By Christoph Meier

The human heart is a very special organ, not just symbolically but because of its biological structure. A fine example of its uniqueness is its cardiac muscle cells. In contrast to skeletal muscle cells, which contain multiple nuclei, those of the heart have only a single nucleus, by the means of which they form an end-to-end connection and can thus build a network capable of contracting. The contraction of cardiac muscle cells is not voluntary. The basis of this automatic contraction is provided by big, complex protein structures, called myofibrils. Another special characteristic of cardiac muscle cells is that, if they differentiate, they can no longer renew themselves by cell division. The consequence is that damage to heart muscles in most cases is irreversible and has fatal consequences.

New insights into the biology of cardiac muscle cells was the subject of the 4th conference entitled "Cardiomyocyte Cell Biology: Stem Cells, Differentiation, Cellular Functions" that took place this year on the Monte Verità in Ascona. Around 90 scientists attended the conference from 13th–17th April. The organisers, including the ETH professors, Jean-Claude Perriard and Hans Eppenberger, were careful to assure the participation of young researchers. Participation fees for 19 young researchers were covered by the "Swiss Cardiovascular Research & Teaching Network" and 5 were supported by the organisation committee.

Participants listening with great attention to the talks given by researchers in the well-equipped lecture room (picture: Stephan Lange). large

Fly's heart and other delicacies ...

One main theme of the conference, where talks and lectures followed in rapid succession, was the development of the heart. In this context, Rolf Bodmer from Ann Arbor (Michigan), for example, showed that mutations in the Drosophila, in the gene "chico", of which a homologous gene is known to exist in vertebrates, leads to a lengthening of life with better heart performance.

Small differences, however, are crucial when cardiac function is impaired. For Jean Claude Perriard this is very neatly illustrated by the work of Rui-Ping Xiao from NIH in Bethesda. This researcher discovered that as far as cardiac muscle cells are concerned two similar receptors, beta-1 and beta-2, can cause contrasting reactions when stimulated. Activating beta-2, for example, can protect cardiac muscle cells, while a stimulus of beta-1 leads to a programmed death of the cells.. Other talks also made clear that a combination of diverse factors can also often lead to pathological phenotypes.

Stem cells for the heart

With regard to heart disease Perriard reminds listeners that heart and circulatory diseases are still the major cause of death in nearly all industrialised countries and that, unfortunately, they will remain so in the near future. Even though vascular medicine has progressed, a basis still needs to be found for effective therapy for cardiac muscle cells. This also applies to corresponding trials with stem cells.

Opinions at the conference were divided on the potential of these widely discussed cells. According to Perriard, Izhak Kehat from Haifa is optimistic that stem cells will be used for therapeutic purposes in a few years time. The Israeli bases his optimism on his own work, where he has managed to develop therapy for miniature pigs with heart attacks using human embryonic stem cells. Bernd Fleischmann, newly in Bonn, is more sceptical on the possibilities of stem cell therapy because of the danger of tumours. His work leads to the conclusion that stem cells should only be transplanted after they have differentiated into cardiac muscle cells.

The unique atmosphere of the ETH seminar centre Stefano Franscini on the Monte Verità (picture: Alain Hirschy). large

More on the subject of cardiac muscle cell mutation was presented by Marisa Jaconi from Geneva. Jaconi, the first researcher in Switzerland to be granted permission to work with human embryonal stem cells, showed that the addition of reactive oxygen species in low concentrations to embryonal stem cells actually encourages the development of cardiac muscle cells in mice. Independently of the therapeutic possibilities that such trials might initiate, they could also be important in another area. They might provide a basis for the establishment of stable cell lines that differentiate into cardiac cells. The lack of such cell lines is still a major obstacle for cell biology in this area.

Thomas Eschenhagen from Hamburg demonstrated that new forms of therapy need not necessarily focus on stem cells. Eschenhagen activates primary cardiac muscle cell cultures that had been embedded in a collagen matrix by rhythmical stretching. The artificial tissue thus obtained has the ability to contract automatically and after transplantation lead to better health of rats with heart disease.

In the nucleus of the cardiac muscle cells

The issues surrounding therapy was not, however, the only subject of the conference. Many lectures addressed the composition and function of cardiac muscle cells. The big protein complexes that underly the contractions are a relatively open field of research. It is not yet clear, for example, how the sarcomere, the smallest functional unit of cardiac and skeletal muscle cells, is built up in detail and maintained. With regard to this, Robert Decker from Chicago explained how the de-phosphorylation of the protein MyBP-C can be associated with the malfunctioning of contraction. The pathologically enlarged heart is characterised by a reconstruction of the end-to-end connection of cardiac muscle cells in mice, according to Elisabeth Ehler, who works in Perriard's group. Alain Hirschy from the same group showed that beta-Catenin also seems to play a special role in mechanical stress assimilation.

Endangered cardiobiology

As to what will be the hot issues at the next conference, Perriard believes that several new results will be presented on big proteins and stem cells. The ETH researcher also foresees a greater understanding of how hormones, or similar factors, influence cardiac muscle cells. All in all, Perriard is convinced that the conference will continue to be an important link between fundamental research and clinics. The number of contributions that will come from ETH Zurich, however, is uncertain. Because at the moment the continuation of the field of cardiobiology at this university is far from certain.

With the addition of specific antibodies micro X-ray fluorescence is used to examine the molecular order of cardiac muscle cells. The wild type cell (above) was stained with antibodies against beta-Catenin (light blue) and a colorant that registers actin (red). Below a cell without beta-Catenin, but with actin: it shows a slightly modified structure made manifest by the derangement of the myofibrils. This defect occurs when a transgenic mouse without beta-Catenin is paired with a mouse that has an additional defect. Many of the young of such a a union develop heart disease (picture: Alain Hirschy). large