by Daniel L. Cox and Rajiv R. P. Singh, professors
The outbreak of the Mad Cow Disease epidemic in the United Kingdom during the 1990's and the subsequent confirmation of transmission of the disease to humans has caused a significant public health scare. Hundreds of thousands of cows developed the normally rare, but deadly neuro-degenerative disease, and millions were slaughtered in efforts to control it. Over one hundred humans have died of a new-variant Creutzfeld-Jacob Disease (nv-CJD) believed to be caused by eating infected beef. Variants of this disease are widespread in other mammals as well. For example, as much as 30 percent of the wild deer and mink population in the United States may have such diseases.
How did this disease arise? What causes its transmission? How significant a public health threat is it? Can it be treated? These questions remain at the forefront of biomedical research today.
The 1997 award of the Nobel prize in medicine to Dr. Stanley Prusiner of UC San Francisco, the man who coined the name Prion for "protenacious infectious agent", shows a growing acceptance of his theory that these diseases are different from other transmissible diseases. Most diseases are spread by nucleic-acid-containing viruses and bacteria. The infectious agent in Prion diseases is a misfolded protein, which autocatalyzes its own misfolding. Prusiner's theory asserts that a rapid gro-wth in the number of misfolded proteins, or prions, is respon-sible for the disease onset and death, although the detailed mech-anism by which prions cause neu-ronal death is not known. How sign-ificant is the threat to public health?
Epidemiologists estimate the number of potential human deaths from 1990's Mad Cow epidemic to range from a low of a few hundred to a high on the order of a million. One reason for this very large uncertainty is the decades-long incubation time, during which the disease silently incubates inside a body without any apparent symptoms. What causes such long incubation times? Do they have a well-defined statistical distribution? Can they be made longer than the normal lifetime, thus preventing the onset of the disease altogether?
It is these questions that motivated our group to develop a model for incubation times in prion diseases. Our model is built upon the idea that the misfolding of proteins is tied to their aggregation into clusters. Indeed, no misfolded protein monomers are ever observed. A common post-mortem feature of these diseases is the presence of plaques consisting of clusters of misfolded proteins. Our model provides a simple explanation for the long incubation times in terms of a slow stochastic aggregation process, which needs to reach a critical size before a more castastrophic exponential growth takes over. We calculate the distribution of incubation times, which corresponds rather closely with the observed distributions in the epidemiological data. Our model also leads to clear predictions for dose species. This fact can be rationalized at a simple level by the idea that the proteins in different species are not identical. Although the particular protein implicated in prion diseases is 90 percent homologous in all mammals, it still varies from species to species, and that difference gives rise to a barrier for transmitting the disease across species. An intriguing aspect of the species barrier is its asymmetry. Mouse prions readily infect hamsters for instance, but hamster prions do not cause the disease in a mouse. In our work, we suggested a treatment protocol for these diseases exploiting this asymmetric species barrier. Our idea is that adding a normal form of suitably chosen alien-proteins can help coat any infectious seeds with alien prions which will then become relatively immune to further incubation times, thus prolonging the disease onset. This idea of fighting prions with prions has resonated in the popular reporting of our work, though it remains to be seen if it will actually help in developing treatments for these diseases. In closing, we note that as various sciences approach the molecular level, the strict boundaries between disciplines are bound to disappear. Thus it should be possible for individuals to contemplate problems ranging from medicine to biology to environment to material science to basic physics and chemistry. Our department and our university has a commitment to grow in this nanoscale science.
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