We all have prions, the cause of mad cow, but why?
The early-morning news from Stockholm in October 1997 was a shocker: Neurobiologist Stanley Prusiner had received the Nobel Prize in medicine for his pioneering work on prions, the mysterious misshapen proteins that cause mad cow disease. The prize was immediately controversial because many researchers still thought the idea was nuts.
After all, as infectious disease agents, prions break all the rules. They seem to have no genetic material of their own. They are not subject to immune attack. And they can't be "denatured" by heating, digesting them with enzymes or hitting them with chemicals. Many of the important answers were still missing.
Almost seven years later, the first case of mad cow disease has been confirmed on US soil, and many important answers are still missing. Nonetheless, Prusiner's work -- and similar work by dozens of other research teams -- is looking better and better.
"We do have some understanding of this agent" and how a simple protein can wreak such havoc in the brain, said Susan Lindquist, director of the Whitehead Institute for Biomedical Research in Cambridge, who has spent years studying prions.
It's now clear that a prion protein -- in its dangerous, abnormal form -- has a sort of "Midas touch" that ruins normal prion molecules that it contacts. When a bad prion meets its normal neighbor, normal becomes abnormal, and then goes on to convert other normals into bad guys.
Also, it's just a change in shape, not a change in chemistry, that makes everything go haywire. The normal prion protein seems to twist into a new, more stable abnormal form that persists in damaging brain cells. As each abnormal prion kicks others into abnormal shape, it's rather like an atomic chain reaction, only slower. The disease progresses as bad prions accumulate, kill nerve cells and eventually leave the brain in tatters.
Research has shown that the normal prion protein, in its nonpoisonous form, must be playing some important role in the body, especially in the nervous system. It is found in all tissues, but is particularly abundant in cells of the spinal cord and brain. This tells scientists the protein is there for an important reason.
"It is a natural protein with a natural function, something specific for neural function," said neuroscientist Huntington Potter, formerly at Harvard, now interim director of the Alzheimer's Center and Research Institute in Tampa, Fla. "But it also has a natural tendency to flip into an alternate shape, and it forms long fibers that accumulate and kill brain cells."
Additionally, scientists at the Whitehead Institute, an affiliate of MIT, and at Columbia University in New York City, have uncovered hints that the abnormal prion protein may not really be a villain. The new work, published last month in the journal, Cell, suggests that the "normal" folding of the protein might actually be a resting or dormant phase, while the supposedly toxic form is the active version, perhaps playing some role that helps with memory.
Lindquist collaborated in this work with a team led by Nobel laureate Eric Kandel at Columbia. And their findings suggest that the poisoning effect may be derived from something else, perhaps a toxin of some sort that is produced in response to accumulating prions.
"We don't know what protein is the toxic species," Lindquist explained.
Lindquist also said there is some evidence that the victim's own immune system somehow helps infectious prion particles -- those that arrive in the gut from eating an infected animal -- get into a new host's tissues. First, she said, the entering prions somehow avoid being chewed up by acids and enzymes in the gut.
Then "the immune system is what does us in," she said. Rather than attack the prion as a foreign invader, or just ignore it, "the immune system carries it in," apparently through small areas in the gut called Peyer's patches. How that occurs is also not known.
Researchers hope that by focusing intensively on understanding the disease, they can find ways to stop it, or repair the damage. So far, nothing really works, although there are hints of potential drug treatments that may yet emerge.
"It is a deadly disease, invariably fatal, and we don't know how to attack it therapeutically," said Giuseppe Legname, a member of Prusiner's team at the University of California at San Francisco. "But we have a [potential] treatment -- an antimalaria drug -- that is working in laboratory animals and is very promising."
No tests have been done in patients there, however, in part because there are so few patients who can be studied.
Other researchers, such as Lindquist, have been focusing in part on using truly modern weapons, called monoclonal antibodies, against prions. These molecules, made by the immune system, can now be tailored in the laboratory to recognize almost any protein and then stir the immune system to attack it. The problem has been that because a prion protein is inborn -- a part of the body rather than a foreign microbe -- the immune systems tends to view it as "self," something to be ignored.
"You can't imagine how hard we've worked to get antibodies that will recognize only the abnormal form" of the prion protein, she said. If that can be done, it may be possible to alert a patient's immune system to destroy only the bad prions, leaving the good proteins undamaged. Antibodies could also provide a basis for quick and accurate tests for diagnosing animals and people.
Tests also might become available to spotting prion contamination of donated human blood. At present, according to the American Red Cross, the blood supply is being protected by abstinence; donors are asked not to give blood if they've lived six months or more in Europe, or three months in the United Kingdom, where mad cow disease hit hardest.
The human prion diseases known so far are Creutzfeld-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, Kuru, and Alpers syndrome. To some degree they seem to be inherited -- a mutant gene may be involved -- yet Kuru and mad cow disease proved that prions can be infectious, transmitted via nervous system tissues included in foods.
