Saturday, February 6, 2016

Rules for Rare Diseases

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

For today, please consider these three biological "Rules" that I use when I'm trying to convince my colleagues of the importance of rare disease research.

Rule - Rare diseases are not the exceptions to the general rules of disease biology; they are the exceptions upon which the general rules are based.
Brief Rationale - All biological systems must follow the same rules. If a rare disease is the basis for a general assertion about the biology of disease, then the rule must apply to the common diseases.

Every rare disease tells us something about the normal functions of organisms. When we study a rare hemoglobinopathy, we learn something about the consequences that befall when the normal hemoglobin is replaced with an abnormal hemoglobin. This information leads us to a deeper understanding of the normal role of hemoglobin. Likewise, rare urea cycle disorders, coagulation disorders, metabolic disorders, and endocrine disorders have taught us how these functional pathways operate under normal conditions (1).

Rule - Every common disease is a collection of different diseases that happen to have the same clinical phenotype.
Brief Rationale - Numerous causes and pathways may lead to the same biological outcome.

Consider the heart attack; its risk of occurrence is elevated by dozens, many hundreds of factors. Obesity, poor diet, smoking, stress, lack of exercise, hypertension, diabetes, disorders of blood lipid metabolism, infections, male gender; they all contribute to heart attacks. Regardless of the contributing factors, a common event precedes and causes the heart attack; the blockage of a coronary artery. Blockage is often caused by an atherosclerotic plaque. Consequently, rare inherited conditions that produce atherosclerotic plaques can produce the common heart attack (e.g., inherited disorders of lipid metabolism). We infer that for every common disease, there are rare, inherited disease that account for a small subset of cases.

Rule - Rare diseases inform us how to treat common diseases.
Brief Rationale - When we encounter a common disease, we look to see what pathways are dysfunctional, and we develop a rational approach to prevention, diagnosis, and treatment based on experiences drawn from the rare diseases that are driven by the same dysfunctional pathways.

Many heart attacks are caused by atherosclerotic plaque blocking a coronary artery. Many conditions produce atherosclerotic plaque, but a rare condition known as familial hypercholesterolemia is associated with some cases of coronary atherosclerosis that occur in young individuals. Studies on familial hypercholesterolemia led to the finding that statins inhibit the rate-limiting enzyme in cholesterol synthesis (hydroxymethylglutaryl coenzyme A), thus reducing the blood levels of cholesterol and blocking the formation of plaque. The treatment of a pathway operative in a rare form of hypercholesterolemia has become the most effective treatment for commonly occurring forms of hypercholesterolemia, and a mainstay in the prevention of the common heart attack (2).

[1] Wizemann T, Robinson S, Giffin R. Breakthrough Business Models: Drug Development for Rare and Neglected Diseases and Individualized Therapies Workshop Summary. National Academy of Sciences, 2009.

[2] Stossel TP. The discovery of statins. Cell 134:903-905, 2008.

- Jules Berman (copyrighted material)

key words: rare diseases, biological rules, disease funding, common diseases, complex diseases, precision medicine, jules j berman