DR. ALMOND: Ladies and gentlemen, it looks like my computer has crashed. All of my slides are on my computer. So I'm going to have to ask you to bear with me for a few moments until I reboot it. I'm sorry about that.

I'm sorry. Everything was set up so I could just come up here and touch the buttons, and it's obviously crashed.

CHAIRMAN BROWN: Jeff, this is not the first time, nor will it be the last time that computer programs have disappointed the speaker. Do you think we're talking, you know, a minute or two or a more extended rebooting?

DR. ALMOND: I hope we're talking about two minutes.

CHAIRMAN BROWN: Okay. We'll just wait then.

(Whereupon, the foregoing matter went off the record at 9:37 a.m. and went back on the record at 9:43 a.m.)

CHAIRMAN BROWN: The speaker is ready. Can we reconvene after this unscheduled break?

The podium is yours, Dr. Almond.

DR. ALMOND: Okay, Mr. Chairman. Thank you very much for your patience and understanding. I'm sorry that my computer let me down at the last minute, but that's it with this new technology. It always does.

I would like to thank you for the invitation to speak to you, and I want to talk to you really about my least favorite subject. The reason I say it's my least favorite is because it has been an extremely sensitive subject, particularly in the United Kingdom where we, serving on this Spongiform Encephalopathies Advisory Committee of our government, felt obliged to raise the question simply as a question: Is there a danger, a possible danger from BSE having reentered the sheep population?

You can imagine that the farming communities were very sensitive to that question being raised even though, and I will stress at this point, there is absolutely no evidence there is any risk at all from BSE in sheep either in the U.K. or in any other country, and I want to make that position absolutely clear before I continue.

However, I feel it was important, and the committee felt it was important, to address this issue and actually to simply pose the questions and try and decide what further information was required to try and reassure ourselves that there was, indeed, no such risk.

So the SEAC Committee established a subcommittee of which I was chairman around about a year ago to look at this question, and we had meetings and several drafts of the report, and the report was eventually published, I think, in March or April of this year.

So let me take you through some of the issues that we talked about and some of the key points that I think may be relevant to your deliberations here today.

First of all, just to make the point about BSE in sheep or is it scrapie in sheep? Our previous speaker, Dr. Asher, has pointed out, and he did so in much more detail than my first sentence does here, that really there is no correlation between the geographical presence of CJD and the consumption of scrapie-infected ovine products. In other words, there's as much CJD in Australia as there is in Europe, where we have scrapie-infected sheep, and we eat a lot of sheep meat, and no difference again really statistically between Europe and Australia and the United States, where again you have scrapie, but you eat a lot less sheep meat certainly than we do in the U.K. and in England.

So there's a conclusion from that that scrapie does not pose a significant human health risk that we can detect.

But the issue really of BSE is that it may be different, and I'll come to the points later on. There is evidence from Moira Bruce and colleagues and from John Collinge and colleagues working at St. Mary's, Bruce, at Edinburgh and Collinge at St. Mary's in London, that the characteristics of the BSE agent, what I've called here the BSE strain phenotype -- and I don't want to go into the scientific basis of this because I'm sure many of you are very familiar with it, but the BSE phenotype as defined by Moira Bruce is the incubation time of BSE in a panel of mice, of different breeds of mice, and on the pathology that develops in those mice. BSE gives a distinct pattern, a distinct incubation time, and a distinct pattern of lesions, which is characteristic.

And, indeed, all of the cattle that have so far been tested give more or less exactly the same phenotype, and indeed, she's shown that the TSEs that we've observed in our country in antelope species, like kudu and oryx, also in cats, have that same BSE phenotype.

And the important thing is that in experimental transmissions to a sheep and, indeed, to a pig and, indeed, to a goat, that BSE phenotype as measured in mice was stable. So it looked like, in other words, the BSE characteristics were retained when BSE infected a sheep.

John Collinge provided similar data on some of those species in relation to glycotype in terms of its migration on gels.

So there is an issue then because of those studies that BSE may behave differently, if it was in sheep, than natural scrapie does.

Just again as background to give you what was our thinking on this SEAC Committee in relation to BSE and variant CJD, just to quickly review the evidence, the evidence as we saw it was, first of all, the space-time correlation.

New variant CJD emerged in the U.K. in 1984-85. Principally, apart from one case in France, it is a disease of the United Kingdom. The figures to date are 40 cases, with any real discernable increase in their rate of presentation, but nevertheless they are in the U.K.

They are also in this time era, that is, the time era in which we have had BSE in our country, and they are in the sort of time that you might have expected to see a new disease appearing in humans if BSE were to transmit. In other words, the first cases of new variant were seen about eight or nine years after the first cases of BSE were seen.

So the first thing linking them together then is what I call the space-time link.

The second is the work of Domenic Dormont and colleagues that one of the characteristics of new variant CJD, that of the unusual pathology of the florid plaques, the extensive plaque deposition in the cerebrum, the cerebellum, and the spinal cord is reproducible in another primate species, and that was in his case macaques where Domenic Dormont showed that that unusual pathology was reproduced quite spectacularly in that primate species.

So BSE can cause that unusual type of pathology in a primate species.

The third piece of evidence was John Collinge's which said that the glycotypes, the migration pattern of the PrP-RES was, again, indistinguishable in variant CJD and cases of BSE from cattle, cases of BSE from cats, and indeed, the macaque that I've just referred to in the previous study, and that that glycoform profile, that glycotype was different in the variant CJD cases, identical among them all, of course, but different from other sporadic CJD that we'd experienced up until then.

And then, of course, there was Moira Bruce's data, which I referred to already, but it was published in Nature about a year and a half ago, which is that the strain characteristics as defined in mice on pathology and incubation time of BSE and variant CJD are indistinguishable.

That sort of evidence says that the people who have got new variant CJD in Britain are highly likely to have got it through some contact with the BSE agent. At the present time, there is no data that I'm aware of that distinguishes the BSE agent from the new variant CJD agent. But we did not and have never concluded that, therefore, these people have got new variant CJD from eating contaminated beef or, indeed, that they've got it directly from cattle.

The obvious conclusion of saying that the BSE and the variant CJD agent are the same is, of course, to think of a causal relationship like this, that whatever caused in the first place the BSE outbreak did so, and that it's through human contact with that BSE outbreak that we've now seen the emergency of variant CJD.

But you could also, of course, have a relationship like this, that whatever was the original cause, of course, may have infected cattle and caused the BSE outbreak there and may have independently, from some unknown route, infected the humans to cause the new variant CJD, and that there may not be a line connecting these two things.

Now, that remains a formal possibility on the basis of the evidence we have. You can also think of a third possibility, which is whatever it was that caused BSE did so, that BSE has then caused another spongiform encephalopathy, and we've of course seen it in cats and kudu and oryx, and that that has caused the variant CJD, and again, you can't formally rule out this possibility.

So although we think of it like this, these other two possibilities remain formally possible, and of course, there are other possibilities that you have something like this, Cause X causing BSE, but you may also have transmission to a third species, and that, too, as well as cattle can cause new variant CJD. It's imply impossible at this stage to know where these 40 victims have become infected from.

What we do know, however, is that we did have a huge BSE epidemic in the United Kingdom. The present figures, up until this month or actually up until the end of May, just over 177,000 cases of clinical BSE, and they're still occurring at the rate of around about 250 to 300 a month in our older cattle.

That contrasts with the peak rate, which was over 4,000 cases a month, and the peak rate was actually February 1993.

This is BSE in cattle, but one of the things that I want to point out here is that the feed ban which, of course, removed the source of that BSE to a very large extent, was introduced fairly early on in this epidemic, and in fact, it was July 1988, just about 19 or 20 months after the first description, the first histopathological confirmation of BSE.

But the level of contamination of our meat and bone meal, of our animal feed at that time when it was used in this period was manifestly quite high because we had this huge epidemic. And of course, a lot of you are very aware that this represents only a small proportion of the number of infected animals. The estimates are that there were probably a million infected animals, and we ate about 800,000 of them before they had a chance to develop the BSE.

The point was that we introduced the ban in July 1988. It didn't stop the epidemic, but it certainly has been a principal factor in the cause of its decline one incubation period further on from the introduction of the ban.

I mention this ban, and I mention the extent of the contamination of the meat and bone meal that is evident from this slide because of the fact that when we think about sheep, we have to bear in mind that sheep, too, were exposed to the meat and bone meal that were so contaminated.

So if I could just look at this slide for a moment and put the issues to you: Is BSE present in U.K. sheep? I'm talking now the BSE agent with BSE characteristics.

Well, in support of the possibility, Moira Bruce and Chris Bostock's work has shown that sheep are infectable orally by BSE, by cow brain. As little as .5 of a gram of infected cow brain has transmitted BSE to sheep, where then the analysis of the spongiform encephalopathy that develops in those sheep, using the mouse panel, strain typing, shows that it does retain the BSE characteristics.

Second, my point here, which is that sheep were fed contaminated meat and bone meal up to July 1988 when that ban came in, and it's important to remember when the ban came in, it was a ban not only to stop the use of that meat and bone meal in cattle feed. It was to stop that meat and bone meal being used in ruminant feed. So it did cover sheep and goat food at that time.

But I think you're all aware that the ban was not 100 percent effective. We estimate probably 95 percent plus effective, but there was a little leakage after that date.

The other thing I should point out is that although sheep were exposed, the practice of using high concentrate feeds on sheep-to-sheep flocks and sheep farms is much, much less widespread than it was on dairy farms. Most sheep eat just grass, but there are a few high output farms which bring their lambs on very early, which do use concentrates from time to time, particularly during the winter months.

We estimate that there were several hundred thousand tons of meat and bone meal that went into sheep feed, but the proportion as compared to that that went into cattle feed was really quite small, probably of the order of five percent.

The other point to mention which supports the possibility -- and I want to put it no more than a possibility that the BSE was present in sheep -- is that scrapie does transmit readily from sheep to sheep. We know it can become endemic.

So one point that has been raised is that if BSE got into sheep from the meat and bone meal, could it be sustained there by transmission mechanisms akin to those for scrapie in sheep.

There is another point, which is the evidence to date -- and the next speaker, I think, will deal with this in more detail -- but the evidence to date from Moira Bruce and colleagues, and some of this is unpublished, and I'm unable to development it fully, but the evidence to date is that BSE in sheep, unlike BSE in cattle, is more lymphoreticular. It involves lymph nodes and spleen, more lymphyoreticular than BSE in cattle, and this sort of lends support to the notion that it may therefore more readily transmit animal to animal than BSE seems to do in cattle, where there is no evidence, no firm evidence at all, for transmission of BSE from cow to cow.

Okay. So these concerns then were in the backs of our mind when we considered the question of is or was BSE present in U.K. sheep. Arguments against that possibility were as follows.

Certainly when we consider the U.K. sheep flock today, we have to bear in mind that feeding of meat and bone meal really did stop to certainly 95 percent, and in sheep feed probably higher than that, and almost all sheep that will have received meat and bone meal in the period up to July 1988 will by now have been slaughtered.

The demographics of the sheep flocks in our country are such that most animals don't live beyond about five or six years of age, and we're talking now more than a decade since this ban. So it's highly unlikely that there are any sheep left in our country that would have been exposed to the feeds that were contaminated before this date.

Secondly, the point I've already made, that the quantity of meat and bone meal in sheep feed was much less than that in cattle actually in several ways. One was the practice was much less widespread to feed concentrates, but secondly also, sheep are a little bit more discerning in their diets, and they don't like it. So if you put the meat and bone meal in there at more than two or three percent, the sheep don't eat it.

Cattle will tolerate meat and bone meal at a higher proportion than that. So the sheep, in fact, have good noses on them, and they knew when to say no. So the amount of meat and bone meal for that reason, too, was less in sheep feed.

The other point, and this is a little bit flimsy because we don't have good evidence on this, but there is some evidence to suggest that only certain PrP genotypes in sheep would be susceptible to BSE. I say this is limited data, and it's difficult to get firm data on this when some of the genotypes that one would want to look at in the U.K. have endemic scrapie.

And the final point in the points against the possibility is that there has really been no evidence at all for a large scale epidemic in sheep of a spongiform encephalopathy, although there are some flocks which have a high incidence of scrapie like disease or scrapie. Generally speaking, throughout the country as a whole, there is no evidence of anything going on that is anywhere near approaching the scale of that that we've seen in our cattle.

But bear in mind there is endemic scrapie. The surveillance of that epidemic scrapie is rather difficult and incomplete. So there is the possibility, the faint possibility, I think, that the presence of scrapie might mask BSE if it were present in sheep. I'll come back to that point in a moment.

CHAIRMAN BROWN: Let me interrupt you for just a second because a question occurs to me that may occur to other people. In the animal or animals that were infected with BSE orally, were they in any way clinically distinguishable from scrapie infected sheep?

DR. ALMOND: That is on my next slide. So I'll deal with it in just a moment.

Before I get there, the question that was put in the context of this meeting was what about European sheep as well, and my first point is very strong: no evidence at all that there has been any BSE in European sheep, but some meat and bone meal was exported to Europe and some may have been used in high production sheep-milking flocks, although I hesitate to say this because I am aware that the vast, vast majority of meat and bone meal that was exported went into pig and poultry feed, but it's difficult to exclude.

Second, there is a recent report of an epidemic of a TSE in sheep and goats in Italy, but this is being investigated as apparently not the Type 4 pattern. So the evidence at the moment says that it's not BSE.

But we should also bear in mind that scrapie is endemic in several European countries. Surveillance is limited. So, again, you have the possibility that very small numbers of BSE affected sheep could be effectively masked by the presence of that endemic scrapie.

It's two slides ahead.

Just a few words about the levels of TSEs or scrapie in sheep in the U.K. We've decided on the committee that we need to know more about this. The data that we have are incomplete. There isn't a routine analysis of sheep that die on the farms. They're not routinely tested for spongiform change in the brain, and it's absolutely the case that in many sheep flocks, farmers accept a certain proportion of their ewes dying every year from illnesses which are poorly defined, and it's just part of the turnover of their sheep population. It may range from anything of sort of two or three up to ten percent of the ewes might die during a lambing season where there's particular stress.

Most of those cases, the vast, vast majority of those cases are never investigated, certainly not at the level of post mortem. So it's difficult to know how much endemic scrapie might be out there.

We're trying to address this question now with a postal survey which guarantees anonymity, asking farmers to be honest about observing in sheep diseases that could be TSE-like, scrapie or anything else, but that will not tell you that it's BSE.

We've also considered and, indeed, put in place the random sampling of brains of sheep from abattoirs, but there is a real issue here, and I know Linda Detwiler is here, and she may have some comments on this. There is a real difficulty about how to diagnose that.

So if you take a sheep brain from an abattoir or lymph nodes and tonsils, you can also look at the criteria for deciding whether those are definitely positive for TSE in the absence of any clinical signs in the sheep are not well defined.

What do you do if you get a positive Western and negative immunocytochemistry, for example, or a positive SAF and a negative Western? What does that mean? What if you get a positive tonsil and a negative brain or a negative brain and a negative tonsil, but you get a positive lymph node?

At the moment we don't have good criteria for allowing us to decide firmly whether a preclinical animal has definitely got a TSE. So random sampling of brains in sheep from abattoirs is a little bit tricky to interpret at the present time.

Now, bear in mind that it's difficult to get information on TSEs generally. It's even more difficult to get any information as to whether any of that, a very small proportion of it perhaps, could be BSE. There are ways of doing it. For example, you could focus on high incidence flocks and ask by glycotyping -- that's the John Collinge method -- do we see any Type 4 patterns, and that is an approach that has been suggested, but it's not yet validated. We don't know how many different glycotypes there are in the sheep population. We don't know what significance it would be if we saw something that was indistinguishable from the Type 4 glycotype that has been associated with BSE in cattle and new variant CJD.

If we saw that in a sheep at this point in time, we couldn't be certain that, therefore, it meant that sheep had BSE. It could be a different scrapie strain that happened to look similar.

The strain typing of Moira Bruce, one could make a similar criticism about it, but I think at the moment this is the test which has defined the characteristics of the BSE phenotype. So if one looked at sheep and found by the strain phenotype a BSE-like phenotype, I think that would be probably taken as a strong indication that that sheep had BSE.

However, it's important to bear in mind that this type of test is very time consuming, takes two or three years; very expensive, we estimate in the region of 20,000 pounds per sheep; and to date only nine such tests or nine sheep with scrapie have been tested by that method. All of them were scrapie. They were not BSE, but it's obviously a very small number.

Coming to the point about whether you could tell the difference between BSE and scrapie clinically, the observations on those infected animals to date, both ones which were orally infected and ones which were intracerebally inoculated, there is no good data to say that you could distinguish clinically BSE in a sheep from regular scrapie in a sheep.

But I have to say that the observation of the animals through the illness period was perhaps not as robust as one would want to make it if one was really posing that question, nor is the number of animals that have been infected been good enough yet to see any particular patterns emerging.

But at the moment, I think we would conclude that it's probably indistinguishable from scrapie clinically, certainly at the level of asking a veterinarian or a farmer to distinguish between the two.

The same is true histopathologically. There is nothing remarkable as far as I'm aware about BSE in terms of its histopathology in a sheep brain as compared with scrapie, and again, you have a range of levels of spongiform change and amyloid plaque depending on breed and so on.

So this just reinforces the point that BSE would be difficult to detect in sheep and could possibly be masked by epidemic scrapie; histologically and clinically, probably indistinguishable; and the fact that scrapie is endemic in some of our sheep flocks.

The next point, of course, to bear in mind, which again, the previous speaker alluded to, is the question, well, if you found BSE in sheep, what does it mean anyway. If you had excellent surveillance and you found a case out there in the sheep population, what would it mean?

And bear in mind that we don't know the origin of BSE for certain, but the most likely explanation for the origin of BSE was that, in fact, it came from sheep. So if you go out and look for it in sheep and you suspect that's what cause the BSE in the cattle, you might simply conclude, well, okay, there it is. It's been there for hundreds of years. It's never posed a problem when it was in the sheep, but it caused then the BSE epidemic in cattle and, of course, since then the scare and the worry and, of course, the big outbreak in cattle.

But the point I'm making is finding it in sheep could indicate one of two things. One is that you found the origin of the BSE epidemic in cattle. The second is that you found BSE which may never have been in sheep, but it's gone back there via the meat and bone meal that was fed up until July 1988.

I wouldn't like to distinguish between those two interpretations if I found a single case of BSE in sheep. So it's very difficult.

The next point is that if BSE has gone back into sheep or established itself in sheep, does it retain or will it retain all of the characteristics of the BSE phenotype, including this apparent potential to transmit to other species, including humans, and it could be that once BSE goes from sheep to sheep to sheep, it actually becomes scrapie again and, therefore, poses no risk to humans whatsoever.

So there are a lot of imponderables, a lot of unknowns in this, and even if BSE was there, you wouldn't necessarily conclude that it posed a substantial risk to the human population.

This little chart which is in, I think, the pre-read papers that were circulated just makes the point that finding a low level of BSE among scrapie would be very, very difficult. This table relates to the number of samples that would need to be strain typed using either the Moira Bruce test or a validated glycotyping. That would need to strain typed to be 95 percent certain of detecting at least one BSE case within a population of 5,000 suspected scrapie cases, and that's when the proportion of those cases that were BSE would be ten percent. You'd need to look at 29 animals, and I go back to the point that so far only nine have been looked at by the strain typing method.

If it's five percent of those, you'd need to look at 59. If it's one percent, you'd need to look at 290; 0.5 percent, 554; and 0.1 percent, you're into the thousands. Actually doing this number of sheep analyses by the classical strain typing test of Moira Bruce which, as I said, involves inoculating into several panels of mice and then analysis of the histopathology, is actually unrealistic. It's extremely expensive, demands large numbers of animals, and the time scale would be awful.

Indeed, we'd have a hard time collecting anything like this number of samples of brains from around the country from suspected scrapie cases. There certainly aren't that many out there, and even the ones that you see it, it's sometimes difficult to get them in an uncontaminated state that you'd be happy with to carry out such strain analysis.

DR. LURIE: Can I just ask a question for comparative purposes?


DR. LURIE: At its peak, what was the prevalence of BSE in British cattle?

DR. ALMOND: I can't give you a figure for the population as a whole. The size of our cattle population was around 12 million at the beginning of the BSE epidemic. It's around ten million now. So it declined during the period.

In the high incidence affected herds, there were some herds that got up to eight to ten percent, but the cohorts within those herds which were exposed, it was even higher, and there's occasionally a very high level percentage cases in particular cohorts within a herd, both cohorts I'm talking about.

But as for the population as a whole in the cattle, it was probably -- probably of the order of .5 to one percent because the average within herd incidence was around 2.5 percent. That's those herds that were affected. About 60 percent of our dairy herds were so affected, and about 15 percent of our beef suckler herds, and I think that represents about something, 35 percent of our total number of herds were affected. Average within herd incidence, 2.5. So if you divide that by three or somewhere there for the average incidence of BSE during the peak in the U.K. cattle. Okay?

This is not really relevant to the Committee, but it just illustrates the sort of difficulty that we were faced with when considering this. If you find BSE in sheep, what would you do? The answer would be it's very difficult to know what to do. An offals ban, such as we introduced in cattle, would probably not be sufficient because of the lymphoreticular nature of the spread of BSE in sheep, the much greater involvement of the spleen and the lymph nodes and the tonsils and so on.

Targeted culls would be difficult. We know that it would be difficult to distinguish BSE from scrapie. You wouldn't want to conclude that certain flocks had scrapie and that was all. So culls would be also very difficult.

And clearly, policy, if you found BSE in sheep, would be extremely difficult to recommend on. It depends how widespread it is, whether we really do perceive a risk to humans. It will also depends if it ever happens on what the current state of the variant CJD situation is.

If that begins to turn down, if the variant cases dry up over the next few years, I think we can breathe a big sigh of relief, and our concern about whether BSE has been in sheep or is in sheep will, of course, diminish substantially from that point onwards.

The SEAC Subcommittee did, of course, pose a number of questions and recommended research be done on these questions. We don't know how readily BSE transmits to sheep as compared with cattle. There are further experiments ongoing that look at the effective dose, the amount of cow brain you need for an LD50 in cattle. We don't have a good figure for that at the present time, and we certainly don't have it for sheep at all.

If sheep are, in fact, 1,000 or 100 or tenfold less infectable orally than cattle, again, that would imply that the level of meat and bone meal that they receive prior to July '88 posed a very small risk of developing BSE as compared with that of the cattle population, but at the moment we don't have a comparable figure for how readily BSE transmits to sheep versus cattle.

This has been the big question. Has it transmitted and would it be maintained there. Of course, my whole talk has been about that, and the answer is we don't know, but we think the likelihood is quite small, but it's extremely difficult to make a certain no to that question.

Is the BSE strain phenotype stable in sheep? I've raised this a few moments ago. The answer is, again, we don't know. Only passage to passage within the sheep population will allow us to address that, but that, again, may depend on the breed of sheep, the genotype of the sheep, and so on.

And how can any risk to humans from BSE in sheep versus BSE in cattle be assessed? Again, quite difficult. There are transgenic models now which might enable you to titrate into a human PrP transgene, cow brain infected with BSE versus sheep brain infected with BSE. If those transmit to the transgenic mice with different efficiency, that may allow you to draw some conclusions about what might any possible risks be if BSE was found in sheep, and indeed, the same question can be posed about whether BSE in sheep poses a risk to other species through natural transmission.

Okay. So our recommendations to our government in relation to the sheep issue, which were published in the report, as I mentioned, which was published in March-April of this year, was that we do need to improve ascertainment and diagnosis of TSEs in sheep. We do need to improve the methods and the speed of differential diagnosis which might distinguish BSE from scrapie in sheep.

We do need to identify which tissues in sheep that are experimentally infected with BSE carry infectivity, therefore, defined properly any risk tissues that may exist.

And we also eventually want to support the development of disease control programs of scrapie as well as any other TSE, with the ultimate aim of eradication of scrapie in the U.K. If scrapie was, indeed, the cause of the BSE epidemic, then it does become public enemy number one as we get rid of BSE because we sure as hell don't want another adventure in our country comparable to the BSE that we've had over the last ten to 15 years.

Another recommendation was that we need to perform a detailed clinical analysis of BSE, clinical signs and pathology in sheep in relation to our Chairman's question. There is a question of whether carrier states of TSEs exist in sheep, and we recommended that some work be initiated to investigate that possibility and then to assess what implications that might have for scrapie control.

And then as I mentioned -- well, the last point I dealt with on the previous slide.

Okay. I think I'll stop at that point, and I'm happy to answer our questions, and I'd just like to reiterate, as I did at the start, this whole talk has been about a "what if" question. There is no evidence at all that there is BSE or has been BSE in U.K. sheep or sheep from any other country, and the farming community very sensitive to the implication that it might be there.

Indeed, the fact that I raised the question at one point had me branded in the newspapers, indeed, in the Times in the U.K. as a scientific terrorist because I was suggesting that this might have happened and, therefore, the farming community would have to bear the consequence of another food scare.

I don't want to suggest that that has happened. I don't want to in any way give the impression that there is evidence that BSE is there, but I think it's fair that we raise the question and think carefully about what it would take to reassure ourselves that BSE was not there and also in the meantime to consider what best public health measures we should put in place applying the precautionary principle. What would be reasonable to put in place just to safeguard against any possible risk that might have existed?

Thank you very much.


CHAIRMAN BROWN: Thanks very much, Jeff. That was a very thorough and lucid presentation.

I have a comment, I guess, and maybe you can correct me. The more I think about scrapie, the more puzzled I am. Mainly why scrapie doesn't infect humans is just a very peculiar matter.

The question I have is that it seems to me that of all of the recommendations and experiments that you outlined, one is of overarching importance, and that is what happens to the glycotypes and the biological panel behavior on passage.

DR. ALMOND: Absolutely.

CHAIRMAN BROWN: Because on initial reintroduction into sheep, BSE already takes a scrapie phenotype, clinically and neuropathologically indistinguishable from scrapie so far as one knows, with certain limited data.


DR. ALMOND: Well, let me make several points.

First, on your first point, why doesn't scrapie transmit to humans? I don't know the answer.

CHAIRMAN BROWN: No, of course not.

DR. ALMOND: But I would just point out that BSE from what we know about it is more promiscuous in terms of its potential to transmit to other species than any known scrapie strains hitherto.

Bear in mind we've had a spongiform encephalopathy in cats, an FSE epidemic in the U.K. on top of the BSE. There was no evidence in the past that cats got TSE from scrapie. They do appear to have got a TSE during that BSE era, and the Moira Bruce analysis says that that is a strain which is indistinguishable from BSE.

The same is true of the kudu and the oryx, the ocelot, and the other species that we've seen in our zoos, the big cats, the tigers, the cheetahs. So --

CHAIRMAN BROWN: Let me interrupt, Jeff. I didn't actually ask the question. That was the background.


CHAIRMAN BROWN: The question is since on first passage to sheep BSE is essentially indistinguishable clinically and neuropathologically from scrapie, therefore the only markers that you've dealt with that you've got at transmission that is, in fact, BSE is the glycotype and the mouse panel --

DR. ALMOND: Correct, correct.

CHAIRMAN BROWN: -- if they disappear --

DR. ALMOND: Correct.

CHAIRMAN BROWN: -- on passage, you might as well fold up your tent because you'll never find out whether BSE is present in sheep at the present point or not. So there's really nothing to do because there's nothing to detect.

DR. ALMOND: Absolutely, and those experiments are, of course, in progress. They are difficult in that you know the example in mice. If you pass BSE in VM mice, you get a change in the phenotype in the Moira Bruce type analysis of BSE, whereas if you passage BSE in these other species that I just referred to, you apparently do not.

There is, therefore, the possibility that passing BSE through different genotypes of sheep may affect those profiles differently. So it's difficult to prove that the BSE phenotype is never stable on sheep-to-sheep passage. So it's very difficult.

But I take your point absolutely. The only markers that we've got of BSE in sheep is BSE, as opposed to scrapie, is the Moira Bruce type test, but then that's the only marker that we've got -- and the glycoform as well, of course -- that has been the only marker we've had in relation to these other species, including humans and new variant CJD.

It's been on the basis of the Moira Bruce type strain analysis and the glycoforms that we've concluded the strains are indistinguishable.

CHAIRMAN BROWN: Yes, we have -- who was first? Let me ask Linda because I rarely look over at this side of the table. Linda.

DR. DETWILER: I just wanted to add a comment about scrapie as far as phenotypes. I don't even know if you can define scrapie as a typical phenotype because there's such a variation in clinical presentation, and I think we've had to broaden our definition to capture more, and we've seen even almost a movement some, even within the Suffolks breed, from an intense itching to hardly that sign, and see, owners wouldn't report it if they didn't itch, to more of the motor, the incoordination and the motor signs.

And histologically we've even observed in different breeds different patterns where if you used a certain criteria, that we found that it was difficult to diagnose in other breeds. With the inclusion of PrP-RES detection, we've been able to capture those now. So that's just my addition on scrapie.

But I had one comment on Europe. I guess that I would add for Europe per say is that I totally agree with you that there's been no evidence of a case of BSE in sheep, but I think in all fairness and not to have this total false sense of security, the continent is behind in the U.K. in detection and looking and into discern it's scrapie or BSE and even some of the practices and the enforcement of controls with the feed bans to they're not where the U.K. is.


DR. ROOS: I wondered whether you could comment on surveillance of scrapie in U.K. because one might at least at first glance wonder whether there might be an increased incidence of scrapie if, in fact, it was related to contamination of feed or are animals slaughtered before you might see the clinical disease, which might make that not as informative as one might hope.

DR. ALMOND: I think people within the Ministry of Agriculture accept that the data we have on scrapie is poor. It's incomplete. The reasons we say that is that scrapie sort of bumps along. It's a few hundred cases per year. Then something happens like there is a collection effort where we pay or the ministry paid for brains to be used in a rendering experiment, and suddenly the number of declared cases of scrapie shoots up. It doubles sort of overnight because the farmers can get something for their dead sheep.

Then scrapie becomes notifiable because we decide it's important to know which of the flocks that have this disease, and the incidence plummets, goes down to half of what it had been before or even less.

So it's difficult to know what's going on. Hence, the need for increased surveillance, and as I said, we're doing it through abattoir survey, with all of the difficulty that that poses. Linda may comment again on this. It's not easy to make a firm diagnosis.

Well, it is easy to make a firm diagnosis where everything's positive, but when you get mixtures of positives and negatives, what does it mean?

And the postal survey, we believe, is a good way forward because it asks farmers to be honest. We know that not all of them will be. It makes it anonymous so that they're not going to get their knuckles rapped if they hide things, and it puts it to them that this is actually for the good of their industry to help us with scrapie eradication and surveillance so that, you know, they really should play ball.

And we can do estimates on the proportion of farmers that really do play ball and report honestly by sort of follow-up questionnaires and so on. So the postal survey, I don't know if it's yet got started, but there has been a pilot survey and the main survey will go ahead, and I think that will probably be the best way of giving us some data, but it won't be hugely reliable.

Over the BSE era, it's difficult to know whether there's anything been going on. There are a few flocks which have been really quite high incidence, up to ten percent of the animals dying of scrapie each year, and some of those had meat and bone meal. Some of them became high incidence flocks during the BSE era, but, again, it's difficult to conclude that they are BSE as opposed to scrapie.

One or two of the sheep from such flocks were included in the nine that were looked at, and they were not BSE by the Moira Bruce type strain typing analysis.

CHAIRMAN BROWN: Larry, you had a question.

I may interrupt momentarily because we have Richard Race not quite on the phone, but when he comes on the phone, we'll stop things.


DR. SCHONBERGER: Jeff, a great talk, and I just wondered if you could clarify the issue of is not the leading hypothesis for the origin of BSE in cattle the presence of scrapie in sheep, and if so, why would you be charged with scientific terror to do what you've done in looking for BSE agent in sheep?

And second, your talk started with saying, I thought, that 0.5 infectious gram of brain of cattle when orally given to sheep led to the sheep coming down, but then you said you weren't sure about the sensitivity of sheep --

DR. ALMOND: Versus cattle.

DR. SCHONBERGER: -- to -- versus cattle. Does that means that cattle are even much more sensitive than 0.5 grams?

DR. ALMOND: Yes. I perhaps should have put some more scientific background in slides.

The attack rate study, which was carried out by the Ministry of Agriculture attempted several years ago to estimate an LD50 for cattle via the oral route, and cattle were given 300 grams, 100 grams, ten grams, and one gram, ten cattle in each group.

All of those cattle seven years later became infected. So the experiment failed to define the LD50, but it's clearly less than a gram for cattle.

A new experiment is in progress which goes down, I think, to .1 of a milligram, but it will be several years before we have an outcome to that experiment. So it will be several years before we know what the LD50 is for cattle. That's cow brain infecting cattle via the oral route.

You would want to do the same experiment in sheep to make the comparison, and all we have in sheep at the moment is that the Bruce and colleagues experiments, which were published in Veterinary Record, 1st of June 1996, was that one out of three animals that were fed 0.5 grams of infected cow brain came down with disease.

Since that time other animals have been infected orally, but they've received five grams. So they've received more. So they don't help in relation to defining what the oral LD50 is for sheep that are fed cow brain. So that's where we are.

CHAIRMAN BROWN: Thank you very much.

We now have the next speaker on the speaker phone, and that is Dr. Richard Race, who I imagine is talking to us from the Rocky Mountain Lab, is he not?

DR. RACE: Right.

CHAIRMAN BROWN: And he's going to tell us a little bit about tissue infectivity in scrapie infected sheep and goats.

Dr. Race, welcome.