How do scientists go about studying HD? Gusella and MacDonald explained the approach they take to their research. They look at HD from a genetic angle, choosing to study the basics - in other words, the root cause(s) of the disease - not just the symptoms and pathology (the clinical aspect that interests doctors). If we envision the disease cascade as a timeline, Gusella and MacDonald work at the very beginning, understanding the various mechanisms that trigger the disease, including the early biochemical and metabolic changes that take place. Clinicians, on the other hand, work near the end of the cascade, looking not at the cause(s) of the disease, but rather at the consequences (the movement, cognitive, and psychiatric symptoms). Whereas clinicians generally try to intervene toward the end of the disease cascade with drugs or other therapies, Gusella and MacDonald attempt research that aims to intervene at the start of the cascade via experimental methods on the level of RNA, most notably RNA interference (RNAi), which will be discussed later. The researchers even anticipate that someday they may be able to change the slope of the cascade so that the age of onset is later and the symptoms are less severe. (As you may already know, the later the age of onset, the less severe the symptoms.)
Genetic disease is fundamentally different than non-genetic disease in that it has a definite starting point, even if symptoms are not yet apparent. In contrast, non-genetic disease usually has apparent symptoms that clinicians try to block, but not always an easily identifiable starting point. In the study of HD, researchers like Gusella and MacDonald have the broadest definition for the “disease” part of Huntington’s disease. They define it as the genetic mutation present at the time of conception all the way to the last stages of the cascade near the end of the person’s life. Neuropathologists (professionals who study diseases of the nervous system) define the disease as nerve cell death. Clinicians, who have the narrowest definition, consider it to be the visible symptoms in the last stages of the cascade.
MacDonald argues that huntingtin protein aggregation and eventual nerve cell death are not the causes of the disease, but rather the consequences. She and Gusella, therefore, strive to discover the things that happen before, without worrying about integrating the results of their experiments into the HD “story.” For a decade, the HD story has sounded the theme of huntingtin aggregation as a cause of HD. Here the term “story” describes a paradigm created by the scientific community - something of an umbrella idea under which many subsequent research findings huddle. While a story of this kind may one day be proven false, the scientific community has a hard time letting go or changing the paradigm. Similar to the HD story, the Alzheimer’s story emphasizes the buildup of amyloid plaques in the brain as the cause of the disease (the events that start the disease cascade). This story, too, may turn out to be inaccurate. Protein clusters may not cause either disease, but are considered to be the result of events that occur further upstream in the disease cascade. In other words, once the original trigger (as yet unidentified) sets off the disease cascade, it often takes a long time for protein clumps or tangles to form.
Last Modified: 05/22/2009
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