Organoid Research Offers Intriguing View of a World with Less Heart Disease

By Chuck Carlson

Dr. Aitor Aguirre, Michigan State University Associate Professor of Biomedical Engineering, can see a future where, well, let him explain his vision.

"I like to say this phrase," he said. "I want to make the technologies necessary to grow human hearts like grapes on a vine, so one day there is a company that has the hearts just hanging there, and they are ready to use, for heart replacement."

It would not be just any new heart we have come to know from a donor, alien to your body and prone to breakdown. No, it would be a heart created and grown from your own stem cells, so there is no immune rejection, and would basically be a copy of your original heart. "And in 10 years, if it fails, they will have another one ready for you," he said of his vision. "That is my final goal."

It is an ambitious goal, Dr. Aguirre admits, and the prospects of a pick-your-heart process are decades away. But the National Institutes of Health-sponsored work being done in MSU labs, by Dr. Aguirre, his research assistant Brett Volmert, and Pharmacology & Toxicology Assistant Professor Dr. Adam Lauver is an intriguing prospect. It is also a unique collaboration between the Pharmacology & Toxicology Department and the Institute for Quantitative Health Science and Engineering (IQ).

And their manuscript, written by those three and other authors, has been recently published by the prestigious journal Nature Communications. Titled, "A Patterned Human Primitive Heart Organoid Model Generated by Pluripotent Stem Cell Self-Organization," it paints a dramatic and possibly game-changing direction in the treatment of heart disease.

Dr. Lauver, whose specialty is safety pharmacology, has been working with Dr. Aguirre and Volmert for the past 18 months, assessing the technology as a model to detect possible electrical disturbances caused by drugs. These changes in the way cardiomyocytes depolarize can lead to lethal arrhythmias. Therefore, evaluation of new drugs for their potential to cause this dangerous side effect is an essential hurdle in the development process.

"I would say we're at the cusp of substantial engineering advances that are going to not only make repair of cardiac tissue possible, but also improve the predictive nature of preclinical arrhythmogenicity studies," he said.

The work has been done by creating mini hearts, called organoids, that are grown in dishes using induced pluripotent stem cells, or cells that are primed to turn into any cell in the body and can be derived from any person alive. Literally, each dish has human tissue, the size of a sesame seed, that grows an individual heart. In that way, researchers can test various drugs to see how the organoid reacts and to judge the effect the drug could have on a patient.

It is part of a growing field known as precision medicine.

"What we can do with that is we can make medicine much more evidence-based and specifically tailored to the patients," Dr. Aguirre said. "This can be useful, for example, for reducing trial and error when prescribing medicines and by improving cardiac safety of drugs in the market. We can also use this technology to study disease mechanisms and develop new therapeutics for your heart. So, it's precision medicine, or personalized medicine, because we can develop therapies specifically tailored to the people who are sick."

From the pharmacology perspective, Dr. Lauver sees this research as an ideal opportunity to take precision medicine to the next step.

"In addition to using this technology as a development tool, we can evaluate the response to specific drugs based on an individual patient's particular genetics, and that's the definition in precision medicine," he said. "That's really amazing, and we're getting closer to that."

For Ph.D. candidate Brett Volmert, this has been a project he's been studying since high school.

"When I was 15 years old, I learned about what stem cells were, and I thought that it was really interesting," he said. "My father and my grandfather's side of the family has a lot of heart disease problems, so I've been wanting to combine cardiology and stem cell research for the past 10-15 years, and so that was the principal reason I came to MSU. I was really interested in Aitor's research in cardiac tissue engineering and stem cell research, so I came to his lab, and he has given me a lot of guidance. It's been a great mentorship."

Through the research on heart organoids, the research team can zero in on all forms of heart disease – from detecting the potential for heart attacks to congenital heart conditions in newborns.

"Our final goal is to one day make human hearts for transplants." Dr. Aguirre said. "But we are not there yet, and on the trip to get there, there are many important milestones. One of those is the modeling of congenital heart defects, which are a very significant and common source of problems in newborns."

He said one out of 100 newborns have congenital heart malformation. However, many factors affecting maternal health – such as diabetes, drugs for treating pregnancy nausea or depression, and many others -- can dramatically increase the risk of malformations to as high as one in 10 newborns. The reasons why congenital heart defects occur are, however, very poorly understood.

The testing of these "mini-heart" organoids could provide answers as to why these heart issues occur, and provide new drugs for pregnant women to treat the underlying issues.

"If we understood what causes them then we could prevent them and we could decrease the risk overall, improving the lives of children and their families," Dr. Aguirre said.