By David N. Leff
Suddenly, the number of people in Britain dead of Creutzfeldt-Jakob disease (CJD) has jumped off the charts.
Tomorrow¿s issue of The Lancet, dated March 20, 1999, carries a communiqui updating the widely dreaded death watch that began in 1995, when the first three victims of CJD died.
Unlike the century-old pattern of the rare ¿ one-in-a-million ¿ brain dementia which afflicted the elderly, these three, and the 38 who have died since, were in the prime of life. This variation from the norm has led to identifying the current outbreak as ¿variant Creutzfeldt-Jakob disease¿ (vCJD).
Its victims succumbed in a matter of months after first symptoms of the disease appeared, whereas those with classical CJD took a year or more to die, from what was described as a ¿slow virus.¿ Now it¿s recognized that the pathogen is neither viral nor bacterial nor fungal, but an elusive molecule called the prion (standing for proteinaceous infectious particle).
The Lancet¿s fast-track, one-page report, bearing the cryptic title ¿Deaths from variant Creutzfeldt-Jakob disease,¿ was made public by the British National Creutzfeldt-Jakob Disease Surveillance Unit. Its corresponding author is medical statistician Simon Cousens.
Two years ago, when 10 new vCJD deaths had brought the death toll to 13, Cousens predicted that the epidemic¿s future course was unpredictable. (See BioWorld Today, Jan. 17, 1997, p. 1.)
As his current report documents, by the third quarter of 1998, total mortality stood at 29, ranging from one per quarter to five.
Then that incidence suddenly doubled, to nine in the last quarter of 1998 plus one in January of 1999.
¿If we were to continue observing a small number of cases each year,¿ Cousens told BioWorld Today two years ago, ¿and there were evidence of a sharp increase in CJD incidence, we might predict 25 to 50 to 100 cases over several years ahead. On the other hand,¿ he added, ¿if we see a sharp acceleration over the next few years, we¿re looking at the possibility of thousands and thousands of cases.¿
This ominous outlook stemmed from the epizootic outbreak of ¿mad cow disease¿ ¿ bovine spongiform encepha lopathy (BSE) ¿ that decimated British cattle beginning in 1985. ¿In the following years,¿ the Lancet reports, ¿the incidence of confirmed [bovine] cases increased rapidly, from about 60 cases in 1986, to more than 600 in 1987, and more than 3,000 in 1988.¿ By a decade later, toward the end of January 1999, the bovine body count had reached 173,718.
Under pressure from the European Union to forestall the export of infected beef, British authorities have slaughtered some 4 million head of cattle from the country¿s total stock of 11 million. (See BioWorld Today, April 8, 1996, p. 1.)
The current report in the Lancet made the point that the ¿unusually high number of deaths from variant CJD occurring in the last quarter of 1998 should be interpreted with caution.¿ One interpretation, the article suggested, might be that clinical diagnosis has improved since 1996. But, it added, ¿even if there had been under-ascertainment of cases, it seems unlikely that there would have been a sudden improvement towards the end of 1998.¿
It concluded that the death rate in the coming years ¿will provide a clearer indication of whether the apparent increase in deaths towards the end of 1998 was a chance observation or marks a change in the underlying mortality rate.¿
The same telltale spongy perforations that riddle the brains of infected BSE cattle occurred in vCJD victims. Also, the infective bovine and human prions appeared to be identical. In 1996, vCJD was first described clinically, and its etiology tentatively linked to BSE.
When neurologist Stanley Prusiner, at the University of California in San Francisco, propounded his discovery of the prion in 1981, he described it as a protein devoid of nucleic acid. In fact, he said, the prion particle was 100,000 times smaller than the smallest virus.
Besides infecting cattle with BSE and humans with CJD, prions also cause a number of less well known, equally lethal neurodegenerative maladies, notably fatal familial insomnia and Gerstmann-Strassler-Scheinker syndrome. Prusiner has also implicated prions in Alzheimer¿s disease. Just how the brain prion protein transmits its infection remains clouded in mystery, but breaks in those clouds are beginning to appear.
How Prion Protein Switches From Benign To Infective
Today¿s Science, dated March 19, 1999, carries a report by the British Prion Disease Group titled ¿Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations.¿ Its senior author is neurologist John Collinge, the group¿s director.
¿There are two major building blocks from which proteins are constructed,¿ Collinge explained, ¿known as alpha helices and beta sheets. Normal prion protein [PrP] is nearly all alpha structure, while the rogue form is largely beta. Using a genetically engineered form of normal, soluble prion protein, we have managed to capture, for the first time, the moment when the change occurs.¿
His group¿s research disclosed that the conversion involves breaking a single bond in the prion molecule. ¿This remarkable property of prion protein,¿ Collinge pointed out, ¿is unprecedented. No other protein has yet been shown to be able to exist in two such entirely unrelated shapes. Furthermore, this protein, when placed in concentrations of salt seen normally in the brain, forms clumped, aggregated fibril-rich material indistinguishable from the rogue form, which accumulated in the brain in BSE and CJD. For the first time, this provides an explanation of how these prions actually replicate.¿
Prion diseases are widely thought to be transmitted from one host to another when abnormal, infective prions rich in beta sheets gain access to the brain and cause normal, alpha-helix-rich proteins to misfold and assume the abnormal structure.
A spokesperson for Britain¿s Wellcome Trust, which co-funded the group¿s work, observed that its findings should enable making antibodies that detect infective beta-PrP, permitting new diagnostic tests for human and animal prion diseases.
Collinge concluded, ¿While this leads to the possibility of developing much better diagnostic tests, our eventual goal of an effective treatment for these devastating brain diseases will remain an enormous challenge.¿