BSE is a normally extremely rare neurological disorder that affects the central nervous system of  the animal.   BSE is a Transmissible Spongiform Encephalopathy (TSE) .  TSE's are also referred to as "Cannibal Diseases" and "Slow Viruses".  TSE's are most commonly spread by unnatural feeding practices such as cannibalism, but can also be transmitted through organ transplant, blood supply and contaminated medical instruments. In TSE's the brain of the infected species is slowly, progressively and severely damaged in which case it can not be treated or cured.  An Encephalopathic condition means that the brain is pathologically damaged and Spongiform means that if one examines the diseased brain tissue, the diseased tissue is spongy - porous - no longer intact. 
 

The first reports of Bovine Spongiform Encephalopathy (BSE)  also known as Mad Cow disease  surfaced in Great Britain in 1986, and were thought to be linked to the recent practice of feeding cattle rendered ruminant proteins.  A ruminant is a cud chewing animal with a four chambered stomach which include the animals cows, sheep, goats and deer.  Mad Cow disease was linked to the ruminant feeding of sheep due to the remarkably similar attributes shown by sheep which have the TSE scrapie. Sheep with scrapie rub their bodies against walls and fences until the skin is completely raw. Eventually, the animal succumbs to the degeneration of the brain. Similarly, cattle become more and more unmanageable and eventually must be destroyed. When the brains of these cattle were examined, there was clear evidence of Spongiform Encephalopathy. 

TSE's are caused by similar uncharacterized agents that produce spongiform changes in the brain. TSE's include scrapie (which affects sheep and goats), Bovine Spongiform Encephalopathy, Transmissible Mink Encephalopathy, Feline Spongiform Encephalopathy, chronic wasting disease of deer and elk, and in humans, Kuru, CJD , Gerstmann- Straussler syndrome, fatal familial insomnia, and nvCJD.

All of these diseases result in eventual spongiform encephalopathy, which are possibly transmitted by a relatively new kind of suspected infectious agent called a prion - the term prion is an acronym coined several years ago by the scientist, Stanley Prusiner. The acronym stands for: proteinaceous infectious particle. Prusiner studied the best documented spongiform encephalopathy, sheep scrapie, and determined that the only identifiable thing which could transmit this disease from animal to animal was unlike any other infectious agent before identified, since there was no immune system response to the symptoms of the disease.  The disease appeared to be transmitted by pure protein, alone.   Stanley Prusiner was awarded the Nobel Prize in Medicine in 1997 for his identification and characterization of the prion and the association of this protein with neurological disorders.
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        Country                                  Number of cases
1.     Northern Ireland                                             1705
2.     Guernsey                                                          564
3.     Isle of Man                                                       464
4.     Switzerland                                                       214
5.     Rep. of Ireland                                                  124
6.     Jersey                                                                120 
7.     Portugal                                                               37
8.     France                                                                 20
9.     Germany                                                               4
10.   Alderney                                                               2
11.   Italy                                                                      2
12.   Denmark                                                               1
13.   Canada                                                                  1
14.   Oman                                                                    1
15.   Falkland Islands                                                    1

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TSE's have been observed to be inactivated by substances that modify proteins such as proteases, detergents, phenol, urea and protein specific reagents, but unaffected by agents that alter nucleic acids, such as nucleases, UV irradiation and substances that react with nucleic agents.  The antagonist in question of TSE's is called a prion. A prion is a hydrophobic glycoprotien that interacts with a natural protein causing the protein to become stable and insoluble.  TSE is also in the family of amyloidosis diseases, in which proteins that are normally globular and soluble are deposited as stable insoluble fibrils in the extra cellular space of tissues, such as the brain.  These fibril proteins are made of anti parallel beta sheets. 
The actual synthesis of these proteins is still currently questioned, but the best possible answer is that susceptible cells carry a gene that codes for the corresponding prion protein, (PrP).  PrP is a widely expressed product with a normal cellular gene that has no apparent function, but infection of these cells by prions (Prn-p) activates the gene and/or alters its protein product in some autocatylitc pathway.  Prn-p is transcribed at similar levels in both normal and infected brain tissue.  The Prn-p genes occur in all vertebrates as well as invertebrates. 
 

fig. 1 Hamster (scrapie) prion - (res. 90-225) - Binding of antibodies to res 219 - 225 (green) C-terminus, inhibits binding PrPSc , although antibody binding at other sites did not inhibit. Residues 90 - 145 (blue) N-Terminus crucial for alpha-beta conversion

fig. 2                                      Human prion

fig. 3                                             Bovine prion

The most studied TSE system was that of the scrapie disease found in sheep.   The abnormal partially protease resistant isoform of normal cellular glycoprotein is called PrPSc (Scrapie) which is a conformation change that came from a cellular precursor, PrPC (cellular).  The reason it is an autocatylsis is PrpSc induces PrpC to convert to PrpSc. PrPC is shown to have a high alpha helix content (42%) and very little beta sheet structure (3%).  PrpSc has a high beta sheet content (54%) and a lower alpha helix content (21%)  The abnormal PrP is thought to be responsible for the central nervous system dysfunction and neuropathology.  A single amino acid difference is a mutated PrP molecule determines which population of neurons is vulnerable and is then the resulting clinical syndrome.  A common substitution of Methioine to Valine with PrP codon 129 is found in inherited iatrogenic and sporadic forms of CJD.  Current studies show that PrPSc is a template for the conversion of PrPC  to PrPSc. This is most efficient when the interacting protein share the same primary structure.  The amino acid sequence determines which prions get transmitted between species, this is also called the species barrier.  New variant CJD, (nvCJD) is thought to be transmitted by BSE.

TSE infected human brain tissue

TSE infected Bovine brain tissue

Light microscope cross sections of spiroplasma infected brain tissues were essentially identical to the pathology seen in CJD.   Spiroplasma have produced persistent brain infection in rodents and have been isolated over 800 days following incubation, but blends into the tissue background that makes them unidentifiable by electron microscopy.  A characteristic and diagnostic feature of CJD and other TSEs in the presence of unique fibrils seen by electron microscopy in homogenized/protease treated infected brain tissues. 
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TSE's  are caused by a infectious protein known as a prion. TSE's share the following common characteristics: 

            a. a prolonged incubation period of months or years; 
            b. a progressive debilitating neurological illness which in all cases is fatal; 
            c. when examined by electron microscopy, detergent treated extracts of 
                   the brain tissue from animals or humans affected by these
                   diseases reveal the presence of scrapie associated fibrils (SAF); 
            d. pathological changes appear to be confined to the central nervous system and
                   include vacuolation, and astrocytosis; 
            e. the transmissible agent elicits no detectable specific immune
                   response in the host which has inhibited the development of a live
                   animal diagnostic test. 

Physiological effects of TSE's in:

   BSE and Scrappie;
             a. symptoms are noticeable 18-64 months after incubation; 
             b. usually occurs is middle aged animals;
             c. first signs are an absent minded like state;
             d. signs of disease progression are aggressive, restless and jittery actions;
             e. later stages of disease progression are clumsy gait, easily tired, uncontrollable 
                    scratching, nibbling at skin and uncontrollable shivering;
             f. final stage of disease progression is rapid weight loss, loss of locomotion,
                   loss of vision, partial paralysis and epileptic like seizures.
             g. death is inevitable 3 to 6 months after initial symptoms.

   nvCJD and Kuru;
             a. symptoms can be noticed up to 8 years after incubation;
             b. usually occurs in the sixth or seventh decade of a human's life, but
                    cases range from 20 to 79 years old;
             c. early symptoms include clumsiness, poor vision, fatigue and rapid weight 
                    loss;
             d. later symptoms are blindness, loss of speech and paralysis;
             e. death is inevitable 6 to 9 months after initial symptoms;

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The National Institute of Health's goal in handling TSE is to search out the causative agent of TSE and provide the basis for a pre clinical test for this disease. However, in the past 15 years, $75 million have been invested in one research laboratory.  As a result of this it has impaired efforts to develop a pre clinical test where it is necessary to have a lead to either an agent specific nucleic acid or protein.  This prion is now realized to be simply a reaction product of the infection.  Links between Spiroplasma and CJD have been concluded that the morphological identity of the unique Spiroplasma fibril proteins to scrapie associated fibrils which had become pathognomonic for TSE.  The immunological cross reactivity of anto-scrapie antisera with Spiroplasma proteins was also concluded.  Additional information supporting morphological evidence including Golgi studies showing the marked similarity of the neuropathology of experimental Spiroplasma infection in the rat model to CJD.  NIH was very reluctant in funding these research, because it thought that the problem was solved and the prion was the causal agent. 
The actions of the Food and Drug Administration  in monitoring food safety has been stymied by the lack of pre clinical test for this disease.  Also the lack of research into basic studies of model system has force the agency to make uniformed decisions.  Data that were presented at the FDA meeting showed that hemophiliacs had a 100% chance of coming in contact with a possible TSE contaminant.  In 1995, the FDA reported the possible contamination of blood supply by eight professional blood donors with CJD since the early 1980's. 
The Center for Disease Control reports show that the deaths of CJD has remained stable at one per million with deaths under 30 years old being extremely rare.  Physicians tend to minimize the seriousness of the disease to minimize the publicity so that the patient can rest peacefully.  The CDC was also involved in the debacle in the handling of the possible contamination of blood products by CJD infected professional blood donors.  CDC and FDA proceeded with massive withdrawals of blood products with the realization that we are still ten years away from the recombinant DNA production of the blood factors.  The current methodology of the filtration of blood products is likely inadequately in controlling contamination by the TSE agent.
The USDA  have held several symposia and national meetings to deal with the problem.  They also have invited participation of the British who have dealt with the problem since 1986.  APHIS has appeared to be very responsible in surveillance efforts to verify that the US is free of BSE.  USDA has cooperated with industry in dealing with the reliability of rendering processes and it is particularly encouraging that they have placed the science on the table.  Certain measures have been taken such as the June 1988 action to make the disease reportable in the United Kingdom, the July 18 1988 ban on feeding ruminant derived protein supplements to other ruminants, the August 1988 order to slaughter and incinerate BSE suspected cattle, the November 1989 ban to exclude specified beef offal for human consumption, and the September 1990 ban on the use of specified bovine offal in any animal feed has resulted in an apparent significant decrease in BSE in Britain with a presumed decrease in danger to humans.  In 1989 the importing of processed beef and live cattle from Britain into the US was stopped.  Any food products are strictly prohibited by US custom to bring into the US. 

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Great Britain has slaughtered approximately 3.7 million infected cattle of their 10 million cattle since 1986.  With the United States having over 100 million cattle, TSE's could possibly to destroy the United States cattle industry and the cattle industry of the world.  Since 1989 there have been zero reported cases of BSE in the United States supported by the governments 11 year survey of US cattle has produced results with high confidence that BSE has not infiltrated the US.  This is in part due to the government's bans on imported beef byproducts and strict customs control of our boarders.  Also, with new tests to detect for TSE's in the United States livestock industry. the risk of humans being infected by the food that they consume is drastically minimized by technical advances in science and medicine.
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1982                                  Stanley Prusiner identifies “ proteinaceous infectious particles” or “prions" as the agents that cause transmissible spongiform encephalopathies
November 1986                 A recognized from of neurological disease appears in cattle in United Kingdom; the disease is identified as bovine spongiform encephalopaty by Gerald A. H. 
                                          Wells and  John W. Wilesmith of the Central Veterinary Laboratory after a post-mortem study of an affected cow
November 1986-               Approximately 150,000 cases of BSE confirmed from
May 1995                          Approximately 33,500 herds of cattle in the UK
June 1987                          Transmission studies begin; normal time for disease to develop in mice proved to be about 10 months
5 December 1987              Initial epidemiology studies completed which conclude that ruminant derived meat and bone meal in feed was the only viable hypothesis for cause of BSE
21 April 1988                    UK Government indicates that legislation would be instated to make BSE noticeable and to ban feeding of rations that contain protein derived from ruminants
21 June 1988                     Provisions of BSE Order 1988 come into effect to make BSE noticeable and to provide fro isolation of BSE suspects when calving
18 July 1988                      Ruminant feed ban comes into force
8 August 1988                   Slaughter and compensation policy comes into effect, which provides 50% compensation for confirmed BSE cases, 100% for negative subject to a ceiling
October 1988                    Transmission to mice reported, following intracerebral inoculation of BSE brain tissue
28 November 1988            BSE made notifiable and slaughter policy introduced in Northern Ireland
30 December 1988            Feed ban prolonged, use of milk from infected animals prohibited except to feed cow's own calf
1989                                  Importing of processed beef and live cattle from Britain into US is stopped
11 January 1989                Use of animal protein in ruminate feed banned in Northern Ireland
28 July 1989                      European Commission bans export of cattle born before 18 July 1988 and offspring of affected or suspect animals
13 November 1989            Bovine Offal Regulations come into force in England and Wales, banning the use of specified bovine offal (SBO)
30 January 1990                SBO bans come into effect in Scotland and Northern Ireland
31 January 1990                Announcement that five antelopes have succumbed to a spongiform encephalopathy
3 February 1990                Cattle to cattle transmission following intracerebral and intravenous inoculation of BSE brain tissue and into mice via the oral route reported in Veterinary Record
14 February 1990              Full compensation fro infected animals introduced; no surge of cases associated with this introduction
30 March 1990                 Administrative ban on export of specified offal and certain glands and organs (for uses other than human consumption to other EU member states
April 1990                         Spongiform Encephalopathy advisory Committee SEAC0 is established in the UK
1 April 1990                      Disease made of establishment of permanent advisory group n spongiform encephalopathies under Chairmanship of Dr David Tyrrell
11 April 1990                    Humberside County council withdraws British beef from school meals
10 May 1990                    Announcement of a cat with spongiform encephalopathy
17 May 1990                    Announcement that decisions about breeding from offspring of affect cows should be left to individual farmers and their veterinary advisors
12 July 1990                      Tyrrel Committee reports on why no need to give official advice on breeding from offspring of BSE cases 
24 September 1990           Laboratory transmission of BSE to a pig announced; Tyrrell committee advises no implications for human health, but as precaution on animal health, 
                                          will ban specified offal's in all animal feed including pet food)
25 September 1990           Ban extended on use of SBO to any animal feed; exports of such feed also effectively banned to other member states 
2-5 October 1990             OIE Conference in Sofia (Bulgaria; recommendations made regarding trade, prevention, control and surveillance of BSE, the support of research and the need 
                                          for  further consideration on trade in live animals
15 October 1990               Order passed to introduce new record keeping arrangement requiring cattle farmers to maintain breeding records; these and movement records to be retained for 
                                          ten years
27 March 1991                  First case announced in BSE offspring born after ruminant feed ban
6 November 1991              BSE Order 1991 consolidates existing BSE legislation and introduces new provisions to prevent the use of meat and bone meal produce from SBOS as a 
                                          fertilizer
1992-1993                         in Britain, 900 to 1,000 cows per week contract BSE 
4 March 1992                    Results of further experiments on the host range of BSE announced; also that the Tyrrell Committee had considered the latest BSE research and conclude that 
                                          the  measures at present in place provide adequate safeguards for human and animal health
14 May 1992                     EC Decision prohibits intracommunity trade in bovine embryos derived from BSE suspect or confirmed dams or dams born after 18 July 1988
14 July 1993                      100,000th confirmed case of BSE in Great Britain announced in response to a parliamentary Question, as and update to the UK Progress Report to the OIE
24 June 1994                     Commission decision prohibits the feeding of mammalian protein to ruminants throughout EU other than Denmark
30 June 1994                      Industry voluntarily extends SBO ban
27 July 1994                      Commission decides to introduce new measures on beef export; requires bone-in-beef for export to come from cattle certified not to have been on holdings 
                                          where BSE has been confirmed in previous six years
2 November 1994              SBO ban on human food of calves under six months of age slaughtered for human consumption; spongiform encephalopathies made notifiable in cattle, sheep 
                                          and goats
6 March 1995                    Restriction on use of milk, gelatin, amino acids, dicalcium phosphate and dried plasma and other blood products from mammalian tissues in feed stuffs for 
                                          ruminants
1 April 1995                      Regulation put into effect which makes it a requirement to stain SBO with a solution of blue ink
15 August 1995                 SBO Order enacted, which consolidated and streamlines the old rules on SBO; main changes include: tighter control on record keeping, dedicated lines for 
                                          rendering plants processing SBO, a prohibition on the removal of the spinal cord from the vertebral column except in slaughter houses
May 1995                          BSE reported from ten countries and areas outside the UK to date; in France, Portugal, republic of Ireland and Switzerland, BSE occurred in native cattle; in 
                                          Falkland Islands, Oman Sultanate, Germany, Canada, Italy and Denmark, cases only identified in cattle imported from the UK
14 December 1995            Government bans the use of the bovine vertebral column in the manufacture of mechanically recovered mean (MRM) and other products, and prohibits the 
                                          export for human 
                                          consumption of MRM made from the vertebral column
December 1995                 British Agriculture Minister Douglas Hogg says, “I am absolutely certain that British beef is wholly safe”
20 March 1996                  SEAC states: “On current data and in the absence of any credible alternative thee most likely explanation at present is that these cases are linked to exposure to 
                                          BSE before the introduction of the SBO ban.”  Upon advice from SEAC, the Government announces that carcasses from carrel aged over 30 months must be 
                                          deboned in specially licensed plants and that the trimming be kept our of any food chain; also that the use of mammalian meat and bone meal in feed for all farm 
                                          animals be banned
21 March 1996                  First announcement of a newly recognized variant of CJD (nv-CJD) in humans; the variant affects young patients, mean age of 26.3 years, and has a relatively 
                                          long duration of  illness, mean of 14.1 months; the hypothesis is announced that nv-CJD may be linked to exposure to a BSE agent
24 March 1996                  McDonald’s suspends use of British beef in burgers
26 March 1996                  Advisors confirm that nv-CJD could be lined to BSE before the offal ban
29 March 1996                  New regulation announced which treats entire head as SBO
2-3 April 1996                   WHO, FAO, and OIE participates on consultation regarding transmissible spongiform encephalopathies; report calls for more research, and a moratorium on 
                                          use of potentially infected tissues from entering any food chain.
10 April 1996                    The Center for Disease Control and Prevention (CDC) in the US initiates the tracking of CJD occurrences in four states: Minnesota, California, Connecticut and 
                                         Oregon
12 April 1996                    The US Department of Agriculture issues a report saying that transmission of BSE to humans is virtually impossible 
16 April 1996                    New 550 million scheme to prevent cattle most at risk from entering the food chain: all beast over 30 months old will be bought and destroyed, the purchase to 
                                          be  70 % funded by EU
18 April 1996                    The Government bans mean and bone meal from sale and use as a fertilized on agricultural land
30 April 1996                    Government announces the introduction of a voluntary plan whereby farmers can use a passport to show the age of cattle; other than cases where it can be prove 
                                          that the animal  is no more than two years and six months old at the time of slaughter, all cattle with more than two permanent incisors are prohibited from sale for 
                                          human consumption
May 1996                          MAFF reports that "if there is no significant source of infection other than feed the measures already in place will lead to the eradication of BSE”
3 May 1996                       Government announces plans for a new scheme under which cattle over the age of 30 months from herds that can be identified as low risk on the basis of strict 
                                          eligibility criteria may be slaughtered for human consumption
June 1996 UK                   Advisory Committee on dangerous Pathogens (ACDP_ acknowledges that uncertainty remains as to whether there is a causal link between BSE and human 
                                          spongiform encephalopathies
6 June 1996                       Five new cases of nv-CJD are announced
14 June 1996                     Article in Nature reports findings of study in which macaque monkeys were injected with BSE; produced pathology similar to nv-CJD
July 1996                           US International Food Information Council (IFIC) issues an occupational warning stating that contact with, or consumption o, the brain of spinal cord of BSE 
                                          infected animals are activities that lead to risks of contracting CJD
24 July 1996                      Government announces 100 million aid plans for breed producers who were affected by the fall in prices
9 August 1996                   Government announces new “Beef Assurance Scheme” which allows farmers to register herds with no known risk of BSE (i.e., grass fed cattle) to be used for 
                                          human consumption up to the age of 42 months
4 October 1996                 Liechtenstein reports its first case of feline spongiform encephalopathy
16 December 1996            British Government announces a change in culling plans into include cattle that were reared with animals that have died of BSE and may have eaten infected feed; 
                                          also includes cattle born to cows that died of the disease
1996                                  Total number of confirmed cases of nv-CJD is 14. 52.5 % drop in confirmed BSE cases in 1996, compared to 1995
January 1997                     United States Food and Drug Administration proposes ban on use of rendered cow, sheep, goat, deer and elk tissue in animal feed
2 January 1997                  An article in Nature reports that BSE cost the EU $2.8 billion in subsidies to the beef industry
15 January 1997                30,000 tons of hamburgers, sausages, pies and lasagnas are buried in British landfill sites
30 January 1997                UK Government announces decision to appoint a Food Safety Advisor, who will coordinate the work of existing committees and advise on the safety, quality 
                                          and labeling procedures
22 February 1997              A coalition of consumer groups, veterinarians and Federal meat inspector asks the US Government to improve the meat inspection system and to include hogs in 
                                          the list of  banned tissues mentioned in the proposed FDA rule
March 1997                       WHO announces that three groups of people at risk for CJD should be barred from donating blood.  These include recipients of growth hormones in the 1980s. 
                                          recipients of  durra mater, and members of families with known CJD occurrences
25 March 1997                  One case of BSE diagnosed in the Netherlands in a herd that did not import cattle from known BSE countries.  The cow was the offspring of a Dutch dam and a 
                                          bull of American decent Paul Brown of the NIH announces that intracerebral injection of CJD infected mice blood can transmit CJD to healthy mice
30 March 1997                  A 62-year-old man in Indiana dies of CJD.  The price of cattle traded on the Chicago Mercantile Exchange down by maximum allowable 1.5 cents to 68.8 cents 
                                          a pound for April contract.  Corn and Soybean also suffered
April 1997                         The UK Government admits that it suppressed a list of burial sites of 617 cattle infected with BSE.  European and UK guidelines say that carcasses should be 
                                          incinerated
16 April 1997                    USDA restricts importation of meat and by products from ruminants in the Netherlands
5 June 1997                       UK Government announces new control for scrapie which orders all sheep suspected of having the disease to be slaughtered
7 August 1997                   US FDA final rule Enacted which bans the use of slaughter animal parts (except pork or horse, and not including blood, gelatin, or milk) in livestock feed.  This 
                                         rule effective 4 August 1997, does not apply to pet food, or chicken or hog feed
6 October 1997                 Dr Stanley Prusiner awarded the Nobel Prize for Medicine for his discovery of the prion
3 December 1997              On the advice of   SEAC the UK Government makes a statement to the effect that they will take action  to require that no beef with the bone in from cattle over 
                                          6  months old  should be sold to the consumer

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1)   Branden, Carl.  Introduction to Protein Structure.  Garland Publishing, 1999. 

2)   Chabry, Joelle.  American Society of Microbiology. Hamilton, National Institute of    
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3)   Horiuchi, Motohiro.  Laboratory of Persistent Virial Disease.  Hamilton, Rocky Mountain 
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6)   Rampton, Sheldon, and Straber, John.  Mad Cow U.S.A..  Monroe: Common Courage            
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7)   Ratzan, Scott.  The Mad Cow Crisis.  New York:  Washington Square, 1998.

8)   Voet, Donnald and Voet Judith.  Biochemistry.  John Wiley and Sons Inc, 1995.
 

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