Roland Heynkes on BSE

Listserve and Correspondence through 10.10.96
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Roland Heynkes email  Home Page
52072 Aachen
Tel: 0241/93207-0 - Fax: 0241/93207-2 (oder -1)

The German veterinary who was wrongfully terminated for blowing the whistle on BSE is Dr. Margit Herbst in Bad Bramstedt. Although I know her story from several talks with her, you should ask her personally to avoid mistakes of transmission. Dr. Kari Koester-Loesche is also very familiar with this proceedings. The other case is that of a british veterinarian, who refused to manipulate certificates. You can find the informations on Steven Dealler's site, who seems to be very familiar with this case.
I have extrapolated from the known data to the whole lifespan of cattle (about 22 years) with the assumption that the BSE incidence would not decrease with the age of the cow. Then I get a putative maternal transmission rate of 30-45%. A transmission rate of 45% will normally result in more than one infected female calf per cow, but only one of four of this infections will be lethal within 7 years.
The abrupt decrease is the consequence of the drastic reduction of the main source of infetivity. The reduction is more than proportional to the reduction of infectivity, because many infections fall under the threshold of a within about 7 years lethal dosis.

Manipulated are the mean incubation time and the rate of BSE infected animals not with the intention of a manipulation, but simply because of the loss of retainability of a cow with decreasing condition.

A drop in milk production has been noted as typical first symptom of BSE. Dr. Beat Hoernliman, the Swiss BSE- coordinator told me, that a drop of milk productifity as the first symptom has been reported by the owners of about half of the swiss BSE cases. They only have not had the idea to quantify this. Ray Bradley also stated in an answer to my question, that a reduction of milk productivity is a well known symptom of BSE.

The increase and decrease of the BSE epidemie is obviously caused mainly by changes in the titer of infectivity within the ruminant food. This is a further factor, totally independent from the possible factor milk productivity. You should not mix them in the statistical analysis

. The maternal transmission study will not give us much more evidence with respect to the BSE incidence of older cows, because they were killed when they became 7 years old."

Hans Anderson responds:

Yes. Colin Whitaker, the vet that discovered the first cases of BSE, wrote in his report regarding the first 10 cases at the same farm outside Ashford, Kent:

"Milk yield gradually drops and there is loss of condition in the later stages." (Presentation at a meeting of the British Cattle Veterinary Association in July 1987)

"In my paper I had a list of differential diagnosis, and the last one was 'a new scrapie-like syndrome'. The Ministry (MAFF) asked us not to use that (at the meeting in '87) - or told us not to use the word 'scrapie-like'. I think they were concerned that it would effect the sheep market." (Sept 23 1996)

The word was blacked out at the meeting. Colin Whitaker's report was published one year later, in its original version.

"The problem is that neither the UK or German government followed any Precautionary Principle. For example I can not see any endeavour of the British government to wipe out scrapie, and in germany meat bone meal is still made of this British sheep. Different to the new British regulations in Germany this meat bone meal is still used in the food stuff of pigs, chicken and fish and the fat of this partially scrapie infected sheep can be still be used to feed german calves.

It is legal to mix gelatine, fat from all animals and even blood products into the milk substitute for German calves. Furthermore meat bone meal does not have to be made with the famous German method with 133 degree Celsius at 3 bar pressure for 20 minutes. It only has to be dried if it comes from not obviously sick animals. I described that for Germany but as we all know the British circumstances are not better.

Every governmet that has to tighten its standards because they didn't follow any Precautionary Principle in the past."

"The situation became much better since 1988, but the feeding of MBM to non ruminant mammals has been stopped only years later, while the production of the infectious meat bone meal has not been stopped, there was no messure on gelatin production, the export of sheep is going on and the British government did not control whether the exported calves are from herds without BSE or at least from mothers without BSE. If I were British, I would be very unhappy with this governmet and the SEAC."
"It is easy to find references to experimental results which show that the sensitifity of the BSE-tests have been very low. D.M. Taylor mentioned the problem in his well known paper (Veterinary Record 1995 137, 605-610) about rendering procedures.

Also remember the old article of Dickinson et al. in Nature 1975; 256 732-3. No test is sensitive only because of other less sensitive tests and tests are much more sensitive if there is no species barrier and if the normal life span of the inoculated animal is longer than that of mice. Cutlip et al. for example only have to wait 14-18 months after ther the inoculation of new born calves until the symptomes became visible (J.Inf.Dis. 1994; 169: 814-20). After that minimum incubation time you can wait more than 20 years for the symptomes if you are interested in a maximum of sensitivity with a biological functional test."

"Peer reviewing removes many mistakes from scientific articles and even many articles that would only waste our time. This is very important, if recipients are not familiar with the described experiments and need the help of specialists. The specialists themselves do not need this help so much because they are able to distinguish valuable data from glaring gaff.

On the other hand the specialists lost a lot of time because it takes months or even years until an article has been accepted and finally published. This aspect is less important for the broader publicum, which can wait for the qualitiy proven articles. Therefor I do not want to replace the scientific journals, but I only want to get an additional tool for the specialists of a field of research, as physicists, chemicists, mathematicians and psychiologists have it. If many specialists discuss an article, they will find even more mistakes and erroneous ideas than only two reviewers.

Scientists may view peer review as an invaluable resource to confirm, clarify and substantiate research articles, but at the same time many of them suffer from the described delay. The quality of research will not suffer from APADS, because they do not replace the qualitiy check of scientific journals."

"Possible roles and effects of the glycosylation of the prion protein: it seems not to influence the conversion of the normal to the proteaseresistent form (Kocisko,D.A.; Priola,S.A.; Raymond,G.J.; Chesebro,B.; Lansbury,P.T.; Caughey,B. - Species-specificity in the cell-free conversion of prion protein to protease-resistant forms - a model for the scrapie species barrier - Proceedings of the National Academy of Sciences of the United States of America 1995 Apr 25; 92(9): 3923-7). For me this article is the most important of the last years and at the same time it is tragic, that they did not see the chance to proof or disproof the Prion Theory with this simple experiment within a few days.

The Glycosylation influences the transport of the cellular prion protein to the surface (Lehmann,S.; Harris,D.A. - Effect of 2 pathogenic mutations on the cellular processing of the mouse prion protein - Journal of Cellular Biochemistry 1995; 1995(S21B): 104). Incorrect Glycosylation may cause artificial results of the Collinge experiments with transgenic mice. The article of Kocisko et al. demonstrates, that glycosylation is not required for the transmission of strain attributes to the normal prion protein.

Literature List:
Atouf,F.; Scharfmann,R.; Lasmezas,C.; Czernichow,P. - Tight hormonal
 control of PrP gene expression in endocrine pancreatic cells - Biochemical
 and Biophysical Research Communications 1994 Jun 30; 201(3):
Bendheim,P.E.; Brown,H.R.; Rudelli,R.D.; Scala,L.J.; Goller,N.L.;
 Wen,G.Y.; Kascsak,R.J.; Cashman,N.R.; Bolton,D.C. - Nearly ubiquitous
 tissue distribution of the scrapie agent precursor protein - Neurology 1992
 Jan; 42(1): 149-56
Borchelt,D.R.; Koliatsos,V.E.; Guarnieri,M.; Pardo,C.A.;
 Sisodia,S.S.; Price,D.L. - Rapid anterograde axonal transport of the
 cellular prion glycoprotein in the peripheral and central nervous systems -
 The Journal of Biological Chemistry 1994 May 20; 269(20):
Borchelt,D.R.; Rogers,M.; Stahl,N.; Telling,G.; Prusiner,S.B. -
 Release of the cellular prion protein from cultured cells after loss of its
 glycoinositol phospholipid anchor - Glycobiology 1993 Aug; 3(4):
Borchelt,D.R.; Scott,M.; Taraboulos,A.; Stahl,N.; Prusiner,S.B. -
 Scrapie and cellular prion proteins differ in their kinetics of synthesis
 and topology in cultured cells - The Journal of Cell Biology 1990 Mar;
 110(3): 743-52
Brown,H.R.; Goller,N.L.; Rudelli,R.D.; Merz,G.S.; Wolfe,G.C.;
 Wisniewski,H.M.; Robakis,N.K. - The mRNA encoding the scrapie agent protein
 is present in a variety of non-neuronal cells - Acta neuropathologica 1990;
 80(1): 1-6
BTeler,H.; Fischer,M.; Lang,Y.; Bluethmann,H.; Lipp,H.P.;
 DeArmond,S.J.; Prusiner,S.B.; Aguet,M.; Weissmann,C. - Normal development
 and behaviour of mice lacking the neuronal cell-surface PrP protein [see
 comments] - Nature 1992 Apr 16; 356(6370): 577-82
Castelnau,P.; Lazarini,F.;
 Deslys,J.P.; Dormont,D. - Prion protein gene expression in cultured
 astrocytes treated by recombinant growth hormone and insulin-like growth
 factor - Experimental Neurology 1994 Dec; 130(2): 407-10
 Whittington,M.A.; Sidle,K.C.L.; Smith,C.J.; Palmer,M.S.; Clarke,A.R.;
 Jefferys,J.G.R. - Prion protein is necessary for normal synaptic function -
 Nature 1994 Jul 28; 370(6487): 295-7
Denman,R.; Potempska,A.; Wolfe,G.;
 Ramakrishna,N.; Miller,D.L. - Distribution and activity of alternatively
 spliced Alzheimer amyloid peptide precursor and scrapie PrP mRNAs on rat
 brain polysomes - Archives of Biochemistry and Biophysics 1991 Jul; 288(1):
Forloni,G.; Angeretti,N.; Chiesa,R.; Monzani,E.; Salmona,M.;
 Bugiani,O.; Tagliavini,F. - Neurotoxicity of a prion protein fragment -
 Nature 1993 Apr 8; 362(6420): 543-6
Fournier,J.G.; Escaighaye,F.;
 Devillemeur,T.B.; Robain,O. - Ultrastructural localization of cellular
 prion protein (PrPc) in synaptic boutons of normal hamster hippocampus -
 Comptes Rendus de l'Academie des Sciences Serie III - Sciences de la Vie
 1995 Mar; 318(3): 339-44
Gabriel,J.M.; Oesch,B.; Kretzschmar,H.; Scott,M.;
 Prusiner,S.B. - Molecular cloning of a candidate chicken prion protein -
 Proceedings of the National Academy of Sciences of the United States of
 America 1992 Oct 1; 89(19): 9097-101
Halabi,G.; Morelon,E.; Lavery,P.;
 Loertscher,R. - Beta(2) microglobulin (beta(2)m) supports the transport of
 the cellular prion glycoprotein (prpc) to the cell-surface - Kidney
 International 1995; 48(N1): 298
Harmey,J.H.; Doyle,D.; Brown,V.; Rogers,M.S.
 - The cellular isoform of the prion protein, PrP(C), is associated with
 caveolae in mouse neuroblastoma (N(2)a) cells - Biochemical and Biophysical
 Research Communications 1995 May 25; 210(3): 753-9
Harris,D.A.; Lele,P.;
 Snider,W.D. - Localization of the mRNA for a chicken prion protein by in
 situ hybridization - Proceedings of the National Academy of Sciences of the
 United States of America 1993 May 1; 90(9): 4309-13
Harris,D.A.; Huber,M.T.;
 van-Dijken,P.; Shyng,S.L.; Chait,B.T.; Wang,R. - Processing of a cellular
 prion protein: identification of N- and C-terminal cleavage sites. -
 Biochemistry 1993 Feb 2; 32(4): 1009-16
Harris,D.A.; Falls,D.L.;
 Johnson,F.A.; Fischbach,G.D. - A prion-like protein from chicken brain
 copurifies with an acetylcholine receptor-inducing activity - Proceedings
 of the National Academy of Sciences of the United States of America 1991
 Sep 1; 88(17): 7664-8
Horiuchi,M.; Yamazaki,N.; Ikeda,T.; Ishiguro,N.;
 Shinagawa,M. - A cellular form of prion protein (PrPC) exists in many non-
 neuronal tissues of sheep - Journal of General Virology 1995 Oct; 76(Part
 10): 2583-7
Hornshaw,M.P.; McDermott,J.R.; Candy,J.M. - Copper binding to
 the N-terminal tandem repeat regions of mammalian and avian prion protein -
 Biochemical and Biophysical Research Communications 1995 Feb 15; 207(2):
Huang,Z.W.; Cohen,F.E.; Prusiner,S.B. - Structural basis of prion
 diseases - Journal of Cellular Biochemistry 1995; 1995(S21B):
Huang,Z.W.; Gabriel,J.M.; Baldwin,M.A.; Fletterick,R.J.; Prusiner,S.B.;
 Cohen,F.E. - Proposed three-dimensional structure for the cellular prion
 protein - Proceedings of the National Academy of Sciences of the United
 States of America 1994 Jul 19; 91(15): 7139-43
 Prusiner,S.B.; Stowring,L.E.; DeArmond,S.J. - Scrapie prion proteins are
 synthesized in neurons - American Journal of Pathology 1986 Jan; 122(1):
Kurschner,C.; Morgan,J.I. - Analysis of interaction sites in homomeric
 and heteromeric complexes containing bcl-2 family members and the cellular
 prion protein - Molecular Brain Research 1996; 37(N1-2):
Kurschner,C.; Morgan,J.I. - The cellular prion protein (PrP)
 selectively binds to Bcl-2 in the yeast two-hybrid system - Molecular Brain
 Research 1995 May; 30(1): 165-8
Lazarini,F.; Castelnau,P.; Chermann,J.F.;
 Deslys,J.P.; Dormont,D. - Modulation of Prion Protein Gene Expression by
 Growth Factors in Cultured Mouse Astrocytes and PC-12 Cells - Molecular
 Brain Research 1994 Mar; 22(1-4): 268-74
Loertscher,R.; Lavery,P.; White,M.;
 Lazarovits,A.I. - Cellular prion protein (prpc) clusters with beta(2)
 microglobulin (beta(2)m) on the cell-surface of human- lymphocytes - Kidney
 International 1995; 48(N1): 298
Manson,J.C.; Clarke,A.R.; Hooper,M.L.;
 Aitchison,L.; McConnell,I.; Hope,J. - 129/Ola mice carrying a null mutation
 in PrP that abolishes mRNA production are developmentally normal -
 Molecular Neurobiology 1994 Apr-Jun; 8(2-3): 121-127
Manson,J.C.; West,J.D.;
 Thomson,V.; McBride,P.; Kaufman,M.H.; Hope,J. - The prion protein gene: a
 role in mouse embryogenesis? - Development 1992 May; 115(1):
McBride,P.A.; Eikelenboom,P.; Kraal,G.; Fraser,H.; Bruce,M.E. - PrP
 protein is associated with follicular dendritic cells of spleens and lymph
 nodes in uninfected and scrapie-infected mice - Journal of Pathology 1992
 Dec; 168(4): 413-8
Moser,M.; Colello,R.J.; Pott,U.; Oesch,B. - Developmental
 expression of the prion protein gene in glial cells - Neuron 1995 Mar;
 14(3): 509-17
Nakahara,D.H.; Lingappa,V.R.; Chuck,S.L. - Translocational
 pausing is a common step in the biogenesis of unconventional integral
 membrane and secretory proteins - The Journal of Biological Chemistry 1994
 Mar 11; 269(10): 7617-22
Oesch,B.; Moser,M.; Coufal,F.; Prusiner,S.B.;
 DeArmond,S.J. - Distribution of the prion protein and its ligands -
 implications for spongiform encephalopathies - Journal of Cellular
 Biochemistry 1995; 1995(S21B): 106
Shyng,S.L.; Moulder,K.L.; Lesko,A.;
 Harris,D.A. - The n-terminal domain of a glycolipid-anchored prion protein
 is essential for its endocytosis via clathrin-coated pits - The Journal of
 Biological Chemistry 1995 Jun 1; 270(24): 14793-800
Stahl,N.; Baldwin,M.A.;
 Hecker,R.; Pan,K.M.; Burlingame,A.L.; Prusiner,S.B. - Glycosylinositol
 phospholipid anchors of the scrapie and cellular prion proteins contain
 sialic acid - Biochemistry 1992 Jun 2; 31(21): 5043-53
 Scott,M.; Semenov,A.; Avraham,D.; Laszlo,L.; Prusiner,S.B. - Cholesterol
 depletion and modification of COOH-terminal targeting sequence of the prion
 protein inhibit formation of the scrapie isoform - The Journal of Cell
 Biology 1995 Apr; 129(1): 121-32
Toh,B.H.; Gibbs,C.J. Jr; Gajdusek,D.C.;
 Tuthill,D.D.; Dahl,D. - The 200- and 150-kDa neurofilament proteins react
 with IgG autoantibodies from chimpanzees with kuru or Creutzfeldt-Jakob
 disease; a 62-kDa neurofilament-associated protein reacts with sera from
 sheep with natural scrapie. - Proceedings of the National Academy of
 Sciences of the United States of America 1985 Jun; 82(11):
Whatley,S.A.; Powell,J.F.; Politopoulou,G.; Campbell,I.C.;
 Brammer,M.J.; Percy,N.S. - Regulation of intracellular free calcium levels
 by the cellular prion protein - Neuroreport 1995; 6(N17):
Whittington,M.A.; Sidle,K.C.L.; Gowland,I.; Meads,J.; Hill,A.F.;
 Palmer,M.S.; Jefferys,J.G.R.; Collinge,J. - Rescue of neurophysiological
 phenotype seen in prp null mice by transgene encoding human prion protein -
 Nature Genetics 1995 Feb; 9(2): 197-201

"There are mainly two problems with the Weybridge maternal transmission study:

1) The calfs of the negative control group came from the same herds as the calfs from obviously BSE affected cows. Nobody knows whether the mothers of the control group have been BSE infected or not. It is hard to believe, but they can even not exclude that their calves consumed infectious foodstuff. This was a really poor experimental design.

2) The shortened the time of observation from possible 20 years down to only 7. In my oppinion they did this in order to reduce the total number of affected animals and eventualy to hide an increase in the BSE incidence with the age of the animals. As I mentioned before the British BSE statistic shows a decline of the BSE incidence after the age of 6, which may be caused by a BSE driven drop of milk productivity. The aborted experiment was a singular opportunity to demonstrated the true development of the BSE incidence without any covering factor of selection. In eyes it was a crime against science and public health to kill the remaining animals.

What SEAC did with the Weybridge data was so stupid, that it not relly deserves a comment. They subtracted the less than 5% of BSE in the control group from the more than 15% in the other because allegedly 5% of all calves eat infectious foodstuff and died of that. Does anybody wonder why they didn't see the possibillity of infcted mothers in both groups? Than they concluded without data that the risk of maternal transmission has to be 10% within the last 6 months before the mother dies and 0% if this timespan is 1 day longer. Then they divided this 6 months by the never experimentally proofed 60 months of mean BSE incubation time to get a risk of only 1%. A cow gets its first calf after 27-30 months and that the BSE incidences are equally when they get their third, fourth or fifth calve. Are the members of SEAC scientists or what?

How long did they live after they have born the control calves? Even if they lived for additional 10 years this could not proof that they were not infected. But I am sure they were killed much earlier. Can you tell us why this dams did not live at least until the end of the study?

It is not possible to exclude BSE at early stages histopathologically. It is much better do use immunological tests, but I do not know any experiment that demonstrates the detection of early stages of BSE. Can you give us such a reference?

The WKeybridge experiment has not proven that the calves must have been infected by maternal transmission. Indeed it is impossible to proof something with statistics, but you can calculate probabilities and it is very likely that the reason for the difference of BSE incidences between both groups is a difference of the effectivity of maternal transmission in relation to the stage of BSE of the mother.They did not compare calves from BSE cows with calves from not infected cows, but calves from late stage BSE cows with calves from non late stage BSE cows."

"The whole calculation of BSE transmission is very complicated because you have compensate for the shortened incubation time, the under-estimation of the BSE incidence and the mean incubation time within the British BSE statistic, and the experimental conditions.

I did that in July and sent my calculations to the British embassy in august. They were not very happy with that"

"In germany we have a lot of F1 generation cattle from UK, but whereas most of their parents have been killed, our authorities do not want to think about the F1 problem. There are also legal problems, because we are not allowed to kill cattle without a good reason. Furthermore it is very hard to kill whole herds and to destroy the breeding work of generations. There are herds which represent the last samples of a race with special regional adaptations.

If the incidence of BSE does only decline with the age of older cows because of a selective slaughtering of cows with unsatisfactory milk production, than the rate of maternal transmission is not 9-14%. If the real BSE incidence only stays constant, then the rate of maternal tranmission is 30-45%. If I am right and the BSE incidence increases with the age of a cow, then the rate maternal transmission would be much higher."

" sporadic CJD is also acquired >from sheep, pigs, or cattle. There have been transmissions from all "types" of Creutzfeldt-Jakob diseases to monkeys and rodents and statistically there were some slight differences. I didn't care so much on this because in my oppinion the Gerstmann-Straeussler- Scheinker-Syndrom, the fatal familiar insomnia and Kuru are only variants of the Creutzfeldt-Jakob disease beside others and the sporadic cases are nothing else then Creutzfeldt-Jakob disease without a known reason. It is not astounishing that the source of a disease with such a long incubation time is not known in most of the cases. Even with the so called iatrogenic or familial the reason is not really known. I don't believe that there is a remarkable amount of cases which are not familial and not caused by an infection. I am quit sure that at least in germany we are nearly all infected mainly by british sheep and german pigs."
"WHO experts do their job by far not as carfully as you seem to believe. Do you remember that they concluded on 14-16 May 1996 from nine different studies on the maternal transmission, that to date maternal transmission could not be excluded but that, if it is occuring, it is at a level so low as to be undetectable ( Only 2 months later the SEAC came out with 10-15% maternal transmission and by the way demonstrated the quality of some of the world's foremost prion experts expertise. Only a few months earlier the famous WHO experts and the EU scientific veterinary commitee demonstrated their ability to read scientific reports. They stated that the procedures of gelatin production destroys the TSE infectivity. They did this because the european gelatin industry told them that experiments of Inveresk Research International demonstrated that. Even students can easyly see that the results of this study demonstrated no inactivation of the scrapie agent at all. Your foremost prion disease experts made fools of themselves as they already made many times before."
"I am not familiar with the circumstances in the USA, but we have two cases of dismissed veterinarians in Germany and UK. They had to go because they didn't want to overlook BSE.

In the USA Gibs et al. within the ministry of agriculture inoculated cattle with scrapie as early as 1979 and knew about the transmissibility of scrapie to cattle since 1980. Perhaps the british BSE epidemy could have been minimized if they had published that result. But they published it in 1990!"

When now dose response transmission experiments are started, the BSE infectivity in the cattle herds will have reached a relative negligible level, before the results of the study will be available. Probably more than 99% of the overall BSE infectivity will have been consumed then. We don't know how many persons will die because of this infectivity, but whatever we do now, it will change the situation only slightly. With exception of the development of usable CJD and BSE tests and a therapy. But also for this the monkey doasage test would come much to late. Therefore I ask you, do we really need this tests, that will cost the lives of many, many monkeys?