Illuminating Biological Interactions

Professor Entcheva Leads an International Study on Cardiac Function

May 8, 2024

Professor Emilia Entcheva

By 2030, it is estimated that 12.1 million people in the United States will have atrial fibrillation, one of the numerous rhythm abnormalities of the heart called arrhythmias. Therefore, understanding the complex biological functions that allow the heart to function normally and what disruptions cause these abnormalities that may lead to other life-threatening conditions is of utmost importance to researchers like Professor of Biomedical Engineering Emilia Entcheva.

Biological complexity arises from the intricate arrangement of subcellular and multicellular structures and the synchronized communication among specialized organelles. In heart muscle cells, calcium release is critical for the seamless and flawless coordination of events linking electrical messages to the mechanical contraction of each beat. 

Precise management of subcellular calcium stores ensures normal heart function, while proximity allows rapid adjustments of ion levels to alter the localized calcium concentration to respond to the demands of mechanical work. However, improper communication between the main calcium store and additional storage organelles, such as mitochondria or lysosomes, can cause disruptions leading to the development of arrhythmias. 

Over the next three years, Entcheva will lead the first-ever study investigating these interactions in human stem-cell-derived heart cells, alongside international collaborators Michael Colman from the University of Leeds and Moritoshi Sato from the University of Tokyo. Supported by a $1.2M grant from the Human Frontier Science Program (HFSP), the project, titled “Optogenetic Control of Organelle ‘Chatter’ and Effects on Calcium Dynamics in Human Cardiomyocytes,” aims to uncover the biology behind these phenomena using optogenetic tools and computational modeling.

HFSP is a unique mechanism that brings together multiple governments to support innovative, risky, basic research at the frontiers of the life sciences. This extremely competitive program only accepts 5% of applicants with strict rules for each project, requiring them to represent a new research direction for each collaborator, establish a new partnership between researchers who have never worked together before, and chart new territory. 

The novelty of Entcheva’s study is that it permits the ability to assess how secondary calcium storages shape heart activity. Entcheva says the discovery in recent years of how close these organelles are using new imaging techniques has made the time ripe for this research, contributing to the selection of their study out of the 730 submitted proposals.

“It is surprising how intertwined some of these organelles are. The centuries-old view of the cell as a ‘bag of water’ with a lipid membrane and some proteins and organelles inside is changing. Over the last decade, we have seen how densely packed the cell cytosol is, and how structured and closely positioned the key organelles are,” Entcheva said. “If organelles are this close, then there must be some sort of communication between them, which we have been ignoring.”

In this project, the research team will employ new optogenetic tools to selectively move subcellular organelles closer together using light in a precise, quick, and reversible manner to increase communication. They will assess the effect of this light-controlled organelle engagement on the electrical and mechanical functions of the heart to mimic disease conditions or boost muscle performance.

These engineered light-responsive structures, known as photoswitches, come in polarized pairs that attract each other like magnets. When expressed in cellular components in the presence of light, they can help move organelles closer together. To imagine it, Entcheva says to think of two magnets with opposite fields and when you shine a light they come together.

“It is very hard to study organelle interactions without destroying the cell as a whole. To manipulate distances in a live cell, optical means provide the best non-destructive approach,” said Entcheva. “I have always loved methods for optical imaging and optical control of biological systems because they’re non-invasive and can be scaled up.”

Each researcher will play a distinct role in carrying out this project. Sato, a leader in the molecular design of photoswitches, will develop new optogenetic tools that Entcheva will adapt to heart cells and deploy to quantify effects on heart function. Using the obtained experimental data, Colman, a physicist and computational scientist, will design predictive computational models of how these organelles talk to each other via critical calcium release events for both health and disease.

Out of the 34 projects chosen as 2024 Research Grant Awardees, this project is one of six being led by U.S.-based researchers, showcasing Entcheva’s recognized expertise in optogenetics. In fact, her lab, the Cardiac Optogenetics and Optical Imaging Laboratory, played a key role in bringing optogenetics to the cardiac field by validating its use experimentally and computationally. 

For students involved in her lab, this project is an opportunity to gain invaluable experience in cutting-edge research to uncover new biology. Undergraduate and graduate students will assist her in deploying the new optogenetic tools, developing new optical imaging and optical actuation systems, and analyzing cardiac function. Entcheva highlighted the importance of staying at the cutting edge of biomedical engineering to cultivate a competitive workforce. This project not only aligns with that goal but also offers a pathway for providing GW Engineering students with a truly state-of-the-art education.

On a broader scale, this research is projected to advance fundamental knowledge of critical events during the heartbeat and lead to new approaches to control these events and generate new therapeutic solutions to prevent and treat cardiac arrhythmias. It is a national priority to develop new biotechnology approaches and deploy them safely to control biological processes, which as seen in the Covid-19 pandemic, is vital.