Chapter 1
Cells and Tissues in Health and Disease

Very simply, medicine is the study (and maintenance) of health. Health requires appropriate organ structure and function. Health that has gone awry or out of balance is disease. To understand how and why things go wrong in the body, we need to understand what is normal - normal anatomy, normal physiology, and normal function. The starting point and basis for all health and disease is the cell (Cotran et al., 1999). Cells form tissues that form organs that are responsible for an organism's life.

The eukaryotic cell is a remarkable creation! Self-sustaining, it contains all that is needed to survive and reproduce - mechanisms to replicate, create energy, create proteins and molecules to make substrates it needs, a storage depot, a way to import and export signals, and a way to remove and/or destroy waste. Each of these functions is mediated by specific organelles, that is, membrane-bound "factories" that carry out their specific tasks (Figure 1.1).

Figure 1.1 Diagram of a normal eukaryotic cell (GraphicsRF/Adobe Stock Photos).

The cell and each organelle within it are surrounded by a membrane. The primary functions of the membrane are to enclose and protect the integrity of the cell and to mediate movement of molecules and signals in and out of the cell. The membrane is composed of a lipid bilayer with proteins either located within the bilayer and/or protruding out either end. This structure supports the optimal function and flexibility of the cell.

The director of all activities in the cell (and body) lies within the genetic material, which resides in the nucleus. The eukaryotic nucleus houses DNA within genes tightly bound together in structures called chromosomes. When needed, these tightly bound structures will "unwind" to permit cell division or replication (mitosis) and/or protein formation.

Cell division, or mitosis, is simply replication of the cell. DNA normally exists in a diploid state - two copies of the DNA per cell (i.e., two copies of each chromosome with all their genes within). In general, mitosis is preceded by S phase of interphase (during which DNA replication occurs) and is often followed by metaphase, telophase (chromosomes split and spread apart), and ultimately cytokinesis. In cytokinesis, division of the cytoplasm, organelles, and cell membrane occurs and two new cells are created, each containing roughly equal shares of these cellular components.

Gamete production occurs by meiosis, a process like mitosis but with distinct differences. In meiosis, the chromosomes duplicate (during interphase) and homologous chromosomes exchange genetic information (chromosomal crossover) during the first division called meiosis I. The daughter cells divide again in meiosis II, splitting up sister chromatids to form haploid gametes. Gametes are haploid, that is, they have only one copy of DNA such that when the gametes from a male and female fuse to form a zygote, the diploid condition is restored. This process only occurs in the organs that produce gametes, i.e., the ovaries and testicles.

Energy, in the form of adenosine triphosphate (ATP), is created inside the mitochondria of cells. Energy is produced by oxidative phosphorylation (aka aerobic respiration), which requires oxygen. Mitochondria have a double membrane system where there is an outer membrane surrounding the mitochondria and an inner membrane within the mitochondria that forms the substrate where ATP is produced. Mitochondria also have a function in cell cycle regulation and regulate some other essential processes. Unique to this organelle is the presence of its own mitochondrial DNA (mtDNA), which is distinct from nuclear DNA (nDNA). Mitochondrial DNA is passed down by the females (matrilineal).

The endoplasmic reticulum in concert with the Golgi apparatus is involved in the production and movement of cellular products out of the cell. The rough endoplasmic reticulum (RER) contains ribosomes that are used to produce proteins targeted for release out of the cell. The smooth endoplasmic reticulum (SER) has enzymes that metabolize steroids, lipids, some drugs, and glycogen. When the cellular products are ready to be released or excreted from the cell, they merge with the Golgi vesicles which then fuse with the cell membrane and discharge the contents outside the cell (Figure 1.2).

Figure 1.2 Diagram of an animal cell indicating the processes for excreting molecules and waste out of the cell. Molecules tagged for export out of the cell leave the Golgi vesicles, which merge with the membrane and expel their contents. Secondary lysosomes filled with waste also expel their contents after merging with the membrane.

Source: Fancy Tapis/Shutterstock.

Lysosomes are organelles that serve as waste receptacles for the cell. These organelles contain enzymes that can degrade molecules and other waste products. After degradation of waste, these secondary lysosomes fuse with the membrane and discharge their contents ("empty the garbage") out of the cell (Figure 1.2). Membrane integrity is critical for this organelle to prevent the enzymes within them from leaking out and degrading all other components of the cell.

The cell cytoskeleton is formed by microfilaments, microtubules, and intermediate filaments. Each of these has a separate role in cell movement and shape. Microtubules are involved in mitosis when the cell divides into half and moves apart. Intermediate filaments help certain cell types to move. For example, desmin is an intermediate filament involved in skeletal muscle contraction. In addition to proteins that reside on the outer surface, the cell may have "appendages," which stick out of the cell surface. These are small structures, such as cilia, which can help the cell sense the environment or move. Within the limits of the cell membrane is a watery, gel-like substrate (the cytoplasm) in which the filaments and organelles reside.

When the cell processes are all working well, the cell is in homeostasis. Homeostasis is the range of conditions wherein all cellular processes are functioning normally. Cells, tissues, organs, the organism, and the environment all have their own homeostatic parameters. When conditions change, which challenge the organism's or the cells' homeostasis, it must respond to restore balance. It all starts with the cell.

The cell responds to challenges or stimuli by adapting and changing to restore homeostatic balance. These adaptations are often reversible, and the cell can change back once the imposing challenge/stimulus has resolved and/or ceases. In situations where the challenging stimulus does not immediately resolve, the cell can exist in this altered "homeostatic" state. Should the challenging stimulus persist, the cell may undergo irreversible changes that may ultimately lead to its death. In this latter situation, the greater the number of cells that die, the more damage the tissue/organ will incur.

Reversible Cell Adaptations

Reversible changes of the cell vary according to the cell type that is affected. There are four basic types of reversible cellular changes: hypertrophy, hyperplasia, atrophy, and metaplasia. Hypertrophy is the increase of size or function of the cell, which results ultimately in enlarged organ size. The enlarged cell size is due to the synthesis of more structural components of the cell. This type of response is seen in cells that do not regularly divide, such as muscle, nerve, etc. The stimulus for hypertrophy is increased functional demand (by pathologic or physiologic causes) and/or by stimulation from hormones or growth factors. An example of pathologic hypertrophy would be cardiac hypertrophy; the heart muscle increases in size to increase pumping force to overcome a downstream blockage (e.g., faulty valve). An example of "physiologic" hypertrophy in humans would be weightlifting. Lifting weights puts a stressor on the arm muscles (e.g., biceps and triceps) to increase force to lift the weights. The net effect of the former is an enlarged heart; the net effect of the latter are thicker, bulging arm muscles.

Hyperplasia is the increase in numbers of cells that can also result in larger organ size. The mechanism of increased cell numbers is by the stimulation of stem cells or the proliferation of mature cells. This adaptation is common in cell types that normally continually divide (e.g., epithelium of the gastrointestinal tract). As in hypertrophy, hyperplasia can be induced by physiologic or pathologic stressors. Physiologic hypertrophy occurs under hormonal influence in certain organs, such as in the mammary gland, during pregnancy. Approaching parturition (birth), mammary gland cells divide and increase in number for milk production, resulting in mammary gland enlargement. Pathologic hyperplasia can be caused by excess of hormones or growth factors resulting in pathologic conditions, such as endometrial hyperplasia or prostatic hyperplasia.

Atrophy is the reduction in cell size or function (often due to underutilization), which results in a reduction in organ size. The decreased cell size can be due to decreased protein synthesis and/or increased protein degradation, as the cells are not in use and have much lower metabolic demand. As in the adaptations above, causes can be physiologic or pathologic, and atrophy is a common mechanism employed during embryo/fetal development. When a muscle has a reduced workload, such as when one has a cast over a broken bone, the decreased...