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Setting a pace

Hollywood is working on yet another blockbuster. Perhaps, the biggest of them all. But this time it is not coming to a hall but to a hospital near you.

A team of medical scientists —including Indian-origin researcher Nidhi Kapoor — from Cedars-Sinai Heart Institute (CSHI) in West Hollywood has shown that only a jab is needed to get an erratically beating heart back in order. If the scientists can repeat in a clinical setting what they have achieved in lab experiments, it would make expensive artificial cardiac pacemakers irrelevant. Globally, the cardiac pacemaker industry is $6 billion strong and more than a million people are living with an artificial pacing device.

The researchers from the CSHI in Los Angeles have been able to coax ordinary heart cells to become exact replicas of highly specialised pacemaker cells by injecting a single gene. Their work was published online in the journal Nature Biotechnology on Sunday.

Kapoor, one of the authors of the study, did her bachelors in biology from Delhi’s Sri Venkateshwara College before moving the US. In 2007, following a PhD from Loyola University, Chicago, for pacemaking mechanism in embryonic stem cells derived from cardiac pacemaker cells, she joined CSHI. “I hoped that someday I could make a biological pacemaker,” Kapoor told KnowHow.

The fact that all heart muscles contract in a synchronised manner to pump blood to different parts of the body is nothing short of a marvel. What makes this possible is the presence of a small set of pacemaker cells located in sinoatrial node (SAN) on the wall of the right upper chamber of the heart. [Out of 10 billion heart cells only 10,000 are pacemaker cells, that is one in a million.] These cells generate electric impulses which spread to other heart cells in an orderly fashion. When these cells, often referred to as SAN cells, go awry, owing to disease or ageing, the heart pumps erratically, often too slow to sustain life.

When an electronic pacemaker is implanted, it in fact supplements this electrical activity of SAN cells and ensures the heart muscle contractions are maintained at a healthy level.

What makes the current study important is that the scientists could reprogramme ordinary heart cells to become pacemaker cells with the help of a gene called Tbx18. These newly-created pacemaker cells — called “induced SAN cells” — took on the distinctive features and function of native pacemaker cells in lab mice as well as in guinea pigs.

“Although primitive biological pacemakers have been created before by others as well as us, this study is the first one to show that a single gene can direct the conversion of heart muscle cells to genuine pacemaker cells,” says Hee Chol Cho, a CSHI scientist and lead author of the study.

“This is the culmination of 10 years of work in our laboratory to build a biological pacemaker,” says Eduardo Marban, director, CSHI, who contributed to the study.

Nidhi Kapoor

“This work is very interesting. Electronic pacemakers currently in use suffer from some inherent problems,” says R. Renuka Nair, head of the cellular and molecular cardiology division at the Sree Chitra Tirunal Institute for Medical Science and Technology at Thiruvananthapuram. Biological pacemakers can become a viable substitute, she says.

“The electronic devices are limited by their finite battery life, requiring battery changes. Complications such as displacement, breakage, entanglement of the leads (electrical wires that are screwed into the heart muscle) are not uncommon and could be catastrophic,” Cho told KnowHow.

There are other problems as well. According to Cho, the incidence of devices with bacterial infection is increasing. Besides, the devices largely do not know if a patient needs to walk faster or run, requiring faster heart rate. And, the device does not “grow” with paediatric patients, necessitating readjustments of device position.

“All these problems could be solved by a biological pacemaker which is microscopic in scale and free from all hardware,” Cho observes.

“The work is in a nascent stage right now. But, if it works it would be a blessing for a large number of patients suffering from arrthymias, particularly bradycardia,” says Aparna Jaswal, an expert in cardiac pacing at the Fortis Escorts Heart Hospital in New Delhi.

Cho, however, is confident. In the first place, the gene (Tbx18) that they used is a human gene. It worked well in two animal species — rats and guinea pigs. “Before this technology becomes a reality, we will verify the findings in a large animal model. Then, safety, toxicity, dose-response and biodistribution studies will need to be done prior to the first clinical trial,” he says. “This may translate to a few years before the first human trial,” adds Cho.

If subsequent studies confirm the findings, the researchers hope that they can administer the therapy by simply injecting Tbx18 gene into a patient’s heart or by transplanting pacemaker cells after growing them in the lab.