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SEAC Draft minutes of the open session of the 89th meeting

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Sep 3, 2005
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Subject: SEAC Draft minutes of the open session of the 89th meeting held on 22nd
Date: November 18, 2005 at 9:54 am PST

90th meeting on Thursday 24th November 2005


Item No
Paper No.

SEAC Chair and Secretary

Approval of draft open minutes from SEAC 89
SEAC Chair
90/1 (167 KB)

Current issues
SEAC Chair

CJD Update
Prof J Ironside (NCJDSU)
90/2* (21 KB)

SEAC Epidemiology Subgroup update
Prof G Medley (Subgroup Chair)
90/3* (30 KB)

BARB case clusters
Prof J Wilesmith (Defra)

Slate paper
SEAC Chair

Horizon scanning
SEAC Assessors

Public Q&A
SEAC Chair

SEAC Chair


* The contents of SEAC 90/2 and Annex 1 and 2 of SEAC 90/3 have not been circulated outside the committee as these documents contain prepublication reports and opinions provided in confidence.

On the afternoon of Thursday 24th November SEAC will consider unpublished data on vCJD infectivity in blood and unpublished research in animal models examining human to human transmission of vCJD and the correlation between abnormal prion protein concentrations and TSE infectivity. This part of the meeting will be held in closed session to allow discussion of this unpublished scientific information. This is in accordance with SEAC's code of practice.



©SEAC 2005


Draft minutes of the open session of the 89th meeting held on 22nd

September 2005

Church House

Dean’s Yard




Members: Professor C. Higgins (Chair)

Dr. D. Brown

Professor N. Hooper

Mr. P. Jinman (Deputy Chair)

Professor C. Lasmézas

Professor J. Manson

Ms. D. McCrea

Professor G. Medley

Dr. P. Rudge

Assessors: Mr. A. Harvey (FSA)

Mrs. E. Lawrence (DH)

DA Assessors: Dr. M. Simmons (NAW)

Technical Advisors: Dr. P. Barrowman (Defra)

Dr. S. Dixon (FSA)

Dr. D. Matthews (VLA)

Dr. J. Stephenson (DH)

Professor J. Wilesmith (Defra)

SEAC Secretary: Miss K. Richards

Secretariat: Dr. T. Barlow

Dr. N. Ebenezer

Dr. P. Keep

Dr. V. Lund

Dr. C. Ravirajan


©SEAC 2005

Also in attendance: Mr. P. Burke (Defra) and

Mr. P. Holley (FSA) for item 4.

Professor A. Colchester (University of Kent) for

item 5.


©SEAC 2005


1. The Chair welcomed everyone to the 89th meeting of SEAC.

2. The SEAC Secretary explained to members of the public that it

was the committee’s policy to conduct as much of its business as

possible in open session. Holding open meetings allowed the

public an opportunity to observe the committee at work and

provided an insight into how an advisory committee provides

independent scientific advice to Government. External experts

and researchers involved in the studies that the committee will be

considering are present. During the meeting the Chair may invite

them to the committee table to present their work. Government

officials are also present as members of the audience. As these

officials are responsible for TSE policy in the various government

departments they may also be invited to contribute to


3. The committee will also hold a reserved session in the afternoon

to allow discussion of unpublished research on BSE in sheep and

to be updated on current research at the Veterinary Laboratories

Agency (VLA). This is in accordance with the SEAC Code of


4. Apologies for absence had been received from Professor

Margaret Stanley and Dr Jacky Chambers. Mr John Bassett

would attend the afternoon session. Members were reminded

that they are obliged to declare any commercial or other interests

they may have in the agenda items. The next meeting would be

held on Thursday 24th November 2005 at the Roxburghe Hotel,


5. The Chair announced that following a recruitment exercise

Professor James Nicoll has joined SEAC to replace Professor

Ironside. Professor Nicoll is Professor of Neuropathology at the

University of Southampton and Consultant Neuropathologist at

Southampton General Hospital and an expert in the field of

neurodegeneration with considerable experience of clinical

neuropathology. Unfortunately Professor Nicoll could not attend

this meeting but will attend the November SEAC meeting.


©SEAC 2005



6. The minutes of the open session of the 30th June 2005 meeting

were agreed as a correct record subject to the following


• paragraph 9, ninth bullet point, line 5, change ”…relied…” to

read “…relies…”,

• paragraph 11, line 6 change “…live diagnostic test for

BSE,…” to “…diagnostic test for BSE in live animals…”

• paragraph 18, line 3 should read “Seprion Western blot test”

lines 5, 7, and 12 change “Prep-specific” to “PrP-specific”

• paragraph 21, line 2 change “…Byroad Platelet …” to

“…BioRad Platelia…”

• paragraph 27, line 4 change “…differential diagnosis…” to

“…definitive diagnosis…”

• paragraph 33, first bullet point, line 6 change “…number of

conditions…” to “…number of clinical conditions…”

• paragraph 65, line 2 change “…genotyping should be

combined if possible…” to “…genotyping data should be

combined if possible for statistical analysis…”

• paragraph 74, line 2 change “…confuse PrPSc with

infectivity…” to “…confuse the amount of PrPSc protein with

levels of infectivity…”


7. The committee was updated on the following issues:

• The Chair will meet the Executive Director of the European

Food Safety Authority (EFSA) at the end of September 2005.

The aim of the meeting is to develop a closer working

relationship between SEAC and EFSA.

• The current DH consultation on draft regulations is in

preparation for full implementation of the Human Tissue Act

(2004). The Chair proposed that SEAC should respond

formally to the consultation in relation to any potential

restrictions to TSE research from implementation of the draft

regulations. The SEAC Secretary had sought the views of

Professor James Ironside (NCJDSU), a past member of

SEAC. Professor Ironside responded that the draft regulations

restricted the use of organs, tissues, microscope slides and

blocks of tissue, collected after 1 April 2006, from hospital

autopsies for research or review without the consent of


©SEAC 2005

relatives or a nominated individual. This may be problematic

for retrospective review of autopsy material for public health

purposes. It was agreed that SEAC would make a formal

response to the consultation in relation to TSE research. The

Secretariat would circulate a draft letter in response to the

consultation along the lines suggested by Professor Ironside

to members for comment.

• The Over Thirty Months Rule would be replaced by a BSE

testing regime, expected to take effect from 7 November 2005.

• A Medical Research Council proposal to monitor the clinical

effect of vCJD treatment with pentosan polysulphate had

recently received ethical approval.

• The Cabinet Office Public Appointments Unit’s newsletter aims

to stimulate interest in public bodies such as SEAC. The Chair

encouraged members to contribute to a possible future feature

on the work of the committee by making themselves available

for interview.

• Following advice from the CJD Incidents Panel (CJDIP), DH

announced, on 20th July 2005, an extension of precautionary

measures to reduce the risk of vCJD transmission through

blood transfusion and surgical procedures. DH had notified

around 100 people, who had donated blood to three people

who later developed vCJD, that they may have a greater

chance of being infected with vCJD compared with the general

population. These people had been asked not to donate more

blood or organs and to inform their medical practitioners

before undergoing dental or surgical treatment. This

notification procedure had gone smoothly. DH is awaiting the

outcome of a CJDIP review of the risk to other recipients

(about 1000) of blood from these donors.

• A TSE Joint Funders Group workshop on the research

potential for TSE diagnostic tests in live animals including

humans will be held on 13-14th December 2005. The Chair

will attend and invited members to suggest other suitable

attendees, especially from outside the TSE research

community that might contribute to discussion about

developing tests.

• Following the discussion at SEAC 88 on atypical cases of

scrapie and possible implications for the National Scrapie Plan

(NSP), the Chair wrote to Defra about the SEAC consideration


©SEAC 2005

of this issue. The Chair will meet Defra policy officials and

Veterinary Laboratories Agency (VLA) researchers in early

November to discuss further research in this area. SEAC or

its Sheep Subgroup will consider this issue further in the near

future. An EFSA opinion on atypical scrapie is expected in

mid-November 2005.

• A pre-publication copy of a paper1 that suggests that

evolutionary selection pressures may have maintained

variation in the prion protein gene in sheep was circulated to

members by email on 21 September 2005. Since the findings

had potential implications for the NSP, members were invited

to send comments to the Secretariat. Two independent

experts would also be invited to comment. SEAC or its sheep

subgroup will be asked to consider the paper in the future.

• A report2 of preliminary findings of natural transmission of BSE

between sheep in an experimental flock had been circulated to

committee members. The committee considered it important

to note that, to date, there has been no finding of naturally

occurring BSE in surveillance of the national sheep flock. This

research would be discussed further in the reserved business


• A report3 describing the use of an automated protein

misfolding cyclic amplification (PMCA) technique to increase

the amount of abnormal prion protein in the blood of scrapie

affected hamsters to a detectable level was considered. After

PMCA, PrPSc had been detected in the blood of 16 out of 18

hamsters showing clinical signs of scrapie. A member

commented that while the method did not appear to give false

positives (PrPSc was not detected in the blood of any of the

non-infected animals) it would be important to examine why

PrPSc was not detected in two of the affected animals since

false negative results would invalidate it as a screening test. It

was noted that the authors suggested that, in these two

samples, PrPSc may not have been sufficiently amplified. It

was noted that the amplification phase of the test in the paper

took several days to complete and the detection was by

Western blot, a relatively insensitive detection method. The

authors had suggested that to develop the test further, the

1 Slate (in press) Molecular evolution of the sheep prion gene.

2 Bellworthy et al. (2005) Natural transmission of BSE between sheep within an experimental

flock. Vet. Rec. 157:206.

3 Castilla et al. (2005) Detection of prions in blood. Nature Medicine published online



©SEAC 2005

time taken for amplification could be shortened, and a more

sensitive detection method used. The member considered it

important to see if the method could detect PrPSc in the blood

of pre-symptomatic animals. In addition, it would be important

to verify that other laboratories could reproduce these results

since some laboratories had reported unsuccessful attempts

at repeating a version of the PMCA technique in the past. A

member noted that laboratories in Italy and Germany had now

successfully used the technique but with fewer rounds of

amplification. It was also noted that the amplification step

required normal brain tissue from the same species, which

may hinder its use to screen human samples. Members

concluded that this sensitive technique was potentially

applicable to detection of abnormal prion protein in the blood

of live animals or humans in preclinical stages of infection.

However, it would require significant further development and

evaluation before it could be used routinely. SEAC

recommended that the method be considered at the TSE Joint

Funders workshop on diagnostic test development.

• A very short report4 and a full report5 about the detection of

abnormal prion protein and infectivity, respectively, in some

tissues of the peripheral and central nervous systems (PNS

and CNS) of BSE cases were circulated. It was noted that the

findings could potentially have implications for specified risk

materials (SRM) controls. The committee noted that the

findings from each study were in single animals at the clinical

stage of disease, and that the level of infectivity detected in

PNS tissue was considerably lower than in CNS tissue. The

issue would be discussed in more detail with unpublished data

in the reserved business session.


8. The Chair informed the committee that Defra and FSA have

asked SEAC to consider the European Commission TSE

Roadmap, published on 15 July 2005.

9. Mr Patrick Burke (Defra) explained the background to the request

and summarised the seven strategic goals outlined in the

Roadmap. The Roadmap envisages amendments to EU TSE

4 Iwamaru et al. (2005) PrPSc distribution of a natural case of bovine spongiform

encephalopathy. In Prions. Food and Drug Safety. Springer-Verlag, Tokyo, 2005.

5 Buschmann & Groschup (2005) Highly Bovine Spongiform Encephalopathy-sensitive

transgenic mice confirm the essential restriction of infectivity to the nervous system in

clinically disease cattle. J. Infect. Dis. 192, 934-942.


©SEAC 2005

controls in light of the decline of BSE in Europe, taking into

account new scientific evidence while continuing the aims of

eradicating BSE and maintaining a high level of consumer

protection. FSA and Defra are preparing for EU discussions on

translating the Roadmap proposals into amendments to

legislation. To inform these discussions, Defra and FSA asked

the committee to consider whether the Commission has identified

all of the risk issues that need to be taken into account. The

committee was not asked to consider the age limit for removal of

vertebral column since it considered this in detail at SEAC 85. It

is intended that Defra and FSA will seek further, more detailed

advice from SEAC in the future on specific proposals as they

develop. While the Roadmap foresees changes to risk

management measures, SEAC was asked to focus on whether

any risk assessment issues have been omitted and whether

additional scientific evidence is likely to be needed in support of

changes to legislation.

10. The committee considered the strategic goals in turn.

Strategic goals for the short- and medium-term (2005 – 2009)

Specified risk material

11. The committee recommended that, since removal of SRM is a

primary TSE-related public health protection measure,

amendments to SRM controls should only be reviewed in light of

emerging scientific findings on the distribution of TSE infectivity.

Measures must maintain the current high level of consumer


Feed ban

12. Members noted that appropriate feed controls are fundamental to

prevent recycling of potentially infectious material in animal feed

and re-emergence of a BSE epidemic. Any potential changes to

feed controls should therefore be considered very carefully.

Members suggested consideration should be given to

assessment of the risks associated with the use of fishmeal in

animal feed as it was unclear whether fish material would be

sufficiently contaminated with BSE to present a risk. Since there

is a great deal of movement of substances used in animal feed

both within and into the EU, potential risks could arise from

contaminated materials used in animal feed imported from

outside the EU. This might also be an area that required further

examination and risk assessment.


©SEAC 2005

13. Members asked why animal feed contamination with bone

fragments had been considered only in relation to beet pulp and

not other root vegetables. It was explained that this was because

beet was processed and used in the manufacture of animal feed.

In contrast, other root vegetables were used, unprocessed, at a

local level.

14. The committee was concerned that beet pulp should not be

considered different from other root vegetables without supporting

data. The committee considered it important to examine carefully

all the constituents of animal feed, the sources of those materials,

and then assess the potential TSE risks.

Monitoring programmes

15. The committee considered that appropriate surveillance is

essential to monitor the potential impact of other changes to

control measures. A member pointed out that measuring the cost

of surveillance in terms of the number of positive cases detected

did not reflect the importance of surveillance, and the cost might

best be expressed in terms of the number of negative cases

detected. It was considered that effective surveillance to

ascertain infection prevalence was very important as a public

health protection measure and an effective system should be


Categorisation of countries according to BSE risk

16. The committee considered that, both within and outside the EU,

BSE surveillance regimes should be adequate in terms of

numbers of animals tested and testing procedures used to

evaluate the relative BSE risk between countries.

Review of culling policy with regard to TSEs in small ruminants

17. Members noted that culling could partly be driven by surveillance,

but because of the widespread distribution of infectivity in small

ruminants, culling could also be a consumer protection measure.

One key consideration in the assessment of future culling policy

appeared to be how often in the past other cases of the disease

had been identified in the same flock through culling.

18. It was noted that whole flock culling may adversely affect the

reporting of cases. The committee commented that, if maternal

or intra-flock transmission was found to be significant in sheep,


©SEAC 2005

this might impact on an assessment of culling as a risk reduction


Cohort culling in bovine animals

19. The committee considered that it was important to determine the

effectiveness of culling as a risk reduction measure and to

consider whether culling a cohort (whether defined by feed or by

birth) remained a proportionate response to risk in light of the

declining BSE epidemic.

UK restrictions

20. The committee agreed that, as the numbers of BSE cases in GB

have declined to similar levels found in the rest of Europe, this

was a logical step. In response to a question about the report of

the recent FVO mission to the UK, Mr Burke informed the

committee that the report was likely to be published soon. Its

conclusions were likely to be broadly favourable to the UK.

Strategic goal for the long term (2009-2014)

To modify measures in line with current technology and new evolving

scientific knowledge

21. The committee agreed that it would be appropriate for SEAC, in

the future, to look at the risks associated with modifying

measures such as SRM rules, in the light of new scientific


22. Members reiterated the view that it would be important to

maintain effective surveillance to ascertain infection prevalence

and to monitor the effect of changes to control measures. An

appropriate level of surveillance of chronic wasting disease

should be maintained in Europe.

23. Professor John Wilesmith (Defra) commented that, in deciding

upon appropriate surveillance measures, it was necessary to

decide upon the reason for the surveillance. Reasons include

preventing diseased animals going into the food chain, to inform

about the epidemiology of disease, or to detect the effectiveness

of control measures.

24. Members suggested that, as a further strategic goal, surveillance

programmes should be capable of monitoring potential changes

to TSE prevalence, and new TSEs or other similar diseases.


©SEAC 2005

There should also be mechanisms in place to deal with any

changes detected.

25. In conclusion, SEAC welcomed the Roadmap and made three

further general recommendations:

• changes to legislation in any one of the strategic areas might

impact on other areas, therefore no single strategic area

should be considered in isolation;

• there should be a watching brief on emerging science that

may impact on any of the measures under consideration.

• in the event of any changes to TSE legislation it would be

important to communicate effectively to consumers the

reasons for change.


26. The Chair introduced a paper by Colchester & Colchester

(Lancet, 2nd September 2005)6 presenting a hypothesis that BSE

was originally derived from a human TSE. The hypothesis

suggested that, in the 1960s and 1970s, mammalian bone and

carcass material used in animal feed was imported into the UK

from the Indian sub-continent, particularly the area around the

Ganges, and contained remains from humans infected with CJD.

27. The Chair explained that he and Mr Peter Jinman (Deputy Chair)

had met with Professor Colchester (University of Kent) and Defra

policy officials to discuss the paper prior to publication. The Chair

thanked Professor Colchester for his willingness to discuss his

hypothesis and for the professional manner in which the

hypothesis was raised and presented, allowing a careful review of

the issue. He thanked Professor Colchester for attending the

SEAC meeting. The committee was asked to comment on the

plausibility of the hypothesis and the areas of research to test the

hypothesis suggested in the paper.

28. The Chair noted that from the discussions with Professor

Colchester and Defra policy officials it was entirely possible that

in the 1960s and 1970s animal feed from the Indian sub-continent

was contaminated with human remains. Although this could not

be proved unequivocally, there was good indirect evidence to

suggest that this may have occurred, and that this was a

6 Colchester and Colchester (2005). The origin of bovine spongiform encephalopathy: the

human prion disease hypothesis. Lancet. 366, 856-61.


©SEAC 2005

plausible route of infection. However, the question remains, how

likely is this route of infection? The committee should consider the

likelihood of whether a human TSE jumped the species barrier to

infect cattle, and the relative amount of such contaminated

material which might have been fed to cattle compared with the

amount of animal (sheep and cattle) carcasses which had been

used in cattle feed, and the biochemical evidence for

similarities/differences between human TSEs and BSE.

29. Members suggested that since prion infections are known to alter

their properties to adapt to new host species, it might be

impossible to establish the origin of BSE from the biochemical

characteristics of prion strains. Currently it is not possible to

predict the ability or likelihood of prion infections to cross species

barriers based on a comparison of the biochemical properties of

prion protein strains in two different species.

30. Dr Mike Simmons (National Assembly of Wales) asked whether it

was more likely that BSE was originally derived from a scrapie

strain or a human TSE. Members noted the possible origin of

BSE from scrapie had been investigated very carefully but it had

not been possible to determine whether or not BSE was originally

derived from a scrapie strain. Dr Danny Matthews (VLA) noted

that when sheep are infected with BSE by the oral route, on

second passage in sheep no reduction in incubation period was

observed. Therefore, it would appear that there is no significant

species barrier for BSE infection from cattle to susceptible sheep.

It was possible that there is also no species barrier for BSE

transmission from sheep to cattle, but this was not known. It was

also possible that BSE may have existed in sheep in the past but

had not been detected. Members noted that, although BSE was

known to be biochemically different from known scrapie strains, it

was also different from sCJD and other prion strains. It was

therefore not possible to establish biochemically whether BSE

originated from CJD, scrapie or other known prion strains.

31. Members noted that, although little information was available on

the relative amounts of human remains that could have

contaminated animal feed in the past, in all probability only a

small amount of human remains could reasonably have entered

feed. In comparison, the quantities of animal remains that

entered animal feed would have been very much larger.

Furthermore, although the size of the species barrier between

cattle and humans was unknown, it was likely that some barrier

existed. Taking both of these factors into account it seemed


©SEAC 2005

much more likely that the BSE epidemic originated from a

disease in cattle or sheep rather than in humans.

32. A member pointed out that bone material from the Indian subcontinent

was also exported to other countries, for example,

Australia, yet this had not caused an outbreak of BSE in these

countries. A member asked if this material was fed to cattle in

India and, if so, why there was not a similar epidemic of BSE in

that country. Professor Colchester responded that, as cattle feed

was prepared and used on a local level, isolated cases of BSE

might have occurred but such localised use would not result in an

epidemic. Since there was no rigorous surveillance of BSE in

cattle in India, isolated cases would not be detected. Dr

Matthews informed the committee that, although there is a

rendering industry in India, meat and bone meal would be fed

mainly to poultry and pigs, but not cattle for religious reasons.

33. Members noted that Professor Colchester’s work had highlighted

the complex nature of production and movement of meat and

bone meal and also the possibility of contamination of feed with

human remains. Mr Burke explained that, although animal byproducts

from India were imported into the UK in the past and

may have been contaminated with human remains, control

measures implemented across the EU would now prevent the

importation of such material for either feed or fertiliser. There are

no EU approved rendering plants in India permitted to produce

meat and bone meal for use in fertiliser in the EU. Professor

Colchester asked for clarification about the controls on exports of

such materials from India to the EU as well as about controls on

imports reaching the UK. Mr Burke explained that exports to the

EU were checked at border inspection posts, but the controls are

rather complex and it would be better if Professor Colchester had

a copy of his report. The Chair said this would be helpful.

34. The Chair asked the committee to comment on the areas of

research to test the hypothesis suggested in the paper. A

number were interesting scientifically but the committee should

consider whether they might be important in terms of Government


35. The committee agreed that examination of the transmission

characteristics of human TSEs in transgenic mice expressing

forms of the human and bovine prion protein gene, or a human

CJD to cattle experiment, while potentially interesting, are unlikely

to inform TSE controls and are therefore not essential to conduct.

A member informed the committee that a number of experiments


©SEAC 2005

to test the transmissibility of BSE, vCJD, sheep scrapie and

sheep BSE in transgenic mice were underway to address

different questions, and may inform the above question. These

studies were using transgenic mice expressing human and

bovine forms of the prion protein that had been produced in

identical ways. Professor Colchester suggested that experiments

in transgenic mice might be less clear than studies that examined

transmissibility of human TSEs into cattle directly. Dr

Stephenson reminded the committee that experimental feeding of

human TSE material to animals was previously considered by

SEAC to be unethical.

36. Members noted that investigations of historic production of animal

feed were extremely difficult to undertake and had probably been

investigated as much as possible. Although it was important to

investigate possible feed related origins of BARB cases, further

investigation of feed manufacture processes in the 1960s and

1970s would not be worthwhile. Appropriate controls now appear

to be in place. The committee considered that the other areas of

research suggested in the paper were not within SEAC’s remit.

37. In summary, SEAC:

• was grateful that the hypothesis was raised and for the

thoughtful and professional way in which Professor

Colchester had raised the hypothesis with the committee,

• considered the hypothesis plausible but for a number of

reasons considered that it was not the most likely origin of


• was reassured that control measures were in place to

prevent possible transmission via the route identified in the


• considered that although a number of interesting areas of

research had been identified, these were unlikely to affect

policy, and that it was also unlikely that the hypothesis could

be experimentally verified,

• agreed to produce a statement on the hypothesis.


38. Professor Graham Medley (Chair of SEAC Epidemiology

Subgroup) updated the committee on the Subgroup’s second

meeting on 13th September 2005 which continued to address the

SEAC request to evaluate the nature and profile of the vCJD

epidemic. The Subgroup had reviewed the available data on the

prevalence of vCJD infection in the UK population and modelling


©SEAC 2005

studies, making extrapolations in areas where data gaps exist.

The importance of data acquisition in removing uncertainty about

the distribution of infection in the population had been highlighted.

Whilst modelling methods are useful to explore hypotheses on,

for example, the influence of age and genotype on infection,

because the disease incubation period and the level of infection

are unknown, any number of hypotheses were plausible. The

validity of hypotheses could only be tested with further data. A

position statement including a table of options for further data

collection would be prepared with the aim of presenting it at

SEAC 90. The Subgroup would meet early next year when

further modelling work was completed.

39. The Chair asked whether the modelling work underway was

sufficient to allow the Subgroup to address the questions SEAC

had asked the Subgroup to consider. It was explained that

modelling work was useful to provide quantification of

uncertainties around the epidemic but it was crucial that more

data were collected to remove these uncertainties and improve

understanding of the epidemic.


40. The Chair explained that during the SEAC 88 discussion on

differential diagnosis of BSE, members expressed an interest in

viewing the DVD supplied to veterinary surgeons on the clinical

diagnosis of BSE in cattle.

41. Mr Burke informed the committee that the DVD had been

produced by a clinical neurologist at VLA and circulated to a

number of bodies including the State Veterinary Service, Meat

Hygiene Service and organisations representing veterinary

surgeons. The committee was shown extracts covering a number

of diagnostic tests for BSE and differential diagnosis of BSE from

other diseases with similar clinical signs.

42. Members welcomed the development of the DVD and noted it

would be very useful in maintaining knowledge of the clinical

symptoms of BSE, particularly amongst individuals who had not

had practical experience of the disease at the height of the



43. There was no other business.



SEAC 90/2


There is no discussion paper for agenda item 90/2, however Professor

Ironside will refer to the following papers during his presentation:

Polymenidou et al. (2005) Coexistence of multiple PrPSc types in individuals

with Creutzfeldt-Jacob disease. The Lancet neurology online, 31 October


Yull et al. (2006) Detection of Type 1 of the Prion Protein in Variant

Creutzfeldt-Jacob Disease. American Journal of Pathology 168, No.1,

January 2006 in Press.



SEAC 90/3



1. To consider a recent paper on molecular evolution of the sheep

prion protein gene1.


2. The susceptibility of sheep to scrapie is known to be influenced by

polymorphisms in the prion protein gene (PRNP) especially at

codons 136, 154 and 171. Fifteen genotypes resulting from

variation at these codons have been identified. The genotypes

occur at widely differing frequencies in different breeds of sheep.

3. The National Scrapie Plan (NSP) for Great Britain consists of a

breeding programme to increase the number of sheep that

genetically are naturally resistant to transmissible spongiform

encephalopathies (TSEs). Its primary aims are to protect animal

health by reducing and eventually eradicating scrapie and to

protect public health from the theoretical risk of BSE (if it is present

and being masked by scrapie) by increasing levels of genetic

resistance to TSEs. The breeding programme consists of different

schemes and initiatives, based on various considerations including

the relative resistance of sheep carrying the ARR allele to scrapie.

4. The NSP implements a recommendation from the SEAC Sheep

Subgroup for a long-term control and eradication programme for

scrapie. At its most recent meeting in July 2004 the Subgroup

concluded that the underlying strategy of the NSP to breed for

scrapie resistance remains appropriate. However, it was

considered that the basis for the strategy should be continue to be

kept under review in the light of emerging scientific findings with

respect to the possible detection of scrapie infections in animals of

genotypes currently thought to be most resistant to infection.

1 Slate (2005) Molecular evolution of the sheep prion protein gene. Proc. R. Soc. B. 272,



5. At SEAC 88, SEAC was informed about a range of studies on

atypical scrapie in sheep. The committee agreed that, now that a

number of issues around atypical scrapie are becoming clearer,

the SEAC Sheep Subgroup should consider the emerging scientific

information in more depth and the possible implications for the

NSP. The Subgroup will meet in January 2006.


6. A paper by Jon Slate (see Annex 1) investigated the evolutionary

selection pressures acting on ruminant PRNP using a theoretical

approach of molecular evolution analyses of ruminant PRNP

sequence data. On the basis of these analyses, the author

concluded that PRNP in sheep has evolved by balancing selection

rather than positive selection. In other words, the natural evolution

of sheep PRNP has resulted in variation in the coding sequence to

include genotypes that are relatively susceptible to scrapie

because variation in the gene is favourable.

7. The author proposes a number of possible hypotheses for the

variation in sheep PRNP:

(i) susceptible genotypes confer some advantage(s) to sheep in

the absence of scrapie thereby maintaining PRNP variation over


(ii) heterozygote genotypes are advantageous because they confer

relative resistance to scrapie compared with homozygous


(iii) relative susceptibility to scrapie is determined by the

compatibility of PRNP genotype of the host and the scrapie strain

such that incompatibility leads to a barrier to infection. Thus,

variation in PRNP could be maintained by exposure over time to

scrapie strains with different compatibilities, and therefore infection

efficiencies, with sheep genotypes.

(iv) variation in an untranslated region linked to PRNP influences

the expression levels of prion protein and therefore, susceptibility

to scrapie, which helps to maintain variation in the coding region.

8. The author suggests that hypotheses (ii) and (iii) appear to be the

most likely. This because there is evidence from humans and

sheep that heterozygote genotypes are more resistant to TSEs. In

addition, there is evidence that conversion of normal prion protein

to an abnormal form is most efficient when the genotype of the


host from which infection is transmitted and the recipient host is the


9. The author notes that the aim of the NSP breeding programme is

to induce positive selection of a single relatively resistant genotype

to scrapie infection. Since this results in depletion in genetic

variation, it runs counter to the natural evolution of PRNP in sheep

that appears to favour variation. One possible implication is that

the NSP may produce a genetically uniform population of sheep

that could be susceptible to rare scrapie strain(s). In view of this,

the author recommends that further investigations of the role of

PRNP variation on resistance to rare scrapie strains and on fitness

and production traits be conducted. In addition, it would be

prudent to preserve existing PRNP variation, as frozen semen and

in managed populations.


10. Due to the specialist nature of the molecular evolution approach

and analyses undertaken, the paper by Slate was sent to two

independent genetics experts. The experts were asked to review

the paper and to comment on the methodology used and the

implications for the NSP. The reviews have been anonymised and

are given at Annex 2.


11. The committee is requested to comment on the findings of the

Slate paper and the possible implications for the NSP.



Slate (2005) Molecular evolution of the sheep prion protein gene.

Proc. R Soc B. 272, 2337-2344.



Independent expert reviews of the paper by Slate


Lancet Neurology 2005; 4:805-814


Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease

Magdalini Polymenidou a, Katharina Stoeck a, Markus Glatzel a b, Martin Vey c, Anne Bellon c and Adriano Aguzzi a

The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively.

We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc.

We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern.

The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.


a Institute of Neuropathology, University Hospital Zurich, Switzerland
b Present address: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
c ZLB Behring, Marburg, Germany

Correspondence to: Dr Adriano Aguzzi, Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland


what i been saying for years, that the diagnostic criteria differentiating between the nvCJD (i.e. 'the chosen ones') and the sCJD (i.e. 'the forgotten ones') has been terribly flawed from the beginning. ....TSS

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