A Selective History of Induction
I. Early Concepts of Embryonic Induction
A. Developmental Anatomy
There are several paths leading to the concept of induction. These include the observations of classical embryology, the humoralist hypotheses of tissue formation, chemical teratogenesis, and tumor pathology.
The Baltic founders of modern embryology, von Baer, Rathke, and Pander each recognized that interactions between parts must be responsible for creating this diverse complexity of embryonic form. After describing the germ layers and their fates, Christian Pander (1) asserted that:
Actually a unique metamorphosis begins in each of these three layers, and each hurries toward its goal; although each is not yet independent enough to indicate what it truly is; it still needs its sister travellers, and therefore, although already designated for different ends, all three influence each other collectively until each has reached an appropriate level.
Similarly, when Karl Ernst von Baer (2) revised Pander's account of the chick germ layers, he noted:
The eye, seems to be an outgrowth of the nerve tube that protrudes through the muscle layer as far as the skin layer, and the outer parts of the eye are changes in the skin evoked as a result [dadurch hervorgerufene].
(Baer's outer parts of the eye are probably the eyelid and nictitating membrane, not the lens and cornea, so he missed presaging one of the great research programs of experimental embryology; see 3). K. E. von Baer was a unstinting epigeneticist, and his work validated and modernized the accounts of epigenetic interactions. He had no models of how these interactions occurred, and he spoke of the possibility that the events of early chick development "might be related to electromagnetism."
Figure 1 Karl Ernst von Baer
B. The Humoralist Hypothesis of Tissue Formation
In evoking electromagnetism, von Baer was relating development to one of the biggest scientific discoveries of his day. Indeed, one of the major theories of organ formation and regeneration concerned the coagulation of serum globules by galvanic currents. Caspar Friedrich Wolff (4), the chief proponent of epigenesis in the early years of the nineteenth century, hypothesized that tissues form from globules that precipitated from the semi-fluid embryonic mass. J.-L. Prévost and J.-B. Dumas (5) had formed such globular accretions by submitting various biological fluids to electrolysis. This work was confirmed by Henri Milne-Edwards (1826) and Henri Dutrochet (1824), and the formation of tissues by the electrical formation of albumen globules became part of the Naturphilosophie of Oken and others (see 6,7,8). One may speculate that this pre-cell theory electrical hypothesis may be the source of the term "induction", since both the embryological term and Faraday's (9) electromagnetic term refer to the ability of one unit to alter the behavior of another unit over a short distance. However, evidence is so far lacking.
The term "induction", however, is not as important as the German term "Ausl?sung." Ausl?sung was the word that most embryologists of the early 1900s used when they encountered evidence for interactions between embryonic parts. Perhaps the most appropriate translation would be that of "permissive induction" (10, 11) since the term implies a process wherein the stimulus releases the expression of a pre-existing potency. This term was part of the vocabulary of Continental sensory physiology, and it was brought into experimental embryology by one of the founders of developmental physiology, Curt Herbst (see 12, 13).
Figure 2 Curt Herbst
C. Herbst's Auslösung Hypothesis
Shortly after initiating these experiments, Herbst (14) began interpreting his results on sea urchin teratogenesis in terms of Auslösung. Herbst attempted to alter the chemical constitution of sea urchin embryos. He fertilized embryos in media containing lithium salts. In some cases, exogastrulation occured, in other cases the pluteus larvae lacked arms and had only a rudimentary skeleton. These experiments were based on the experimental plant physiology of Julius Sachs and on Pouchet and Chabry's experiments on the effects of calcium salts on sea urchin development. However, while Pouchet and Chabry interpreted their larvae's lack of arms as being due to a lack of physical pressure exerted by the skeleton, Herbst interpreted his data in tems of morphogenetic stimuli and Auslösung (13). In the summary of his work (15), he reports:
I emphasized what escaped Pouchet and Chabry, the character of Auslösung...and I came to the conclusion that the pluteus larvae with skeletons rudimentary or completely lacking had no arms because the intensive growth on part of the ciliary ring concerned did not take place on account of the cessation of the stimulus which the growing skeletal rods would otherwise have exerted upon them. [Herbst's emphases]
According to Herbst, the ability to respond was already present, but it needed to be triggered. He likened this to the opening of a valve that allowed steam to escape and initiate a mechanical movement. While the notion of Auslösung was commonly used in German physiology, Herbst credited the concept to Rudolf Virchow. The Virchow article referenced discusses the formation of tumors, but generalizes to all cellular systems the concepts of formative stimulus and the ability to react to it.
This Auslösung manifested itself not only in diffusible cues from the mesoderm to the ectoderm, but also in tactile cues provided to the mesodermal skeletal cells by the ectoderm. Herbst viewed the primary mesenchyme cells as being directed to their ultimate locations by an unseen force [richtende Kraft]. Herbst's friend and travel companion, Hans Driesch, performed an experiment that became one of the main supports of the Auslösung hypothesis. He shook the mesenchyme cells to displace them on their journey to the lateral midline of the ectoderm. These displaced cells were then seen to move to the position that they would have otherwise found and to form spicules there. Driesch interpreted these results in terms of the response of the migrating cells to the tactile stimuli coming from the ectoderm (16).
Auslösung also included environmental forces that directed morphogenesis. Herbst's 1901 book on formative forces included a section concerning such observations as environmental sex determination, the effects of temperature on butterfly color patterns, and the influence of gravity on frog embryo cleavage. However, it was the internal effects which captured Herbst's imagination. Indeed, he thought it possible "to establish the occurrence of formative stimuli which are exerted from one part of the embryo to another, and to demonstrate eventually the possibility of a complete resolution of the entire ontogenesis into a sequence of such inductions." This prediction of inductive cascades was a bold statement, given that no sequence of events had yet been observed.
D. Hans Driesch: Embryonic Induction and Organismal Individuality
Hans Driesch was "gifted with the confidence that results from a strong mind, backed by seemingly unlimited financial means, and driven by a brilliant intellect trained at the best institutions within reach..."(17). He traveled widely in Europe, India, Ceylon, Java, Japan, North and South America, and China. When young, he used these excursions to collect specimens, especially hydrozoans. He became fascinated with their colonial growth patterns and attempted to describe them mathematically. He came to the conclusion, however, that the mathematics of his day was not adequate to the task. (He would no doubt be fascinated by the fractal analysis of development that has been done on corals and other animals (see 18,19,20). He "gave up" on this analysis, but then happened to read Roux's paper on Developmental Mechanics. He thought that he could now analyze embryonic development physiologically. In 1891 and 1992, he did his (now) classic experiments showing that derangement and rearrangement of blastomere cells and nuclei could still give rise to normal pluteus larvae (see 21). Here, he would conclude:
"The relative position of a blastomere within the whole will probably, in a general way, determine what shall come from it; if it be situated differently, then it will give rise to something else; or stated another way: its prospective relation is a function of its place." (Driesch, quoted in 17). Thus, at age 24, he had overthrown Roux's notion of mosaic development.
Figure 3 Hans Driesch
In 1894, Driesch wrote his remarkable 180-page theoretical essay Analytische Theorie der organischen Entwicklung. Here (22), he wrote that
Development starts with a few ordered manifoldnesses; but the manifoldnesses create, by interactions, new manifoldnesses, and these are able, by acting back on the original ones, to provoke new differences, and so on. With each new response, a new cause is immediately provided, and a new specific reactivity for further specific responses. We derive a complex structure from a simple one given in the egg.
He also hypothesized that the "ontogenetic chemicals" responsible for these interactions didn't originate in the nucleus but "arise under their guidance in the cytoplasm." He related these chemicals to enzymes. Not all cytoplasms, however, are equally receptive to these stimuli, and this ability to change is predicated on previous stimuli making the cytoplasm receptive.
Driesch's book was not written for amateurs. In fact, he said in the preface that "I hope that a superficial reader will not at all understand it." Driesch got his wish. This book remained largely unread (or misunderstood) by his colleagues. Had Driesch died while that book was in press "he might have become the Franz Schubert of developmental biology," the genius whose early death deprived us of what would undoubtedly have been remarkable insights (23). However, Driesch was to lead a long (and relatively happy) life; but his reputation in biology was ruined by his becoming a vitalist. In 1909, already a famous biologist, he moved to Heidelberg and became a Professor of Natural Philosophy. A cosmopolitan and pacifist intellectual, he appeared to embody all that was noble in German high culture. He interpreted his experiments on sea urchins as showing that life is not run by physicochemical laws, and he even became the honorary president of the International Congress of Parapsychology. His vitalism was an extension of Immanual Kant's notion that the organism develops as if it had a purposeful intelligence. Driesch dropped the "as if", claiming that his research had shown that such a purposeful intelligence ("entelechy") allowed the egg to know what the outcome ("telos") would be (23, 24). Most embryologists were not convinced. As Edwin Conklin (25) wrote about Driesch's reasoning, "But this may mean no more than that the living machine is more complex than any that Driesch had in mind." The advances in both molecular biology and information theory strongly suggest that Conklin was correct.
Driesch was a complex person of strong convictions. He was appalled that the Nazis were using his vitalistic theories for propaganda purposes. He was forcibly retired when the Nazis came to power in 1933 because he refused to retract his support of two faculty members, pacifist E. Gumbel and the Jewish philosopher Theodore Lessing (26).
E. Runnström and Hörstadius: Gradients and Induction
Like Driesch, John Runnstr?m of Stockholm thought that biological knowledge was necessary for philosophical studies. However, unlike Driesch, Runnstr?m never felt that he had enough knowledge of biology to do philosophy. He kept postponing his philosophical studies so that when he died at age 82, he still felt that more work was needed (27). Runnstrom was deeply influeced by Driesch's early work and tried to find the mechanims though which sea urchin cells were assigned their fates. In the 1920s, he was writing that there must be preformed gradients in the sea urchin eggs; but his student Sven H?rstadius, was the experimenter who showed that gradients of animalness (ectodermal determination) and vegetalness (endodermal determination) existed in the 16- and 32- cell embryos. The notion of two opposing gradients interacting with each other to specify cell fate became extremely important during the 1950s. Here, it was used to model how the notochord could specify the fates of the ectodermal cells they were inducing. Inducers of anterior neural fates ("archencephalic factors") were seen to interact with inducers of caudal neural fates ("mesodermalizing factors") to create the anterior-posterior polarity of the neural tube.
Figure 4 Sven Hörstadius
Literature Cited
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2. von Baer, K. E. 1828. Über Entwickelungsgeschichte der Thier. Beobachtung und Reflexion. Quoted in Oppenheimer, op. cit., 1963.
3. Oppenheimer, J. M. 1963. K. E. von Baer's beginning insights into causal-analytic relationships during development. Devel. Biol. 7: 11-21.
4. Wolff, C. F. 1812. Über die Bildung der Darmcanals im bebrüteten Huhnchen. (J. F. Meckel, trans). Halle.
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11. Saxén, L. 1977. Direct versus permissive induction: a working hypothesis. In eds. J. Lash and M. Burger Cell and Tissue Interactions. Raven, NY; pp. 1-97.
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13. Oppenheimer, J. M. 1970. Some diverse backgrounds for Curt Herbst's ideas about embryonic induction. Bull. Hist. Med. 44: 241-250.
14. Herbst, C. 1893. Experimentelle Untersuchungen über den Einfluss der veränderten chemischen Zusammensetzung des umgebenden Mediums auf die Entwicklung der Thiere. II. Wierteres über die morphologische Wirkung der Lithiumsalze und ihre theoretische Bedeutung. Mitt. d. zool. Station Neapel. 11: 136-220.
15. Herbst, C. 1901. Formative Reize in der tierischen Ontogenese. Ein Beitrag zum Verständnis der tierischen Embryonalentwicklung. Georgi, Leipzig.
16. Oppenheimer, J. M. 1991. Curt Herbst's contributions to the concept of embryonic induction. In Gilbert, S. F. (ed.) ref (5) Pp. 63- 89. 17. Sander, K. 1992. Shaking a concept: Hans Driesch and the varied fates of sea urchin blastomeres. Roux Arch. Devel. Biol. 201: 265-267.
18. Kaandorp, J. A. 1994. Fractal Modeling: Growth and Form in Biology. Springer-Verlag, New York.
19. Meinhardt, H. 1995. The Algorithmic Beauty of Sea Shells. Springer. New York.
20. Webster, G. and Goodwin, B. 1996. Form and Transformation: Generative and Relational Principles in Biology. Cambridge University Press, New York.
21. Gilbert, S. F. 1997. Developmental Biology. Fifth edition. Sinauer Associates, Inc., Sunderland, MA.
22. Driesch, H. 1894. Analytische Theorie der organischen Entwicklung. Engelman, Leipzig. Quoted in Sander, K. 1992. Hans Driesch the critical mechanist: Analytische Theorie der organischen Entwicklung. Roux Archiv. Devel. Biol. 201: 331-333.
23. Sander, K. 1993. Hans Driesch's "philosophy really ab ovo". or why to be a vitalist. Roux Archiv. Devel. Biol. 202: 1-3.
24. Sander, K. 1993. Entelechy and the ontogenetic machine: work and views of Hans Driesch from 1895-1910. Roux Archiv. Devel. Biol. 202: 67-69.
25. Conklin, E. G. 1929. Problems of development. Seventh Sedgwick Memorial Lecture, New York.
26. Harrington, A. 1996. Reenchanting Science: Holism in German Culture from Wilhelm II to Hitler. Princeton University Press, Princeton, New Jersey.
27. Nedergaard, J. and Cannon, B. 1995 A polar development: The Runnström tradition in Swedish developmental biology. Intern. J Devel. Biol. 39: 687-696.
Gilbert, S. F. (1996). A brief history of premolecular induction studies. Seminars Cell Dev. Biol. 7: 67 -76.