Vision Statement: Even to the naïve observer, it is intuitively obvious that there are patterns of size and shape in biology, patterns that Julian Huxley characterized as the differences in the sizes and shapes of the underlying organs. Darwin was the master at delineating these patterns and defining a process by which they may have evolved through descent with modification. But without an understanding of how and why evolution has occurred we cannot take advantage of the underlying principles, particularly as they might apply to human biology and medicine. This problem arises over and over again in various ways that are characterized as ‘counterintuitive’, which is an expedient way of dismissing observations that cannot be explained using the contemporary descriptive paradigm. For example, why is it that organ systems have co-evolved to link fat metabolism and respiration (the mammalian lung), photoreception and circadian rhythms (the pineal as the ‘third eye’), fluid volume control and erythropoiesis, the lens with digestive enzymes; I believe that this is due to a lack of perspective on the process of evolution. We must rethink evolution in its cellular context because that is where the driving force originated. Such a paradigm shift would allow us to distinguish ‘forest and trees’ and how an understanding of the evolution of structure and function lends itself to the application of genomics to medicine. It seems intuitively obvious that there are fundamental commonalities between ontogeny and phylogeny, given that both start from single cells, and progressively form complex structures through cell-cell interactions mediated by growth factors and their receptors. By systematically focusing on such cell-molecular developmental mechanisms as serial homologies and their underlying gene regulatory networks across vertebrate classes it may finally be possible to elucidate the mechanisms of evolution.

We have applied this concept to lung biology and pathobiology (1), and we have exploited it as a Systems Biology approach through a number of avenues (see Schematic 1). Embryologically, as I have already indicated, the PTHrP signaling pathway is up-stream from the endocrine mechanisms that determine lung development, incorporating the endocrine system into the model. Furthermore, the lung is derived from the gut, which develops through similar gene regulatory pathways, thus incorporating the gut, liver and pancreas in the model. These phenotypic interrelationships can be further exploited by characterizing the gene regulatory networks (GRNs) that determine them (see Schematic 2; note that Time is used in the algorithm as a way of ordering the information hierarchically). For example, we have demonstrated the centrality of both the Wnt/beta catenin and G-Protein coupled Protein Kinase A pathways in the epithelial-mesenchymal interactions that determine lung structure and function. These same epithelial-mesenchymal interactions determine the structure and function of a broad variety of tissues and organs (kidney, liver, pancreas, gut, thyroid, adrenal, thymus, eye, skin). And the emergence of PPAR gamma in the lung fibroblast GRNs engenders such disparate tissues and organs as the brain, bone marrow, liver, and adipose tissue.

The networks of genes that derive from the proposed algorithm are generated using a Self-Organizing Map approach (see Schematic 2) linking specific phenotypes of health and disease together in a way that offers new tools for the diagnosis and treatment of disease.

By identifying the causal relationships between health and disease, disease predisposition and progression can be identified in their pre-clinical stages (as biologists have done all along), allowing for the prevention of the full-blown clinical manifestations. And like the Periodic Table of Elements, which predicts new elements, the biologic algorithm will predict novel GRNs (1). Ultimately, this biologic space-time hologram will reveal the underlying rules for the first principles of physiology.

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Schematic 3. Evolutionary Biologic Mobius Strip.
A mobius strip is one continuous surface created from a surface with two sides. If Biology is represented as one side of the ‘surface’ and Evolution as the other, then forming a Mobius Strip by connecting the two ends with a half-twist one can see how they are ‘flip sides’ of the same space-time continuum.