Every third death worldwide is due to cardiovascular disease. What happens on the cellular level, however, is still barely understood. Bayer researchers are collaborating with scientists from the renowned Broad Institute of MIT and Harvard to find out what goes on during this process. In the long term, this research could open new avenues of exploration that will lead to new medications.
Modern medicine is aiming to deepen our understanding of cardiovascular diseases in terms of individual heart cell types that have remained largely unstudied to date.
Researchers from Bayer and the renowned Broad Institute in the United States are investigating individual heart cells on the level of their gene activity. Their aim is to find the molecular causes that lead to cardiac dysfunction.
With a deeper understanding of how the individual heart cell types work and interact with one another, pharmaceuticals manufacturers will be able to develop better drug products for severe cardiovascular disorders.
The human body consists of approximately 37 trillion cells, of which there are at least 200 different types: skin, muscle, nerve cells and many others. Each of these cells has a specific role to play in our bodies, and they work together in a complex balanced system to ensure our sustained health and survival. If just a few cells do not function properly, serious problems can result. Take, for example, the heart cells that initiate the steady beat of the heart muscle, thereby maintaining the flow of blood through the body. If these cells, known as pacemaker cells, do not function properly, the consequences can be life-threatening. At present, we do not yet understand cardiovascular diseases at the level of the different cell types involved, because researchers lack the tools to investigate them. A new technology, however, now makes this possible. Bayer researchers working together with scientists from the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, are using this method to better understand cardiovascular diseases.
“Our heart is made up of many types of cells: heart muscle cells, connective tissue cells, immune cells, cells that line the blood vessels and others,” says Dr. Christian Stegmann, head of the Joint Precision Cardiology Laboratory run by Bayer and the Broad Institute. This rough breakdown is not sufficient to understand the causes of complex cardiovascular diseases at the cellular level. That’s why the lab‘s researchers want to find out more. “We assume that there might be subtypes of heart cells whose function or dysfunction we can link to a disease.”
Every year, some 17.9 million people worldwide die as a result of a cardiovascular disease.
The researchers are currently focusing on two areas: heart failure and atrial fibrillation. Heart failure, also known as cardiac insufficiency, indicates a state where heart-muscle function is diminished. The heart is able to temporarily compensate for this lower performance, but this puts extra strain on the heart, leading ultimately to failure. The second area of focus is atrial fibrillation, which is when the heart beats irregularly. “In this condition, there are individual cells that cause the heart muscle to beat as though it were out of step,” explains Dr. Joerg Hueser, head of Cardiovascular Research at Bayer.
When the heart muscle beats irregularly, the flow of blood is uneven, which can increase the risk of thrombosis in the patient. A thrombus, or blot clot, can block heart vessels or blood vessels in the brain. According to the WHO, approximately 17.9 million people worldwide die from the complications of cardiovascular disease every year, and of these deaths, around 80 percent are due to a heart attack or stroke. “That is why the Precision Cardiology Laboratory will also be looking beyond atrial fibrillation and heart failure. Our aim is to understand the cellular mechanisms that lead to cardiovascular disease,” emphasizes Stegmann. To do this, as a first step, the researchers compare the cellular characteristics of healthy people with those who suffer from heart disease.
This is done with a technology called single cell transcriptomics in which researchers can analyze the complete set of transcripts produced by thousands of individual cells. These molecular working copies of the genes are an intermediate step in cell metabolism. When genetic information (DNA) is transcribed, it is translated into a transcript, and the cell forms a protein based on this molecule. Proteins are the molecules that primarily enable biochemical cell function. The transcripts themselves contain sufficient information to allow researchers to deduce “which program is currently running in the cell and which genes are active,” explains Dr. Patrick Ellinor, head of the Precision Cardiology Laboratory for the Broad Institute. Crucially, the researchers working with Ellinor and Stegmann are analyzing the transcriptome, that is, the entire set of transcripts in each cell, which is what makes the analysis so complex. “This should be revised to “For each cell, we analyze 1,000 to 4,000 genes; and in one experiment, we examine between 40,000 and 50,000 individual cells,” explains Ellinor.
Bayer’s researchers are benefiting from the experience of their counterparts at the Broad Institute. Summarizing their long-term perspective, Stegmann says “This will allow us to better understand how diseases occur, by pinpointing the responsible processes and genes in the cell. This will give us much greater clarity in where we need to intervene and ultimately help us to develop new medications.”
The Precision Cardiology Laboratory is an independent collaboration comprising academic researchers from the Broad Institute and industry researchers from Bayer. It began its work in July 2018. The collaboration brings together molecular biologists, physicians and bioinformaticians. “Our scientists complement each other very well,” concludes Ellinor. There are currently ten researchers from the Broad Institute working side by side in the Precision Cardio Lab with five scientists from Bayer. “We first want to establish our technique on specific cells, and that will certainly keep us busy for another year. However, the first preliminary results are already promising,” says Hueser.
The collaboration is initially scheduled to run for five years. By then, the researchers aim to have established the basis to allow the optimization and pharmaceutical development of two new substances. As Stegmann explains, “This type of collaboration model is completely new for us, so in many respects we are working in pioneer mode.” This trailblazing spirit is palpable in the labs, where the researchers are well aware of the daunting task ahead of them, but set their sights on the systematic exploration of the cardiovascular system for fundamental new insights with the potential to open a new era of highly specific cardiovascular treatments.
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