The Nature, Origin, and Evolution of Life: Part IV Cellular Differentiation and the Emergence of Multicellular Life

Introduction

As discussed in the last commentary, the emergence of complex life among eukaryotic cells was largely enabled by the evolution of a unique method for capturing and storing large quantities of cellular energy in the phosphate bond of ATP (1). This, in turn, was enabled by the process of cellular respiration and the resulting proton gradients across the largely impermeable inner membrane of mitochondria (2). The availability of such enormous energy provided eukaryotes with nearly unlimited potential for both diversity and ultimately the development of multicellular organisms (3). Subsequently, cellular differentiation and specialization greatly enhanced an organism’s ability to compete and evolve within a constantly changing environment. While bioenergetics was necessary for these revolutionary developments, the resulting cellular specialization was, in fact, controlled by information stored in nucleic acid polymers and the resulting DNA (4). The enzyme-enabled processes of transcription of the coded information into RNA and subsequent translation into polymers of amino acids or proteins resulted in the specialized structural and highly functional behavior of cells in multicellular life.

As we will see, structural and functional differentiation is largely enabled by molecular and enzymatic constraints imposed upon the transcriptional process over time and further constrained by the interactions with the cellular environment. Finally, while cancer has often been described as a ‘block’ in the normal differentiation process, it more closely represents a release from the constraints responsible for normal cellular differentiation. As a result, each individual cancer cell remains mostly undifferentiated enabling continuous and largely unrestrained cellular proliferation limited only by the availability of nutrients from blood and surrounding tissues.

Control of transcription over space and time

The molecular fundamentals of gene transcription and translation have been elaborated in considerable detail in both prokaryotes and eukaryotes (5). Like the cracking of the genetic code and the sequencing of the human genome, this detail provides a fair degree of reassurance that the fundamental processes involved are self-evident (4). In eukaryotes, the coding sequence of most genes are preceded by a promotor region to which RNA polymerase attaches to a regulatory region. Gene expression proceeds by transcription to RNA regulated by regulatory transcription factors (enhancers and repressors) that attach to the promotor region turning genes on and off as a part of the of a transcription initiation complex. The primary RNA transcript includes both coding exons and non-coding introns, the later of which are removed by a novel splicing process to form the final messenger RNA subsequently translated into chains of amino acids or proteins through the ribosome representing a complex of RNA and protein. Proteins then move from the ribosome-containing rough Endoplasmic reticulum (ER) to the smooth ER and the Golgi apparatus where glycosylation occurs and from whence they move into vesicles to their needed location inside or outside of the cell. In the end, different cells constituting various tissues or organs each have a unique collection of proteins needed to support their specialized structure and function controlled by the highly regulated processes modulating gene expression.

Fundamentals of cellular controls

A deeper look suggests that there is far more unknown currently than known about how complex multicellular life actually works and including the development and evolution of organisms. The turning on and off of gene transcription and eventual translation into specialized tissues of the developing organism over time is at the heart of a large, almost fathomless, gap in our understanding of the functionally continuous, developing, evolving living organism (6). Much of the control over the network of negative and positive feedback processes clearly resides within a multitude of enzymes and other proteins. However, there must be additional control mechanisms dependent upon the location (tissue, organ etc) and development of these specialized areas over time. Undoubtedly, such controls involve interactions among proteins and in turn their interaction and modification by intracellular membranes. In addition, and perhaps even more dramatically, such controls emerge out of direct cell-cell interactions including the action of selective cell signaling molecules exerting their effect through receptor responses to signals emerging from other cells and tissues. Signal transduction signals through effectors from other cells results in a highly complex network of molecular controls, the overriding blueprint of which is not at all well understood.

Most of our limited understanding of the basic elements of cellular control networks has emerged from studies in disease settings where mutations have resulted in abnormal control or the absence of proper control often apparent at the local cellular or tissue level. For normal activities as well as cellular specialization, intricate control is needed to enable the synthesis of specific proteins at the proper time and in the specific cells required for normal development.

Cellular signaling and signal transduction

Importantly, all cells live in an environment surrounded by other cells with which they can and must interact and communicate. Such cell-cell signaling is fundamental to cellular control as well as organismic development ensuring cells take on their proper structure, function and location with the organism (6). Signaling molecules from outside of cells interact with highly specific sites on receptors, usually consisting of transmembrane proteins embedded in and spanning the relatively impermeable cell membrane. The signal/receptor complex is then modified or transduced in a manner that the cell interprets generating the appropriate response as the result of a cascade of molecular interactions and changes terminating in the desired final action. The various signal transduction pathways utilized by multicellular organisms coordinate and amplify the message of the signal. Other molecular control processes may act as transcription factors controlling gene expression or directly activate existing enzymes through phosphorylation as a protein kinase. Most signal transduction pathways are part of a signaling network providing the opportunity for cross talk between them thus relating a variety of inputs with a range of responses enabling greater feedback and overall control. Secondary messengers including calcium and cyclic AMP further enhance or modulate cell-cell communication. Adding to the diversity of cellular control in multicellular organisms is the observation that similar receptors may activate different types of signal transduction pathways and responses.

Fundamentals of multicellular controls

All living organisms develop from a single cell and yet have their coded information and capacity to develop into highly diverse multicellular organisms with trillions of cells and a multitude of different cell types most of which are specialized both structurally and functionally. The initial fertilized egg has the potential to divide rapidly as do early progeny utilizing the mRNA and proteins present in the zygote. Interestingly, early progeny are morphologically similar across species while retaining the ability to develop into the entire organism.

With further development and despite enormous diversity and cellular specialization, each cell in the mature organism retains in its nucleus all of the genetic information in coded form necessary for the entire organism and all of its component parts (7). However, constraints on gene expression in subsequent progeny gradually result in cellular determination, specialization or differentiation by narrowing or constraining the structural and functional behavior of the cells. The genes expressed are highly constrained by both internal and external transcription factors from other genes and cell-cell interactions among other factors. The determination or commitment of cells to develop specific shape, form and function of the living organism depends upon external factors including cell-cell interactions, cell signaling and ultimately the formation of morphogenetic patterns resulting in the final organism including the process of programmed cell death.

Thus, subsequent development characterized by cellular differentiation and organogenesis resulting in the final organism are the result of space- and time-dependent constraints on gene expression by enzymes and other proteins in a complex and incompletely understood sequential pattern. Determination appears to be a gradual process eventually resulting in a fully differentiated or specialized cell. On a final note, stem cells persist in many tissues of adult organisms capable of dividing and differentiating into a limited number of cell types replacing damaged or dying cells.

The emergence and control of multicellular organisms

A multicellular organism can be viewed as similar to a mosaic where the various individual cells fit together in a living form with vast interconnections producing an entire functional, developing and evolving whole. Perhaps most perplexing and largely misunderstood is how this vast array of cells and cell types result in a highly integrated whole organism with each cell and cell type supporting and supported by the entire organism. Needless to say, our understanding of how this vast array of parts constitute a living, developing and evolving whole organism is extremely limited. Despite the nearly unfathomable complexity and incredible need for coordination and control, it all works consistently over the course of time of development and from generation to generation. Clearly factors beyond the genetic code and present in every cell must influence and control the expression of the genetic information, cellular differentiation and the subsequent development of specialized tissues resulting in the whole functioning organism. Importantly, a breakdown in the control and coordination of this complex network may result in a release from normal constraints and potentially result in unconstrained growth and behavior such as tumor growth, invasiveness and spread to other tissues. How this might or actually does happen as a result of mutations or epigenetic changes will be the topic of future editorials.

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