By David N. Leff
Then there were 19.
That's the number of young British men and women - 14 dead, five dying - who so far this year are victims of variant Creutzfeldt-Jakob disease - vCJD. That's equal to the total number, 19, who succumbed to vCJD through the entire year 1999. Since 1995, when the first three clinical cases were diagnosed postmortem, vCJD deaths in Europe have aggregated 77 - 74 in Britain, plus two in France and one in Ireland.
This 5.5-year figure works out to an average annual mortality of 14. Last year, and so far this year, have sharply beaten those odds. At this rate, by the end of 2000 vCJD deaths will total 38, double the 19 of 1999.
These grim body counts are compiled by the British National Creutzfeld-Jakob Disease Surveillance Unit. Its medical statistician, Simon Cousens, told BioWorld Today three years ago, "If we were to continue observing a small number of cases each year, and there were evidence of a sharp increase in vCJD incidence, we might predict 25 to 50 to 100 cases several years ahead. On the other hand," he warned, "if we see a sharp acceleration over the next few years, we're looking at the possibility of thousands and thousands of cases."
That horrendous "possibility" led to the preventive slaughter of some 4 million cattle in Britain, in an attempt to stem the spread of mad cow disease - bovine spongiform encephalopathy (BSE). ("Spongiform" denotes the spongy holes that perforate the brains of BSE and vCJD cases alike.) The brain disease had by the end of last year fatally infected 173,718 British cattle - up from 3,000 head in 1988 and 60 in '86. That geometric progression is a grim statistical parallel to the upward curve of human deaths from vCJD. (See BioWorld Today, March 19, 1999, and Dec. 21, 1999, both p. 1.)
BSE and vCJD are prion diseases. The word "prion" stands for "proteinaceous infectious agent." Infectious prion particles are found in the stricken brains of both BSE cows and vCJD people. Teams of cell and molecular biologists on both sides of the Atlantic are in hot but baffling pursuit of how these puzzling prion particles infect and kill their prey. Their bafflement reflects the all but incredible fact that a prion - 100 times smaller than a virus, and with no nucleic acid in its structure - can replicate and cause lethal infections in humans and cattle without benefit of genes or DNA.
At Last: 'Protein-Only' Hypothesis Proven
"The Holy Grail of the mammalian prion research field," observed molecular biologist Mick Tuite, at the University of Kent in Canterbury, UK, "has been to create in the test tube an infectious form of the prion protein. And they have signally failed - at least in the published literature." Tuite is author of an editorial in today's Science, dated July 28, 2000. Its title: "Sowing the protein seeds of prion propagation." It comments on a paper in the same issue of Science, which bears the title: "Evidence for the Prion Hypothesis: Induction of the yeast [PSI+] factor by in vitro-converted Sup35 protein." Its senior author is cellular and molecular pharmacologist Jonathan Weissman at the University of California, San Francisco.
"According to the 'protein-only' hypothesis," Tuite explained, "an 'infectious protein' (prion) adopts an altered conformation, forming a 'seed' that induces normal cellular versions of the protein to adopt the aberrant form. In this way, the infectious protein can be propagated and transmitted to other cells in the absence of nucleic acid. Weissman and his co-authors have done the experiment in yeast that the mammalian field are desperate to do."
Though yeast - Saccharomyces cereviseae in this case - is far removed from mammals, both are eukaryotic forms of life. "Doing experiments on mammalian prions," Tuite pointed out, "you have to have infectivity cycles of up to two years. So you infect the organism - the mouse, the rat, whatever you're working with - and it takes up to two years to manifest the disease [vCJD much longer]. With yeast prions it takes between 48 and 72 hours."
The molecular structure of normal prions features four alpha-helices. Its conversion to a pathogenic conformation centers on flat, misfolded beta sheets.
Protein chemist Alex Santoso, a co-author of the Science paper, told BioWorld Today, "Scientifically, it's good to have confirmation of the prion hypothesis. In terms of its implications for the mammalian field - with which most people are concerned because of its medical relevance - this showed that yeast prions, which are easier to work with than mice, for instance, might be a very good model for studying the mammalian diseases."
A New Kick For Mother Nature?
"It also goes to a more basic scientific question," he added, "which is how exactly is the genetic information encoded. Here is an exciting possibility that nature might have chosen an alternative route a long time ago in encoding genetic information in terms of protein conformation. Our paper showed that an altered conformation of a protein can be infectious in a very direct manner. That is, we introduced an infectious form of the prion protein and it indeed caused that infection to occur. The mammalian people have been trying to do this for a very long time and found it very hard to show, because they were unable to purify the normal mammalian prion protein in its infectious form."
"Prions' ability to make copies of themselves by inducing other proteins to take on the deformed prion shape," observed Weissman, "is not only a novel form of infection, but at least in yeast constitutes a new mode of inheritance."
"I would think," Santoso concluded, "that this paper is the nail in the coffin for a lot of people who still don't believe that altered protein conformation can be responsible for prion diseases. And that is quite important because many of them still blame viruses, or other non-proteinaceous elements."
As for the work's relevance to prion infections in medical practice or animal husbandry, Tuite summed up, "In order to stop something from happening, you have to know how it happens."