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Dialectics, systems biology and embryonic induction
Differentiation 81 (2011) 209–216
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Theoretical Article
Dialectics, systems biology and embryonic induction Christof Niehrs a,b,n a b
Division of Molecular Embryology, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany Institute of Molecular Biology, Mainz, Germany
a r t i c l e in f o
abstract
Article history: Received 8 April 2010 Received in revised form 26 October 2010 Accepted 29 October 2010
A hallmark of embryonic development is the temporal-spatial continuum of cell–cell interactions, which gives rise to the trajectory of progressive cell differentiations. Despite the great reductionists’ success in dissecting the mechanistic basis of developmental processes, the call for more holistic system theories never ceased during the last century. Various system theories were proposed to provide a more adequate understanding of biological systems, including development. Although widely ignored by modern biology, the first systematic system theory was Hegel’s dialectics. Here I examine the process of embryonic induction as elaborated by Hans Spemann in the light of dialectics. I conclude that embryonic induction and its underlying molecular mechanisms can be re-interpreted in terms of Hegel’s dialectics. The example highlights that despite its shortcomings, dialectics can be of heuristic value as a theory of systems biology. & 2010 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved.
Keywords: Dialectics Embryonic induction Hegel Spemann organizer Systems theory
I am the Spirit that denies! Part of that Power which would the Evil ever do, and ever does the Good. Goethe, Faust I.
1. Introduction A cornerstone and key to the spectacular success of modern biology is the reductionist tenet that living systems are composed of units or modules, such as macromolecules, organelles, cells, organisms etc., each of which can be dissected, analyzed and understood as part of the whole. From the application of this research paradigm, biology ultimately emerged as the leading discipline (Leitwissenschaft) in the natural sciences in the second half of the 20th century, culminating with the sequencing of the human genome. In parallel with the revolution in information technology the reductionist tenet is that biological information is akin to a computer program, that the egg may be computable (Wolpert, 1994) and as such can be deliberately reprogrammed. It may hence be no coincidence that ‘‘reprogramming’’ has become a fashionable attribute in many recent biomedical publications. This is very much in n Corresponding author at: Division of Molecular Embryology, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany. E-mail address: [email protected]
the tradition of the precursor of molecular biology, biochemistry, which successfully demonstrated that by grinding up cells in the test tube, fractionating their components and studying biomolecules in isolation, we can learn an enormous amount about how cells work and indeed how to manipulate cells deliberately, e.g. using pharmacological inhibitors. Yet, despite this spectacular success the reductionist view in biology was challenged periodically because it provides no definitive answers to questions, such as: What is a gene? What is a species? Why do we age? How did sex evolve? Why have dolphins not reverted lungs into gills during evolution? How can we predict the behavior of an ecosystem? What are evolutionary units of selection? What is the significance of modularity in nature? Typically, these are problems where dissection of a single biological module is inadequate but where a holistic view is required, which takes into account many dimensions of biological systems and multiple layers of cause and effect, including the historical perspective of evolution. Consequently, for over 100 years holistic alternatives to pure-bred reductionism were formulated that aimed at a more complete understanding of biology. Examples are vitalism, organicism, process philosophy, evolutionism (‘‘Nothing in biology makes sense except in the light of evolution’’), biological cybernetics, biological system theory, chaos theory, catastrophe theory and dissipative systems theory as applied to biology, and more recently systems biology (Kauffman, 2000; Riedl, 1978; Lovejoy, 1911; Kirschner et al., 2000; Gilbert and Sarkar, 2000; Shishkin, 2006; Mayr and Provine, 1998; Mosekilde and Mosekilde, 1991; Waddington, 1974; Prigogine
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and Stengers, 1984; Kitano, 2002; Wiener, 1948; von Bertalanffy, 1950; Sanderson, 1990). In general these system theories as adapted by biologists emphasized the process over structure; rather than considering biological systems as composed of ‘‘things’’ they should be regarded as processes of individual character with many relations to other processes. These theories take their origin from Heraclit’s famous dictum panta rhei, ‘‘all is flux’’. Similarly the ancient Buddhist sage Nagarjuna held that ‘‘Things derive their being and nature by mutual dependence and derive nothing in themselves’’ (cited from Gilbert and Epel, 2009). In this tradition, Goethe held that nature’s archetypes are not static but ‘‘never-ending streams of becoming’’. The first systematic systems theory, which is largely ignored by the natural sciences, is dialectics. Developed into an all encompassing Universaltheorie by the German philosopher Georg Friedrich Hegel in the early 19th century, dialectics is a theory that rejects reductionism, since by dissecting the universe into elementary units, essential aspects and relations that also define such units are lost. According to dialectics, a complete understanding of an object or idea needs to take into account all possible relationships. The truth is the whole (Das Wahre ist das Ganze). Between the 1920s and 40s there was a large current of socialist biologists (e.g. Needham, 1936, 1943; Haldane, 1937; Waddington, 1940) applying dialectic materialism to biology in the tradition of Engels’ ‘‘Dialectics of Nature’’ (Engels, 1934). After WWII few attempts have been made outside Russia to approach biology from a dialectical ¨ and Wessel, 1983; Horz, ¨ point of view (Horz 1987; Salthe, 1993; Mackay, 2004; Kolb, 2006; Rand, 2007). Often these attempts suffered from some kind of ideological or sociological connotation, which made them unpalatable for a greater audience. A notable recent exception is the reductionist critique by Levins and Lewontin (1985). Here I will discuss an elementary process in developmental biology and embryonic induction, in the light of dialectics. Embryonic induction occurs in all animals and during different phases of development, which in metazoans leads to the unfolding of the body plan during embryogenesis. Embryonic induction presents a number of surprising formal similarities to dialectics. The affinity of development to dialectics has been pointed out by the socialist embryologist Joseph Needham who was, as reviewed elsewhere (Haraway, 1976), intrigued by the question of as to how biological form is maintained in the face of the continual flux of metabolism. He concludes that all levels of biological organization, from cells to animal populations, represent stabilized dialectical syntheses (Needham, 1943). In this tradition, Haraway (2008) and Gilbert and Epel (2009) recognized reciprocal embryonic induction as an elementary dialectic process and metaphor for interspecies relationships. While I will discuss aspects of the dialectics of nature in relation to developmental biology, a modern critique of dialectics is beyond the scope of this article and the reader is referred to more comprehensive treatises (Bunge, 1981; Salthe, 1993; Rosser, 2000).
out systematic transplantation experiments of cells from one region of a donor gastrula to a different region of a host embryo. When donor cells differentiate according to their region of origin this indicates that they are already committed. Conversely, when they harmoniously integrate into their new environment, the cells are still plastic and naı¨ve (Spemann, 1962). One of Spemann’s experiments yielded an unexpected result and became famously known as the Spemann organizer experiment (Fig. 1). In this experiment Spemann’s student Hilde Mangold transplanted the dorsal blastopore lip from a gastrula embryo. The fate of the cells of the dorsal blastopore lip is to give rise to the notochord and somites: axial organs which run through the entire length of the tadpole embryo. The dorsal blastopore lip was transplanted to the opposite side of a host embryo, from which skin normally develops. The surprising result was the formation of a Siamese twin embryo with head structures such as brain, central nervous system and axial organs in the flank of the host. Importantly, the majority of the cells making up this secondary embryo were recruited from the host embryo and organized under the influence of the transplant to form a harmonious twin, having apparently ‘‘forgotten’’ their normal fate. The dorsal blastopore lip was thus discovered as an organizer, which induces the formation of the embryonic axis. Following the discovery of the Spemann organizer, its inductive properties were systematically analyzed and separate head, trunk and tail organizers were distinguished. Furthermore, Spemann discovered that the outcome of the transplantation was much influenced by the host cell environment, indicating that the induction was the result of interplay between donor and host tissue. The discovery of the organizer hit a prepared mind in Spemann. He had discovered embryonic induction many years earlier in the context of eye development. The vertebrate eye consists of the optic cup and the lens, which are derivatives of the central nervous system and the epidermis, respectively. Spemann discovered that heterotopic transplantation of an optic cup leads to the induction of a lens from the host epidermis. Yet, the optic cup being a derivative of the central nervous system is itself the result of neural induction by the Spemann organizer and hence represents an inducer of 2nd order, while the organizer itself represents an inducer of 1st order. Spemann therefore concluded that development is organized in a hierarchical manner into chains of inductions. Indeed, we now know that embryonic induction occurs during many different phases of development and in all animal species so far investigated.
2. Embryonic induction Embryonic induction was shown to be a central mechanism of development by the German embryologist Hans Spemann, for which he received the Nobel Prize of Medicine in 1935. Working on amphibian embryos, Spemann was an experimentalist in the then emerging field of Entwicklungsmechanik, which sought a mechanistic understanding of the principles of embryonic development. Following fertilization, the amphibian embryo undergoes a phase of rapid cleavages to reach a stage called gastrula, which is composed of a few thousand cells. At gastrula complex morphogenetic movements take place, which completely reorganize the embryo and the relationship of its cell layers. Spemann addressed the question whether cells of the gastrula embryo are already committed towards particular fates, or whether they are still plastic. He therefore carried
Fig. 1. The organizer experiment. (A,B) Transplantation of the upper dorsal blastopore lip of a gastrula of Triturus cristatus to the ventral side of a gastrula of T. taeniatus. (C) Neural plate of host embryo. (D) Induced secondary neural plate. A white, narrow strip of unpigmented donor tissue can be seen. (E) Secondary embryo on the flank of the primary embryo. From Hamburger (1988), after Spemann and Mangold (1924).
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Fig. 3. Molecular interactions in the Spemann organizer. Wnt and TGF-beta growth factors are secreted by ectodermal (and mesodermal cells; not shown for simplicity) and inhibit organizer formation. The organizer secretes antagonists (Chordin, Noggin, Dickkopf and Cerberus) which neutralize Wnt and TGF-beta growth factors. Reciprocal inhibition between growth factors and their antagonists regulates patterning of the early embryo and differentiation of neural ectoderm. Reciprocal inhibition is formally similar to dialectic negation of the negation.
Fig. 2. General scheme of embryonic induction. Two cell types interact and as a result a third cell type is induced at their interface. The new cell type can likewise interact with the preceding ones, leading to new inductions. Induction chains show formal similarity to the dialectic process.
It represents a fundamental process, which is part of the tool box of the embryo, leading to cell diversification through cell–cell interaction. Importantly, induction depends as much on the inducer as on the reactive tissue, often involving a reciprocal communication between different cell types. Generalizing, induction may occur when two cell types (A, B) interact and as a result cells at their interface change their fate to differentiate into a third cell type (C). However, cell type C can also interact with cell types A and B and lead to new inductions at their interfaces and further cellular diversification (Fig. 2). Development can therefore be envisaged as a chain or cascade of inductions, which play a key role in generating the diversity of the about 400 cell types that make up the human body (Vickaryous and Hall, 2006).
factors of the Wnt and TGF-beta family play a central role in the organizer phenomenon. They represent two families of secreted glycoproteins, which bind to cell surface receptors to induce cell growth, cell proliferation and changes in cell differentiation. In the early vertebrate embryo these growth factors are secreted by ectodermal and ventral mesodermal cells and they promote epidermal and ventral tissue differentiation, while inhibiting the function of the organizer in their vicinity. The organizer cells in turn secrete antagonists which neutralize Wnt and TGF-beta growth factors, thereby promoting differentiation of neuroectoderm (future central nervous system) (Fig. 3). The mutual antagonism between cells secreting Wnt and TGF-beta growth factors and organizer cells secreting the antagonists ultimately leads to the development of the embryonic axis (De Robertis and Kuroda, 2004; Niehrs, 2004). This mutual inhibition is formally similar to Hegel’s negation of the negation, as discussed below. It should be noted that the interaction of growth factors with their antagonists is not restricted to the embryo but also occurs in the adult during tissue homeostasis. Further work showed that the combined action of growth factor antagonists leads to differential inhibition of TGF-beta and Wnts and hence a qualitative mechanism operates to generate the different head, trunk and tail organizer activities. However, head, trunk and tail are not uniform structures but tissue continuums. For example, the central nervous system of the head alone consists of forebrain, midbrain and anterior hindbrain. How can a three-partite head–trunk–tail organizer account for this complex pattern? One answer is that TGF-beta and Wnts act in a concentration-dependent fashion within these regions to orchestrate tissue patterning (De Robertis and Kuroda, 2004; Niehrs, 2004; Meinhardt, 2008; De Robertis, 2009). Rather than a simple on–off switch these growth factors act as morphogens, which elicit distinct cellular responses at different threshold concentrations. If a responsive embryonic tissue is under the influence of a morphogen, it can induce a tissue pattern in a dose dependent fashion (Fig. 4). The role of the cocktail of antagonists secreted by the organizer is to generate the Wnt and TGF-beta morphogen gradients. Transplantation of the organizer generates two mirror image morphogen gradients and hence embryonic twinning. Such a transformation of quantity into quality is one of the principles of dialectics.
4. Dialectics of nature 3. Molecular basis of the Spemann organizer The chemical nature of the organizer was uncovered in the last 20 years by a molecular biological reductionist approach. Growth
The confrontation of cells during embryonic induction, which leads to the emergence of a new cell type, is formally similar to the dialectic process. The term dialectics is derived from the Greek
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dialegein, to select; dialektike techne means the art of conversation. In Socratic dialogue it represents the famous rhetoric technique of pro and contra, the weighing of for and against, which leads to a new conclusion. Dialectics was the basis of the scholastic method developed in the middle ages at the University of Paris, which found its highest exponent in the philosophical works of Thomas Aquinas. The term dialectics acquired its full philosophical momentum with Hegel, who elevated it to an all encompassing universal theory, a law of motion of life. Stripped of its metaphysical elevation and grossly abbreviated, the dialect process can be formulated as the well known dialectic triad: A thesis, which provokes an antithesis contradicting or negating the thesis, and a synthesis resulting from the resolution (‘‘sublation’’) of the former two. The synthesis does not simply deny the preceding thesis and antithesis but incorporates their valid elements in a more general or higher point of view. Yet, the synthesis represents a new thesis in its own right and hence is at the origin of a new dialectic motion. Thus, as the dialectic process proceeds to ever higher truths, every higher step encompasses the preceding ones as sublated contradictions (Fig. 5). Developing from this idea Hegel emphasized that our concept of truth and reality remains incomplete, unless we describe each element with all of its complex interactions and relations to the universe. The universe is a system of connected processes, rather than a set of finite objects or ideas and dialectics drives these processes and establishes the interrelationships between the elements.
Hegel’s dialectic Universaltheorie also encompassed the natural sciences. While his own scientific examples often suffered from the limited scientific insight available at the beginning of the 19th century as well as his own miscomprehensions, Friedrich Engels, rooting in Hegel and with much broader scientific foundation, developed a (unfinished, posthumously published) Dialectics of Nature (Engels, 1934) and posited three dialectic laws.
4.1. The law of the transformation of quantity into quality and vice versa In his ontology, Hegel distinguished between quality and quantity and that gradual increase of a unit eventually can transform into a new quality, e.g. the phase transition of water at different temperature. Hegel and Engels considered this transformation as a universal law, applicable also outside the natural sciences.
4.2. The law of the interpenetration of opposites According to this law two things which apparently oppose or exclude each other, actually belong together and cannot exist without each other in a quasi-dualistic or yin and yang fashion. Engels cites the definition of an individual organism, which becomes very obviously vague when considering a coral, which may constitute either a colony or an individual. Similarly, is the pregnant mouse one or two organisms? According to Engels, dialectics relates between these opposites and rigid definitions. Dialectics knows no hard and fast lines and reconciles opposites by recognizing besides ‘either–or’ also ‘both this– and that’.
4.3. The law of the negation of the negation
Fig. 4. Morphogens and dose dependent induction. Schematic drawing of a morphogen gradient in a field of tissue. Cells within the field react to the morphogen at distinct threshold concentrations and differentiate into different cell types, leading to tissue patterning. Dose dependent patterning by a morphogen bears formal similarity to the dialectic transformation of quantity into quality.
While in formal logic the negation of the negation of a proposition returns to the starting-point, i.e. the original proposition, in Hegel’s and Engels’ philosophy it is transforming into a synthesis, which extends its predecessors. This law represents the sublation in the mentioned dialectic triad. One example is the succession of epistemological theories: rationalism (Descartes, Leibnitz) which was negated by empirism (Locke, Hume) and resolved in a synthesis by Kants transcendental philosophy. Another example is electrostatic neutralization of positively and negative charged objects that may be considered to negate each other and dissipate heat.
Fig. 5. Determinism in embryonic induction and dialectics. The progressive development controlled by embryonic induction is stereotypical for each animal species, leading deterministically to the adult organism (left). According to dialectics, cultural development (e.g. of philosophical theories or history) progresses deterministically towards an absolute truth.
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5. Dialectics of embryonic induction In the following I will briefly compare key elements of dialectics with properties of embryonic induction, which is summarized in Table 1. 5.1. Negation of the negation During embryonic induction two different cell types interact, i.e. they communicate with each other via signaling molecules. As mentioned, the molecular analysis of the Spemann organizer revealed that organizer cells and ectodermal cells antagonize each other and that as a result of their interaction neuroectoderm arises as a new cell type at their interface (De Robertis and Kuroda, 2004). While neuroectoderm has properties different from both preceding cell types, it shares specific cell biological and molecular properties with its predecessors, e.g. like ectoderm, neuroectoderm has epithelial character and like organizer cells it secretes BMP antagonists. With Hegel one might thus formulate that organizer and ectoderm negate each other and that this reciprocal negation is resolved in the induction/sublation of the neuroectoderm. Hence, a hallmark of the organizer is this process of mutual interaction. To highlight this aspect, one may more adequately refer to the organizer as a process than a structure. Mutual antagonism is widespread in biology, from the molecular to the organismic level. During embryonic development mutual antagonism via genetic regulatory networks can not only lead to induction but also generates tissue boundaries. 5.2. Transformation of quantity into quality Phase transitions and bifurcations are commonplace in the natural sciences including biology. Hence, morphogen gradients as they occur in the organizer phenomenon are but another example of this widespread phenomenon. Wnt and BMP growth factors functioning during early embryonic induction do not simply act in an all-or-none fashion but dose dependently to induce distinct cell fates to gradually pattern the embryo. These gradients are at the heart of specifying the body plan in amphibians and indeed it appears that a Cartesian coordinate system of Wnt and BMP signaling specifies bilaterian body axes across the animal kingdom (Niehrs, 2010).
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One may criticize that Hegel’s notion of transformation of quantity into quality is now commonplace, has little heuristic value per se, and rather distracts from the need to analyze the underlying mechanistic details. However, this does not invalidate its fundamental importance, including its significance in the process of embryonic induction. Incidentally, Spemann himself was rather opposed to morphogen gradients and quantitative mechanisms.
5.3. Hierarchy and historicity Embryonic development can be viewed as a chain or cascade of inductions, which give rise to the multitude of tissues as the embryo grows. Pluripotent stem cells give rise to multipotent stem cells, to less multipotent stem cells, to progenitor cells, and finally to differentiated cells. Historical contingency is thus the rule and as a consequence what a growth factor does will depend on the history of cell interactions. The growth factor BMP4 will tell one type of cells to become ventral ectoderm; it will tell another group of cells to become bone; it will tell yet another group of cells to initiate apoptosis. The cell response depends on what other gene regulatory factors are present in the cell; i.e., what other cells the cell had previously interacted with. Thus, inductions and development build historically and hierarchically on each other in a similar fashion, as the development of history of philosophy in the dialectic view. In embryonic development as in dialectics, the complexity of a historical process is therefore due to a hierarchical system of interactions. In dialectics as in development the top of the evolving hierarchy is generally considered to be at some ‘‘higher level’’, or complexity than the preceding or subordinate levels. Consequently, for Needham the embryo is like history interpreted from a Marxist viewpoint, ‘‘time slice of a spatio-temporal entity’’ (Needham, 1936). Moreover, reciprocal induction does not end with embryogenesis but rather can be viewed as a metaphor for interspecies relationships as emphasized by Donna Haraway (2008). Citing the work of Margulis and Sagan (2002), which deals with how symbiosis creates novelty, complex life forms are the continual result of ever more complex association with other life forms. These life forms are in constant dialogue as in reciprocal induction, influencing each others’ physiology and morphology, and as a consequence they co-evolve. Haraway concludes that this dialogue extends beyond symbiosis, wherever species meet, including the
Table 1 Elements of embryonic induction and dialectics. Embryonic induction
Dialectics
Spemann (Stuttgart) Law of development Embryo Tissues, cells, biomolecules Biomolecules New cell type, organ Constitutive principle (e.g. morphogens) Constitutive principle; feedback of Cause and effect Hierarchically different causal layers
Hegel (Stuttgart) Law of development Mind and matter, culture, history Objects, ideas, individuals, societies Physical, language, human acts Novelty Constitutive principle Constitutive principle; feedback of Cause and effect Subject and object
Constitutive principle (e.g. growth factor antagonism)
Hierarchical Deterministic (ontogeny) Contingent (phylogeny)
Constitutive principle Hierarchical Deterministic (e.g. absolute idea) Contingent (e.g. free will)
System
Dynamic process Holistic
Dynamic process Holistic
Final cause
Biological adaptation, biological fitness
Creation, providence, Weltgeist
Main author Theory Subject Interaction of Communication via Result of interaction Transformation of quantity in quality Interpenetration of opposites
Negation of the negation Developing structure
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domestic animal and man, and that as in dialectics, relations rather than ‘‘things’’ rule. 5.4. Interpenetration of opposites In the holistic world view of the dialectician, all things of the universe are interrelated, they are in a causal relationship, albeit that this causation is ever so weak or difficult to prove in the individual case. Instead of reductionist linear chains of events, dialectics considers networks where subject and object, cause and effect interpenetrate each other. In biology this view is held in particular by system theoreticians (Riedl, 1975; Kauffman, 2000; Levins and Lewontin, 1985; Gilbert and Epel, 2009). According to this stance, organisms are not merely passive objects of evolution, which adapt to a habitat, but are also subjects that shape their ecosystem and thereby enforce new adaptations. Atmospheric oxygen, for example, is the product of photosynthetic bacteria and algae and has steered evolution in new directions. Therefore, organisms are cause and effect of their own evolution. In case of embryonic induction, such causal feedback is observed as well. Growth factors, which mediate organizer induction, are not restricted to early development but also function during later developmental processes and even in adult cell and tissue homeostasis, e.g. in the immune system and in the brain. In turn, these biological systems sharing a common growth factor regulation system are evolutionarily coupled. The reason for this coupling is that mutations in genes belonging to a growth factor system will manifest in different organs. Such mutations are called pleiotropic. For example, a mouse carrying a mutation in the Spemann organizer gene Dickkopf1, encoding a Wnt growth factor antagonist, displays malformations of the head, limbs and the skeleton because of the diverse roles of this antagonist in development (Mukhopadhyay et al., 2001). This coupling of organs through shared regulatory systems blurs linear cause and effect relationships. On the one hand the skeleton is a structure which during development is both temporally and causally subordinated to the Spemann organizer. However, this causal relationship may become reversed on an evolutionary time scale. If selection pressure acts on the skeleton and leads to changes in its regulating Wnt growth factor system, e.g. higher affinity of the growth factor for its receptor, these molecular changes may secondarily feedback on organizer function. One consequence of pleiotropy is therefore co-evolution of such molecularly coupled organs (Riedl, 1975; Wagner, 1984; Schlichting and Pigliucci, 1998). The concept, whereby organisms may modify selection pressures and act as codirectors of their own evolution and that of other species has recently been termed niche construction. As pointed out by Laland et al. (2008), reciprocal induction during development can be regarded as an example of niche construction. When two tissues meet, a complex dialogue and cell responses ensues, and these responses may themselves evolve. Moreover, as the authors forcibly argue, reciprocal induction may be extended to interactions between different organisms, e.g. between bacterial symbionts and their developing hosts. We are thus reminded of Engels who questioned in the wake of Hegel if there is such thing as an ‘‘individual.’’ 5.5. Chance and necessity Depending on the vantage point embryonic induction and dialectics are either deterministic or chance (contingent) processes. If one considers an animal species, e.g. the alpine salamander utilized by Spemann, then the sequence of inductions in healthy animals will reproducibly take place in a deterministic fashion and give rise to a more or less stereotypic adult with its
characteristic morphology. Indeed, the concept of the species is the very consequence of deterministic development. However, if one considers evolutionary time scales the result of embryonic induction is subject to chance and change. All bilateral animals, including salamanders and man descend from an extinct common precursor, called urbilateria (De Robertis and Sasai, 1996). Mutations in the genes regulating embryonic induction led to variation in development in the descendants of urbilateria, which became fixed by natural selection and over millions of years led to the unpredictable evolution and diversity of vertebrate species. Thus, embryonic induction is ontogentically deterministic but phylogenetically contingent. Another important example of the dualism of chance and necessity during development is the response of embryos to environmental stimuli, i.e. developmental ecology (Gilbert and Epel, 2009). Unlike in the laboratory, with its constant experimental conditions, embryos in the wild can be subject to substantial environmental fluctuations, including e.g. temperature, light, salinity, presence of predators, etc. These parameters can have a great influence on development and lead to adaptive responses, ranging from e.g. morphological differences, pigmentation, thermotolerance to sex ratio. While the environmental conditions under which embryos develop may vary unpredictably in the wild, the response of the embryo falls within a certain reaction norm, or continuum of phenotypes, whose range and specificity is genetically deterministic. A similar dualism between chance and necessity exists in dialectics. Hegel’s dialectics is fundamentally deterministic, where providence and the Weltgeist direct the grand course of history and reality. On the other hand he concedes that contingency does exist, reflected, in particular, in the autonomy and free will of the human being. The freedom of man and hence the element of chance, contradict Hegel’s determinism. In an exemplary dialectical manner this contradiction was dissolved by Engels where he states (Engels, 1934): The evolution of a concept y in the history of thought, is related to its development in the mind of the individual dialectician, just as the evolution of an organism in palaeontology is related to its development y in the single embryo. That this is so was first discovered for concepts by Hegel. In historical development, chance plays its part, which in dialectical thinking, as in the development of the embryo, is summed up in necessity. In this remarkable phrase, Engels compares biological evolution to historic development, both of which are contingent. Deterministic development of the individual embryo mirrors the contingent evolutionary process: The human embryo displays gill pouches because it descends from an amphibian ancestor. Ontogeny as recapitulation of phylogeny, Ernst Haeckels biogenetic law (refuted in its literal sense but famous when Engels wrote his text), is expressed here. This is similar to the dialectician, who views the course of history, while contingent in details, as a long-term deterministic process. Thus, chance and necessity act dualistically in embryonic induction and in dialectics.
5.6. Holism Dialectics is fundamentally a holistic theory, similar to various biological theories. As mentioned, despite its spectacular success in many fields, reductionist biology and in particular molecular biology fails to explain ‘‘why’’ questions or to tackle biological systems in their entirety. Unless biological systems are analyzed, e.g. in evolutionary and ecological context, which are driving forces for their adaptations, their understanding remains fragmentary. Ultimately, biology, as indeed physics if one includes cosmogony, seeks
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an understanding of causal networks1 in a comprehensive fashion, and hence in this ultimate aim, both sciences are holistic.
6. Isomorphism of dialectics and embryonic induction If we conclude that there are formal similarities between Hegel/ Engels dialectics and embryonic induction the question arises what these similarities are due to. The similarities could be coincidental and superficial. For example embryonic induction and electrical induction share a number of similarities, including the same term, yet there is no direct relationship between the two. More likely, the isomorphism between dialectics and embryonic induction is due to the fact that both deal with transformations, or developmental processes. Dialectics is fundamentally an evolutionary theory of ¨ and Wessel, 1983). It addresses the questions universal scope (Horz of how a system arose, how it develops and how it will behave in the future. We distinguish cosmic, chemical, geological, biological and cultural evolution and these processes may be viewed like elements of one continuous evolutionary chain or a system of circles in circles (Hegel, 1986). It seems that Engels ‘‘laws’’, or better rules, would at least partially apply for these evolutionary processes, as they do for embryonic induction. Yet, they are too general to have specific predictive value in biology. What then may be the benefit of a dialectic approach to biology? The history of biology is pervaded by evolving schools of thought that drive research. Under the spell of the great discoveries in intermediary metabolism in first half of the 20th century, even embryologists sought ‘‘metabolic gradients’’ to explain pattern formation. The rise of information theory after WWII generated entire institutes devoted to biological cybernetics. With the advent of nanophysics in the early 21st century came the reinterpretation of molecular assemblies in terms of nanobiology. The continuous emergence of holistic theories in biology, in its most recent guise termed systems biology (Kitano, 2002), highlights the need for a comprehensive and integrated analysis which transcends the study of individual subsystems. Thus, the benefit of dialectics for modern biology may be that of a general framework that directs reductionist biology to system level analysis. Even if western education and experimental constraints force the reductionist biologist to categorize and dissect biological system into building blocks or ‘‘things’’, for a more adequate understanding we should be reminded of the importance of relations and processes as a fundamental unit, which is what dialectics is all about. As the embryologist Waddington pointed out, a scientist’s metaphysical belief is not a mere epiphenomenon but has a definitive influence on the work he produces (Waddington, 1969). Thus, we may formulate modern dialectic research rules for biological elements such as biomolecules, molecular networks, cells, tissues, etc. such as
treat biological elements as processes rather than ‘‘things’’, consider the evolutionary historicity of biological elements, search for negating elements (e.g. inhibitors, repressive elements),
search if a biological effect may feedback on its biological cause and
search for a transformation of quantity into quality. It may also be fruitful to consider the sociological aspect of scientific progress in light of dialectics. As pointed out by Needham (1943), clashes between theories are no sign of failure of science, 1 As used here: complex systems, whose elements are simultaneously cause and effect of each other’s state.
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they are dialectical contradictions out of which much better approximations to truth will later arise. A clash of doctrines is not a disaster, it is an opportunity. A recent good example for this type of dialectic advance comes once again from research in the context of embryonic induction. The notion that inhibition of BMP signaling leads to neural induction (default model) was challenged on the basis that in the chick embryo BMP inhibitors failed to induce neural tissue. Instead the growth factor FGF8 is a potent neural inducer in chick and was suggested to be the instructive molecule (FGF model), ˜ oz-Sanjua´n and rather than BMP inhibitors (reviewed in Mun Brivanlou, 2002). The dialectical synthesis resolving these confronting theses was the subsequent finding that FGF8 signaling blocks BMP signaling pathway intracellularly. Hence both the default- and the FGF model are valid but were sublated in a new model, which incorporates its precursors at a higher level (reviewed in De Robertis and Kuroda, 2004). Dialectics can be justly criticized as trivial (transformation of quantity in quality), fuzzy (selection of any antithesis to the thesis is arbitrary) or illogical (contradictions decide between right or wrong but cannot lead to novelty themselves). Importantly, dialectics has without doubt been cruelly abused by ideologists, including biologists such as Lyssenko, and Popper has forcibly criticized Hegel’s dialectics to be at the roots of totalitarian tyranny in the 20th century (Popper, 2002). However, as I tried to argue with the example of embryonic induction’s highlights that despite its shortcomings the key elements of dialectics are surprisingly modern and that this venerable systems theory may be of heuristic value in other areas of biology as well.
Acknowledgements I thank two anonymous referees for their insightful comments, which improved this manuscript. References Bunge, M., 1981. Scientific Materialism. Reidel Publishing. De Robertis, E.M., 2009. Spemann’s organizer and the self-regulation of embryonic fields. Mech. Dev. 126, 925–941. De Robertis, E.M., Kuroda, H., 2004. Dorsal–ventral patterning and neural induction in Xenopus embryos. Annu. Rev. Cell Dev. Biol. 20, 285–308. De Robertis, E.M., Sasai, Y., 1996. A common plan for dorsoventral patterning in Bilateria. Nature 380, 37–40. Engels, F., 1934. Dialectics of Nature. Progress Publishers. Gilbert, S.F., Sarkar, S., 2000. Embracing complexity: organicism for the 21st century. Dev. Dyn. 219, 1–9. Gilbert, S.F., Epel, D., 2009. Ecological Developmental Biology: Integrating Epigenetics, Medicine, and Evolution. Sinauer Associates, Sunderland, MA. Hamburger, V., 1988. The Heritage of Experimental Embryology. Oxford University Press, New York. Haldane, J.B.S., 1937. A dialectical account of evolution science and society. Sci. Soc. 1, 473–486. Haraway, D., 1976. Crystals, Fabrics, and Fields: Metaphors of Organicism in Twentieth-Century Developmental Biology. Haraway, D., 2008. When Species Meet. University of Minnesota Press, Minnesota. ¨ Hegel, G.W.F., 1986. Enzyklopadie der philosophischen Wissenschaften im Grundrisse. Suhrkamp Verlag, Frankfurt a.M. ¨ Horz, H., 1987. Dialectics and evolution. Biol. Philos. 2, 493–508. ¨ Horz, H., Wessel, K.-F., 1983. Philosophische Entwicklungstheorie. Verlag der Wissenschaften, Berlin. Kauffman, S., 2000. Investigations. Oxford University Press, p. 129. Kirschner, M., Gerhart, J., Mitchison, T., 2000. Molecular ‘‘vitalism’’. Cell 100, 79–88. Kitano, H., 2002. Systems biology: a brief overview. Science 295, 1662–1664. Kolb, V.M., 2006. On the applicability of the principle of the quantity-to-quality transition to chemical evolution that led to life. Int. J. Astrobiol. doi:10.1017/ S1473550405002818. Laland, K.N., Odling-Smee, J., Gilbert, S.F., 2008. EvoDevo and niche construction: building bridges. J. Exp. Zool. B: Mol. Dev. Evol. 310, 549–566. Levins, R., Lewontin, R., 1985. The Dialectical Biologist. Harvard University Press. Lovejoy, A.O., 1911. The meaning of vitalism. Science 33, 610–614. Mackay, A.L., 2004. From ‘‘the dialectics of nature’’ to the inorganic gene. Found. Chem. 1, 43–56.
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Contents lists available at ScienceDirect
Differentiation journal homepage: www.elsevier.com/locate/diff
Theoretical Article
Dialectics, systems biology and embryonic induction Christof Niehrs a,b,n a b
Division of Molecular Embryology, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany Institute of Molecular Biology, Mainz, Germany
a r t i c l e in f o
abstract
Article history: Received 8 April 2010 Received in revised form 26 October 2010 Accepted 29 October 2010
A hallmark of embryonic development is the temporal-spatial continuum of cell–cell interactions, which gives rise to the trajectory of progressive cell differentiations. Despite the great reductionists’ success in dissecting the mechanistic basis of developmental processes, the call for more holistic system theories never ceased during the last century. Various system theories were proposed to provide a more adequate understanding of biological systems, including development. Although widely ignored by modern biology, the first systematic system theory was Hegel’s dialectics. Here I examine the process of embryonic induction as elaborated by Hans Spemann in the light of dialectics. I conclude that embryonic induction and its underlying molecular mechanisms can be re-interpreted in terms of Hegel’s dialectics. The example highlights that despite its shortcomings, dialectics can be of heuristic value as a theory of systems biology. & 2010 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved.
Keywords: Dialectics Embryonic induction Hegel Spemann organizer Systems theory
I am the Spirit that denies! Part of that Power which would the Evil ever do, and ever does the Good. Goethe, Faust I.
1. Introduction A cornerstone and key to the spectacular success of modern biology is the reductionist tenet that living systems are composed of units or modules, such as macromolecules, organelles, cells, organisms etc., each of which can be dissected, analyzed and understood as part of the whole. From the application of this research paradigm, biology ultimately emerged as the leading discipline (Leitwissenschaft) in the natural sciences in the second half of the 20th century, culminating with the sequencing of the human genome. In parallel with the revolution in information technology the reductionist tenet is that biological information is akin to a computer program, that the egg may be computable (Wolpert, 1994) and as such can be deliberately reprogrammed. It may hence be no coincidence that ‘‘reprogramming’’ has become a fashionable attribute in many recent biomedical publications. This is very much in n Corresponding author at: Division of Molecular Embryology, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany. E-mail address: [email protected]
the tradition of the precursor of molecular biology, biochemistry, which successfully demonstrated that by grinding up cells in the test tube, fractionating their components and studying biomolecules in isolation, we can learn an enormous amount about how cells work and indeed how to manipulate cells deliberately, e.g. using pharmacological inhibitors. Yet, despite this spectacular success the reductionist view in biology was challenged periodically because it provides no definitive answers to questions, such as: What is a gene? What is a species? Why do we age? How did sex evolve? Why have dolphins not reverted lungs into gills during evolution? How can we predict the behavior of an ecosystem? What are evolutionary units of selection? What is the significance of modularity in nature? Typically, these are problems where dissection of a single biological module is inadequate but where a holistic view is required, which takes into account many dimensions of biological systems and multiple layers of cause and effect, including the historical perspective of evolution. Consequently, for over 100 years holistic alternatives to pure-bred reductionism were formulated that aimed at a more complete understanding of biology. Examples are vitalism, organicism, process philosophy, evolutionism (‘‘Nothing in biology makes sense except in the light of evolution’’), biological cybernetics, biological system theory, chaos theory, catastrophe theory and dissipative systems theory as applied to biology, and more recently systems biology (Kauffman, 2000; Riedl, 1978; Lovejoy, 1911; Kirschner et al., 2000; Gilbert and Sarkar, 2000; Shishkin, 2006; Mayr and Provine, 1998; Mosekilde and Mosekilde, 1991; Waddington, 1974; Prigogine
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and Stengers, 1984; Kitano, 2002; Wiener, 1948; von Bertalanffy, 1950; Sanderson, 1990). In general these system theories as adapted by biologists emphasized the process over structure; rather than considering biological systems as composed of ‘‘things’’ they should be regarded as processes of individual character with many relations to other processes. These theories take their origin from Heraclit’s famous dictum panta rhei, ‘‘all is flux’’. Similarly the ancient Buddhist sage Nagarjuna held that ‘‘Things derive their being and nature by mutual dependence and derive nothing in themselves’’ (cited from Gilbert and Epel, 2009). In this tradition, Goethe held that nature’s archetypes are not static but ‘‘never-ending streams of becoming’’. The first systematic systems theory, which is largely ignored by the natural sciences, is dialectics. Developed into an all encompassing Universaltheorie by the German philosopher Georg Friedrich Hegel in the early 19th century, dialectics is a theory that rejects reductionism, since by dissecting the universe into elementary units, essential aspects and relations that also define such units are lost. According to dialectics, a complete understanding of an object or idea needs to take into account all possible relationships. The truth is the whole (Das Wahre ist das Ganze). Between the 1920s and 40s there was a large current of socialist biologists (e.g. Needham, 1936, 1943; Haldane, 1937; Waddington, 1940) applying dialectic materialism to biology in the tradition of Engels’ ‘‘Dialectics of Nature’’ (Engels, 1934). After WWII few attempts have been made outside Russia to approach biology from a dialectical ¨ and Wessel, 1983; Horz, ¨ point of view (Horz 1987; Salthe, 1993; Mackay, 2004; Kolb, 2006; Rand, 2007). Often these attempts suffered from some kind of ideological or sociological connotation, which made them unpalatable for a greater audience. A notable recent exception is the reductionist critique by Levins and Lewontin (1985). Here I will discuss an elementary process in developmental biology and embryonic induction, in the light of dialectics. Embryonic induction occurs in all animals and during different phases of development, which in metazoans leads to the unfolding of the body plan during embryogenesis. Embryonic induction presents a number of surprising formal similarities to dialectics. The affinity of development to dialectics has been pointed out by the socialist embryologist Joseph Needham who was, as reviewed elsewhere (Haraway, 1976), intrigued by the question of as to how biological form is maintained in the face of the continual flux of metabolism. He concludes that all levels of biological organization, from cells to animal populations, represent stabilized dialectical syntheses (Needham, 1943). In this tradition, Haraway (2008) and Gilbert and Epel (2009) recognized reciprocal embryonic induction as an elementary dialectic process and metaphor for interspecies relationships. While I will discuss aspects of the dialectics of nature in relation to developmental biology, a modern critique of dialectics is beyond the scope of this article and the reader is referred to more comprehensive treatises (Bunge, 1981; Salthe, 1993; Rosser, 2000).
out systematic transplantation experiments of cells from one region of a donor gastrula to a different region of a host embryo. When donor cells differentiate according to their region of origin this indicates that they are already committed. Conversely, when they harmoniously integrate into their new environment, the cells are still plastic and naı¨ve (Spemann, 1962). One of Spemann’s experiments yielded an unexpected result and became famously known as the Spemann organizer experiment (Fig. 1). In this experiment Spemann’s student Hilde Mangold transplanted the dorsal blastopore lip from a gastrula embryo. The fate of the cells of the dorsal blastopore lip is to give rise to the notochord and somites: axial organs which run through the entire length of the tadpole embryo. The dorsal blastopore lip was transplanted to the opposite side of a host embryo, from which skin normally develops. The surprising result was the formation of a Siamese twin embryo with head structures such as brain, central nervous system and axial organs in the flank of the host. Importantly, the majority of the cells making up this secondary embryo were recruited from the host embryo and organized under the influence of the transplant to form a harmonious twin, having apparently ‘‘forgotten’’ their normal fate. The dorsal blastopore lip was thus discovered as an organizer, which induces the formation of the embryonic axis. Following the discovery of the Spemann organizer, its inductive properties were systematically analyzed and separate head, trunk and tail organizers were distinguished. Furthermore, Spemann discovered that the outcome of the transplantation was much influenced by the host cell environment, indicating that the induction was the result of interplay between donor and host tissue. The discovery of the organizer hit a prepared mind in Spemann. He had discovered embryonic induction many years earlier in the context of eye development. The vertebrate eye consists of the optic cup and the lens, which are derivatives of the central nervous system and the epidermis, respectively. Spemann discovered that heterotopic transplantation of an optic cup leads to the induction of a lens from the host epidermis. Yet, the optic cup being a derivative of the central nervous system is itself the result of neural induction by the Spemann organizer and hence represents an inducer of 2nd order, while the organizer itself represents an inducer of 1st order. Spemann therefore concluded that development is organized in a hierarchical manner into chains of inductions. Indeed, we now know that embryonic induction occurs during many different phases of development and in all animal species so far investigated.
2. Embryonic induction Embryonic induction was shown to be a central mechanism of development by the German embryologist Hans Spemann, for which he received the Nobel Prize of Medicine in 1935. Working on amphibian embryos, Spemann was an experimentalist in the then emerging field of Entwicklungsmechanik, which sought a mechanistic understanding of the principles of embryonic development. Following fertilization, the amphibian embryo undergoes a phase of rapid cleavages to reach a stage called gastrula, which is composed of a few thousand cells. At gastrula complex morphogenetic movements take place, which completely reorganize the embryo and the relationship of its cell layers. Spemann addressed the question whether cells of the gastrula embryo are already committed towards particular fates, or whether they are still plastic. He therefore carried
Fig. 1. The organizer experiment. (A,B) Transplantation of the upper dorsal blastopore lip of a gastrula of Triturus cristatus to the ventral side of a gastrula of T. taeniatus. (C) Neural plate of host embryo. (D) Induced secondary neural plate. A white, narrow strip of unpigmented donor tissue can be seen. (E) Secondary embryo on the flank of the primary embryo. From Hamburger (1988), after Spemann and Mangold (1924).
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Fig. 3. Molecular interactions in the Spemann organizer. Wnt and TGF-beta growth factors are secreted by ectodermal (and mesodermal cells; not shown for simplicity) and inhibit organizer formation. The organizer secretes antagonists (Chordin, Noggin, Dickkopf and Cerberus) which neutralize Wnt and TGF-beta growth factors. Reciprocal inhibition between growth factors and their antagonists regulates patterning of the early embryo and differentiation of neural ectoderm. Reciprocal inhibition is formally similar to dialectic negation of the negation.
Fig. 2. General scheme of embryonic induction. Two cell types interact and as a result a third cell type is induced at their interface. The new cell type can likewise interact with the preceding ones, leading to new inductions. Induction chains show formal similarity to the dialectic process.
It represents a fundamental process, which is part of the tool box of the embryo, leading to cell diversification through cell–cell interaction. Importantly, induction depends as much on the inducer as on the reactive tissue, often involving a reciprocal communication between different cell types. Generalizing, induction may occur when two cell types (A, B) interact and as a result cells at their interface change their fate to differentiate into a third cell type (C). However, cell type C can also interact with cell types A and B and lead to new inductions at their interfaces and further cellular diversification (Fig. 2). Development can therefore be envisaged as a chain or cascade of inductions, which play a key role in generating the diversity of the about 400 cell types that make up the human body (Vickaryous and Hall, 2006).
factors of the Wnt and TGF-beta family play a central role in the organizer phenomenon. They represent two families of secreted glycoproteins, which bind to cell surface receptors to induce cell growth, cell proliferation and changes in cell differentiation. In the early vertebrate embryo these growth factors are secreted by ectodermal and ventral mesodermal cells and they promote epidermal and ventral tissue differentiation, while inhibiting the function of the organizer in their vicinity. The organizer cells in turn secrete antagonists which neutralize Wnt and TGF-beta growth factors, thereby promoting differentiation of neuroectoderm (future central nervous system) (Fig. 3). The mutual antagonism between cells secreting Wnt and TGF-beta growth factors and organizer cells secreting the antagonists ultimately leads to the development of the embryonic axis (De Robertis and Kuroda, 2004; Niehrs, 2004). This mutual inhibition is formally similar to Hegel’s negation of the negation, as discussed below. It should be noted that the interaction of growth factors with their antagonists is not restricted to the embryo but also occurs in the adult during tissue homeostasis. Further work showed that the combined action of growth factor antagonists leads to differential inhibition of TGF-beta and Wnts and hence a qualitative mechanism operates to generate the different head, trunk and tail organizer activities. However, head, trunk and tail are not uniform structures but tissue continuums. For example, the central nervous system of the head alone consists of forebrain, midbrain and anterior hindbrain. How can a three-partite head–trunk–tail organizer account for this complex pattern? One answer is that TGF-beta and Wnts act in a concentration-dependent fashion within these regions to orchestrate tissue patterning (De Robertis and Kuroda, 2004; Niehrs, 2004; Meinhardt, 2008; De Robertis, 2009). Rather than a simple on–off switch these growth factors act as morphogens, which elicit distinct cellular responses at different threshold concentrations. If a responsive embryonic tissue is under the influence of a morphogen, it can induce a tissue pattern in a dose dependent fashion (Fig. 4). The role of the cocktail of antagonists secreted by the organizer is to generate the Wnt and TGF-beta morphogen gradients. Transplantation of the organizer generates two mirror image morphogen gradients and hence embryonic twinning. Such a transformation of quantity into quality is one of the principles of dialectics.
4. Dialectics of nature 3. Molecular basis of the Spemann organizer The chemical nature of the organizer was uncovered in the last 20 years by a molecular biological reductionist approach. Growth
The confrontation of cells during embryonic induction, which leads to the emergence of a new cell type, is formally similar to the dialectic process. The term dialectics is derived from the Greek
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dialegein, to select; dialektike techne means the art of conversation. In Socratic dialogue it represents the famous rhetoric technique of pro and contra, the weighing of for and against, which leads to a new conclusion. Dialectics was the basis of the scholastic method developed in the middle ages at the University of Paris, which found its highest exponent in the philosophical works of Thomas Aquinas. The term dialectics acquired its full philosophical momentum with Hegel, who elevated it to an all encompassing universal theory, a law of motion of life. Stripped of its metaphysical elevation and grossly abbreviated, the dialect process can be formulated as the well known dialectic triad: A thesis, which provokes an antithesis contradicting or negating the thesis, and a synthesis resulting from the resolution (‘‘sublation’’) of the former two. The synthesis does not simply deny the preceding thesis and antithesis but incorporates their valid elements in a more general or higher point of view. Yet, the synthesis represents a new thesis in its own right and hence is at the origin of a new dialectic motion. Thus, as the dialectic process proceeds to ever higher truths, every higher step encompasses the preceding ones as sublated contradictions (Fig. 5). Developing from this idea Hegel emphasized that our concept of truth and reality remains incomplete, unless we describe each element with all of its complex interactions and relations to the universe. The universe is a system of connected processes, rather than a set of finite objects or ideas and dialectics drives these processes and establishes the interrelationships between the elements.
Hegel’s dialectic Universaltheorie also encompassed the natural sciences. While his own scientific examples often suffered from the limited scientific insight available at the beginning of the 19th century as well as his own miscomprehensions, Friedrich Engels, rooting in Hegel and with much broader scientific foundation, developed a (unfinished, posthumously published) Dialectics of Nature (Engels, 1934) and posited three dialectic laws.
4.1. The law of the transformation of quantity into quality and vice versa In his ontology, Hegel distinguished between quality and quantity and that gradual increase of a unit eventually can transform into a new quality, e.g. the phase transition of water at different temperature. Hegel and Engels considered this transformation as a universal law, applicable also outside the natural sciences.
4.2. The law of the interpenetration of opposites According to this law two things which apparently oppose or exclude each other, actually belong together and cannot exist without each other in a quasi-dualistic or yin and yang fashion. Engels cites the definition of an individual organism, which becomes very obviously vague when considering a coral, which may constitute either a colony or an individual. Similarly, is the pregnant mouse one or two organisms? According to Engels, dialectics relates between these opposites and rigid definitions. Dialectics knows no hard and fast lines and reconciles opposites by recognizing besides ‘either–or’ also ‘both this– and that’.
4.3. The law of the negation of the negation
Fig. 4. Morphogens and dose dependent induction. Schematic drawing of a morphogen gradient in a field of tissue. Cells within the field react to the morphogen at distinct threshold concentrations and differentiate into different cell types, leading to tissue patterning. Dose dependent patterning by a morphogen bears formal similarity to the dialectic transformation of quantity into quality.
While in formal logic the negation of the negation of a proposition returns to the starting-point, i.e. the original proposition, in Hegel’s and Engels’ philosophy it is transforming into a synthesis, which extends its predecessors. This law represents the sublation in the mentioned dialectic triad. One example is the succession of epistemological theories: rationalism (Descartes, Leibnitz) which was negated by empirism (Locke, Hume) and resolved in a synthesis by Kants transcendental philosophy. Another example is electrostatic neutralization of positively and negative charged objects that may be considered to negate each other and dissipate heat.
Fig. 5. Determinism in embryonic induction and dialectics. The progressive development controlled by embryonic induction is stereotypical for each animal species, leading deterministically to the adult organism (left). According to dialectics, cultural development (e.g. of philosophical theories or history) progresses deterministically towards an absolute truth.
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5. Dialectics of embryonic induction In the following I will briefly compare key elements of dialectics with properties of embryonic induction, which is summarized in Table 1. 5.1. Negation of the negation During embryonic induction two different cell types interact, i.e. they communicate with each other via signaling molecules. As mentioned, the molecular analysis of the Spemann organizer revealed that organizer cells and ectodermal cells antagonize each other and that as a result of their interaction neuroectoderm arises as a new cell type at their interface (De Robertis and Kuroda, 2004). While neuroectoderm has properties different from both preceding cell types, it shares specific cell biological and molecular properties with its predecessors, e.g. like ectoderm, neuroectoderm has epithelial character and like organizer cells it secretes BMP antagonists. With Hegel one might thus formulate that organizer and ectoderm negate each other and that this reciprocal negation is resolved in the induction/sublation of the neuroectoderm. Hence, a hallmark of the organizer is this process of mutual interaction. To highlight this aspect, one may more adequately refer to the organizer as a process than a structure. Mutual antagonism is widespread in biology, from the molecular to the organismic level. During embryonic development mutual antagonism via genetic regulatory networks can not only lead to induction but also generates tissue boundaries. 5.2. Transformation of quantity into quality Phase transitions and bifurcations are commonplace in the natural sciences including biology. Hence, morphogen gradients as they occur in the organizer phenomenon are but another example of this widespread phenomenon. Wnt and BMP growth factors functioning during early embryonic induction do not simply act in an all-or-none fashion but dose dependently to induce distinct cell fates to gradually pattern the embryo. These gradients are at the heart of specifying the body plan in amphibians and indeed it appears that a Cartesian coordinate system of Wnt and BMP signaling specifies bilaterian body axes across the animal kingdom (Niehrs, 2010).
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One may criticize that Hegel’s notion of transformation of quantity into quality is now commonplace, has little heuristic value per se, and rather distracts from the need to analyze the underlying mechanistic details. However, this does not invalidate its fundamental importance, including its significance in the process of embryonic induction. Incidentally, Spemann himself was rather opposed to morphogen gradients and quantitative mechanisms.
5.3. Hierarchy and historicity Embryonic development can be viewed as a chain or cascade of inductions, which give rise to the multitude of tissues as the embryo grows. Pluripotent stem cells give rise to multipotent stem cells, to less multipotent stem cells, to progenitor cells, and finally to differentiated cells. Historical contingency is thus the rule and as a consequence what a growth factor does will depend on the history of cell interactions. The growth factor BMP4 will tell one type of cells to become ventral ectoderm; it will tell another group of cells to become bone; it will tell yet another group of cells to initiate apoptosis. The cell response depends on what other gene regulatory factors are present in the cell; i.e., what other cells the cell had previously interacted with. Thus, inductions and development build historically and hierarchically on each other in a similar fashion, as the development of history of philosophy in the dialectic view. In embryonic development as in dialectics, the complexity of a historical process is therefore due to a hierarchical system of interactions. In dialectics as in development the top of the evolving hierarchy is generally considered to be at some ‘‘higher level’’, or complexity than the preceding or subordinate levels. Consequently, for Needham the embryo is like history interpreted from a Marxist viewpoint, ‘‘time slice of a spatio-temporal entity’’ (Needham, 1936). Moreover, reciprocal induction does not end with embryogenesis but rather can be viewed as a metaphor for interspecies relationships as emphasized by Donna Haraway (2008). Citing the work of Margulis and Sagan (2002), which deals with how symbiosis creates novelty, complex life forms are the continual result of ever more complex association with other life forms. These life forms are in constant dialogue as in reciprocal induction, influencing each others’ physiology and morphology, and as a consequence they co-evolve. Haraway concludes that this dialogue extends beyond symbiosis, wherever species meet, including the
Table 1 Elements of embryonic induction and dialectics. Embryonic induction
Dialectics
Spemann (Stuttgart) Law of development Embryo Tissues, cells, biomolecules Biomolecules New cell type, organ Constitutive principle (e.g. morphogens) Constitutive principle; feedback of Cause and effect Hierarchically different causal layers
Hegel (Stuttgart) Law of development Mind and matter, culture, history Objects, ideas, individuals, societies Physical, language, human acts Novelty Constitutive principle Constitutive principle; feedback of Cause and effect Subject and object
Constitutive principle (e.g. growth factor antagonism)
Hierarchical Deterministic (ontogeny) Contingent (phylogeny)
Constitutive principle Hierarchical Deterministic (e.g. absolute idea) Contingent (e.g. free will)
System
Dynamic process Holistic
Dynamic process Holistic
Final cause
Biological adaptation, biological fitness
Creation, providence, Weltgeist
Main author Theory Subject Interaction of Communication via Result of interaction Transformation of quantity in quality Interpenetration of opposites
Negation of the negation Developing structure
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domestic animal and man, and that as in dialectics, relations rather than ‘‘things’’ rule. 5.4. Interpenetration of opposites In the holistic world view of the dialectician, all things of the universe are interrelated, they are in a causal relationship, albeit that this causation is ever so weak or difficult to prove in the individual case. Instead of reductionist linear chains of events, dialectics considers networks where subject and object, cause and effect interpenetrate each other. In biology this view is held in particular by system theoreticians (Riedl, 1975; Kauffman, 2000; Levins and Lewontin, 1985; Gilbert and Epel, 2009). According to this stance, organisms are not merely passive objects of evolution, which adapt to a habitat, but are also subjects that shape their ecosystem and thereby enforce new adaptations. Atmospheric oxygen, for example, is the product of photosynthetic bacteria and algae and has steered evolution in new directions. Therefore, organisms are cause and effect of their own evolution. In case of embryonic induction, such causal feedback is observed as well. Growth factors, which mediate organizer induction, are not restricted to early development but also function during later developmental processes and even in adult cell and tissue homeostasis, e.g. in the immune system and in the brain. In turn, these biological systems sharing a common growth factor regulation system are evolutionarily coupled. The reason for this coupling is that mutations in genes belonging to a growth factor system will manifest in different organs. Such mutations are called pleiotropic. For example, a mouse carrying a mutation in the Spemann organizer gene Dickkopf1, encoding a Wnt growth factor antagonist, displays malformations of the head, limbs and the skeleton because of the diverse roles of this antagonist in development (Mukhopadhyay et al., 2001). This coupling of organs through shared regulatory systems blurs linear cause and effect relationships. On the one hand the skeleton is a structure which during development is both temporally and causally subordinated to the Spemann organizer. However, this causal relationship may become reversed on an evolutionary time scale. If selection pressure acts on the skeleton and leads to changes in its regulating Wnt growth factor system, e.g. higher affinity of the growth factor for its receptor, these molecular changes may secondarily feedback on organizer function. One consequence of pleiotropy is therefore co-evolution of such molecularly coupled organs (Riedl, 1975; Wagner, 1984; Schlichting and Pigliucci, 1998). The concept, whereby organisms may modify selection pressures and act as codirectors of their own evolution and that of other species has recently been termed niche construction. As pointed out by Laland et al. (2008), reciprocal induction during development can be regarded as an example of niche construction. When two tissues meet, a complex dialogue and cell responses ensues, and these responses may themselves evolve. Moreover, as the authors forcibly argue, reciprocal induction may be extended to interactions between different organisms, e.g. between bacterial symbionts and their developing hosts. We are thus reminded of Engels who questioned in the wake of Hegel if there is such thing as an ‘‘individual.’’ 5.5. Chance and necessity Depending on the vantage point embryonic induction and dialectics are either deterministic or chance (contingent) processes. If one considers an animal species, e.g. the alpine salamander utilized by Spemann, then the sequence of inductions in healthy animals will reproducibly take place in a deterministic fashion and give rise to a more or less stereotypic adult with its
characteristic morphology. Indeed, the concept of the species is the very consequence of deterministic development. However, if one considers evolutionary time scales the result of embryonic induction is subject to chance and change. All bilateral animals, including salamanders and man descend from an extinct common precursor, called urbilateria (De Robertis and Sasai, 1996). Mutations in the genes regulating embryonic induction led to variation in development in the descendants of urbilateria, which became fixed by natural selection and over millions of years led to the unpredictable evolution and diversity of vertebrate species. Thus, embryonic induction is ontogentically deterministic but phylogenetically contingent. Another important example of the dualism of chance and necessity during development is the response of embryos to environmental stimuli, i.e. developmental ecology (Gilbert and Epel, 2009). Unlike in the laboratory, with its constant experimental conditions, embryos in the wild can be subject to substantial environmental fluctuations, including e.g. temperature, light, salinity, presence of predators, etc. These parameters can have a great influence on development and lead to adaptive responses, ranging from e.g. morphological differences, pigmentation, thermotolerance to sex ratio. While the environmental conditions under which embryos develop may vary unpredictably in the wild, the response of the embryo falls within a certain reaction norm, or continuum of phenotypes, whose range and specificity is genetically deterministic. A similar dualism between chance and necessity exists in dialectics. Hegel’s dialectics is fundamentally deterministic, where providence and the Weltgeist direct the grand course of history and reality. On the other hand he concedes that contingency does exist, reflected, in particular, in the autonomy and free will of the human being. The freedom of man and hence the element of chance, contradict Hegel’s determinism. In an exemplary dialectical manner this contradiction was dissolved by Engels where he states (Engels, 1934): The evolution of a concept y in the history of thought, is related to its development in the mind of the individual dialectician, just as the evolution of an organism in palaeontology is related to its development y in the single embryo. That this is so was first discovered for concepts by Hegel. In historical development, chance plays its part, which in dialectical thinking, as in the development of the embryo, is summed up in necessity. In this remarkable phrase, Engels compares biological evolution to historic development, both of which are contingent. Deterministic development of the individual embryo mirrors the contingent evolutionary process: The human embryo displays gill pouches because it descends from an amphibian ancestor. Ontogeny as recapitulation of phylogeny, Ernst Haeckels biogenetic law (refuted in its literal sense but famous when Engels wrote his text), is expressed here. This is similar to the dialectician, who views the course of history, while contingent in details, as a long-term deterministic process. Thus, chance and necessity act dualistically in embryonic induction and in dialectics.
5.6. Holism Dialectics is fundamentally a holistic theory, similar to various biological theories. As mentioned, despite its spectacular success in many fields, reductionist biology and in particular molecular biology fails to explain ‘‘why’’ questions or to tackle biological systems in their entirety. Unless biological systems are analyzed, e.g. in evolutionary and ecological context, which are driving forces for their adaptations, their understanding remains fragmentary. Ultimately, biology, as indeed physics if one includes cosmogony, seeks
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an understanding of causal networks1 in a comprehensive fashion, and hence in this ultimate aim, both sciences are holistic.
6. Isomorphism of dialectics and embryonic induction If we conclude that there are formal similarities between Hegel/ Engels dialectics and embryonic induction the question arises what these similarities are due to. The similarities could be coincidental and superficial. For example embryonic induction and electrical induction share a number of similarities, including the same term, yet there is no direct relationship between the two. More likely, the isomorphism between dialectics and embryonic induction is due to the fact that both deal with transformations, or developmental processes. Dialectics is fundamentally an evolutionary theory of ¨ and Wessel, 1983). It addresses the questions universal scope (Horz of how a system arose, how it develops and how it will behave in the future. We distinguish cosmic, chemical, geological, biological and cultural evolution and these processes may be viewed like elements of one continuous evolutionary chain or a system of circles in circles (Hegel, 1986). It seems that Engels ‘‘laws’’, or better rules, would at least partially apply for these evolutionary processes, as they do for embryonic induction. Yet, they are too general to have specific predictive value in biology. What then may be the benefit of a dialectic approach to biology? The history of biology is pervaded by evolving schools of thought that drive research. Under the spell of the great discoveries in intermediary metabolism in first half of the 20th century, even embryologists sought ‘‘metabolic gradients’’ to explain pattern formation. The rise of information theory after WWII generated entire institutes devoted to biological cybernetics. With the advent of nanophysics in the early 21st century came the reinterpretation of molecular assemblies in terms of nanobiology. The continuous emergence of holistic theories in biology, in its most recent guise termed systems biology (Kitano, 2002), highlights the need for a comprehensive and integrated analysis which transcends the study of individual subsystems. Thus, the benefit of dialectics for modern biology may be that of a general framework that directs reductionist biology to system level analysis. Even if western education and experimental constraints force the reductionist biologist to categorize and dissect biological system into building blocks or ‘‘things’’, for a more adequate understanding we should be reminded of the importance of relations and processes as a fundamental unit, which is what dialectics is all about. As the embryologist Waddington pointed out, a scientist’s metaphysical belief is not a mere epiphenomenon but has a definitive influence on the work he produces (Waddington, 1969). Thus, we may formulate modern dialectic research rules for biological elements such as biomolecules, molecular networks, cells, tissues, etc. such as
treat biological elements as processes rather than ‘‘things’’, consider the evolutionary historicity of biological elements, search for negating elements (e.g. inhibitors, repressive elements),
search if a biological effect may feedback on its biological cause and
search for a transformation of quantity into quality. It may also be fruitful to consider the sociological aspect of scientific progress in light of dialectics. As pointed out by Needham (1943), clashes between theories are no sign of failure of science, 1 As used here: complex systems, whose elements are simultaneously cause and effect of each other’s state.
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they are dialectical contradictions out of which much better approximations to truth will later arise. A clash of doctrines is not a disaster, it is an opportunity. A recent good example for this type of dialectic advance comes once again from research in the context of embryonic induction. The notion that inhibition of BMP signaling leads to neural induction (default model) was challenged on the basis that in the chick embryo BMP inhibitors failed to induce neural tissue. Instead the growth factor FGF8 is a potent neural inducer in chick and was suggested to be the instructive molecule (FGF model), ˜ oz-Sanjua´n and rather than BMP inhibitors (reviewed in Mun Brivanlou, 2002). The dialectical synthesis resolving these confronting theses was the subsequent finding that FGF8 signaling blocks BMP signaling pathway intracellularly. Hence both the default- and the FGF model are valid but were sublated in a new model, which incorporates its precursors at a higher level (reviewed in De Robertis and Kuroda, 2004). Dialectics can be justly criticized as trivial (transformation of quantity in quality), fuzzy (selection of any antithesis to the thesis is arbitrary) or illogical (contradictions decide between right or wrong but cannot lead to novelty themselves). Importantly, dialectics has without doubt been cruelly abused by ideologists, including biologists such as Lyssenko, and Popper has forcibly criticized Hegel’s dialectics to be at the roots of totalitarian tyranny in the 20th century (Popper, 2002). However, as I tried to argue with the example of embryonic induction’s highlights that despite its shortcomings the key elements of dialectics are surprisingly modern and that this venerable systems theory may be of heuristic value in other areas of biology as well.
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