse disease dose infect the hamsters. She analysed the amino acid sequence of the mouse and hamster prion proteins and swapped single amino acids to try to discover how many of them were controlling the species barrier.
P. . Between the mouse PrP and the hamster PrP there are 16 aa differences and what we were able to do is that we can control the formation of the protein by changing just one amino acid. So one change out of 245 could be enough to allow the formation of this abnormal prion protein. If you get the formation of this abnormal protein you probably will get the disease. One of the things that this piece of work implies is that very minor changes in the PrP protein between two different species can really have a dramatic effect as to whether or not you are get formation of this abnormal protein.
Narrator. With this discovery Dr. Priola had begun to decipher in the test tube the complex rules of the species barrier. But although promising this is painstaking work. And it will be years before it can answer the key question about cows and humans. Meanwhile a new scientific technique had been developed. One which might at last indicate whether we would be susceptible to BSE Scientists had found a way to manufacture substitute human beings; Transgenic mice.
JC . Transgenic mice are mice that contain a foreign gene that has been inserted into them. And you can make these mice by taking a single cell embryo, a fertilised egg from a mouse and injecting DNA containing another gene. That can be another gene form another mouse. It can be a gene from another species. In this way it is possible to make mice that make a human prion protein. So they can now be a model for a human being. What we can do is to inject mice with BSE and see how susceptible they are to BSE and this may give us an idea of how effective the real species barrier is between cattle and humans.
Narrator.. This work has been started in 1995. But before it could be completed the human experiment produced its first results. In March 1996 the Government announced that they believed the first humans had died of mad cow disease. Science had failed to find the answer in time.
AA. . Like everyone else we were very shocked. Everybody was thinking that there might be a theoretical risk of the transmission of BSE to humans but one thing is to say there is a theoretical risk but another is to see patients dying of it. So this came as a very sobering experience to us.
DT. . I am on record as being of the opinion that BSE would not represent a risk to the human population. I accept that I may have to revise that view in light of the vCJD and of course we still have to wait to see if these are really associated with BSE.
PB . If these ten people have really died of BSE then essentially the entire population of Britain is at risk.
Narrator. In this warehouse in America. Brain samples are stored from all patients with SE. Including those from the only epidemic that we have known; kuru in Papua New Guinea. Scientists ask whether we in Britain are heading for the second epidemic and how big that epidemic might be. Tomorrow night Horizon asks who is at risk and how many may die.
Also remember http://www.evening.d emon.co.uk/gareth. Contains in the science section a good description of BSE in simple discussion.
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