Research into BSE and CJD

This contains the research up to 1997 but full research lists as well as research currenly taking place is now to be found at www.priondata.org


This clearly cannot contain information on all the research that is being carried on that would be of relevance to BSE. Part of this is because the subject is potentially so large, and part of this is because scientists, and particularly in this subject, keep things under wraps until publication is available. This cannot be true for the Ministry of Agriculture in the UK, which has to justify its income, and nor is this true for many researchers outside academia. If you have any suggestions, please send them to us.

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EU research:  Up to 1997, the amount of data on the internet was not great.  The details about BSE research in the UK is found below.  The information on that funded from the EU is on www.priondata.org

UK research: Up to 1997 this was on Government documents that were available from them directly and are present below.   Much greater information is available from:

Government sponsored research in other countries: This information is not available here.

Concerning Research up to 1997:

 Quick transfers:

Dont forget that plans became available in 1996 as suggestions as to which direction research to carry on. Although the one from the DofH is not on the Internet, two others are. 
Underway 95

Research underway and at least partly complete, known to be organised by MAFF and BBSRC

Infectivity of various tissues from an animal with BSE. OC8808.
This has been done by inoculation into mice, but the sensitivity of the mouse was not known and appears to be low currently. As a result, the inocula are being put into cattle as well as mice. The results are not expected until the year 2000.
Evidence for the inheritence of susceptibility to BSE. OC8943
Experimental transmission of feline spongiform encephalopathy to mice OC8946.
This may well have been completed already and we have evidence that experts have the data.
Large scale isolation of abnormal prion protein from BSE infected tissue OC8954
BSE deactivation studies OC8964
It is not clear how they are expecting to measure the levels of infectivity remaining without a sensitive animal apart from cattle.
Further studies on oral transmission of BSE to mice OC9033
Investigation of the role of the embryo in maternal transmission of scrapie in sheep OC9038.
I have been told that the embryo appears to be come infected in utero and that this result is soon to be published.
Potential role of anti-PrP in BSE OC9106
Transferrin ion binding in normal and abnormal plasma OC9133.
Genetic susceptibility of cattle to BSE. OC9225.
Currently there appears to be no association between the genetic aberrations and clinical disease.
BSE epidemiological studies SEO201.
This is presumably the continuance of the study that has been going on for the past 7 years. The publication of the problems now found with feed transmission being the whole story in terms of the epidemic do not seem to have been published yet.
BSE study to determine occurence and incidence of maternal transmission SEO202.
This uses a control the offspring of another cow from the same herd as the calf that is the offspring of a cow with clinical BSE. Evidence suggests now that both the mothers may actually be infected and, despite all the hard work that has gone into this study it may be difficult to separate the two groups.
Longitudinal studies of the brain pathology of BSE SEO203
This is the study that is following the changes in pathology as the disease epidemic progresses and will produce many publications on the way. e.g. an assessment of the cattle that have been slaughtered as having BSE but found to not have the changes in histopathology. Why this has remained at approximately 15% as the disease has risen is unclear and may suggest that the negative pathology may not be the full story.
Clinical and epidemiological correalates of the vacuolar profile in BSE SEO205
An attempt to assess the changes seen in the brain with those found in the animal while alive.
Correalation of the histopathological diagnosis of clinically suspect but histopatholgically unconfirmed BSE SEO206
see above
Comparative neuropathology of recently recorded scrapie-like encephalopathies in animal species other than cattle SEO207.
Identification of BSE infection in cattle tissue SE1401
The problem with diagnosis of the disease from clinical changes and from the brain after death is that it means that asymptomatic cattle with BSE would be sent to the slaughterhouse and used for human food. As such it is very important to look for methods of diagnosis that could be used for a clinically well animal.
Transmission of BSE and natural scrapie into sheep and goats by intracerebral and oral routes SE1402.
This has already been successful in that the sheep and goats have died following both routes of inocula but the experiment will continue until all the goats and sheep are considered to be passed clinical disease.
Strain typing of BSE pathogens in mice and comparisons with natural sheep scrapie SE1403.
Apparently BSE was found to be the same strain throughout the epidemic and, from inoculation into mice, was not found to be like the strains of scrapie that we were aware of. As such BSE is presumably either not derived from scrapie or is from an odd strain.
Significance of PrP and putative anti-PrP genes on susceptibility to transmission of TSEs SE1717.
BSE embryo transfer studies. SE1801.
This required cattle from abroad to be brought in to the UK, in order that they might be inoculated with the embryoes. Foreign countries are aware of the problem but MAFF seems to be happy to export embryoes despite the lack of results currently available from this experiment.
Transmissibility of BSE to pigs by injection with brain homogenate SE1802
See 'gossip'
Transmissibility of BSE to pigs by oral exposure to brain homogenate SE1803
See 'gossip'
Transmissibility of BSE to cattle by oronasal exposure to placentae of infected cattle SE1804.
Transmissibility of BSE to domestic fowl by injection of brain homogenate SE1805.
Transmissibility of BSE to domestic fowl oral exposure to brain homogenate SE1806.
Transmissibility of BSE to mink by intracerebral and oral exposure to brain homogenate SE1807
The work from the USDA at Pullman in the USA has made it quite clear that oral transmission is by small doses of brain.
Comparative efficiencies of the bioassay of BSE infectivity in cattle and mice SE1809
This was demanded by various groups after the assay for BSE infectivity was found to be apparently poor in mice.
Peripheral tissue distribution of the agent of spongiform encephalopathy in kudu. SE1810.
The last kudu died about 2 years ago and the worry that infectivity might have remained in the pen has been dropping.
Injection of bovine embryos with BSE/PrP infectivity SE1811.
BSE transmissibility to cattle by injection with brain homogenate SE1812.
The reason that this is still underway is that the incubation period seemed to be so long. Here were cattle dying of BSE at 2 years, apparently from eating the disease in feed ..and yet the intracerebral inoculated ones were taking much longer. This was used by one group as an indicator that the cattle may be being infected in utero.
Transmissibility of scrapie to pigs by oral exosure to brain homogenate SE1813.
Pathogenesis of experimental BSE in cattle SE1901.
Effect of oral inoculum dose on attack rate and incubation period of BSE in cattle SE1902.
This is essential in that, for some reason, despite the huge increase in dose that must have appeared in the feed, the incubation period seems to have stayed the same in the farm cattle. The reason for this must be found.
Targetting PrPBSE immunohistological localisation SE1903.
Neuronal morphology in BSE SE1906
Morphometric and immunohistochemical studies of BSE SE1907
Ultrastructural, mophological and immunocytochemical studies of transmissible degenerative encephalopathies SE1908
Susceptibility of BSE and scrapie isolates to rendering practices SE1404
Susceptibility of BSE to chemical and physical inactivation procedures applicable to the field/laboratory SE1405
What does not seem to be clear is exactly what levels of infection remaining after inactivitation actually represents a problem and this may be difficult to find out.
PrP gene variants and their potential as markers for natural and experimental scrapie susceptibility in sheep SE1406
Analysis of nucleic acid and differences between control and scrapie/BSE infected animals SE1407
This seems to be being done in many parts of the world as PCR is the popular process of the day
Diagnosis of BSE by detection of abnormal deposits of PrP and other BSE infection specific antigens SE1408.
Electrophoretic analysis of body fluids to identify diagnostic markers in BSE and scrapie SE1705
The French group that noticed a change in the chemistry of the urine may have given rise to this but the test might not have been specific for scrapie. I am worried that MAFF may withdraw funding for this if it starts to show anything useful. It seems to have been taken over by the Reading company Electrophoretics. Try Dr Pears (?spelling)
Identification of BSE and scrapie infected animals by the detection of a urinary metabolite SE1706
see above
Sensitivity studies of fibril detection techniques used in electron microscopy for the diagnosis of scrapie SE1707
It is not how this can be done without Narang and his specific techniques being involved.
Biochemical approaches to the differential diagnosis of BSE in the live animal SE1708.
Sensitivity of scrapie associated fibrils from different breeds of sheep to proteinase K digestion SE1709.
TSE fibril immunolabelling studies SE1710
Establishment of the in vitro culture of bovine cells for veterinary research SE1711
Production of sera suitable for the developement of immunodiagnostic tests for TSE SE1712.
Gain information on use of resistant rams as method of controlling or eradicating scrapie SE1713
Scale up isolation of abnormal PrP from BSE infected tissue SE1714.
It is not clear how they are expecting to carry this out.
Studies of the PrP gene of species naturally and experimentally infected with TSE. SE1716.
Aetiological studies of brain stem chromotosis SE1913.
A disease found for the first time because histopathologists were looking for BSE.
Sequential observations of neurological signs in BSE SE1914
most of this seems to have been published already.
For BSE work with ADAS SE2101
It is not clear what this is.
Survey of the cases of CJD in the UK
This also included complex studies looking to see if specific foods are associated with disease. The main problem with this is that bovine tissue is eaten by such a high percentage of the population that it will be many years before the control and test groups could be expected to be separated.
The inoculation of brain tissue from the farmers that have died of CJD recently into mice, and the distribution of pathology tested following clinical murine disease.
The reason for this is that BSE seems to retain its distribution in mice, from whichever animal it has actually come from. For instance it is the same when inoculated with the TSE from cattle, kudu and cats. If it is similar from humans then it would be sensible to accept that the farmers had caught BSE.
Inracellular trafficking and scrapie in vitro BSE00293
Targeting and cellular pathology of scrapie infection BSE00294
Effect of mutagens on the biological properties of strains of scrapie BSE00295
Non-lymphoid cells in scrapie pathogenesis BSE00296
Chemical characterisation of spongiform encephalopathy agents BSE00297
Expression of PrP gene during development in mouse and sheep BSE00298
The expression of PrP in lymphoid tissues of healthy and BSE-infected animals BSE00299
Purification of the scrapie agent: identification of candidate molecular species BSE00300
Antigenic structure of murine and ovine PP isoforms BSE00301
Prodction of truncated PrP protein in mice by site directed mutagenesis and gene targeting BSE00302
A cell culture based assay for scrapie agent and its use for mutagenesis BSE00303

Research in progress currently (14 October 1996)

These seem to be the titles of the projects organised and funded by the BBSRC in the UK. The total of funding that is taking place, with money to be spent over the next several years is 5.95 million. The fact that this disagrees quite dramatically with the figure put out through Parliament suggests that the Parliamentary figure is giving the impression of much more research going on that actually is doing so. 

Diagnosis

SE0214 Selective studies of neurological disorders in cttle to aid the clinical differential of diagnosis of BSE.
This is partly because they are determined that the BSE is disappearing and so there must be a way that clinically the veterinary officers can pickout the cases from the other neurological disoriders before providing quite large amounts of compensation.
SE1409 Development of an antemortem test for BSE and natural scrapie infection through the detection of abnormal deposits of PrP
The work of Schreuder in Holland might have given the impression that other lab signs of disease can be looked for.
SE1705 Electrophoretic analysis of body fluids to identify diagnostic markers in BSE and scrapie
this follows the work of a french worker who was quite determined that scrapie urine contained a small molecule that precipitated. All slightly hopeful because so far it has been shown in the CSF but not looked for in urine.
SE17 Molecular characterisation of a single-stranded DNA observed in scrapie infected hamster and mouse brain.
So far 29,000 has been put in to this. The exact reason is unclear as Dr. Harang tells us that MAFF have refused to carry out any of the research and deny that there is any SS DNA present.
SE1718 Identification and characterisation of the scrapie agent from low protein, high infectivity fraction of brain
SE1719 Transcriptional control of the PrP promoter.
This has not really been looked at adequately by anyone.
SE1720 Antibodies against the BSE agent
Some Americans have made a good paper of the ability of different species to produce antibodies.
SE1721 Molecular characterisation of bovine PrP
SE1722 The molecular nature of the agents of TSEs
SE1723 Production of antisera to highly purified bovine PrPsc
SE1724 Biochemical changes in the SEs.
Presumably to look for other diagnostic markers.
SE1725 Studies of the enhancement of reproducibility of PrPsc detection after cold storage of scrapie affected tissues.
The exact reason for this phenomenon is not clear.
SE1726 Continued large-scale isolation of abnormal PrP from BSE affected tissues.
The actual reason for this is unclear. ?research ?immunisation ?other. No further data available currently.
SE1727 Identification of putative nuceliac acid pmponents of the etiologic agent of the TSEs.
This is being carried out at the Univ of Edinburgh centre for Genome research.
SE1728 Production and properties of PrP: EC IVth framework collaboration.
SE1729 PrP gene codon 171 and species susceptibility to scrapie like diseases.
Thoroughly hopeful but a chance to look for a way to produce a PrP gene that stops scrapie being transmitted.
SE1730 Electrophoretic analysis of body fluids to identify disease specific proteins in ruminant SE.
rather similar to 1705
SE 1731 Production of polyclonal antisera to highly purified bovine PrPsc.
They seem to be getting somewhere with this as it has been going for some time but many methods being used to make the PrP more antigenic have not been very good. Currently polyclonal antisera have been produced by a private company but turned down by BBSRC.
SE1732 Collaboration agreement with Electrophoretics international to develop 2DE techniques for BSE diagnosis.
It is not clear what this means. Also no budget is put towards it.
SE1917 Scrapie infection in neural and extraneural cell lines
SE1922 Studies of the sensitivity and specificity of the methods of PrPsc detection in animal TSEs
An ongoing study to simply see how well things are progressing.

Pathogenesis

SE1414 Studies on the species barrier in scrapie and BSE.
For some reason this was not started until 1995.
SE1415 Strain typing of BSE pathogen in mice and comparison with strains from sheep scrapie
SE1416 Development of mouse models for the study of BSE
SE1420 Identification of BSE infection in cattle tissue
These are really all very vague but probably include the experimets to see if BSE is the cause of CJD-2
SE1810 Peripheral tissue distribution of the agent of SE in kudu.
So far there appears to be little done to find the sensitivity of the tests to the disease and there does not seem to be transgenic mice being used. These results will be similarly criticised to those from cattle.
SE1901 Pathogenesis of experimental BSE in cattle
SE1904 Spinal cord pathology in BSE
SE1905 Extraneural pathology of natural and experimental BSE in cattle
SE1906 Neuronal morphology in BSE
SE1909 Studies of the cellular and humoral responses of distal ileum mucosa and mesenteric lymph nodes in the pathogenesis of BSE
SE1910 The demonstration and immunostaining of small virus like particles in experimental scrapie rodent brain.
This follows the work at the Koch Inst in Berlin but was argued about at the time of publication in the Lancet.
SE1912 Investigation into links between oxidative stress and BSE.
SE1915 Magnetic resonance imaging of the bovine brain
This was shown to be poor in humans and Dr. Will did not feel that further research was useful in them.
SE1916 Morphometric analysis of scrapied mice.
SE1917 Scrapie infection of sheep neural and extra neural cell lines
SE1918 Effect of oral inoculum dose on attack rate and incubation period of BSE in cattle
A long term project. One of themajor problems is that they used such enormous doses, often starting at 10g of brain, when really the orally infective dose would probably have been 0.001g
SE1919 Studies to identify possible homologies between TSEs.
SE1920 Ultrastructural, morphological and immunocytochemical studies of TSE.
This should have been done really very quickly but seems to have a long and high.
SE1921 Immunohistochemical studies of cell death in murine scrapie
SE1926 Species specificity of the cell-free formation of protease-resistant human PrP.
This is probably a waste of time as they will simply find them to be completely specific for the species.
SE1927 Immunohistochemical detection of cellular perturbations in formalin-fixed brain from cattle with neurological damage due to BSE.

Transmission

SE1418 BSE transmission in sheep
SE1423 Transmission studies for the detection of BSE in sheep
SE1713 Gain information on the use of resistant rams as method of controlling or eradication scrapie
SE1804 (became 1818) Transmissibility of BSE to cattle by oronasal exposure to placentae of affected cattle
SE1805 Transmissibiity of BSE to domestic fowl by injection
SE1806 Transmissibiity of BSE to domestic fowl by oral exposure
SE1808 Transmissibility of BSE to marmosets by stereotaxic intracerebral inoculation of brain homogenate.
SE1814 To determine if scrapie can be passed by transfer of embryos from ewes infected with scrapie to uninfected ewes.
SE1816 Transmissibiity of BSE to pigs by injection
SE1817 Transmissibility of BSE to cattle by oronasal exposure to placentae of affected cattle.
SE1819 BSE embryo transfer studies
The worry is that BSE might be transferred from one cow to another by the embryo and might be carried to foreign countries by it.
SE1821 Comparative efficiencies of the bioassay of BSE infectivity in cattle and mice.
This has vertually been completed and a species barrier of about 1000 was found. What it showed, of course was that mice could not be used easily as BSE assays and this made much of the previous work of the groups looking for BSE infectivity in tissues invalid.
SE1822 Transmissibiity of BSE to pigs by oral exposure
SE1823 Investigation of the role of the embryo in maernal transmission of scrapie in sheep.

Epidemiology

OC9425 Investigation of scrapie infectivity and prP genotype in clinically normal cast ewes from infected flocks.
SE0209 BSE: Epidemiological studies
This has the biggest budget of all, 511,558 and it can be seen that this was the one that produces much of the interesting information but which was not published or drawn to statisticians attention.
SE0211 BSE:Study to determine the occurrence and incidence of maternal transmission
SE0212 Comparative neruopathology of recently recorded scrapie-like encephalopathies in animal species other than cattle.
SE0213 An epidemiological study of sheep scrapie to determine means of natural transmission
SE0215 BSE: Study to determine the occurrence and incidence of maternal transmission
Remarkably similar to SE0211. Presumably this is the ADAS group.
SE0216 The neuropathological monitoring of suspect BSE cases born in 1992
SE0217 Cattle and sheep products audit trail
SE1412 PrP gene variants and their potential as markers for natural and experimental scrapie susceptibility in sheep
This has really been going for some time and it is not clear why the results are not quickly available.
SE1417 The effect of PrP genotype on the thermostability of scrapie agent
What has been found so far is that the genotype is really quite important and that BSE is relatively thermostable.
SE1421 BSE and scrapie agent susceptibility to laboratory facsimilies of rendering practices.
So far they have found that the agent is not really adequately affected by the rendering and that this did not depend on the use of solvents for the removal of tallow as had been previously thought.
SE1422 Practical aspects of inactivation of BSE and scrrapie agents
These last two projects are having to use relatively low infectivity material because its infectivity is being measured in non-transgenic mice. A difficult problem.

Treatment

SE 1911 Potential role of anti-PrP in BSE
 This has been discussed a few times in the literature and nobody seems to know the answer. One problem is that it may actually make things worse by allowing macrophage uptake of infective PrPsc even faster.

Research in progress outside official organisations

Looking for tubulofilamentous particles in EM from human brain with CJD
Mainly being done by Narang, but quoted from elsewhere.
Surveys into the eating of bovine tissue by the medical profession in UK
Assessment of the percentage of cases of BSE that are being reported to MAFF.
Studies into the distribution of BSE in asymptomatic cattle.
Genetic research into TSEs appears to be being carried out everywhere.
Epidemiological studies into BSE as potential vertical transmission.
The separation of an agent in the urine that is visible only in infected cattle or humans under EM.
Assessment of human risk using calculations
The use of alkaloidal glycosidase inhibitors as a potential method of changing the strain of disease
The use of various chemicals to either cause disease (organophosphorus insecticides, selenium derived from rape seed etc) or to prevent it.
Genetic changes involved in making an animal more open to disease infection but not actually causing the disease per se.
It seems that the Europeans are moving infast on the genetics side. They seems to be particularly involved with also the pathogenesis
The statistical side of BSE seems to be particularly inviting. The groups involved with human life insurance may be getting figures together concerning human risk
The posibility that research funding might actually come from another part of the research budget may mean that people involved in other things may move into the BSE field.
The specific use of DNA fragments to prevent the production of the PrP in vitro cell cultures (this must surely be a long way off)

Research funding

This is an initial run on the subject. It is not clear exactly where the funding is coming from However......
 
 
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