The hunting of the organizer: an episode in biochemical embryology

Abstract

In the first few decades of this century, it was the newly fledged field of biochemistry that seemed to offer the best hopes of understanding biological phenomena at a fundamental level, beyond mere descriptionk The work of Frederick Hopkins on essential food factors, of Harden and Young, Embden, Meyerhof and Warburg on intermediary metabolism, and the recognition by Sumner that enzymes were proteins, illustrates the vigour and excitement of biochemical research of this period. One field in which it was confidently expected that biochemistry would reveal basic mechanisms was embryology. Needham in the Epilegomena of his massive work Chemical Embryology published in 1931 wrote: 'The future of embryology lies in the closest contact between biochemistry and Entwicklungsmechanik [equivalent to experimental embryology], and the biologist who will deserve most the gratitude of posterity will be he who finds the way to fuse these studies into one '2. Attempts to achieve this fusion have continued to the present day, and are currently to be found in the application of the techniques of molecular biology to embryological phenomena, exemplifted by the analysis of the function and distribution of homeoboxes 3. However, this is by no means the first occasion when it seemed that a biochemical approach was about to reveal the mysteries and marvels of embryological development. The case I want to discuss was not concerned with such a lowly organism as the fruit fly, but was nothing less than the discovery of an organizer responsible for laying down the main axis and associated structures of the vertebrate embryo. To appreciate why this was such an important finding and why it was tackled so enthusiastically by biochemists, it is necessary to go back to origins of embryology as an experimental science. There are detailed discussions of points raised here in various essays in Ref. 4. embryology and evolution. Called the 'germ-plasm theory', it postulated that the cell nucleus contained a 'determinant' responsible for the special characteristics of that cell type. The germ plasm contained determinants representative of all cell types, and during embryogenesis the determinants become segregated so that eventually each cell contained only a single determinant. A consequence of this is that the two cells resulting from the first cleavage of the fertilized egg differ in the determinants they contain, and so should develop differently. In one of the classic experiments of embryology, Wilhelm Roux 5 killed one of the cells (blastomeres) at the two-cell stage of frog development and found that a half-embryo resulted, as expected on Weismann's theory. Roux became the chief propagandist for an experimental approach in embryology, and must be regarded as the founder of twentieth century experimental embryology. (No matter that his result was shown later to be a technical artefact; by then his espousal of experimental analysis in embryology was fully vindicated.) One of the early converts was Hans Driesch, who followed Roux's example by separating the cells of the sea-urchin embryo by shaking them 6. To his amazement he obtained two small but normal larvae and not two half larvae; the ceils at the two-cell stage could regulate their development to give two wholes. Driesch could not conceive of a mechanistic explanation of this phenomenon, and introduced an external, vitalistic entity, the notorious 'entelechy', responsible for creating order in morphogenesis. (Driesch eventually became Professor of Philosophy at the University of Heidelberg.)