What did you study for your master’s thesis?
I have used three different heart muscle cell lines to characterize the phenotype of the disease hypertrophic cardiomyopathy (HCM). The original cell line was derived from skin cells from an HCM patient, which were then used to generate so-called induced pluripotent stem cells (iPSCs). These iPSCs can be differentiated into heart muscle cells (cardiomyocytes). The cardiomyocytes and an added matrix complex can be used to engineer artificial heart tissue. The cell lines I worked with carried different or no mutations (1x naturally generated and 1x artificially inserted) in the gene coding for myosin binding protein C (MYBPC3). I was able to generate heart tissue from these three cell lines and examine their physiological and molecular characteristics. This cell-based model should help to gain a better understanding of the disease. The second part of my master’s thesis aimed to treat HCM on the cellular level by gene therapy.
What is hypertrophic cardiomyopathy, and what are the symptoms?
It is a hereditary disease that is inherited autosomal dominant. The left half of the heart continues to grow because the heart muscle cells are hypertrophic. This can lead to cardiac arrhythmia, hardening of the heart muscle, or, in the worst case, sudden cardiac death. During the "normal" progression of the disease, patients often do not notice that they are sick. They may experience shortness of breath, dizziness, or headaches, but often patients remain asymptomatic, which makes it very difficult to diagnose. The most common diagnostic method to identify myocardium thickening is ultrasound - but this is not always the case.
Figure 1: Comparison of a normal heart (left) and a hypertrophic heart (right). Note the myocardium thickening highlighted in yellow.
How did your discoveries coincide with the clinical picture?
I'm afraid it's very hard to say. We have been able to demonstrate some typical characteristics, but unfortunately the significance is not very high. The model is still very young and very complex. If you look at the results of other laboratories, you come to the conclusion that there is still no clear phenotype for this disease.
How common is HCM?
It is estimated that one person in 200 has HCM. It should be noted that this disease may not always have a genetic origin, but it is by far the most common cause. As for heart disease, it is also the most common disease caused by a genetic defect.
How dangerous is HCM?
The mortality rate is only about 1% per year. The disease often goes undetected, and it usually develops very slowly over the years. If the disease is noticed in old age, it can be effectively treated with medication. A change in lifestyle, such as a healthy diet and more exercise, also has a positive effect. In children and young athletes, this disease can lead to sudden cardiac death more often than in adults. This is due to the physical strain of the athletes, but also, and much more importantly, to the severity of the disease, which influences the course of the disease.
What is the current state of research for HCM?
Many mutations have been linked to the disease, which makes the diagnosis easier. But the mechanism by which this disease occurs is not yet fully understood. This is partly because genetic defects are not limited to just one gene. However, most of the damaged genes that lead to this disease are found in the genes of cardiomyocytes that code for the sarcomere. The most common mutated gene leading to HCM is the MYBPC3 gene, which was also the gene affected in my master’s thesis. It is extremely important for the organization but not for the development of the sarcomere.
What are the common therapeutic approaches against HCM?
In the worst case, the heart has to be replaced by a transplant. There are also minor surgical procedures, such as installing a small defibrillator/pacer. This is an attempt to stabilize/normalize the heart. The disease can also be treated with drugs that work against heart rhythm disturbances. ACE inhibitors or beta-blockers can also be given.
Figure 2 : Top view (left) and side view (right) of a 3D printed heart in a tissue bath. Scale bar is 0.5 cm. Image used from N. Noor and A. Shapira et al., 2019 under Creative Commons CC-BY license.
How have you tried to treat HCM?
With the help of gene therapy, i.e., the "exchange" of the defective gene. We used viruses that carried a functional protein in their genome. The cardiomyocytes were infected with these viruses, which led to the expression of the "healthy" protein in the cells. We were then able to locate the viral protein. We also found that the healthy full-length protein was inserted at the right place in the cell. Unfortunately, our cells, as well as the tissue strips generated from them, showed no physiological improvement. One of the greatest challenges of gene therapy is to treat only the affected cells (if only one type of cell should be affected) in the living organism. With our specific viruses, we have succeeded in expressing the healthy gene in a cell mixture only in the cardiomyocytes.
You mentioned engineering artificial heart muscle tissues earlier in the interview. Are synthetic hearts being explored for heart transplants today?
In our laboratory, heart muscle tissues strips are usually about 1 cm long and several mm wide. The biggest ones are up to 5x5 cm in size. In 2019, a heart the size of a rabbit heart was produced in Israel using a 3D printer. Unfortunately, it did not beat properly. One problem with their design is that it only consisted of one cell type, not a composition of several cell types like a real heart. For example, pacemaker cells must be generated in a synthetic model.
What are you going to do after your master’s thesis?
I would like to do my PhD in a similar research area.
Good luck and thank you for the interview!