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Turing-child energy field drives biological development and regeneration

21 August 2008

authorsDr Yoram Schiffmann

Missing link between the molecular and macroscopic levels

The problem of the relationship between the molecular genotype and the macroscopic phenotype was considered to be the fundamental open problem of biology throughout the twentieth century and our recent better understanding of the molecular level has not changed this unfortunate situation (Schiffmann, 1997). We better understand correlations at the molecular level such as the order of nucleotides in DNA and RNA and its relation to the order of amino acids in proteins, the correlation of these ordered sequences with the 3D structures of proteins and self-assembled complexes. But, why, for example, does a particular genetic mutation result in a change of 5 fingers into 6 fingers? Why in Drosophila does a particular genetic mutation result in a leg in a place normally reserved for an antenna? Why does a certain faulty gene cause cleft lip and palate? Schrodinger (1944), who was intrigued by the inheritance of a disfigured lower lip in the Habsburg dynasty over hundreds of years despite the random heat motion, suggested that the code for this lip and for the orderly macroscopic development of an organism is based on the specific intra-molecular order since only the strength of the chemical bond would withstand the thermal agitation and thus prevent frequent spontaneous mutations. He thus announced the idea of a genetic information-rich program and implicitly dismissed all notions of 'preformation' apart from intra-molecular order. He likened these molecules to an aperiodic solid, stressing the highly improbable nature of biology's informational macromolecules from the point of view of chemistry: only relatively few biological macromolecules are chosen by natural selection from the huge number of molecules that chemistry allows. The order within biology’s macromolecules 'somehow' dictates the ordered ‘anti-thermodynamic’ development of biological organisms. This is Schrodinger’s order from order principle. It is the word 'somehow' that has bedeviled molecular biology for a long time (Schiffmann, 1997).

Instability of the homogeneous state

The problem of the black-box relationship between molecular structures and macroscopic structures separated by spatial scale of orders of magnitude is connected to the problems of epigenesis, localization, spontaneous symmetry breaking and self-organization, i.e. the spontaneous emergence in biological development and regeneration of increasing macroscopic heterogeneity starting from homogeneity and without external or internal spatial cues or signals. For many years the dominant theory in developmental biology has been 'Induction Theory' which purports to explain epigenesis and differentiation but does not explain self-organization (Schiffmann, 2005). The appearance of chemical heterogeneity out of homogeneity is a challenge to the second law of thermodynamics since the requirement of a system to be open and far from thermodynamic equilibrium is only a necessary condition for the lowering of its entropy. Turing's (1952) mathematical idea about the instability of the homogeneous state in a specific chemical reaction-diffusion system provided the sufficient theoretical conditions for the emergence of chemical heterogeneity. Since then the problem has been to identify the Turing instability in biological systems. This elusive nature of the Turing morphogens in biological systems led to alternative non-chemical theories of self-organization where the instability of the homogeneous state is provided by mechanical or electrical or elastic properties instead of chemical. However, these theories neglect the specific order in biology's informational macromolecules (Schiffmann, 1994).

I have suggested that cAMP and ATP are the elusive Turing morphogens and that biochemistry is organized so that these molecules fulfil Turing's conditions of instability of the homogeneous state. Furthermore, the 'improbable' molecules involved in processes downstream of the Turing field, the field that results from the instability, are also specifically structured so that they will be affected by the field. The overall astronomical chemical improbability involved in choosing the totality of these molecules by natural selection assures us that this is the unique and universal Turing field that operates in all stages of development of all organisms (Schiffmann, 1994, 1997). This system provides the missing general rule for the transition between the molecular and macroscopic levels, a transition that hitherto has been locked in a black box. It is the symmetry-breaking Turing instability that opens this black box and explains the 'somehow' in Schrodinger’s order-from-order principle .

The Turing-Child field

Child's metabolic gradient is an experimental phenomenon that has been known for a century (Child, 1941), but whose origin could not be explained. It was considered an epiphenomenon and has been almost totally ignored in the last half a century. But the identification of the Turing system in biological systems predicts and explains Child's metabolic gradient. The Turing field is the spatial distribution of [cAMP] and [ATP]. Its shape can be predicted mathematically from the nonlinear (bifurcation) elaboration of Turing's theory. This shape is largely dependent on the geometry and boundary conditions of the reaction-diffusion domain and independent of the details of the chemical mechanism (Schiffmann, 1980). Child's metabolic gradient, also called the physiological gradient, is a gradient in the rate of energy metabolism. It is a vector field whose field lines are perpendicular to the isoconcentration contours of the Turing morphogens and pointing in the direction of the greatest decrease in the concentration of the Turing-Child morphogens (Schiffmann, 2007).

The Turing-Child field concerns not matter but biochemical reactions. Hence the importance of working in live biological material in order to observe it experimentally. In dead biological material, for example in fixed material or when inhibitors of the electron transport or uncouplers are added, the Turing-Child patterns disappear. The Turing-Child pattern is appropriately called a biological dissipative structure, or a process structure, or an autopoietic structure, to signify its dependence on dissipation of energy and on-going chemical reactions. The spontaneous succession of the Turing-Child patterns are the primary events that drive the development of all organisms in all stages of their development. These self-organizing patterns are spatially differential energy patterns which are suitable as primary events on a priori grounds. Indeed, it is the provision of localized energy that precedes all localized downstream events including those involved in cell differentiation and morphogenesis. Furthermore, because these spontaneously emerging spatially differential energy patterns drive all downstream events simultaneously, they explain the problem of coherence and coordination between all downstream processes, including the all-important differentiation and morphogenesis.

Future work

Child found that regeneration (reconstitution) largely imitates normal development. The Turing-Child framework is appropriate for understanding the problem of form regulation, including how to get a normal whole organism, or a whole organ, from a part (Schiffmann, 2001; 2005). Many of the currently hot topics in medicine (and agriculture) involve this problem of transforming a part into a whole, including the topics of Assisted Reproductive Technologies (ART), regenerative medicine and stem cell biology. A better understanding of the primary events in differentiation and morphogenesis would allow the more effective development of therapeutic strategies in pre-natal intervention to minimize birth defects, and in tissue restoration in cases of diseases and injuries in the adult. Many diseases are due to a failure of differentiation and morphogenesis. There is even a long-standing view that cancer is primarily due to a failure of spatial order and differentiation.

Now that the whole human and other genomes have been sequenced, and in view of other ongoing large-scale projects at the molecular level such as in proteomics, the correlation between the molecular and the macroscopic levels is particularly timely. Therefore what is now desirable is a large-scale effort to determine the Turing-Child field in the development of various organisms, and to correlate these results with the downstream events such as differential gene expression, morphogenesis, gastrulation, neurulation, organogenesis and convergent extension. The shape of these downstream events reflects the shape of underlying Turing-Child patterns (Schiffmann, 2005; 2006). These experimental underlying patterns can also be compared with the theoretically predicted patterns obtained by the modern mathematical theory of the Turing system. Large-scale determination of the Turing-Child field would complement existing strategic differential gene expression programs, for example as described in Lindsay S. and Copp A. J. (2005).

  • Child, C.M., 1941. Patterns and Problems of Development. University of Chicago Press, Chicago, Il
  • Schrodinger, E., 1944. What Is Life. Cambridge University Press. Cambridge, U.K
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  • Lindsay, S., & Copp, A. J., 2005. "MRC-Wellcome Human Developmental Biology Resource: enabling studies of human developmental gene expression", Trends in Genetics, 21, 586-590
  • Schiffmann, Y., 1980. Physics Reports, 64, 87-169
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  • Schiffmann, Y., 2001. Prog. Biophys. Mol. Biol. 75, 19-74
  • Schiffmann, Y., 2005. Prog. Biophys. Mol. Biol. 89, 36-92
  • Schiffmann, Y., 2006. Prog. Biophys. Mol. Biol. 92, 209-231
  • Schiffmann, Y., 2007. Prog. Biophys. Mol. Biol. 95, 50-59

Yoram Schiffmann

Title:    Dr
Advanced degrees: Professor
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Position 1: Dr
Affiliation: Department of Applied Mathematics and Theoretical Physics Centre for Mathematical Sciences
Country: United Kingdom
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