Try this not-so-trivial multiple-choice question:
Q: How many electronic pacemakers are implanted in American heart patients during a typical year?
A: (a) 20,000; (b) 250,000; (c) 300,000; (d) 2 million.
If you chose (b) or (c) you're correct, according to molecular biologist Eduardo Marb n, at the Johns Hopkins University School of Medicine in Baltimore.
"Cardiologists in the U.S. put about a quarter-million of these electronic devices in annually," Marban recounted. "In the year 2000, we called around to all the major U.S. pacemaker manufacturers, and came up with a total of 255,000 devices implanted in the year 1999. The number of such procedures," he added, "has gone up in the last two or three years because of new indications. So I think it's now closer to 300,000 devices - at very considerable economic cost. The 10-year expense for a patient probably averages $30,000 to $40,000. That covers not only the device itself, but all the yearly checkups and battery changes."
These facts of cardiac life impelled Marban "to pursue ideas of going in with a catheter percutaneously and injecting one very small part of the heart non-invasively under X-ray, and creating a natural pacemaker. The patient," he foresees, "walks away and never needs a battery change or hardware implanted."
Marban is senior author of a Brief Communication in today's Nature, dated Sept. 12, 2002. Its title: "Biological pacemaker created by gene transfer."
"We've been able to create this," he told BioWorld Today, "by converting normally quiescent muscle cells in the heart into pacemaker cells. We see this as a potential alternative to electronic pacemakers. It's the first instance," Marban continued, "in which gene therapy has been used to alter the function of an organ, or a bit of an organ."
Converting A Jalopy Into A Hot Rod
"The potential applications," he asserted, "are limited only by one's imagination. With 30,000 human genes available to use, we have all the applications we can imagine. Anything in which there's some kind of deficiency or error in the body could in principle be fixed or repaired using this method. It's analogous to taking a very clunky car and, if you had access to all of the good mechanics in the world, plus all of the components in parts warehouses, you could transform that lackluster jalopy into a hot rod.
"Along those lines," Marban pointed out, "what we've reported here is selectively suppressing one particular gene in the heart, and thereby changing a garden-variety cardiac cell into a pacemaker that beats its own rhythm.
"We started off," he recalled, "facing the challenge of how to fashion a biological pacemaker, using gene therapy We realized that if we go back to when the embryo is very young and its heart just forming, it would be in an incipient human at 2 or 3 weeks of age. Every cell in the heart at that point has intrinsic pacemaker activity, so can set the rhythm. But very quickly thereafter, another couple of weeks in the embryo, the heart differentiates into very discrete regions, only one of which can normally pace. And that sets the rhythm for the heart for the rest of one's life - until disease or some kind of degeneration associated with aging leads to failure of the normal pacemaker mechanism.
"What happens in that heart as it becomes more and more adult," Marban said, "is that only a few thousand cells possess this intrinsic pacemaker activity. The rest of them are mostly muscle cells, there to beat - to do the job of the heart. And that's nice, because then some of the cells can focus on beating, and others on pacing. If a few thousand of those pacemaker cells get sick," he pointed out, "or if scar tissue forms around them, the heart develops standstill. That's when people will faint, and that's when electronic pacemakers are put in."
Tracking Pacer From Embryo To Old Age
"Using the fact that the embryonic heart possesses the intrinsic ability for every individual cell to beat," Marban went on, "we thought, What if the cardiac muscle cells lose their ability to beat spontaneously because they develop an electrical braking mechanism?' So we identified a specific potassium channel that we thought was that braking mechanism. It had precisely the right characteristics to stop the heart and keep it quiescent. So we engineered a gene-transfer construct designed specifically to block that electrical brake. And, lo and behold, it liberated rhythmic spontaneous pacemaker activity.
"These channels that I have likened to an electrical brake are present in all the muscle cells of the heart, but they're absent in the pacemaker cells," Marban explained. "So we put the gene into the ventricle, which is the major muscle chamber of the heart, and converted a few of those ventricular muscle cells into pacemaker cells. In some instances, that sufficed to take over and drive the heart and initiate the heartbeat.
"We then created a poison-pill genetic construct. It's a mutant version of the gene that is normally expressed, which forms this potassium channel. Thus, we were able to cripple the body's own normal products of that gene in those cells where it was expressed."
For their in vivo experiments, the co-authors rounded up 25 guinea pigs, some dedicated to testing electrophysiology, others to electrocardiograms. "Both those measures of efficacy turned out to be real," Marban related. "In about 70 percent of the cells that we studied, we were able to induce pacemaker activity from a normally quiescent ventricular myocyte, and turn those into spontaneously beating biological pacemakers. What's more, in 40 percent of the animals, we saw evidence that their hearts were driven by these pacemakers that we created in the ventricle.
"We would never do it this way in real life, in a human," Marban mused. "We would go in with a catheter and locally convert a few thousand cells into pacemaker cells. For safety, efficacy and durability studies, we are now doing experiments in full-grown pigs, using clinically available catheters and X-ray equipment, with a view," he concluded, "to establish preclinical groundwork for eventual Phase I human studies three to four years from now - if all goes well."