Beef blamed for causing CJD deaths
Dealler on Collinge, Aguzzi-Weissmann, prion glycosylation, BSE stats, epidemic
Known on-going research into BSE
BSE: an update on the statistical evidence.
Bovine spongiform encephalopathy and public health.
Gossip from Dealler's home page

New research bolsters support for EU ban
Present safeguards 'are tight enough'
Mad Cow, Human Disease Linked
Laboratory mice carry secret of human BSE risk
Conference message: Vegetarians lead miserable lives
Farmers demand urgent action to lift ban on beef
Mad Cow Disease: Further evidence of BSE link with humans
Be grateful for BSE aid, Hogg tells farmers
Scientists find Mad Cow Disease link

John Collinge: warning after new laboratory tests

Beef blamed for causing CJD deaths

The Times: Britain: October 24 1996
BY NIGEL HAWKES, SCIENCE EDITOR

POWERFUL evidence that "mad cow" disease has passed to people through contaminated beef has been produced by a new biochemical test, scientists announced yesterday. The test shows that the new variant of Creutzfeldt-Jakob disease which has been diagnosed in 14 people is quite different from other versions of the disease ­ but virtually identical to BSE.

While not formal proof that eating beef gave the victims the disease, the scientist who led the research, said: "All lines of evidence converge on this conclusion." Professor John Collinge added: "I think we should take it very seriously. We cannot predict how many future cases there may be. We need to start talking very seriously about developing therapeutic drugs in case the worst-case scenario arises."

The test developed by Professor Collinge and his team from Imperial College and St Mary's Hospital in London is the first to identify a molecular "marker" for the new strain of CJD and it may ultimately make it possible to diagnose the condition from blood samples. At the moment, CJD can be formally diagnosed only after death.

It will also help scientists to determine whether sheep thought to have scrapie might actually have been infected with BSE and pose a threat to public health. BSE, CJD and scrapie all belong to the same family of fatal brain diseases known as spongiform encephalopathies, which cause the victim to become unsteady and confused.

The new research is unlikely to force any change in government policy, however, since for the past six months that has been based on the assumption of a link between infected beef and the new variant of CJD. The Department of Health said: "This is the first time that we have had experimental evidence to support our view that there may be a link between BSE in cattle and the new strain of CJD. The evidence is not conclusive, but it is persuasive."

The findings are likely to increase European pressure on the Government to accelerate the cull of British cows, but farmers insisted that British beef was safe to eat. Sir David Naish, president of the National Farmers' Union, said: "This will cause concern, but the findings merely confirm what was already suspected. Ever since March 20, the safeguards which have been put in place have assumed a worst-case scenario. It does not seem to me that anything more needs to be done."

Professor Collinge's team started work on the test after a number of CJD patients were found to have unusual symptoms. CJD usually affects older people, but these patients were younger and scientists concluded that they had probably become ill from infected beef. It was not, however, possible to prove that they were suffering from a distinct strain of CJD. Professor Collinge's team has discovered that not only was their variant quite different from other versions of CJD, but it was identical to BSE ­ and to BSE transmitted to mice, cats and macaque monkeys.

The test will now be used to investigate whether other species, most especially sheep, have caught it. There are fears that sheep may be carrying BSE after being fed food contaminated with infected material from cows. If so, they could pose just as great a health risk as beef.

The research could also clarify whether BSE originally came from scrapie, as has long been supposed, or whether it arose independently in cows and was spread through contaminated feed. The test developed by Professor Collinge ­ who has published his findings in the scientific journal Nature ­ is based on comparing the size of proteins in the brain. All the spongiform encephalopathies are believed to be caused by an aberrant form of the prion protein, and the test provides a way of distinguishing between versions of this rogue protein.

The prions are extracted from the brain, placed on a jelly-like material, and subjected to an electric field which makes them migrate across the gel, leaving a pattern. The team reports that the pattern from "new" CJD is quite different from that of normal CJD. It is, however, closely similar to that of BSE.

So far the test has been used only on brain tissue, but the team believes that samples from lymph nodes or tonsils may also harbour enough of the rogue prion to show up positive. Ultimately, even blood samples may be used.

Families affected by CJD welcomed the new research last night. Clive Eves, chairman of the CJD Support Network, said: "This is a substantial step forward. It is essential that the health service prioritises early diagnosis of CJD, given the rapidity of this new variant."

Professor Collinge declined to guess how many cases of new variant CJD may appear. Much depends on the "species barrier" between cows and human beings. Experiments at his laboratory with mice genetically engineered to carry human prions have been encouraging: none of the mice has developed the disease. Professor Collinge says that suggests a reasonable barrier ­ "But we have to remember that we are only testing 50 mice, while millions of people eat beef."


Dealler's reading of Collinge et al

An attempt to compare the electrophoretic patterns of PrPsc from various forms of CJD and to compare these with that from BSE infection in cats, mice, and macaque monkeys. What was found was that the pattern depended on the glycosylation of the prion protein to some degree but that there was a further pattern that was still different between 4 separate human groups when the glycoside chains were removed. It was not noted as to the inefficiency of the enzyme used to remove the glycoside chains. The most important finding was that the cats, mice and macaque monkeys had the same pattern as humans with new variant CJD. It was explained how this could have taken place and how this might indicate that this was derived from BSE. The introduction is a good explanation of the arguments concerning the presence or absense of any nucleoside with the prion protein to make the infective agent.

What is mentioned but not brought forward much is the fact that, if glycosylation is so important, then there may well be methods of both diagnosis and treatment for this sort of disease (published by Dealler. Medical Hypotheses 1994;42:69-75).


Dealler's reading of Aguzzi and Weissmann commentary

This explains in layman's language what the previous paper had said. It puts forward the idea that it is the glycosylation that decides the strain of the agent (published by Dealler. Medical Hypotheses 1994;42:69-75). As such it might be possible to look for the glycosylation factors in the peripheral tissues of the animals and use that as a method of diagnosis. They put forward that we should now assume that variant CJD is derived from BSE until evidence appears aginst this. Alkaloidal glycosidase inhibitors (AGIs) as the cause of sporadic scrapie, and the potential treatment of both transmissible spongiform encephalopathies (TSEs) and human immunodeficiency virus (HIV) infection.

AGIs and prion glycosylation

Dealler S 
Med Hypotheses 42: 69-75 (1994)
York District Hospital Microbiology Department, UK. 
AGIs are produced by plants and microorgansims in the environment. They are absorbed from the gut, distributed throughout the body and are concentrated inside cells. AGIs alter the glycan chains of cellular glycoproteins (CGP) during their formation so that the same CGP produced by different clones of cells (and hence with different glycan chains) becomes structurally the same. Prion protein (PrP), a CGP, is rendered indestructable to cellular mechanisms (as PrPi) by the TSE infective process; it is suggested that AGIs could both cause and prevent this by altering the primary structure of PrP. HIV envelope protein, gp120, carries glycan chains that are decided by the clone of the cells by which it is produced. Each cellular clone would be expected to add a specific group of glycan chains, making the gp120 antigenically separate. As HIV infection progresses, infected clone numbers rise, the antigenic diversity of gp120 may rise as would antibody production, trying to keep pace. Antigenically stimulated CD4+ cells carrying HIV genes, increase HIV production with gp120 antigenically different from its stimulant. AGIs prevent the glycan diversity and may prevent the extension of HIV infection.

BSE: an update on the statistical evidence.

 S. Dealler and John Kent 
British Food Journal 1995, volume 97, p3-18 
Medical Microbiologist, Burnley General Hospital, Burnley, UK
Professor of Statistics, University of Leeds, Leeds, UK
The article explains that, as a fatal disease, with no method of treatment, inadequate methods of diagnosis and no method of prevention in any animal afer infection has taken place, this subject should be studied closely. Infectivity is presumed, if like in other TSEs, to be present in many tissues and to not be destroyed by cooking. One of the major problems is in trying to calculate the number of infected animals that are being eaten and at what point in their incubation period this takes place. It seems that there is adequate data now available from MAFF for this to found. The major findings of the article are:

* Cases of BSE are becoming severely under-reported. For instance only 40% of clinical cases of BSE reached UK Government statistics in 1993. * BSE may continue in the UK for many years, with cases born each year, showing symptoms 3 to 8 years later.

* BSE may not be derived from the disease of sheep, scrapie and if it is, we cannot rely on it to carry the same properties as that disease. The UK Government used the idea that BSE was scrapie originally to suggest that BSE would not infect humans although this was invalid at the time.

* 1,800,000 cattle incubating BSE will have been eaten before 2001 even if no cases are born after 1991. This figure assumes that all cattle with BSE were always reported by farmers to veterinary officers, that the VOs always accepted them, and that histological diagnosis was always correct (up to 1991). It is therefore likely to be an underestimate of the true BSE incidence. Many of the younger cattle incubating BSE would have been exported to Europe.

* The epidemiology of BSE in the UK is that of an infection passed down from the mother to the offspring but where the mother would show symptoms later in life. It may be that BSE cases that we see are derived from infections in their mother and it was the mother that ate infected food. If this is true then the total number of infeced cattle eaten in the UK will be around 8,000,000 by 2001.

* UK Government advisors have suggested that there is little risk from eating liver, kidneys, nerves and muscle from infected cattle. The article shows that this cannot be true if these tissues contain the same amount of infectivity as is found in other species with a similar disease.

* The acceptable levels (UK Government) of infectivity to found in food may be 10,000 times the amount that could be seen as acceptable under WHO directives used for other potentially fatal diseases.

* UK Governernment Advisory Committee on Dangerous Pathogens reported in October 1994 showing that cattle that may be infected should be treated as if they are infective. They say that some tissues should not be even touched (e.g. liver) that the UK Government continues to tell its population as being acceptable to eat.

* The risk to humans in Europe from BSE is unacceptably high but cannot be stated precisely at this time. The article states again that the cumulative amounts of BSE in our diet in the UK is expected to be between 10,000 times and 100,000 times the amounts of scrapie that we would be eating.

* No directions are given as to whether bovine tissue in the UK should be considered toxic.


Bovine spongiform encephalopathy and public health.

W. J. Patterson, S. Dealler
J. Public Health Medicine. Volume 17 number 3, 1995, pages 261-268
Symptomatic cases of BSE in British cattle now total more than 146,000. As BSE is one of a group of transmissible and fatal spongiform encephalopathies (TSEs) affecting both animals and humans this has raised concern regarding possible risks to human health. The infective agent in TSEs, thought to be a prion has not been clearly described. There are no early diagnostic tests, incubation periods are prolonged (possibly up to 30 years in humans) and the pathological process which leads to a rapidly progressive and fatal encephalopathy has yet to be explained.

It is not yet known if the BSE agent can cross the human species barrier to infect humans. It has now been transmitted to 18 species and to 16 of these (possibly 17 if pigs are included) by mouth.

Given the importance of beef in the human diet, it is essential that control measures to protect health are rigorous, comprehensive and objective. In this respect there are four factors which are important in assessing risks. These are the likely magnitude of the species barrier between cattle and humans, the dose (single or cumulative) that are needed to transmit the disease, the method of exposure (oral or subcutaneous) and the likely period before symptomatic disease appears.

To assist knowledge and understanding in these areas we recommend the wider involvement of public health professionals in the existing nationally co-ordinated multi-agency research programme. We also recommend further studies into the oral transmissibility of the BSE agent to primates, an acceleration of the search for diagnostic tools and treatments for established prion infection and enhanced surveillance of neurological disease in humans.

It is now clear that probably a large percentage of the population will have been exposed to BSE in the UK. Humans will have eaten 1,800,000 infected cattle by 2001 and will have eaten tissues that have been shown to be infective in other species, but inadequately tested in cattle. Humans have already taken risks in eating bovine products that have now been banned. The recurrent banning of foods or procedures by MAFF will not help the people that have been exposed before the ban. It is possible that further action such as this by MAFF will seriously damage the public's respect for its action.

The article's most important part is to show that the World Health Organisation's publicised opinions on how to decide whether or not the exposure of a human to a specific amount of an infective agent could not have been carried out as inadequate information was available with which to decide the action. As a result of this it was important that Government action should assume a tolerable level for human exposure to BSE to be very low indeed, possibly 10,000 times less then the amount felt acceptable by MAFF.


Gossip adapted from Dealler's home page

John Wilesmith seems to have been out of contact.

Nobody is really sure why but John Wilesmith has not been at work for quite some time, or at least has not responded to telephone calls or faxes. The next thing that turned up was that he took his name from being an author on a paper being published in Nature (we are not sure which one). The rumour going around is that he may be going to be removed from his post in the same way as Mike Richards.
Nature ignored earlier study than Anderson's.
It seems that Nature had been submitted a much more aggressive article on BSE, which did not come out with happy news and that this had been pushed around the desks in Nature before Anderson's appeared (and was published very quickly). It seems that Anderson's 'dont worry folks,. its all going away' was grabbed by the UK government as an excuse not to carry out a cull. However the other paper was not quite so good news and would not have permitted the cull to be abandoned.
Powergen is unhappy
The incinerated material left after the burning of rendered meal may not be completely free of the proteins that they thought would disappear.
MAFF is looking in the fields for mites that may carry prions.
The amazing results from Staten Island showing that the mites from the land in Iceland actually had enough prion chemical to be found using blotting, must mean that the agent might be kept in the land by these arachnids. The worry is, of course that the land might also keep BSE.
John Collinge looks unhappy about CJD in the UK.
What does he know that we do not? Behind the scenes the groups from the UK at the Vienna meeting were saying that they thought the epidemic of CJD in the UK to be big and we are talking about hundreds of thousands of cases. Worrying.
MRC has turned down major research projects
The finding by Collinge's group that the strains of disease may actually be due to glycosylation variation may well be good news. What does not seem to have been realised is that the Medical Research Council actually turned down 4 research projects looking for methods of diagnosis and treatment that might work if this was true. As far as I know no other research projects took this into account.
Weissman's report will be out soon
How to get one is not clear. The initial release was simply a short affair that said that we would have to do an awfully large amount of research and not sit and wait. It seems as if the main report is quite a lot longer and again says that current research is inadequate. Apparently it should be possible to get a copy from John Collinge's office.

Farmers demand urgent action to lift ban on beef

The Times: Britain: October 24 1996
BY MICHAEL HORNSBY, AGRICULTURE CORRESPONDENT

MORE than 2,000 farmers voiced their anger over the Government's handling of the BSE crisis at a protest rally in London yesterday and called for urgent negotiations to get the European Union ban on British beef lifted. Sir David Naish, the president of the National Farmers' Union, drew loud applause as he declared: "I am appalled at the extent of government mismanagement and stupid delays that we have experienced throughout this whole catastrophic affair."

Farmers drove by coach from all over the country to the Methodist Central Hall, many carrying banners proclaiming "British beef is best" and "Give Hogg a roasting" ­ a reference to Douglas Hogg, the Agriculture Minister, whom they blame for worsening their plight. Sir David later delivered a box of beef joints, steak and mince from Devon cattle to 10 Downing Street. Similar unsolicited gifts of British beef were presented to the embassies of EU states in London.

The rally was overshadowed by the release of new scientific evidence pointing strongly to a link between recent cases of a new strain of Creutzfeldt-Jakob disease in humans and "mad cow" disease in cattle.

Sir David said: "Essentially the findings merely confirm what was already suspected. All the safeguards which have been put into place since the possibility of a link was disclosed on March 20 have assumed a worst-case scenario. Consumers need have no doubts about the safety of beef in the shops." At the rally, Sir David called on the Government to proceed with a selective cull of 120,000 cattle identified as being at special risk of developing BSE, as agreed at the EU summit in Florence in June. That, he said, was the key to getting the export ban lifted.

"Repeated signals from our minister that there will be no significant selective cull ­ that the UK has changed its mind ­ are taken in the rest of Europe as meaning that the UK is breaking the Florence agreement."

To cheers, he added: "So, let us get on with the Florence agreement. Let us give ourselves the chance to export. Get your MP, particularly if he is a Conservative MP, to tell the minister to stop prevaricating." Mr Hogg announced at the end of September that the plans for a selective cull had been suspended. He saw no point in the cull because most EU states were determined to maintain the beef ban whatever Britain did.


Known on-going research into BSE

Adapted from Dr. Stephen Dealler's home page

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 SE1708.
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 i 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 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)

Mad Cow Disease: Further evidence of BSE link with humans

By Alison Maitland in London

Financial Times ... Thursday October 24 1996

British scientists today publish the strongest evidence yet that the new strain of a fatal human brain disease is caused by BSE.

Their research, a further blow to the embattled beef industry, shows that the new strain of Creutzfeldt Jakob Disease that has affected 12 young people in Britain over the past two years is wholly distinct from other types.

It also opens the possibility of a live blood test for CJD in the next couple of years. The findings will help to determine whether bovine spongiform encephalopathy (mad cow disease) has crossed the "species barrier" into sheep, posing a potential further threat to human health.

Professor John Collinge of the Imperial College School of Medicine at St Mary's Hospital, London, said his team's research, published in Nature magazine today, should be taken seriously. "We can't predict how many further cases of new CJD there will be, but we need to start thinking very seriously about developing therapies and drugs in case the worst case scenarios come to pass," he said.

On March 20, the UK government triggered the beef crisis by announcing that the victims of the new CJD strain were likely to have got it by eating infected cattle material, before certian types of offal were banned from the human food chain in 1989.

The Department of Health said yesterday: "This is the first time we have had any experimental evidence to support our view that there may be a link. It's not totally conclusive, but it's persuasive."

The findings will be considered by the government's advisory committee on BSE and CJD at a meeting later this month, in case further health measures are needed.

However, Prof Collinge said the government was already working on the assumption that BSE could harm humans and measures were in place to protect public health.

Cattle organs such as the brain, spleen and spinal cord were banned from the human food chain in 1989 because of the possibility they could contain BSE.

The research team identified a molecular "marker" or signature that distinguishes the new variant of CJD and is also seen in BSE in cattle and other infected animals.

Prof Collinge said the molecular markers could identify CJD strains in days rather than the one to two years previously needed in tests on mice.

The research is published as the Meat and Livestock Commission today holds a "festival of British beef" to try to restore confidence in the safety and quality of the meat.


Be grateful for BSE aid, Hogg tells farmers

By David Brown, Agriculture Editor

Daily Telegraph ... Thursday 24 October 1996

Farmers risk losing public sympathy over the beef crisis by constantly complaining, Douglas Hogg, the Agriculture Minister, said yesterday.

He also accused farmers of ignoring the "unprecedented" £3 billion in aid being poured into the industry by the taxpayer.

The attack came after more than 2,000 farmers gathered in London to lobby Parliament in protest at the Government's handling of the beef crisis. Many of the protesters carried placards calling for Mr Hogg to be sacked.

Mr Hogg sent a letter to Sir David Naish, President of the National Farmers' Union of England and Wales, spelling out the level of cash aid farmers were receiving.

It said: "There can be no greater measure of the Government's commitment to the industry and to rural communities. It is a credit to the British people that, as taxpayers, they have been prepared to stand by farmers in this way.

"This kind of support goes well beyond that received by other sectors who have gone through periods of real difficulty, for example the construction industry.

"To overlook these facts, and in particular, the scale of the assistance that has been given to British agriculture, is to risk losing public sympathy, and could do great damage to the reputation of British farming."

Senior Whitehall officials described the letter as a "stop whingeing and count your blessings message'. Sir David had earlier delivered a scathing attack on what he called "Government mis-management" of the beef crisis. He said it was a "catastrophic affair".

Sir David accused Mr Hogg of taking steps which worked against the agreement on beef reached by the Prime Minister at the Florence Summit in the summer.

This, he said, had hindered efforts to persuade the European Union to lift the export ban on British beef.

Nearly 700,000 animals have been slaughtered so far

Two weeks ago the NFU ruling council passed a vote of no confidence in Mr Hogg's abilities as farms minister.

But Downing Street sources have made it clear that the Prime Minister will not tolerate any interference on who he chooses to have in his Cabinet.

It was a measure of Mr Hogg's anger at yesterday's protest that he released the text of his letter, which also took stock of the steps taken by the Government to resolve the crisis, and to provide financial aid to farmers.

The Government, he said, had implemented the much-criticised culling programme of cattle more than 30 months of age, at the request of the NFU.

Nearly 700,000 animals had been slaughtered so far under this scheme and another £16.6 million aid had been approved to increase the slaughter rate to as many as 55,000 cattle a week.

On Oct 8, he said, the Government had introduced another £29 million of additional cash aid.

The Government had introduced a calf processing scheme in which farmers were paid £103.47 for every surplus calf they killed. Nearly 300,000 had been killed so far under this scheme.

Another £110 million in additional aid had been agreed at the July meeting of the EU Council of Farm Ministers. This produced increases of £19.70 a head in beef special premiums, and £23.13 a head in suckler cow premiums.

In addition, Mr Hogg said that the Government had paid temporary aid to the rendering industry of £118 million and £110 million to slaughterhouses.

He said: "These measures amount to an unprecedented level of support for the farming community. The total bill to the taxpayer is likely to run to almost £3 billion."

Scientists 'find Mad Cow Disease link'

By Aisling Irwin and George Jones

Daily Telegraph ... Thursday 24 October 1996

The first experimental evidence that mad cow disease has been passed to humans is published today.

Scientists have discovered a critical similarity between the new type of Creutzfeldt-Jakob disease which has infected humans and bovine spongiform encephalopathy in cattle.

The finding adds powerful backing to claims that BSE has crossed the species barrier between cattle and humans.

The characteristic signature sets the new strain distinctly apart from other forms of CJD - but it is almost indistinguishable from the molecular hallmark of BSE.

Scientists see this as strong supportive evidence that the new CJD variant arose from BSE in beef.

The Government said last night that the findings did not require any additional measures to protect the public or restrict the consumption of British beef.

Roger Freeman, the minister co-ordinating the Government's response to the BSE epidemic, said present measures had been introduced after the new variant of CJD was first acknowledged earlier this year.

But Labour's health spokesman, Chris Smith, called for an immediate Government statement on the implications of the research, to be published in the magazine Nature.

Prof John Collinge, who made the discovery, called for his test to be used to find out whether scrapie, a similar disease in sheep, originated from BSE in cattle. "If BSE is in sheep it should be treated with the same respect as BSE in cattle," he said.

A team of scientists led by Prof Collinge at the Imperial College School of Medicine at St Mary's, London, examined the prion protein, the infectious agent that appears to cause BSE and CJD.

They developed a test that identifies the molecular differences between the strains of prion, and found that the prion present in patients with "new variant" CJD were almost identical to the prions found in cattle with BSE.

New research bolsters support for EU ban

The Times: Britain: October 25 1996
FROM CHARLES BREMNER IN BRUSSELS

THE latest evidence of a human link to mad cow disease was viewed across Europe yesterday as further proof that no British beef should be sold abroad without tougher measures to eradicate BSE in Britain.

The media and politicians greeted the scientific findings of John Collinge's team as fresh vindication of the beef ban, imposed last March. The reaction, as usual, was strongest in Germany, where officials said the research had reinforced their belief that the ban could not be lifted for a long time.

Suddeutsche Zeitung said: "The message is clear: there is not the slightest reason to ease up the fight against BSE ... Perhaps London will listen at last to serious researchers in its own country." Bild said: "Thank goodness German politicians did not wait for more and more evidence but acted in good time." Germany was first to impose a ban on British beef last March.

In France, Liberation said the apparent proof that humans could be infected by eating beef should serve to ensure that politicians were kept under the pressure of public opinion to take the strictest measures.

The European Commission, which co-ordinates EU action against BSE, said there appeared no reason to change its approach to the British beef crisis. It repeated its demand, shared by all 14 other member states, that Britain immediately implement the selective slaughter of 140,000 cattle, which it promised in the agreement on easing the ban in Florence in June. The Government suspended the cull in September after scientists reported that BSE would die out without further measures early in the next century.

Gerry Kiely, the spokesman for Franz Fischler, the Farm Commissioner, said: "In terms of the pace at which the ban is lifted, the first step is totally in the hands of the British Government." Since 1989, the Commission had acted on the assumption that there could be a link between BSE and CJD, and the latest British findings showed that the approach of the Florence accord was correct, he said.

Britain's suspension of the cull has been greeted with incomprehension. Herr Fischler said that the new British findings "show how serious the crisis is. We must make sure all the measures which have been put in place are maintained, because now we have to face the fact that the disease can be transmitted to people."

Britain is preparing to apply to the EU to start lifting the ban for cattle from certified BSE-free herds in Northern Ireland. With emotions stirred again by the latest report, the Government is expected to delay its formal request for the action, British sources said. The Commission is not happy with a British proposal to implement the selective slaughter only in Northern Ireland in return for EU approval to renew exports from the province.

The Commission is itself under criticism for its handling of the epidemic. The European Parliament, which is leading the attack, yesterday agreed to extend for three more months a committee of inquiry which is investigating the alleged mishandling of the epidemic by the Commission and Britain.


Present safeguards 'are tight enough'

BY MICHAEL HORNSBY The Times: Britain: October 25 1996

DOUGLAS HOGG, the Agriculture Minister, said yesterday that he saw no need for any new safeguards arising out of the latest scientific evidence on a link between BSE and the fatal CJD brain disease in humans. "We have been working on the assumption for a long time now that BSE was capable of being transmitted," he told The Times. "Therefore the measures that we first put in place at the end of the Eighties, and subsequently reinforced, were directed to guarding the public against any risk.

"Now what Professor Collinge has done is to provide evidence which tends to corroborate the assumption which we previously had made for working purposes. So I see no need for further measures." The Prime Minister came to Mr Hogg's support, telling BBC Television's Breakfast News that beef was "perfectly safe". He added: "So there ought to be no fresh public concern because the action that would be necessary has been taken, in some cases six or seven years ago, and enlarged upon fairly recently.

"There is no need for any more action and, because the action has been taken, there is no need for the European Union to panic." John Pattison, head of the scientific committee advising the Government on BSE, also said he would eat beef "without any reservations", because of the safeguards that were in place.

Mad Cow, Human Disease Linked

AP Science InSCIght 24 Oct 96

LONDON--A team of British scientists today announced new evidence linking a fatal degenerative brain disease that has killed 10 people in Britain since 1994 with bovine spongiform encephalopathy (BSE), a neurological condition popularly known as "mad cow disease" that has infected more than 150,000 British cattle.

İİİİİ The researchers have developed a test that reveals strong similarities between proteins thought to be responsible for the human disease--a new variant of Creutzfeldt-Jakob disease (vCJD)--and those connected with BSE. "This is the most suggestive evidence so far that the new variant of Creutzfeldt-Jakob disease came from BSE," says Byron Caughey, a biochemist at the National Institutes of Health's (NIH's) Rocky Mountain Laboratory in Montana. Not all experts agree, however.

İİİİİ At a press conference this morning, John Collinge of Imperial College School of Medicine at St. Mary's Hospital, London, explained that the simple test distinguishes differences between the infectious proteins, or prions, isolated from the brains of infected humans or animals. The researchers break down prions with an enzyme and separate them according to the number of sugar groups attached to them. The relative abundances of proteins with different numbers of sugar groups produce patterns characteristic of BSE, classical Creutzfeldt-Jakob disease, and the new vCJD strain. Collinge's report will appear in tomorrow's Nature.

İİİİİ Collinge's team found that the prion pattern of vCJD--which has stricken victims up to age 45--resembles the BSE pattern far more closely than that of people suffering from classical Creutzfeldt-Jakob disease, a more common, albeit rare, condition that tends to strike older people. But because the new test requires brain tissue, it is normally only possible to run after a patient has died. The team is now hoping to detect the proteins in another body tissue that could be sampled while a patient is still alive. They are analyzing lymph nodes and tonsils, where prions replicate. Collinge hopes to have results on such a test in a matter of months. With a test potentially able to detect the disease early on, "we should think seriously about developing therapeutics," says Collinge.

İİİİİBut some experts are greeting the findings with caution. "It's an interesting idea but not persuasive," says Paul Brown, a neuroscientist at NIH's main campus in Bethesda, Maryland. Brown says he's skeptical that differences between prion forms revealed in the new test account for variations in Creutzfeldt-Jakob disease, and he's waiting for results of experiments in transgenic mice. The mice produce the human prion that, when altered, is linked to vCJD. The mice were injected with brain tissue from vCJD victims, but so far, none have contracted Creutzfeldt-Jakob disease. Final results are due next year.


Laboratory mice carry secret of human BSE risk

The Times: Britain: October 25 1996 BY NIGEL HAWKES, SCIENCE EDITOR

A GROUP of elderly mice in a London laboratory could be the key to the future spread of Creutzfeldt-Jakob disease. The longer they live, the lower the risk of a massive epidemic. The mice are genetically engineered to produce a human version of the prion protein implicated in the brain disease. More than 18 months ago, they were injected with material from the brain of a cow with BSE. The experiment is designed to show whether, and how soon, the humanised mice succumb to the disease. Normal mice do so after an average of 400 days; these mice are still healthy ­ although some have died of old age ­ after more than 500 days.

That looks encouraging, but it is subject to a number of caveats, according to John Collinge of Imperial College and St Mary's Hospital, whose 23-strong group of scientists is conducting the experiment. He knows that if these humanised mice are challenged with CJD rather than BSE, they get sick quickly ­ in about 200 days. This is because their prions are human, and CJD is a human disease: there is no "species barrier" to jump. The way to measure the height of that barrier is to compare the time taken for the mice to succumb to BSE with the 200 days it takes them to die from CJD.

The barrier between cows and mice, measured in this way, is 250 days. Since the humanised mice challenged with BSE are still alive at 500 days, we know that the barrier between humans and cows is as large, if not larger. The longer the mice stay healthy, the higher that barrier must be, and the lower the number of people who will acquire BSE from beef.

If mice eventually die of old age without developing any symptoms, the experiment will continue by taking extracts from their brains and injecting them into other mice. If the first group are incubating CJD, their brains might cause the disease more swiftly in the second group.

Even if all the mice survive, humans could still be in danger. "We only infected 50 mice to start with," Professor Collinge said. "If the disease affected, say, one in a thousand, I wouldn't see it. But there could still be 50,000 people infected in Britain."

Just who those people would be could depend on a genetic lottery. The evidence is that only about half the population is likely to be susceptible, because of the particular prion genes they carry.

Prions are found in all higher creatures, and are en coded by a gene consisting of 800 nucleotide bases, the "letters" of the genetic alphabet. There are two versions of the gene, called V and M.

Each person carries two copies of each gene, one maternal and one paternal, allowing three possible combinations: MV, MM, or VV. Half the population has MV; the other half divide equally between MM and VV. Almost all cases of CJD occur in people with two identical copies: MM or VV. Those with a mixture of M and V seem to be immune.

The probable reason is that a mixture is less easily converted to the rogue form of the prion which causes the disease. Infection with CJD occurs when a rogue prion getting into the body acts as a "seed", encouraging abnormal changes to other prions, and eventually loss of brain function and death.

In theory, drugs to counter the process are possible. Professor Collinge said that what was needed was to establish a test-tube system in which the prion changes could be observed. "Then you could use modern techniques to screen thousands of different compounds to see if they would stop the change taking place. Once you find one, you try to improve it, and eventually you would have a drug that would stop the process."


Conference message falls on empty seats

The Times: Britain: October 25 1996 BY ROBIN YOUNG

AS PARTY poopers biochemists take some beating. More than 600 invitations to the Festival of British Beef in London were issued; with headlines everywhere about Professor Collinge, BSE and death from CJD only 200 people took them up.

"We hoped there would be more people here," said the chairman of the Meat and Livestock Commission, Don Curry, as speeches began to rows of empty seats in the Queen Elizabeth II conference centre, Westminster. "With 130,000 catering outlets around the country it is sometimes difficult to get our message across."

Here then, for the benefit of those who unfortunately could not attend, is the message: "Professor Collinge's research has not changed a thing. The safeguards that have been put in place were already based on the worst case assumption that there was a link between BSE and CJD. So far as safety is concerned, this research has no implications."

Having disposed of the bad news, how about some good news? "The quality of British beef has never been better," Mr Curry gamely insisted. "Retailers are reporting sales 85 per cent of pre-BSE scare levels. No other product could have withstood the publicity beef has suffered and still come out so strongly."

Kevin Taylor, the Agriculture Min istry's deputy chief veterinary officer, told the conference that his wife causes chaos in restaurants by refusing anything but British beef on grounds of safety. "Gives a whole new meaning to 'mad cow'," muttered a restaurateur in the audience.

Bob Gledhill, deputy editor of Caterer & Hotelkeeper, tried to reassure the audience by putting media scares in context. BSE made so many headlines, he suggested, only because "mad" and "cow" were such conveniently short words, and because pictures of dairy cattle came much cheaper than news photographs. "Sales of beef will recover," promised Michael Gottlieb, chairman of the Restaurateurs' Association of Great Britain, admitting that sales through his own Smollensky's restaurants were still only half of what they had been in 1989.

Vegetarians led miserable lives, he said, observing that they complained more in restaurants than anyone else. "It has nothing do with the quality of the food and everything to do with the state of their minds. A disproportionate number of journalists are vegetarians. This might explain why BSE gets so many column inches."

Upstairs there was lunch: three Thai recipes for beef, plates of salt beef with garnishings, and several tureens of beef in beer stew. At least five people refused to eat beef in any of its forms, sticking to vegetables and salads.