Volume 2: Science
Part 3: Research into TSEs - a narrative account
MAFF's TSE research
1987
1988

6.129 This Part of Chapter 6 reviews the way in which MAFF initially developed a research programme and sought funding for it. We focus on the earlier stages of the process, which laid the foundations for the way the research programme developed.

6.130 From 1988, the CVL/NPU research programme was subject to scrutiny by the committees of experts appointed by the Government to advise it on BSE and measures necessary to address the disease. The first of these was the Southwood Working Party, whose work is considered in detail in vol. 4: The Southwood Working Party, 1988-89. The second was the Tyrrell Committee (the Consultative Committee on Research into Spongiform Encephalopathies), set up in 1989 and chaired by Dr David Tyrrell. The third was the Spongiform Encephalopathy Advisory Committee (SEAC), set up in 1990 and also chaired by Dr Tyrrell. A full account of these two committees is given in vol. 11: Scientists after Southwood.

1987

6.131 Having been responsible for identifying the new disease via the network of Veterinary Investigation Centres, the CVL initiated the earliest research into BSE. Initial investigations were aimed at characterising the new disease and studying its epidemiology. So far as the former was concerned, early indications suggested that the disease was a transmissible spongiform encephalopathy (TSE), and by the beginning of June 1987 investigations had already been set in train to confirm this. These aimed to establish whether the disease was transmissible to experimental animals (hamsters were used initially), and whether SAFs, known to be associated with TSE diseases, could be detected in treated samples from brains of affected animals.

6.132 Study of the epidemiology of the disease was instigated on 3 June 1987, when Mr Wilesmith, head of the CVL Epidemiology Department, was asked to investigate the new disease. Within a week, he had designed a pro-forma questionnaire and had begun to visit farms on which cases of the disease had been reported. ¹ The subsequent epidemiological work is described in Chapter 3 of vol. 3: The Early Years, 1986-88.

6.133 At this stage Dr Watson, Director of the CVL, asked his colleague Mr Bradley to coordinate the research work on BSE. ² A 'BSE group' was formed whose members were to carry out the initial investigation and experimentation relating to BSE. ³ Mr Bradley immediately began discussions with the members of the group about the required experimental work. ⁴

6.134 Dr Watson recognised that a great deal of expertise in TSE diseases existed at the NPU in Edinburgh. Indeed, the NPU was the only centre in the UK involved in TSE research and was experienced in the transmission of scrapie to experimental animals. Dr Watson therefore instigated discussions between the two institutes at the end of May 1987. The question of whether the initial contact might have been made earlier is considered in Chapter 2 of vol. 3: The Early Years, 1986-88.

6.135 At Dr Watson's request, Dr Richard Kimberlin of the NPU visited the CVL on 9 and 10 June 1987, to discuss the coordination of CVL-NPU collaboration and the future course of a research programme. ⁵ He met the Experiment Leaders, as well as Dr Watson and one of his Deputy Directors, Dr Shreeve. ⁶

6.136 On the basis of proposals from the Experiment Leaders and the discussions with the NPU, specific objectives for a BSE research programme began to be formulated. During the coming months, through a process of consultation with the Experiment Leaders, Mr Bradley, Drs Watson and Shreeve, the NPU and others, the ideas for experiments evolved and were refined into firm project proposals.

6.137 Consideration was given at an early stage to the need to obtain funding for the necessary programme of research. Mr Bradley noted in a minute to BSE group members on 10 June 1987 that, while some of the work was considered to fall within the CVL's existing services, some was clearly R&D, and would require funding. He asked for indications at the earliest opportunity of the outline for the programme and some estimated costs, including work that might be done elsewhere as part of the planned programme, in order to develop a case for funding from the Chief Scientist's Group (CSG). ⁷ Dr Watson, too, noted the importance of obtaining funding. He told us:

I was very aware that the budget for research and development for BSE needed to be sufficient, and that the research that would need to take place was occurring against a backdrop of cuts of both staff and budget at CVL, that had been continuing for some years. Research officer and scientific officer posts, along with support staff, were being cut in many departments and the budgets reduced. Wherever possible, commercial funding had to be obtained to support research projects. During the late 1980's, three groups of scientists from the poultry, biochemistry and bacteriology departments, and some in parasitology, were mainly committed to commercially funded work. Nevertheless, the BSE programme had to be put into place. The resources necessary for the programme was an issue that was under constant review and is mentioned throughout this statement. The budget for the SVS, including the CVL, was apportioned through the Director General of ADAS. In order to secure further funding for any area of research, I would approach the CVO and the Chief Scientists Group ('CSG'). The CSG was ultimately responsible for approving expenditure on research and development commissioned by MAFF, which included the research on BSE. If the funding was not available, then I would have to either not run the experiments, or reallocate funding from other projects. ⁸

6.138 By 23 September 1987, Dr Watson was in a position to brief Dr Shannon, the Chief Scientist (Agriculture and Horticulure), on BSE, and to outline the proposed experimental work. Dr Shannon agreed that further detailed investigations and an experimental programme were necessary, and they decided that detailed project proposals with costings would be prepared and submitted to him 'as a marker for the expenditure required.' ⁹ Dr Watson asked Mr Bradley to prepare the proposals. ¹⁰

6.139 Mr Bradley told Dr Shreeve in a minute dated 29 September 1987 that he was working on the project draft. At the same time he put forward proposals for registering a BSE research project. He said that it was envisaged that there would be four experiments (composed of sub-experiments). These represented the four areas into which the proposed work fell: epidemiology, transmission, clinico-pathology and molecular biology (including SAF) studies. The four experiments would be formally submitted to the Directorate for approval, and then registered. ¹¹ Dr Shreeve agreed with this approach. ¹² The four experiments were eventually approved by Dr Shreeve (the Programme Manager) and Dr Watson in late November 1987. ¹³

6.140 Meanwhile, by 22 October, Mr Bradley had completed a project draft for submission to the CSG. ¹⁴ He noted that it would at this stage comprise four experiments, with potential for a fifth genetic breeding experiment later. Dr Watson forwarded the draft to Dr Shannon on 5 November 1987. Dr Watson pointed out that the fourth experiment, molecular biology, was a proposed package of collaborative work involving the NPU and the CVL. The NPU would therefore be looking for commissioned funding. He also pointed out that, in the CVL R&D programme as a whole, several projects had been curtailed or stopped to allow resources to be switched to work of higher priority, and that a further shift of resources to the BSE project would exacerbate these problems. ¹⁵ Dr Watson therefore asked Dr Shannon to look at the commissioned R&D in other ADAS services and elsewhere with a view to identifying work of lower priority that could release funding to support the required work on BSE.

6.141 Dr Shannon replied on 22 December 1987. He expressed the view that new funding would be difficult to find. He was prepared to consider supporting the work at the NPU from the 'special fund'. However, as to the work necessary at the CVL, he said that the only possible way forward would be to reappraise current programmes, and he identified certain work that he regarded as being of lower priority than BSE work. ¹⁶ We note that the special fund could not be used for in-house work: funding would therefore have to be identified by reordering of priorities. ¹⁷

6.142 By 20 December 1987, Mr Bradley had prepared a paper on the 'logical approach' to BSE research. In his covering minute to Dr Watson, he identified a number of questions to which answers were needed:

A Is BSE transmissible to primates? (& by inference to man).

B What tissues contain the agent? - and in what concentration. Likewise for milk. What is the minimal infective dose for (a) a primate (b) a calf?

C How can the agent be destroyed?

He went on to suggest experimental action from which answers might be obtained and concluded:

There are clearly a large number of experiments we could do & should do. The first thing to decide is where to put the effort and decide the priorities. Can we please discuss in the light of the documents presented & decide a practical short list of experiments we can conduct concurrently given the resources to do so. I can then plan & cost the outline. ¹⁸

6.143 Mr Bradley's logical approach to research was as follows:

1. Demonstrate transmissibility.

Inoculum - richest likely source of agent Recipients - a) same species b) likely laboratory species a) and b) concurrent Routes - most likely to transmit i/c + i/p

2. Demonstrate agent titres in organs, tissues, body fluids.

Brain* Muscle* Bone Skin Spleen* Red offals Blood *More important Placenta* Other offals Milk*

3. Demonstrate agent titres as in 2 at different intervals after infection.

4. Demonstrate agent resistance to

heat pasteurisation (milk) radiation chemicals - chloral - NaOH - other.

5. If 1 successful attempt transmission to other species.

Primates Horses ) i/c brain

Sheep Pigs)? primates also: milk oral

Mink Poultry ) meat "

6. Demonstrate transmissibility of sheep scrapie to cattle.

7. Demonstrate minimal infective doses for cattle, primates and laboratory model - BSE and scrapie.

8. Investigate means of eliminating BSE infection from herds - (a) embryo transfer (b) calf snatching.

9. Develop tests to identify resistant and susceptible animals & cheaper tests for detection of infection preferably ante mortem.

6.144 By this stage, some work was already in hand. In a minute to Dr Watson on 31 December, intended for inclusion in a submission to Ministers, Mr Bradley noted that work in progress included: epidemiology, clinico-pathology, molecular biology (identification of SAFs), transmission to hamsters (CVL), cattle (CVL) and mice (NPU) and investigation of pedigrees of affected and control animals. ¹⁹ He also identified proposed extensions to these studies, namely transmission to marmosets (being initiated in association with medical colleagues); inoculation of placenta and milk into cattle and hamsters (CVL); and inoculation of heat-treated brain into hamsters to determine the heat sensitivity of the agent.

6.145 In a separate minute to Dr Watson, Mr Bradley listed the non-BSE work that had by this stage been stopped, reduced or delayed in order to divert resources to BSE work:

1. in the Pathology Department, projects on emerging diseases other than BSE, and research on bovine foetal development and sarcocystis, were scaled down. Work on border disease and renal dysgenesis was stopped, while planned work on chlamydia and bluetongue was postponed; and
2. in the Epidemiology Department, work that was stopped included research on TB in badgers and on sheep pulmonary adenomatosis. ²⁰

1988

6.146 Attempts to progress the comprehensive research programme continued throughout 1988. Mr Bradley revised his draft material for inclusion in a submission to Ministers in January 1988, and prepared a complete draft submission in March, ²¹ although it does not appear that either was subsequently presented to Ministers. ²² Mr Bradley also prepared a further paper for Dr Watson discussing and prioritisingthe experiments that were required. ²³ He suggested that experiments should be sequential, rather than concurrent. While primary studies were carried out, time should be spent designing the secondary experiments well and ensuring that the resources were obtained to undertake them. ²⁴

6.147 Among proposed primary studies, Mr Bradley included developing a laboratory model for transmission, and establishing a genetic marker test for use in live animals to identify the genotype controlling disease expression. ²⁵ Mr Bradley's secondary experiments included: 'Determine the transmissibility of scrapie from sheep to cattle with a view to validating the current epidemiological hypothesis of the origin of the agent from sheep entering the feed chain.'

6.148 In April 1988 Dr Hope of the NPU expressed concern that no definite funding for even the top priority experiments had been forthcoming. Mr Bradley asked Dr Watson whether more could be done via the Minister or the Permanent Secretary. ²⁶ Dr Hope visited the CVL in early May. Mr Bradley reported to Dr Watson that Dr Hope agreed that the genetic marker studies needed to be completed before cattle could be used for experimentation. This therefore had a very high priority. Moreover, Dr Hope agreed that they could only proceed with BSE studies sensibly when an experimental animal model, or cattle, were identified as hosts. Scrapie experiments on the other hand, could proceed, and it was suggested that they try and confirm experimentally how infection started in cattle. ²⁷

6.149 Existing studies and proposals for further research into BSE were evaluated and discussed by Dr Shreeve and CVL scientists in May 1988. ²⁸ At this stage, the fifth experiment under the BSE project had been initiated, namely molecular genetic studies. ²⁹

6.150 This discussion in May formed the basis of a submission to Mr Donald Thompson, the MAFF Parliamentary Secretary, in June 1988. ³⁰ The CVO indicated in his covering minute that, subject to Mr Thompson's agreement, discussion would begin with the CSG on the possibility of obtaining funds for commissioned R&D (other than near-market elements of the programme). The submission noted that the projects/experiments which made up such a programme were dependent on the questions to which answers were required. Nine questions were listed and, for some, experiments that might provide answers were discussed. Among these was the question whether vertical transmission could occur from dam to offspring: a study of selected offspring of affected cows was proposed to address this. Another of the questions was whether the natural or modified scrapie agent was the cause of BSE in cattle, and a transmission experiment to answer this question was proposed.

6.151 Mr Bradley continued to try and progress the BSE R&D effort. On 16 June he wrote to Dr Watson:

There has recently been much discussion on future R&D with a whole series of proposals put forward. It is time to take stock of these proposals and select a short list for serious investigation. Without this approach we are in danger of doing nothing or being blown by the wind.

We need some guidance and direction here so that we can harness our skilled resources to the task in hand. It seems to me the pressures from the rendering industry . . . are aiming us in one direction whereas the availability of resources for semen and ET work are going in another. We must also heed the scientific validity and sequencing of various options.

Can we please discuss, sort the corn from the chaff and develop some specific objectives and determine the experiments to meet them? ³¹

Interim recommendations from the Southwood Working Party

6.152 The work of the Southwood Working Party is discussed in detail in vol. 4: The Southwood Working Party, 1988-89. They first met on 20 June 1988, and Sir Richard Southwood wrote the next day to Mr Andrews, the MAFF Permanent Secretary, making four interim recommendations. ³² Three of these were of direct relevance to the research planning that was taking place. The first was a recommendation that an expert working party on research should be established by the MRC (and possibly the AFRC) to advise on the research that was in hand, and on what was required. An urgent question for the body would, he suggested, be a review of the current laboratory work on the transmissibility of the agent. vol. 11: Scientists after Southwood discusses the steps taken over the following months to implement that recommendation.

6.153 The second interim recommendation was that MBM should be given to cattle and laboratory animals to test the hypothesis that scrapie was the origin of the disease, and also that experiments should be conducted with scrapie (as a proxy for BSE) to determine the likelihood of its transmission via milk or muscle.

6.154 The third interim recommendation was that priority should be given to the epidemiological work on transmission of the disease in cattle herds. Sir Richard said that, in practice, this meant that arrangements must be made to ensure that the offspring of about 150 cows with BSE were identified and monitored (even if this involved some financial compensation for the farmers).

6.155 The CVO, Mr Cruickshank of MAFF's Animal Health Group, and Dr Watson met Mr Thompson on 7 July. Mr Thompson felt that all necessary research on BSE should be carried out 'whatever the cost', and he agreed that the CSG should be approached. ³³ Following the meeting, Dr Watson directed that certain experiments be initiated and that others be progressed. ³⁴ Mr Bradley told the BSE group that financial resources required to carry out the programme were being sought immediately. He asked the relevant Experiment Leaders to identify necessary staff resources, expertise and capital expenditure.

6.156 Mr Bradley visited the NPU during July 1988. He reported to Dr Watson on his visit and on the NPU R&D programme.

6.157 In early August Dr Shreeve reported that the Prime Minister had apparently directed that BSE R&D should be afforded high priority, and that it was becoming clear that the Government would fund most if not all of the research. ³⁵ He identified as possible sources of funding money obtained from near-market savings at the CVL and elsewhere, Vote 3, Dr Shannon's Open Contracting Fund, ³⁶ and a supplementary bid. Accordingly, a five-year R&D programme for the CVL was required, to be submitted to the Minister early in September, ie, within three weeks. It was envisaged that the programme could then be put to the advisory group on research proposed by the Southwood Working Party. Following production of the programme, 'initiatives should be put in hand to obtain appropriate funding'.

6.158 A programme was subsequently prepared by Mr Wilesmith in August 1988 and a revised version was forwarded by Dr Watson to the CVO, Mr Meldrum, on 9 September. ³⁷ Mr Meldrum in turn forwarded it to Professor Bell, MAFF's Chief Scientific Adviser, and, because he understood it was needed for the Minister's PES meeting with the Treasury, to Finance Division. ³⁸ Mr Meldrum said that, in addition to future needs, extra funds for R&D for the current financial year were needed to allow R&D that had been stopped in other areas to be resumed. He suggested that some of this might be available from the CSG. Mr Meldrum also reported his efforts to obtain industry funding. He anticipated that future research would be considered by the BSE R&D coordinating group recommended by the Southwood Working Party, once it was established. ³⁹

6.159 During September, the annual bilateral PES meetings between the Chief Secretary to the Treasury and the Minister of Agriculture took place. Mr MacGregor, the MAFF Minister, made a late bid for additional funds to support R&D in a number of areas, including BSE, but was unsuccessful. ⁴⁰

6.160 One piece of research that was already in hand produced results during September 1988. Researchers at the NPU achieved transmissions of BSE to a particular strain of mice. ⁴¹ This was an important step towards identifying a suitable model for infectivity experiments, which was one of the factors that had been identified as delaying such research.

6.161 Dr Shannon, to whom Mr Meldrum had copied the R&D programme, contacted Professor Bell on 12 October. He said:

As I see it the aim within MAFF should be to have in place (or planned) the programme of work which we feel is necessary to meet our responsibilities in relation to BSE. If we have done our job properly this will then be endorsed by the Research Committee in due course. The work proposed by Mr Meldrum is principally at CVL. If the programme is to gain acceptance it will need to involve a wider range of laboratories (AFRC and Universities) where there is appropriate expertise. We will need to carry interested research partners with us.

It has not been made clear where the funding (and any additional funding) will come from but on the assumptions that it will involve funds for which I have responsibility I would wish Dr MacOwan to be involved fully in the discussions. ⁴²

6.162 Representatives of MAFF (including the CVL) and the IAH (including the NPU) met at the CVO's office on 17 November 1988 to discuss BSE R&D. ⁴³ Dr Watson explained that CVL had not received any extra funding, and that BSE R&D had been funded by closing other projects. Dr Hope explained that the NPU's work had been funded by diverting resources from its scrapie programme (then funded by DES). The work in hand was reviewed in detail, and there was discussion of the future R&D programme. One project that was now said to have a lower priority was the scrapie-to-cattle experiment, since this work had been done in the US but not published. ⁴⁴ Professor Bourne said that it was not anticipated that the NPU would conduct experiments in cattle; it was agreed these would be done by the CVL. ⁴⁵

Further input from Sir Richard Southwood

6.163 Vol. 4: The Southwood Working Party, 1988-89 discusses Sir Richard's meeting with Ministers on 24 November, following the second meeting of his Working Party. During the course of the meeting, he again emphasised the importance of keeping the cohort of offspring of affected animals intact. ⁴⁶

6.164 On 14 December 1988 Mr Bradley updated the R&D programme paper that had first been prepared in August. ⁴⁷ The following day, the second of the regular (approximately twice-yearly) BSE R&D meetings between the CVL and NPU took place. ⁴⁸ In a minute to Dr Watson prepared following the meeting, Mr Bradley outlined the actual and proposed programme of R&D by the CVL and NPU. He recorded his view:

It is essential that appropriate funding and resource allocation is provided immediately without the prelude of time-consuming administrative procedures. An exception must be made for this work. Documentation can be dealt with concurrently or following fund allocation and provision. Progress (initiation for some experiments) is currently stagnating due to absence of funds and other resources. ⁴⁹

6.165 Mr Bradley's updated R&D programme paper outlined the aims of the CVL programme, the work that was already taking place, and the proposed work. The position on the five experiments at the end of 1988 was:

1. Epidemiology: by December 1988 Mr Wilesmith's epidemiological studies had identified MBM as the medium through which, on current evidence, BSE had spread (see Chapter 3). The future objectives were directed at two key aims of the programme: investigating further the hypothesis that MBM was the source of BSE, and determining whether BSE transmitted naturally in cattle, either vertically from dam to offspring (maternal transmission), or horizontally between animals (or both). However, no maternal transmission experiment was in place at this stage.
2. Clinico-pathological studies to describe the histopathology of BSE were in progress.
3. Transmission: by December 1988 a number of transmission studies were in progress. Hamsters and calves had been inoculated at the CVL; marmosets had been inoculated at the MRC/CRC ⁵⁰ laboratory (Northwick Park - funded by the MRC); mice had been (by now successfully) inoculated at the NPU (funded by AFRC/MRC); goats had been inoculated at the NPU; and plans to inoculate mink at the CVL were at a fairly advanced stage. Sheep had also been inoculated at the NPU, although this was not included in Mr Bradley's paper. ⁵¹Transmission experiments to determine the infectivity of specific tissues were also being planned. Tissues specifically identified were the placenta (experiment at design stage), semen (still at design stage, although semen from one BSE-infected bull had been collected) and embryos (at design stage). Testing of other tissues and a pathogenesis study were also envisaged, but all of these experiments awaited the establishment of a suitable animal model.The stated aims of these experiments were to determine whether BSE was transmissible; to determine whether the BSE agent could be transmitted by semen or embryos from infected and affected cattle; to determine whether the BSE agent was identical to the natural scrapie agent or a modified scrapie agent, and whether there were multiple BSE strains; and to determine the conditions required for sterilisation and to make rendered material safe.
4. Molecular biology: SAFs had been identified in February 1987, and confirmed by western blotting in October 1987. Work in progress, which was aimed at determining whether the BSE agent was identical to the natural scrapie agent or a modified scrapie agent, and whether there were multiple BSE strains, included assembling a lesion/SAF/PrP profile for brains, which might correlate with the agent strain. This would be extended to other tissues once the techniques were optimised.
5. Molecular genetics: studies to determine any genetic factors involved in disease expression in cattle, and to determine whether an equivalent to the sinc or sip genes existed in cattle, were in the planning stage. Some suitable animals/herds had been identified and blood samples were being collected and stored.