A Cambridge biochemist, David Brown, believes he has evidence to suggest that animals need prions as protection against that highly necessary, but potentially lethal, activity known as breathing oxygen. All living things, save for a few lowly bacteria, need oxygen, but dealing in this vital currency of respiration risks exposure to the chemical's highly reactive form, called superoxide. Dr Brown suggests that the reason why prions are so common is because they are a crucial line of defence against superoxide.
"All animals need oxygen and as a consequence of using oxygen they produce superoxide, which is basically oxygen with an extra electron stuck on to it," says Dr Brown. "This is quite dangerous because the electron can shoot off and damage cells. Anything to make this superoxide less harmful is of benefit."
If the prion protein does serve this function, Dr Brown has solved a mystery that goes back several decades, when scientists first linked prions to such deadly nervous diseases as scrapie in sheep, bovine spongiform encephalopathy (BSE) in cows and Creutzfeldt-Jakob disease (CJD) in humans. Prions are directly involved, and may even be the cause of these strange illnesses, yet for all the research that has been done on them, no one has yet understood why we need such proteins, if they are so potentially fatal.
The original name for a prion was protease-resistant protein (PrP) because it could exist in a form that was not broken down by digestive enzymes. In fact, this was how it came to the attention of scientists. Isolating the protein soon led to finding out its primary structure - the sequence of 253 amino acids that made up the protein chain. Then scientists found that the PrP gene responsible for the human protein resides on chromosome 20 and is highly "conserved" between different species, meaning that it is virtually identical between one animal and the next. It indicated that it must serve some common function dating back many millions of years in evolutionary history - a key indication that the normal form of the PrP protein has a pretty important role.
For 20 or more years, however, the nature of this function remained elusive. The most that scientists were able to do was to categorise the nature of the illnesses resulting from defects in the protein. For example, small mutations in the gene can result in a wide variety of inherited diseases. Substituting one amino acid for another at the 102nd link in the protein chain, for instance, results in Gerstmann-Straussler-Scheinker disease in humans - an unusual brain disorder. Substituting the 200th amino acid causes a type of CJD seen in Libyan Jews, and changing the 129th amino acid can cause the highly distressing condition known as fatal familial insomnia, which causes people to die after months of being incapable of catching even a minute's sleep.
But it is the non-inherited, transmissible forms of prion disease - notably BSE - that have caused the most intense interest. A curiosity is that the amino acids of PrP protein are exactly the same as normal PrP in both healthy cows and those with BSE, as they are in healthy sheep and sheep with scrapie. Stanley Prusiner, the California University scientist who won a Nobel Prize for his prion hypothesis, believes the disease is caused by deformed versions of the protein (deformed, that is, in its three-dimensional shape) triggering a similar deformity in normal, healthy versions of the protein.
Yet this still does not explain why we need prions. Dr Brown, who leads a team in Cambridge's department of biochemistry, discovered what he thinks is the crucial clue to the protein's normal function when he found that it can strongly bind to copper. Proteins that bind to this metal could have a role as an enzyme involved in coping with superoxide. Other enzymes, called superoxide dismutases, are known to do this and the PrP protein may perform a similar task, Dr Brown says. "Usually copper in a protein can be effective in bringing this about. Like wires, they can shuttle electrons around. Probably what happens in this case is that the electron is shuttled on to the prion protein itself and oxidises the prion protein. A particular amino acid in the protein can become oxidised and is quite stable. The cell can get rid of the superoxide in this way."
The evidence for this comes from experimental results to be published in the Biochemical Journal. Dr Brown manufactured pure PrP protein by inserting the mouse PrP gene into bacteria that grew in fermentation. He found evidence that the protein, when bound up with copper, acted like a superoxide dismutase enzyme - to destroy the harmful molecule. He repeated the experiment with chicken PrP protein and found it, too, did the same.
Dr Brown believes the protein has an especially important role to play at the junctions - synapses - between brain cells, moping up superoxide before it has a chance to damage these all-important connections within the central nervous system. "The implications are that we now know what the normal protein does. The main aspect of prion diseases is that the normal protein is turned into this pathological form that causes the disease; we are now at a point where we can try to find out about the abnormal form."
Knowing the normal role of the PrP protein in the body should shed light on what happens when the abnormal prion protein appears. It may be that the body loses its prime defence in the brain against superoxide. Or it could be that a build-up of defective prions causes a dangerous build- up of copper.
Although Dr Brown's research says nothing about the mysterious nature of how a prion "infects" other prions, he seems to have come close to answering one of the more enduring problems of prion disease. In man or mouse, prions are there to stop oxygen burning us up.