As the panic over BSE builds in Europe, you might be surprised to know that we still don鈥檛 know for sure where the disease came from. Britain鈥檚 Phillips inquiry may have rubber-stamped the idea that BSE emerged spontaneously in cattle. But many scientists believe that sheep must not be ruled out of the picture. Mike Scott is one of them. And he is adamant that Britain鈥檚 plans to eradicate scrapie could backfire. Scott works with Stanley Prusiner, who won a Nobel prize for discovering that rogue proteins cause BSE-type diseases. Scott told Ehsan Masood why it鈥檚 too soon to close the book.
What makes you think that BSE came from scrapie-infected sheep?
Scrapie is pretty endemic in sheep in Britain-I believe that about 2 out of every 1000 sheep have the infection. There鈥檚 no evidence that sheep scrapie has been transmitted to humans. And we know that when people have infected cattle with sheep scrapie in experiments they get a different disease, they don鈥檛 get BSE. But this does not necessarily mean that BSE cannot exist in sheep, or in the sheep with scrapie. What really got me thinking about this was that we鈥檇 spent many years in our laboratory studying the origin of prion strains. Prions cause both scrapie and BSE and are a 鈥渞ogue鈥� variety of a normal protein that鈥檚 called PrP. There鈥檚 something very unusual about BSE. If you pass, say, a scrapie prion into another species, the structure of the prion strain will often change. But if you do the same for BSE, the BSE prion never changes. It won鈥檛 change even if you inject it into lots of different species, and back again into your original species. You鈥檒l always end up with BSE.
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Do you have any examples of prion strains that change structure when passed between species?
There are at least two examples I know of where cloned prion strains changed their properties after being transmitted to other animals. One is a mouse prion strain called Me7, which was injected into Syrian hamsters where it became a new hamster strain called Me7H-the H is for hamster. When we passed Me7 on to some transgenic mice that make an artificial PrP protein, and then into hamsters, we expected our Me7 strain to look something like Me7H. In fact we found not Me7H, but a completely different strain. We came to believe that we had actually changed the prion鈥檚 structure by passing it through the transgenic mice. There鈥檚 a similar story for prions connected with transmissible mink encephalopathy, or TME. The late Richard Marsh and his colleagues from the University of Wisconsin transmitted cloned TME prions to hamsters. When the experiment was completed, they found not one, but two strains of prions in the hamsters.
What does that tell us about the origins of the BSE prion?
I began to think about why BSE was different. And I realised that in fact, most isolates of scrapie probably comprised more than one strain. Although there would always be one dominant scrapie strain, in some cases the isolate could include a 鈥渃ryptic鈥� second strain that was BSE. In Britain, cattle were fed products made from sheep, including scrapie-infected sheep, so the sheep scrapie that was fed to cattle could include BSE as the second prion strain. When we pass sheep scrapie on to transgenic mice that have been genetically modified to express bovine PrP, we find that the sheep scrapie transmits very efficiently. In fact, it takes less time to become infective in these mice than BSE does. That means there鈥檚 no species barrier and this suggests that there鈥檚 nothing blocking the transmission of sheep scrapie prions to cattle. Because our experiments suggest that sheep scrapie has the potential to be transmitted very efficiently to cattle, this leads to the interesting possibility that the BSE strain might actually have originated in sheep, even if it was present at very low levels.
We know that rendering meat from carcasses using heat and chemicals kills off scrapie prions, but not BSE. How would this affect your theory?
John Wilesmith of the government鈥檚 Central Veterinary Laboratory in Surrey did a study where he found that changes in the method of rendering meat and bonemeal from the carcasses of cattle in the early 1980s may have activated BSE. Basically, the changes involved removing solvent extractions and reducing the temperature of the rendering process, which allowed the BSE prion to survive. I understand that this theory is being challenged now. However, whether or not there was a change in the process is immaterial to our hypothesis, because we believe that rendering inactivates most scrapie strains, but not the BSE strain.
Why?
The BSE strain is able to survive exposure to extreme heat during rendering. The other sheep scrapie strains would have been eliminated by the rendering procedure, because they were more sensitive to heat. So, irrespective of where it originated, it鈥檚 pretty clear that BSE could now be transmitted by feeding the remains of one animal to another following rendering of meat and bone meal.
So how can you prove your hypothesis?
We have to find out what happens to the structure of different prions when you simulate the rendering process-by treating prions with heat or chemicals. What we need to do is to take sheep scrapie samples and treat them at a particular temperature with a chemical known as a denaturant. This will inactivate the sheep scrapie prions, just as in rendering. If there鈥檚 any BSE left in the mixture, you should be able to identify it.
How would you tell them apart?
Proteins are long chains of amino acids. If you look at them closely, you鈥檒l see that they鈥檙e folded into a three-dimensional structure with lots of loops and folds. When you treat them with heat or chemicals, they begin to unfold and become inactive. We can find conditions where the scrapie prions unfold, but the BSE prions do not.
This experiment sounds pretty straightforward so why hasn鈥檛 it been done before?
Yes, we believe it鈥檚 a fairly simple experiment. I think people tend to assume that if BSE was in sheep, it would be a single strain. I know that the British government is screening the sheep population to see if there鈥檚 incidence of BSE in sheep. Perhaps as part of this surveillance they could try to develop a specific technique to see if scrapie-infected sheep contain BSE prions at a very low level.
The British government is also planning to eradicate scrapie by breeding sheep with the ARR gene, which is believed to confer resistance to all prion diseases. If BSE came from sheep, could this plan get rid of BSE forever?
Probably. But consider what we think caused the BSE epidemic: the rendering process inactivated sheep prions, but BSE survived. The same could happen here. If BSE is part of a mixture of two prion strains and one of them is scrapie, if you inactivate the scrapie prion, you might be left with a BSE strain (or even something worse), which is pathogenic to humans. I鈥檓 not criticising the government programme. I鈥檓 sure they have thought about this. But I think you鈥檝e got to be careful before trying to eradicate scrapie. We do know that the ARR sheep are resistant to BSE from cattle, but I鈥檓 not sure if anybody knows if they are resistant to 鈥渟heep BSE鈥�.
If the origins of BSE are so unclear, why did the Phillips inquiry conclude that the disease originated spontaneously in cows?
This is still a possibility. BSE could have arisen from a rare case of 鈥渟pontaneous鈥� BSE in cattle.
But both theories are equally plausible. Why should Phillips go for one and not the other?
The background to the other theory is similar to CJD emerging in humans spontaneously. It just happens every once in a while. In the same way, you could argue that one cow in a million spontaneously became sick with BSE and was recycled into the cattle food chain, which led to the epidemic. It鈥檚 a nice, simple theory, and it鈥檚 a possibility. But unless it was some freak event, we ought to see BSE arising spontaneously in other countries, such as the US. It should happen at some low but detectable frequency.
Is there any evidence of BSE in the US?
We鈥檝e never found BSE in cattle. And there鈥檚 never been a BSE problem in the US.
Do you think the US is BSE-free because of differences in rendering methods and cattle feed?
I don鈥檛 know of any significant differences. It鈥檚 not important to our theory, because BSE may not exist in sheep with scrapie in the US so it鈥檚 easy to explain why BSE in cattle never arose there.
The British scientist Harash Narang thinks that scrapie vaccinates sheep against BSE. What do you make of this?
I don鈥檛 really understand that theory. But we think there is a distinct possibility that the presence of scrapie in a sheep might inhibit the spread of BSE in the same animal. Researchers from Britain鈥檚 Neuropathogenesis Unit in Edinburgh showed that something similar happens with two different scrapie strains in mice.
Could that mean someone who has eaten scrapie-infected lamb might be immune to vCJD, the human form of BSE?
That I don鈥檛 understand. I don鈥檛 think we have any evidence that there鈥檚 an immune response in people who have eaten scrapie-infected lamb.
Suppose that scrapie does vaccinate humans against vCJD-or at least stop it spreading. Wouldn鈥檛 that be another reason not to clear out scrapie from the British flock?
Well, yes, presumably. But I don鈥檛 think it鈥檚 very likely. I don鈥檛 see any way in which eating sheep scrapie could ever be a good thing.
If BSE exists in sheep at a low level, do you think eating scrapie-infected lamb or mutton could be a cause of vCJD in humans?
No, that鈥檚 what is new about our theory. We think that the BSE strain is not a significant risk to humans when it is present in sheep with scrapie because there are normally other sheep scrapie strains that compete with it and prevent it from accumulating to hazardous levels. So the BSE strain would always be a very minor component, unless something unusual, such as extreme heat, caused the other strains to be inactivated and then it was transmitted to another susceptible animal, where it could accumulate to dangerous levels because the other scrapie strains that normally prevent this from happening are gone.
Do you eat British beef or lamb?
I do. I frequently go to Britain, and I have eaten beef there. Although these days I have to admit that I don鈥檛 feel so comfortable doing it. I still think that there is a finite risk, but it鈥檚 pretty low. And the same is true of lamb. Given the choice, I鈥檒l always eat Australian or New Zealand lamb, because they don鈥檛 have any scrapie there.
What鈥檚 the biggest lesson we can learn from the BSE affair?
I think the biggest lesson is that the feeding of any kind of recycled animal protein back to animals in the human food chain is just too dangerous and must cease as soon as possible.