INTRODUCTION
As your eyes scan this article, eager to learn about the innovation of biohybrid fish, tiny muscles behind your eyelids contract and extend in response to motor signals from the brain. The movement of the muscles enables reading. Humans engage in similar movements constantly, ranging from minuscule blinks to massive running strides. These actions are made possible by millions of muscle cells within human tissue. In addition to managing motor functions, muscle cells regulate the pace at which an organism’s heart beats. For individuals with irregular heartbeat, a condition known as arrhythmia, ion channel gene mutations in muscle cells may have potentially fatal consequences. To find therapies for these dangerous genetic mutations, Harvard University and Emory University are utilizing stem-cell-derived cardiac muscle cells to build the world’s first biohybrid fish.
Arrhythmia: Causes, Casualties, Cure?
Invention is paramount when treating diseases like arrhythmia, a condition that cannot be cured by cell therapy alone. Arrhythmia is caused by irregular cardiac action potentials–sudden changes in membrane voltage of heart cells in response to a stimulus– from poorly regulated Na+ and K+ ion channels (ScienceFacts 2025). To maintain homeostasis–equilibrium between intracellular and extracellular charges–ion channels or membrane proteins open and close to allow ions, atoms with a net positive or negative charge, to flow in and out of a cell.
Whenever arrhythmias are present in cardiac cells, the ion channels have mutated, leading to a “loss of function” or “gain of function” in the sodium (Na+) and potassium (K+) ion channels (Delisle et al. 2004). Ionic channel mutations can mean one of two things. Firstly, during depolarization—the phase when the membrane potential becomes less negative following an action potential—a mutation in the ion channel reduces potassium ion (K+) currents flowing through the membrane. Arrhythmia mutations result in the ion channels closing more slowly than in the wild type—the non-mutated cardiac cells—, thereby prolonging the duration of the cardiac action potential. Secondly, normal inactivation of the sodium ion channels can fail, increasing (gaining) the Na+ current and the duration of cardiac action potentials. Further, the less effective inactivation of the sodium channels can lead the cells to fire second action potentials before they are fully reset (before their relative refractory period is over), leading to an even more depolarized membrane, imbalancing the electrical membrane potential in these cardiac cells. The extra-depolarized membrane is a problem because it can lead to issues with electrical signaling and messaging between cardiac cells due to an altered ionic flow (of sodium and potassium ions) through the membrane.
Arrhythmia-specific mutations may be lethal. These ion channel mutations disrupt the “repolarization of the cardiac action potential,” which operates under a “delicate balance between inward and outward currents” (Heitmann et al. 2021). Repolarization is the process of resetting heart cells’ electrical state so they can beat (firing an action potential) again. Think of a heartbeat as tossing a ball upwards and repolarization as gravity–you cannot toss the ball up again until gravity pulls it back into your hand. Without the ability to rapidly reset, the mutated heart cells get stuck in a non-excitable state, creating the potential for fatal health catastrophes. Therefore, with an irregular heart rhythm, when the coordinated contraction of the heart muscle is interrupted, it reduces the heart’s efficiency in pumping blood. Without proper regulation, arrhythmias can increase the risk of blood clot formation because blood begins pooling in the heart’s chambers. As clots form, they may “block blood flow to the brain,” potentially leading to a “stroke or permanent brain damage” (Cleveland Clinic 3). Conversely, this irregular beat may produce a malfunctioning atrium that prevents blood from pumping into the ventricles, increasing the potential for brain damage similar to what is seen in blood clot formation. While arrhythmia-causing mutations are disadvantageous, current technologies, like pacemakers, exist to help manage the condition.
Biohybrid Organisms: The Intersection of Biology and Technology
To monitor a consistent heartbeat and ensure normal blood flow, it is necessary to implant a device into the patient’s body. However, there are many issues with modern-day cardiac biotechnology. For starters, current pacemakers and cardiac-assist devices employed in arrhythmia patients can adversely affect the body when erroneously implanted, resulting in infection, swelling, and collapsed lungs. The hazards present in cardiac assist devices, while rare in nature, have led scientists and healthcare researchers to begin to look for safer, less invasive therapies. Biohybrid organisms propose an enticing pathway to a solution: providing researchers with data to improve biotechnologies while posing far fewer health risks.
Biohybrid organisms are “devices containing biological components” that “provide a way to study physiological control mechanisms in living organisms” (Science, Lee et. al, 2022). In our example of arrhythmia, biohybrid organisms allow scientists to visualize heart muscle contractions and expansions, so researchers can attempt to recreate these movements artificially. Currently, scientists at Harvard University and Emory University are collaborating to do just this: creating biohybrid fish to study anatomical muscle movements.
Stem Cells: The Key to Unlocking Cell Differentiation
To further understand the purpose of biohybrid fish, we must learn the complexities of stem cell function. Stem cells maintain muscle tissue and repair the body after injury. These special cells are characterized by two unique abilities: self-replenishing capabilities and differentiation (Mayo Clinic Staff 2024). Stem cells auto-renew, or self-replicate, to replace deceased and damaged cells. Depending on their location in the body, stem cells can differentiate into an array of specialized cells–a characteristic known as pluripotency. Stem cells can become blood cells, skin cells, and even brain cells, a capability no other cell has.
However, while differentiation provides the gift of cellular specialization, there are significant drawbacks, namely, mistakes during stem cell transformation. The vast majority of fatal diseases can be attributed to errors in cell differentiation–the process by which cells transform from general cells into specialized ones. For example, if a stem cell differentiates into a platelet (a cell involved in blood clotting) instead of a cardiac muscle cell (a cell aiding in heart contractions), the resulting imbalance may restrict blood flow in muscle tissue. The decreased flow triggers symptoms such as fatigue, discomfort, and blood clots. Similar errors in differentiation may cause disease, cell damage, and death.
Irrespective of the potential drawbacks of differentiation errors, stem cells are integral to cultivating cures for mutations that occur at a cellular level. Studying the stem cells in biohybrid fish allows scientists to explore the development of ion-channel mutations and potentially discover preventive methods. Understanding differentiation processes in greater detail is fundamental to developing cures for cellular errors and cell therapies for conditions like arrhythmia.
From Stem Cells to Biohybrid Fish: Innovation at Harvard and Emory
Muscle cells, supported by stem cell maintenance, are essential in creating contractions and expansions within limbs. Without them, humans would be unable to move, circulate blood, or control their organ systems. However, in patients with diseases such as arrhythmia, heart contractions and expansions occur irregularly, so uncomfortable symptoms like chest pain, discomfort, and in severe cases, death are experienced by diagnosed patients.
This is where the work of Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at the Harvard’s School of Engineering and Applied Sciences (SEAS), comes in. By utilizing “human stem-cell derived cardiomyocytes”—the cardiac muscle cells that form the ventricular walls—and “leveraging cardiac mechano-electrical signaling between two layers of muscle,” researchers recreated a feedback loop in which each contraction is triggered by the stretching on the opposite side of the biohybrid organism (Burrows 2,5). The biohybrid fish represents a closed-loop or self-maintaining system. Ion channels within the muscle tissue are activated by muscle contractions on one side of the fish, initiating a stretch on the opposite side. The now stretched side of the biohybrid fish directs the muscle cells to send signals that open protein channels, inducing muscle contractions on the stretched side. The process of alternating open and closed protein channels continues, with subsequent contractions and stretches, creating a self-propagating, beating rhythm.
Parker’s work at SEAS provides a glimpse into the structural mechanisms underlying cardiovascular function and physiology. In particular, the biohybrid fish “suggest[s] an opportunity to revisit long-standing assumptions of how the heart works in biomimetic (synthetic processes which mimic biochemical ones) systems”(Lee et al.).
Future Directions: What does the future of stem cell and biohybrid research look like?
The future of stem cell research poses a myriad of possibilities, ranging from gene editing to implementing stem cell therapies into the healthcare system. Through the pluripotent nature of stem cells and their inherent versatility, these cells show “promise in addressing previously untreatable conditions, such as neurodegenerative diseases, spinal cord injuries, and cardiac disorders”(Stem Cell Regeneration Center 4). Despite the potential drawbacks of differentiation errors, stem cells are heavily researched today. By directly observing stem cell behaviors and operations, scientists visualize the cell differentiation process so they can curate “cell therap[ies]” to “offer the possibility of a renewable source of replacement cells and possibly tissues to treat a myriad of diseases, conditions, and disabilities” (Massachusetts Center for Regenerative Medicine 3). Stem cell research provides the key to unlocking the future of regenerative medicine.
Biohybrid technologies also play an essential role in fostering this technological progress by providing scientists with invaluable data and posing as potential blueprints for tech-based remedies to disease. Kit Parker’s research at Harvard and Emory “could be applied to design ‘biological pacemakers,’ a potential alternative to electronic cardiac pacemakers”(Eastman 3). Implementing biological pacemakers would remove the necessity of “box change” surgeries–procedures where pediatric pacemakers and wires are cut out of a child and replaced with adult-sized wires and pacemaker technology, effectively making diseases like arrhythmia less surgically taxing. Overall, biohybrid technologies pave the pathway for less invasive procedures in modern medical practices and provide indispensable information on muscle and organ physiology.
References
Action Potential – Definition, Phases, Examples, and Graph
Biology of Cardiac Arrhythmias | Circulation Research
Arrhythmogenic effects of ultra-long and bistable cardiac action potentials – PMC
Ischemic Stroke (Clot): What It Is, Symptoms & Treatment
Stem cells: What they are and what they do – Mayo Clinic
Frequently Asked Questions About Stem Cells
An autonomously swimming biohybrid fish designed with human cardiac biophysics | Science
Biohybrid fish made from human cardiac cells swims like the heart beats
An autonomously swimming biohybrid fish designed with human cardiac biophysics
Researchers Create ‘Biohybrid’ Fish, Powered by Human Heart Cells
Stem Cell Research: The Future with Regenerative Medicine