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Original URL: http://www.jsonline.com/news/gen/apr04/226068.asp

Maverick researcher impugns prion theory

He thinks bacteria affect proteins, causing ills such as chronic wasting

By JOHN FAUBER
Posted: April 29, 2004

San Francisco - More than 20 years ago, maverick researcher Stanley Prusiner endured ridicule when he proposed that a rogue protein molecule devoid of any DNA could replicate itself and cause a family of fatal brain disorders in people and animals, including mad cow disease.

His idea was revolutionary, and in 1997 Prusiner won the Nobel Prize. His prion theory is considered dogma by many in the field of neuropathology.

Now, another loner is facing criticism for his own sacrilegious scientific concept: that Prusiner's prions are not the infectious agents and that the real culprit in the diseases is an unusual bacterium.

In research presented Thursday, Frank Bastian, a professor of neuropathology at Tulane University, said he has found bacteria known as spiroplasma in brain tissue samples from people and animals that died of so-called transmissible spongiform encephalopathies, including chronic wasting disease in deer, scrapie in sheep and Creutzfeldt-Jakob disease in people.

Spiroplasma were not found in matched brain samples of the animals and people who did not have those diseases.

Bastian said he believes that TSE diseases begin when spiroplasma attach to normal prion protein in brain cells, leading to a variety of invariably fatal brain disorders.

His latest work was presented Thursday at the American Academy of Neurology's annual meeting in San Francisco.

If he is right - and at the moment few scientists think he is - the prion theory may face a major setback.

At the same time, Bastian said, it could open up possibilities for early detection of those diseases and new treatments.

Herds of wild deer could be given food laced with a vaccine that could halt the spread of chronic wasting disease, or a diagnostic test could identify people with Creutzfeldt-Jakob disease early enough so they could be given a drug to stop the advance of the disorder.

Such scenarios border on science fiction at the moment.

And Bastian and the few other contrarians in the field face a daunting task in proving that microbes cause the diseases.

The overwhelming majority of researchers and neuropathologists who work with TSE diseases largely have accepted the prion hypothesis: that an abnormally shaped protein, with no DNA or other genetic material, can cause normal protein in the brain to adopt its misfolded shape, leading to the irreversible death of brain cells.

But Bastian, 65, a single-minded researcher who tends to give long, rambling answers to questions, methodically has plodded along with his controversial theory ever since he first found the presence of spiroplasma while doing an autopsy on the brain of a Creutzfeldt-Jakob patient in 1976.

"Frank Bastian has been chasing spiroplasma for 20 years now," said Michael Hart, professor and chairman of pathology at the University of Wisconsin-Madison. "He's been ridiculed by the prion community. I don't think he deserves that."

Hart noted that there is intense competition for research money as well as the fame that comes with future breakthroughs.

"He's just threatening to other people's research," Hart said. "There's an awful lot of jealousy in the field."

Already two Nobel Prizes have been handed out for TSE-related research.

If Bastian or someone else proves that a pathogen is involved, a third Nobel should be awarded, Hart said.

Hart, the editor of the leading neuropathology journal in the U.S., himself has taken flak for publishing Bastian's work. In 2001, the Journal of Neuropathology and Experimental Neurology published one of Bastian's first studies showing the presence of spiroplasma in 13 of 13 Creutzfeldt-Jakob cases and five of nine sheep scrapie cases, but in zero of 50 control brains.

"I was really upset with Michael Hart for even publishing that," said Stephen DeArmond, a Prusiner colleague and a professor of neuropathology at the University of California, San Francisco.

An overwhelming amount of research has established the prion theory, DeArmond said. There is no organism such as spiroplasma that is causing TSE diseases, he added.

"Nobody else has duplicated it (Bastian's work), and nobody else in the world believes it," he said. "Right now, he is a loner."

Bastian has a lot of work to do, DeArmond added. In addition to verifying the presence of spiroplasma, it has to be shown that different strains of the pathogen cause different forms of TSE disease, DeArmond said.

Bastian also has to show that purified spiroplasma, just like prions, are resistant to radiation and heat.

"Stan did all that," DeArmond said.

Prusiner was not available for comment. But DeArmond said he has discussed Bastian's work with Prusiner and whether his lab, one of the premier TSE facilities in the country, should research spiroplasma.

Prusiner's reaction, DeArmond said, was "Why should I do that? We have our own hypothesis."

Long way from proof

Indeed, so far Bastian has shown only an association between spiroplasma and TSE diseases. He has not proved that the organism actually causes the disease.

On the other hand, evidence of the infectivity of prions also has been indirect. No one yet has been able to purify and isolate prions from infected brain tissue and show that they cause disease.

Bastian said he believes that spiroplasma attaches to normal prion protein in brain cells and causes it to misfold.

"I have to prove this," he concedes.

But he noted that last year Japanese researchers showed that brucella bacteria, which cause brucellosis, could bind to normal prion protein.

If brucella can do it, why not spiroplasma, Bastian said.

"There is something else binding to that protein," he said. "Whether I'm right or wrong (about spiroplasma), we should be going in a different direction."

Spiroplasma are very small pathogens, roughly about the size of some disease-causing viruses. They have no cell wall and are resistant to heat and chemicals. Spiroplasma are found in many insects and plants.

The coiled microbes "move around like jack-in-the-boxes," Bastian said.

Prion theory skepticism

Bastian is one of a small group of scientists who remain skeptical of the prion hypothesis.

Laura Manuelidis, professor and head of neuropathology at Yale University Medical School, said the most likely explanation for TSE diseases is a stealthy, slow-acting virus.

"I don't believe protein is infectious," she said. "I think it's as likely to find infection with that protein as it is to find weapons of mass destruction in Iraq."

Manuelidis said, so far, Bastian has not provided convincing proof of his theory.

But his point of view deserves to be explored, she said.

"I just find it odd that everybody who writes something different is ridiculed," she said. "That's what they do in this field. It's stingy, small and graceless."

In recent years, a small but growing number of scientists have raised questions about the prion theory, said Bruce Chesebro, a leading TSE researcher with the National Institutes of Health.

Chesebro said he believes that eventually the real infectious agent will be found to have DNA.

Spiroplasma is a "tantalizing idea," but Bastian has not published enough research to be convincing, Chesebro said.

"I don't think it's close to being proven," Chesebro said.

As scientists have done for decades, Bastian on Thursday stood by a blown-up copy of his findings that was posted to a bulletin board in a room filled with dozens of other scientists standing by their own posters.

A Japanese researcher walked by and quizzed him about his work. They exchanged e-mail addresses. The Japanese researcher then took a digital picture of Bastian standing next to his poster.

"In the past 25 years, I haven't seen anything that has dissuaded me from this," Bastian said. "I'll work on this until I die or until we solve it.

"I'm having fun."


From the April 30, 2004 editions of the Milwaukee Journal Sentinel