Prions are "rogue" forms of normal proteins. They defy conventional scientific knowledge. We know that they work to terrifying effect on the brain, eating it away and turning it into sponge. What we cannot explain yet is how they work.
Prions act in the place where chemistry and geometry intersect. Many scientists now think that CJD and BSE diseases are not triggered by a conventional infection caused by a virus or a bacteria. Instead it seems they are set off by an entirely new infectious mechanism: a protein that abruptly changes shape, like a child's bendy toy, which then sets off a disastrous chain reaction in other cells.
BSE, CJD and scrapie - the form of the disease takes in sheep - differ significantly from the sorts of diseases we learn about at school. Conventional thinking says infectious diseases are caused by bacteria and viruses - living agents with their own genetic instructions encoded in DNA (or its chemical and genetic relative, RNA). They invade a host cell and their genetic material sets that cell to work making copies of the invading cells, which then infect more host cells.
The first step in the discovery of the entirely different infectious mechanism came in 1957, when two scientists studying tribes in Papua New Guinea noted a disease that the natives called kuru, or "the laughing death". It was a disorder in which loss of co-ordination was rapidly followed by dementia and death. It was spread because the tribespeople indulged in ritual cannibalism. But the scientists' research found no infectious agent to explain the disease. The first clue that something else was at work was a strange sponge-like appearance to the victims' brains.
That same sponge-like appearance is found in cows that die of BSE. Here too the infectious agent is elusive - yet incredibly hardy. You can do a lot to infected tissue samples: douse them in antiseptics, boil them in water, shine ultraviolet light or even high-energy gamma rays on them. Any one of those would destroy a bacterium or a virus. But not BSE, CJD or scrapie.
The turning point in the understanding of these diseases came in 1972. Stanley Prusiner, a neurologist at the University of California's school of medicine in San Francisco, watched one of his patients die from CJD. Upset, but intrigued, he began reading the scientific literature on CJD and related conditions - which he found electrifying. Finding the infectious agent became his life's work.
After setting up a laboratory in 1974, it took Prusiner and his colleagues eight years to established two facts: the infectious agent involved in these diseases was unaffected by any process that would destroy DNA or RNA, yet it lost its effect when treated with substances that broke down proteins.
In his first significant publication on the topic, in 1982, he dubbed the agent a "prion" (he pronounces it "pree-on", though most people find "pry-on" easier on the ear), for "proteinaceous infectious particle". His research team subsequently established that the scrapie prion contained only one protein, which they dubbed PrP - for "prion protein".
Prusiner's iconoclastic suggestion that something without any genetic element could cause an infectious illness "evoked a good deal of scepticism", he observes. There was also the question of where PrP came from in the first place. That was answered when scientists discovered several animals - hamsters, mice, cats, elk, mink, sheep and humans - have genes that control the making of PrP.
But if we all produce PrP, why doesn't everyone die of CJD? "One interpretation was that we had made a terrible mistake and that PrP had nothing to do with prion diseases," Prusiner said later. But then he recalled that the biological action of most proteins depends on their physical shape - the way their molecular constituents are folded together. (Why proteins, which start as long, simple chains of amino acids manufactured by genes, spontaneously fold into the shapes they do remains one of the greatest unsolved mysteries in modern biology.)
Prusiner's next step was to suggest that there could be two shapes of PrP: the normal form found in healthy mammals and the diseased, "scrapie" form. This was confirmed by experiments with enzymes called proteases, which break down proteins found in cells as part of the body's self-regulation. Enzymes are like locks: only the correct shape of protein fits them. Experiments at the University of California showed that "scrapie" PrP resisted being broken down by protease enzymes, while normal healthy PrP did not. Chemically they were the same protein; but geometrically they were different shapes. A build-up of diseased PrP proteins, then, would throw a body's self-regulation out of kilter because they are immune to enzymes.
What Prusiner could not explain was why the "scrapie" PrP had a different shape, and more importantly why it seemed able to encourage other proteins to change shape as well. Prusiner decided to investigate other "prion diseases" in humans.
In 1988, he obtained copies of a PrP gene from a man with a disease, known as Gerstmann-Straussler-Scheinker disease, which resembles CJD. Prusiner's team found a tiny mutation in the man's gene. Out of 750 "instructions" - called base pairs - on the gene's DNA, a single one was unusual. This meant that instead of making the amino acid proline, as a healthy PrP gene would, it made one called leucine. That, in turn, meant that the PrP protein was a different shape. As long as your PrP proteins retain the correct shape, you will remain healthy.
But even after painstaking research over many years, there were still the twin questions of how the infection was spread and how it worked inside a body. Why could "scrapie PrP" easily infect some animals, such as mice, sheep or cows, yet be hard to pass to others, such as hamsters?
Prusiner, with fellow researcher Michael Scott, found that the amino acid sequences of cow and sheep PrP proteins are relatively similar. Prusiner suggests that "the more the sequence of a scrapie PrP molecule resembles the PrP sequence of its host, the more likely it is that the host will acquire prion disease."
Human PrP genes and proteins differ quite substantially from those of cattle, but not by so much that it rules out BSE passing from cows to humans.
The key to the way the disease spreads through the body is the way PRP changes shape and induces other proteins to follow suit. Experiments at the Massachusetts Institute of Technology have shown that when diseased PrP and normal sheep PrP are mixed in a test tube, the normal form converted to the diseased form. There might then be a cascade effect as more and more proteins change shape.
It is known that they become concentrated in the spinal cord and the brain. This concentration of the diseased protein causes cells to die slowly. The collapse of the cellscreates the spongy appearance of the brain in post-mortem.
But how many "diseased" proteins are needed to set off the cascade? How long does it take? Can the "flipped" BSE prion induce the normal human prion to flip? To these vital questions, even the crusading Prusiner does not have the answers, yet.
Prions: When changing shape means death
The prion is a standard protein that changes shape - apparently spontaneously - and then causes brain degeneration and death.
1) The normal form of the PrP protein exists in the "folded" shape in many cells of the body. Its exact function is unknown.
2) Somehow, the protein "flips" to a stretched form. Because it originates in the body, the defence mechanism of the white blood cells does not break it down. The "flipped" PrP, or prion protein, now begins to affect the normal version in other cells in the body.
3) "Flipped" copies of the PrP protein gather in brain cells, where they cause fibrous deposits - "plaques" - which cause the cells to die and collapse.
4) Post-mortem examination shows how the collapsed cells leave the brain with a sponge-like appearance, shot through with holes.
How we might catch CJDfrom BSE
1) Meal infected with prions from a cow with BSE (bovine spongiform encephalopathy) is eaten.
2) Prion proteins that cause BSE in cattle are absorbed through the stomach wall.
3) Over a period of time - which may be between 10 and 30 years - the prion protein spreads throughout the body and "encourages" normal copies of the same protein in the body to change shape to the diseased form.
4) Diseased forms of the prion protein begin to gather in the brain and spinal tissues, where they lead to degeneration of the grey matter. Eventually CJD sets in, leading to dementia and death within a year or two.