Thesis defense Bas Molenaar: “Uncovering new cardiac biology by the application of novel techniques in the adult heart”

The heart is a vital organ. It pumps blood through the body to supply other organs with sufficient oxygen and nutrients. Heart disease leading to heart failure results in a decline in quality of life and high early mortality rates. Current treatments aim at reducing the symptoms, but cannot cure the various forms of heart disease. In order to find more effective treatments, and eventually develop a cure, it is important to increase our understanding of the biological processes that occur in both healthy and sick hearts.

Novel techniques

To gain more insight into biological processes that occur in the heart, Molenaar and his colleagues used two novel techniques. They made changes to the DNA of mice using a technique called CRISPR-Cas9. This technique cuts DNA in two, which damages surrounding nucleotides – the building blocks of DNA. When the DNA repairs itself, it replaces the damaged nucleotides with new ones, thereby leaving alterations in the DNA. Additionally, the researchers used sequencing technology to determine the order of nucleotides in the RNA. The RNA is a copy of the DNA and involved in the (de)activation of genes. Combining CRISPR-Cas9 and sequencing technology, Molenaar and his colleagues studied the adult heart of mice in the highest resolution possible so far.

Heart contraction

The high resolution with which they could study the heart, led the researchers towards several discoveries. First, they identified a new biological player: a very small protein called smORF4. This protein plays a role in keeping calcium levels stable – also called calcium homeostasis. This is crucial for controlling heart contraction. They also identified more than 100 other very small proteins in the heart that were previously overlooked, but might have crucial functions in the healthy and/or diseased heart. Additional research on these proteins is important to gain an all-round insight into biological mechanisms at play in heart biology.

Heart attack

Second, Molenaar and his colleagues identified two genes that influence heart function after a heart attack. The gene B2M seems to cause the formation of too much scar tissue after a heart attack. The gene Ckap4, on the other hand, was found to limit the amount of scar tissue being developed following a heart attack. Scar tissue replaces the heart tissue that was lost due to the heart attack and makes the heart stiffer. Therefore, the amount of scar tissue influences how well the heart can contract. With the identification of the B2M and Ckap4 genes, we gain more insight into heart recovery and -function following a heart attack.

Improved treatment

During his PhD, Molenaar together with his colleagues developed large new datasets that can also be used by other researchers. Further investigation of the data allows us to obtain better insights in the biological processes taking place in the heart and thereby contribute to a better understanding of heart disease. Hopefully, this will lead to new and improved therapies.