CWRU Magazine - Summer 2001  |  F e a t u r e

If the human form of mad cow disease appears in the United States, CWRU pathologist Pierluigi Gambetti likely will make the devastating discovery.

In the small room adjoining the office of Pierluigi Gambetti, his assistant, Donna Neylon, is wincing her way through a conversation about a man who is nearing the end of a terrible disease.

A woman has telephoned to report that she is afraid her husband is dying of the human form of mad cow disease. She wants to know what she’ll need to do to have his brain shipped for analysis to Dr. Gambetti, the University Pathologists of Cleveland Professor of Pathology at the CWRU School of Medicine, and director of the Division of Neuropathology at the school and University Hospitals of Cleveland.

Dr. Gambetti is also director of the National Prion Disease Pathology Surveillance Center. The federal government’s Centers for Disease Control and Prevention and the American Association of Pathologists established this center at CWRU in 1997 to monitor and diagnose cases of prion disease (pronounced PREE-on). Both mad cow, or bovine spongiform encephalopathy (BSE), and its human counterpart, variant Creutzfeldt-Jakob disease (vCJD), are diseases caused by abnormal prion proteins. The New York Times has described Dr. Gambetti as the most likely person to spot vCJD if and when it appears in the United States.

Ms. Neylon has fielded many of these calls over the past few years, but that doesn’t make this one any easier. “I understand,” she tells the woman over and over, then outlines the stark details of the center’s requirements for tissue samples as gently as possible. When the phone call ends, she slumps a little in her chair and takes a deep breath. “These calls are really tough,” she sighs.

Tough, indeed. Still, the fact that the woman called is a good sign—an indication that word of the center’s mission is spreading, albeit much too slowly for Dr. Gambetti. He has publicized the center’s mission among neuropathologists and general pathologists around the country. Still, he and his crack team of CWRU research scientists are not receiving enough samples from people who have died with symptoms of Creutzfeldt-Jakob disease—either the classical form (CJD) that scientists have been tracking for decades or the new variant.

“We are not really successful yet in examining the population thoroughly,” says Dr. Gambetti, who became acknowledged as one of the world’s prion experts ten years ago when he and his collaborators showed that a rare disease called fatal familial insomnia was caused by rogue prions. Prion proteins are normally found throughout the body, attached to the outside of our cells for some as-yet unknown purpose, but become pathogenic through a change in conformation.

Even though Dr. Gambetti sits at the center of the mad-cow storm, he is calm and gracious if perhaps a bit weary: He pushes aside a slide carousel and a huge stack of papers to rest an arm on his desk as he talks. “During the last three years, we have seen about thirty to forty percent of the CJD cases that are suspected to occur in the United States. The incidence of prion disease is calculated to be one case per million, so in the US we would expect to have nearly 300 new cases each year.”

Three hundred new cases! Such a statement seems guaranteed to strike terror into readers who have been following the macabre details of Europe’s prion panic. First, in the 1980s, there was the British outbreak of BSE, a new prion disease in cattle caused by animal feed containing offal from sheep that had another prion disease called scrapie. Then there was the dreadful discovery in the 1990s that some Britons who had eaten the BSE-tainted beef came down with a form of prion disease themselves, called vCJD. Then, the discovery that BSE and its human counterpart were spreading—and continue to spread—throughout Europe in the wake of exported British cattle and feed. As of this writing, there have been around one hundred deaths from vCJD, mostly in Britain but also a handful in Western Europe. These deaths followed quickly upon the onset of symptoms, which include loss of motor control and personality change.

In addition, everything most of us have heard about prion disease is not only bad but grotesquely so. That the first recorded instance of an infectious prion disease in humans was kuru, or the “laughing death,” caused by ritual cannibalism in New Guinea, in which the victims staggered about with a strange smile on their faces. That scrapie, the disease in sheep, earned its name because the sheep become so frantic with itching that they nearly scrape off their skin on trees. That hundreds of deer and elk in the western United States—wild animals that crop up routinely in suburban neighborhoods—seem to have developed yet another prion affliction, called chronic wasting disease.


Lookout Post

Dr. Gambetti, however, explains that his expectation of 300 new cases of CJD per year in the United States is unrelated to the mad cow scare. He knows he should be seeing more cases of the classical (also called “sporadic”) CJD, a predictably occurring disease that has been around for decades—in fact, the first famous victim was the dancer George Ballanchine, who died of CJD about twenty years ago. Most victims are over the age of sixty-five, leading scientists to believe that sporadic CJD is a disease related to the aging process, possibly triggered when the cellular protein-making mechanism spontaneously goes awry.

Is it possible that this classical form of CJD has always been around? “There is no reason not to think so,” Dr. Gambetti says with a shrug. “Remember, though, that this disease is very age dependent. In the Roman Empire, life expectancy was only about forty-six years. If we look at the CJD cases today, very few people under the age of forty-six have this disease.”

The surveillance center at CWRU examined 170 samples in the year 2000. Of these, 111 were positive for sporadic CJD, 12 for an inherited form of the disease, and one for iatrogenic CJD—meaning the person was among the tiny handful of unfortunates who contract CJD in the course of a medical procedure in which growth hormone, organ transplants, or even medical instruments are tainted with someone else’s CJD. The other samples turned out to be false alarms: The people died from some other progressive illness, not CJD.

Variant CJD has not yet been spotted in this country, but this doesn’t necessarily mean it isn’t here: Given the wide discrepancy between the expected incidence of sporadic CJD and its documented presence, Dr. Gambetti and his colleagues know they’re not seeing all there is to see. Thus they continue to look at all suspicious neurological cases to make sure that the variant hasn’t arrived on US shores—and also to make sure that yet another variant of the disease hasn’t developed.

Some of this examination is done with advanced technology, but some can be done with the naked eye. “I compare it to freckles,” Dr. Gambetti says, selecting images of tissue from the brain’s cerebral cortex from his slide carousel and holding them up against the afternoon sun that slants into the CWRU Institute of Pathology’s windows. The light reveals the telltale lesions and resulting sponge-like brain structure that are the mark of prion disease. “With classical CJD, you see very fine dots, like someone who has little freckles. When you see the variant, there are huge dots—big, big freckles.”

The center’s most significant investigations, however, occur on a molecular level. There, Dr. Gambetti and his colleagues in the pathology department—Professor Man-Sun Sy, associate professors Robert Petersen and Witold Surewicz, and assistant professors Shu Chen, Qingzhong Kong, and Neena Singh—look for differences among the various kinds of prion disease, isolating and identifying the molecular signatures of different forms of CJD. They also try to figure out the chain of events that leads an ordinary prion protein to change its conformation, thus becoming a deadly infectious agent. Several are working on ancillary projects that could have an impact on the war against prion disease, including a blood test for early detection of BSE and vCJD and new methods of sterilization for surgical instruments that will kill rogue prions.


Proteins Gone Wrong

Even in its normal state, the prion protein is a mystery. Computer images show that it looks a little like what’s left on the floor after a New Year’s Eve celebration: a jumble of streamers and confetti and the torn-off ends of party blowers. When the prion protein becomes abnormal, its conformation changes and it becomes resistant to the instructions that cells issue to proteins. The new, rogue prion not only stops obeying orders; it also begins to form clusters with other prion proteins and convert them to the new, abnormal conformation. With sporadic CJD, the damage seems to begin in the brain. With the variant, the prions seem to change conformation in the stomach or intestine, as a result of contact with BSE-tainted beef. This sets off a chain reaction that reaches the brain after some undetermined period of time.

It appears that not everyone who is exposed to rogue prions actually develops the disease. “Sometimes you go near someone with a cold and you get a cold, but sometimes you don’t,” Robert Petersen points out. “In both cases, you were exposed to a virus. As infectious agents go, prions are not the most efficient. For example, only about ten percent of the individuals injected with contaminated human growth hormone actually develop disease.” There is currently no cure for any of the prion diseases, which are the first illnesses known to pass from one living creature to another via protein—not a bacterium or virus, the usual infectious culprits.