A surgeon’s response to a researcher’s query triggers hypothesis that could improve outcomes for babies with coarctation of the aorta.

Majesky 220x180One in 100 children are born with a heart problem. Roughly 4.5 million children were born in the U.S. in 2010, which translates into around 45,000 pediatric heart ailments in this country alone. Many of these children require medication, surgery or, in rare cases, a total heart transplant.

While these tools can be effective, they’re also imperfect — they carry risks of complications and can require long recovery times. To address this situation, cutting-edge researcher Dr. Mark Majesky is teaming up with one of Seattle Children’s renowned heart surgeons, Dr. Gordon Cohen, on an innovative project that could render certain heart surgeries obsolete. Their long-term goal is to reprogram an individual’s own cells so they help the heart heal itself from the inside out.

The unlikely story of how their collaboration came together — its spark was an offhand comment in a casual meeting — illustrates how chance plays a role in scientific research, and how Seattle Children’s is designed to encourage an interplay between researchers and clinicians that can spawn breakthrough ideas.

Unraveling a congenital heart defect

The story starts with an intricate piece of biological choreography that has long fascinated Majesky, director of Seattle Children’s Research Institute’s Myocardial Regeneration Initiative. As an embryo’s cardiovascular system develops, it reaches a potential breaking point. Rapidly increasing blood pressure threatens to hemorrhage the embryo’s fragile blood vessels. To contain this pressure, the vessels must acquire a lining of smooth muscle. But that’s a tricky enterprise because this muscle tissue needs to be produced very quickly and distributed across a huge number of blood vessels.

Cohen 220x180Biology has developed an elegant solution: The embryo manufactures the muscle cells in different places and instructs them to migrate to particular vessels. These instructions are so precise that scientists can identify distinct boundaries between cells produced in one location and those made in another. But the question of how these boundaries are formed and maintained has barely been studied, and this was simmering in Majesky’s mind when he sat down for a get-to-know-you meeting with Cohen, clinical co-director of Seattle Children’s Heart Center.

The eureka moment came when the conversation turned to coarctation of the aorta, a birth defect characterized by narrowing of the heart’s main blood vessel. Majesky knew this coarctation usually occurs when tissue from a neighboring vessel, the ductus arteriosis, grows into the aorta. So he asked Cohen, who estimates he corrects aortic coarctation between 15 and 20 times a year, a simple question. When he surgically corrects the coarctation, how does he identify the tissue that needs to be removed? Cohen’s answer — that a visible boundary delineates where the tissue should be cut — triggered a hypothesis about why

It became immediately clear to me that something goes wrong in determining the boundaries of those cells. The stop sign isn't working." ~Dr. Mark Majesky

coarctation occurs and how it could be corrected or prevented.

While Majesky was sitting in Cohen’s office, it dawned on him that the answer may lie in the boundaries between cells manufactured in different locations. In the case of aortic coarctation, the ductus cells may be receiving flawed instructions or may have lost the ability to obey those instructions, causing them to grow into an area where they don’t belong.

“It became immediately clear to me that something goes wrong in determining the boundaries of those cells,” Majesky says. “The stop sign isn’t working.”

A path to new clinical therapies

Majesky and Cohen are spearheading a project to understand why the cells go awry. Their ultimate goal is to reprogram invading cells to obey the right boundary, thus warding off the coarctation.

It’s a complicated endeavor. Majesky thinks the problem stems from chemorepulsive signaling pathway molecules, which instruct migrating cells where not to go. Once his team identifies the molecules that aren’t working, they will try to find the genetic reason for why the signaling breaks down. Then they’ll start the heady work of reprogramming the cells.

This might be easier than it sounds. Recent research has revealed that introducing genes that change cells from one type to another could be a straightforward process. “Theoretically, manipulating these cells is a lot less complicated than we thought just a few years ago,” Majesky says.

The potential payoff is enormous. The research could lead to new reagents allowing Cohen and other surgeons to see the invading cells’ boundaries more precisely. This could boost the success rates of surgeries to correct aortic coarctation and other birth defects.

It could also lead to cellular therapies that instruct tissues to repair themselves, without surgery’s risks and complications. And the therapies developed for aortic coarctation, which is relatively easy to study, might translate into treatments for Williams syndrome and other congenital heart problems that are more complex.

The project highlights how Seattle Children’s cultivates an environment where researchers and clinicians can work together to solve some of medicine’s most complex problems. As conversations like the one between Majesky and Cohen take place across the organization, Majesky believes in their potential for triggering other important breakthroughs.

“Throughout science there are problems ready to be addressed, solutions waiting to happen,” Majesky says. “And these collaborations can be what pushes them across the threshold.”