Treat the Patient, Not Just the Cell!
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Recently we have used reductionist and integrative approaches as pioneered by the seminal work of Sanguinetti and Keating to link human arrhythmias with gene mutations that alter the biophysical activity of channel proteins. But as we begin to seek new methodologies to treat heart disease, we are faced with a myriad of data that clearly simple cell-based assays or culture models cannot address on their own. Is it time to change course?
We all remember when in our ninth grade biology class, we first learned about the cell membrane. It was after all, critically important in that it held in the essential components of a cell allowing it to function. Many of us continue to be fascinated by the proteins (ion channels, transporters, and receptors) that traverse the membrane to synchronize cellular function at baseline and in response to physiological or pathological signaling. Over the past 2 decades, we have refined our approaches from whole animal physiology to highly quantitative biophysical, structural, and molecular technologies. These approaches, combined with refined human clinical phenotyping, have illustrated that gene variants in membrane proteins, particularly ion channels, are the source of potentially fatal forms of arrhythmia. Such an approach was pioneered by the work of Sanguinetti et al1 that linked long-QT syndrome with gene variants that altered the biophysical activity of voltage-gated potassium channels. Today, we have extensive experimental toolboxes to explore the role of ion channels in physiological signaling and disease. These approaches have aided our understanding of noncardiac forms of excitable cell disease. Most importantly, beyond fundamental scientific discovery, findings in our generation have aided in the diagnosis and treatment of disease in patients of all ages and backgrounds. In our current era, not a week goes by where new data link familial and acquired forms of heart failure and …