Saturday, August 2, 2008

From Structure to Structure-Process Duality: A Paradigm Shift in Biology

(The following excerpt is from a book manuscript which is being prepared for Springer, New York, for possible publication in 2009-2010. I thought it might be of some interest to this group because it advocates a ’triadic biology’ based on the idea that the function stems from the triad of structure, process, and mechanism, in contgrast to the traditional dyadic biology which is based on structure and function. This is reminescent of Peirce's triadic semiotics as compared to de Saussure's dyadic semiology. The excerpt is rather long, but, if you have time to read it and have any questions, comments, or suggestions for improvements, I would appreciate hearing from you.)


Structure (e.g., DNA) and processes (e.g., gene expression) are both essential to account for life on the molecular level. In other words, structure (S) and processes (P) are fundamental to life on an equal footing, and yet contemporary biologists have been emphasizing structures over processes, probably influenced in no small measure by the discovery of DNA double helix in 1953 and its astounding successes in subsequent decades as well as by experimental constraints that favor the study of stable structures over transient, dynamic processes.

Biologists probably can learn from a similar experience that physicists went through between the 17th and 20th centuries in the form of the wave-particle duality debate on the nature of light. As is well known, the Huygens, Bohr and their followers thought that light was a wave (on the basis of interference phenomena, for example), while Newton, Einstein and their followers firmly believed that light was a stream of particles (as evidenced by the photoelectric effect). The wave-particle duality problem was not resolved until the early decades of the 20th century when the new science of quantum mechanics was established in the hands of Planck, Einstein, de Broglie, Heisenberg, Dirac, Schrődinger, Pauli, and Born. The resolution came in the form of the de Broglie equation, λ = h/p, where λ is the wavelength associated to the particle moving with momentum p. That is, quantum mechanics informs us that all particles have wave-like properties and all waves have particle-like properties. The reason macroscopic particles do now show any wave-like properties when they move is because their wavelengths calculated from de Broglie equation are too short to be detected.

Available evidence indicates to me that the 21st century biology is faced with the ‘structure-process’ duality problem that may be analogous to the ‘wave-particle’ duality paradox encountered in physics in the past century. I offer the following three examples as evidence for the need to make a transition from the traditional structure-centered perspective to a new paradigm for the biology of the coming decades that is based on ‘structure-process duality’, i.e., the perspective treating structures and processes on an equal footing.

1) Microarray experiments
With the invention of the DNA microarray technique in the mid-1990's,
biologists have been able to measure RNA levels of tens of thousands of genes simultaneously. The mistake (in my opinion [1]) that many biologists have been making unwittingly in this field over the past decade or more is this: When the microarray technique is used to measure the so-called gene expression profiles (i.e., time-dependent RNA levels) and ascribe to the genes encoding these RNAs the role for regulating their levels, biologists are measuring P (i.e., ‘changes’ in RNA levels) and reducing it to S (i.e., DNA ‘sequences’) without specifying any mechanisms. “Changes” are processes and “sequences” are structures and these cannot be connected or correlated without specific mechanisms. It is analogous to physicists who measure particle properties of an object and interpreting them in terms of waves or vice versa, under the conditions where no such interpretations are allowed by the de Broglie equation.

Interpreting the kinetics of the changes in RNA levels in terms of their DNA templates is misguided because it ignores the well-known mechanisms of the control of RNA levels inside the cell: Intracellular RNA levels are determined not by their DNA TEMPLATES but by the balance between two opposing PROCESSES – i.e., transcription and transcript degradation, and the DNA sequences serving as the templates for RNAs have little, if any, to do with transcript degradation process [1].

Just as the wave-like and particle-like properties of material objects cannot be correlated in physics outside the domain of the validity of the de Broglie equation, so structures and processes in living systems may not be correlated unless realistic physicochemical mechanisms can be found. For convenience, we may refer to interpreting P as correlated to S (or S as correlated to P) without proposing any underlying mechanisms in biology as the 'P-S conversion error'.

One way to avoid committing the ‘P-S conversion error” is to treat S and P as independent entities on an equal footing (S-P democracy ?), while acknowledging that S and P cannot be interconverted or correlated in the absence of proper mechanisms for doing so, just as physicists (after the mid-1920’s) treat particles and waves as independent entities on an equal footing, until and unless they can be correlated through the de Broglie equation.

Biologists are not alone in committing the ‘P-S conversion error’. It seems that process philosophers in the Whiteheadian tradition have eliminated S all together in favor of P, in contrast to biologists who have tended to eliminate P in favor or S. Perhaps both process philosophers and biologists can learn from each other and from what is referred to as the “rest-motion” duality (see Table 1) which appears to be a principle universally applicable to physics and biology.

Although the content of Table 1 is more or less self-explanatory, the following features are important to be pointed out.

1) The particle-wave duality and the structure-process duality may be connected through the following two identities (see Row 4 in Table 1):

Particle = structure
Wave = process

2) Particles and waves are related through motions. Examples include the oscillatory motions of atoms in molecules generating electromagnetic waves. Oscillatory motions, in turn, implicate both rest (at the position where the velocity changes its direction) and motions (in between rests). Therefore, what is common to both particle-wave duality and the structure-process duality may be construed to be the ‘rest-motion’ duality. It seems possible that the rest-motion duality is also related to the equilibrium-dissipative structure duality advocated by
Prigogine (1917-2003) at least under non-isolated (i.e., non-adiabatic) conditions (see Row 5).

3) As indicated in Row 3, the wave-particle duality may be predominantly confined to microscopic domain, whereas the structure-process duality can be applied to both microscopic (e.g., fundamental vibrational modes of enzymes leading to low-frequency conformational transitions effecting catalysis) and macroscopic (e.g., DNA sequences determining the behavior of a person).

4) ‘Mechanisms’ in biology may play the role of ’mathematical equations’ in physics (see Row 2). Although mechanisms and mathematical equations are very different in appearance, they may serve as equally valid and efficient presentations of physical laws and principles. In other words, there may be two classes of physical laws and principles – those describable in terms of mathematical equations and those that cannot. In the latter case, one way to represent them may be in terms of mechanisms, a set of processes implemented by the motions of structures. The idea of putting mechanisms on an equal footing with mathematics may be referred to as the ‘mathematics-mechanisms’ duality (MMD), in analogy to the wave-particle duality and now the structure-process duality. The conception of MMD goes against the traditional belief, probably first clearly articulated by David Hilbert in the late 19th century, that no deep problems in physical sciences can be solved without the help of mathematics, which may be analogous to the Newtons and Einsteins claiming that all wave-like properties are ultimately derivable from particles or to Huygens and Bohrs asserting that all particle-like properties are derivable from waves.

Table 1. The ‘rest-motion’ duality in physics and biology.

#. Parameter = Physics = Biology
1. Duality = particle-wave = structure-process

2. Constraint = de Broglie equation = mechanisms

3. Domain of validity = microscopic = microscopic and macroscopic

4. Connection = particle (wave) = structure (process)

5. Universality = rest-motion duality = rest-motion duality

2) The definition of a gene
Prior to 2007 when the results of an international research effort known as the ENCODE (Encyclopedia of DNA Elements) Project was announced, the definition of gene was simple: DNA segments encoding RNAs leading to protein synthesis [2]. But the ENCODE project has unearthed numerous new findings that cannot be readily commodated by this simple conception of a gene and a new definition of a gene is called for. The failure of the pre-ENCODE conception of a gene can be traced ultimately to the following fact: Biologists have been measuring the functions of genes (i.e., P) and reduced the results to nucleotide sequences of DNA (i.e., S) without specifying requisite mechanisms: i.e., the 'P-to-S reduction error’ again. One way to resolve the problems revealed by the ENCODE project is to postulate that there are two equally important classes of genes -- the S-genes and P-genes. The former is identified with the pre-ENCODE conception of genes (also called the Watson-Crick genes [3]) and the latter is a new class of genes called the Prigoginian genes [3]). S-genes are analogous to sheet music (or written language) and P-genes are analogous to audio music (or spoken language) [4, 5]. Just as the sheet music is converted into audio music by a pianist, so the Watson-Crick genes are postulated to be transduced into Prigoginain genes by conformons, the sequence-specific conformational strains of enzymes [3]. Thus, conformons are analogous to the de Broglie equation, since mechanisms based on conformons can convert structure (S-genes) to processes (P-genes) in cells [3, 6], just as the de Broglie equation can convert the particle-like properties of moving objects to their wave-like properties. If this analogy turns out to be true upon further theoretical scrutiny, it may be predicted that conformons will resolve the structure-process paradox in molecular cell biology in the 21st century just as the de Broglie equation solved the wave-particle paradox in particle physics in the 20th century.

3) Free radicals and human diseases
Free radicals are defined as any chemical species carrying one or more unpaired electrons. Examples include the superoxide anion free radicals (an oxygen molecule with one extra electron), nitric oxide (NO), and carbon-centered free radicals generated during air oxidation of phospholipids constituting cell membranes.

Many free radicals are generated in cells as the results of normal metabolism as during mitochondrial respiration responsible for generating ATP but do not cause any harm because their concentrations are strictly controlled not to exceed critical levels (reminiscent of nuclear reactors wherein nuclear chain reactions are controlled to proceed at desired rates by inserting or withdrawing graphite rods). They cause cell damages only when such control mechanisms malfunction or go awry due to environmental toxicants or pathogens. Therefore it seems reasonable to postulate that there are two kinds of free radicals in cells and tissues -- "good" and "bad" free radicals, depending on HOW MUCH of them is produced WHERE, WHEN, and for HOW LONG [6]. In other words, not all free radicals are bad (as many biologists have been assuming), since it is not the chemical structures of free radicals (i.e., S) but rather their spatiotemporally organized concentration distributions in living cells and tissues (i.e., related to P) that determine whether they are good or bad for human health. To remedy the shortcomings of the traditional paradigm in biomedical research, therefore, it appears necessary to make a transition from the traditional 'equilibrium structure-based' (i.e., S-based) paradigm to the 'equilibrium-dissipative structure duality-based' (i.e., S-P dual) paradigm. The drugs developed under the S-P dual paradigm may be referred to as the "dissipative structure-targeting drugs (DSTDs)" as compared to those developed under the traditional S-based paradigm as "equilibrium structure-targeting drugs (ESTDs)" [7]. It is possible that DSTDs will become an increasingly important form of drugs in the coming decades.

With all the best.


Sungchul Ji, Ph.D.
Department of Pharmacology and Toxicology
Rutgers University
Piscataway, N.J. 08855


[1] Ji, S., Chaovalitwongse, A., Fefferman, N., Yoo, W., and Perez-Ortin, J. E. (2008). Mechanism-based Clustering of Genome-wide RNA Levels in Budding Yeast: Roles of Transcription and Transcript Degradation. In: Clustering Challenges in Biological Networks (Chaovalitwongse, A., ed.) (in press).
[2] Gerstein, M. B., et al (2007). What is a gene, post-ENCODE? History and updated definition. Genome Research 17:669-681.
[3] Ji, S. (1988). Watson-Crick and Prigoginian Forms of Genetic Information. J. theoret. Biol. 130: 239-245.
[4] Ji, S. (2009). Molecular Theory of the Living Cell: Conceptual Foundations, Molecular Mechanisms, and Applications. Springer, New York (to appear) .
[5] Ji, S. (2009). Words, Sounds, and Meanings of DNA. Imperial College Press, London (in preparation under invitation from the publisher).
[6] Ji, S. (1991). Biocybernetics: A Machine Theory of Biology. In: Molecular Theories of Cell Life and Death (Ji, S., ed.), Rutgers University Press, New Brunswick. Pp. 1-237. See the section on FSDM Hypothesis of Disease Development on pp. 191-194, available at, under Publications.
[7] Ji, S. (2010). Cell Model-Based Pharmacotherapeutics and Toxicology (in preparation).

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