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Pentosan: earlier studies
Cumulative distribution anomaly in known human CJD mutations
Doxycycline control of prion protein
Prion gene sequence, neigbors, synteny, and pseudogenes
Dog prion anomaly confirmed
Can TSEs be diagnosed from urine?
Molecular screening of sheep for BSE
Structural aspects of Congo red
Phenotypic variability of GSS
The BASES Project:European research project on BSE policy-making and scientific research

Pentosan: earlier studies

30 Nov 98 Medline highlights: 'Pentosan and scrapie' 
Caughey B, et al. 
Binding of the protease-sensitive form of PrP (prion protein) to sulfated
glycosaminoglycan and congo red.
 J Virol. 1994 Apr;68(4):2135-41.
"Congo red and certain sulfated glycans are potent inhibitors of protease-resistant PrP accumulation in scrapie-infected cells. One hypothesis is that these inhibitors act by blocking the association between protease-resistant PrP and
sulfated glycosaminoglycans or proteoglycans (e.g., heparan sulfate proteoglycan) that is observed in
amyloid plaques of scrapie-infected brain tissue. Accordingly, we have investigated whether the
apparent precursor of protease-resistant PrP, protease-sensitive PrP, binds to Congo red and heparin,
a highly sulfated glycosaminoglycan with an inhibitory potency like that of heparan sulfate....These
results are consistent with the idea that sulfated glycans and Congo red inhibit protease-resistant
PrP accumulation by interfering with the interaction of PrP with an endogenous glycosaminoglycan or

Caughey B, et al. 
Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells. 
J Virol. 1993 Feb;67(2):643-50. 

"Pentosan polysulfate, like the
amyloid-binding dye Congo red, potently inhibited the accumulation of PrP-res in these cells without
apparent effects on the metabolism of the normal isoform. The inhibition was due primarily to
prevention of new PrP-res accumulation rather than destabilization of preexisting PrP-res." 

Ladogana A, et al. 
Sulphate polyanions prolong the incubation period of scrapie-infected hamsters. 
J Gen  Virol. 1992 Mar;73 ( Pt 3):661-5. 

"The effect of the organic sulphated polyanions, pentosan sulphate
(SP54), dextran sulphate 500 (DS500) and suramin, have been tested on golden Syrian hamsters infected
with the 263K strain of scrapie by the intraperitoneal (i.p.) or the intracerebral route. SP54 had the
greatest effect in prolonging the incubation period of the disease when administered within 2 h of the
i.p. inoculum...." 

Diringer H, et al. Chemoprophylaxis of scrapie in mice. 
J Gen Virol. 1991 Feb;72( Pt 2):457-60. 

"Three applications of the polyanion pentosanpolysulphate about 2 months before
infection of mice with scrapie completely protected animals infected with up to 100 LD50, and
considerably prolonged the lifespan of those infected with 100 to 10,000 LD50." 

Ehlers B, et al.
Dextran sulphate 500 delays and prevents mouse scrapie by impairment of agent replication in spleen. 
Gen Virol. 1984 Aug;65 ( Pt 8):1325-30. 

"Treatment of scrapie-infected mice with dextran sulphate (DS)
500 resulted in considerably reduced spleen titres over a long period of time. Subsequently, the
central nervous system disease was delayed or even prevented during the 350-day period of observation.
Both effects increased after multiple injections of the compound. The potency of DS 500 to protect
against scrapie was greatest when treatment and infection were carried out simultaneously. Under these
conditions the lethality of 500 to 1000 LD50 was reduced to almost zero. Treatment as early as 10
weeks before infection still prolonged the incubation periods. Of several other polyions tested,
dextran sulphate 5 and pentosan polysulphate also impaired scrapie pathogenesis."

Cumulative distribution anomaly in known human CJD mutations

1 Dec 98 webmaster
The graphic below shows the cumulative distribution anomaly in known human CJD mutations ( a set which has grown lately). They are strongly clustered in a small distal region 5/6 of the way down but not clustered in any evident way in 3 dimensions, seemingly more associated with post-translational modifications whose absence might affect happenings in the endoplasmic reticulum.

Looking at 102 prion sequences from 77 mammalian species to see how conservative the affected residues are in other species, one finds:

P102L: proline in all species
P105L: proline in all species
A117V: alanine in all species
M129V: leucine seen in elk allele, methionine all other species
Y145-: tryptophan seen in all rodents, tyrosine all other species
N171S: serine is wildtype in great apes, except gorilla is asparagine
D178N: aspartate in all species
V180I: valine in all species
T183A: threonine  in all species (glycosylation site)
H187R: histidine in all species, possible arginine in cat
 46198S: phenylalanine in all species, leucine in spider monkey
E200K; glutamate in all species
D202N: aspartate in all species
R208H: glutamine seen in sheep, goat alleles
V210I: valine in all species
Q212P: glutamine in all species
Q217R: glutamine in all species
E219K: glutamate in primates, glutamine all other species, possibly arginine in nyala
M232R: alanine in rodents and carnivores, valine in artiodactyls, methionine in primates, threonine in mouse, isoleucine in baboon

Note from this analysis that N171S is very likely to be neutral, contrary to one report. Codon 232 is very curious: it comes at a critical place immediately downstream of the GPI splice junction, yet is probably the tolerant to substitution of any residue in the entire post-cleavag residues are very highly conserved; however 3-4 residues upstream of the splice junction are also highly variable. This could just as well be a stragegy for controlling GPI cleavage (and release of prion into extra-cellular space) as for the extent of GPI attachment -- the relative proportions may vary by species or cell type.

R208H is worrisome to see in sheep and goat as alleles -- I wonder what the incidence of early scrapie is in this genotype with the new tests. M129L in elk is of interest in CWD. The more sequences that build up, the odder these seem.

129V is commonly said to be a neutral polymorhism but that is a poor fit to the evolutionary data. I looked briefly to see if, after adjusting for allele frequency, whether sporadic CJD was more common in V129V than M129M (though of course if some or all sporadic CJD is food-bourne it would be from M129M since all food except elk sausage has this and like-like would suppress statistics for V129V): but MM:VV was 2.7:1 {Windl] in sporadics whereas MM:VV alleles were 2.8:1. Growth hormone statistics favored V129V by a factor of 2.5; affected donor genotypes were not known and may have been too few to be a proportional mix. 20

Of course CJD isn't the selective pressure on residue 129 or anything else because historically it had no effect to speak of on reproductive success, disease having such late onset and lifespans being so short. If we ever get an enzymatic activity for normal prion protein, I will be curious to see if V129V compares somewhat unfavorably. The same holds for all the other non-synapomorphic positions, ie, these mutations likely have adverse effects on normal function as well as cause CJD.

However, CJD mutations must have their effect in heterozygotes to be detectable whereas disruption of normal function might be partly masked or compensated by the normal allele. That is why the 3 rare homozygous cases of K200K would warrant such careful study _if_ their condition had been detected before the onset of CJD (through early genetic screening of a known kindred).

The mutations not seen are just as informative as the ones observed. That eliminates bad thermodynamics per se. Safir et al. have raised the issue of rate of clearance of bad conformer as perhaps more critical than rate of formation. In other words, it is not enough for a mutation to give rise to bad conformer, that bad conformer must also have exceedingly slow clearance by proteases. V210E is much more extreme than V200I though also a single base change -- perhaps it is not suble enough in its effects and forms lots of bad conformer that turns over too rapidly to give CJD. That is a quantifiable feature of the above list -- the mutations observed are on the bland side of mutationally accessible change. (A third are CpG hotspots which have preordained directions of change but many potential hotspots are not producing observable mutation -- again, possibly not bland enough.)

Doxycycline control of prion protein transgene expression modulates prion disease in mice

Tremblay P et al. PNAS Vol. 95, Issue 21, 12580-12585, October 13, 1998
Highlights of article:

"Use of the tTA system to control PrP expression allowed production of Tg mice with high levels of PrP that otherwise cause many embryonic and neonatal deaths. It makes use of a transactivator (tTA) obtained by fusing the tetracycline repressor with the transactivation domain of the herpes simplex virus VP16 transcription factor. The tTA binds specifically with high affinity to the tetracycline operator (tetO) and activates transcription from a minimal promoter linked to the target gene. Binding of doxycycline, a tetracycline analog, to tTA prevents the protein from binding to the tetO region, thereby preventing target gene expression.

To test the hypothesis that developmental compensation in PrP-deficient mice prevented any recognizable dysfunction in adult mice, we used the tTA system in Tg mice to regulate PrP expression. The proportion of double Tg mice (24.0%) that survived through weaning was restored to the expected Mendelian ratio when mating pairs were kept on doxycycline during the entire pregnancy and through weaning of the litters (Table 4). The use of the tTA-regulated PrP transgene expression revealed that high levels of even wild-type PrPC are often incompatible with neonatal development, as most Tg(tTA:PrP) mice died within the first 3 weeks of life (Table 4).

A time course of repression and induction was performed by using doxycycline administered orally (2 mg/ml) to Tg(tTA:PrP)1 mice (Fig. 1B). PrPC expression was repressed 50% after 2 days of treatment and nearly fully repressed after 7 days; baseline levels were found in Tg(tTA:PrP)1 mice sacrificed after 30 days of treatment. Stopping doxycycline after 7 days produced an 50% reinduction of PrPC expression within 2 days, and complete reactivation was observed by 7 days. After 30 days of doxycycline treatment, PrPC expression was substantially repressed (Fig. 1B), with residual expression still detectable within the cingulate gyrus, caudate nucleus, hippocampus, thalamus, entorhinal cortex, and cerebellum

The ability to control PrPC expression should allow the establishment of Tg mice expressing higher levels of wild-type or mutant PrP than was previously possible. Such mice may demonstrate unique sensitivities to prion infection and provide the basis for a truly rapid bioassay.

Reversing the course of prion diseases by blocking the production of PrPSc through repression of PrPC expression will allow us to measure the removal of PrPSc. Such clearance studies, which were not previously possible, are a prelude to the development of effective therapies where drugs that block PrPSc formation are administered at the earliest onset of symptoms to patients with sporadic Creutzfeldt-Jakob disease. At present, we have no understanding of how much PrPSc can be tolerated by the CNS and how rapidly it will disappear once synthesis of its precursor, PrPC, is repressed. "

Complete genomic sequence and analysis of the prion protein gene region from 3 mammalian-species

GenBank entries: U29185 human prion, 35,522 base pairs; mouse 38,418 bp, and sheep 31,412 bp
Genome Research 1998; 8(N10): 1022-37
Lee,I.Y.; Westaway,D.; Smit,A.F.A.;...Baskin,D.; Cooper,C.; Yao,H.; Prusiner,S.B. and Hood L.
This appeared earlier as a chapter article in the 1966 Erice symposium book [appeared June 1998] and the resultse were thoroughly commented on earlier.There may be substantial advances in the Genome Research text; the journal has not yet reached the univ.iversity library shelves. They did a very nice job indeed, in providing a large context for human-sheep-mouse prion genes, in figuring out what most of the 89 intervening sequences were, and in doing large scale alignments.

There was a bit of bad luck in that they did not pick up neighboring genes either 5' or 3' to the prion gene in any of these species [no extra CpG islands or extended ORFs, that is]. According to the human genome project, 3% of the genome has content. Since exons 1, 2, 3 of the human gene total about 3% of the 35,522 bp sequenced, they were very close, statistically speaking, to determining the linked genes on both sides.

The latest human chromosome radiation hybrid G3 map of 33,000 genes (Deloukas, P. Science 282, 744-746, 1998. or NCBI or direct).

The nearest neighbors known are 'M-phase inducer phosphatase 2' and 'human mRNA for KIAA0168 gene' which have no immediate relationship to the prion gene.

No one expects a eukaryotic operon of course though sometimes adjacent genes do in fact have related functions (hemoglobins). More likely are prion pseudogenes and paralogues. That is, there have been 2-3 global duplications of the mammalian genome since the common ancestor with Amphioxus (and more recent ones in lobed fish such as salmon). Local tandem duplications are also common.

The prion gene is said from hybridization studies to be single copy (though there is that pesky anti-prion). Extra copies generally get lost through divergence to another function (paralogy), inactivation through accumulated stop codons, and eventually through disruption via deletion or retrotransposon insertion.

The question is, what has happened to all these extra copies of the prion gene? Chromosome 20 may not have been the site of the original prion gene (though extensive synteny exists with mouse chromosome 2 though not immediately around the prion gene), see

44122478..44127562  + 1695557254 mouse sialoadhesin
44242549..44242785  + 79200533   mouse prion
44243893..44247307  + 26253602   DNA polymerase delta auxiliary protein
The Resourcenzentrum (RZPD) has made gridded genomic libraries of the keystone chordates available to anyone. There are six cosmid libraries: Ciona intestinalis (Hemichordate), Branchiostoma floridae (Cephalochordate), Lampetra fluviatilis (Cyclostoma), Xiphophorus maculatus, and Danio rerio (Osteichthyes) and Fugu rubripes. See Genomics 1998 Sep 1;52(2):230-2.

These species could quickly provide -- after 78 years and 6,000 papers -- the normal function of the prion protein.

Normal function, early diagnosis, and therapeutics are a 3-legged stool. A stool cannot function with 1 or 2 legs.LBJ's War on Cancer of 1964 is reminiscent of current prion research: a huge push on diagnostics and screening of chemicals, little for basic biology, and what did it do -- cancer is worse than ever.

Dog sequence anomaly confirmed

Fri, 27 Nov 1998 Dr. Deirdre Doyle
Question (webmaster): I noticed that the GenBank sequence AF042843 for dog prion protein has an extra G in the post-signal region CKKRPKPGGWNTGGG, which is ggg ggt ggg as dna. No other species has that, including other carnivores. Is there a possibility of error here?

Answer: ( D. Doyle): There is no mistake in the sequence. We noticed this seemingly extra G ourselves but it is present in both dog sequences that we sequenced. However both dogs are greyhounds and whether this is common to other breeds, I cannot comment on.

Comment (webmaster):

Thank you very much for taking reviewing the original data. I am comfortable now with the extra G even though I expected the extra to be a duplicated codon with the same silent position as happens with extra G's in the repeat region. ggg ggt ggg seen, ggg ggg presumed source. There was a similar improbable anomaly downstream with pigs, a unique alanine at a conserved site(226 human numbering) requiring two base changes that nonetheless has recently been confirmed by a European group in 18+ pigs of 6 breeds and a wild boar as well.

No question, inbred animals, whether pets, farm, or lab, could fix odd alleles. There has been the same concern with mule deer and CWD, that the herds are very small and genetically isolated because of habitat fragmentation. Here is the codon use in 93 species for gly-gly, which suggests that the extra gly in dog is the ggt codon.

First G codon use #spp
  gga  18
  ggg  64
 total 93

Second G codon use #spp
  gga  13
  ggc  33
  ggg  47
 total 93
The GGT codon for glycine is a bit unusual -- here are some statistics from GenBank, codon use per 10,000 codons from 259 dog sequences at GenBank. Nothing cosmic here though odd how depleted ggc is in first G relative to popularity overall, suggesting change is unsaturated.
ggt 123
ggc 234
gga 169
ggg 172

ggt g 110
ggc g 235
gga g 167
ggg g 167

ggt 120
ggc 231
gga 179
ggg 161

ggt 113
ggc 253
gga 164
ggg 173

Can TSEs be diganosed from urine?

Thu, 26 Nov 1998
Pr Jeanne Brugere-Picoux
Pathologie medicale du betail et des animaux de basse-cour
Ecole nationale veterinaire d'Alfort
Tel : 33 (1) 43 96 71 22
Fax : 33 (1) 43 96 09 67
"Urine Tests [claims on Maff web site]

"Alternative diagnostic tests in the live animal involve the detection of disease-specific physiological or metabolic markers. These are secondary substances produced as a result of infection. Such markers, apparently related, have been identified in serum and in urine. Whether or not they are specific to BSE or scrapie remain to be proved.

Changes have been detected in the constituents of urine of CJD patients, sheep with scrapie and cattle with BSE. Molecules which may be disease specific... Changes have been found in cattle and further work is in progress to develop and validate a diagnostic test. The time of appearance of this substance at detectable levels in the disease is not known. Work is underway to determine when these changes are first detectable during the long incubation period of BSE." Comment (Pr Jeanne Brugere-Picoux):

"It is not a specific test but perhaps a possibility of ante-mortem help in the diagnosis of spongiform encephalopathy in animals (there is not problem of Alzheimer disease in food animal production). " [AD also gives positive -- webmaster]

"Here is a bibliography of French work. The first results obtained in France (with the collaboration of Weybridge giving us sample of urine of cows with BSE during years 1991/92) are at the origin of the same work made later in Weybridge (Dr Jackman) and after in this european project."

Recherche d'un tÈmoin biochimique urinaire de l'infection du mouton par la tremblante.

H. Brugere, C. Banissi, J. Brugere-Picoux, J. Chatelain et R. Buvet
Bull. Acad. VÈt. de France, 1991, 64, 139-145

Mise en Èvidence par micro-Èlectrolyse urinaire d'un marqueur biochimique des affections cÈrÈbrales dÈgÈnÈratives primaires humaines.

B. Planques, H. Brugere, C. Banissi-sabourdy, C. Jeannin, J. P.David, C. Di Menza, J. Brugere-Picoux, J. Chatelain et R Buvet 
(Poster):C.R. de la RÈunion Francophone sur la Maladie d'Alzheimer et les syndromes apparentÈs, Toulouse, 22-23 Novembre 1991

Electroanalytical characterization of Alzheimer's disease and ovine spongiform encephalopathy by repeated cyclic voltametry at a capillary graphite paste electrode

C. Banissi-sabourdy, B. Planques, J.P. David, C. Jeannin, M. Potel, M. Bizien, C. Di Menza, J. Brugere-Picoux, H. Brugere, J. Chatelain et R. Buvet
Bioelectrochemistry and Bioenergetics, 1992, 28, 127-147

Electrochemical analysis of urine from sheep with scrapie and cows with BS

In "Transmissibles spongiform encephalopathies" Ed. R. BRADLEY, B.
MARCHANT, Proceedings of a consultation on BSE with the Scientific
Veterinary Commission of the European Communities held in Brussels, 14-15
September 1993., p 359-368, Edition C.C.E.Bruxelles 1994.
H. Brugere , C. Banissi-sabourdy, J. Brugere-Picoux

Electrochemical analysis of urine in Alzheimer patients and in ruminants with spongiform encephalopathies (scrapie and BSE).

III. International symposium on Transmissible subacute spongiform encephalopathies : prion diseases ,  Paris, Val de Gr’ce, 18-20 mars 1996.
H. Brugere , C. Banissi-Sabourdy, B. Planques, J. Brugere-Picoux, J.
Chatelain, M.C. Tournaire Et R. Buvet (poster)

Molecular screening of sheep for bovine spongiform encephalopathy.

Neurosci Lett 1998 Oct 23;255(3):159-62 
Hill AF, Sidle KC, Joiner S, Keyes P, Martin TC, Dawson M, Collinge J
BSE may have transmitted to sheep through feed and pose a risk to human health. Sheep BSE cannot be clinically distinguished from scrapie, and conventional strain typing would be impractical on a significant scale. As human prion strains can be distinguished by differences in prion protein (PrPsc) conformation and glycosylation we have applied PrP(Sc) typing to sheep. We found multiple Western blot patterns of PrP(Sc) in scrapie, consistent with the known scrapie strain diversity in sheep. Sheep passaged BSE showed a PrP(Sc) banding pattern similar to BSE passaged in other species [Collinge, J., Sidle, K.C.L., Meads, J., Ironside, J. and Hill, A.F., Nature, 383 (1996) 685-690], both in terms of fragment size following proteinase K cleavage and abundance of diglycosylated PrP.

However, none of the historical or contemporary scrapie cases studied had a PrP(Sc) type identical to sheep BSE. While more extensive studies, including sheep of all PrP genotypes, will be required to fully evaluate these findings, these results suggest that large scale screening of sheep for BSE may be possible.


Note first that Neurosci Lett is supposed to be a vehicle for rapid communication, yet 37 days have elapsed between publication and submission of the abstract to Medline. Most journals today are simultaneous or better.

The article provides no support for the idea that BSE originated in sheep. However, there are many genotypes of sheep prion, some quite rare, and not all strains of scrapie have necessarily been found.

Structural aspects of Congo red as an inhibitor of protease-resistant prion protein formation.

Demaimay R, Harper J, Gordon H, Weaver D, Chesebro B, Caughey B
J Neurochem 1998 Dec;71(6):2534-41 
Congo red (CR) has been shown to inhibit the accumulation in scrapie-infected cells of prion protein (PrP) in the abnormal protease-resistant form (PrP-res). However, it was not clear if this effect was due to a direct interaction of CR with either PrP-res or its protease-sensitive precursor (PrP-sen) or to a less direct effect on living cells. Here we show that CR inhibits PrP-res formation in a simple cell-free reaction composed predominantly of purified PrP-res and PrP-sen. Structurally modified CR analogues were also compared in both the cell-free conversion reaction and scrapie-infected neuroblastoma cells. Methylation of the central phenyl groups at the 2,2' positions diminished the inhibitory potency by > or 10-fold. In contrast, there was little effect of 3,3' methylation of the phenyls, deletion of one phenyl, or addition of an amido group between the phenyls. The relative activities of these compounds were well correlated in both cellular and acellular systems. Molecular modeling indicated that CR and 3,3'-methyl-CR have little rotational restriction about the biphenyl bond and can readily adopt a planar conformation, as can phenyl-CR and amido-CR. In contrast, 2,2'-methyl-CR is restricted to a nonplanar conformation of the biphenyl group. Thus, planarity and/or torsional mobility of the central phenyl rings of CR and its analogues is probably important for inhibition of PrP-res formation. On the other hand, variations in the intersulfonate distance in these molecules had little effect on PrP-res inhibition. These results indicated a high degree of structural specificity in the inhibition of PrP-res formation by CR and related compounds.

Phenotypic variability of GSS is associated with prion protein heterogeneity.

J Neuropathol Exp Neurol 1998 Oct;57(10):979-88 
Piccardo P, Dlouhy SR, .. Gibbs CJ Jr, Gajdusek DC, Bugiani O, Ironside J, Tagliavini F, Ghetti B
GSS, a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the prion protein gene ), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants.

Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L.

This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.

Comment (webmaster):

The J Neuropathol Exp Neurol forgot to send in a whole issue, #5 of this year, to Medline This contained an important earlier article by Young, K, Piccardo, P et al describing a new point mutation causing CJD, namely Q212P. The full reference is J Neuropathol Exp Neurol. 1998 Jun;(5) 57:518 'GSS with a prion mutation at position 212.'

The first article above has further details on Q212P and D202N (still unpublished). Among other interesting points, the introduction states that 40 kindreds are known for P102L. Numbers of distinct kindreds for the other classes of familial CJD are harder to come by, except for repeat insertions. P102L is a CpG mutational hotspot having to do with demethylation of C and C to T change, the only instance of this (though there are 6 CpG resulting in G to A. There could easily be ascertainment issues as well as these frequency issues.

Basically none of the15 patients here were diagnosed correctly ante-mortem. Alzheimer, familial Parkonson, olivopontocerebellar degeneration, etc. were proposed.

The article appeared simultaneously with "Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L GSS" PNAS 1998 95: 8322-8327, Parchi, P et al. but was not integrated with it, even though some authors were on both papers. Both papers find a 7-8 k fragment as well as a 21k in immunoblots; the former seems characteristic of GSS plaque and the latter for spongiform degeneration. The small fragment is said to be unglycosylated, react with antibody AS6800 (residues 89-104), colocalize with the multicentric amyloid plaques, and be lost upon transmission; the ragged termini are N-terminus 74-83, C-terminus is 147-153, along the lines of the Y145stop mutation.

The BASES Project:European research project on BSE policy-making and scientific research

1 Dec 98
Dr Erik Millstone
SPRU - Science and Technology Policy Research
Mantell Building
Sussex University
Brighton BN1 9RF

Tel: (44) (0)1273 877380 Direct
Tel: (44) (0)1273 686758 ext. 7380 via our switchboard
Fax: (44) (0)1273 685865
We would like to inform subscribers to the BSE-L List of a new European research project on BSE policy-making and scientific research. We will be analysing how the regulatory regimes and research systems in different Member States, and in the Commission, have responded to the emergence of evidence and information on BSE and other TSEs, over the period from 1979 to 1998. At its simplest, the project aims to learn the lessons of the BSE saga for food and agricultural policy in the EU and, in particular, for the relationship between science, expertise and public policy.

The project is funded by DG XII and is entitled 'Building A Common Data Base on Scientific Research and Public Decisions on TSEs In Europe' (BASES). The project is being conducted by researchers from both the social and the natural sciences in research centres in the UK, France, Portugal and the Netherlands. A list of the institutions and contacts is provided at the end of this message, and more information is available on the BASES WebPage ; the URL is: /BASES

We are posting this message in case our work could help subscribers to this list, and in the hope that information which subscribers have could assist with our project.

Overview of the BASES project

One of the main tasks of this project is to construct an integrated relational data base which will include, in a detailed chronological form, information on the emergence of scientific information on BSE and other TSEs, and the responses to those developments in the form of research programmes and projects and in the form of expert and official advice and regulations. The creation of such a data base will facilitate the analysis of public decision-making in a complex and uncertain context. While the primary objective of the project is to learn the lessons of the BSE saga for EU policy, we will also examine the feasibility of designing a monitoring and 'early listening' system, and what such a system might imply for the ways in which institutions are organised.

The BASES project will focus primarily on the participating EU Member States (France, the Netherlands, Portugal and the UK) and, where relevant, the EU Institutions. However, we will also gather less detailed information on the ways in which the BSE saga has evolved in most of the remaining member states (and Switzerland) as well as the structure of the relevant research and regulatory regimes and their responses to BSE.

The main participating institutions (and contacts) are:

Project Co-ordinator: Pierre-Benoit Joly at the Institut National de la Recherche Agronomique (INRA), Laboratoire d'Economie, Grenoble, France (contact : < > or Marc Barbier )

SPRU - Science and Technology Policy Research, Sussex University, Brighton, UK (contact : Paddy van Zwanenberg < p.f.van-zwanenberg@sussex> and/or Erik Millstone )

The Instituto Superior de Ciencias do Trabalho e da Empresa (ISCTE), Lisbon, Portugal (contact : Maria Eduarda Goncalves <>)

The Laboratorio Nacional de Investigacao Veterinaria (LNIV), Lisbon, Portugal (contact : Luciano Goncalves

The Department of Philosophy of Science and Technology, University of Twente, The Netherlands (contact : Wim Smit and/or Frank van der Most ) Comment (Roland Heynkes):

"As I built my own database with more than 5500 articles about prion diseases during the last 8 years, I am interested in your project. Especially full texts of political decisions would be helpful, if you can add abstracts in which you translate the legal terminology into an understandable language. But I have some questions.

Why do you restrict your search to articles later than 1978, when a lot of scientific data about scrapie and CJD already had been published. In my opinion you cannot decide what should have been known in 1985 about BSE, without knowledge about all the early articles about CJD and scrapie from before 1979. For me it would be still not enough, but with Medline you can easily go back into the sixties.

It is always a good idea to learn from former mistakes, but we already do that with the BSE inquiry and several conferences (the last ended yesterday in Brussels). Wouldn't it be better to get a valuable tool for future work? What we really need is a database where biomediacl scientists can find legal regulations in an understandable form and a large review connected with a really complete database, where politicians, the whole public and even prion researchers can read what is already known about TSEs. I am sure that there is absolutely nobody who knows all the facts about TSEs and it would need many of the best experts in order to collect all the TSE articles into one database and to extract and sort all the information from this many more than 6000 articles into a working review.

I had a look on your web site, but could not find the TSE experts. Who are the TSE experts in your team? In my opinion you will need several in order to understand what really should have been known at a specified point of time.

It should be no problem to assist your project, but how do you want to organize cooperation?

Theoretically such a chronology may be helpful for an inquiry, but much less for actual and future scientific progress. Furthermore a relational data base is not made for chronology. Why don't you simply sort the records of your data base in an organized text file? This would make it easily transportable, easy to handle with any word processor, and you could import it into any information retrievel program for complex searches. But there is a further problem. If you want to sort your records chronological, you have to know when the information appeared and this is not so easy. Normally you cannot simply use the date of publication, because the data where circulating in inner circles, conferences, or ministries months or even years earlier. How do you want to fix this problem?

I think we already learned a lot about how mismanagement increased the BSE crisis and should start to improve some structures now. The EU commision and the british government in contrast to most national governments already learned that in the long run transparency and a priority of public health over market interests works better than down playing of potential risks. The SSC works much better now than former scientific committees and its transparency is very helpful.

But unfortunately the totally obsolete and overcharged mechanisms of scientific communication in biology and medicine are still the same. I don't see any efforts to improve them. Everybody asks for scientific information about TSEs, but we still loose months or even years until data become published. One reason is the peer review process and therefore we should get a preprint system for biomedical science as soon as possible.

Another reason is a pitiable lack of cooperativity among scientists on a very competitive field with comercial interests. When the data finally become published, it is quit impossible to find all of them, because the databases cover only some 3500 biomedical journals. Even if you find the mostly english written articles of this selected journals, you get only bibliographical information and in most cases an abstract. So have to spend a lot of time and money in order to get the full articles. In my opinion this is not acceptable so many years after the very successful introduction of the preprint system in physics. They easily find every article as full text that just has been sent to a journal for publication.

Finally the analysis of the published data has to be organized. It's a pity that we still don't have a theoretical biology and medicine, but this must be a consequence of the fact that only the most intelligent people study physics, whereas most biologists and physicians have many problems with simple mathmatics. What we easily could do now is to come together in a permanent internet conference with the aim to reach agreement whereever possible about what the known facts are and how they can be interpretated. All together we should write a review about what science knows about TSEs and put it on the internet as a working base for scientists and politicians and in order to inform the public. Is it really too much to ask for cooperativity among the mostly tax payed scientists when people already die from BSE infections?

You will never get a valuable picture about the evolution of knowledge about TSEs, if you don't include all publications all over the world.

Could you please give us all participating institutions? Shouldn't there be much more and from many more countries? 500.000 Ecu are not too much for this project, even hardly enough for my personal data base. So I only can hope that you will be able to do something which will be really helpful.

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