In 1957 the first man-made pacemaker was created by Earl Bakken to help people with heart defects live their lives without being plagued by symptoms like rapid heart beat, dizziness, fainting or death. This has saved countless lives and since then the race has been on to create a newer biological counterpart. At the moment pacemakers require a major operation weakening patients and leaving them prone to infection, something especially worrying in older patients but the hope is with a biological version this stress and risk can be avoided. Finally this week a group of cardiologists from the Cedars-Sinai Heart Institute in Los Angeles have made a breakthrough in biological pacemaker research using gene therapy!
Pacemakers are generally required because sometimes due to faulty signalling by the sinoatrial node the heart beats irregularly or cannot respond to changes in activity like needed. The mechanical pacemakers fitted take control of the beating of the heart and emit electrical signals, mimicking that of the sinoatrial node at regular intervals which sustains controlled and regulated blood flow. They consist of a small metal box attached to wires called pacing leads which run to your heart. They change the rate at which electrical impulses are sent out according to what your body requires. For example if they sense your heart is beating too slowly the pacemaker will send out signals but if it thinks you’re doing okay on your own, it’ll stop sending them – pretty clever huh?
The ‘pacemaker’ created by the scientists uses gene therapy to insert a gene into the heart which affects heart cells and can transform them into pacemaker cells. Gene therapy is a method where a gene is inserted into a vector, which can be a virus, liposomes or even just naked DNA. More recently there have also been hybrid methods developed such as virosomes, which are a combination of liposomes and viruses. With viruses the gene is inserted into the DNA that is already present in the genome of the virus (though this will have been adapted to create an attenuated or inactive version of the virus), so that when the virus is injected into the body the desired gene enters too.
The type of vector used in this particular gene therapy was an adenovirus, which has the gene Tbx18 inserted into it. Previous research published has shown that the gene Tbx18 can be used to create sinoatrial (SA) nodal cells from normal myocytes (heart cells) and therefore create biological pacemaker activity originating from the site of injection in the heart. TBX18 is an embryonic transcription factor (T-box 18) so it is present in foetal development but is usually non functional during adult life.
The experiment involved injecting the adenovirus containing TBX18 into pigs (there was also a fluorescent control) and hoping that the TBX18 started doing it’s usual job of creating SA node cells. Within just two days the heart cells infected with the virus began to change into ‘pacemaker’ or sinoatrial nodal cells as the Tbx18 turned on genes driving SA nodal cell development and turned off the genes leading to cardiomyocyte development. This means the cells began to act as a pacemaker and initiate the regular beating of the heart. As the research paper says ‘Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block’.
The new cells began to work with minimal mechanical help for the next two weeks and even adjusted signals according to activities such as sleeping versus moving around. However, after the initial two-week period the immune system began to attack the cells injected by the virus, leading to activity ceasing after this period. At the moment unfortunately there is no way to stop this immune attack as the gene is inserted under the guise of the adenovirus, which is naturally obliterated by the human body.
Despite these setbacks this is a wonderful and groundbreaking breakthrough in modern scientific research, and can currently still be used as a temporary solution for example for patients having issues with their current pacemakers. Animal trials are still on going by the research team and predictions are that we may be able to start running human trials in as little as two or three years if approval is gained from the correct governing bodies.
The original research paper published this week:
Hu, Y., Dawkins, J., Cho, H., Marban, E., & Cingolani, E. (2014). Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block Science Translational Medicine, 6 (245), 245-245 DOI: 10.1126/scitranslmed.3008681
Prior research showing Tbx18 can create sinoatrial nodal cells:
Kapoor N, Liang W, Marbán E, & Cho HC (2013). Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nature biotechnology, 31 (1), 54-62 PMID: 23242162