1998 Society for Neuroscience meeting

[Guest guest]

Of Prusiner And Prions

by Green

Fittingly enough, for the opening day's special lecture of the 1998 Society

for Neuroscience Annual Meeting, the special guest, neurologist Stanley B

Prusiner of the University of California at San Francisco, came bearing a

special pathogen: the prion. Since 1982, Prusiner has famously contended that

the prion, a mutant isoform of a normal cellular protein called PrP, is the

agent for a host of neuro-degenerative diseases. These include scrapie in

sheep, bovine spongiform encephalopathy (BSE) in cattle and a newcomer that

appears to be caused by the same agent as BSE and has in the last four years

claimed 28 human victims in Britain and France: new variant Creutzfeldt-Jakob

Disease (nvCJD).

Of more relevance to Prusiner's own research are the 17 other human variations

of these invariably fatal neuro-degenerative disorders, called transmissible

spongiform encephalopathies (TSEs): sporadic Creutzfeldt-Jakob Disease (CJD),

fatal familial insomnia (FFI), kuru and Gerstmann-Straussler-Schenker Syndrome

(GSS). While these are the rarest of killers, at best claiming one in a

million, the spectre of BSE appearing in humans in Britain and the extreme

nature of the claims Professor Prusiner has made for the prion since coining

the term in 1982 have vaulted them to the forefront of neurology and molecular

genetics. Even his fiercest critics, including retired neuro-pathologist Hugh

Fraser of the Neuropathogenesis Unit (NPU) in Edinburgh, insist, " He deserves

enormous credit for elucidation of PrP and the advancement of protein

chemistry. " And enormous credit he has received. Last year Professor Prusiner

received the Nobel Prize for Medicine for promoting the notion that TSEs are a

school of diseases with distinct strains that, unlike viruses and bacteria, do

not necessarily involve an agent with an independent genome. In fact, as he

conceded in his lecture, for the prion to satisfy epidemiological evidence,

TSEs would have to be not simply novel, but positively acrobatic: spontaneous,

inheritable and transmissible, too.

His address to the Society, titled " Molecular Biology of Prions Causing

Neurodegeneration - A Scientific Odyssey from Heresy to Orthodoxy " , set out a

multi-disciplinary barrage of evidence to argue just that. Working to the whir

and click of the projector, Professor Prusiner quickly trotted through his

ascent through the field - his first encounter with a CJD patient in 1972, his

attempts to isolate TSE agents using mice, his switch to hamsters for their

faster incubation times, isolation of the PrP protein from unwieldy mass of

diseased brain using a succession of detergent and enzyme purification

techniques, the genetic sequencing of PrP in its normal form, the discovery of

what appeared to be strain-specific mutations at tell-tale codons in the

roughly 210 amino acid sequence of PrP, the importance of cleavage sites where

the protein breaks during misfolding in the disease process, then molecular

assaults using transgenic mice to explore which polymorphisms might signal a

genetic predisposition to TSEs.

It was an address that jumped scientific specialisms in a manner bespeaking a

mightily endowed lab, but one which, vaulting dramatically from discipline to

discipline, left much of the audience behind. For the neuro-pathologists,

there were beautifully stained samples of amyloid plaques in slides of

diseased brains, for cell biologists there was a quick explanation of the life

cycle of the prion from its birth in the cell center, its traverse to the cell

membrane where it may serve in synaptic function. And then, for the

biochemists, there were the illustrations of the mis-folding of diseased PrP,

and hypothetical mechanisms whereby the prion might somehow come in contact

with an as yet undefined co-factor, probably a second protein - " Protein X " -

after which domino mis-folding is initiated and PrP converted to prions.

For the molecular geneticists, there were his lab's latest immuno assays using

antibodies to investigate structural variations in the amino acid sequence of

PrP that may correspond to TSE strains. These are reported in the October

edition of Nature Medicine (Safar et al., vol 4, no 10, pp1157-1165).

Finally, there was rich fodder for his critics. " We have created prions de

novo, " he told the audience, repeating it three times lest its importance

escape the uninitiated. This would take care of the spontaneous part of the

prion hypothesis. The claim is not new, and first arose over a GSS trial in

which Prusiner claimed that transgenic mice spliced up with a GSS mutation

spontaneously developed disease which in turn proved transmissible. In June of

this year, at the only independent lab to attempt to repeat the work,

molecular geneticist Jean Manson of the NPU in Edinburgh found GSS transgenic

mice lived up to 750 days of age with " no signs of neurological disease " while

the inoculated animals succumbed relatively quickly, supporting the idea that

the disease is transmissible, but not necessarily spontaneous (Statement No.

59, BSE Inquiry, www.bse.org.uk).

By way of more red flags for his detractors, Prusiner took pains twice to

emphasize: " The prion has no nucleic acid. " To be precise, while it has a gene

telling it to be a protein, unlike any known pathogen, the prion as proposed

by Prusiner does not require the help of disease-specific nucleic acid to

propagate. And, propagate the TSE agent does as anyone familiar with the BSE

epidemic can testify. . Whether or not the prion can propagate via its

hypothetical chain of chemical conformation outside slide shows at scientific

meetings remains one of the hottest arguments in modern science. However, this

Sunday morning, the argument was not audible, and did not involve Professor

Prusiner. The last words of his exactly hour-long address were: " There is no

time for questions. "