Mad cow sleuths at odds over cause

April 13, 2001 The Hartford Courant by Garret Condon

Some years ago, Dr. Laura Manuelidis had a nightmare. In the dream, she was working in her Yale lab, purifying brain matter infected with a human disease similar to mad cow disease. She purified and ran tests and purified some more, and still, she could not find the disease-causing agent.

"So it's nothing," she woke up saying. "The agent is nothing."

The nightmare was pretty close to what was happening in her lab. Manuelidis, 58, has spent more than two decades delving into a mysterious class of rare, brain-eating diseases - much of this work side-by-side with her husband, Dr. Elias Manuelidis, who died at age 74 in 1992. But she has never found the disease-causing agent and, she says, neither has anyone else.

This view puts her at odds with most scientists in the field and with the Nobel Assembly, which gave the 1997 Nobel Prize in Medicine to Dr. Stanley Prusiner of the University of California at San Francisco for his discovery of prions (pronounced PREE-ons) - a normal protein that can become misshapen and cause illness. Prusiner and others believe prions cause mad cow and related diseases.

This is no mere ivory tower tiff. Mad cow disease (bovine spongiform encephalopathy) emerged in Britain, beginning in the mid-1980s. And in the mid-1990s, doctors confirmed that a related human disease, a form of Creutzfeldt-Jakob disease, was linked to eating infected beef. No one yet knows whether numbers of cases of the grisly, brain-wasting human disease have hit a plateau (there have been about 100 cases so far - mostly in Britain) or whether there will be an explosion in years to come.

Both sides in the prion debate accuse the other of hindering progress toward tests and treatments.

In person, Manuelidis, a professor and head of neuropathology at Yale, is an expansive woman with sharp, deep-set eyes who seems equally at home with classical sonnets as with amino acids. She is given to poking fun at herself, but it's clear that she can dig in her heels and relishes a scrap.

"I don't think [the prion] is the infectious agent," Manuelidis says. "Everyone just accepts it. It's dogma."

Every dogma has its day. In the early days of research into these illnesses - called transmissible spongiform encephalopathies or TSEs - Manuelidis and her husband suspected a slow-acting, as-yet-undetected virus, and most other biomedical researchers agreed.

Prusiner's prion theory, when first proposed, was considered radical and too far-out. His notion was that a normal protein - the prion protein - gets folded wrong, like molecular origami gone awry. When this misshapen prion comes in contact with normal prion proteins, it causes a kind of chain reaction, making them fold in the wrong way, too, which gradually damages brain tissue.

What sets the prion idea apart from what is known about other infectious agents like viruses, bacteria, fungi or protozoa, is that prions lack nucleic acid - the DNA or RNA that all organisms use to replicate and transmit themselves. This action was considered necessary for infectious agents - until Prusiner introduced the idea of an infectious protein without nucleic acid.

"Fifteen years ago, if you were handicapping this field, you would have been more likely to bet on the ideas that Laura Manuelidis and her husband were championing than the ones Stanley Prusiner was championing, but that's no longer the case," says Dr. Fred Cohen, a professor of medicine and pharmacology at UCSF who has collaborated with Prusiner for 11 years. "The less likely hypothesis has become the accepted answer, and it didn't have to go that way, it just did."

What changed, Cohen says, is that experimental evidence in support of the prion theory has been piling up for 15 years. Meanwhile, the alleged virus has remained elusive, despite improvements in the technology for detecting such agents.

Manuelidis and a handful of others believe that the prion alone isn't a sufficient explanation for mad cow and related diseases. They believe that prion proteins have something to do with how people (and other animals) get these diseases and that abnormal prions may be the result of infection, but they don't believe that prions start the process. They believe that something else - perhaps an uncommon form of nucleic acid - is at work. And since the prion theory flies in the face of everything that is known about infection, they say it's up to Prusiner and company to produce gold-standard proof.

What would that be? Prion skeptic Robert Rohwer, director of the molecular neurovirology laboratory of the Veterans Affairs Medical Center in Baltimore and associate research professor of neurology at the University of Maryland School of Medicine, says it should be possible to produce normal prion proteins in a lab, and then get some of them to become abnormal. He says scientists have had "more or less success" with this part, creating prions that look like the bad ones. However, although they should cause disease when injected, he says that this hasn't happened so far.

And that's not all. Manuelidis has a bunch of prickly questions for the prion partisans. How come the amount of prion protein in a given sample isn't directly proportional to its potential to cause infection? Why are some tissue samples without any misfolded prions still infectious? Skeptics also question how there can be strains of prions - adapting to different animal hosts and behaving in different ways - without nucleic acid playing a role, as it does in the creation of strains in other organisms.

Cohen says solid, published studies support the infectivity of prions. As for strains, he observes that several experiments - most recently with yeast prions - show prions to be flexible shape-shifters able to infect a variety of normal prion proteins.

Manuelidis and her husband were drawn into the study of TSEs long before mad cows, when it was a scholarly backwater. One person who helped lure her toward the field was the late Dr. Lewis Thomas, the renowned physician, poet and essayist ("The Lives of a Cell"), who became a friend while he was at Yale from 1969 to 1973. "He would always say, `It's a great problem,'" she recalls.

She was raised with a taste for big challenges by her architect-artist father and drama teacher mother in Brooklyn, N.Y. (She and her husband passed this trait on: One grown son is a lawyer, and another is a doctor, a dermatology resident at Yale.) It was challenge enough to be a woman in any medical school in 1963, the year she came to Yale after studying poetry at Sarah Lawrence College.

At Yale, she fell in love with and married her husband, who had been one of her professors. Dr. Elias Manuelidis was a Constantinople-born Greek who was trained in Germany and engaged in the study of brain diseases. The Manuelidises produced a steady stream of research on CJD and related illnesses that appeared in top-shelf journals. But it hasn't been all lab work. Until a few years ago, she dealt directly with patients and families and still responds tirelessly to inquiries from survivors of CJD victims. "I consider it part of my medical obligation, and I hope I can help them," she says.

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