Study Lends Support to Mad Cow Theory
By SANDRA BLAKESLEE

Published: July 30, 2004

Scientists are reporting that, for the first time, they have made an artificial prion, or
misfolded protein, that can, by itself, produce a deadly infectious disease in mice
and may help explain the roots of mad cow disease.

The findings, being reported today in the journal Science, are strong evidence for
the "protein-only hypothesis," the controversial idea that a protein, acting alone
without the help of DNA or RNA, a cousin of DNA, can cause certain kinds of
infectious diseases.

The concept was introduced in 1982 by Dr. Stanley Prusiner, a neurology professor
at the University of California, San Francisco, who led the new study. The
hypothesis is still unsettling to many scientists who have been taught that only
bacteria and viruses containing genetic information can spread infectious diseases.

Over the years, the idea that a misfolded prion protein, because of its shape alone,
could trigger an infectious disease has been gaining acceptance, but it has never
been conclusively proven. Proteins, which are strings of amino acids, fold into
distinct shapes to carry out various functions in the body. It is not completely known
what makes proteins fold incorrectly. But the theory is that when a misfolded prion
comes in contact with other prions, they, too, become misfolded and a disease is
spread.

In this study, Dr. Prusiner said, researchers essentially created a man-made prion
and injected it into mouse brains and produced disease. Then, they took tissue from
the diseased mice and injected it into other mice, which also got the same disease.

Dr. Prusiner said in a telephone interview that he was "flabbergasted" that it took 22
years to prove the hypothesis, but that his laboratory was able to overcome earlier
technical difficulties with a new set of experiments. "We have compelling evidence,"
he said. "We've done it all."

Dr. Christopher Dobson, a professor of chemical and structural biology at
Cambridge University and an expert on protein folding, said: "This is the key
experiment everyone was waiting for. While there is never absolute proof in
science, this experiment puts the protein-only theory of transmission beyond
reasonable doubt."

Still, some said the evidence was not sufficient.

Dr. Bruce Chesebro, chief of the Laboratory of Persistent Viral Diseases at the
federal Rocky Mountain Laboratories, said the experiment showed that the prion
produced something in the mice. But he said it was still unclear whether the prion
was causing the infection or just exposing an underlying infectious process.

Dr. Laura Manuelidis, a neuropathologist at the Yale University Medical School, one
of Dr. Prusiner's most vocal critics, said the prion strain that turned up in the
experiment looked like a mouse prion frequently used in Dr. Prusiner's laboratory.
She said that meant that something else might have caused the infection.

"Basically I think the data look like contamination," Dr. Manuelidis said, possibly
stemming from "inadequately washed instruments.''

Dr. Prusiner, who won the 1997 Nobel Prize in Physiology or Medicine for his prion
research, said some of his critics would never be satisfied. "They'll say we need to
do 10 more years of experiments," he said. "It's just silly.''

Dr. Prusiner predicted that the newly gleaned information would lead to more
effective ways to diagnose and treat a family of deadly diseases called
transmissible spongiform encephalopathies, or T.S.E.'s, believed to be caused by
aberrant proteins.

The stakes are enormous. Last week, a British citizen who died from other causes
was found to have been infected by a human form of T.S.E. from a routine blood
transfusion. The human form, called variant Creutzfeldt-Jakob disease, is
contracted from eating cattle infected with mad cow disease. At least two people
who died from the variant disease gave blood before falling ill, which means many
more Britons could be infected. The disease can take years to manifest itself in
humans.

American agriculture officials are testing thousands of cattle in an effort to
determine if mad cow disease is a problem in this country, but the tests are
notoriously imperfect. A deeper understanding of protein diseases should lead to
tests that can diagnose the disease even in cattle that show no symptoms.

The biology of protein diseases is new and often difficult to grasp, Dr. Prusiner said.
He said that many proteins caused disease when they adopted an abnormal shape
and formed toxic fibrils that created havoc in the brain or body. Alzheimer's disease,
Parkinson's disease, Type 2 diabetes and at least two dozen other human disorders
may be caused by misshapen proteins, he said. Those diseases, however, do not
involve prions, which are the only misfolded proteins known to be infectious.

The hallmarks of a T.S.E. are spongy holes and inflammation in the brain. Some of
the diseases also feature clumps of fibrils called amyloids.

When Dr. Prusiner introduced the protein-only hypothesis, he was greeted with
skepticism. Laboratories around the world have tried many times to inject synthetic
prions into mice, but the experiments never worked, because the mice never got
sick, Dr. Prusiner said. But this time, he said, the mice did get sick from the
synthetic prion. The protein fragment was synthetic to avoid the possibility that
something in a live cell might have contributed to the disease.

In this experiment, Dr. Prusiner injected a protein fragment that he reasoned could
be the core source of the infection.

"We waited," he said. "And waited. At 300 days, none of the animals got sick. We
thought the experiment had not worked."

But over the next 200 days, every animal developed spongiform degeneration, Dr.
Prusiner said. A brain extract from a sick animal was injected into normal mice with
different prion structures. They, too, got sick.

SOURCE: New York Times, NY
http://www.nytimes.com/2004/07/30/national/30protein.html

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