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Injury and death in the embryo development process: hypothesis of biological self-organization.


Self-organization of biological systems is discussed on the basis of embryo development process framework. This animal multicellular hypothesis of self-organization highlights the structural response to injury that results from both cellular invasiveness and cellular induction, which are linked to the competitive interactions among cell groups that are proper to embryo development. Such disturbances produce cellular damage and death together to field topography disruption, which alter the previous organization of the whole organism and lead to reorganizative mechanisms for the final organization of the embryo. In order to support and illustrate this hypothesis of self-organization, we describe how cellular damage and death play a role in several embryo developmental stages including: fertilization, parthenogenesis, early embryo development, morphological differentiation and modeling events.


The ability for self organization in live organisms, based on the cellular model described in the hypothesis of "autopoiesis," (1) highlights two main cellular structural features: 1) a dynamic and continuous interaction of all cellular components; 2) an inner space separated from the milieu by a boundary through which matter and energy are continuously exchanged.

The aim of this paper is to propose an animal multicellular hypothesis for biological self organization, based on multicellular dynamics proper to the embryo development process, characterized by continued competitive interactions among cell groups. The hypothesis includes: 1) cell to cell injury performed through boundary trespassing, displayed during the different morphogenetic stages along the embryo formation; 2) the "injuring" inductive interactions of different cellular systems composed by large groups of cells with a strong cross-talk relationship, as shown by the action of specific cell groups--as the ones in the endodermal and mesodermal organizer centers-, on the surrounding cells; 3) physical and chemical "injuring" inductive phenomena such as parthenogenesis and modeling events in the embryo/post-embryo development; 4) field topography disruption resulting from interphases produced by large cellular injury.

Instead, those mechanisms adjusting for structural maintenance (i.e., cellular structure and homeostatic feedback), embryonic "multicellular autopoiesis" would be ruled by the structural response to injury that challenges morphostasis by producing cellular damage and death. Under this scope, we will review and analyze every possible embryological evidence that supports a central role for injury and death on the embryo organization:

1. Fertilization and Morphological Differentiation as a Result of Invasive "Injuring" Phenomena.

The processes of modeling structure in an individual start with fertilization and continue throughout the several steps of morphogenesis. A common feature of multi-cellular organisms is the necessity of cells to establish and maintain contact amongst themselves. Cells regroup and keep in contact after division, furnishing structures and functions as a product that derives from the pattern of association between cells and four-dimension coordination in space and time. (2) From this point of view, invasiveness is conceptualized as an extensive property linked to associative relationship.

1.1 Fertilization and Subsequent Phenomena

Fertilization may be conceptualized as a consequence of the injury caused by cell penetration into another cell- a phenomenon that leads to a breakdown of the ovocyte cortex with granule burst, subcortical cytoplasmatic rearrangement and deep changes in metabolic/ respiratory pathways.

Another phenomenon where injury and cell death interact in the generation of life is featured by the embryonic implantation within the uterine wall, through intense destructive mechanisms, as described in the rhesus monkey embryonic development between the eighth and ninth day. Here, intense aggressive and self-aggressive interactions, through traumatic and violent injury, are induced by the trophoblast invading the endometrial stroma, which in turn stimulates the destructive activity of the former. (3)

1.2 Morphological Differentiation

Cellular invasion may be seen as the persistence of the injuring cellular potential displayed in ovocyte fertilization, enduring throughout the whole embryonic development, acting over a previous generative order.

During the gastrula stage, structures are shaped through morphogenetic movement of tissue (mesoderm), injuring and disorganizing the invaded tissue architecture, which in turn promotes consequent proliferation and differentiation. When the cordomesoderm inductively injures the ectoblast, active cell proliferation and differentiation proceed; the former slows down until the completion or closure of structures, concluding with the formation of the central neural system. Self-organization, a succession of states of morphological differentiation in response to injury (plate, grove, channel and neural tube), follows.

2. Early Embryo Organization as a Result of "Injuring" Inductive Cellular Interactions

Cellular death seems a fundamental axis in the embryo organization since its early stages: in a mouse blastocyst, relevant cell death is observed in vivo, suggesting that it plays an important role in normal development. Specifically, by the 64-cell stage in mice, the inner cell mass that gives rise to the fetus and germ line is composed of 15 cells of which only three cells would eventually produce the embryo. (4,5) As programmed cell death is a widespread feature in the blastocysts of many vertebrates, injuring cell interactions may be important steps in shaping the early embryo organization.

The organization of the embryo development has been well studied in two amphybian species (Xenopus Laevis and Bufo arenarum). In these models, the developmental program of the organizer center -field operator-, is 'switched on' by cellular inductive signals that correlate to disturbing/injuring events in the permissive field. This organizer is constructed through several successive steps: initially, the endodermal organizer -Nieuwkoop center sends signals to specific cells of the dorsal marginal zone into prechordal head mesoderm. Together with the second organizer (body axis organizer--Speann organizer), differentiation is triggered and the permissive territories evolve into mesodermal and neural structures. This association of cellular inductive signals with disturbing/injuring events in the permissive fields is further expressed by cellular inductive inter-territorial signals that act on overlapping cell layers. This has been demonstrated during the regional specification of dorsal axial mesoderm in Xenopus embryos. All such cellular diffusible inductive signals,which exchange continuously and alternatively at local and distant levels, and are made up of molecules foreign to the tissues wherein they function, may be considered as endogenous injury, leading in turn to the further release of injury factors with putative inductive reorganizative functions. (6) Such substances may initially originate from cellular degradation products shed after sublethal damage or cellular death, thus acting secondarily as inductive signals on the surrounding cells. (7)

Endogenous injury substances can be represented by well-known factors that control apoptosis, shown to be codified by genes [ced-3, ced-4, ced-9 and Xwnt-8]. These substances induce cellular death in histogenesis and different morphogenetic processes, such as the integrative mechanisms in the modeling of form during the dorsoventral organization. These mechanisms of apoptosis mediated by inducing factors under genetic control play a role in morphogenetic processes of various other species, (8) shown as being involved in the modeling of the shape of several territories -as sculpture of the limb zone, interdigital tissue, posterior zone of the wing bud, Mullerian ducts atrophia and mesoblast regression in mandibular remodeling.

A twofold destructive/proliferative action of injury itself is fundamental in the organizative phenomena during the late blastula, gastrula and neurula stages, as shown in the Bufo arenarum species when specimens are submitted to experimental exogenous injury. For example:

1. If cells from the presumptive embryo organizer territory are mechanically destroyed, the morphogenetic field becomes structurally unstable, triggering cells into active transformation. (9) These cells are then redirected to the field program reinstalling organizational gradients and recovering field continuity. (10)

2. When the presumptive embryo organizer territory is permanently injured by chemicals, the remaining cells show irreversible chaotic variability leading to new structure formation. (9)

In brief, both endogenous and exogenous injuries carry out a primary disturbing action that is exerted through blocking or interfering with the cell program, thus stimulating proliferation, differentiation, re-organization and probably also the biologic phenomenon of adaptative preconditioning in rats, as described by Vogt, et al. (11,12) The initial embryo organization trends may also be "re-started" in puberty through the activation of gonadal functions, which is to be mediated by the same inductive substances that control the basic early embryonic organization events. Some of these factors inducing apoptosis under genetic control -as the Nieuwkoop head organizer and the body axis organizer, which are both equivalent to the Spemann organizer center- are related to the transforming growth factor-beta [TGF-beta] superfamily, demonstrated to play a key role in the development and differentiation of the mammary gland, together with FGF control proliferation and cellular differentiation phenomena.

3. Parthenogenesis and Modeling Events in the Embryo/Post-Embryo Development as a Result of Physical and Chemical "Injuring" Inductive Phenomena

The characterization of an injuring inductive action over cells by physical/chemical stimuli may be demonstrated on several activation events occurring in: 1) ovocytes, in parthenogenesis, (13) and 2) tissues that are to be replaced in order to display a new tissue organization -modeling events- in the embryo and postembryo development, such as those proceeding to the transformational changes related to life cycles and to the repair/regeneration processes.

3.1 Parthenogenesis

In fertilization, ovocyte self-activation constitutes a basic injury located at the origin of life, which can be triggered by the concentration of molecules coming from cellular catabolism. This event known as virginal parthenogenesis, relates to seasonal factors that damage the cortical layer of the ovocyte and may be mimicked as well by natural -as it happens in aphidians, bees, wasps, rotipherians, turkeys and rabbits--or experimental environmental agents. (13) Injury therefore may come from both "internal" metabolic products and "external" factors.

3.2 Modeling Events in the Embryo/ Post-Embryo Development

The modeling effect of cell death is mediated through different factors that involve embryo and postembryo interphases in the upper and lower vertebrates, and may be classified in: 1) transformational changes associated to life cycles and 2) repair/ regeneration events.

3.2.1 Transformational Changes Related to Life Cycles Functional Processes

Within functional processes, normal embryo development is accompanied by cell death occurring in very restricted regions as a consequence of functional changes, which culminate with the disappearance or atrophy of primitive organ sketches -i.e., the closure of ductus arteriosous, the modeling of aortic arches in the cardiorespiratory system in response to blood circulation and changes of gas and intravascular blood pressure. On the contrary, when tissue death does not take place, malformation occurs. Metamorphosis

Metamorphosis -an evolutive jump within the survival pathways traced by determined animal species- may also be an example to show sharp structural changes, which involve recurrent organizative and reorganizative developmental processes in response to injury. From an evolutionary standpoint, metamorphosis dynamics appear as a response to exogenous injury triggering endogenous factors that are responsible for unfolding a successive series of movements, which encompass massive tissue death, and therefore, leading to a significant reduction of the living mass together with structural reorganization. In amphibians--where metamorphosis' changes evolve secondarily to endogenous regulated injury-, the constructive events that follow after mass reduction are directly related to the intensity of the hormonal trigger.

3.2.2 Repair/ Regeneration Events

The repair/regeneration events may be seen as tissue responses to exogenous physical or chemical injury in which inductive substances play a central role. These phenomena resemble the morphogenetic movement of embryo development, as it follows similar tissue invasive mechanisms through cellular movement and is tailored upon a mesenchymal matrix of mesodermic derived cells ["fluid mesoderm" according to Mechtnikoff (1893)]. Contrarily to what has been described for morphogenesis, these processes are not primarily invasive injuring phenomena, rather they develop as a reaction to injury, pursuing hiatus closure, where: 1) the intensity of injury is a decisive factor, (14) and 2) the invasive mesoderm interference with the original tissue pattern is secondary to the release of cell products--growth-promoting factors--by the damaged cells. (15) This reactive tissue response to exogenous injury--defined as inflammation--hence promotes endogenous injury circuits mediated by mesodermic derived cells on the epithelial tissue milieu. In experimental studies on the cirrhosis injury model of repair/ regeneration, inflammation followed by cellular death leads to the release of "growth factors" by damaged/ necrotic cells participating in the parenchyma regenerative events (Bustuoabad, data not shown).

In the repair/regeneration processes, the new structures arise from the bimodal destructive/ proliferative actions induced by injury, which mimic the embryo response. New functions are also promoted as the development of resistance to injury--as featured by tubular resistance after glomerular inflammation, produced by nephrotoxic injury and similar phenomena described in myocardium, lung and pancreatic cells. (12)

4. Field Topography Disruption

In the embryonic stages of gastrula and neurula, active cell movements lead to disruption of tissue topography with production of empty spaces in the morphogenetic field by electrical decoupling of intercellular joints. Such spaces are electrochemical hiatus rendering structural instability into the morphic fields, in turn triggering cellular rearrangement within the growth embryo patterns. (16) A vacuum effect -abruptly altering field stability-, would then reactivate the capacity of morphic regulation of organized biological systems by modeling new structural sketches.

Concluding Remarks

The herein proposed hypothesis claims that injury and death play a basic role in self-organization. Conversely to the unicellular model of self organization--sustaining an equilibrium of intracellular and milieu interactions, as described in the hypothesis of "autopoiesis" (1)--this animal metacellular hypothesis, which is based on the embryonic development process, stresses that the main biologic organizational force leading to the self organization is the structural response to injury, which are triggered by disturbances caused by competitive cell clusters that finally result in cell proliferation and differentiation [embryonic autopoiesis].

The multicellular interactive injuring patterns during embryo organization characterized as cellular invasiveness and cellular induction, produce cellular damage and death together with field topography disruption of the morphogenetic fields, as featured by electrochemical hiatus. This latter disturbance in the field program by electrical disengagement of the cell, leads to blocking, interfering or distorting cell communication. (16) If gap-junctions communication between adjacent cells plays a role in the regulation of information during normal embryonic development -when messages cannot be properly interpreted- instability is generated along with alteration of the organization capacity within the morphic field. (17) In such an unstable, "enthropic" system, new dynamics are being constructed, such as those described for dissipative systems, in which disruption and fluctuation behave as creative components under unbalanced conditions. A multicellular system therefore displays unexpected potentials, which favor the construction of new orders and more complex structures, such as those that belong to the embryo development process. (18) From this point of view, new embryo organizations could be presumed as transitory formations that are triggered by a phenomenon of "life activation" in response to injury and death--a highly paradoxical notion when regarding fertilization.

We hope that this metacellular animal hypothesis of selforganization, as posing new perspectives of understanding about a dynamic role of injury and death in the biological organization, may lead to a prolific line of thought in order to review the functioning of self-organizative systems in various biologic realms--i.e., those that hold permanent reorganizative processes of structures, both in the evolutionary perspectives of animal development, as well as in the pathological mechanisms that lead to tumor development.


We wish to thank Dr. J. Herkovits for his support of this theoretical approach, Dr. H. Rios for his aid in the bibliography and Dr. C.D. Pasqualini, Lic. We extend our gratitude to Sonia Gomez, Maria Ines Alvarez and Victoria Bustuoabad for their help in the English writing of the paper.


(1.) Varela, F.J., Maturana, H.R. and Uribe, R. (1974). Autopoiesis: The organization of living systems, its characterization and model. Biosystems, 5, 187-196.

(2.) Herkovits, J. and Faber, J. (1978). Shape: its development and regulation capacity during embryogenesis. Acta Biotheoretica, 27 (3/4), 185-200.

(3.) Enders, A.C., Hendrickx, A.G. and Schlake, S. (1983). Implantation in the rhesus monkey: initial penetration of the endometrium. American Journal of Anatomy, 167, 275-280.

(4.) Gilbert, B.M. (1997). Cleavage: creating multicellularity. Development Biology,5, 181-183.

(5.) Carlson, B.M. (1988). Patten's Foundations of Embryology, 5th edition. New York: McGraw Hill.

(6.) Karasaki, S. (1957). On the mechanisms of the dorsalization in the ectoderm of Triturus gastrulae caused by precytolytic treatments. I. cytological and morphogenetic effects of various injurious agents. Embryologia, 3, 317-334.

(7.) Yamada, T. (1950). Dorsalization of the ventral marginal zone of the Triturus gastrula. I. Ammonia-treatment of the medioventral marginal zone. Biol. Bull., 98, 98-121.

(8.) Brison, D.R. and Schultz, R.M. (1997). Apoptosis during mouse blastocyst formation: evidence for a rol survival factors including transforming growth factor alpha. Biology Reproduction, 56, 1088-1096.

(9.) Bustuoabad, O.D., Salas, P. and Pisano, A. (1979). Comparative study of the monovalent cations on development of Bufo arenarum eggs. Acta Embryologiae Experimentalis, 2, 121-139.

(10.) Bustuoabad, O.D. and Pisano, A. (1974b). Estudio de las interrelaciones celulares por intercambios de blastomeros en Bufo arenarum. Acta Embryologiae Experimentalis, 2, 137-148.

(11.) Coffey, D.S. (1998). Self organization, complexity and chaos: The new biology for medicine. Nature Medicine, 4, 882-885.

(12.) Vogt, B. A., Shanley, T. P., Croatt, A., Alam, J., Johnson, K. J., and Nath, K. A. (1996). Glomerular inflammation induces resistance to tubular injury in the rat. A novel form of acquired hemeoxygenase-dependent resistance to renal injury. Journal Clinical Investigation, 98, 2139-2145.

(13.) Chang, M. C. (1954). Development of parthenogenetic rabbit blastocysts induced by low temperature storage of unfertilized ova. Journal Experimental Zoology, 125, 127-149.

(14.) Polezhayev, L. W. (1946). The loss and restoration of regenerative capacity in the limbs of tailless amphibia. Biol. Rev, 21, 141-147.

(15.) Menkin, V. (1941). Cellular injury in relation to proliferative and neoplastic response. Cancer Research, 1, 548-556.

(16.) Yamasaki, H., Enomoto, T., Martel, N., Shiba, Y., and Kanno, Y. (1983). Tumour promoter-mediated reversible inhibition of cell-cell communication (electrical coupling). Experimental Cell Research, 146, 297-308.

(17.) Levin, M. (2002). Isolation and community: a review of the role of gap-junctional communication in embryonic patterning. Journal Membrane Biol,185, 177-192.

(18.) Davidson, E. H. (1993). Later embryogenesis: regulatory circuitry in morphogenetic fields. Development, 118, 665-690.

Oscar D. Bustuoabad and Julio E. Correa

Departamento de Patologia, Centro de Estudios Oncologicos, Division Medicina Experimental, Instituto de Investigaciones Hematologicas, Academia Nacional de Medicina, Pacheco de Melo, 3081,1425 Buenos Aires, Argentina. E-mail:
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Title Annotation:News & Views
Author:Bustuoabad, Oscar D.; Correa, Julio E.
Publication:Frontier Perspectives
Geographic Code:3ARGE
Date:Mar 22, 2004
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