Mad Cow: Prion research misguided?

Millions of federal dollars being spent to find treatments and diagnostics for mad cow disease and similar brain disorders in humans might be misguided and actually delaying the development of effective medications that could cure or prevent these deadly disorders, experts have told United Press International.

Millions of federal dollars being spent to find treatments and diagnostics for mad cow disease and similar brain disorders in humans might be misguided and actually delaying the development of effective medications that could cure or prevent these deadly disorders, experts have told United Press International. Although prions, as the suspicious proteins are called, generally have been accepted as the pathogens that cause mad cow disease and its human equivalent, variant Creutzfeldt-Jakob disease, so far investigators have been unsuccessful at demonstrating the agents are infectious. This leaves open the possibility, as a growing body of research suggests, the diseases are caused by some other pathogen — possibly a virus or bacteria. The National Institutes of Health in Bethesda, Md., openly acknowledges prions have not been established fully as a cause of any disease. Yet nearly all of the $27 million the agency doled out last year for studies on transmissible spongiform encephalopathies, or TSEs — a group of diseases that includes mad cow, chronic wasting in deer and elk, scrapie in sheep and vCJD in humans — went toward studies focusing on the prion hypothesis. Little of the money has been slated for research examining alternative causes of the disorders. In addition, the NIH has handed out $9 million to private companies for five-year contracts to develop blood-based tests for prions. TSEs, so named because they “eat” holes in the brain, yielding a sponge-like appearance, have no treatment and are always fatal. Infected patients develop mental deterioration and physical incoordination that progresses to dementia and they often die within months. Prions are proteins normally found in the body. Their function remains uncertain, but in some cases they can malfunction. Proteins fold into 3-D shapes, but prions sometimes can misfold and assume incorrect shapes. The current hypothesis holds abnormal prions are infectious and cause the brain destruction seen in TSEs. Some experts insist, however, there is scant scientific evidence to support this. “The best-kept secret in this field is that (prions) in any form have never shown infectivity,” said Laura Manuelidis, head of the neuropathology section at Yale University’s surgery department in New Haven, Conn. Most researchers working in this field “know the data just aren’t there” to support the hypothesis prions are the cause, Manuelidis told UPI. She has pointed out the lack of evidence supporting the role prions play in causing TSEs since the idea first was proposed in the 1980s. Some researchers in this field think the mutant prions are the result — not the cause — of the disorders. These dissenting scientists theorize some other, as-yet-unidentified pathogen, such as bacteria or a virus, causes prions to misfold, which is what damages the brain. But they said it is nearly impossible to obtain funding to investigate alternative causes of TSEs. The divergent theories represent a major medical research problem: If the prion concept turns out to be wrong, current efforts to find diagnostics and treatments for TSEs could be wasting both time and money. The potential problem extends far beyond the research community, however. The recent discovery of a cow in Washington state infected with mad cow disease shows how TSEs could be making their way into the U.S. food supply. Other cases could go undetected because current mad-cow screening methods are based on detecting abnormal prions — which show up in advanced stages of the disease but do not seem to be present in the early stages. Some animals that die might never show any evidence of misfolded proteins, said Frank Bastian of Tulane University in New Orleans, who thinks the disorder is caused by a bacteria. He recently presented evidence backing up his claim at a national scientific meeting. This means if a virus or bacteria does cause the disorder, then current tests might never pick up animals that are infected but do not yet have symptoms. Even if the prion hypothesis is correct, the millions of dollars being spent on that type of research should have led to a treatment by now, Bastian said. “Why don’t we have it solved?” he asked. “I believe we’re going in the wrong direction.” The race to find treatments for TSEs has generated urgency in recent years because of a mad cow outbreak in the United Kingdom that crossed over into humans in the mid-1990s, infecting more than 100 people with variant CJD. Since then, 22 other countries have detected the disease in their cattle — including the United States and Canada, which reported their first domestic cases this year. Along with the first U.S. case of mad cow, the country is experiencing a growing outbreak of a similar disorder called chronic wasting disease in deer and elk in the Midwest and West, and there are concerns this could be transmitted to cattle and humans. Other countries — even those that have experienced mad cow outbreaks — also have failed to fund research proposing alternative ideas, according to Heino Diringer, a retired biochemist who was affiliated with the Robert Koch Institute in Berlin. He also doubts the prion hypothesis. “Who’s looking for (alternative causes) in Germany?” Diringer asked. “Nobody. In England? Only (one) group in Edinborough. But if researchers apply for looking for the agent there’s no money because the agent has been discovered, according to the Nobel prize committee.” This is a problem, Diringer said, because “it will turn out that the prion concept is wrong.” The NIH — the agency responsible for dispensing U.S. federal research funds for diseases ranging from TSEs to cancer — acknowledges prions have not been shown conclusively to be the agent that causes TSEs. Some researchers consider the prion hypothesis unproven. “Formally, I agree with them,” said Chris Beisel, the National Institute of Allergy and Infectious Diseases program officer who funds prion research. He said NIAID is not funding many studies looking at alternative causes because few researchers are proposing this type of inquiry. “I’m not aware of anyone who desperately wants to address this issue who has been turned away for funding,” Beisel told UPI. “The money is there if somebody puts in a good application.” One factor holding up funding is the quality of the research being proposed, Beisel said. “It’s not that the individuals (in charge of funding) are averse to totally dumping existing dogma, but if you’re going to challenge something, they don’t want to throw a lot of money at something that isn’t likely to produce good results. They want to see good solid experiments that are well-controlled (and) that are going to produce a definitive answer, one way or the other.” Several researchers, including an NIH scientist, claimed the research community is not applying for grants because there is a perception of bias — pursuing funding for alternative hypotheses is futile because such applications will be rejected. “A lot of people have given up on (doing research to look for alternative causes) because they have been unable to get funding,” said the NIH scientist, who requested anonymity and who doubts prions are the primary cause of TSEs. The idea prions cause mad cow disease, CJD and other similar deadly illnesses got its start in the early 1980s. Although the scientific community initially attacked the idea as invalid, the concept gained steam until it generally was accepted by most working in the field. Dr. Stanley Prusiner, of the University of California, San Francisco, who first proposed the prion hypothesis, won the Nobel prize for his work in 1997. Since then and even several years before, NIH funding into mad cow and similar diseases has focused primarily on the prion concept, ignoring alternative causes. A survey done by Science magazine found Prusiner’s lab ranked first among all those receiving NIH funding in 2001. That year Prusiner’s lab received some $12.5 million, several million dollars more than the next-highest-funded project. Prusiner’s lab even received more money than any single facility working on AIDS, cancer or heart disease and he continues to be heavily funded by the agency for his projects to develop diagnostic tests for TSEs based on detecting abnormal prions. Dr. Jiri Safar, an associate professor working in Prusiner’s lab, defended the prion concept and said although prions have not been proven to be infectious, several other lines of evidence indicate the misfolded prions are the cause of TSEs. So it becomes illogical to think something else may be the cause, he said. Safar conceded “theoretically” that dissenting scientists “may actually be correct” and TSEs are caused by some other pathogen. If so, he said, they need to prove their hypotheses. Long before the prion theory was proposed, he noted, scientists had searched, unsuccessfully, for a virus that might be the cause of TSEs. Other NIH agencies also are not funding many non-prion studies. The National Institute of Neurological Disorders and Stroke doled out more than $14 million to study TSEs in 2002, but nearly all of the money went to research focused on prions. NINDS officials maintain they are open to proposals to investigate alternative causes of TSEs, but like the NIAID, the agency has received few applications proposing such research. Even if the number of proposals increased, a procedural limitation skews how NINDS could approve research into alternative causes of TSEs. The bulk of the proposals received focus on the prion theory and because it can fund only about 23 percent of those applications, nearly all of the research grants go for prion studies. A second researcher who requested anonymity said no scientist would waste the time to apply for grants to study alternative causes of TSEs. “Nobody is fool enough to put in a grant that they know is going to be turned down,” the researcher said. “It’s just a waste of time and money … then it’s the end of your career.” He added such researchers would be left without money to fund their labs because they would have “spent all their time writing that grant.” The researcher also said NIH grant review committees, which include 18-to-20 scientists from various fields, are comprised largely of researchers who support the prion theory and are predisposed to shoot down alternative ideas — a contention NIH officials denied. The NIH could put out a special call for studies proposing to look at alternative reviews, as it has done in the past, such as when it urgently wanted to initiate research on treatments for bioweapons, malaria and severe acute respiratory syndrome. Beisel said, however, that would be futile. “No matter how much we get out there (to scientific meetings) and say we want to see the grants … researchers are still going to take that with a grain of salt because they think people sitting on these review committees are going to be stymieing them,” he said. This is a distorted perception, he said, because the committees actually are probably rejecting the proposals because of technical problems rather than their overall concept. Asked if there were concerns about delaying treatment for TSEs if the prion concept turns out to be misguided, Beisel said: “Could we have additional opportunities? Maybe. But we’ve known about HIV for years (and there is no cure), so just knowing what the agent is doesn’t guarantee you’d be able to advance it.” Safar said much still is not known about prions, so more research should be conducted on the basic mechanism of infection in TSEs. “We can learn a lot, not only about the prions but also about other diseases caused by malfunctioning proteins,” such as Alzheimer’s and Parkinson’s, he said. Learning more about the basic biology of prions also could help uncover targets that medications could attack, he added. Safar noted studies about the basic biology of the human immunodeficiency virus helped pave the way for more effective medications to fight AIDS and they continue to help researchers design vaccines that one day might be used to prevent infection. Prion research might do the same for TSEs. One of the biggest mysteries of prions is how an agent that lacks DNA and RNA — used by all other living organisms to reproduce — makes copies of itself and amplifies itself in the brains of those it infects. Also, it remains unclear how prions destroy brain tissue. As Safar put it, “We are essentially shooting in the dark.” Yet NINDS officials said they are not concerned hindering funding into alternative causes of TSEs could delay therapies. Michael Nunn, the agency’s program director, said NINDS relies on researchers in the TSEs field to help determine the validity of the prion concept. He said many of these researchers will spend their entire careers in this field and therefore they would not want to waste their time. So they spend a lot of time thinking about the possibility of alternative causes of TSEs. “Everybody who’s working on these ideas have fully considered that possibility … (and) are keeping their eyes open for other factors,” Nunn told UPI. If there are indications prions are not the cause, the scientists themselves would be the first to make that known, he said. The second anonymous researcher, however, doubted those buying into the prion concept would be eager to make it known prions are not the cause of TSEs. “If it turns out not to be true, that’s not good for them,” the researcher said. “There is a vested interest. At a certain point, they block themselves into something that doesn’t allow anything else.” Manuelidis and her colleagues have tried repeatedly to make known their doubts about prions, but so far their comments have fallen on deaf ears. She said she thinks the problem is not the NIH but the general scientific community working in this field. Top journals only are interested in publishing papers about prions, not alternative ideas, she said, and this in turn spills over into the smaller journals, creating an atmosphere that accepts only prions as the possible cause of TSEs. When negative findings are published about prions, researchers often do not acknowledge the possibility prions might not be infectious — as is done with other infectious diseases — and younger researchers have been so inundated with the prion concept they tend not to stop and examine the evidence for themselves. In addition, the big names in this field stand by the prion concept. These scientists tend to receive the most funds and are revered by journals and scientific organizations, so they are able to exert enormous influence over the rest of the field, Manuelidis said. One problem with pinpointing prions as the cause of TSEs is it is very difficult to isolate them. Laboratory preparations also contain other things, which could include unidentified bacteria or viruses. Therefore, even if the sample appears to infect animals and cause the disease, it is impossible to be sure prions are the cause, not other substances found in the preparation. Manuelidis said she thinks current evidence suggests a virus as the culpable agent. She has shown sterilization procedures that should kill viruses can reduce infectivity of prion-containing preparations by 99.9 percent. Yet the prions, which are very resistant to sterilization techniques, are not damaged. This indicates the causative agent is an as-yet-unidentified virus, she explained. This view is shared by the NIH researcher who noted that by itself an abnormal prion does not appear to be infectious or cause disease. “So something is missing and one possibility is that what’s missing is a virus,” the NIH researcher said. One plausible mechanism is the virus interacts with normal prions and causes them to assume an abnormal shape, which is how TSE diseases damage brain cells. The virus theory would help explain why only certain individuals become ill with these diseases. Not all mice with mutated prions fall ill. It also could be having abnormal prions makes people vulnerable to infection with the virus, the NIH scientist speculated. Manuelidis and the NIH researcher conceded, however, efforts to develop treatments based on prions might not be entirely futile because the abnormally folded proteins appear to play some role in the diseases. Safar pointed out antibodies and other agents that block prions have had some success in stopping the progression of TSEs. That also means the prion-based diagnostic tests being developed also might be useful because detecting misfolded prions does indicate the presence of the diseases. Still, if they are caused by a virus or bacteria, being able to find the infectious organism would enable faster detection of the diseases and, if a treatment is developed, initiation of medication before the brain is damaged. Safar’s group is developing a test that can detect the disease soon after infection. Early detection is critical because if the disease is not detected until advanced stages, it is too late to prevent or reverse the brain destruction, he said. One alternative idea that has received NINDS funding is a small project by Bastian. He has uncovered evidence a bacteria could play a role in causing TSEs. The grant is only $185,000, however, a far cry from the millions heaped upon researchers focusing on the prion concept. Yet Bastian has made progress. He presented research at the American Association of Neuropathology meeting in Orlando in June showing DNA from a type of bacteria carried by many insect species — spiralplasma — can be found in brains of people with CJD and in sheep brains infected with scrapie. The bacteria cannot be found in normal, healthy brains. The bacteria, found in ticks and mosquitoes, also have been shown to cause a type of spongiform disease in rats and mice, Bastian said. “There’s really clear evidence that there’s an association of the bacteria with this disease,” he said. He said he suspects the bacteria could cause prions to mutate and fold abnormally, and this could cause the brain destruction. To Bastian, the idea that bacteria carried by insects cause these diseases fits with what currently is known about how they are transmitted. One unexplainable phenomenon about scrapie in sheep is the animals can catch the disease without having contact with infected individuals. To explain this, some researchers have proposed the disease can arise spontaneously. However, sheep in New Zealand display no evidence of the disease — yet they should have experienced at least a few cases if it arises spontaneously. If TSEs are transmitted by insects, Bastian explained, and if the insects in New Zealand do not carry the bacteria, this would explain why sheep in that island country are free of the disease. The insect/bacteria hypothesis also fits with the pattern of bouts of chronic wasting disease seen in deer and elk in the Midwestern and western United States. Animal researchers there have been baffled by the disease, which appears to jump from herd to herd even though the animals do not come into contact with one another. Bastian hopes to develop a screening test for scrapie, human CJD and chronic wasting disease in the next few months based on the spiralplasma bacteria. If his theory is correct, and the test works, he said it would go a long way toward detecting those infected and perhaps help elucidate the role prions play in these dangerous diseases. (Source: United Press International (Via Comtex), MEDLINE Plus, Dec, 2003)