The role and limits of a gradient based explanation of morphogenesis: a theoretical consideration NIKOLOZ TSIKOLIA* Institut für Biochemie, Medizinische Fakultät, Universität Leipzig, Germany ABSTRACT Development of an organism is a multi-dimensional process leading to the genera- tion of complex species-specific structures. This specificity suggests machine-like organisation. The uneven distribution (gradient) of soluble substances (morphogens) and specific receptor- ligand interactions are known to cause differential gene expression. Therefore gradients of morphogens are used as a causal explanation of developmental processes. However each attempt to describe development causally should take into account both the local fine organisation and global robustness of morphogenesis. The classical view of the role of morphogens will be critically considered and possible alternative proposed. The core idea of my proposal is that the main function of morphogenetic substances could be a context dependent modification of cell behaviour. Both history and different features of morphogenetic fields create the framework for the activity of morphogenes. KEY WORDS: embryonic development, gradient, morphogenesis, epigenetic factor, developmental pathway Causality and explanation: the role of boundary condi- tions The issue of the causal factors in morphogenesis and develop- ment is both fascinating and fuzzy. In order to clarify some important concepts of developmental biology it seems appropri- ate to make some general statements about explanation and causation. In philosophy the metaphysics of causation is subject of never ending discussion. At the same time the natural sciences, especially biology, use this concept in an oversimplified manner. In my opinion the high complexity of biological questions and the enormous knowledge accumulated in the last few decades calls upon natural scientists to be more careful with our explanations. At the same time I believe that philosophical discussions will benefit from the clarification made feasible by increasing interdis- ciplinary discussion. Natural science has come of age and is increasingly able to use complex causal explanation. In order to understand developmental processes we need insight into math- ematics, as Gilbert and Sarkar (2000) have recently argued: the “combination of microarray and computer technology may finally allow us to have a multivariable developmental biology of the kind that Bertalanffy and Weiss would have appreciated”. This how- ever makes it necessary to re-evaluate our theoretical approaches to biology in general and to development in particular. Hence theoretical and philosophical suggestions cannot be ignored. The explanation of any event in nature requires a description of its Int. J. Dev. Biol. 50: 333-340 (2006) doi: 10.1387/ijdb.052053nt *Address correspondence to: Dr. Nikoloz Tsikolia. c/o Dr. Frank Gaunitz, Institut für Biochemie, Medizinische Fakultät, Universität Leipzig, Liebigstrasse 16, 04103 Leipzig, Germany. Fax: +49-341-97-22-109. e-mail: nikoloztsikolia@hotmail.com 0214-6282/2006/$25.00 © UBC Press Printed in Spain www.intjdevbiol.com Abbreviations used in this paper: AP,anterior-posterior; bcd, bicoid; BMP, bone morphogenetic protein; DPP, Drosophila Decapentaplegic protein; FGF, fibroblast growth factor; RA, retinoic acid; Shh, sonic hedgehog; SVZ, subventricular zone; TGF, transforming growth factor; ZPA, zone of polarising activity. context or (boundary) conditions. I define here boundary condi- tions as the necessary conditions of the phenomena under investigation. We can observe physical laws and forces only within certain contexts. This is very trivial: we cannot observe free fall of the stone so long we hold it. Every state could be described as a configuration (pattern) of different physical forces, every change of the state as change in this pattern. Aristotle in his theory about causality already used (boundary) conditions as explana- tory significant factors. He introduces four different forms of an explanation or a cause (αιτια) (see e.g. Barnes, 1982). One of them, causa formalis, is especially important for our purposes; this can be described as the pattern or nature (what is?) of the phenomenon. Other causes are material or substratum, purpose or good and source of the change (Metaphysics B:I, P:3). In posterior analytics (A. Post, B:II, P:2) Aristotle asks “What is a [lunar] eclipse” and gives the answer “The privation of the moon‘s light by interposition of the earth”. Thus the pattern of the circum- stances including moon, earth and light is used as explanation of an eclipse. Since for Aristotle the question “What is.?” is identical with “What is the reason of.?”, the pattern could be considered as