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Chapter 1

Introduction

In this book, we’ll cover a diversity of human diseases to increase our understanding of the human cell. Cancer will be examined from a variety of standpoints with foci on cell adhesion and communication as well as cell movement and chemotaxis. Diseases such as Tay-Sachs disease will enlighten us to the critical role of enzymes that at one time were considered to function only during digestion but are now known to be central to cellular and human survival. An analysis of hypercholesterolemia will reveal how molecules selectively enter cells and are subsequently processed through a series of steps that involve carefully regulated movements and fusions of vesicles. Other chapters will look at the cellular basis of bacterial and viral infections and how they use mimicry to infect human cells. These are but a few examples of the novel approach that is taken to understand the role of human cell biology in normal and diseased states.

The Unit of Life and Disease

It has often been said that the cell is the “unit of life.” In other words, anything less than a cell is not considered to be a living creature. The cell is the sole unit that possesses all the criteria that define life. It is able to survive, grow and reproduce on its own. A virus is not considered to be living because it cannot reproduce on its own—it needs to use the machinery present in a living cell to reproduce. The cell is also the “unit of disease” because all human diseases operate at the cellular level. Thus a virus can’t get a disease but it can cause a disease by infecting cells. Unlike viruses, bacteria are cells. Bacteria can also cause human diseases—they do so by infecting cells. Again, this reflects the cell as the basis of disease. This is true for human cells just as it is for the cells of all living creatures. In this book we will look at how the human cell is constructed and, by focusing on specific components and events, understand how it functions. By focusing on a select group of diseases that affect the diverse components and functions of cells further insight will be gained into the normal and abnormal functioning of the human cell.

The survival and normal function of every cell requires an ongoing, dynamic interaction between all of its internal components. When these processes go wrong or when agents interfere with them, then problems arise. The internal functions of cells must also work in concert with events occurring both at the cell surface and outside the cell in the extracellular environment. The goal of this book is to introduce the reader to these interactions to set the stage for an understanding of the complexity of cellular structure and function. Several diseases will be discussed to show how the cell serves as the “unit of disease.” We will do this by first dismantling the cell and discussing many of its constituents. After discussing how they function and how they interact with other components, we will begin to show how the cell is more than the sum of its parts. In each case we will show how disrupting cell function through genetic mutation, chemical intervention or infectious agents can lead to various diseases.

The Cell Inside-Out

We will begin with basic cell structure and cellular compartmentalization to set the stage for subsequent chapters. As shown in Figure 1.1, each and every human cell is surrounded by a cell membrane. It is an organized structure comprised of lipids, proteins and carbohydrates. The cell membrane is the interface between the cell and its environment. If the cell membrane is disrupted the cell will die. The membrane still must remain flexible and able to respond appropriately to external conditions. Human cells do not have cell walls. Plants, microbes, fungi and bacteria have cell walls that exist outside of their cell membranes serving as support and protection.

Figure 1.1. The major components of human cells.

After covering the structure of the human cell membrane, aspects of its functions will be introduced with a focus upon how cells adhere to each other and how they communicate. As transducers of extracellular events that lead to cellular responses, receptors in the cell membrane will be analyzed, leading into a discussion of how an extracellular signal such as a hormone can lead to a cellular response. This area of signal transduction will introduce the diversity of cellular signaling while focusing on well characterized systems beginning with cyclic AMP- and calcium-mediated signaling. For example, the pharmaceuticals that are used to correct erectile dysfunction in men developed from this understanding of signal transduction.

Cell signaling requires that pathways can intercommunicate to ensure proper cell functioning. After examining this we will concentrate on a few intracellular systems that are regulated by signaling events. If cellular events are to function properly they must be organized within the cell. At this point we will examine the cytoskeletal system of cells and its involvement in cell shape and motility. All of these component structures and events will ultimately be linked together to explain issues such as cancer cell metastasis. The subject of biomembrane fusion will also be discussed as it underlies not only tissue formation but also the uptake of essential molecules as well as infectious viruses and bacteria.

Human cells are packed full of membrane compartments, vacuoles and vesicles. The lysosome is a comparatively simple structure with critical cellular roles. The way proteins and other components are targeted to specific cellular locales such as lysosomes will be covered followed by an analysis of how the cytoskeleton moves proteins and organelles within the cell. This will bring up topics such as Tay- Sachs disease, Huntington’s disease and the inflammatory response. Receptor-mediated endocytosis and intracellular vesicular movements will complete the picture and bring us back to our first and subsequent chapter topics. Ultimately, each chapter in one way or another impinges on other chapters revealing the importance of each cellular constituent in cellular function.

To look at this another way, we can consider the cell to be a functional ecosystem where proper functioning requires that all parts are working together to maintain homeostasis, the normal functioning of a cell. The following graphic (Figure 1.2) summarizes some of the interactive events in a human cell to give an idea of this interplay between and interdependence of different cellular regions, compartments and components. This is not meant to be a complete summary but serves only to show some of the major interactions that occur.

As the reader proceeds through this volume, many of the specific interactions that are depicted by the directional arrows will be elaborated. In addition, new players (e.g., extracellular matrix and external environment) will be revealed.

Figure 1.2. Some of the interactions (denoted by arrows) that occur between the different regions and compartments in the human cell.

The Nucleus and the Human Genome

The nucleus contains our genome—the genes that encode all of the RNA and proteins that underlie normal and abnormal cell functions. Mitochondria also possess a unique set of genes but they are not part of the genome, they are part of the mitochondrial gene pool. While this is not a molecular biology textbook, it is important to understand some basic information that will enhance the understanding of the topics that follow.

As Figure 1.3 shows, DNA contained within our 46 chromosomes encodes the genes which define cell function. The DNA is replicated during each cell cycle prior to cell division. For protein synthesis during normal and abnormal cell function, embryonic development and other events, specific genes are transcribed as messenger RNA (mRNA). Other RNAs (e.g., transfer, ribosomal, etc.) are also transcribed but not translated into proteins (not shown). These RNAs function in protein synthesis and as regulatory molecules among other things.

Figure 1.3. The flow of genetic information from the genome to the cytooplasm.

The initial mRNA is processed to a functional RNA that moves via nuclear pores into the cytoplasm where it is translated on ribosomes to direct the formation of a polypeptide. (Nucleoplasmic translocation will be discussed later only in terms of protein movements into and out of the nucleus.) The formed polypeptide may immediately fold to become a functional protein or it may be changed in a diversity of ways to become a functional protein. These post-translational events may occur when the protein is initially made or these changes may occur in response to various events within the cell such as signal transduction. While it is not shown in the figure, molecules must also move into the nucleus to regulate genes and serve as enzymes and subunits for DNA and RNA synthesis among a multitude of other events.

Amino Acids—Basic Units of Protein Structure

Since this book is primarily about proteins and their functions in normal and diseased cells, it is important to understand how they are constructed. Proteins are made up of twenty amino acids. The types of amino acids and how they are arranged not only plays a role in the way proteins fold, they also define the attributes of proteins. As we will learn, certain protein sequences determine where proteins will locate within the cell. Others will affect how proteins interact with other proteins. Yet others will serve as active sites within enzymes. Sequences of hydrophobic amino acids are important for allowing proteins to insert and reside within cell membranes. Each of these topics and others will be detailed throughout this book. At this point we will simply list the primary amino acids grouping them into related categories.

Hydrophobic Amino Acids

Alanine (Ala or A), glycine (Gly or G), isoleucine (Ile or I), leucine (Leu or L), methionine (Met or M), phenylalanine (Phe or F), proline (Pro or P), tryptophan (Trp or W), valine (Val or V)

Hydrophilic Amino Acids

Asparagine (Asn or N), cysteine (Cys or C), glutamine (Gln or Q), serine (Ser or S), threonine (Thr or T), tyrosine (Tyr or Y)

Charged Amino Acids

Arginine (Arg or R), aspartic Acid (Asp or D), glutamic Acid (Glu or E), histidine (His or H), lysine (Lys or K)

Sequences of amino acids also play a role in certain diseases. In Huntington’s disease, long stretches of glutamine are present in huntingtin protein. Amino acids can also be modified as covered later in this book. Thus serine, threonine and tyrosine can be phosphorylated to form phosphoserine (pSer), phosphothreonine (pThr) and phosphotyrosine (pTyr). These post-translational changes are often critical to the normal and abnormal function of proteins. Among other modifications to amino acids are acetylation (e.g., acetyllysine) and methylation (e.g. methyllysine).

Cell Biological Techniques

The understanding of cell structure and function began with simple microscopy by the likes of the Dutch scientist Antony van Leeuwenhoek who observed little “animalcules.” This progressed to the development of a diversity of light microscopes followed by various kinds of electron microscopy. As the cell was experimentally dissected and its components evaluated and quantified, areas that used to be separate now began to become part of the field of cell biology. Today the previously distinct fields of physiology, genetics, biochemistry, molecular biology and anatomy, to name a few, are at times considered to be sub-fields of cell biology. While this is not necessarily a widely accepted view it does emphasize one point: to truly understand cells requires knowledge in a number of these areas. Today, researchers who study cells make genetic mutants, quantify specific proteins, analyze a cell’s molecular composition, carry out physiological assessments and use various microscopic analyses. Some of the most common techniques are summarized in Appendix I (Some Common Techniques Used in Cell Biology) and II (SDS-PAGE, and Western Blotting). This volume attempts to integrate this information into a cohesive story of how normal cells work and how this work can be undermined in different ways by disease.