Institute Explorations

Radcliffe fellow Christine Mummery has been working with Kevin (Kit) Parker of the Harvard School of Engineering and Applied Sciences to find a way to put new heart cells into damaged hearts.

During a heart attack, heart cells are deprived of oxygen and die. If the patient survives, the dead cells are replaced by scar tissue that cannot contract, and cardiac function decreases. What if there were a way to put new heart cells into a damaged heart? That's the goal for one of this year's Radcliffe fellows, Christine Mummery, a professor at the Hubrecht Institute for Developmental Biology and Stem Cell Research in the Netherlands.

Her goal is not unique. Some biologists have tried to accomplish it by injecting bone marrow or fetal heart cells into mice who have weathered an experimentally induced heart attack, and early results from human clinical trials in which bone marrow was injected into heart attack patients looked promising. In many of these experiments, however, the improvement in cardiac function lasted only a few months.

Mummery had a different idea. She hypothesized that cardiac function could be permanently restored if actual heart cells, not just stem cells, were injected. So Mummery's group developed a technique for prompting embryonic stem cells to produce heart cells, or cardiomyocytes, in vitro, and then injected these new cells into the hearts of mice after artificially induced heart attacks. Much to the researchers' delight, the injected cells did indeed help to restore cardiac function. Everything looked good for three or four weeks, but then, just as in the bone marrow experiments, the improvement began to fade. When asked the reason, Mummery says with a wry grin, “That's exactly why I'm here at Radcliffe.”

The root of the problem is that the injected cardiomyocytes were not lining up and integrating properly in vivo. Looking at them under an electron microscope, researchers saw that the structure of the injected cells was disorganized, rendering them unable to “pull” effectively with the native heart cells. A healthy, mature cardiomyocyte should have a cylindrical shape with a length-to-diameter ratio of seven to one. “Our cardiomyocytes in culture looked like triangles,” says Mummery. “At that point I knew that we, as a research group, just did not know enough about the basics of cardiomyocyte structure to figure out what was going on.”

When Kevin (Kit) Parker, an assistant professor of biomedical engineering in the Harvard School of Engineering and Applied Sciences, heard Mummery speak at a conference, he invited her to address last year's Radcliffe science symposium, “Frontiers of Tissue Engineering.” During the symposium, Parker and then Dean of Science Barbara J. Grosz encouraged Mummery to consider applying for a Radcliffe fellowship. “It was a perfect idea,” says Mummery. “I needed to understand more about how the structure of the cardiomyocyte correlates with its functional abilities, and Kit Parker is one of the few researchers in the world who focus directly on that question.”

Now at Radcliffe for the fall semester, Mummery has been working closely with Parker's group to learn the techniques required to study cardiomyocyte structure and function. Parker's team is able to coax cardiomyocytes into a variety of different shapes in vitro—the ideal cylinder or the disordered triangle, for example—and then measure the ability of each shape to contract. “You can look at it at all sorts of levels,” says Mummery. “You can look at differences in the ability to pull, as Kit does, or you can look at differences in electrical properties, or you can look at changes in gene expression and protein expression.”

After just two months of work, it has become clear to Mummery that the answer to her research question about how to add heart cells to a damaged heart is not going to involve injecting cells. Instead, she envisions building tissues in vitro that can be grafted onto a heart. Beginning with stem cells, such tissues will be engineered to contain only properly organized cardiomyocytes that have a mature structure.

“What I think is so great about Radcliffe is that you can come here with a problem and people will think about it with you,” says Mummery.

True to those words, Mummery has been using her time at Radcliffe to collaborate with several other members of Harvard's cardiac research community as well. She has been working with Ken Chien, the Charles Addison and Elizabeth Ann Sanders Professor of Medicine and a professor of cell biology at Harvard Medical School and the Harvard Stem Cell Institute, in his efforts to prompt human embryonic stem cells to differentiate into cardiac progenitor cells. She has also teamed with David Mooney, the Gordon McKay Professor of Bioengineering in the Harvard School of Engineering and Applied Sciences, to look at whether umbilical cord blood cells that have been tissue engineered to form new blood vessels can restore the cardiac function of mice after a heart attack.

Parker cites Mummery's time at Radcliffe as an example of how the benefits of the fellowship program work both ways. “Christine is reinforcing the connectivity in the cardiac research community here,” he says. “We will reap the benefits of being much tighter collaborators even after she goes.”

Photo by Paul Foley

Image courtesy of Dr. Mark Bray, Disease Biophysics Group

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