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Beating Heart Disease Through Research

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Kate Lipovsky ’13 identifies the difference between iPS cells and heart cells while playing a video of the beating tissue. With this approach, called the monolayer or sandwich method, the cells are all spread out across the slide. 

When Kate Lipovsky ’13 arrived in the Olin Hall science lab on May 22, she thought she would be conducting another routine procedure. All that changed when she looked into the microscope: “I saw something move and thought, ‘Wait a second! What? Did I hit the table?’” Then, she saw the movement again and immediately picked up the phone and called Dr. Craig Cady, associate professor of biology.

What Lipovsky saw was the synchronized beating of heart cells she helped create from stem cells in a Bradley lab. However, they were not your typical stem cells; they were skin cells that underwent a process that turned them into induced pluripotent stem (iPS) cells, which function like but are not embryonic stem cells. Yet, they too are capable of becoming any cell in the body.

Bringing iPS Cells to Bradley

Originally developed in Japan in 2006, iPS cells allow researchers to avoid the complicated and controversial ethical issues involved with using traditional embryonic stem cells since the iPS cells come from adults. Plus, they offer an added advantage: because an adult’s own cells can be used to produce iPS cells, an individual could have new cells made for him or herself without the risk of rejection.

The iPS cells in Bradley’s lab came from Dr. James Thomson’s lab at the University of Wisconsin, Madison, where Cady attended training on their use. That experience gave him the right to purchase the cells — one small vial for $2,000. Since then, his team has expanded the collection hundreds of times. “We have to grow them out, so we have enough to do all our experiments,” Lipovsky elaborated. “You can purchase a vial that has maybe 500,000 cells in it, but you need millions just to do one experiment.”

The iPS cells are transferred from one culture dish to another under a sterile hood to avoid bacterial or fungal contamination or growth. The pink-colored substance in the pipet is a highly specialized fluid that allows the iPS cells to grow and increase in numbers.

Cady noted that most people don’t understand the importance and rarity of these cells. “We’re one of a limited number of research laboratories in Illinois — including many at large universities — using iPS cells,” he remarked. However, the cells are unique in another way.

“These cells are very difficult to use because they’re grown without antibiotics,” Cady explained. “The air is polluted with pollen, bacteria, yeast, and mold, but most of our cultures have no antibiotics to protect them.” This trait makes handling the cells quite precarious since everything must be sterile. Even a tiny speck of dust from a lab coat could contaminate and set back their work, which happened when they first started manipulating the cells.

Fortunately, the University came to the rescue. “They were contaminated because the air quality was very bad, so Bradley installed a new ventilation system,” Cady said, adding that the lab has “the cleanest air on campus right now.”

Producing Beating Heart Cells

The team first tried the 3D or embryoid body form, in which the cells collect in a sphere; however, it only resulted in limited beating on the periphery. 

Once the researchers conquered the air-quality issue, they began looking at their processes. “We were trying a different method last year to make the cells beat,” Lipovsky noted. “We didn’t have as much success as we were hoping, so we switched our method.” She described the difference between the two approaches as a 3D form versus a monolayer form. The 3D form cultures the cells in an orb-like cluster called an embryoid body (due to its similar appearance to an embryo), while the monolayer form, also referred to as the “sandwich method,” is grown flat in a dish. Although they achieved minor beating on the periphery of the 3D form, they found true success with the monolayer option. “We see large areas beating in unison,” Lipovsky said. “It’s not just a twitch; it’s very much a beat.”

Lipovsky and Erin Koch ’15, another of Cady’s students, based their monolayer protocol on one published by the University of Wisconsin. In addition to following the recommended concentration of Matrigel, an extracellular matrix used to coat lab surfaces that touch the cells, they also tested a custom concentration. In the end, it was their version that succeeded. “The cells are very dynamic,” Lipovsky detailed. “Even though they had iPS cells and we had iPS cells, they’re still different because they came from different individuals.”

For 17 days, the team considered starting over. The protocol from Wisconsin had indicated that maximum beating would occur at Day 9; they didn’t see it until Day 26. But when they did, it confirmed one important fact — their grown-out iPS cells were functional. “Had this failed,” Cady noted, “we would start questioning whether the cells we expanded in the lab were capable of differentiating. If they weren’t, we would have had to start a fresh line and begin all over.”

Although she wasn’t in the lab when the beating was first spotted, Koch was thrilled to learn of the development and told Lipovsky to send her video right away: “We’d been trying for a very long time with different methods, so to hear Kate say the cells were beating … I almost didn’t believe it!”

Benefitting from Experiential Learning

Hearts for Healthcare

While working with iPS cells in Dr. Craig Cady’s lab, Kate Lipovsky ’13 and Erin Koch ’15 focused on finding a treatment for heart disease, the leading cause of death in the United States. They also conducted preliminary research on Parkinson’s disease. Cady explained the work is not about recognition or status — it’s the people they are trying to help who matter most: “Whether it’s a student or faculty member, we all share the passion to help the people who are counting on us for a solution. It’s not for personal gain. Yes, these are our careers, but it is the passion to help that really drives us to be here every day.”

An unusual aspect of this entire project is the team — two undergraduates. While many universities use student researchers, they’re typically graduate students — a reality that is not lost on Lipovsky and Koch. “Usually big universities save these opportunities for graduate students or postdoctoral fellows, so being an undergraduate working on this type of research is incredible,” remarked Lipovsky, who started graduate school in August at Washington University in St. Louis for a doctoral degree in Developmental, Regenerative and Stem Cell Biology. “If it wasn’t for this research lab and Bradley allowing undergrads to do research, I wouldn’t have known that this is what I want to do.”

Koch, who joined Cady’s team as a freshman, echoed that sentiment: “I am so glad I had this opportunity. I have a lot of friends who went to bigger schools who do not have the opportunities Bradley offers its students.” She also said that “it’s fun because you get to look at studies and experiments that you wouldn’t get to look at, try techniques that you wouldn’t learn, and apply what you’re learning in the classroom. It really gives you an edge.”

Cady often commends his student researchers, and these two are no different. He repeatedly acknowledges their hard work and their dedication to the demanding project. The students must commit a considerable amount of their time to the cells, not just when it’s convenient but whenever the cells need them. They must be fed every day whether it is spring break, final exams or a holiday. 

“I learned that things tend to take longer than I think they will, so I take that into consideration when planning my schedule for school,” Lipovsky said. “If I have an exam during a busy week, I study way ahead because I don’t know what’s going to happen in the lab. The cells may need me, and I may not be able to study the way I needed if I didn’t work ahead.”

Cady expanded on her thought adding, “It is a major effort. With a lot of failure, to keep at it and to keep going in different directions to troubleshoot problems is a very big part of science. They had the confidence to try and the background to develop a successful plan for these cells. There was a lot of work, a lot of insight, and a lot of creativity from these two.”

Dr. Craig Cady, associate professor of biology, mentored Erin Koch ’15 (far left) and Kate Lipovsky ’13 while they created beating heart cells from stem cells in his lab: “In my career, I’ve seen some fabulous things, but this was remarkable — even for us scientists! Frankly, in the laboratory, to see striking results is quite rare. We’re usually looking at data points on a graph; this is on a different level.”

Contributing to the Greater Good

The ultimate goal of the heart cell project is to find a treatment for heart failure. According to Cady, “all cardiologists can do now is keep giving patients drugs to reduce the stress on their hearts. Eventually, they die unless they receive a transplant.” So, he is hoping the work in his lab can help change that outcome. How?

Imagine you have a heart attack. Cady’s team could collect some of your skin cells and insert the four stem cell-associated genes into them to generate iPS cells. Then, the iPS cells would be differentiated, or transformed, into new heart cells — customized to your body — that could be injected into your heart to repair the damage.

In addition to heart disease, Cady also heavily focuses on Parkinson’s disease research. In fact, the team next plans to work on differentiating iPS cells into dopaminergic neurons. Since patients with Parkinson’s have a lack of dopamine in their brains, the creation of dopamine-producing neurons would be the first step toward finding a treatment or possibly a cure — a goal that keeps them all going.

“So many people have visited the lab to see these cells,” Koch said. “Watching their faces light up when they see them … much of it is the hope we can give.”

Lipovsky agreed, noting, “Dr. Cady knows quite a few Parkinson’s patients, and they give money to our lab. Talking to them is inspirational. They are so grateful for the work we do, and that really makes it worth it.”

With committed researchers like Cady and his students in its labs, Bradley is poised to one day play a leading role in a field populated mostly by larger schools, helping contribute real solutions to the major illnesses that affect humankind.   

— Clara Miles, MA ’05
Photography by Duane Zehr