NARRATOR (JO UNWIN): We in Britain know we may be facing a human epidemic of Mad Cow Disease. The question is: how big might the epidemic be and who of us is at risk? This is the story of the scientific search for answers. Long before BSE appeared, the human form of the disease was well-known - CJD, Creutzfeldt Jakob Disease. In 1990 the government set up a small research unit with one sole purpose - to detect the earliest signs of a human epidemic of Mad Cow Disease. They were to study every case of CJD in Britain to look for any change in the normal pattern of disease, a new variant that would reveal that BSE had crossed into humans. One member of the team had the job of examining the brains of everyone in Britain who died of CJD, looking for anything unusual. But a CJD autopsy is unlike any other a neuropathologist ever has to perform.
DR DR JAMES IRONSIDE: I've now changed into the clothes I'll wear to do an autopsy in a case of suspected CJD and these garments are disposable because they will be incinerated after the autopsy. These are the gloves, on the top is a chainmail hand piece and this is flexible and allows my hand to be protected from any cuts while the autopsy's being performed and I wear another pair of rubber gloves on top of this just to make the whole thing as waterproof as possible, and this is the helmet, I'll just put it on. The instruments that I use in the post-mortem room and the instruments the technicians use in our dedicated laboratory really we regard these as being permanently contaminated, so we use those for CJD cases alone because there's no effective way of guaranteeing decontamination in this disease and unlike other viruses and bacteria it can resist extremes of heat, cold, chemicals, enzymes, everything practically and I don't think any of us believe that we can fully decontaminate anything with this agent.
DR MARTIN ZEIDLER: I would travel throughout the whole of the country to see patients with Creutzfeldt Jakob Disease as the geographical distribution is, is completely random. We would normally be referred cases by the neurologists, or pathologists and then asked whether or not the family know the diagnosis. If they do and they're happy to see us, we will then arrange to go and see the patient normally within a few days or a week or so. Most patients with Creutzfeldt Jakob Disease by the time that I visit them are severely demented, so they're unable to communicate. They're usually mute, lying in bed, unable to move, and they have jerking movements of their limbs, what's called myoclonus. They can also not infrequently be blind and even though they can't see their brain is producing hallucinations which can make, can make them very frightened.
NARRATOR: Rob Will is the consultant neurologist. He had seen hundreds of cases of CJD over the years, but now he was looking for a change in the normal pattern of the disease, because the first signs of an epidemic of BSE in humans would show up as some new variant of CJD.
ROBERT WILL: What we know about CJD is that it nearly always affects people who are aged between about 50 and 75 and the striking thing about CJD that makes it different from other causes of dementia is that it progresses really very quickly.
WOMAN: She's a patient, 81-year-old...
ROBERT WILL: There are a number of possible things we could look for including a change in the number of cases that might be identified every year, for example looking at change in occupation to see whether the people who were in contact with cows or with BSE tissue might be more at risk and also to look at any change in the age of the patients or the other clinical features and finally to look at the neuropathology to see if that had changed in any way. Laboratory activity
NARRATOR: The brain is the key to diagnosing CJD. It is here that the infectious agent, prion protein, accumulates over many years and eventually creates microscopic holes that turn the brain to sponge. Creutzfeldt Jakob Disease has long existed in the human population. Because it's rare and strikes people at random, it is sometimes known as sporadic CJD. The classic signs of sporadic CJD are well-known. Brain slides being examined
DR JAMES IRONSIDE: Well in the typical form of CJD in older patients we find the appearance of holes which look like a sponge down the microscope. They're accompanied by accumulations of prion protein which you can see as distinct lumps or deposits. We really had no idea what we were looking for. Our mission statement if you like was to identify every case of CJD in Britain and to study the clinical and pathological features to monitor any change cases being studied
NARRATOR: For 5 years they looked at hundreds of cases of CJD, examining them for the slightest sign that a new form of the disease had emerged that could be linked to BSE.
ROBERT WILL: I felt that the risks from BSE were likely to be remote, as many other authorities commented, and I very much agreed with that, so I thought that we would probably be looking at CJD for many years without necessarily finding anything that was linked to BSE. I thought that it was extremely unlikely that the pattern of CJD would change in view of the BSE epidemic.
NARRATOR: And then one day in 1994 a young man called Stephen Churchill began to fall ill. He was 18 years old. Stephen's sister and cousin watched his slow decline, not knowing what it was that was causing his illness.
HELEN CHURCHILL: I came home more and more regularly from university and just noticed a sort of steady decline in his conversation. He stopped talking, he wasn't interested in anything, he didn't respond to anything anybody said.
KEITH WRITER: I didn't expect there was anything seriously wrong with him at all. I just thought it was just A-level blues which everybody at some stage suffers from.
HELEN CHURCHILL: One of the first things we noticed when Steve became ill was that he started hallucinating. It, it started off that he'd be watching television and he'd get very enthralled in what was going on. If there was fire on the television he'd feel as though he was burning, or if it was like an undersea, underwater scene he'd feel as though he was drowning and then it got to a stage where he was just seeing things that just weren't there, or he'd try and pick up a cup of coffee, but he'd miss, but he wouldn't realise, he'd still continue to look as though he was drinking and hadn't realised that he hadn't actually picked up the cup, and these became more and more frightening for him. He was absolutely terrified of whatever he was seeing, but he wasn't able to explain to us what had happened.
KEITH WRITER: He also had very jerky movements and he could suddenly decide to try and get up and walk when he wasn't capable of doing any kind of action which would often result in him injuring himself or falling over if there was nobody around to help him. I next actually saw Steve in February 1995 when he was in the hospital. It was a great shock to see him. He had lost a lot of weight, he was lean anyway, but with weight loss on him he looked very emaciated, he had a kind of grey pallor about him and his eyes were sunken. He looked awful.
HELEN CHURCHILL: We saw CJD and a question mark written on the notes and that was the first sign that they had maybe an idea of what it was, and obviously we didn't know anything about CJD at the time. I'm a dental student in Cardiff so I have a fair amount of medical knowledge, so I went back to University, the library and started trying to find but anything we could. I found out that it was a very strange disease, possibly linked to Churchill family scrapie and BSE and that type of thing, but I also found out it was only really found in 50, 60, 70-year-olds and although a lot of the symptoms seemed to fit the age group didn't. Steve died May 21st 1995.
ROBERT WILL: June 1995 we heard about one young patient with CJD, a teenager with CJD. This was clearly very unusual and then a few months later we heard about another case in another teenager. Now this was clearly exceptional. In December we began to be referred a number of other younger patients with CJD in their 20s and 30s and over the early months of this year in January and February we identified I think by then 8 cases of CJD in young people with a very unusual clinical presentation.
MARTIN ZEIDLER: They didn't show the typical appearances which is in the brainwave recordings that we see in sporadic Creutzfeldt Jakob Disease. This is brainwave recording from a patient with sporadic Creutzfeldt Jakob Disease and it shows the classical appearance associated with CJD. These sharp waves are occurring in all the, all across the tracing, coming from the various parts of the, the brain and they occur regularly, usually once or twice every second. However, in the new patients none of them have that classical appearance, and what we saw was just slow waves. They didn't show the typical appearances associated with the sporadic form of the disease.
DR JAMES IRONSIDE: The first time I saw the new variant of CJD was in a, a brain biopsy from a young patient and I can remember being very struck even in this very small piece of tissue the changes there were very different from anything that I'd ever seen before.
NARRATOR: The Unit had developed a computer system that could analyse brain slides and highlight all the classic features of sporadic CJD. The scattering of microscopic holes and the tiny "plaques" or lumps of prion protein that accumulate in the brain were outlined in red.
DR JAMES IRONSIDE: When we first set up the project we were anticipating that perhaps the changes would be rather subtle. However when the first new variant cases emerged the changes were so striking even on initial examination that we were overwhelmed by the differences. As well as the spongy change in the tissue there were large numbers of these plaques, these aggregates of prion protein, but it wasn't just the plaques. They had a particular shape, they were large, they were rounded and they were surrounded by a ring or a halo of spongiform change and I had never seen anything like that before. For me I think the key event was doing an autopsy in January 1996 on the same day on two young patients and when the histology of these two cases came through in February 1996 I think I realised then that undoubtedly this was something different, something new, something very disturbing and something for which we had no explanation.
MARTIN ZEIDLER: I recall one day speaking to Bob Will and really for the, for the first time I think we all had to agree that this was something unexplainable and that we couldn't just put it down to a chance occurrence.
ROBERT WILL: The timing of these cases is possibly of some importance, and the reason for that is the incubation period. If the population of the UK were exposed to the BSE agent in the mid-1980s it would not be unexpected if there were a link that cases would start to occur in the mid-1990s.
DR JAMES IRONSIDE: The striking similarity in both the clinical features and the pathology in these cases suggest that a common agent is operating and this I think points towards BSE as the most likely cause.
MARTIN ZEIDLER: I think the most likely explanation is that these cases occurred because of BSE. SEAC meeting
NARRATOR: On March 8th the Unit informed the government's scientific advisors, SEAC, that something disturbing was happening.
ROBERT WILL: We kept the Spongiform Encephalopathy Advisory Committee informed about the findings of the study and Dr Ironside and I gave a presentation to the SEAC committee on March 8th and I think that was a fairly tense occasion.
DR JAMES IRONSIDE: Obviously we were aware of the severe potential implications of the findings and while the room was darkened and I was showing the slides, the graphs, the pictures, I could hear gasps of astonishment and comments of almost disbelief coming from some of the members.
JOHN COLLINGE: I remember that SEAC meeting very well of course. It was tremendously tense as we heard about all the cases. It was something that none of us had ever seen before and really underlined what we already knew from the ages of these people that this was something quite new.
PROF. JOHN PATTISON: I think that we were (a) impressed by what Bob and James told us and (b) we were stunned by the implications of what they were telling us because they were saying there is what we went on to describe as a new variant of Creutzfeldt Jakob Disease. We couldn't help focusing on the fact that there was something new happening in the human population in the middle 1990s approximately 8 or 10 years after a new epidemic, BSE, happened in cattle. At that point I think we knew that we simply had to quite rapidly tell the Chief Medical Office and the Chief Veterinary Officer and thereby their Ministers that we had verification that there were 8 cases of what appeared to be a new variant of CJD with all the implications of BSE being a probable cause.
MINISTER: With permission, Madam Speaker, I would like to make a statement about the latest advice which the government has received from the Spongiform Encephalopathy Advisory Committee. There remains no scientific proof that BSE can be transmitted to man by beef, but the committee have concluded that the most likely explanation at present is that these cases are linked to exposure to BSE before the introduction of the specified bovine offal ban in 1989.
HELEN CHURCHILL: I was just sat at home having my lunch after I'd been to college one day and it took a while for me to realise, but there was actually somebody on television telling me that my brother had died because of something that he'd eaten and I just felt so angry and very frustrated and it was just completely out the blue. Nobody had warned us that anything was going to be said and there was an MP stood there saying that, you know, Steve had died from, from beef.
NARRATOR: The news shocked the world,. By then there were 10 cases. But still the link with BSE was unproven.
JOHN COLLINGE: Well now of course much effort is revolving around understanding whether the new variant of CJD is really caused by BSE. It seems the most likely explanation. We need to produce some direct evidence for that.
NARRATOR: Last month Professor Collinge succeeded in providing that evidence. When analysed chemically, brain samples from new variant CJD had an identical molecular signature to BSE. This was close to proof. But knowing that these people did die of BSE doesn't tell us how many more are now incubating the disease, or how large the human epidemic might be. Scientists can only hypothesise.
JOHN COLLINGE: Certainly if we are seeing one or two more new variant cases occurring every month, and I don't think we are seeing quite those numbers, but if we were seeing, seeing those numbers that might be consistent with, with an epidemic doubling time of 6 or 12 months, and that would, that would be very concerning if that were happening I think.
NARRATOR: There have been 4 more confirmed new variant cases since the announcement in March. This brings the total to 14. There are other suspected cases, but those figures are not officially released.
HELEN CHURCHILL: At the moment I think the government have to assume the worst, they have to assume that BSE is a huge problem and that they can't take the risks of people's lives. Too many people have died already.
JOHN PATTISON: One of the next questions that we must ask is: how many people in the UK population have been exposed and how many are likely to develop the disease having been exposed? That's going to be a very complex question to answer because of course beef is commonly eaten and beef products were, are popular foods, so it may be that quite a large percentage of the population were exposed to the dangerous tissues before the bans.
NARRATOR: It is notoriously difficult to predict the size of any epidemic in its early stages. For example, in the first year of BSE only 10 cows fell ill and no-one expected the huge numbers that followed. Most of the information that would allow us to predict a human epidemic simply doesn't exist, but scientists do now know the questions that urgently need answers, if we're to estimate how many of us are susceptible to BSE.
DR ADRIANO AGUZZI: The question is really what are the risk factors. Is there anything that will allow us to predict whether it's a specific person, a specific individual will develop the disease, the new disease once exposed to the BSE infectious agent, and this is a very important question. Why do we have only a dozen of cases? Is it because only very few people are susceptible to contracting the disease, or is it just the beginning of a huge epidemic?
HELEN CHURCHILL: I wonder why Steve got CJD and not me. We were still living at home when he got infected, we ate the same food. Maybe he got it at cubs or school or, but you do wonder why, why Steve and not somebody else or why not me? The chances are when Steve had whatever it was he ate that infected him that the chances are I was there too and I quite probably ate the same thing.
DR JAMES IRONSIDE: One of the main questions we have to address now is: why only this small group of patients has developed this disease. If you believe that this is BSE then potentially millions of us in Britain have been exposed to the agent in the food chain, so what is special, what is different about these people that in a way allowed them to develop the disease?
NARRATOR: ,Since March the CJD Surveillance Unit has searched every detail of the lives of the people who died of new variant CJD, looking for a common link, a reason why they got BSE.
HELEN CHURCHILL: Somebody came down with a questionnaire and asked us questions about lifestyle and eating habits, where we'd been on holidays, that sort of thing. Obviously with Stephen being 19 Mum and Dad knew exactly the medical treatments he'd had, his eating, that sort of thing, 'cos he was still living at home at that time.
NARRATOR: The one puzzling thing about all these people was their age. They were all so young to get CJD. For a while this seemed significant.
ROBERT WILL: I think that the age distribution of cases is still unexplained and I, I personally think what will happen is that if we do have more cases of this type of CJD that we will probably see cases throughout the age range with time.
NARRATOR: This is already beginning to happen. A recent victim was 51 years old. Scientists now believe that all ages may be at risk.
ROBERT WILL: We've looked for any common link between all these patients and have really found nothing.
ROBERT WILL: For example we haven't found any common geographical link or any common occupational link, and of course this is a matter of concern because it would be very much easier to understand these cases and to assess the risk if we knew some factor that linked all the patients together.
HELEN CHURCHILL: Steve was no different to anybody else. He didn't have any operations that would have put him at risk, he didn't eat anything strange, he just, he was a, he was a normal, a normal child and he was a normal 18-year-old up until he became ill.
KEITH WRITER: He did eat beefburgers, but he ate sausages, he, he ate all sorts of things, no more or no less than most other people, so completely normal in that respect. JOHN COLLINGE: It is possible that these people were just particularly unlucky and had some, some foods that were heavily contaminated with BSE, and there's really no way of working that out now.
NARRATOR: However there is something about the new variant cases that may link them together - their genetics.
ROBERT WILL: There is some evidence from CJD that people of a particular genetic make-up are particularly susceptible to CJD and that's those individuals with aparticular gene make-up at codon 29 of the PRP gene.
NARRATOR: We all inherit two copies of the gene that controls our response to prion diseases - one from our mother and one from our father. At a particular place along this gene we can either inherit a methianine or Valine amino acid. If we inherit one methionine and one valine from each parent we seem to be largely protected from prion diseases. If we inherit two valine we're more vulnerable, but if we inherit two methionines at this point we are methonine homozygote and they seem to be the people most susceptible to new variant CJD.
ROBERT WILL: The first two published cases were known to be methianine homozygots and earlier this year we began to get the results back on the other new variant cases and this established that there was a link between them and that was that they were all methionine homozygotes at codon 129 of the PRP gene. Looking at the distribution of methianine homozygocity in the United Kingdom population, it's not really all that reassuring because about 18 million people in Britain are probably methianine homozygotes.
NARRATOR: There's no point in testing the British population for methionine homozygocity because we don't yet fully understand whether our genetics can really protect us, or simply delay the onset of disease. Scientists have to assume that the whole population is at risk. To know how many of us might now be incubating BSE, we need to know how much BSE got into the human food chain over the years. There is very little data on this question.
JOHN PATTISON: Well I think we do know that the most dangerous tissues in cattle by far are the brain and spinal cord. Some of that went into mechanically recovered meat which would find its way into the rather cheaper burgers and pies and sausages, so prior to the specified bovine offals bans, because those tissues were banned in 1989, you would have expected some brain or spinal cord to be in those foodstuffs.
NARRATOR: But how much? A starting point is to establish how many cows got BSE. the official figure is 160,000. But the true scale of the BSE epidemic has only recently come to light, through the work of a team of epidemiologists in Oxford.
PROF. ROY ANDERSON: Well since BSE became notifiable in 1988, the government scientists have compiled a very extensive database on all the cases of BSE in the cattle herds in the UK. Up until very recently that database has not been available for independent analysis.
NARRATOR: For 8 years this leading team of researchers was denied access to the essential raw data. The government would not release the information.
ROY ANDERSON: Our own unit was allowed to have access to the data in April of 1996, and since that time we've completed a very extensive analysis of it.
NARRATOR: The group calculated the real statistics of the epidemic. The government only published the number of diagnosed cases, but BSE has a very long incubation period. Professor Anderson added in the cattle who were incubating the disease, but who were never diagnosed with BSE. They went to slaughter looking healthy while actually infected. When the new figures were calculated, it was quite a surprise.
ROY ANDERSON: Given that you've got 160,000 cases reported, by back calculating the numbers of infected, we can show that in essence about 1 million cattle have been infected. Abattoir activity
NARRATOR: Most of those one million cows ended up in human food, but in 1989 the government banned the most infected parts of the carcass - the brain and spinal cord. It was the cows eaten before that ban that were the most dangerous to humans because then we were still eating infected offal mixed in to beef products.
ROY ANDERSON: Prior to the offal ban in November 1989, about 440,000 infected animals would have entered the human food chain.
NARRATOR: That figure assumes that after the ban all brain and spinal cord was removed from the carcass, but we now know that didn't always happen. Recently, it was discovered that the offals ban was not properly implemented by some abattoirs and infected tissue was still getting into human food until the end of 1995.
JOHN PATTISON: We had always assumed that the ban was being fully implemented. I think we were alarmed at that point and I think the phrase we used was that we were gravely concerned. I mean it was always the sort of central pillar of the protection of public health, the removal of those tissues which you knew, or suspected, might contain the transmissible agent of BSE, so if they weren't being removed properly that was a serious problem.
ROBERT WILL: I was horrified to hear what had happened in relation to that, and of course I think it's absolutely crucial that since then there's been a great tightening up of the application of the regulations, and I think that's absolutely, really very important.
NARRATOR: Over the years several tons of infected offal may have entered the human food chain. It would be impossible to estimate how many contaminated burgers, sausages, pies and patties we ate, but anyone who ate these products was likely to have been exposed to the agent. It was therefore crucial to find out how much infected material a human being would have to eat to trigger the disease. What was the fatal dose to humans? The Ministry of Agriculture has concentrated its research on questions of animal health, but their experiments have revealed just how infective BSE really is. A £1 million study, begun in 1992, has now established the minimum fatal dose to cows. They fed varying doses of BSE to a herd of test cattle.
JOHN WILESMITH: The experiment that we've done is to take infected brain from terminal cases of BSE and feed them at varying doses, and we've gone from one gram to 100 grams.
NARRATOR: Every 6 weeks the cattle in the study were examined for early signs of BSE. Timidness, fear, anxiety. The cattle given the largest doses died early in the experiment. Scientists waited to see what would be the smallest dose to kill a cow. The results were astonishing.
JOHN WILESMITH: In our study just one gram seems to be capable of infecting a calf and that's just a quarter of a teaspoonful.
NARRATOR: A quarter of a teaspoon of BSE infected material, given only once in a cow's life can kill it. However, this tells us little about what would kill a human because we know that it usually takes a larger dose to pass infection from one species to another than it does within the same species.
ADRIANO AGUZZI: The precise amount of BSE infectivity that will provoke disease in humans, if any, is completely unknown. It's actually anybody's guess, but we, we can try to extrapolate from, from other experiments.
NARRATOR: Work in primates may provide a clue. In the 1990s macaques were injected with BSE. They died after receiving a tiny dose - 50 milligrams, one hundredth of a teaspoon. But critics of this experiment pointed out that this dose was injected straight into the brain, by far the most lethal route. Experiments in mice have shown that to trigger disease through feeding would require a dose 100,000 times larger. It would be difficult to imagine many people ate that much BSE, which seems reassuring.
JOHN COLLINGE: It's often said that injecting prions directly into the brain of an animal is about 100,000 times more effective than feeding the same dose. That's true when you're within the same species, but when you're jumping from one species to another that ratio doesn't always hold, and the oral route may be surprisingly effective.
ADRIANO AGUZZI: It would appear that in the case of BSE the difference, the relative difference between the inter- cerebral administration, the injection into the brain, and the administration through the mouth is not so huge as is the case in the mouse, and this of course is dismal news.
NARRATOR: The next question that worried scientists was whether seemingly insignificant amounts of BSE could accumulate in our bodies until they reached the fatal level.
JOHN COLLINGE: We don't know yet whether there's a cumulative dose in factor. We know in animal models that there's, there's a minimum dose that you have to give to produce the disease. We don't know yet if you divide that dose up into small portions and give it over a long period of time whether it would also be effective, and this is an important issue with respect to BSE in humans. It may be that you have to have a very large exposure to BSE over a short period of time to get the disease, it may be that small amounts over years could build up to produce the disease and we really don't know the answer to that question, but there's likely to be some cumulative element to it, simply because the infectious agent itself is so persistent in the body. It can stay there for a long period of time so it's bound to build up to some extent.
ADRIANO AGUZZI: There is unfortunately no data yet about this question, but obviously if you think that in food there might have been contamination, repeated contamination with small amounts of BSE prions this is a high priority or something that has to be answered urgently.
NARRATOR: If insignificant doses can accumulate, this could have profound implications. If minute levels of infectivity exist in the meat we think of as perfectly safe, and therefore regularly eat, they might build up and eventually trigger disease.
JOHN COLLINGE: It would certainly be nice to know whether there's any infectivity at all in tissues that we eat such as beef and muscle, whether there's any infectivity in blood, in BSE infected animals.
NARRATOR: Unfortunately the government's experiments cannot detect low levels of infectivity. In 1988 government scientists tried to find out which parts of a cow were infectious. The only way to do that was to take samples from each tissue and organ of the infected carcass, liquidise them and inject them into mice. The mice injected with brain and spinal cord succumbed to BSE very quickly, so it was clear these were the most heavily infected parts of the carcass. They were banned. But mice injected with muscle, blood, liver and kidneys didn't get ill at all. These meats were considered safe for human consumption. But to infect mice, the dose of BSE must be large enough to cross into a new species. So if parts of a cattle carcass contained levels of BSE too low to cross the species barrier into mice, they would not have been detected. If these tests had been done in cows rather than mice there would have been no species barrier to cross. Even minute amounts of BSE will trigger disease in a cow, so cattle tests are the most effective way of detecting low levels of BSE in meat. These tests were never done. They would have been more expensive but much more sensitive, and we're only just beginning to understand how much more sensitive.
JOHN WILESMITH: It was important to examine the sensitivity of the mouse test because it is known in these diseases that when one is putting tissues from one species into another that there is this species barrier, so the studies that have been set up are inoculating the same tissues into cattle as into mice. Those results are still coming forward, but we do know now that cattle are more sensitive than mice and that is of, is at least of the order of 1,000-fold difference.
NARRATOR: So it takes 1,000 times more BSE to kill a mouse than it does to kill a cow. We may have been eating minute doses of BSE in some meat that wasn't detected in the mouse tests.
JOHN COLLINGE: Well the only way to be sure there's no infectivity in these other tissues is, is to study them in calves yes because there may be levels of infection there that we simply can't detect in mice, but what we can say from the, from the mouse study is, is that, is that if there is any infectious material, for instance, in, in muscle or milk, it's of a very, very much lower order than there is in the brain and the spinal cord, at least a million-fold less.
JOHN PATTISON: What we're considering doing at the moment is to call for extra transmission experiments from cattle to cattle because that's the most sensitive way of detecting the agent of BSE. Only limited numbers of those experiments have been done to date and so we are advising that there should be more tissues from cattle put into cattle transmission studies.
NARRATOR: The cattle tests could have been done 10 years ago and we would now know the answers. If they start them now we won't have the results for years. In this test-tube there is enough purified BSE to kill 10 million cows. It's main component is a protein, the mysterious and unpredictable prion. Prions can only cause disease if they reach the brain. That's where they do the irreparable damage that leads to death. But the prion has to make a tortuous journey through the body to get from the gut to the brain.
ADRIANO AGUZZI: We do not know all the details, but what we know is that at first we have infectivity in the gut and then from the gut we find it in the spleen which is somewhere here, and then from the spleen we find it's probably in the peripheral nerves and from then on it goes into the spinal cord and then from the spinal cord is crawls all the way up to the brain and then it infects all the brain.
NARRATOR: There are many obstacles along this path through the body, so every time you eat infected food there's a chance that the prions' route will be blocked.
JOHN COLLINGE: Each time you're exposed to prions you're taking a small chance and you might be unlucky and that small dose of prions might trigger production of prions in your brain and cause the disease, and each time you're exposed you're taking an additional chance. You're filling out another lottery ticket as it were.
NARRATOR: The first obstacle for the prion protein is in the gut because here there are gastric juices specially designed to break proteins down. But we do know that there are brief moments when the gut will let a whole protein slip through into the body.
PROF. ANNE FERGUSON: When we eat a protein we have an extremely efficient digestive process that breaks the protein down into building blocks and a very efficient system for transporting these little building blocks into the tissues of our body to make our own proteins. It was known for about 30 or 40 years that perhaps one in a million, one in 10 million protein molecules escapes this breaking down process and indeed intact molecules can actually cross the lining of the gut to reach the inside of the body.
We know that there are many, many situations in which briefly or for a longer period of time the gut becomes leaky. I'll give you a few examples. The morning after drinking half a bottle of whiskey, somebody who eats some aspirin tablets, for a day or two around the time somebody has acute gastro-enteritis or food poisoning, if you get Montezuma's revenge when you've been off on holiday somewhere.
However, what's particularly interesting in terms of these prion diseases, is the other route by which proteins cross into the body because scattered throughout the bowel there are also little nodules called Peyers Patches. These are part of the immune system. In order that material from the gut is seen by the Peyers Patch cells there seems to have evolved a very special surface lining, a layer of little cells that are very good at taking material from the inside of the gut into the tissues, so proteins, but viruses, bacteria, agents that it's useful for the immune system to see, are speeded through this special surface lining and handed to the cells of the Peyers Patches.
We already know that a number of infections enter the body through the Peyers Patches, typhoid for example, in human beings. We already know that in the sheep and in the cow the Peyers Patches are almost certainly the route by which the prion agents enter the body, so if prion diseases are found to affect man via the gut then it's very likely that the route is through the Peyers Patches and diseases of the Peyers Patches might be the explanation why some people are particularly vulnerable and on the other hand, manoeuvres to protect the Peyers Patches and strengthen their function may be an important protection.
NARRATOR: The gut is only the first obstacle in the long journey the prion takes to the brain. We don't yet know what other defences the body may have along the way, or what physical characteristics would make a person more at risk. In fact, 10 years after BSE first appeared in this country, we still have too many unanswered questions.
JOHN COLLINGE: It's very hard to try and perform any sort of real risk assessment as to what, what the outcome of this might be, how many people might get infected, what sort of exposure might be a risk? We really know so little, in fact none really of the key ingredients that you'd need to know to make a risk assessment.
JOHN PATTISON: Of course it would have been helpful to have much more experimental data than we now have, but I think the situation is we haven't and we can only start from where we find ourselves now and set up those experiments anew.
HELEN CHURCHILL: I feel that the scientific research has been very slow to start. It was years and years and years before enough research had really started and with the disease being so slow to develop the research takes a long time to do. We'll get the answers in maybe 5 years' time, but by then the damage is done. The work should have been done a long time ago.
NARRATOR: Many scientists now feel the urgent need is to search for a cure, to prepare for a worst case scenario.
ROBERT WILL: There are a lot of people who are very interested in trying to find some form of cure or treatment that might prevent disease developing or progressing, and I think it's clearly a very important issue currently.
ADRIANO AGUZZI: If you want to treat the disease you need to understand how the disease proceeds and thereby you can identify ways of attacking it, of interfering with it.
JOHN COLLINGE: One approach to treatment would be to develop drugs that block the interaction of prion proteins, that block that interaction and that's something we're actively investigating. Because of the nature of work on these diseases which takes a long period of time, you know we are in a very difficult situation, a difficult race against time to have an effective treatment ready before any epidemic arose.
JOHN PATTISON: It's very difficult to predict when you will find a cure for any disease or a way of preventing any disease and that's true of CJD as it is of any other. However, I, I think one must admit that we're starting a long way back in terms of our approach to the modification of CJD as a disease and I think it would be wrong to say that anything is likely to emerge very rapidly.
DR JAMES IRONSIDE: I think it's fairly unlikely that a cure for CJD would be developed in the foreseeable future which means if we do see an enormous increase in numbers of patients in Britain there will be no prospect of specific treatment for them.
HELEN CHURCHILL: I think that we've got to assume that there could be a lot more cases. We don't know, but there could be a lot more cases of CJD in young people and because of this there's got to be some kind of plan of how these people are going to be taken care of. With Stephen we had a lot of problems finding an appropriate place and the care for him. In April '95 we started looking for a nursing home for Steve to live and obviously there, there isn't anywhere for a 19-year-old in that situation, and we wanted him to be close to his friends, we didn't want him to be in a hospice a long way away, so in the end we found what was a very nice nursing home, but it was, it was an old people's home.
People shouldn't have to go through that kind of problem at a time like that. The, I believe the government really have got to put together some kind of care package and give the opportunity for people to have their relatives looked after and be close to home, but where, where they will be looked after properly and their needs will be catered for.
JOHN PATTISON: There is no way at the moment of predicting whether these were the only people who were susceptible enough to get it, or whether in fact they are the start of a larger number of people who were exposed and are going to develop new variant CJD. The figures could have been much more alarming by now, but the fact that they are rather small doesn't mean that we're not going to have a significant epidemic, not yet.
JOHN COLLINGE: I'll be very surprised if there were no more cases of new variant CJD and that, that's true in a sense whatever's causing them because they're such an unlikely cluster of cases that, that there's clearly something going on here which has to be explained. You know I'm of the opinion that the most likely explanation for them is BSE and I think we will see more cases, but it's far, far too early to say what sort of epidemic that's going to be, whether it's just going to be 20 or 30 cases over, over several years, or whether it's going to be hundreds or potentially thousands of cases. We have to wait and see.
ROY ANDERSON: Given this long incubation period or hypothesised long incubation period, clearly if there was an epidemic of the new variant CJD it would be a number of decades probably before it reached its peak.
The BBC TV Horizon programme on BSE on 18 November, screened John Wilesmith of Central Veterinary Laboratory saying that experiments suggested that the calf assay could detect of the order of 1000th of the inoculation dose of BSE infectivity that the mouse assay could detect.
I had a long conversation with John Wilesmith on 19 November, in which it emerged that Horizon included only part of the facts.
The reported calf assay conclusion was in fact part of a long-term programme, started about seven years ago, of experiments with calves from a CVL-managed herd the "members" of which have been carefully monitored throughout the ensuing years. The experiments consisted of feeding trials with different amounts of brain tissue from BSE infected cows (briefly referred to in the early part of the Anderson et al "Oxford study", Nature, 382, 29 August 1996, bottom of page 779); and intracerebral inoculation trials.
In the latter, different amounts of brain tissue from confirmed BSE infected cows were inoculated into calves. It was from this set of experiments that it was concluded that calves succumbed to around 1000th of the dose that affected mice, as reported in the Sunday Times and on Horizon.
What Horizon did not include was the fact that parallel inoculation tests were carried out inoculating into calves lymph tissue and spleen, respectively, from confirmed BSE infected cows, and that by this calf assay, no infectivity was found in either of them after around seven years.
If any of the tissues or secretions (other than brain, spinal cord and retina) contained infectivity at levels lower than could be detected in the mouse assay, lymph tissue and spleen must be prime candidates; and the fact that infectivity has not been found in them by the more sensitive calf assay is encouraging. Nevertheless, SEAC is right to call for testing of other tissues, particularly muscle meat and milk, by the calf assay.
I was also informed that all this information was in the hands of SEAC in March 1996 and taken into account when they did their risk assessment exercise.
No indication was given about how the selected calves were known not already to be incubating BSE.