From Physiology, Genomes, Systems, and Self-Organization to Systems Biology: The Historical Roots of a Twenty-First Century Approach to Complexity - Systems Biology of Metabolic and Signaling Networks - page 8

depend more on the underlying dense gene interactive network. The outcome of a
developmental process (represented by the rolling ball) depends on its dynamic
trajectory, and its path through the different valleys (i.e., differentiation states) can
arise from bifurcations. Morgan ( 1934 ) had previously noted that different groups
of genes will come into action as development proceeds.
Waddington ( 1957 ) stressed the important implications of time in biology,
distinguishing the biochemical (metabolic), developmental (epigenetic), and evo-
lutionary, as the three realms in which time plays a central role in biology. Later,
Goodwin ( 1963 ) adopts the metabolic, epigenetic, and genetic systems as basic
categories for defining a system (e.g., cell) with respect to its environment.
The concept of epigenesis is a precursor of what is now known as “epigenetics,”
a whole new research field. Historically, the term “epigenetics” was used to
describe events that could not be explained by genetic principles. Originally,
Waddington defined epigenetics as “the branch of biology which studies the causal
interactions between genes and their products, which bring the phenotype into
being” [Waddington ( 1942 ), quoted in Goldberg et al. ( 2007 )]. Consequently, a
phenotypic effect or an organism following a developmental path is not only
brought about by genetic variation but also by the environment.
Today, we know that in addition to primary DNA sequence information, much of
the information regarding when and where to initiate transcription is stored in
covalent modifications of DNA and its associated proteins. Modifications along
the chromatin involve DNA cytosine methylation and hydroxymethylation, and
acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation of the
lysine and/or arginine residues of histones are thought to determine the genome
accessibility to transcriptional machinery (Lu and Thompson 2012 ). Recent data
indicate that information about a cell's metabolic state is also integrated into the
regulation of epigenetics and transcription; cells constantly adjust their metabolic
state in response to extracellular signaling and/or nutrient availability. One of the
challenges is to visualize how levels of metabolites that control chromatin modifiers
in space and time, translate a dynamic metabolic state into a histone map (Katada
et al. 2012 ).

1.6 The Core of the Living: Biochemistry and Genomes

The elucidation of the basic biochemistry of living systems and the recognition of
its similarity across kingdoms and phyla represent major achievements of the
twentieth century research in biology. The description of metabolic pathways,
mechanisms of energy transduction and of genetic transmission, replication, regu-
lation, and expression stand out as main ones.
The pathways utilized by cells to break down carbohydrates and other substrates
like lipids, roughly divided into glycolysis, respiration, and -oxidation, were

already known to biochemists by the 1950s. Respiration includes the complete
breakdown of the two carbon unit acetyl-CoA into carbon dioxide—discovered by

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