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In a Heartbeat

Though the virtual-heart project is of global scope and has no official headquarters, it is widely agreed that its front line lies beyond the University of Oxford’s ancient, stately colleges, in a drab, modern building that looks out of place among its crenellated neighbors. Here, in a four-floor wing dedicated to cardiac science, is a research center equally uncharacteristic of its surroundings. Instead of stainless-steel tables, microscopes, and flasks of cells, this modest suite of offices is packed with computer workstations whose monitors are filled with strings of software code. This is the domain of Denis Noble, a man credited with almost single-handedly creating the field of cardiac modeling nearly 45 years ago. These days Noble, head of Oxford’s Cardiac Electrophysiology Group, is easy to spot among the graduate students and postdocs: a lean 67, he is the most hiply dressed and also appears to hold a solid edge in energy as he dashes among team members whose work ranges from hard-core computer programming to basic tissue dissection. Cardiac modeling, Noble says, necessarily combines the talents of researchers who might never otherwise come in contact. “This is a new form of biological science,” he says. “Being highly collaborative is essential.”

In a sense, the cardiome project began in 1960 when Noble came up with a set of equations that describe how the electrical activity of cardiac cells is largely controlled by the flow of potassium ions through their membranes, which leads to waves of activity that spread through neighboring cells and ultimately generate the coordinated beating of the heart. While the idea of describing physiological activity in terms of mathematical equations seemed groundbreaking at the time, Noble’s original model appears almost quaint compared to those his lab works with now-monstrous formulas with 23 variables accounting for 12 different types of cellular ion flows. Crunched on a computer, these models churn out a millisecond-by-millisecond simulation of a cardiac cell’s activity.

But modeling a single heart cell gets you only so far. Helping patients diagnosed with diseases from high blood pressure to congestive heart failure requires a model of the entire organ. Enter Peter Hunter, a former Oxford colleague of Noble’s. Where Noble works on individual cells, Hunter has taken on the task of modeling the heart’s large-scale structure and mechanics-that is, the beating of the heart muscle itself. When Noble visited Auckland in 1991, he found Hunter’s group making ultraprecise measurements of hearts extracted from dogs. “These people were shaving down a preserved heart a fraction of a millimeter at a time, like old-fashioned anatomists,” recalls Noble. Hunter’s intent was to build a model that would bridge the gap between heart science at the cellular level and the structure and function of the whole organ. In other words, he wanted to map out exactly how all those ion flows in cardiac cells teamed up to create a heartbeat, and in particular where things were going wrong in diseased hearts.

Today, the efforts of Hunter’s and Noble’s labs have been combined into whole-heart models whose behavior reflects the independently calculated activities of up to 12 million virtual cardiac cells. A real heart has closer to a billion cells, but even today’s fastest supercomputers can’t track that many cells in a reasonable amount of time. As it is, some of the Auckland models-which represent human, dog, pig, guinea pig, and mouse hearts-are so complex that it takes eight hours or more of a supercomputer’s time to crank through a single heartbeat. Explains Hunter, “The models show how electrical activity originates at the cellular level, how the activation wave spreads to other cells, how the electrical wave is converted to mechanical contraction of the heart wall, how the contracting walls cause blood to flow through the heart, and how energy is distributed through the whole system.”

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Tagged: Biomedicine

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