Building a Biological Pacemaker

15 December 2012
Posted by Ben Valsler.

Normal heart cells can be converted into specialised pacemaker cells using gene therapy, and this could pave the way to building a biological pacemaker, according to research published in the journal Nature Biotechnology.

Schematic diagram of normal sinus rhythm for a human heartA heartbeat originates from a small region of the heart known as the sinoatrial node, which contains a small number of specialised cells which act as the pacemaker.  There are fewer than 10,000 of these cells in a typical adult heart, which may contain around 10 billion other cells.  They function by initiating an electrical signal that creates each heartbeat in a smooth coordinated way.

If these cells are injured by disease or through ageing, the heartbeat can become uncoordinated, stopping the heart from being able to pump blood properly.  The only available treatment is to fit an expensive electronic device known as an artificial pacemaker.  For the last decade, research has been ongoing to find a biological alternative.

Now, Nidhi Kapoor and colleagues at the Cedars-Sinai Heart Institute, in Los Angeles, California, report that they have been able to convert adult rat heart muscle cells, called cardiomyocytes into pacemaker cells using gene therapy.  They examined a number of candidate genes, all known to be expressed during embryonic development of the heart, and settled upon a gene called Tbx18.

When Tbx18 was loaded into a adenovirus vector and expressed in adult cardiomyocytes, they become "faithful replicas" of pacemaker cells, exhibiting the correct epigenetic markers and functioning in the right way.

Further tests confirmed that the cells operate the same clock mechanism, respond to external stimuli such as hormones in the same way as natural pacemaker cells, and even took on the small size and characteristic shape of natural pacemaker cells.  This was the case both in the dish and in animal models of heart disease, where the gene therapy was local, effective and long lasting.

Furthermore, they retain this new function even after the gene stops being expressed, so further treatments aren't needed.

The researchers call these new cells iSAN, or induced SinoAtrial Node cells, and suggest that in the future, we could grow a clump of pacemaker cells before transplanting them, or simply inject a gene therapy agent directly into a patient's heart, doing away with the need for artificial pacemakers.

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