2.1 Cellular and Molecular Biology Basics

Cells are the fundamental unit of life, and understanding how they work is essential for biomedical engineering. Whether you're designing drug delivery systems, engineering tissues, or developing diagnostic tools, everything traces back to cellular and molecular biology.

This section covers eukaryotic cell structure, how cells produce energy, the flow of genetic information from DNA to protein, and how cells communicate with each other.

Eukaryotic cell structure and function

Cell types and organelles

Eukaryotic cells are cells that contain a true nucleus and membrane-bound organelles. All human cells are eukaryotic. By contrast, prokaryotic cells (bacteria and archaea) lack a membrane-bound nucleus and organelles. In biomedical engineering, you'll mostly be working with eukaryotic cells, but prokaryotes matter too (think bacterial infections, microbiome engineering, and recombinant protein production).

• The plasma membrane is a phospholipid bilayer that separates the cell interior from the external environment. It exhibits selective permeability, meaning it controls which molecules enter and exit the cell. This property is critical for maintaining the cell's internal environment and is a key consideration when designing drug delivery systems.
• The nucleus houses the cell's DNA and is where DNA replication and transcription occur. It's surrounded by a double-layered nuclear envelope with nuclear pores that allow selective transport of molecules like mRNA and proteins.
• Ribosomes are the sites of protein synthesis (translation). They can be free-floating in the cytoplasm or attached to the rough endoplasmic reticulum.

Endoplasmic reticulum, Golgi apparatus, and lysosomes

These three organelles work together as a kind of manufacturing and shipping system for the cell.

• The endoplasmic reticulum (ER) is a network of membranous channels involved in synthesis, modification, and transport.
  • The rough ER has ribosomes on its surface and handles protein synthesis and initial modification (like folding and adding sugar groups).
  • The smooth ER lacks ribosomes and is involved in lipid synthesis and detoxification of drugs and toxins.
• The Golgi apparatus is a stack of flattened membrane sacs that receives proteins and lipids from the ER, further modifies them (through glycosylation, phosphorylation, etc.), and sorts them into vesicles for delivery to their final destinations within or outside the cell. Think of it as the cell's post office.
• Lysosomes are membrane-bound organelles packed with digestive enzymes. They break down damaged organelles, macromolecules, and foreign particles. This "cellular waste disposal" function is essential for maintaining homeostasis. Lysosomal dysfunction is linked to diseases like Tay-Sachs and Gaucher disease, which are relevant targets in biomedical research.

Mitochondria and energy production

Mitochondria generate most of the cell's ATP through cellular respiration. A few key structural and functional details:

• They have a double membrane structure. The inner membrane is folded into cristae, which increase surface area for the reactions of the electron transport chain.
• Mitochondria contain their own DNA and ribosomes, evidence of their evolutionary origin as engulfed prokaryotic cells (the endosymbiotic theory).

ATP (adenosine triphosphate) is the cell's primary energy currency. It consists of an adenosine molecule bonded to three phosphate groups. The bonds between the phosphate groups are high-energy bonds; when the terminal phosphate is hydrolyzed, energy is released to power processes like active transport, biosynthesis, and muscle contraction.

Cellular metabolism and energy production

Cellular respiration and ATP production

Cellular metabolism refers to the sum of all chemical reactions in a cell. These fall into two broad categories:

• Catabolism: breaking down molecules to release energy
• Anabolism: building complex molecules using energy

Cellular respiration is the catabolic process that breaks down glucose to produce ATP. It proceeds in three main stages:

1. Glycolysis takes place in the cytoplasm. It's anaerobic (no oxygen required) and splits one glucose molecule into two pyruvate molecules. Net yield: 2 ATP and 2 NADH.
2. The Krebs cycle (also called the citric acid cycle) occurs in the mitochondrial matrix. Pyruvate is first converted to acetyl-CoA, which enters the cycle. Per glucose molecule (two turns of the cycle), it generates 2 ATP, 6 NADH, and 2 $FADH_2$.
3. The electron transport chain (ETC) is a series of protein complexes embedded in the inner mitochondrial membrane. Electrons from NADH and $FADH_2$ are passed along the chain to the final electron acceptor, $O_2$. This electron transfer pumps protons across the membrane, creating a gradient that drives ATP synthase to produce ATP through chemiosmosis. This stage generates the bulk of ATP, roughly 30–32 ATP per glucose molecule.

Photosynthesis and carbon fixation

While photosynthesis isn't directly relevant to human physiology, understanding it provides useful context for energy conversion principles in biomedical engineering (e.g., bio-inspired energy systems).

• Photosynthesis occurs in chloroplasts in plants and other autotrophs. It converts light energy into chemical energy stored in glucose.
  • Light-dependent reactions occur in the thylakoid membranes and produce ATP and NADPH.
  • Light-independent reactions (the Calvin cycle) occur in the stroma and use that ATP and NADPH to fix $CO_2$ into glucose.
• Carbon fixation is catalyzed by the enzyme RuBisCO (ribulose bisphosphate carboxylase/oxygenase), which attaches $CO_2$ to ribulose bisphosphate (RuBP). The resulting molecules are then reduced to form glucose using energy from the light-dependent reactions.

Central dogma of molecular biology

DNA replication and structure

The central dogma describes the flow of genetic information: DNA → RNA → Protein. DNA is transcribed into RNA, and RNA is translated into protein. This unidirectional flow is fundamental to how cells function and pass on genetic information.

DNA replication duplicates the cell's genome before cell division. Key features:

• It's semiconservative: each new double helix contains one original strand and one newly synthesized strand.
• Replication begins at origins of replication and proceeds bidirectionally.

The process involves several steps:

1. Helicase unwinds the double helix at the origin of replication.
2. Primase lays down a short RNA primer to give DNA polymerase a starting point.
3. DNA polymerase adds nucleotides in the 5' to 3' direction, following complementary base pairing rules (A pairs with T, G pairs with C).
4. The leading strand is synthesized continuously. The lagging strand is synthesized in short fragments called Okazaki fragments.
5. DNA ligase joins the Okazaki fragments into a continuous strand, and the RNA primers are replaced with DNA.

Transcription and RNA processing

Transcription copies genetic information from DNA into a complementary RNA strand. It's catalyzed by RNA polymerase and occurs in the nucleus.

The three stages of transcription:

1. Initiation: RNA polymerase binds to the promoter region upstream of the gene.
2. Elongation: RNA polymerase moves along the template strand, synthesizing mRNA in the 5' to 3' direction.
3. Termination: The completed RNA transcript is released, and RNA polymerase detaches from the DNA.

Before the mRNA can be translated, eukaryotic cells perform three post-transcriptional modifications:

• 5' capping: A 7-methylguanosine cap is added to the 5' end. This protects the mRNA from degradation and helps ribosomes recognize it for translation.
• 3' polyadenylation: A poly(A) tail (a string of adenine nucleotides) is added to the 3' end, enhancing mRNA stability and translation efficiency.
• Splicing: Non-coding sequences called introns are removed, and coding sequences called exons are joined together to form the mature mRNA. Alternative splicing can produce different proteins from the same gene, which is one reason humans can make far more proteins than we have genes.

Translation and the genetic code

Translation is the process of decoding mRNA to build a polypeptide (protein). It occurs on ribosomes in the cytoplasm.

• The mRNA is read in the 5' to 3' direction. Every three nucleotides form a codon, and each codon specifies a particular amino acid.
• Transfer RNA (tRNA) molecules serve as adapters. Each tRNA has an anticodon that base-pairs with a specific mRNA codon, and it carries the corresponding amino acid. Aminoacyl-tRNA synthetases are the enzymes that charge each tRNA with the correct amino acid.

The genetic code has several important properties:

• There are 64 possible codons: 61 code for amino acids, and 3 are stop codons (UAA, UAG, UGA). AUG serves as the start codon and codes for methionine.
• The code is degenerate (redundant), meaning most amino acids are specified by more than one codon. For example, leucine is encoded by six different codons.
• The code is nearly universal across all life forms, with only minor exceptions in some mitochondria and certain organisms.

Cell signaling and communication

Signaling molecules and receptors

Cell signaling is how cells communicate with each other and respond to their environment. It's essential for development, tissue homeostasis, immune responses, and virtually every physiological process.

Signaling molecules (ligands) include hormones, neurotransmitters, and growth factors. They bind to specific receptors on or inside target cells. Some examples:

• Insulin (a peptide hormone) regulates blood glucose levels
• Acetylcholine (a neurotransmitter) triggers muscle contraction
• Epidermal growth factor (EGF) stimulates cell proliferation

Receptors fall into two broad categories:

• Cell surface receptors bind to ligands that can't cross the plasma membrane (like peptide hormones):
  • G protein-coupled receptors (GPCRs): Activate intracellular signaling cascades through G proteins. Examples include adrenaline and glucagon receptors. GPCRs are the target of roughly 34% of all FDA-approved drugs.
  • Receptor tyrosine kinases (RTKs): Initiate signaling through phosphorylation of tyrosine residues. Insulin and many growth factor receptors are RTKs.
• Intracellular receptors bind to ligands that can cross the membrane (like steroid hormones):
  • Nuclear receptors: Bind steroid hormones (estrogen, testosterone) and directly regulate gene expression by acting as transcription factors.

Signal transduction and cellular responses

Signal transduction is the relay of a signal from the receptor to the cell's interior machinery. It typically involves a cascade of molecular interactions that amplify the original signal, so a single ligand binding event can trigger a large cellular response.

Second messengers are small molecules that propagate the signal inside the cell. Common examples:

• Cyclic AMP (cAMP): Produced by adenylyl cyclase in response to GPCR activation; activates protein kinase A
• Calcium ions ($Ca^{2+}$): Released from the ER; involved in muscle contraction, neurotransmitter release, and many other processes
• Inositol trisphosphate ($IP_3$): Triggers $Ca^{2+}$ release from the ER

Cell signaling pathways can produce a range of cellular responses depending on the cell type and signal:

• Changes in gene expression: Activation or repression of specific genes, altering which proteins the cell produces
• Changes in metabolism: For example, insulin signaling promotes glucose uptake and glycogen synthesis
• Cell division and differentiation: Growth factors regulate cell cycle progression and cell fate during development
• Cell migration: Cells move directionally in response to chemical gradients (chemotaxis) or mechanical cues
• Apoptosis: Programmed cell death triggered by stress, DNA damage, or developmental signals

Disorders related to cell signaling

When signaling pathways go wrong, disease often follows. Understanding these connections is central to biomedical engineering approaches for diagnostics and therapeutics.

• Cancer: Mutations in genes that regulate cell growth and apoptosis (such as p53, Ras, and Bcl-2) can lead to uncontrolled cell division. For instance, about 30% of all human cancers involve activating mutations in Ras proteins.
• Diabetes: In type 2 diabetes, cells become resistant to insulin signaling, leading to chronically elevated blood glucose and metabolic dysfunction.
• Autoimmune disorders: Immune cells are inappropriately activated, attacking the body's own tissues. Examples include rheumatoid arthritis and multiple sclerosis.
• Neurodegenerative diseases: Disrupted signaling in neuronal survival pathways contributes to conditions like Alzheimer's and Parkinson's disease.

Biomedical engineers contribute to treating these diseases through several approaches:

• Small molecule inhibitors and monoclonal antibodies that block specific signaling molecules or receptors (e.g., imatinib targeting the BCR-ABL kinase in chronic myeloid leukemia)
• Gene therapy to correct mutations or modulate expression of genes involved in signaling
• Personalized medicine strategies that tailor treatments based on a patient's genetic profile and the specific signaling alterations driving their disease