Making It (Im)personal
Better understanding of human biology presents us with an opportunity to combat disease on two fronts – targeting individual variation on one hand and universal mechanisms on the other.
Julian Solway |
Recent years have seen dramatic gains in our understanding of human biology and disease. In my own field of respiratory medicine, it has become abundantly clear that what we call asthma is not a single disease. The term “endotypes” has emerged to reflect the different underlying pathophysiological mechanisms that lead to similar clinical manifestations, leaving us with the question: How best to tackle these several diseases called asthma? I suggest the answer lies in both personalized and impersonalized medicine.
A constellation of genetic predispositions, pathophysiological mechanisms and, importantly, social factors come together to make each case unique. Personalized or precision medicine is aimed at (better) tailoring treatment to these characteristics of specific patients. For truly personalized medicine, the social experience and environmental exposure histories throughout a patient’s entire life, and probably their parents’ and grandparents’ lives, will have to be taken into account. As the pulmonary research community identifies differences among pathogenetic mechanisms operating in the several asthmas, we’re poised to develop therapies that target those pathogeneses in a selective way, through the biologics currently in development or through entirely new approaches.
However, our understanding of the effector pathways involved in airway function and dysfunction also presents an opportunity for “impersonalized medicine”. This concept involves targeting pathways or pathogenetic mechanisms that operate virtually the same way in every patient. I can offer an example from my own work. One goal of my research is to develop a drug that prevents contraction of the airway smooth muscle. During an asthma attack, this muscle contracts, thereby constricting and narrowing the airway. Targeting the smooth muscle isn’t new – widely used β2 agonist drugs relax airway smooth muscle by binding to β2 adrenergic receptors on the cell surface and activating intracellular signaling mechanisms, resulting in a cascade of events that ultimately inhibits contraction. The problem is that while β2 agonists work very well in some people, some of the time, they are by no means a solution for everyone, all of the time. Genetic variations in the receptors and signaling pathways involved, plus inter-pathway crosstalk modulated by inflammation, can all interfere with the function of the drugs. The impersonalized medicine approach we’re taking bypasses all of that genetic and physiological variation to target the very end of the pathway – the contractile apparatus.
Specifically, the drug we’re trying to develop impairs contraction of the smooth muscle by targeting myosin – a key component of the molecular motor of airway muscle. Since the part of the myosin molecule targeted has little variation among individuals, we would hope to see a response in a much greater proportion of patients (if indeed our early preclinical development program eventually produces a compound suitable for testing in patients!). Of course, airway smooth muscle contraction is only one of multiple mechanisms of airflow obstruction in asthma. Other important mechanisms, including mucus hypersecretion and airway fibrosis and remodeling, would also have to be addressed, as would the underlying inflammation present in the airway walls of most asthmatics. Conceivably, an impersonalized medicine approach might be applicable to these pathogenetic mechanisms in asthma, or to pathogenetic mechanisms in other diseases, if other suitable molecular targets with little variation can be identified.
It’s important to note that personalized medicine and impersonalized medicine are not opposites – in fact, they are complementary, as both approaches can be pursued at the same time. I believe our best chance of success in treating complex “diseases” like asthma lies in a combination approach – impersonalized drugs to help all sufferers, and individualized medication to treat the specific pathophysiology of each patient.