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Guest Blogger: Findacure – Understanding The Common Through The “Rare”

August 25, 2014

The Orphan Druganaut Blog is honored to have Rhys Dore, an Oxford University medical sciences student and a Findacure volunteer, as a Guest Blogger. Findacure is a charity which focuses around fundamental diseases – rare, often genetic, diseases from which the basic mechanisms of dysfunction can be extrapolated and applied to our understanding of more common conditions.

Rare diseases are the magnifying glass. They magnify and expose the importance of affected genes. The necessities of the disrupted physiological mechanisms are shown by the frequently severe symptoms which are found in such patients. These mechanisms are not solely affected in rare diseases; they are often altered in more common conditions. Thus these rare diseases can be regarded as fundamental to understanding the foundations of illness.

For example, take a rare deficiency in CD73 enzyme. This results in increased levels of a molecule called adenosine, leading to abnormal calcium deposits in the arteries and joints. This type of deposits parallels that found in cardiovascular disease and certain bone abnormalities. This discovery has paved the way for further investigations into the role of adenosine in these conditions. This is but one of many insights which are found to cross the boundary between fundamental and common diseases. Many fundamental diseases additionally have similar pathological parallels which are often more extreme and earlier-presenting. An extreme example of this is the group of progeroid syndromes which are characterised by premature ageing. Studying these syndromes not only provide a useful model upon which to analyze the detriments of ageing, but certain forms reveal the process of ageing in specific organs.

It is also beneficial to assess the differences found between similar fundamental diseases and their subtypes. Conditions such as Bardet-Biedl Syndrome and Alström Syndrome are similar in pathology; both are due to defective cell-signalling components called cilia and result in problems such as sensory defects and obesity. However, patients diagnosed with Alström Syndrome are significantly more likely to develop type II diabetes. Therefore studying what differs between these syndromes may reveal a contributing factor to the development of hereditary diabetes. These key differences are frequent due to fundamental diseases typically presenting as a collection of various pathologies rather than one key identifiable dysfunction.

Many fundamental diseases have proven vital for the basics of research investigations. This is particularly important for research based upon extreme animal models where the basic underlying mechanisms have a reasonable level of similarity to human physiology. Immunological research heavily depends on this system. One mouse model has been found to be reasonably similar to the human autoimmune condition APS type-1; both lack the Aire gene. This has allowed extensive research on the disease’s interaction with inflammatory messengers and antibodies. Such results too provide information concerning general autoimmunity and may be applied to a range of common diseases that have been associated with Aire-mechanism dysfunctions such as systemic sclerosis, alopecia, vitiligo, and even type I diabetes.

Furthermore, it should be noted that basic mechanism elucidation is only the first step of research. There is much potential for the repositioning of drug treatments from fundamental to common diseases. This is shown in hereditary hyperhomocysteinaemia (HHH), a disease of excess homocysteine resulting in increased cardiovascular disease. The original therapy for HHH involves using B-vitamins to reduce homocysteine levels, which reduces cardiovascular complications and has the potential for preventing cerebral infarctions otherwise. Interestingly, this B-vitamin treatment is also currently being investigated for its preventative effect against Alzheimer’s. Drug repositioning leads to huge cost reductions as drug treatments will often already be in production and be optimised for safety.

The altruism of fundamental disease patients to partake in clinical research is itself essential for the advanced progression of many therapies. As highlighted in Gorlin syndrome research; a disease characterised by excessively frequent basal cell carcinomas starting in adolescence. These are benign skin cancers which were found to result from an overactivation of the ‘Hedgehog pathway’. An inhibitor of this pathway, vismodegib, was discovered and tested using Gorlin Syndrome subjects as their high incidence of skin cancers allows more extensive data to be gained. These studies were found to be successful and vismodegib has since gained FDA approval for the use of such cancers in Gorlin Syndrome and otherwise; a particularly wide-reaching achievement as basal cell carcinomas are the most common form of skin cancer worldwide.

So perhaps the magnifying glass analogy is not quite correct. Fundamental diseases do not simply highlight the problems; they provide a gateway through which research and innovation can be applied to common disease. Fundamental diseases are the looking glass, leading to a so-called ‘Wonderland’ of heightened understanding and novel therapies applicable to both rare and common conditions alike. It is this revelation that Findacure: The Fundamental Disease Partnership ( aims to promote and explore via collaborating with patients, researchers and pharmaceutical industry to guide us into an era of appreciation of the fundamental diseases.

Logo courtesy of Findacure.

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