Scientists at Harvard University have developed a new way to model congenital heart disease. Though researchers have previously generated heart cells derived from patients in a petri dish, this time scientists did so with groundbreaking ‘organ-on-a-chip’ technology—proving that this new type of technology can replicate a genetic disorder in the lab.

The research, which was published Sunday in Nature Medicine, describes how the Harvard team painstakingly grew human heart tissue that mimicked a type of congenital heart disease called Barth syndrome.

Barth syndrome, a type of congenital heart disease normally affecting boys, is caused by a single genetic change, or mutation, in the gene called TAZ. There is currently no way to treat or cure Barth syndrome. So in recent years scientists have looked toward regenerative medicine first to try and replicate the disease in a dish, with the ultimate goal of finding a way to fix it.

Though the team focused on Barth syndrome, these findings offer hope for any number of known genetic mutations that lead to congenital heart disease. It is estimated that 1 out of every 100 babies are born with some form of congenital heart defect—some of which can be fatal. But there is still much to learn, and as Dr. Kevin Kit Parker, one of the study’s lead authors stated in yesterday’s news release:

“You don’t really understand the meaning of a single cell’s genetic mutation until you build a huge chunk of organ and see how it functions—or doesn’t function.”

The researchers started by taking skin cells from patients with Barth syndrome, manipulating the cell samples with the help of induced pluripotent stem cell (iPS cell) technology to transform them into embryonic-like stem cells. This would normally be the time where the researchers would attempt to grow heart muscle cells from these iPS cells in a petri dish. But here is where the Harvard team took a different approach.

Instead of growing these cells in a dish, the team instead grew them in a specially designed chip, lined with human proteins that mimicked the cells’ natural environment: the underlying architectural matrix of the heart. And when comparing cells derived from Barth syndrome patients with those of healthy people, the team noticed a clear difference. As Parker explained:

“In the case of the cells grown out of patients with Barth syndrome, we saw much weaker contractions and irregular tissue assembly. Being able to model the disease from a single cell all the way up to heart tissue, I think that’s a big advance.”

Upon studying the newly generated tissue, the researchers were able to see for the first time an underlying metabolic mechanism that leads to the disease. They found that the TAZ mutation causes cells to produce an excess of something called reactive oxygen species, or ROS, a cellular byproduct equivalent to exhaust from the tailpipe of a car. A certain amount of ROS is normal, but too much can be a bad thing—harming essential cellular processes. But in the second part of the study, Dr. William Pu, the study’s other lead author, describes a potential solution:

“We showed that, at least in the laboratory, if you can quench the excessive ROS production then you can restore contractile function. Now, whether that can be achieved in an animal model or a patient is a different story, but if that could be done, it would suggest a new therapeutic angle.”

As Pu suggests, the team’s immediate next steps are to test their approach in animal models, while at the same time using the current ‘heart disease on-a-chip’ model to screen for small molecules that might help reduce excess ROS. And while it’s still early days, Parker is optimistic that this technology could speed the development of treatments for Barth syndrome and other congenital diseases:

“We tried to thread multiple needles at once and it certainly paid off. I feel that the technology that we’ve got arms industry and university-based researchers with the tools they need to go after this disease.”

How are CIRM-funded scientists using stem cell technology to fight heart disease?

Anne Holden