Unraveling the Cause of a Complex Disease

Unraveling the Cause of a Complex Disease

Written by Becky Orfinger, Staff Writer, RedCross.org

BSE only
Variant CJD is a complex disease, capable of jumping the species barrier from cattle to humans. In this photo, taken in the UK, a worker disposes of BSE-infected cattle remains.

May 24, 2001 — In the late 1990s, concerns arose about an emerging disease called variant Creutzfeldt-Jakob disease (vCJD), a human form of bovine spongiform encephalopathy (BSE, commonly called "mad cow disease") that appeared to have jumped the species barrier from cattle to humans in the United Kingdom (UK). In 1999, the U.S. Food and Drug Administration (FDA) enacted a ban on blood donors who had spent more than six months in the UK between 1980 and 1996, the years when the BSE epidemic in cattle was at its height. On January 18 of this year, an advisory committee to the FDA voted that the agency should widen the blood donation deferral criteria to include people who have lived for 10 years or more between 1980 and the present in France, Portugal and Ireland-three European countries where the number of BSE cases is on the rise. According to the Wall Street Journal, the FDA is evidently now considering further widening their donor ban, although the time period has yet to be specified.

In September, the American Red Cross will implement a new blood donor deferral policy — one which could potentially reduce the pool of eligible donors by 8 percent — because of another concern: the rising number of people in the UK and Europe diagnosed with vCJD. The new Red Cross ban will exclude any donors who have lived in the UK for a cumulative total of three months or more since 1980, resided in any European country for six months since 1980, or received a blood transfusion in the UK since that time.

Although concern over vCJD has arisen relatively recently, other related diseases have been identified and closely studied for decades. vCJD belongs to the family of brain diseases known as transmissible spongiform encephalopathies (TSEs), which includes, among others, BSE and scrapie, a similar disease that affects sheep. "Classic" CJD, another TSE that affects humans, was first identified in 1920 by two German scientists and affects approximately one person per million each year worldwide. The first vCJD cases, involving two British teenagers, were identified in 1995 and initially diagnosed as classic CJD. Further research showed that the cases were distinct from classic CJD. Both classic and variant CJD cause psychiatric and neurological abnormalities and are fatal. vCJD, however, affects a younger population, progresses more slowly and its effects on the brain can be distinguished from those of classic CJD.

What Causes vCJD?

Although there is no direct evidence that vCJD can be transmitted through human blood or blood products, research at the American Red Cross Jerome H. Holland Laboratory for Biomedical Science in Rockville, Md., and elsewhere indicate that this route of infection in rodents is possible. Research suggests that blood or blood components can be infectious in some animal models of TSEs, according to a paper recently published in the Journal of Laboratory and Clinical Medicine, by Dr. Paul Brown of the National Institutes of Health and Larisa Cervenakova, Ph.D., an American Red Cross scientist. Because there is no test available to detect whether a person has vCJD, and the disease is thought to remain dormant in the body for quite a while (perhaps as long as 20 years) before symptoms become apparent, the Red Cross and other blood banks screen potential donors by asking about their travel history.

Bacteria or viruses cause most diseases, but scientists believe that the infectious agent responsible for TSEs is a normal protein, called a prion, that has been converted to an abnormal shape. Normal prions are not infectious, and both their normal and abnormal forms are invisible to the immune system. When prions become infectious, scientists believe they can convert nearby normal prions to the abnormal, infectious form.

Malformed prions are extremely hard to eliminate from the body and from surgical instruments — studies have shown that they can withstand common sterilization procedures such as extremely high temperatures and radiation. In fact, the British government now requires that surgeons use disposable, single-use instruments for certain surgical procedures because of the risk of lingering prions on instruments sterilized by traditional means. Research shows that high temperature with high pressure and very strong concentrations of chlorine bleach appear to inactivate infectious prions.

Prion
The protein on the left is a normal prion protein which refolds to become the disease-causing form shown on the right by the unfolding of some of the alpha-helical regions (purple helices) and the refolding of these regions into an extended beta-sheet region (green arrows). Photo courtesy of the University of Texas.

David Hammond, Ph.D., executive director for Plasma Derivatives at the American Red Cross, said that vCJD is a prion disease, but it is distinct from other TSEs that have been studied in the past, so there are still a lot of unanswered questions. He said that there is now considerable evidence suggesting that vCJD is a human form of BSE, presumably transmitted through ingestion of contaminated products from BSE-infected cattle. Laboratory experiments confirm the possibility of oral transmission of BSE.

Whether or not infectious prions are present in the blood of humans with classic CJD is under investigation at the Red Cross Holland Lab (since 1995) and elsewhere. Scientists know that on several occasions, classic CJD was transmitted to patients who received human growth hormone or brain-associated tissue from infected humans. It does not appear that classic CJD has been transmitted via blood transfusion or blood-derived products. However, studies continue to determine whether vCJD will have the same transmission characteristics as classic CJD

One of the issues that concerns scientists is the presence of abnormal prions in the spleens, lymph nodes and tonsils of vCJD patients-organs of the lymphoreticular system. The lymphoreticular system, which is involved in the transport of infection-fighting white blood cells and other types of cells, is in direct contact with the blood. Because of this contact with blood, there is a need to determine whether the blood of vCJD patients is infectious.

The Search for a Test

Holland Laboratory scientists are looking at patterns of vCJD infectivity. They are trying to determine what blood products are at risk for transmitting vCJD. Ideally, the research performed by American Red Cross scientists will lead to a blood test to detect vCJD, even in people who may not have symptoms. For technical reasons, developing a test for vCJD is a challenging task. Consequently, American Red Cross scientists continue to work proactively to find a way to remove prions from blood products.

Development of a blood test to detect vCJD is likely years away, but scientists are learning more about this emerging fatal disease. Until more questions are answered, the Red Cross feels that is it prudent to tighten the blood donor deferral period to exclude more people who might have eaten BSE-infected beef. As Dr. Bernadine Healy, president and CEO of the American Red Cross, wrote in a recent Science editorial, "If these efforts turn out to be unnecessary, we have advanced medical science. If, however, they turn out to be needed, we will have taken steps none too soon."