Keywords
Biogenetic lawCongenital heart abnormalitiesGenetic screensHeart fieldHistomeresFunctional systemsFunctional threefoldnessNerve-sense systemRhythmic systemMetabolic systemThreefold cardiovascular systemThe idea that the development of a single organism indicates the evolutionary changes passed on through the forebears was first proposed by K. E. von Baer and J. Müller based on their studies of invertebrates. Müller’s student, Ernst Haeckel, an avid proponent of Darwin’s evolutionary theory, developed the hypothesis further and called it the “biogenetic law.” In its simplified version, the law states that during the embryonic development, the organism recapitulates the overall evolution of its ancestors. Although the details and the applicability of the law have been subject to considerable debate among the specialists, it is nevertheless true that early developmental stages, e.g., morula and gastrula, are similar in all animals [1, 2]. What is of interest in the present context is that individual animal phyla represent an explicit, as if “frozen in time” developmental stage of a particular organ system. For example, the hypoplastic left heart syndrome, the fourth most common congenital heart abnormality in humans, can be considered a developmental delay at the level of the three chambered amphibian heart. A much rarer condition of double right ventricular outlet morphologically resembles a reptile heart. Several other cardiac developmental abnormalities exist for which a corresponding animal model can be found. Large-scale genetic screens have been documented which catalog cardiovascular abnormalities in zebrafish [3]. Besides, zebrafish mutants have been identified with cardiac abnormalities, which resemble those in humans, such as obstructive and dilated cardiomyopathies [4].
The question arises whether a deeper link exists between the patterns of heart development between higher and lower vertebrates and possibly humans? Genetic analysis of cell fate maps is one approach where enormous efforts have been made in the past few decades to unravel some of these complicated relationships. For example, a close connection is known to exist between the cardiac progenitor cells and vascular markers in fruit flies (Drosophila) and mammals (mice) [5, 6]. Likewise, Drosophila [7] and frog (Xenophus) [8] embryos deficient for tinman gene fail to develop the heart primordium. A similar group of transcription factors controls the early heart and skeletal muscle development in mice [9], suggesting that the regulatory mechanisms of heart expression may be conserved even between distant species. However, inhibition of similar transcription factors in mice does not inhibit the development of heart progenitor cells but results in severe malformation, such as failure of looping and of development of the right ventricle, suggesting that organ formation is subject not only to single genetic developmental cues but also to their products, i.e., neighboring tissues [10]. It is apparent that there is a hierarchy of genes and their regulators which trigger the development of the entire or parts of the organ systems. Finally, the growth and the function of the heart need to be integrated into the rest of the organism. The current theory draws on the concept of “heart field” which originated in the 1930s [11] and has recently been reviewed in light of current knowledge [12]. According to the theory, three tissues in the cardiogenic plate of the early vertebrate embryo contribute to spatial orientation and patterning of the heart. The first is the so-called organizer, which originates from the dorsal lip of the blastopore just before the onset of gastrulation.1 This is the heart-forming mesoderm, without which no heart would develop (cf. Chap. 1). It is also responsible for its axial symmetry. The presence of endoderm is needed for proper myofibrillogenesis and contractile function of the developing myocardium. The ectoderm, on the other hand, appears to exhibit an inhibitory effect on the heart development, possibly controlling its size [12].
A complementary method to genetic analysis between distantly related species was explored by Heidenhain (referenced in [15]) who, in an effort to characterize growth and regeneration of tissues, adopted a functional approach. In his theory of “synthetic morphology,” he proposed that the organism consists of a hierarchic order of interdependent organ parts which goes beyond the atomistic theory of cells and genes. According to Heidenhain, the organism consists of interpenetrating units or “histomeres” which are functional, rather than anatomical entities. The histomeres dominate over the single cells and arrange them into organ systems. More recently, Rohen developed the concept further by combining these units into functional systems that are shared equally between simple and complex organisms [15]. For example, in a unicellular organism such as the ameba, the basic functions of digestion, respiration, movement, reproduction, and rudimentary sensation are all contained into a seemingly simple mass of protoplasm, containing several nuclei. While in multicellular organisms some of these functions are integrated into organs which increase in number as we move up the evolutionary tree, the individual cells continue to possess some or most of the basic functions. According to Rohen, all the possible functions that can develop in an organism are encompassed by three elementary functions: (1) exchange of substance or metabolism, (2) respiration and transport distribution, and (3) exchange of information.2
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