Building pacemakers out of the body's own cells

Dr. Michael Rosen has long been fascinated by fundamental questions about the human heart. What causes it to beat? How is the process initiated?

For over 30 years, he has collaborated with colleagues at Columbia and Stony Brook to examine those questions, driven solely by a thirst for knowledge. Around 1995, Rosen and his colleagues had a revelation. Perhaps the insights they had gained into the workings of the human heart could have an immediate practical application: They could be used to create a natural “pacemaker” that would replace the synthetic ones currently in use.   

“All of us were motivated much more by the idea of learning something that wasn’t known before -- why things work, why things happen,” he says. “But we realized that we had built a pacemaker using biological materials and we asked 'could this be better than electronic pacemakers?'”

Rosen believes the answer is ‘yes.’

Traditional pacemakers, he notes, have a number of serious drawbacks. They operate on batteries which must be replaced. They are inserted using a surgical procedure, and rely on a catheter vulnerable to fracture, that could perforate the heart and cause infection. Patients must be monitored at regular intervals, and the pacemakers must be replaced every five to ten years.

What if instead you could simply instruct the body to build a new colony of its own natural pacemaker cells to do the job? 

Rosen and his collaborators had stumbled upon a mechanism to do just that. Cardiac cells function like batteries -- they generate a negative charge across their external membranes, of about -80 to -90 millivolts in the ventricles. When the cell membrane is electrically stimulated, sodium channels in the membrane open up, allowing positively charged ions to flood into the cell, which cause that cell to generate an action potential that can pass an excitatory impulse to the cell next to it – which repeats the process. The cumulative impact: The heart beats and blood is pumped through the body.

Rosen and his colleagues have been working with the gene which codes for those ion channels, known as “pacemaker channels.” They reasoned that if a member of this gene family, known as HCN, were over-expressed in one part of the heart where it doesn’t normally function, perhaps you could initiate a heartbeat, compensating for a loss of function elsewhere.

It was an idea with significant implications. Under normal circumstances, the heart beat is initiated in the heart’s sinus node in the right atrium, and passed on to ventricular chambers through the atrioventricular (AV) node. But many patients suffer from a condition that deletes the function of the AV node – which makes it impossible for the signals from the sinus node to get to the ventricle.

“Before electronic pacemakers,” Rosen notes, “they were often dead within six months.”

When the sinus node is functioning normally, electronic pacemakers work by bridging the gap – they pick up signals from the sinus node and then deliver a shock to the ventricle. When the sinus node fails to function normally, electronic pacemakers are programmed to fire about once every second to make sure the heart keeps on beating.

But if you could somehow created a new pacemaker tissue modeled after the sinus node in a region of the ventricle,  the modified tissue could pass on the signals to beat directly by generating action potentials (replacing the function of an electronic pacemaker). And that is exactly what Rosen and his collaborators have been doing.

One method involves injecting a virus carrying the over-expressed HCN gene into a region of ventricle – a technique they have successfully demonstrated in large animal models. They also have succeeded with a separate approach. They load adult stem calls with the pacemaker gene, and inject the stem cells into the region of the heart where they want to create the new source of pacemaker current. Neither method is yet ideal – stem cells tend to migrate after a time, and the viruses used to date express pacemaker function only transiently.  

Rosen and collaborators are working to refine their techniques, and hope to be ready for long term animal trials in one to two years.

To view technologies from Dr. Rosen's lab, please click here