January 18, 2004 Plain Dealer by Regina McEnery

The grainy wedge of tissue belonged to a 69-year-old woman who may have died of Creutzfeldt-Jakob disease, a deadly neurodegenerative condition sometimes caused by eating contaminated beef. From Our Advertiser

It's the job of the National Prion Disease Pathology Surveillance Center, where Liu works, to make sure the diagnosis is correct. The center is based at Case Western Reserve University School of Medicine's neuropathology division.

The center is part of the university's growing effort to research prions, a type of protein associated with a number of brain-wasting diseases in humans and animals, the best known being mad cow in cattle.

Case is home to one of the largest prion research groups in the world. It was awarded $5.5 million in grants last year.

About 40 scientists are pursuing different hypotheses of this relatively new class of "germs," from how the infectious agents change shape in the brain and what the reshaped proteins look like.

Researchers are investigating whether chronic wasting disease, a prion disease endemic in deer and elk, is transmissible to humans. They are trying to develop rapid screening tests for mad cow and other prion diseases in humans and animals, and they are evaluating a possible second strain of mad cow in Italy.

"From a research standpoint, prions are one of the most exciting things you could possibly imagine studying right now," said Witold Surewicz, a protein chemist and biophysicist who has been conducting prion research at Case since 1996.

Though much of Case's research is done at the molecular level, its laboratory diagnoses of human prion diseases make it unique in this country. The center, the only one funded by the Centers for Disease Control and Prevention, examines spinal fluid and brain tissue to confirm diagnoses of Creutzfeldt-Jakob, a rare condition that causes memory loss, loss of balance and eventually death but that is tricky to diagnose clinically.

"Where are you going to start today?" Liu is asked by colleague Kay Edmonds. After spending about 15 minutes donning layers of protective clothing, the two women are faced with the samples from three sections of the elderly woman's brain.

Liu starts with the cerebellum, the section of the brain that controls balance. Loss of movement is a key symptom of CJD, so this a good area to scan for clues.

First they have to tidy up the tissue. Liu wants to make sure the surface is smooth, free of the permafrost, before subjecting it to an enzyme test designed to expose the harmful protein.

Personal safety is paramount. Her hands, protected by four sets of rubber gloves, warm the tissue until it becomes more malleable.

Then she drops a strand of tissue into a test tube and passes it off to Edmonds, who places the cylinder on a scale. The weight dictates how much enzyme solution is required.

Liu, a research assistant, and Edmonds, chief specimen coordinator, repeat the process twice more, using samples from other sections of the brain.

They required a newspaper reporter to wear a biohazard suit and plastic face mask before entering the lab and sealed her notes in plastic bags after their tests, a precaution in case the paper became contaminated with CJD.

Were it not for the presence of mad cow disease and the awarding of a prestigious international prize, prion researchers would probably still be relatively obscure, trying to unravel the secrets of new infectious agents that seem capable of operating without the typical tools of bacteria and viruses - DNA and RNA.

But, in 1996, the British government announced that cattle with mad cow disease were the most likely cause of a variant strain of CJD in humans. The cattle were believed to have eaten contaminated sheep waste.

The following year, Stanley Prusiner, a University of California at San Francisco researcher who has collaborated with Case on several studies, received the Nobel prize for medicine for his discovery of prions. Prusiner began his search in 1972 after one of his patients died from dementia resulting from CJD.

Prusiner determined that prions are innocuous under normal conditions, but that they can convert into harmful structures. Prusiner also concluded that prion diseases may be inherited or transmitted or may occur spontaneously.

Since the late 1990s, more than 100 Europeans - most of them from Great Britain - have been diagnosed with variant-CJD caused by mad cow disease. There have been no cases of CJD traced to contaminated American beef, but last month the United States identified its first case of mad cow in an animal.

Case's prion research took off in the early 1990s when Dr. Pierluigi Gambetti, an neurologist and neuropathologist, discovered the gene behind fatal familial insomnia, a prion disease even rarer than CJD. Gambetti joined the Case faculty in 1977 to study Alzheimer's disease.

The same year that Prusiner won the Nobel prize, Gambetti published a paper that used molecular features - a more objective measure - to classify different types of CJD.

The method Gambetti developed made it easier to determine how CJD was acquired. It also made it easier to distinguish clusters - that could be linked to mad cow- and to identify new variants of the disease.

While Case's significant prion studies have been at the molecular level, its role as the CDC-funded surveillance center for human cases of CJD has generated the most public interest.

The center began in 1997 with a $60,000 federal grant.

Since 1997, neurologists and pathologists have sent brain tissue and spinal specimens from 1,221 individuals to Case, which confirmed 732 cases of CJD. Only one case was the variant form of CJD, a Florida woman who contracted the disease in Great Britain after consuming contaminated beef. Case received $1.3 million last year from the CDC, 70 percent for the surveillance center and 30 percent on overhead, said Gambetti, the director of the center.

Though the number of referrals has been growing, Case receives only about 40 percent of the expected cases, seriously impeding attempts to determine how many cases of CJD stem from mad cow or other factors.

While most CJD cases are thought to occur spontaneously, there have been clusters of CJD cases diagnosed in a handful of states in recent years, suggesting a common exposure.

Experts know the cases are being underreported because CJD occurs once in every million people, meaning there should be about 300 cases diagnosed yearly. In 2002, only 151 cases were reported, and only 131 were reported during the first 11 months of 2003. In contrast, between 70 percent and 80 percent of cases in Germany and Canada get reported.

Experts blame the poor reporting efforts on a number of factors, including lax or nonexistent reporting requirements in some states and fears of mentioning mad cow as a diagnosis to worried families.

But Gambetti believes the primary reason is lack of awareness. Many specialists continue to confuse CJD with more common neurological disorders, such as Alzheimer's.

Last December, the Ohio Department of Health drafted a letter urging doctors to report suspected cases of CJD to their local health department immediately and to raise the issue of autopsy with the patient's family.

To reach this Plain Dealer reporter:

rmcenery@plaind.com, 216-999-5338