Dr Rosalind Ridley and Dr Harry Baker - scientists at the Dept of Psychology at the University of Cambridge, and authors of 'The Fatal Protein.' They are experts on prion diseases and the history of research in this area.

Could you explain the history of prions, widely believed to be the agent of BSE and vCJD?
HB: It's a kind of complex story, but it starts way back in the 60s when CJD and a rather obscure disease called kuru which affects the cannibals of Papua New Guinea, both neurodegenerative brain diseases were shown to be transmissible experimentally into animals. What this involved was taking bits of brain, injecting them into the brains of monkeys and waiting for up to 2 years before these animals got sick.

Now, this is an awful long time for a viral disease, and in any case people were unable to find viruses: using all the techniques available for identifying viruses, including denaturation studies in which you try to destroy the viruses, all those things that normally destroyed viruses didn't seem to destroy the infectious agents in these brains.

Some little while later Stanley Prousner and his team in the States were looking at the brains of infected animals, experimenting on infected animals and normal animals and trying to see what differences they were between them. And they isolated a protein from the infectious animals they called a 'proteinatious infectious material', which they contracted into the term 'prion'. It was later discovered that normal animals make prion proteins but those proteins are destroyed in the extraction process of denaturation, so it seemed as though the normal animals did not have them, whereas in the infected animals, the prion protein is not destroyed to the same extent and could be detected.

They then used the techniques of reverse genetics to find out where this prion protein was coming from - was it some kind of external agent was being expressed, say by a virus, or was it something that the animal itself was producing? They identified a piece of DNA which was producing prion protein in both the normal and infected animals, but in the case of the infected animals, the prion proteins had undergone a change in its structure, it was a different shape, and therefore this conferred on it a sort of resistance to denaturation.

Do we know how the normal prion protein is converted to the abnormal, malignant form?
RR: It took quite a while for this idea of the prion protein to be accepted because it at first sight appeared to challenge some of the most fundamental ideas about molecular biology. Of course, we're used to the idea that infections are caused by bacteria, which are large and can be seen, and viruses, which can be sometimes rather more obscure. Now, here we had a situation where we had an infection but apparently no virus, and viruses contain nucleic acid and this was just a protein. And I think people probably misunderstood in the first instance, and thought that a protein was making more copies of itself, whereas the fundamental dogma of molecular biology says that the information required to make proteins is contained in nucleic acid which then has to be converted into the production of proteins.

Of course, it later became obvious that the prion hypothesis doesn't actually challenge the fundamental laws of molecular biology at all, because the DNA that is responsible for making the protein is in the host - the animal that was infected - and indeed it's in all animals and all people. What happens is the abnormal protein directs the conversion which produces more abnormal protein from normal protein, but not from nothing, it doesn't make it itself, it still has to be made originally under the instructions of nucleic acid. It's just the conversion of its shape which is directed by the protein to another protein molecule. It wasn't as heretical as some people first thought, but it is wholly new, because it's a new way in which information can be transferred from one molecule to another without going through nucleic acid, which is the normal repository of information in biology.

HB:The mechanism by which normal form of the prion protein acts as a template for the conversion of the normal to the abnormal is not yet clearly understood. We do have quite a lot of information about this interaction and it goes back, funnily enough, to some of the human cases of CJD. There are some cases where CJD runs in families and having established that prion protein is involved in this process it did not take long before we were able to examine the prion gene in the families in which CJD was inherited. And we found mutations in that gene, they were coding for very slightly different prion proteins from the normal ones.

How easy is it for prion disease to transfer from one animal to another?
HB: There's a phenomenon which we ought to be aware of, the phenomenon of the species barrier. If you take an animal infected with prion disease and you inject some of its brain into an animal of a different species, that animal may or may not get prion disease, it may take a long time, it may take a short time. If it takes a longish time but gets the disease and then you transmit to another animal of the same species, that time gets shorter. The first transmission is known as going across the species barrier.

We know, for example, that if you have mice which carry hamster genes and you infect the mice with hamster infectious prion protein, then the animals will get sick. But a normal mouse infected with hamster prions takes an awfully long time to get sick. So we clearly know now that an infectious (abnormal) prion protein from one species will convert normal prion protein from that species much more readily than it will the prion protein from another species, where the difference might lie in small amounts of the primary structure.

What is the story of the outbreak of BSE and of vCJD in humans?
RR: What seems to have happened in the case of BSE and vCJD is that BSE started in GB some time in the early 1980s. It's origin is not entirely clear, but it certainly transmits from cow to cow via eating with considerable ease. And one of the ways in which cattle are fed is to take rendered material from a wide variety of species and make pelleted cattle cake out of it, and this was fed back to cattle and other species as well. So once there were a few animals with BSE in the country, then the uneaten remains of those would be rendered down and made into cattle cake and fed back to cattle. And because the species barrier when you are going from one animal to another animal of the same species isn't there, then transmission was very easy from cow to cow via that mechanism.

Of course, it's a very long incubation period for BSE, about 5 or 6 years, and so this process was going on very quietly in the background without any cattle actually becoming sick, because they're usually killed and eaten at an earlier time. So Britain was then hit, as it were, by a large number of infected animals and really before we knew about the existence of the disease at all a fair amount of beef and beef products had been eaten from animals which were incubating that disease. It wasn't possible to know in the first instance whether BSE would transmit across the species barrier to humans.

As far as we know, scrapie, the similar disease which occurs in sheep, does not transmit across species. But the prion protein from different animals has a very slightly different shape and depending on the compatibility between the prion protein in cows and people or sheep or experimental animals such as mice or hamsters, you will get different lengths of incubation period. In some cases the species barrier is so big that it doesn't transmit at all. Unfortunately that wasn't the case for BSE and vCJD.

What evidence is there that vCJD is caused by BSE?
RR: When I heard about the first few cases of vCJD I was very worried that people were jumping to conclusions that just because they had occurred in GB at the time of the BSE epidemic and shortly after it that we might actually be missing some other, and therefore potentially very important source of infection. So I was rather sceptical originally. But then I think a very key experiment was done that convinced me that vCJD did come from BSE.

If you take BSE from cows or from animals to which it has also been transmitted - because BSE did transmit to some cats and to some antelopes at the zoo and things like that - and you then inject those various sources of BSE into one particular strain of mouse then you get a particular pathology. If you inject material from someone with CJD or from a sheep with scrapie, you get a different pattern of pathology. So that was a key background against which the crucial experiment was done, which was to inject material from the brain of a patient with vCJD into that type of mouse, and to look at the pathology and to compare it with the cluster of those which were of BSE origin and the cluster of those which were of other origin. And it came out looking like BSE, and that was the moment that I was convinced that we didn't have to look for another source of infection for vCJD, it came from BSE in some form or another.

Is the evidence you have concrete proof of the link between BSE and vCJD?
HB: It's actually very difficult to get definitive proof - you'd have to do an experiment, you'd have to inject humans with BSE infected material from cows and prove that they got the same disease as that which we recognise now as vCJD. The problem is, when a scientist does an experiment and he's pretty certain that the outcome says something about BSE, the government then says to the scientist, 'is this the case or is this not the case'. And scientists can't say 'it is the case', what scientists would say is, 'well we think it is, with a probability of such and such'. But this isn't enough to satisfy the public, they want to know whether it's safe to eat meat or not safe.

RR: There's also a difference between doing an experiment and demonstrating an historical event, they're really very, very different things. So even if you were to inject a person with brain from a BSE infected cow and they got sick, that would prove that they got sick, but it wouldn't actually prove what happened in history. A similar problem arises with our understanding of how kuru was transmitted amongst the people of Papua New Guinea. That they contaminated each other I think is not something which anybody would argue about, precisely how they came to contaminate each other is not clear. It is believed that they were cannibals and that they ate the brains of their relatives, including their sick relatives when they had died and that they transmitted it in that way. Whether it was through the brain going through the alimentary canal or whether it was through going through cuts in the skin or holes in their teeth or something is not something that we can now prove.

HB: But it doesn't in a sense matter very much now that we can't prove conclusively that kuru was transmitted by cannibalism. What we know now is enough about the agent that we wouldn't allow cannibalism, because we would think that was a risky procedure. And even though we can't prove definitively that vCJD arose from BSE, we think the evidence is strong enough to make sure we get rid of BSE from the herd, in order to minimise the risk of vCJD.

Is BSE transferred to humans through eating infected meat?
RR: The precise route by which it got through is a problem that is actually very, very difficult to answer. People have tended to blame meat, meat products, all sorts of things, and certainly it must have come from cows in some form or other. We can be fairly sure that it's not some means of transmission, like milk, we are confident that milk is not infected. We're confident that muscle is a very, very low source of infection, so eating what is obviously a piece of meat is probably not one of the higher risk factors. We do know that brain is very infectious, and brain is incorporated into food not as much as people imagine, but it certainly is to some extent - precisely which products are responsible for causing the infection is not at all clear. People have made many assumptions about how much beef they eat and really it's not possibly to say precisely how it was transferred across.

To what extent do the experiments you have done test transmission through eating infected material rather than injected transmission?
HB: For scientific experiments, most of the transmission is done by injections directly into the brain of brain tissue from infected animals, in order to maximise the infection rate and to minimise incubation period. But as far as the BSE / vCJD story is concerned, it's unlikely that the victims of vCJD got it from brain injections. The question is, if these people are getting their disease from BSE, how is it getting in? And the obvious candidate is by the oral route, they're eating it.

Now, there have been some experiments on feeding infected material to experimental animals and it's known that the infectivity rate is much lower, by the order of perhaps 100 000 times less efficient. So relatively few experiments have been done using the oral transmission route. BSE has been transmitted orally from infected cow brain to experimental calves, and these animals have become sick after a very long incubation period and a very low rate. Transmission of disease from non-brain tissue, for example muscle meat, has not been achieved, even though muscle meat does contain nerve endings. But we must assume, we do assume, that vCJD probably arose from eating meat, and it's probably meat which has been combined with brain tissue and other tissues from peripheral nervous areas and stuff like that.

RR: The problem is where you have very, very low levels of infectivity, you would have to inject into an enormous number of animals in order to show that there was no infectivity. In fact, logically you can never do that, and of course in the BSE epidemic the recipients unfortunately were potentially 50 million people and there's no way you can do an experiment that has 50 million recipients to show that something won't happen.

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Content last updated: 17/07/2006

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