Pacing the heart; studying the underlying principles of biological pacemakers

The heart of vertebrates has a leading pacemaker, the sinoatrial node, which initiates each heartbeat. This sinoatrial node contains pacemaker cells that spontaneously generate action potentials and form a synchronizing network that activates the atrial muscle of the heart. While sinoatrial node function is robust, and can withstand insults, dysfunction of the sinoatrial node occurs frequently in the human population, and is the most common cause of bradyarrhythmia. The mammalian sinoatrial node is highly complex and heterogeneous, and understanding its structure-function relations has remained challenging. The sinoatrial node shows huge variability in size, architecture and complexity between different species (e.g., zebrafish, anole lizard, mouse, human), and is much less complex in embryos at developmental stages when pacemaker function is initiated. These observations indicate that a set of general, elementary principles underlies the assembly of a functional pacemaker that is able to drive the heart of embryos, fish and adult mammals. Taking advantage of the variability between species and simple composition in embryos, we propose to elucidate the elementary principles and minimal requirements to assemble a functional pacemaker. To identify these basic principles, we take a novel approach by assessing conserved mechanisms of pacemaker tissue development and composition in evolutionary divergent species (fish, mouse) and use this knowledge to rebuild and optimize a cardiac pacemaker model in silico and in vitro from human pluripotent stem cells. We hypothesize that by rebuilding and optimizing a functional cardiac pacemaker, we converge towards understanding the principles underlying its structure and function. These insights should inform efforts to generate biological pacemakers for sinoatrial node regeneration, for exploring disease mechanisms, and for applications to drug testing, leading to personalized medicine. Our consortium consists of experts in developmental biology, in human stem cell differentiation, tissue engineering and microfabrication, in mathematical modelling of tissue patterning, in cellular electrophysiology, and in the biochemistry of cellular interactions. The cell biological and molecular patterning principles shared between species will be studied in genetically-engineered fish and in mouse developmental models using state-of-the-art single cell technologies and live imaging. We will generate mathematical simulation models to define the minimal requirements for the assembly of functional pacemaker-atrial tissues with input from the in vivo observations in fish and mouse. The predictions from the mathematical models will be used to assemble and test simplified pacemaker units on a chip using differentiated cells derived from human pluripotent stem cells. We anticipate this project will provide a major step in understanding the generic building plan of a functional pacemaker.