Regenerating hearts and overcoming failure

Heart disease is the leading cause of death in both the U.S. and world. To lessen this large disease burden, researchers are actively investigating why and how people develop heart disease. Cardiovascular researcher Dr. Jared Churko takes a single-cell approach to studying the mechanisms of heart disease. Dr. Churko is an assistant professor of cellular and molecular medicine, physiological sciences, genetics, and biomedical engineering, as well as BIO5 member and Director of the iPSC Core. 

What got you interested in studying heart disease?

I’ve always been super passionate about science, and for most people, you need to go into graduate school for that. 

I entered into a lab for a master's program where they were studying a cell type called satellite cells which are a specific type of cell that can repair injured muscles. If a weightlifter goes to the gym, and they tear their muscle, these cells allow them to regenerate muscle cells. I always thought it was intriguing that there was a specific cell type involved in skeletal muscle itself.  

Then I did a PhD in skin biology and looked at wound healing. Similarly in the skin, there's also different cell types that can regenerate your skin. If you had any kind of wound that might have formed, within a few days that entire wound would be gone, and you’d be able to go along with your day.

Hair follicles themselves are very interesting - they have a certain stem cell niche, or specific types of cells, that can also regenerate the entire hair follicle. I thought it was also amazing that this other organ that is so essential for daily functioning has a specific stem cell population that can regenerate your skin.

I was really intrigued that the heart is the one organ that doesn't have these types of cells to help regenerate. It's almost amazing that the heart itself is beating at 100,000 beats per day, and if you think about it in an analogy, if a car has a water pump or a fuel pump that's going constantly all hours of the day - when you're sleeping, when you get up, when you're driving to work - there's nothing that can replace this water pump. 

That's very unique in terms of our systems in our body that the heart is something that's constantly doing something and it's so essential for life. This is really what intrigued me to get into how we can look for different stem cell populations to be used for regenerative medicine.

How did you build upon traditional methods of studying heart disease with new tools and technology, and what will these innovations do for translational therapy moving forward?

The heart is one of the most essential organs, so you cannot just take our heart cells from an individual's body to study them in a dish - they don't proliferate (divide). If you try to collect any samples from the heart itself, that leaves a permanent scar, so it's very difficult to be able to study human heart tissue itself.

In approximately 2012, there was a discovery that you could generate a certain stem cell type from any cell type in your body. These cells are called induced pluripotent stem cells, and they can then be coaxed to differentiate, or to form, all the different cell types in the heart. That's what my lab specializes in: using this specific type of stem cells that we can generate from patients themselves.

What's really great about these cells is that they have the same genetic makeup that the patient does, so if there's any mutations that might be causing the heart disease, we can look at those cells specifically, model them, and gene correct that specific mutation and model how the disease might be formed in a dish.

When this discovery first came about, I went to one of the labs at Stanford who was specializing in stem cells. They were generating these induced pluripotent stem (iPS) cells from patient skin cells from fibroblasts that were grown after a biopsy. A lot of my work initially was to develop a protocol to be able to generate these iPS specific stem cells from blood.

The work that I'm doing here expands upon the work that I’ve been doing previously during my postdoctoral studies, where we're still collecting blood from patients that have different types of heart disease. We're converting them into stem cells and then differentiating them into the heart cells called cardiomyocytes and all the different cell types in the heart so we can really look at a single cell subtype that's involved in heart disease.

If there is success in what you’re studying and your research does lead to translational innovation, what does that mean for human health?

After the discovery of these iPS cells, there was a huge push to be able to use them for regenerative medicine purposes, where you generate cardiomyocytes in a dish, and then the thought was we can just add these back to the adult heart that might be injured. Then, these cells that we generated can form and almost patch the damaged heart or be able to be used functionally to increase the cardiac output.

Unfortunately, getting these cells into the heart has been a very big challenge. As I mentioned, the heart is constantly beating, so anything that you put onto or into the heart would essentially be beat out of the system, so they weren't integrating properly.

Now there's different engineering approaches where we combine different cell types, not just one single cell type but multiple different cell types, in the dish and then use them to maybe make better engineered types of tissue that can be used for regenerative medicine purposes.

Not only that, but these cells, given that they're from an individual patient, your body itself won't reject them. If you had a heart transplant where you get a heart from a different person, then you have pick different medications to prevent your own body for recognizing that as foreign, whereas these cells, since they're from you, they don't recognize them as being foreign and therefore they're more amenable to different types of cell-based therapies.

These cells themselves, not only just for regenerative medicine and the patient are great, but for the academic community, they've been a real boon for figuring out the disease mechanisms. We can use them now to look at what that one single mutation might be due to the ability of the cells to properly contract or to respond to different drugs.

We've been using the cells now in our lab to be able to look at modeling and understanding the disease pathways - the molecular mechanisms of these pathways - as well as for drug discovery projects.

You’re also the director of the iPSC Core. How does the collaboration and the work of that core enhance these goals?

Given that the cells do have the potential to differentiate into every single cell type in your body, they've definitely opened up a lot of collaborative projects studying everything from generating neurons in addition to model Alzheimer's or ALS to retinal pigment epithelial cells with Dr. John Paul SanGiovanni, who is also in BIO5. Not only that, but we have collaborations looking at endurance types of populations which are the gut and the liver.

Given the potential that these cells are capable of generating every single cell type in your body to be able to study every single disease, they've been a very useful tool to be able to contribute to any research that might be out there. We have collaborations not only within the University of Arizona, but also at ASU, NAU, and TGen, so really it's a statewide initiative to be able to use the cells for more intense and global cross-disciplinary types of applications.

Along the lines of working with people, talk a bit about the importance of mentorship. What’s your mentoring philosophy?

The KEYS program has provided amazing students for our lab, and they really have been outstanding. That ability to recruit and to have students at such a young age to be working in research has been a great benefit for our lab because they are absolutely brilliant.

In general, we love ideas and different skill sets across the board. It doesn’t necessarily have to be specific to cell culture - we definitely look for individuals that can contribute into bioinformatics and computer science-based approaches. Clinically, MD/PhD students can really drive a lot of our research into being something more translational and impactful.

In terms of mentorship style, this is definitely different for a lot of people. I believe that each student has their own mentorship style that I have to modulate to. Some students really like to be checked in on every day, and some people just say, “Hey, just leave me alone, I’d like to think about and do this.” 

Since this is a training type of atmosphere, I want to see them get to the next level, and I want to be the person that gets them there. I definitely don't want to be the bottleneck in the system, so any ways that I could make sure they develop their skill sets independently is beneficial. I like to give people enough room to fail and to be able to understand that research is difficult - you can’t just come in one day and get it done. It's training, it's a skill set. 

I think a lot of people might not realize how much failure is incorporated into doing scientific research. Can you talk a bit about how you handle failure, whether that's a failed experiment or a grant that got rejected or a manuscript that gets rejected? How do you view failure in terms of the larger goal of advancing science?

If research was easy, we would have cures for a lot of these different diseases. 

A lot of the things that we're doing in the lab are not something that has been done before, so it really takes somebody with the initiative and the drive to be able to understand something that might not be known. 

That's really what I love about research: you're doing something that nobody else in the world has ever done, and there's questions out there that nobody's looked into or inquired about. That’s the real beauty of research - to be able to figure out the laws of nature, how this process works, how we can manipulate that. 

You can't just do it once. It is called RE-search - you have to do it multiple times to get the same answer, so doing something once doesn't work. If you think about any skill set, like if you're trying to be a basketball player, you have to work at it. Everybody is born with a certain level of intellect and a certain skill set, but it really does take repetition and constant hours in the lab.

Multiple people around the world are trying to do very similar things for their disease, so I wouldn't say it's more of a competitive environment, but it's definitely not just a local Tucson thing. We're trying to discover things that impact the global environment.

At least for me, with failure, it sucks sometimes when you don't get that grant, but after a while you know that's how the system works, and you just have to keep trying. There is no other option - you keep submitting grants. Even the big shots out there submit multiple grants, so realizing that everybody's faced with similar sorts of failure and to not let it bother you helps you keep going

It's normal to fail, but just keep going.

We like to think of our scientists as superheroes, so if you were a superhero, what would your superpower be?

If you asked me this when I was growing up, I watched a lot of X-Men and read the comics, so I would have said Wolverine, mainly because he has this ability to regenerate.

Now that I've thought about it a little bit more in my age, I think molecular manipulation might be one of the powers, because not only can you heal yourself with that, but you can also control the environment. You can edit a DNA mutation, you can make structures, you can do everything with that, so the ability to actually manipulate molecules would be an amazing superpower.

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