The Keystone Symposium I?m at this week in Santa Fe is billed as being about two related subjects: the molecular mechanisms of cardiac disease and the molecular mechanisms of regeneration. And while the talks on regeneration ? that translates here roughly into stem cell therapy ? are mostly scheduled for today (Wednesday) and tomorrow, the use of stem cells to regenerate the heart is already the loud buzz at poster sessions, and is at least a whisper in talks whose subjects suggest they about pure molecular mechanisms.

Take, for example, Randall Moon, who opened the meeting with a discussion of the role of the Wnt/beta catenin signaling pathway in zebrafish tail fin regeneration. Before you knew it, Moon had jumped very quickly to the suggestion that such a pathway might be a target for improving cardiac regeneration strategies using progenitor cells. He backed that idea with he called ?science fair experiments? showing that in a mouse model, intraperitoneal injection of Wnt-5alpha triples the number of human cells in the bone marrow.

So when Christine Seidman, who studies the genetic triggers of heart failure, made a plea at the beginning of her talk last night, it resonated with me: Before we rush into regeneration strategies for the heart, ?maybe it would be better to figure out how to fix the hearts we?ve got,? she said. I?m not sure how many of the eager stem cell researchers ? or the self-identified ?overeager cardiac surgeon? who asked a question this morning ? understood the distinction she was trying to make. I heard it as a warning that if we don?t understand molecular mechanisms of cardiac disease well enough, adding stem cells, whether they?re adult or embryonic, will only muddle the picture and be unhelpful.

Kenneth Chien, who was lured from UCSD to Harvard last year to direct the Massachusetts General Hospital?s Cardiovascular Research Center, does study stem cells, but his message also threw a bit of cold water on the enthusiasm. He?s working to take the Islet-1 cardiovascular progenitor story, which was the subject of his talk, into the human setting. His results so far with this cell line, including finding them in atrial tissue following neonatal pediatric surgery of congenital heart defects and then renewing them successfully in vitro (see Laugwitz et al Nature 2005 Feb 10;433(7026):647-53), have generated quite a lot of attention. His definitions and approach seemed to ruffle some feathers in the audience, but he seemed to hold his own.

The fact that Chien, someone with solid stem cell credentials, started his own talk with a warning that these are dangerous times for stem cell researchers -- alluding to what he called 'Koreagate' -- brought me back to Seidman?s comments. ?I want to inject a note of caution,? he said. ?The ongoing clinical studies essentially support not the differentiation of stem cells into beating cardiomyocytes, but a paracrine effect.? It may not be the stem cells themselves, but some factors they secrete, or an environment they create, or some such. In other words, if we figure out those molecular mechanisms as Seidman suggested, we might find methods that aren?t necessarily stem cell-based to regenerate the heart.