Prof. A.F.M. Moorman PhD

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Biosketch Antoon FM Moorman

Perhaps not surprisingly to those familiar with the work of Prof Dr Antoon Moorman, and his contributions to cardiovascular research, his career started as it has continued, using innova-tive molecular techniques to answer scientific questions. Only by constantly embracing new ideas and techniques, and integrating molecular, physiological and morphological ap-proaches in a unique fashion, rather than simply rejecting at first hand that which may seem personally challenging or difficult to reconcile, is it possible to spend a lifetime building, chal-lenging, and finally presenting your findings and hypotheses, embraced and acknowledged by the international scientific community. Witness his chapter on cardiac development in the standard textbook of clinical anatomy, the 40th edition of Gray's Anatomy, launched in 2008.
Beginning his research in the Laboratory of Biochemistry of the University of Amsterdam (1973) headed by Prof Piet Borst, and following a postdoctoral stage in Zürich (1977), he continued his career in the department he now heads, namely Anatomy, Embryology & Physiology, now part of the Academic Medical Center in Amsterdam. Although, having been trained as a molecular biochemist and biologist, he was initially somewhat ignorant of the cardiovascular system, he soon found himself in a medical teaching environment. Occupying by then the position of associate professor (1981), he was able to direct his skills developed during his postdoctoral period to serve as his future focus, specifically the definition of cardiac developmental anatomy using molecular techniques.
Dr Moorman developed a series of monoclonal antibodies directed against cardiac myosins, subsequently used in immunohistochemical studies, so as to clarify the intricate 3-dimensional early development of the cardiac chambers and conduction system. By following the expression of such working myocardial proteins, he was able to chart the formation of the cardiac conduction system, this now being one of his chief focuses. Precise knowledge of the anatomical disposition of these conducting tissues is essential for the interpretation of electrocardiophysiological findings. Realizing that the immunohistochemical techniques permitted delineations of these discrete structures, such as the sinus and atrioventricular nodes, he developed a new direction for his research, one which remains to this day.
Today, his laboratory and team are renowned for the excellence of their computer-based 3-dimensional reconstructions, but Dr Moorman had already implemented such techniques to study cardiac anatomy in the early 80’s. By combining the power of immunohistochemistry with the latest advances in microscopy, new and critical insights were gained, permitting a key hypothesis to be generated from his studies, namely that, during development, the myocytes destined to become the ventricular and atrial walls did not form continuous rings of differential zones around the embryonic heart tube, but rather differentiate in localized regions along the heart tube. This innovative feature is now widely known as ballooning. Appreciation of this mechanism revealed that areas which were not ballooning to form working myocardium were still expressing many of the primitive myocardial proteins. Subsequent electro-physiological experiments lead to a revolutionary insight into cardiac development, the persistence of slow conduction. The myocardium flanking the developing atrial and ventricular chambers was shown to represent areas of persisting primary myocardium.
A fascinating picture emerged with the realization that tubular hearts do not need valves, with blood being circulated by peristalsis. Only after formation of the chambers are one-way valves required, these devices allowing the blood to pass in only one direction, and with two valves formed for each ventricular chamber, guarding their inlets and outlets. Dr Moorman's research demonstrated that the persisting primary myocardium serves as sphincteric valves prior to the development of competent one-way valves. This beautiful design had a second captivating corollary, in that slow conduction is a prerequisite for nodal function. The nodes were shown to develop in the slow-conducting flanking regions, with remnants of these regions forming the substrate for life-threatening arrhythmias, such as those which preferentially occur in the right ventricular outflow tract, the atrioventricular junctions, the terminal crest, and the coronary sinus.
Refinement and tuning of these observations were made once more by the introduction of in situ hybridization techniques. This permitted the tracing of patterns of expression of genes during development based on their expression of mRNA. Subsequent molecular studies lead to the key observation that T-box transcription factors are crucial for cardiac design, with Tbx2 and 3 repressing the formation of the chambers, and Tbx3 being a unique marker for the developing conduction system. These studies validated the ballooning model of cardiac development as a molecularly, physiologically, and anatomically integrated concept, and were published in 2003 in Physiological Reviews.
His more recent research has focused on the molecular and anatomic delineation of the different atrial components, such as the systemic venous sinus, the pulmonary myocardium, the atrial appendages, and the atrial vestibules, all of which have different molecular compositions and different embryonic origins, these findings also being of great clinical interest in relation to the development of structural and conduction defects.
The models developed by his group to elucidate cardiac development have also served to provide a clearer understanding of congenital cardiac malformations and conduction defects. They have also provided to put new concepts developed by other groups, such as the second heart field, in a more approachable, and thus verifiable, anatomic context. An example of these advances is the use of novel three-dimensional quantitative reconstructions to demonstrate a caudal centre of growth outside the heart that contributes precursor cells to both the venous and the arterial pole of the heart, with inhibition of the centre leading to one or several hypoplastic chambers, as also seen in certain congenital cardiac malformations.
In line with Dr Moorman's drive to further heart research he integrated all basic and clinical groups working on the heart in the Academic Medical Center in Amsterdam into one research center, the Heart Failure Research Center. On a pan-European scale, he brought together a group of leading scientists from across Europe to collaborate and expand the idea that basic research must serve as the guide for yet another new concept; cellular replacement therapy. In 2006, he spearheaded the development of the FP6 integrated consortium called HeartRepair. One of the central themes of this grant is to use the lessons of the embryo to form and specify cardiac muscle cells. A second, more ge-netically oriented, European project called CHeartED has also been coordinated by Antoon, and was awarded in the seventh framework. This project started this year, the aim being for the group based in Amsterdam to create a 3-dimensional morpho-molecular developmental atlas of the mouse, with the genetic data gathered by the consortium placed in the atlas so as to produce genetically annotated cardiac domains.
 

Prof. PhD A.F.M. Moorman (Cardiac Embryology, Congenital Malformation and 3D Reconstruction)

1. Cardiac Morphogenesis

2. "Evo-devo" of cardiac morphogenesis

3. Medical historical research Museum Vrolik

4. Supervision of students: Marjet Oppelaar, Gijs Roelandt, Emma Groot Hugo van Willigen, Oren Turgman, Bryan Verhoef, Jasmine de Jong, Daniël Smidt, Clara Besselink, Moritz Warmbrunn, Froukje de Kanter, Dylan Henssen, Yoobin Kim, Pepijn van der Linden, Jeroen Pouw, Richard Pesch

PhD J.M. Ruijter (Cardiac Morphogenesis / Quantitative PCR)