Created from stem cells, Israeli researchers grow tiny, beating model of human heart

The size of a third of a grain of rice, organoid connected to sensors reveals previously unknown aspects of cardiac physiology

Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.

A collaborative team of researchers from several Israeli institutions has created a tiny, beating heart the size of a third of a grain of rice.

According to Prof. Yaakov Nahmias, who led the research, it is the first heart model grown from stem cells with all the key structures, including ventricles, atria, an epicardium (outer shell), endocardium (inner lining), and natural pacemakers. (Previous models have been merely clusters of heart muscle cells.)

“What makes this even more groundbreaking is that because we could make this heart in the lab, we were able to put sensors on it that told us how it works and to get some insight into the physiology of the human heart,” said Nahmias, of the Hebrew University of Jerusalem, Technion-Israel Institute of Technology, and Tissue Dynamics Ltd. 

Human organoids provide researchers with unprecedented opportunities, and the findings could lead to drug breakthroughs that may not otherwise happen. For example, the tiny heart model is critical for studying the human organ’s physiology (the hearts of small animal models such as mice differ too much from those of humans).

“If you want to study the heart, you have a huge problem if you’re using animals. A lot of things like the channels in the mice hearts are very different from humans and a lot of the drugs and a lot of the diseases simply don’t translate,” Nahmias told The Times of Israel.

Nahmias and his collaborators published a study in the peer-reviewed Nature Biomedical Engineering journal on August 7 on their discoveries about the metabolic activity in the thousands of tiny hearts — each measuring half a millimeter — grown in the lab.

Heart model with sensors. (Courtesy of Tissue Dynamics)

The scientists found that the metabolic activity of the heart oscillates, or changes, very fast — in milliseconds. This was completely unexpected, as it has been generally understood that metabolism changes more slowly.

“Metabolism is not supposed to be that fast. We think about metabolism changes when you eat a meal, that they happen in hours, maybe minutes. It shouldn’t change in milliseconds,” Nahmias said.

The researchers also discovered that the super-fast metabolic changes were coupled with the heart’s electrical activity. They observed waves of calcium ions in and out of the cell, and in and out of the mitochondria, essentially changing the ability of the heart to breathe. These waves caused a heart arrhythmia.

“This simply does not happen in mice. In mice, we know that metabolism can change, but it changes with the activity of the heart. It’s a function of how much the heart is working. The more it works, the more it needs glucose, for example. But [with the human heart models], it was the electrical activity and not a mechanical activity,” Nahmias noted.

The researchers then turned their attention to the fact that many chemotherapy drugs cause arrhythmias in humans (but not mice). They studied mitoxantrone (which is used to treat breast cancer, non-Hodgkin’s lymphoma, adult acute myeloid leukemia, and multiple sclerosis) and found that it causes arrhythmias by blocking the physiological pathway that was discovered in the micro-hearts. Mitoxantrone closes the channel that allows the ions to flow in and out of the mitochondria.

“So we discovered the reason that this drug is known to potentially cause cardiac events. Then we came in with another drug called metformin, which is used to treat diabetes, to reverse some of the arrhythmia that we saw. The metformin, because it is a diabetes drug, opens the channel back up and essentially increases the safety of the cancer drug,” Nahmias explained.

Prof. Yaakov Nahmias (Courtesy of Hebrew University)

He said it would take a year and a half to two years to design and carry out a large-scale placebo control and quality trial to demonstrate the clinical efficacy of his research group’s findings.

“But physicians with [relevant oncology patients] looking at this work can prescribe metformin right now based on their own insight into the disease and the treatment,” he said.

Using a special robotic system at his company Tissue Dynamics in Rehovot, Nahmias and his team can produce and handle 20,000 human organoids at a time. Because they are so small, it is possible to run huge numbers of studies in parallel.

Tissue Dynamics has already developed fully functioning human kidney and liver models, and now it also has this heart model — all of which can be connected to sensors.

Microchip used to produce micro human heart models. (Courtesy of Tissue Dynamics)

Beyond looking at arrhythmias, Nahmias said he’d possibly like to use the micro-hearts to explore the realm of cardiac ischemia, or heart attack, and how to limit damage and promote regeneration. Another area to explore is the issue of the organ’s aging and the halting of hypertrophy (hardening of the heart muscle).

“In two years, my lab would like to be producing brain organoids. That is the next frontier,” Nahmias said.

“Brains are very complex, but on the other hand, when you’re looking at diseases like epilepsy, you’re looking at a type of arrhythmogenic event in the brain. It’s an electrical disruption… There are a lot of problems in the brain that we should find a solution for,” he said.

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