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‘knockouts,’while at the same time explaining why genetic defects require special conditions to produce a ‘disease phenotype.’Such ‘corrections’ of defects are driven by thermodynamic principles, which can on occasion overcome kinetic blockades. Thus, the interconnected metabolic pathways together act as an integrated unit often able to correct genetic or other insults by ‘seeking out’and/or bypassing the affected enzyme or abnormal substrate. Spontaneous corrections are driven by thermodynamic principles favoring an “increase in rate of energy degradation of available energy of a system, environment plus organism, in dissipative pathways”(refs. 6, 7; Harold Morowitz, George Mason University, Fairfax, VA; and Richard Veech, National Institutes of Health (NIH), Bethesda, MD). Transcription of the genome is regulated by altered concentrations of metabolites: NAD+ and NADH and other synoptic signals represent minute-by-minute changes in the bioenergetic status of the cell. Changes in glucose, steroids, fatty acids, retinoids, and many other metabolites are detected by binding to transcription factors that mediate gene silencing and activation. The expression of the genome is thus regulated through biochemical mechanisms that sense the bioenergetic state of the cell. In terms of the dominant triadic coupling in biology, gene-organism-environment, all of evolution and of individual life may be viewed through the lens of thermodynamics coupled to the constraints arising from kinetic and other interactions of organized molecular systems8.

The important point here is that genetic variations together with environmental and behavioral changes are filtered through the highly conserved and regulated epigenetic networks of gene replication, protein synthesis, and of metabolism and molecular signaling systems. That is, it is within these dynamical, self-organizing protein and small molecule networks that genetic, environmental, and behavioral contexts are brought together and are reconciled in the still ineffable terms of normal versus pathological phenotypes of human disease. All of this negotiation and production of a final phenotype may remain ‘unexplainable,’but it is, nevertheless, a negotiation whose results are made predictable and understandable by fitting the quantitative measurements of biochemistry and of metabolic control analysis to the thermodynamic and kinetic equations of state that describe the many dissipative, work-producing processes essential to a healthy phenotype. If there is