The transformation from a few cells into a fully developed organism, complete with working tissues and organs, is a chaotic but highly synchronized process that requires cells to organize themselves in precise ways and begin to work together. This process is particularly dramatic in the heart, where resting cells must start beating in perfect unison.Now, a cross-campus collaboration led by researchers at Harvard Medical School and Harvard University has provided a look at exactly how heart cells start beating.
In a study of zebrafish, the team found that as calcium levels and electrical signals increase, heart cells suddenly start beating simultaneously. Additionally, the researchers discovered that each heart cell has the ability to beat on its own, without the need for a pacemaker, and that the heartbeat can start in different places. The findings were recently published in the journal Nature.
"People have paid so much attention to the beating of the heart that it has been a focus of research for a long time, but this is the first time we've been able to study it in depth at such high resolution," said co-first author Sean Megason, professor of systems biology at Harvard Medical School's Blavatnik Institute.
For curious biologists, understanding the basic mechanisms of the heartbeat may be interesting in its own right, but it is also critical to understanding what happens when the cardiac system that regulates the heartbeat does not develop properly or begins to malfunction.
Co-first author Adam Cohen, professor of chemistry and chemical biology and physics at Harvard University, said: "In a person's lifetime, the heart beats approximately 3 billion times and never rests. We wanted to see how this incredible machine was turned on for the first time."
The researchers weren't trying to study how the heart starts beating. Instead, they were looking for a scientific question that combined the Cohen lab's expertise in imaging electrical activity with the Megason lab's interest in studying how developing zebrafish cells learn to communicate and cooperate.
Their research goes straight to the heart. The researchers realized that despite thousands of years of studying the developing heart, starting with Aristotle's observations of chicks, the details of how heart cells start beating remained a mystery that they could potentially solve.
"We wanted to answer a fundamental question: How do heart cells go from resting to beating?" Megason explains. "The heart starting to beat is a once-in-a-lifetime event, but how it happens is not obvious."
This was an exploratory study, so they didn't know what they would find. They speculated that maybe a few cells started beating and the beating area slowly expanded; maybe different parts of the heart started beating independently and eventually merged; maybe the heart started beating weakly and gradually became stronger over time.
As it turns out, the answer is neither.
Researchers used fluorescent proteins and high-speed microscopy imaging to capture changes in calcium content and electrical activity in heart cells of developing zebrafish embryos. They were surprised to find that all of the heart cells suddenly transitioned from non-beating to beating - characterized by simultaneous spikes in calcium ions and electrical signals - and immediately began beating in sync, as if someone had flipped a switch.
Further experiments showed that with each heartbeat, one area of the heart fires first, triggering an electrical current that quickly flows through other cells, causing them to follow suit.
Interestingly, the heartbeats of different zebrafish start at different points, suggesting that the cells that fire first are not unique. This finding is counterintuitive because cells in the adult heart behave differently.
"In the adult heart, there is a dedicated population of pacemaker cells that drive the heart beat, whereas most cells in the embryonic heart have the ability to beat on their own, making it difficult to predict where the first beat will be," said first author Bill Jia, a joint graduate student in the Cohen and Megson labs.
Because heart cells start beating in an instant, they must develop the ability to beat and sense the beating of neighboring cells before their first heartbeat—Megason likens this to an army that has to start marching in synchrony without practice.
Jia added: "The heart first has to learn how to keep pace without a clock, and individual cells have to first learn to cooperate without agreeing on their roles. A regular heartbeat is very important, but at the beginning of life, heartbeats quickly go from seemingly an organized mess."
Developing zebrafish provide a convenient model for studying the heart because they are transparent, grow rapidly—it only takes 24 hours to produce a heartbeat—and can be imaged by more than a dozen cameras. However, Megason believes that the same developmental processes may be consistent across species, including humans.
The research team noted that this discovery opens the door to further understanding of the development of heartbeats in different species, and may one day reveal how irregular heartbeats such as arrhythmia occur in humans. By watching the heart develop, we can see how different control mechanisms are layered, which may tell us what happens if these mechanisms break down.