Helping the Heart to Repair Itself

In the spring of 2017, the School of Medicine selected seven promising physician-scientists to receive the first round of the Physician-Scientist Strong Start awards, funded by the Duke Endowment. The award includes $70,000 annually for three years, as well as mentorship from senior faculty and fellowship with the other awardees. Ravi Karra, MD, assistant professor of medicine (Cardiology), is one of the seven who received the inaugural Strong Start award.

As a cardiologist, Ravi Karra sees firsthand the suffering heart failure causes. Many of his patients eventually need heart transplants, which save lives but bring a new set of problems, including fistfuls of daily pills to prevent rejection. “Wouldn’t it be great if instead of needing a new heart, you could repair the one you already have?” asks Karra.

As a physician-scientist, he is investigating ways to make that a reality. “When you’re a kid, your heart has this ability to grow along with you,” he says. “Unfortunately, following an injury to an adult heart, the heart doesn’t seem to be able to grow back or replenish the lost muscle. The goal of my lab is to reawaken those dormant mechanisms and see if we can stimulate growth.”

Karra first began thinking about heart self-repair in humans while working with zebrafish as a postdoc in the lab of his advisor Kenneth Poss, PhD, James B. Duke Professor of Cell Biology and professor of medicine (Cardiology) and biology. Zebrafish have the ability to regenerate injured tissue as adults, including tissues in the heart and spinal cord.

In launching his own research program, Karra wanted to use lessons learned from zebrafish to try to find factors - molecules or pathways - that can prompt heart repair in adult mammals.

That’s a big transition. Heart repair relies on several different types of cells to create new tissue and vascularize it. That means finding several different factors to spur the growth of those particular cells, while making sure not to encourage the growth of other cells that could lead to scar tissue. And in switching from fish to mammals, Karra needed to get up to speed on techniques like growing cardiac cell cultures and carrying out heart experiments with neonatal mice.

It’s the sort of transition that could be overwhelming or even insurmountable for a physician-scientist just getting started. Funding from the National Institutes of Health for physicians doing basic science research has been shrinking in the past couple of decades, especially for young researchers who haven’t had the time and opportunity to build a track record.

Enter Strong Start.

The Physician-Scientist Strong Start Awards Program was the brainchild of former School of Medicine Dean Nancy Andrews, MD, PhD, who wanted to support young physician-scientists who were transitioning to independence. She saw too many talented young researchers becoming discouraged.

Often people managed to scrape together various bits of funding with the help of their mentors, but in the words of Andrew Alspaugh, MD, professor of medicine (Infectious Diseases), who administers Strong Start: “These are really talented investigators. They shouldn’t have to beg and scramble to get resources.”

Karra says of Strong Start, “It’s given us a cushion to try to make these aggressive leaps. It’s allowed us to differentiate my program from others at Duke, so we don’t just have to ask the questions we’ve trained on.”

With funding from Strong Start, Karra and his lab members are looking for factors for multiple cell types at once: cardiac myocytes (to make the heart muscle), endothelium (to vascularize it), and epicardium and fibroblasts (to make connective tissue).

For these experiments, Karra is using a technique refined by Nenad Bursac, PhD, professor of biomedical engineering, for using pluripotent stem cells to create large numbers of cardiac cells. The two scientists use the cells for different ends - Bursac creates tissue “patches” for damaged hearts, and Karra uses them as a tool to understand the biology - but the technique for generating them is the same.

“As my lab has become independent, we have this chance to build collaborations,” Karra says. “Nenad is an expert on developing cell types, and he’s a wonderful collaborator.”

As the scientist in Karra is trying to discover the right combination of factors, the physician in him is wondering how to deliver the factors safely to the heart, and how to detect whether they’ve had an effect. After all, his end goal is not simply to discover the factors in the lab, but to repair the hearts of patients in the clinic.

“We break it down into the three D’s,” he says. “Discover factors and mechanisms, deliver the factors, and detect regeneration.”

To that end, he’s also collaborating with Ashutosh Chilkoti, PhD, the chair of the Duke Department of Biomedical Engineering, to explore mechanisms to deliver factors in a particular place and for a limited duration. To test methods of both delivery and detection, Karra uses mouse models.

All in all, it’s an ambitious program. “It’s going to be a long process,” Karra says. “We realize we’re in it for the long haul.”

Still, with Strong Start, perhaps the haul will be a little less long. “Without Strong Start, we couldn’t be as ambitious with our goals,” Karra says. “I don’t think we’d be able to do things in parallel; everything would be in series.”

In addition to the funding, Karra values the mentorship from the Strong Start senior faculty, and the regular meetings with the other awardees. “What’s fun about that is you get to see how these other scientists in diverse fields are thinking,” he says. “It’s creating a community of physician-scientists, and hopefully as we all gain independence it will allow us to cross-pollinate and create these labs where we’re really pushing the best biology and the best discovery possible.”

Beyond funding and mentorship, Alspaugh says he hopes the award program imparts joy. “What these people are doing is a lot of fun,” he says, “seeing things no one has ever seen before, making creative discoveries, asking questions, using tools to answer them. Something about the joy of discovery has captured them. That’s what we don’t want them to lose - the joy - as they are working hard to make their own programs.”

As for Karra, it’s apparent his work offers just that: “It’s really amazing to be able to literally walk from clinic, where I had an idea, and go to my lab in the afternoon and say, ‘Huh, I wonder if we should try something differently?’”

Read about Dr. Karra's research project funded through Translating Duke Health.

This story was written by Mary-Russell Roberson.