The Science of BSE 2: Blood - July 18, 2006

Scientists and researchers worldwide continue to study BSE and other transmissible spongiform encephalopathies with an eye toward eliminating risk of infection, both in animals and humans. But, as the occurrence of BSE appears to be diminishing naturally, there are questions as to how much society will benefit from this research. This second in a series of five articles looks at research into testing blood for TSEs.
By Chris Clayton
DTN Staff Reporter

ROCKVILLE, Md. (DTN) -- For a disease that can't be diagnosed until the victim is dead, a blood test is a scientific Holy Grail.

Diseases caused by abnormal proteins called prions -- bovine spongiform encephalopathy, chronic wasting disease and variant Cruetzfeldt Jakob -- have long incubation periods and are only conclusively diagnosed by examining brains and central nervous systems after the victims have died. Those who are infected only show symptoms in the last few months of their lives and the signs often can be misinterpreted.

With that in mind, reports are continually declaring someone else may have created the first blood test that can detect BSE in cattle or variant CJD (vCJD) in humans. So far, no government or scientific agency has approved any such tests for use. Nor have any government agencies adopted any guidelines or standards for such tests.

The potential market for a blood test is driving researchers to form companies to develop a test that is safe, accurate, easy, quick and affordable. "It's a race to develop," said Paul Brown, a former National Institute of Health researcher who is now a consultant on transmissible spongiform encephalopathy-related diseases. "It's clear there are different levels of advance from different laboratories, which is nothing to be ashamed of."

Housed in a small generic office building just outside Washington, D.C., a handful of researchers and marketers at Adlyfe Inc. are trying to refine a blood test they believe works. Adlyfe was one of eight companies or research groups working on prospective blood tests that explained their work at a conference in Baltimore in March on prion diseases. The meeting drew about 150 scientists from around the world and focused heavily on the possibility of developing a blood test, particularly for humans.

Adlyfe started in July 2003 when researcher Cindy Orser received a $1.3 million grant to create a prion-detection test from the Defense Advanced Research Projects Agency, or DARPA, an obscure agency within the U.S. Department of Defense. The military has funded prion research because the problem was identified as a threat the country was unprepared to handle. The military has spent about $42 million on prion research during the past five years.

Virtually all the other companies searching for a live blood test base their results on antibodies. Adlyfe takes a different route and uses peptides, which are links of amino acids. The peptides mimic the reaction of the target prions, or abnormal proteins, thereby confirming the presence and amplifying the production of the prions. "Because of that, we are able to measure the prions in a very sensitive manner," said Adlyfe CEO Alan Rudolph, a former DARPA staff member, who joined the company to help recruit potential investors. While millions of sheep and tens of thousands of cattle have been infected by TSEs, the major market is for a human blood test. A vCJD diagnostic test would have an immediate demand in countries such as England, which Rudolph described "is a clear market of need."

England has now had at least 161 documented cases of vCJD, the next highest country is France with 17 known cases. A recent risk assessment in England also showed roughly 3,800 more people, virtually all of whom are under age 30, could be carriers of the abnormal protein that causes vCJD, leaving them susceptible to the disease and able to spread it to others through blood transfusions.

Researchers also suspect at least three people in England have died from vCJD they contracted through blood transfusions from someone who also was later diagnosed as having died from vCJD. Twenty-four other known potential victims in England have been notified they also received blood transfusions from people infected with vCJD. "There is very strong evidence that variant CJD can be transmitted through blood transfusions," Dr. Bob Will of the Creutzfeldt Jakob Disease Unit at Western General Hospital in Edinburgh, Scotland, said at a recent conference on TSEs in London.

More cases of sporadic CJD can affect people in the later stages of life. The U.S. has had 968 such cases of sporadic CJD since 1997, according to the National Prion Disease Pathology Surveillance Center at Case Western University in Cleveland. England has had 586 cases of sporadic CJD since 1997.

A person can conceivably carry misfolded prions in their blood without ever actually getting vCJD. While no therapeutic treatment exists for CJD diseases, a test could at least prevent a person who is positive for prion infection from donating blood. "While the cattle industry, for example, might not be willing to test every cow, blood tests for humans are likely because of a policy that there is zero tolerance for an unsafe blood supply," Rudolph said.

Any potential test is at least two years from being ready to present to a regulatory agency. Researchers who have studied TSEs extensively say companies haven't been able to effectively provide enough research material on their tests. Companies don't have the body of data necessary to make a valid claim. "The tendency at the moment is to have a little bit of data on BSE, a little bit of data on scrapie and a little bit of data on variant CJD and they go around presenting this to naive audiences, shall we say," said Danny Matthews, head of the TSE research group for the Veterinary Laboratories Agency in Weybridge, England, in an interview with DTN.

The most likely market might be tests for people, but studies right now must largely focus on livestock and lab animals. Researchers at companies can continually inoculate mice with a prion diseases and test the blood, but there is only a very limited ability to conduct vCJD tests because of the miniscule number of known cases worldwide, Rudolph said. "There are so few patients you can't run a standard clinical trial," he said. "One of the challenges all of us face is access to samples. There are just not a lot of samples of endemic disease. In the prion field, it's tough."

One of the world's most renowned experts on BSE, German scientist Martin Groschup, is skeptical that a blood test will become viable anytime soon given some disappointing results he has seen while attempting to evaluate research from companies. "I personally don't believe a live test for BSE is around the corner," he said at the London conference.

Several firms such as Adlyfe have reported finding prions in the blood. Scientists for those companies are becoming more convinced blood shows one of the broadest detections of prions, though they are dispersed. Proving prions are in blood doesn't prove they are infectious. It could, however, raise red flags on the precautions used to prevent the spread of prion diseases. "If they prove to be correct, then it shows something has to be happening in the blood that we haven't been able to detect," Matthews said.

While acknowledging much work still is needed, Matthews said he has seen presentations on potential blood tests and wonders if the research is collectively making a case for blood tests. "When you look at the big picture, several different test companies show there is something here to consider," he said.

Matthews' sentiments are echoed by scientists such as Alex Raeber, director of research for Prionics AG in Switzerland, one of the premier global companies in developing current post-mortem BSE tests used today. "If two or three or four tests get the same result, we can feel confident in the result," Raeber said at the London conference.

Rudolph said live tests could prompt some regulatory policy changes. In livestock, for instance, the Food and Drug Administration continues to exempt cattle blood products from the feed ban for ruminants, allowing dried blood products to be fed back to cattle as a protein supplement. "If this continues to be validated that prion misfolds are in the blood and they are infectious, this would be a big issue regarding keeping bovine blood in feed," Rudolph said.

A blood test could be beneficial testing for scrapie in sheep or chronic-wasting disease in the wild animal population. But live testing may be a little late for cattle. The number of positive BSE cases globally, particularly in England, is steadily declining due largely to feed bans and removing risk materials such as brains and spinal cords from the food supply. "As the number of positive animals goes down in Europe there may be less clamoring for more testing," Rudolph said.

USDA scientists are also working on diagnostic tests related to blood, but USDA officials said they are not at a point where they can discuss that work. USDA officials and most meatpacking companies have adamantly opposed testing all slaughter cattle. Even an animal that may carry prion proteins would not show positive until later in life, at least 30 months of age. Only a handful of cases have been recorded globally of cattle testing positive younger than that. Blood tests showing positives in animals before clinical signs occur changes the debate.

If prions are in blood, what about meat? USDA officials maintain meat, from animals of any age, is safe. That's the case even if a blood test found prions in cattle less than 30 months of age. "We never said that the prion isn't found in meat," said Ron DeHaven, administrator for USDA's Animal and Plant Health Inspection Service. "What we're saying is the meat is not infectious. And I say 'we' [meaning] this is what the international scientists are saying."

Still, a government wanting to reopen export trade could blitz-test the cattle herd and show BSE is minimal or not there. Countries with BSE have been required to make dramatic changes to their industries and carcass value has been lost as a result of the risk protections. Using a live blood test, companies could re-establish markets for some lost, previously salable parts of carcasses. Meat plants could certify their slaughter animals and may not have to take out specified-risk materials

"It may be worth it if you look at total market costs," Matthews said. "That might add value to your breeding stock."

Our next installment in the series looks at research on chronic wasting disease.

Chris Clayton can be reached at chris.clayton@dtn.com