Mad Cow Research: Small Steps, Big Questions

Jan. 22, 2001 -- Mad cow disease is so terrifying and perplexing that some researchers have begun to believe it could have alien origins.

Two astronomy and mathematics professors in England announced last month that cows in England and Wales may have picked up the disease after eating grass laced with a sprinkling of interstellar dust. The dust, the scientists proposed, fell as the Earth was bombarded by comets which hosted infectious, extraterrestrial matter.

The notion may seem outlandish (and many scientists think it is), but research shows the disease, itself, is outlandish. And its bizarre nature has stumped many efforts to find effective screening tools and treatment.

"When you're trying to design drugs, it's especially difficult when you don't fully understand the nature of the infectious agent," says Byron Caughey, a biochemist at the Rocky Mountain Laboratory branch of the National Institutes of Health.

Infectious, Warped Proteins

To defeat the disease, however, scientists must understand its nature. So researchers across the U.S. and Europe are furiously studying mad cow and its infectious agent's puzzling behavior to try and come up with treatments as well as better screening tests for the disease.

Creuztfeld-Jacob disease, one of a group of terrible animal and human diseases called Transmissible Spongiform Encephalopathies (TSE), has been recognized as a rare human scourge for decades. But a new variant of the disease emerged in Great Britain in the late 1980s which scientists believe is related to eating beef infected with BSE, or mad cow disease.

Research so far suggests mad cow disease and its cousins, which attack the brain and slowly transform it into a spongy mass of useless tissue, are caused by a most unlikely agent — a protein. These proteins, known as prions, are nearly normal, except that rather than folding into an intricate, orderly pattern, the strings of these proteins are refolded into tough and toxic deposits.

These abnormal prions infect the body by binding with normal prion proteins and triggering them to take on the corrupted structure of the rogue proteins. The body's weapons, known as protease enzymes, which chop up and dispose of unwanted proteins, are rendered useless against the transformed prion proteins.

Heat, a common tool for destroying infectious agents, has also been shown to be less effective against the prion. Paul Brown, a prion researcher at the Bethesda, Md., branch of the National Institutes of Health, has exposed rogue prion proteins to temperatures higher than 1,000 degrees Fahrenheit and found some emerged unscathed.

"That's just unheard of," Brown says.

Particularly puzzling to scientists is how a protein, which contains no genetic information and is usually just a messenger of genetic codes, can direct its own propagation. By understanding how it influences other proteins, scientists hope to find a way to stop its ability to infect.

Solutions From Car Paint?

Last year British researchers located compounds that can stop rogue prions from converting normal prion proteins in animals infected by scrapie, the oldest known TSE disease, which infects sheep and goats. And recently, Caughey and his colleagues at the Rocky Mountain Lab in Montana have zeroed in on other compounds, similar to ones used as pigments in car paints, that have a similar effect.

But there's a glitch: the compounds are only effective if administered at the very beginning of infection. This is a big problem: the symptoms of mad cow-related diseases can take between 10-40 years to surface.

Caughey thinks the trick lies in finding compounds that can enter the brain where defective prions tend to congregate.

"We need to find compounds that can cross the barrier into the brain so they can do their good deeds there," he says.

Since there is concern that mad cow and its related diseases can be transmitted not only through meat consumption but also through blood supplies, researchers at University Hospital in Zurich, Switzerland, are refining a prion-fighting agent that might help disinfect blood tainted by the disease. The agent, a common blood component, attaches to rogue prions, but not to harmless ones, the scientists found.

But some argue it's pointless to find ways of fighting infectious prions without a simple, affordable method to test for them.

New Ways to Diagnose

"Therapies without a screening test are not worthwhile," says Robert B. Peterson, a professor of pathology at Case Western Reserve University in Ohio. "By the time you offer the treatment, you can only stabilize, not eradicate the disease."

Peterson recently took on the role as chief scientific adviser to a two-month-old company formed with the sole focus of finding an effective screening test for TSE diseases. Prion Developmental Laboratories, based in Maryland, has recruited the likes of Peterson as well as the main developer of the AIDS screening test, Robert Gallo of the University of Maryland.

Peterson points out the only way to diagnose mad cow disease or its human equivalent now is by examining brain samples after death at a cost of $50-$100 per test. The company's scientists are looking for ways to amplify the signals of rogue protein prions so that they might be detected while still at low levels in the blood.

A few screening agents have already emerged that might prove effective at doing just that. Researchers at Caprion Pharmaceuticals in Montreal, say they have developed unique antibodies that can tell harmless protein prions from defective ones. The antibodies have already been tested in infected mice, hamsters and sheep.

In Ames, Iowa, Mary Jo Schmerr of the National Animals Disease Center, has produced another hopeful prion detector. Her antibodies, which she developed in lab rabbits, have spotted rogue proteins in elk and deer infected with scrapie.

"With further development," Schmerr writes in an e-mail, "this has good potential for use as screening for detecting TSE's in animals and humans."

The Mad Cow Holy Grail

Despite such recent advances, it's unlikely any highly effective test or treatment will be found until scientists gain a better handle on the biggest question still looming over all investigations of the disease: whether defective proteins, alone, spread the infection.

"Most feel the prion hypothesis is true — that the protein, itself, is infectious," says David Harris, a prion researcher at Washington University. "But everyone also recognizes that it's still hard to definitively rule out other factors, such as a virus or bacterium."

So far scientists have not found any virus or bacterium that helps spread mad cow and related diseases. The Holy Grail, Harris explains, will be to somehow manipulate normal prion proteins in the laboratory to take on the nature of the deformed, infectious prions.

Only then could scientists prove this puzzling, almost alien-like protein is acting alone.