After years of inquiry no-one knows how many lives nvCJD will claim

Sunday 29 October 2000  By Robert Matthews and Lorraine Fraser.  Telegraph

Millions watched Zoe's final hours

AS epidemics go, it could have been worse: a sudden outbreak of media coverage, a rash of unpleasant headlines, some feverish editorials.

Now, just three days after the publication of the Phillips report into government's role in the BSE crisis, those who seemed likely to succumb to its effects appear well on the road to recovery. Some will return to work tomorrow after following spin doctor's orders and staying at home, and avoiding stress - and all media contact.

Yet while the former ministers and civil servants named - and almost blamed - last week have moved on, up or out, one group involved in the BSE debacle has no such obvious escape route. It is that of the scientists, still struggling to understand what went wrong with Britain's cattle, and what might now be in store for humans.

Despite the blanket coverage that it received last week, the Phillips report was really just an exercise in bureaucratic archaeology. It was a study of the BSE epidemic and the response of ministers up to March 1996, when the Conservative government of the day finally conceded a possible link between eating meat and contracting new-variant CJD, the human version of BSE.

Anyone scouring the report will look in vain for definitive answers to such questions as how cattle came to acquire BSE, the origins of vCJD and the likely human toll: no one knows. Indeed, anyone who reads the scientific parts of the Phillips report is likely to be stunned by how little is known even now, four years after the government announcement what so many had feared.

At the centre of the mystery of BSE and vCJD is a microscopic bundle of chemicals known as prion protein. Found in the brains and nerve tissue of animals ranging from mice to men, this protein plays an important role in the nervous system - but what that role is has yet to be ascertained.

In cattle and humans affected by these diseases, healthy prion protein is somehow altered into another, rogue form, with the deadly ability to corrupt other healthy protein around it. The result is damage to the nervous system, first subtle, then progressively more severe. Within as little as a few months, the rogue protein has turned the brain into a spongy mass of dense-looking "plaques", surrounded by holes.

It is this characteristic appearance that first led scientists to link vCJD to eating infected meat. Neurologists had identified several different forms of CJD over the years - ranging from genetic cases passed down families to cases that seem to strike out of the blue. But, under the microscope, none looked exactly like this new variant of CJD.

After finding 10 patients with brain tissue showing the vCJD pattern, scientists at the National CJD Surveillance Unit in Edinburgh tried to find a common link. Unable to find any obvious risk factors such as connections with BSE-blighted farms, the team was forced to conclude that the most likely explanation for the vCJD of these patients was exposure to infected meat products.

The link was strengthened by a search of medical archives for brain tissue showing the vCJD pattern. Not a single case has been found dating before 1994 - as would have been expected if human vCJD had followed the emergence of BSE in cattle. Detailed comparisons of the prion protein in BSE and that in vCJD have since confirmed that the two are, indeed, very closely related.

Yet even now - four years after the government's announcement - there is still no definitive proof that eating infected meat causes the human disease. If anything, as more vCJD cases emerge, the picture has become cloudier. Scientists remain baffled by the fact that most of the 85 cases of vCJD identified so far have occurred in people under 45 years old, with about a third of them under 25. The youngest victim was struck down at the age of just 12.

Classic CJD, in contrast, is chiefly a disease of the old. Yesterday's identification of a 74-year-old man with vCJD has led to suggestions that many cases in old people had been misdiagnosed as other dementia. However, scientists believe that the surveillance systems in place since 1990 are unlikely to have missed large numbers of cases among the elderly.

Equally perplexing is the emergence of a cluster of five vCJD cases around the small Leicestershire village of Queniborough. While chance cannot be ruled out, scientists are trying to find a common factor linking the disease to the village. The growing suspicion is that there is more to the BSE-vCJD link than just eating meat: that some other factor may be involved.

Genetic susceptibility is one possibility. Every case of vCJD so far has occurred among people carrying two copies of part of a gene linked to an amino acid called methionine. The suspicion is that such people are more susceptible to vCJD. As 37 per cent of the population falls into the same genetic class, that means that vast numbers will eventually die of vCJD, unless some other risk factor is involved.

What that factor might be has prompted the most disturbing line of research now under way: that the apparent link between vCJD and meat eating is a coincidence, caused by an environmental factor that struck humans and cattle at the same time.

One potential culprit is organophosphates (OPs), chemicals with potent biochemical action that are widely used in Britain to treat warble fly infection. Since the 1980s, the role of OPs in the BSE-vCJD link has been doggedly pursued by Mark Purdey, an organic farmer in Taunton. Long derided or ignored by establishment scientists, Mr Purdey's research was finally taken seriously by the Phillips inquiry, which conceded that exposure to OPs could boost susceptibility to vCJD.

Mr Purdey has recently uncovered a link between CJD-like diseases and levels of trace metals in the environment. This follows his discovery that CJD-like diseases in animals are more prevalent in areas with low levels of copper but high levels of manganese.

Again, the Phillips inquiry conceded that Mr Purdey's findings might be significant, and pointed to new research by scientists at Cambridge University into the mystery of what healthy prion protein actually does.

Dr David Brown and his colleagues at the university's department of biochemistry have found evidence that healthy prion protein affects the use of copper by the body. The protein also seems to play a role in protecting nerve cells from so-called free radicals, extremely reactive fragments of molecules that can damage DNA.

Dr Brown and his team have discovered that, to perform this protective role, healthy prion protein needs to be bound to copper atoms. If, instead, it is exposed to manganese, the prion protein changes - giving the protein some of the characteristics of the rogue protein that causes BSE and vCJD.

These new findings all support the possibility that the link between vCJD and eating infected meat is an illusion. What might have happened instead is that changes in farming practice subtly altered trace element levels that - perhaps when combined with OP use - led to both BSE and vCJD emerging at about the same time.

While mainstream opinion insists that eating infected meat is the most likely cause of vCJD, even the scientific establishment is now suggesting that it might not be enough by itself.

Professor John Collinge, of Imperial College, and one of the Government's independent scientific advisers, has conceded that the bizarre pattern of vCJD cases so far points to the existence of other risk factors. He has suggested that mouth ulcers and infections of the tonsils or gastro-intestinal tract may increase vulnerability.

As scientists struggle to fill the vast holes in their understanding of vCJD, the truth is unfolding month by month, as new cases are added to the toll. In August, researchers at Oxford University produced the best estimate yet of the figure that everyone now wants to know: how many people will die of vCJD?

With so many unknowns - from the numbers of infected cattle that entered the food chain to the incubation period of vCJD - the task would seem hopeless. Yet the team believes that it has arrived at a fairly reliable overall picture, after checking five million permutations of the various possibilities. According to their computer model, the worst-case scenario is that 136,000 people will eventually succumb - a figure based on the assumption that vCJD has an incubation period of at least 60 years.

While so long an incubation period cannot be ruled out, evidence from other forms of CJD suggests that it could be too pessimistic. Kuru, a form of CJD that appeared in New Guinea in the 1920s among tribesmen who ate the brains of dead relatives, had an incubation period of about 15 years. A similar figure emerged from studies of patients who died from a CJD-type disease after being given human growth hormone.

Assuming that the incubation period of vCJD is between 20 and 30 years, the Oxford University computer model estimates that the number of deaths from vCJD will be a few thousand.

Even that figure could prove too pessimistic, if the growing suspicions about the involvement of other risk factors for vCJD prove correct. What scientists now need to establish is how important those other risks are. The disturbing fact is that some of those scientists are starting to wonder if the link between eating meat and vCJD is an illusion, and that the whole BSE debacle was based on a misconception.