Beefeaters No More

By Josie Glausiusz|Wednesday, May 01, 1996
Can humans catch a fatal disease by eating infected beef? No one knows for sure, but a few suspicious deaths have shaken the British.

Shepherd’s pie, a mashed-potato-and-beef conglomeration foisted upon generations of British children, has been struck off the menu in over a thousand schools throughout the United Kingdom. Gone also are hamburgers, beef stew, beef sausages, and even Yorkshire pudding, that drippings-soaked symbol of British culinary aplomb. Why? Fear of bovine spongiform encephalopathy (BSE), also known as mad cow disease, is sweeping Britain. The disease, thought to be caused by rogue proteins called prions, eats away at cow brains, eventually killing the cows. This nation of beef eaters is worried that mad cow disease may spread to humans.

BSE first broke out in Britain in the early 1980s. These days infections are cropping up in 300 cows a week. Infected cattle are supposed to be destroyed before they reach market, but because BSE’s incubation period is 8 to 12 years, some infected cattle probably show up in slaughterhouses. Public concern has peaked in recent months amid worries that contaminated meat is being sold and eaten.

The outcry, fueled by Britain’s tabloid press, started with the deaths last year of two teenagers from Creutzfeldt-Jakob disease (CJD)-- BSE’s human equivalent, which is also thought to be caused by prions. An extremely rare, incurable disease--only one person in a million gets CJD-- it has an incubation period of up to 30 years, usually appearing in people 45 and over and hardly ever in those under 30. Moreover, within the past three years four British farmers, all of whom apparently had contact with BSE-infected cows, have died of CJD. All this might have been dismissed as freakish had not the incidence of CJD in Britain doubled in the last decade, with 55 cases reported in 1994, the last year for which data are available.

Britain’s prime minister, John Major, evidently thinks beef is safe; he told Parliament last December that there is currently no scientific evidence that BSE can be transmitted to humans or that eating beef causes CJD in humans. But he was contradicted by a former government medical adviser, Sir Bernard Tomlinson, who said he would not eat beef burgers or meat pies under any circumstances.

The cow epidemic has been traced to a protein supplement in cattle feed that included the remains of sheep infected with scrapie, a disease similar to BSE. (While scrapie afflicts sheep in the United States, there is no direct evidence that BSE has infected American cattle.) At the height of the British epidemic three years ago, the disease infected about 1,000 cattle a week. It also showed up in zoo cats--cheetahs, ocelots, and pumas--that had apparently been fed fresh beef.

Whatever causes BSE cannot be killed by boiling or radiation, as viruses can, and it passes through filters that would catch a virus. No virus has ever been found in infected cow brains. But a characteristic protein has--and many researchers believe that this protein alone, dubbed a prion, is the infectious agent. Prions are thought to damage the brain by somehow converting a normal, harmless version of the same protein, found on all types of cells and known as PrP, into new prions. According to one theory, prions clump together and block molecular traffic, killing the cells and leaving spaces where once there were nerves. Even worse, it’s suspected that the new prions are themselves infectious.

But can cow prions infect humans? That is, can a prion from a BSE-infected cow brain alter the normal human PrP protein, converting it into an agent of Creutzfeldt-Jakob? The answer is far from clear. The most direct evidence comes from John Collinge, a neurologist at London’s Imperial College School of Medicine at St. Mary’s, who has run a series of rather complex experiments to try to answer the question. Since he couldn’t experiment on humans, Collinge studied mice genetically engineered to carry only the human gene for PrP and not the mouse one. Unlike normal mice, these can be infected with human CJD: when Collinge injected them with cells from the brain of a patient who had died of the disease, the mice soon developed its characteristic symptoms--hunched posture, a wobbly walk, and a tendency to fall. They died within 200 days. Autopsies revealed the sponginess in the brain typical of CJD.

That told Collinge that his engineered mice are a good way of testing whether prions from BSE-infected cows can also alter human PrP. When he injected cow prions into the brains of normal mice, the rodents developed a mouse version of BSE within 450 days. When he injected the prions into mice with a mixture of human and mouse genes, those mice, too, got BSE--but it seemed it was their normal mouse proteins rather than their human ones that were being converted into prions. (Collinge used antibodies to zero in on which proteins were being hijacked.)

Finally, Collinge did the acid test: he injected cow prions into the brains of mice that carried only human PrP genes. That experiment is still going on. The mice are now more than 400 days old and still healthy-- indicating, perhaps, that BSE prions cannot convert human protein. But normal mice in previous experiments have developed symptoms of BSE as much as 700 days after inoculation, so it’s still possible that the mice with human genes will get the disease. Collinge will have to wait at least another year before giving them the all clear.

Nevertheless, he is cautiously optimistic. Why? The mice with only human PrP genes, he points out, have already lived out nearly half their normal life spans without getting sick. And in the mice with both human and mouse genes, the human proteins apparently have not been converted into prions--only the mouse ones have. There are still plenty of things we don’t know about these diseases, says Collinge, and this is only an animal model. It doesn’t mean that no human is ever going to get BSE. But there is probably quite a good species barrier.

Not everyone agrees. Heino Diringer, a biochemist and virologist at the Robert Koch Institute in Berlin, believes humans can contract CJD from eating contaminated beef. I think there is a good likelihood that this can occur, he says. But there is no proof, of course. Unlike most researchers in the field, Diringer believes that scrapie, BSE, and CJD are all caused by a virus--one that hides itself inside prion protein, which it produces and which protects it from destruction by stomach acids. And although scrapie probably can’t be transmitted from sheep to humans-- studies show that the incidence of CJD is fairly constant around the world, including countries in which scrapie has never occurred--Diringer maintains that the disease, in its passage through cattle, has acquired a new, more dangerous, quality. Somehow, he believes, a mutant form of scrapie has cropped up in cows that is infectious to humans.

Diringer cites experiments in which BSE from cats, pigs, antelopes, and goats was injected into mice. The pattern of brain damage is identical in the mice--but different from that which occurs in sheep. Moreover, says Diringer, if the BSE agent has jumped from cows to cats-- mammals evolutionarily distant from cattle--without changing, then there’s no reason it can’t go from cows to humans.

Diringer’s theory assumes that cats and humans are ingesting prions in contaminated meat. Ian Shaw, a toxicologist at the University of Central Lancashire, also thinks cow prions may jump to humans--but he says the infected English farmers might have acquired CJD by inhaling prion- impregnated dust while raking tainted feed. Shaw suggests that prions, rather than traveling from the gut up the spinal cord to the brain, may take a shortcut from the nose to the olfactory bulb and then spread to other parts of the brain. Some neurotoxic chemicals, Shaw says, are known to reach the brain this way.

This hypothesis is dead easy to test, says Shaw. Get radioactively labeled prions and give them to some unfortunate rat to breathe, and just take out the olfactory nerve and see if you can find the prions. Shaw is thinking about setting up just such an experiment.

Although Shaw’s theory might explain how the four farmers came down with the disease, it provides no insight into why two teenagers--who, for what it’s worth, were known to have eaten beef--should suddenly have died last year from CJD. And it’s these deaths that are most worrying to Collinge. The farmers are rather typical cases, he says. They have onset in their fifties and sixties, which looks like every other sporadic CJD case. But we simply haven’t seen the disease at all in teenagers in the UK before. There are only four cases in the world literature that have ever been reported in teenagers, so it’s as rare as hens’ teeth.

Perhaps, he says, we’re looking so hard at these diseases now that we’re seeing things we might have missed before. But I’m not happy with that explanation, and it really underlines the need to keep a very close eye on the epidemiology. If it is the start of something, then we’ll know over the next year or two because there’ll be more cases. Given the long incubation period typical of CJD, though, a full-scale human epidemic- -if one occurs--would probably take decades to appear.
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