To decode the dynamics of human hearts, researchers at Harvard University and Emory University set up a clever experiment: They created around 500 biohybrid fish, which are artificial other than their tail fins lined with living human heart cells.
Then, the critters came "alive."
"We basically stored them in our incubator, and then we totally forgot about them for two or three weeks," said Sung-Jin Park, a former postdoctoral fellow at Harvard's Disease Biophysics Group. He's also the co-first author of a study on the fish published Thursday in the journal Science. "When we opened the incubator, all of the fish were kind of swimming by themselves."
The heart cells contracted, stretched and generally operated the way real hearts do – causing the tails to move autonomously.
"We don't need any external stimulation," Park said. The fish could simply swim around to the beat of a heart, and oddly enough, they performed better than the real zebrafish theyre based on. "They stimulate themselves, they exercise by themselves and they get stronger," Park said.
"I'd like to display a biohybrid fish in an aquarium" to see how it fares, said co-author Keel Yong Lee, a postdoctoral fellow at Harvard's School of Engineering and Applied Sciences.
To create their fish, the team first derived human heart cells, or cardiomyocytes, from stem cells – which scientists can coax into becoming whatever type of cell they choose. The heart cells were layered on either side of each fish's tail and then the biohybrids were left to their own devices, swimming freely in a pool of nutrients for about 100 days. During that time, the researchers collected information on their movements and they were also able to use light to control the motion of the fish.
Then, they sacrificed the unique aquatic animals and began analyzing data, such as the rhythm and frequency of each contraction. Those parameters, in particular, could help us learn how the hearts of patients with cardiac arrhythmia, or irregular heartbeats, precisely function.
Blasting an aquatic heart to outer space
Park explains that his motivation for developing the biohybrid fish is to go beyond how the human heart is typically studied. Usually, researchers, including Park, generate highly complex 3D structures of the organ to illustrate its architecture.
"I'm more thinking about functional structure," he said. "I'm kind of thinking how to functionally connect each of the individual cells." In fact, this fish is one among a few of his projects dealing with biohybrid cardiac animals, so to speak. In 2012, Park and his team produced a jellyfish-like being and in 2016, a stingray. Both of those, however, were made of rat heart cells, not human.
And way in the future, Park said he wants to send "this kind of biohybrid robotic system to space," calling it the perfect way to study microgravity-induced muscle atrophy, or the breakdown of muscle tissue due to space's lack of gravity.
after long trips to the void, and Park said "maybe we can use that knowledge to understand how aging impacts muscle atrophy, too."
"Many people think that this is going to be Frankenstein," Park said. "I don't know – this cannot be Frankenstein. Right now, it's really focused on cardio applications."
Pacemakers of the future
As a shorter-term goal, Park said the new study's results could pave the way for artificial heart development and help advance the technology behind pacemakers, which are small devices that typically use electrical signals to regulate ailing hearts.
For instance, tissue from the fish could be cultured to generate biological pacemakers that evolve with the human body, especially for children in need of such a device. "Electrical pacemakers cannot grow when a pediatric patient is growing up," Park said. A biological one could.
But there's a limiting step. As it stands, the biohybrid fish tissue "beats" spontaneously, exuding pretty much zero control over its behavior. "We have to remove the spontaneous activity when we put it into the heart," Park said. Otherwise, the heart muscle it's integrated with would run absolutely off the charts.
"Our ultimate goal is to build a [fully functioning] heart, but meanwhile, we're trying to build a more mature cardiac tissue," Park said.
Viewing their squirmy little fish as a stepping stone, the team intends to make an even more complex biohybrid organism next, continuing in the direction of evermore lifelike artificial hearts.