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Seeds of Doubt. Questions of link - BSE and vCJD

Kathy

Well-known member
This article is from the "Telegraph.co.uk" website below. Several doctors here discuss their concerns about TSE science. I recommend you read the whole article.

Link: http://www.telegraph.co.uk/connected/main.jhtml?xml=/connected/2006/05/30/eccow30.xml&sSheet=/connected/2006/05/30/ixconnrite.html

Can this really kill you?
(Filed: 30/05/2006)
The Nobel prize-winning hypothesis that infectious proteins can cause CJD and 'mad cow disease' is still being challenged. Roger Highfield reports

A decade or so ago, the Nobel prize for medicine was awarded to a scientist who had an idea so radical that it was condemned as heresy by his peers. Rather than blame conventional agents such as viruses and bacteria for a series of baffling "spongiform" brain disorders like Creutzfeldt-Jakob Disease (CJD), scrapie and BSE, Stan Prusiner proposed that a novel type of infectious agent was responsible.


A human prion. Does an abnormal form cause CJD (picture)

Prusiner began his long journey to this breakthrough in 1972 after one of his patients died of dementia resulting from CJD. Now a professor at the University of California in San Francisco, he named the culprit the "prion" - "proteinaceous infectious particle".

Unlike viruses, bacteria or parasites, a prion is an infectious protein that contains no genetic material. When he suggested the idea, it was greeted with disbelief since it marked the only lifeform that could multiply without a gene. Scientific ridicule was heaped on Prusiner's head, but in 1997 his dogged persistence paid off and his Nobel prize citation described how "an unwavering Prusiner continued the arduous task to define the precise nature of this novel infectious agent".

Abnormal prions are thought to enter the body through food or cuts to set off a chain reaction: the infectious, abnormally shaped prion causes a domino effect, converting normal forms of the protein into abnormal proteins, creating deposits that cause irreversible brain damage. Because these prion diseases have such long incubation times, it has taken an age to study them in detail and there is still a lot we don't understand.

But even today, and almost a decade after Prusiner's Nobel prize, findings still challenge his hypothesis so that, at best, it seems incomplete and, at worst, it may even be wrong.

One recent example came from Dr Martin Jeffrey at the Veterinary Laboratories Agency. His team studied 50 sheep to see what happened when they ate food contaminated with the spongiform disease scrapie. The team monitored the passage of half a gram of liquified brain containing millions of abnormal prions. They were thought to pass undigested through the gut wall into specialised lymphoid tissue called Peyer's patches, where they multiplied before spreading to the central nervous system and on to the brain.

But his team reports in the Journal of Pathology how the prions did not go to Peyer's patches as expected, but were digested or vanished into the lymph nodes. Separate experiments show that abnormal prions can easily be digested by sheep stomach juices, so even if an animal ingested large quantities of infected feed, hardly any abnormal prions would survive.

In the three sheep that did develop scrapie after being injected with diseased tissue, abnormal prions began accumulating in the Peyer's patches 30 days later, even though all the prions from the original gut injections had long gone. When Dr Jeffrey looked into this, he found that the prions were being formed afresh in the patches.

Because the disease was triggered by liquefied sheep brain, the study raises the possibility that an unidentified agent caused the infection which, a month later, triggered the Peyer's patches to make the abnormal prions. This will remain only conjecture until the infectious agent is identified, but the work shows that the prion hypothesis "is not completely satisfactory", says Dr Jeffrey.

To further undermine the link between prions and spongiform disease, his team has shown that the prions do not seem to build up into clumps of sufficient size and in the right place in animals to link with the symptoms of spongiform disease. Working with Dr Bruce Chesebro of the Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Dr Jeffrey found damaged areas in scrapie brains where there were no prions.

Dr Chesebro's own experiments have raised questions. He exposed two groups of six-week-old mice to different strains of scrapie. Within 150 days of being inoculated with the natural form of scrapie prion protein, all 70 mice in the control group showed signs of infection: twitching, emaciation and poor co-ordination. But in GM mice that made a prion protein that does not anchor to cells, he found clumps of abnormal protein in the brain, brain damage, but no disease. "The mice didn't get sick. That's very significant. The dense accumulations of scrapie plaque in the brain resembled the plaque seen in Alzheimer's, but it wasn't toxic."

These findings once again raise the possibility that the abnormal proteins are a consequence of the disease process, rather than a cause. (Interestingly, a similar argument is raging over the protein deposits linked with Alzheimer's disease.)

The most fundamental issue of all was raised by the Nobel prizewinner Prof Kurt Wuthrich of the Swiss Federal Institute of Technology, Zurich: he pointed out that researchers have failed to produce spongiform disease using laboratory-made prions, the only real way to eliminate the possibility that another agent might be responsible.

That challenge seemed to have been met last year in the journal Cell, in an experiment by Prof Claudio Soto at the University of Texas Medical Branch at Galveston. His team took prions from infected hamsters and placed them in test tubes containing healthy brain proteins. When the healthy proteins had been largely transformed into prions, the samples were diluted over and over again and the process repeated, until the only remaining prions were presumably those that had been newly generated in the test tubes. These were then injected into the brains of healthy hamsters, which died less than six months after inoculation.

But, say the critics, extraordinary claims need extraordinary evidence. The infectivity was tiny and there are questions over how Prof Soto purified the prions and whether a non-prion disease agent could have remained after dilution.

Prof Soto has confirmed his results in other species, and using more stringent conditions. "Indeed, we have a couple of papers currently under review showing that we can generate infectious prions starting from what is estimated to be one single molecule of infectious prion," he says. But although he believes the evidence for prions is overwhelming, he admits that it is "a minor possibility" that "there might be another component necessary for infectivity, including a possible nucleic acid (DNA or RNA genetic material)".

Dr Surachai Supattapone, from Darmouth University in New Hampshire, has repeated the same study using purified protein in which, presumably, no nucleic acids are present and presented his results in March at a conference in Saint Moritz. "I can't give too much detail at this point, but I think that our studies with purified protein cannot rule out a second component," says Dr Supattapone.

Another central tenet of the Prusiner hypothesis is that a single prion protein can give rise to different strains of disease with varying infectivity and other properties, each reflecting different shapes of the prion protein. This seemed to be confirmed in work on yeast by a team led by Dr Jonathan Weissman at the University of California, San Francisco, and Dr Chih-Yen King at Florida State University.

But yeast prions "are quite distinct from mammalian prions in spite of the similar names", commented Dr Chesebro, who remains unconvinced. And when his British collaborator, Dr Jeffrey, looked at the effects of prion shape in sheep, he found that the shape can vary, depending on which sort of cell it inhabits, even though it produces the same strain of disease in mice.

Similar observations that prion shape changes do not alter the strain of the disease have also been reported by Prof Laura Manuelidis of Yale Medical School, who concluded that many facts "are discordant with the prion hypothesis" in a review in the journal Viral Immunology.
Prusiner's idea does not fulfil the classic criteria formulated by Robert Koch in 1884 to link an agent to a disease, says Prof Manuelidis. "Not a single one of Koch's proven postulates of infection are fulfilled by prion proteins."

Such is the hold of the prion hypothesis over the scientific establishment, she says, that "this evidence (or lack of evidence) led one dominant prion proponent to question the use of Koch's postulates".

There is even evidence for viral particles, although she says this has been ignored. "It has also been obvious for a long time that abnormal prion protein is the consequence of infection, but not the causal agent," she says. "You might say that abnormal prion protein lacks the dynamite for weapons of mass destruction, though it certainly has a lot of rhetoric inside it. Those natural truths are not defined by popular vote or cabal."

She is also disturbed by the hostility faced by those who question the prion idea and says she has seen the good work of others trashed by the traditional weapon of choice in scientific disputes - anonymous peer review. "At issue, unfortunately, is public health."

• Roger Highfield will judge the FameLab final at the Cheltenham Science Festival, celebrating its fifth and most successful year, from June 7-11. To mark the occasion, Lord Robert Winston will chair debates on the big science issues: cloning, human genetics and energy. Once again the festival is joined by high-profile names, including environmentalist James Lovelock, humanitarian Terry Waite, director of the Royal Institution Susan Greenfield, neuroscientist Steven Rose, presenter Adam Hart-Davis, physicist Frank Close, architect Charles Jencks and chairman of the Arts Council Sir Christopher Frayling. See www.cheltenhamfestivals.co.uk

Manuelidis chose an interesting comparison: WMD and prions!

I note that in another article, found in the Acres USA magazine, reference is made to the "very effective" usage of "ultrasound" in "shaking mercury loose from sediment".

"We found ultrasound to be very effective at getting mercury out of sediment and into water," they explained (University of Ohio State study) "But then we needed a third party to get the mercury out of the water. That's how we got the idea to add a biological element to the treatment."

An interesting coincidence. Using ultrasound to remove a heavy metal from the soil which it is biologically attached; sounds so familiar since scientists treat prion homogenate with ultrasound before they challenge their experimental animals with them. This always happens when very small amounts of the prion brain material is used in intracranial and drenching transmission experiments.
 
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