In a talk yesterday entitled “Diseases of Animals and Humans Caused by Transmissible Proteins: The Prion and Mad Cow Disease”, Edward M. Scolnick, president of Merck Research Laboratories and Frank H.T. Rhodes Class of ’56 professor described the cause of Mad Cow Disease, and implied prions may be more common than is currently thought.
“[Prions are] an interesting topic in neuroscience and a fundamental topic in biology that will become much more important [in the future],” Scolnick said.
Prions are proteins, like the myosin in muscles and the keratin in finger nails. However, prions are misshapen versions of a normal protein that already exists in the junctions between nerve cells of mammals.
When the faulty prion comes into contact with a normal copy, the normal copy changes shape to resemble that of the prion. This then repeats until all copies of the protein are converted to prions. The accumulation of prions within nerve cells eventually causes the progressive neurological degeneration observed in victims of prion diseases.
In cattle, prions are the cause of Bovine Spongiform Encephalopathy (BSE), or Mad Cow disease, which has caused nearly 200,000 infections in British cows and led to the destruction of scores more in order to eradicate it.
The appearance of variant Creutzfeldt-Jakob Disease (vCJD) in humans, which is thought to be linked to the consumption of tainted beef, has also been cause for concern.
“It’s clearly a major issue in the public interest as well as biochemistry,” said Scolnick. “The evidence [that infected beef causes vCJD] appears to be quite strong.”
Prions can be transmitted by ingestion, but can also be inherited in families or transmitted by contaminated medical instruments or hormonal extracts.
Scolnick’s talk focused on the molecular evidence demonstrating that prions cause BSE and other related diseases.
He started by describing the structure of the normal protein and how the prion may alter it. One end of the normal protein is anchored in the cell membrane of nerve cells, while the free end of the protein binds copper ions.
“There’s evidence for thinking it’s a shuttle protein for copper from the outside [of the neuron] to the inside,” Scolnick said of the protein’s possible normal role.
In normal copies, the middle section of the protein contains very little of a structure called a beta sheet. In copies altered to become prions, this section is beta sheet rich.
“The middle section is what’s crucial for pathogenesis,” Scolnick said.
Unfortunately, studies of the conversion process are “an amazingly primitive field”, due in part to the fact that the prions form dense masses that make it hard for protein chemists to determine their structure.
Scolnick also described a study involving genetically altered (transgenic) mice in which the copy of the protein that is susceptible to prions was deleted. These mice had few, if any, symptoms from this change alone.
“Just knocking out the prion gene on its own causes no disease,” Scolnick said.
However, when these mice were administered prions, they failed to develop disease.
“[Knockout] mice are completely resistant to prions when inoculated with them. The prion doesn’t replicate in those animals.”
However, when the normal protein was reintroduced, the animals again became susceptible to prions.
Currently, there is no cure for the diseases caused by prions. But Scolnick discussed some ways in which laboratory cultures have been cleared of prions in the laboratory. One method involves the use of antibodies which bind to the normal proteins and block prions from contacting and converting them.
“It’s a prevention approach that could some day be converted to a treatment approach,” he said.
Scolnick also discussed the need for an early detection method for the disease in cattle and humans.
“To my knowledge, there is no facile, rapid, sensitive in vivo test,” he said. Current methods involve using tonsils, which are reliable, and urine, which is less so.
The last portion of his talk focused on examples of prions in yeast.
“There is unambiguous evidence for [them] in yeast. It really strengthens the whole prion hypothesis … [and] leads [one] to conclude it must be a more general phenomenon.”
Scolnick concluded by noting that if the phenomenon is common to organisms as diverse as cattle and yeast, it must be more widespread than is currently thought.
“Probably the diseases recognized are the mere tip of an iceberg of a broader biology caused by this molecular process,” he said.
Laurel Southard, director of undergraduate research in biology, who attended the lecture said, “What was new for me was all the studies on transgenic mice. The relationship between the yeast story and the mammalian story is going to be really interesting.”
Archived article by Jennifer Frazer