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Scientists have successfully transformed guinea-pig heart-muscle cells into pacemaker cells, paving the way for a biological alternative to artificial pacemakers.
Pacemaker cells generate electrical activity that guides heart
muscle into beating in an orderly, rhythmic manner. Of the heart's 10 billion cells, fewer than 10,000 are pacemaker cells, which are all clustered in the sinoatrial node of the heart's right upper chamber.
If pacemaker cells go awry due to disease or age, the heart pumps irregularly, at best. Patients whose pacemaker cells have failed, but who still remain healthy enough to undergo surgery often rely on electronic pacemakers
to survive. However, such methods face problems because "electronic devices are limited to their finite battery life," said researcher Hee-Cheol Cho, a cell biologist at Cedars-Sinai Heart Institute in Los Angeles.
Other complications may occur with the devices, including accidental movement away from where the pacemaker was implanted, breakage and entanglement of the electrical wires that are screwed into the heart muscle. Such problems "are not uncommon and could be catastrophic," Cho told TechNewsDaily.
In addition, the devices generally cannot adjust when patients need to change their heart rates to walk faster or run. Moreover, cases of bacterial infection in these devices are rising. "All these problems could be solved by a biological pacemaker that is microscopic in scale and free from all hardware," Cho said.
Previous efforts have also attempted to generate new pacemaker cells by genetically modifying heart muscle cells, but these modified cells still resembled muscle cells more than pacemaker cells. Other researchers have tried to derive pacemaker cells from embryonic stem cells, which in principle can transform into any kind of cell in the body. However, these cells carry a persistent risk of becoming cancerous.
Now Cho and colleagues have developed a simple, new method to create genetically modified pacemaker cells that closely resemble naturally occurring ones. This form of gene therapy also appears free from the risk of cancer.
"This is the culmination of 10 years of work in our laboratory to build a biological pacemaker as an alternative to electronic pacing devices," said researcher Eduardo Marbán, director of the Cedars-Sinai Heart Institute.
This new strategy uses viruses injected into heart muscle to deliver a single gene known as Tbx18. This gene plays a key role in embryonic pacemaker cell development.
In experiments with guinea pigs, Tbx18 could reprogram ordinary heart cells so that they became pacemaker cells.
"Although we and others have created primitive biological pacemakers before, this study is the first to show that a single gene can direct the conversion of heart muscle cells to genuine pacemaker cells," Cho said. "The new cells generated electrical impulses spontaneously and were indistinguishable from native pacemaker cells."
Future therapies could involve injecting Tbx18 into a patient's heart or creating pacemaker cells in the laboratory and transplanting them into the heart. However, additional studies of safety and effectiveness must be conducted before human clinical trials could begin, the scientists cautioned. In addition, it remains uncertain how long the effects of this gene therapy would last.
"We still do not know how long - six months, two years, permanently? - this technology would be able to sustain heart rate," Cho noted.
The scientists detailed their findings online in the journal Nature Biotechnology
on Dec. 16.