Chapter 2: O Man, Know Your Own Body—The Biological Prerequisites of Mental Disorders

Positioning in the Four-Layer Interaction Framework: This chapter provides the prerequisite knowledge for the book's four-layer framework. Before delving into the genetic layer (Chapter 4), developmental layer (Chapter 5), metabolic layer (Chapter 6), and social-environmental layer (Chapter 9), we must establish the basic language of life sciences. Mental disorders are not a matter of "failing to look on the bright side" or "weakness of will"; rather, they stem from biological malfunctions in the brain. And the brain, after all, is merely an organ within the biological system. From genes to organs, this chapter reveals the organizational principles of life layer by layer.

2.1 Genes: The Blueprint of Life, and the Source of Susceptibility

Genes are the basic units of hereditary information in living organisms, representing segments of DNA molecules that carry specific genetic effects. The human genome contains approximately 20,000–25,000 protein-coding genes, which encode all the instructions required to construct and maintain life activities (International Human Genome Sequencing Consortium, 2004, Nature).

2.1.1 The Structure of DNA and Information Storage

The DNA (deoxyribonucleic acid) molecule has a double helix structure, first described by Watson and Crick in 1953 (Watson & Crick, 1953, Nature). Two nucleotide strands are linked through base pairing (adenine A pairing with thymine T, and guanine G pairing with cytosine C). The specific sequence of these bases constitutes the genetic code, determining the amino acid sequence of proteins, thereby storing all the genetic information of life.

The human genome contains approximately 3 billion base pairs, of which only about 1.5% encode proteins, while the rest are non-coding regions. These non-coding regions were once dubbed "junk DNA," but modern research has confirmed that they play a key role in gene regulation (ENCODE Project Consortium, 2012, Nature). Many genetic variations associated with mental disorders (such as the risk loci identified by GWAS) are located precisely within these non-coding regions, suggesting that abnormalities in gene regulation, rather than variations in protein-coding regions, are the primary source of genetic susceptibility to mental disorders.

2.1.2 Gene Expression: From DNA to Protein

The primary function of genes is to direct protein synthesis, a process known as gene expression, which comprises two core steps:

1. Transcription: The gene sequence on DNA is transcribed into messenger RNA (mRNA) by RNA polymerase. This process occurs in the cell nucleus, where the DNA double helix locally unwinds and one of the strands serves as a template to synthesize a complementary mRNA strand. Transcription is precisely regulated by transcription factors and enhancers—the exact same gene can be regulated in entirely different ways across different cell types, developmental stages, and environmental conditions.
2. Translation: The mRNA carries genetic information from the cell nucleus into the cytoplasm, where it is translated into a specific amino acid sequence on ribosomes, which then folds into a protein. Every three consecutive bases (a codon) on the mRNA corresponds to a specific amino acid.

Regulation of Gene Expression and Mental Disorders: Gene expression is not a binary "on/off" operation but a dynamic process subject to multi-layered regulation. Epigenetic modifications (such as DNA methylation and histone modification) can regulate gene expression levels without altering the underlying DNA sequence—this is precisely the molecular mechanism by which environmental factors (such as childhood trauma and chronic stress) are "written into" genes. We will discuss epigenetics in detail in Chapter 5.

2.1.3 Genetic Variation: The Foundation of Evolution, the Root of Disease

Genes transmit genetic information from parents to offspring through precise DNA replication. However, errors can occur during replication, leading to genetic variations:

• Single Nucleotide Polymorphisms (SNPs): The substitution of a single base, which is the most common type of variation in the human genome. Most SNPs are harmless, but certain SNPs can affect gene function or expression levels, increasing disease susceptibility.
• Copy Number Variations (CNVs): Deletions or duplications of DNA segments, typically involving thousands to millions of base pairs. CNVs play an important role in mental disorders—for instance, 22q11.2 deletion syndrome is one of the strongest genetic risk factors for schizophrenia.
• Rare Functional Variants: Mutations with extremely low frequencies but large effect sizes, which can directly cause loss or alteration of protein function.

These variations are the foundation of biological evolution and the root of diseases. The genetic architecture of mental disorders is a superposition of "common variants with weak effects" and "rare variants with strong effects"—an understanding that has profoundly influenced our comprehension of the nature of mental disorders.

2.1.4 Genes Are Not Destiny

Genes determine a wide range of traits, from eye color to disease susceptibility, but they do not act in isolation—they interact with environmental factors through mechanisms like epigenetics to jointly shape the final phenotype. In the field of mental disorders, this understanding is particularly crucial:

• Heritability does not equal determinism—even if the heritability of schizophrenia is as high as 80%, 20% of the variation is still explained by environmental factors.
• Polygenic Risk Scores (PRS) can only predict the probability of risk; they cannot predict whether an individual will definitely develop the disorder.
• Gene-environment interaction (GxE) is the core mechanism of the onset of mental disorders—the same gene can lead to completely different outcomes in different environments.

2.2 Proteins: The Executors of Life, and the Culprits of Pathology

If genes are the blueprint of life, proteins are the direct executors of life. Proteins are formed by amino acids linked by peptide bonds, and their unique three-dimensional structures determine their functions. Dysfunction of proteins is the direct cause of many diseases, including mental disorders.

2.2.1 Core Functions of Proteins

• Structural function: Proteins are the primary structural components of cells and tissues. Collagen maintains the elasticity of connective tissues, cytoskeletal proteins maintain cell morphology, and actin and myosin enable muscle contraction.
• Enzymatic catalytic function: The vast majority of enzymes are proteins. Enzymes are highly efficient biocatalysts that specifically accelerate biochemical reactions within cells. From the synthesis of neurotransmitters (such as tryptophan hydroxylase catalyzing 5-HT synthesis) to their degradation (such as monoamine oxidase MAO degrading 5-HT and NE), almost all metabolic processes are driven by enzymes.
• Signal transduction and receptor function: Proteins act as signaling molecules (such as hormones and neurotransmitters) and receptors on cell membranes, participating in intercellular communication. Neurotransmitter receptor proteins (such as 5-HT receptors, dopamine receptors, and NMDA receptors) are responsible for receiving neural signals, converting chemical signals into electrical ones—these receptors are the very targets of most psychiatric medications.
• Transport function: Hemoglobin transports oxygen, channel proteins and carrier proteins are responsible for the transmembrane transport of substances, and lipoproteins transport lipids.
• Immune function: Antibodies and complement proteins are key components of immune defense. The abnormal activation of microglia (the immune cells of the brain) is closely related to neuroinflammation, which is increasingly recognized as an important pathological mechanism of mental disorders.
• Motor function: Actin and myosin produce muscle contraction, and motor proteins are responsible for intracellular transport.

2.2.2 Proteins and Mental Disorders

Protein dysfunction is directly linked to mental disorders:

• Receptor abnormalities: Abnormal density of dopamine D2 receptors is associated with schizophrenia and substance use disorders; dysfunction of the 5-HT transporter (SERT) is associated with depression.
• Abnormal enzyme activity: COMT (catechol-O-methyltransferase) degrades dopamine, and its Val158Met polymorphism affects enzyme activity, which is associated with schizophrenia and bipolar disorder.
• Protein misfolding: Although classic protein misfolding diseases (such as Alzheimer's disease) are neurodegenerative disorders, growing evidence suggests that disruptions in proteostasis also exist in mental disorders.
• Drug targets: Most psychiatric medications work by modulating protein function—SSRIs inhibit the 5-HT transporter, antipsychotics block dopamine D2 receptors, and lithium inhibits the GSK-3β enzyme.

2.3 Cells: The Basic Unit of Life, and the Carrier of Mind

Cells are the basic structural and functional units of life. The human body is composed of approximately 30 to 40 trillion cells, which vary in shape and possess diverse functions. In the context of mental disorders, the following cell types are particularly critical:

2.3.1 Neurons: The Core of Information Processing

Neurons are the core cells that make up the brain and the entire nervous system, serving as the basic units of information processing and transmission. A typical neuron consists of three parts:

• Soma (Cell Body): Contains the cell nucleus and organelles, serving as the center for metabolism and integration.
• Dendrites: Branch-like projections extending from the cell body that receive signals from other neurons.
• Axon: A long projection extending from the cell body, terminating in synapses, which transmits signals to other neurons or effector cells.

There are approximately 86 billion neurons in the human brain (Herculano-Houzel, 2009, Frontiers in Human Neuroscience), which form about 100 trillion connections through synapses, constituting the physical substrate of human consciousness and cognition. Dysfunction of neurons—such as impaired signal transmission, abnormal connections, and accelerated apoptosis—is the direct cause of many mental disorders.

Action Potential and Signal Transmission: Neurons communicate by generating and transmitting electrochemical signals (action potentials). When the membrane potential reaches a threshold, voltage-gated sodium channels open, causing an influx of sodium ions that depolarizes the membrane and generates an action potential. The action potential propagates along the axon to the synaptic terminal, triggering the release of neurotransmitters—this process is the molecular foundation of all thoughts, emotions, and behaviors.

2.3.2 Neuroglia: The Guardians of the Brain

Neuroglia, or glial cells, are roughly equal in number to neurons. They were once considered mere "support" cells, but are now known to play crucial roles in the development and function of the nervous system (Allen & Lyons, 2018, Science):

• Astrocytes: The most abundant glial cells, which provide nutritional support, regulate ion and neurotransmitter concentrations in the synaptic cleft, maintain the blood-brain barrier, and participate in synapse formation and pruning. Astrocyte dysfunction is associated with depression and schizophrenia.
• Oligodendrocytes: Form myelin sheaths in the central nervous system, wrapping around axons to drastically increase signal conduction speed. Abnormal myelination is directly linked to decreased white matter integrity in schizophrenia and bipolar disorder.
• Microglia: The resident immune cells of the brain, responsible for immune surveillance, clearing cellular debris, and participating in synaptic pruning. Abnormal activation of microglia leads to neuroinflammation, which is closely associated with schizophrenia (excessive synaptic pruning) and depression (chronic inflammation).
• Schwann Cells: Form myelin sheaths in the peripheral nervous system.

2.3.3 Germ Cells: The Transmitters of Genetic Susceptibility

Sperm and egg cells are the starting points of life, carrying only half of the parents' genetic information. During fertilization, the fusion of sperm and egg restores the complete genetic information, developing into a new individual. Germ cells are the foundation upon which genetic susceptibility is perpetuated—the genetic risk of mental disorders is transmitted from parents to offspring precisely through germ cells.

Notably, de novo mutations in germ cells—mutations that arise anew during gametogenesis rather than being inherited from parents—are an important source of certain severe neurodevelopmental disorders. Paternal age is positively correlated with the rate of de novo mutations, which may provide a genetic explanation for the increased risk of schizophrenia and autism in children of older fathers (Kong et al., 2012, Nature).

2.4 Tissues and Organs: The Construction of Complex Functions, and the Battlefield of Pathology

2.4.1 Tissues

Similar cells aggregate and work together to form tissues with specific functions. There are four basic tissue types in the human body:

• Epithelial tissue: Covers body surfaces and lines internal cavities, functioning in protection, absorption, and secretion.
• Connective tissue: Supports, connects, and protects, including bone, cartilage, blood, and fat.
• Muscle tissue: Contracts to produce movement.
• Nervous tissue: Composed of neurons and neuroglia, serving as the physical substrate for information processing and transmission.

2.4.2 Organs and Systems

Different tissues combine further to form organs. The organ systems most directly related to mental disorders are:

• The Brain: Composed of nervous tissue, connective tissue (blood vessels, meninges), etc., it serves as the "command center" of the mental world. Weighing about 1.4 kilograms, the brain consumes approximately 20% of the body's energy—it is the most "expensive" organ in the human body. Brain dysfunction is not the result of "failing to look on the bright side," but rather a direct manifestation of neurotransmitter imbalances, neural circuit disruptions, and structural brain changes.
• The Endocrine System: The hypothalamic-pituitary-adrenal axis (HPA axis) is the core pathway of the stress response. HPA axis dysfunction—especially the chronic elevation of glucocorticoids (cortisol)—is one of the core pathological features of depression and PTSD.
• The Immune System: The immune-brain interaction is at the forefront of psychiatric research. Peripheral inflammation can affect brain function through cytokine signaling, and elevated levels of pro-inflammatory cytokines (such as IL-6 and TNF-α) are associated with the onset and severity of depression.

2.4.3 Insights from Life's Hierarchy: Mental Disorders Are Diseases of the "Body"

From genes to proteins, from cells to organs, and from organs to systems—life is a multi-layered self-organizing system. Mental disorders manifest at every level of this system:

Level	Abnormalities Related to Mental Disorders
Genes	SNPs, CNVs, de novo mutations, epigenetic modifications
Proteins	Receptor dysfunction, altered enzyme activity, transporter abnormalities
Cells	Impaired neuronal signaling, glial cell dysfunction, neuroinflammation
Neural Circuits	Excessive/insufficient synaptic pruning, decreased white matter integrity, abnormal network connectivity
Organ Systems	HPA axis dysregulation, disrupted immune-brain interactions, endocrine imbalance

Understanding this multi-layered organizational principle is the prerequisite for grasping the four-layer interaction framework. Mental disorders are not a "single-point failure" at any one level, but rather the systemic outcome of imbalanced interactions across multiple levels—this is precisely the core thesis of this book.

References:

• Allen, N.J., & Lyons, D.A. (2018). Glia as architects of central nervous system formation and function. Science, 362(6411), 181-186.
• ENCODE Project Consortium. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489(7414), 57-74.
• Herculano-Houzel, S. (2009). The human brain in numbers: a linearly scaled-up primate brain. Frontiers in Human Neuroscience, 3, 31.
• International Human Genome Sequencing Consortium. (2004). Finishing the euchromatic sequence of the human genome. Nature, 431(7011), 931-945.
• Kong, A., et al. (2012). Rate of de novo mutations and the importance of father's age to disease risk. Nature, 488(7412), 471-475.
• Watson, J.D., & Crick, F.H. (1953). Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature, 171(4356), 737-738.