Last author

Despite numerous medical advances, heart disease remains a dominant cause of death worldwide. Many fish and amphibians can regenerate and repair damaged heart tissue; humans, unfortunately, cannot. However, work by Benoit Bruneau at the Gladstone Institute of Cardiovascular Disease in San Francisco, California, and his colleagues has thrown light on the little-understood topic of mammalian and reptilian heart evolution. Two findings, which centre on how the protein Tbx5 regulates the growth of a subset of heart cells, may lead to new treatments for human heart disease. The first revelation was that this protein, along with two others, could be manipulated to induce embryonic mouse cells to develop into cardiac cells (J. K. Takeuchi and B. G. Bruneau Nature 459, 708–711; 2009). Now, Bruneau and his team show that, in two reptiles, Tbx5 is a key determinant in the heart's division into two chambers — and that, in mice, the protein's absence has a drastic effect on heart structure (see page 95).

You began by studying mouse heart-cell growth, then moved on to reptilian hearts. Why the interest in different organisms?

By comparing different organisms, we can often gain insight into similar processes. To try to understand the function of Tbx5 in heart disease, we deleted the Tbx5 gene from specific chambers of the heart, essentially turning the mouse heart into what looked like a frog heart. We then studied reptilian hearts to look into the patterned expression of Tbx5 and gain a broader perspective on the gene's role. We didn't know how important Tbx5 might be in cardiac chamber formation, or in its evolution.

What was the hardest part of the work?

Locating literature on reptilian heart development. The newest paper I could find that described the embryology was a German monograph from 1903. Some of its predictions were right on the money, but there were dissenting responses from others also studying the reptile heart. Reptiles have a broad spectrum of morphology, and no one could make head nor tail of their hearts. People offered differing interpretations of the same morphology in their own papers.

Is your work important to human health?

Now that we understand how important Tbx5 is to ventricular separation, we can focus on how it helps the heart develop a septum. Human Tbx5 mutations cause septation defects, which are very common in children with congenital heart disease. Understanding the role of Tbx5 in building and separating the heart into ventricles will probably be broadly applicable to understanding and treating heart diseases caused by genetic defects.