August 7, 2004 New Scientist by Andy Coghlan

It's a bold claim, and the official response has been scathing: no one in the US has ever been formally diagnosed with variant CJD, the human form of BSE. But back in December the US declared its first case of BSE in cattle, and it now looks as though the disease has been circulating in the national herd for several years. That means it is possible that humans have been exposed to infected meat, which is how people are thought to catch vCJD.

Of course, these facts don't add up to the conclusion that the Garden State cluster is real. In fact, the best available evidence suggests racegoers have little cause for alarm. But the "cluster" raises a wider question: if Americans did start catching vCJD from infected beef, would it be detected? Perhaps not. Critics say US surveillance systems for the disease are inadequate -- in many states doctors are not obliged to report suspected cases. And even when they do, those caused by infected beef could easily go unrecognised. The chilling conclusion is that the US could already be incubating a human epidemic of BSE without knowing it.

Mad cow disease, caused by "rogue" prion proteins accumulating in the brain, emerged in the UK in 1986. It stemmed from feeding cattle the remains of other cattle, allowing each sick cow to infect numerous others. In the late 1980s the UK banned this practice and took other measures to eliminate BSE.

It was too late to stop the disease jumping to humans. In 1996 the national surveillance centre found a new form of Creutzfeldt-Jakob Disease. This disease had been known for a long time, occurring at a rate of about one case per million individuals a year. The commonest form, sporadic CJD, affects only the elderly, and probably results from chance mutations. Post-mortems reveal characteristic clumps of protein in the brain.

But the new form was a different proposition: it affected young people and produced distinct protein clumps. It is now generally accepted that this vCJD is a result of eating BSE-infected beef. So far there have been 142 confirmed cases in the UK.

Since 1997 the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio, has been on the look-out for vCJD in the US. The centre has had 1277 suspected cases of CJD referred to it, of which 792 were confirmed as CJD. Only one was vCJD: a woman who had been brought up in the UK, and is assumed to have caught the disease there. She died in June.

But the centre can only investigate the cases it knows about. In most European countries and Canada, CJD is a notifiable disease, which means doctors are legally obliged to report all cases. In the US only 25 states have a notification policy, so cases in other states could slip through the net. The surveillance centre has sent out 60,000 letters nationwide to physicians, neurologists, pathologists and anyone else who might help, asking them to report suspected CJD cases. "We made a tremendous effort to increase awareness," says Pierluigi Gambetti, the centre's director.

The measures have helped. In 2003 there were 284 referrals, compared with just 94 in 1998. But even now only about 60 per cent of cases where CJD is listed on the death certificate as a possible cause are referred to the centre. And some doctors may not even realise CJD is a possible cause of death.

These concerns that vCJD could, in theory, be overlooked lend at least some plausibility to the Garden State racetrack claims. Janet Skarbek, an accountant from New Jersey with no scientific training, took it upon herself to investigate after a close friend, aged 29, died from a degenerative brain disease four years ago. Skarbek traced 15 other individuals who had met a similar fate. The common thread was that they had all been to the racetrack and eaten at the restaurant between 1988 and 1992. And their deaths had hallmarks of CJD.

After sustained lobbying by Skarbek, the New Jersey Department of Health and Senior Services and the Centres for Disease Control and Prevention (CDC) in Atlanta, Georgia, carried out an investigation, which included autopsies and analysis of stored brain samples from at least half the cases. In May they announced their findings. Three of the 16 people who had died, including Skarbek's friend, had not had CJD. Eleven did have CJD, but the sporadic form. This is no more than would be expected among the number of people attending the race track over that time. The other two cases, as well as one possible additional case, are still under investigation. Unfounded fears

"The cases are spread out over 12 years, and that's not a cluster," says Larry Schonberger, the CDC's coordinator of CJD surveillance. "People who've been to that racecourse are now unnecessarily fearful about their health."

But these results cannot rule out a link with BSE. In February, Salvatore Monaco and his colleagues at the University of Verona in Italy discovered a new form of BSE in cows that produces brain disease patterns very similar to those of sporadic CJD (Proceedings of the National Academy of Sciences, vol 101, p 3065). And in the UK, researchers led by John Collinge at the Medical Research Council's Prion Unit in London have carried out studies in mice that are also worrying. They showed that mice injected with prions that usually cause vCJD can develop brain abnormalities typical of sporadic CJD (The EMBO Journal, vol 21, p 6348). Collinge told New Scientist that his more recent research, still unpublished, suggests it is the strain of the mouse that determines which disease appears. "The implication is that some people exposed to BSE might get disease with pathology which we recognise as sporadic CJD," he says. He warns, however, against jumping to conclusions. "You must be cautious extrapolating from animal models."

The number of sporadic CJD cases in the UK has risen since surveillance began, from 28 in 1990, to 50 in 2000. Some of that is no doubt due to better reporting systems. "The question is whether there's a minority of cases which have another cause," Collinge says. His team is now trying to develop molecular probes capable of identifying a subtype of "sporadic" CJD that may in fact be human BSE.

Perhaps unsurprisingly, Skarbek has jumped on these findings. She has asked Collinge to analyse some of the brain samples, and is lobbying the CDC to carry out a full epidemiological investigation that would delve into the life histories and eating habits of the racetrack goers. The CDC, however, has no plans to comply and denies any suggestion of a cover-up. "There's no conspiracy," Gambetti says. "On the contrary, we're always on the watch for something unusual. If there are cases out there, we want to detect them."