"Methinks sometimes I have no more wit than a Christian or an ordinary man has; but I am a great eater of beef and I believe that does harm to my wit.
- Shakespeare, Twelfth Night (1601), Act 1, Scene 3
BOVINE spongiform encephalopathy (BSE), Creutzfeldt Jakob Disease (CJD) and prions are terms that have suddenly burst into the English language over the last number of years, particularly during 1996. Given Shakespeare's comments, one might question how new these diseases really are.
But what everybody wants to know is whether they can eat beef without the risk of contracting CJD. The simple but unsatisfactory answer is that nobody knows for sure. All one can do during this BSE blitz is to become an informed consumer and make informed decisions.
For Irish farmers and the Irish economy, BSE has been the catastrophe of the century and, as we approach the new millennium, a great uncertainty about these diseases prevails in both the agricultural and the medicoscientific worlds. My main objectives in this article are to look at the current views of the biochemical basis of BSE in cattle and CJD in humans, to see how they are related and to review new tests for their diagnosis.
We know that diseases in general can be caused by genetic mutations, for example, inherited disorders such as muscular dystrophy and cystic fibrosis, by viruses, bacteria and by various chemicals present in the environment. But what makes the spongiform encephalopathies like BSE and CJD so enigmatic is that they appear to be caused by a totally new type of factor.
Biochemical research, mainly by Prof Stanley Prusiner, of the University of California School of Medicine at San Francisco, indicates that it's not a virus, it's not a bacterium and it's not an ordinary toxic chemical agent.
This deadly agent is very stable chemically and capable of resisting heating to normal cooking temperatures, as well as even higher temperatures such as those used for sterilisation, freezing and drying, in other words, all the procedures ordinarily used to rid our food of unwanted bacteria and viruses.
According to Prusiner, the causative agent appears to be a totally new infectious agent, a special type of protein which in 1982 he christened the prion. This remarkable protein is actually produced naturally by the body's nerve cells but there appear to be several forms of this protein, one that behaves normally and others that result in the devastating diseases CJD, BSE and the other prion diseases.
The notion that a protein produced naturally in the body was capable of such destruction was greeted initially with enormous opposition by Prusiner's research competitors. The current theory suggests that the abnormal forms of the prion protein have the amazing ability to change the shape of normal prion proteins to the abnormal form. The characteristic sponginess seen in the brains of CJD patients results from a build up of plaques of prions in the nerve cells.
The emergence of a new form of prion disease called new variant CJD, with 15 cases being reported in Great Britain over the past year, ignited a major public health controversy on the consumption of beef. The United Kingdom Advisory Committee on Spongiform Encephalopathy reported in March 1996 that, although there was no direct evidence, the most likely cause of new variant CJD cases was exposure to BSE contaminated products. Several recent scientific articles have produced additional evidence that this new variant CJD is linked to BSE.
Britain saw the first ever case of BSE back in 1986, with its emergence being attributed to the presence of scrapie infected sheep carcases in cattle feed following changes in the rendering processes of animal offal in 1981-1982. BSE has since been reported from other countries, including France, Switzerland, Germany, Italy and Ireland, with virtually all cases stemming from the original outbreak in Britain.
A ban on the use of cattle and sheep carcases in the preparation of meat and bone meal in 1988 came too late to prevent the epidemic of the decade. Following this, Britain banned the use of brain and spinal cord, as well as tonsil, thymus, spleen and intestine from cattle in all foods destined for human consumption.
It is worth noting that BSE and CJDlike diseases have also been observed in mink, deer, elk and cats. And scrapie, the prion disease found in sheep and goats, has been known in the UK for over 200 years.
In addition to CJD, several other human spongiform encephalopathies known as Gerstmann-Straussler-Scheinker Disease, fatal familial insomnia and kuru have been diagnosed. These diseases are characterised by rapidly progressive dementia associated with sudden spasms of the muscles.
CJD has been recognised since the early 1920s and its incidence is around 0.5 to 1 case per million population per annum. This statistic is true for all countries, including Britain, where BSE is most prevalent.
It mainly affects middleaged and elderly people. while the new variant CJD appears to target a younger age group. Only 15 per cent of CJD cases are inherited, caused by a change in the gene responsible for producing the prion protein. The other 85 per cent of cases are either sporadic (of unknown cause) or iatrogenic, caused by exposure to CJD contaminated surgical instruments or from the use of growth hormone derived from human cadavers infected with CJD.
Evidence for a link between BSE and CJD has recently been reported in Nature, the science journal, by John Collinge and his coworkers in the biochemistry department of the Imperial College School of Medicine at St Mary's, London. Their work demonstrates that it is the change in shape of the prion that makes it dangerous to health and it shows that the new variant CJD prion more closely resembles the BSE prion rather than the prions from other types of CJD.
The abnormal prion protein has the unique ability to resist the action of proteases, enzymes that break down proteins to produce amino acids. In Collinge's research, he used a protease called protease K which breaks the abnormal prion, labelled PrPSc for short, into three distinct fragments, but breaks the normal prion, PrP, down completely to amino acids.
Special biochemical techniques called electrophoresis and western blotting are used to separate the protein fragments, enabling one to identify CJD cases in brain tissue samples. The proteins appear as distinct patterns of small bands unique for each type of CJD.
In the absence of CJD infection, no protein fragments are produced, as the normal prion protein is completely chewed up, so no visual pattern appears after protease K treatment. The most interesting results were those produced from protease K treatment of new variant CJD and BSE, which showed very similar patterns. This provides the strongest evidence so far that new variant CJD is indeed derived from consumption of BSE contaminated products.
The research done by Collinge and his colleagues also confirms the "protein only" hypothesis which is the current scientific basis of the prion diseases. The presence of different prion strains causing different types of CJD had not been proven previously Objectors to Prusiner's concept of the prion protein used this as the focus of their criticism.
Prusiner, Collinge and other researchers say that different strains of CJD can be explained by the prion strains having different molecular shapes. This is borne out by the dissimilar patterns of the prion fragments produced on treatment with proteasem K.
The differences in shape are now thought to be due to a phenomenon known as glycosylation, the addition of sugar molecules to the protein soon after it has been, assembled in cases of BSE and CJD.
A simple diagnostic test for BSE and CJD while the animal was still alive would be a godsend for the entire farming community. At present, BSE is undetectable until the animal displays the symptoms - uncoordinated movement and falling down, together with irritability. These may not appear for up to five years after the animal has contracted BSE.
During this incubation period, the animal could have passed the disease to its offspring or the animal could have been slaughtered and passed into the human food chain. These potential routes of infection could be avoided if a suitable test which could be carried out during life was available.
In the absence of a premortem test for BSE in cattle, differential diagnosis by visible symptoms leads to confusion between BSE and hypomagnesaemia, hypocalcaemia (milk fever), acetonaemia, listeriosis and even DownerCow syndrome. Although the USA claims it has no BSE, it is believed that a proportion of DownerCow syndrome cases there have actually been BSE.
Several scientists are trying to remedy this diagnostic problem and have come up with some interesting solutions which must be simplified before being introduced for widespread use.
Michael Harrington and other scientists from the California Institute of Technology have developed a pre mortem diagnostic test which detects the presence of two particular proteins indicative of CJD and new variant CJD in the cerebrospinal fluid. They are currently investigating the use of this test in the diagnosis of BSE. If this test can be successfully modified, for use in clinical situations, it could be the dramatic turning point in this sensational BSE saga.
Other scientists from the Netherlands acknowledge the urgent need to find a method for the preclinical diagnosis of prion diseases and have suggested a possible test using scrapie in sheep as a model. They based their research on the detection of prions in the tonsils, and spleen of scrapie infected sheep quite early in the infection.
Dr Schreuder and colleagues in the Netherlands have developed an immunohistochemical method using antibodies to detect the scrapie prion in the tonsils of sheep. However, while they admit this method hasn't yet been used to diagnose BSE or CJD, they strongly recommend furthers research into this particular idea.
A tonsil biopsy would certainly be more practical and non invasive as a diagnostic test for CJD and BSE than a brain biopsy. Indeed, just recently, Collinge and his group in London announced in the Lancet medical journal that they could diagnose newvariant CJD in tonsil biopsies.
Despite the lack of definitive scientific information on the prion and its possible health implications, the Minister for Health, Mr Noonan, has stated: "I want to say categorically that Irish beef is safe to eat and there should be no worry about eating it."
Not even the world's leading scientists could come out with such a statement; there is undoubtedly a risk involved and a lot more research has to be done. The risk of contracting CJD is 0.5 to 1 per million inhabitants per year. It is worth comparing this risk to others - for example, the chance of being killed in an airplane crash, at 1 in 100,000; or being killed on the road, at 1 in 10,000.
Of obvious public interest is a cure for these mysterious neurological diseases. Regrettably, no cure seems to be on the horizon, but possibilities are the so called anti sense or anti gene therapies and chemicals that would inhibit the glycosylation of prions.
In Ireland, relatively little detailed research on BSE and CJD is carried out. However, Dr Mark Rogers, in the zoology department of UCD, is conducting molecular studies on BSE prions, and Dr Catherine Keohane, of Cork University Hospital, is investigating the pathological expression and incidence of CJD.