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Introduction

There are these two young fish swimming along, and they happen to meet an older fish swimming the other way, who nods at them and says, "Morning, boys. How's the water?" And the two young fish swim on for a bit, and then eventually one of them looks over at the other and goes "What the hell is water?"

David Foster Wallace, Kenyon College Commencement Speech, 2005

The premise of this book is that the Big Bang of the Universe gave rise to inorganic and organic compounds alike. Both are formed by bonds, the former constituted by inertness, the latter doing quite the opposite by giving rise to life itself. Organic chemistry provided the physical space within which negentropy, chemiosmosis, and homeostasis all acted in concert to form the first primitive cells. Single-celled organisms dominated the Earth for the first 3 or 4 billion years, followed by the generation of multicellular organisms as exaptations. How and why this occurred provides the mechanism for the emergence of human biology, starting with the "first principles of physiology." Such a rendering is way overdue, since the human genome was published more than a decade and a half ago. Without such an effectively predictive working model for physiology, such information is of little value.

Mind the Gap

Let us go then, you and I,

When the evening is spread out against the sky

Like a patient etherized upon a table.

T.S. Eliot, The Love Song of J. Alfred Prufrock

The Michelson-Morley experiment (1887) refuted the notion of luminiferous aether, a theorized medium for the propagation of light, making way for novel thinking about the fundamental principles of physics at the close of the nineteenth century and the beginning of the twentieth. This second scientific revolution was crowned by Relativity Theory (1905), equating energy and mass, a counterintuitive relationship that changed not only the way we see the world around us, but also how we see ourselves. The understanding of the inner workings of the Bohr atom similarly gave insights to physics and chemistry that were previously inaccessible and inconceivable. The twenty-first century has been declared the "age of biology," given our foreknowledge of the genetic makeup of humans and an ever-increasing number of model organisms. Yet the promise of the human genome - the cure for all of our medical ills - has not transpired 15 years hence. We contend that this is symptomatic of our not having attained the level of knowledge in biology that the physicists had reached at the dawn of the second scientific revolution.we are still mired in the sticky, sludgy, stodgy "aether" of descriptive biology. Deep understanding of the inner workings of the cell, particularly as they have facilitated the evolution of multicellular organisms, will herald such breakthrough science. The way in which the cell acts at the interface between the external physical and internal biological "worlds," authoring the script for Life, is a reality play without an ending, reiterative and reinventive. Thus life is formulated to continually learn from the ever-changing environment, making use of such knowledge in order to sustain and perpetuate it.

Duality, Serendipity, and Discovery

The field of biomedical research is characterized by paradoxes, serendipitous observations, and occasional discoveries. This is due to the lack of a central theory of biology, DNA notwithstanding. It is also the reason why we have been unable to solve the challenging "puzzle" of evolution. In lieu of guidelines and principles, we collect anecdotes and make up "Just So" stories based on associations and a posteriori reasoning. This book was written to elucidate how to understand biology based on its origins in unicellular life, evolving in the forward direction of biologic history, both ontogenetically (short-term history) and phylogenetically (long-term history). We use the figure-ground image (Figure 1.1), made popular by gestalt psychology, as a way to express the inherent problem in seeing biologic phenomena as dualities: inorganic-organic, genotype-phenotype, proximate-ultimate, structure-function, health-disease, synchronic-diachronic, ontogeny-phylogeny. It is the latter duality that was the breakthrough for us, realizing that ontogeny and phylogeny, looked at from a cellular perspective, are actually one and the same process, only seen from different perspectives. With that issue put behind us, we could address the "first principles of physiology," beginning with the plasmalemma of protists as the homolog for all of the subsequent traits expressed by multicellular organisms.

Figure 1.1 Figure-ground "faces."

Biology as "Stamp Collecting"

As working scientists, the authors of this book have been involved in studies of developmental physiology for many decades. One of us (J.T.) was first introduced to the concepts of cell biology in reading Paul Weiss, one of the founders of the discipline, when he took advanced placement biology in high school. It was Weiss who admonished us not to ask "how or why" questions, but merely to describe biologic phenomena. That attitude prevailed in biology until the advent of molecular biology in the 1960s, which demanded that we ask how biologic mechanisms functioned, having finally "reduced" the problem to its smallest functional unit, the cell, like the Bohr atom in physics. Yet this reductionist approach has not solved some of the remaining fundamentals of physics, hence string theory, "branes," and multiverses. By analogy, we are of the opinion that we must think in terms of the cell as the smallest functional unit of biology. Conversely, stripping away billions of years of biologic information to focus on DNA is a systematic error that is misleading and misguided, in our opinion. This book is intended to demonstrate how the cell-molecular approach to evolutionary biology provides novel insights to the how and why for the evolution of form and function.

The "why" question has emerged from the New Synthesis of evolutionary biology, particularly after it had embraced developmental biology as evo-devo. But even at that, the evolutionists were not delving into the mechanisms of evolution, seemingly content with random mutation and population selection as the mechanisms of evolution. For working scientists like ourselves, studying how organs develop across species, this didn't seem like a reasonable process since we could see the common denominator between ontogeny and phylogeny at the cellular level, suggesting (to us) that some underlying organizing principle was at large. Not to mention that the ongoing serendipitous, anecdotal nature of both biology and medicine, even in the post-Human Genome Project era, was frustrating given that science is ultimately supposed to be predictive.

Then in 2004 Nicole King published her ground-breaking paper demonstrating for the first time that the complete multicellular genomic "toolkit" of sponges was expressed in the unicellular free-swimming amoeboid form during the life cycle. That reversed everything in biology because up until that point in time physiology was described based on biologic traits in their extant form, not based on how they evolved from the unicellular state. That perspective precipitated our hypothesis that the complete phenotypic toolkit was present in the plasmalemma of unicellular organisms, and raised the question as to how the genome determined complex physiology ontogenetically and phylogenetically, from unicellular organisms to invertebrates and vertebrates.

That question was made all the more pertinent because we had published a seminal paper on the cell-molecular basis of alveolar physiology that had emerged from decades-long study of how the fetal lung develops at the cell-molecular level. Those studies were catalyzed by two landmark observations - the physiologic acceleration of lung development by glucocorticoids, and the observation that parathyroid hormone-related protein (PTHrP) was necessary for alveolar formation. The linking of those two phenomena through the serial paracrine interactions between the lung endoderm and mesoderm culminated in our fundamental understanding of the physiologic principle of ventilation-perfusion matching - essentially how the distension of the alveolar wall molecularly coordinated surfactant production and alveolar capillary perfusion to maintain both local and systemic homeostasis.

The experimental evidence for the coordinating effects of cell stretching on PTHrP, leptin, and their cognate cell-surface receptors on surfactant production and vascular perfusion led to the first scientific documentation of the physiologic continuum from development to homeostasis. More importantly, it begged the question as to how these specific cell types evolved the mammalian lung phenotype, given that the molecular ligand and receptor intermediates involved were highly conserved, deep homologies that could be traced at least as far back as the origins of vertebrate phylogeny in fish, if not all the way back to the unicellular state. If that "story" could be told, it would provide insight to both lung physiology and pathophysiology based on first principles -...