3. Cells

Structure, Function, Membrane Transport, and the Cell Cycle

Learning Objectives

3.1 The Cell Theory and the Diversity of Human Cells

The cell theory, assembled between 1838 and 1858 from the work of Schleiden, Schwann, and Virchow, makes three claims that have survived without amendment:

1. The cell is the structural and functional unit of life. Nothing smaller is alive.
2. The activity of an organism depends on the collective activity of its cells. Organ function is cell function, aggregated.
3. All cells arise from pre-existing cells — omnis cellula e cellula. There is no spontaneous generation, which means every cell in Amara's body is descended by an unbroken line of division from one fertilized egg.

A fourth statement is now standard and matters here: the biochemical activities of a cell are determined by its structures, and structure follows from the genes the cell chooses to express. Two cells with identical DNA look and behave differently because they have built different machinery from the same instructions.

An adult body contains roughly 37 trillion cells of about 200 distinct types. The variation among them is enormous, and it is never arbitrary.

Read the lifespan column against the shape column. Cells that are exposed to damage are replaced quickly; cells whose function depends on accumulated connections are not replaced at all. An intestinal epithelial cell is disposable because everything it knows is in its genome. A neuron is not, because most of what it knows is in its synapses — and a replacement cell would arrive blank.

Cardiomyocytes sit at the wrong end of that trade-off for Amara. They renew at roughly 1% per year in youth and less later; a heart cannot replace lost muscle in any meaningful quantity. This is the single fact that makes myocardial infarction a permanent injury, and Chapter 4 follows what fills the gap instead.

3.2 The Plasma Membrane

Every cell is defined by its boundary. The plasma membrane is about 7–8 nm thick — some five thousand times thinner than a sheet of paper — and it does four things simultaneously: it separates cytosol from extracellular fluid, it controls what crosses, it carries the receptors through which the cell is instructed, and it maintains the electrical gradient that Chapter 11 turns into a nervous system.

The fluid mosaic model

Proposed by Singer and Nicolson in 1972, the fluid mosaic model describes the membrane as a two-dimensional fluid: a phospholipid bilayer in which proteins float, drift, and cluster.

Fluid. Individual phospholipids diffuse laterally within their leaflet perhaps a million times per second, exchanging places with neighbours; a lipid can travel the length of a bacterium in a second. They almost never flip between leaflets on their own, because dragging a charged head group through the oily interior is energetically prohibitive — so the two leaflets have different compositions and stay that way. Enzymes called flippases and scramblases move lipids across deliberately, and that fact becomes important in §3.8.

Mosaic. Proteins constitute roughly 50% of membrane mass, though only about 2% of the molecules, because a protein is so much larger than a lipid. They are not evenly distributed: membranes contain cholesterol- and sphingolipid-rich microdomains often called lipid rafts, which concentrate particular signalling proteins together.

Asymmetric. The two faces differ absolutely. Sugars face only outward. Phosphatidylserine faces only inward — until the cell dies, when its appearance on the outer surface is the "eat me" signal that summons a macrophage (§3.8).

   THE PLASMA MEMBRANE IN CROSS-SECTION — FLUID MOSAIC MODEL
   ══════════════════════════════════════════════════════════════════════
   EXTRACELLULAR FLUID   (Na+ 140 · Cl- 100 · Ca2+ 2.4 · K+ 4 mEq/L)

     ⌇⌇⌇ GLYCOCALYX ⌇⌇⌇  sugar chains of glycoproteins + glycolipids
       ⌇  ⌇   ⌇  ⌇       → identity (ABO), adhesion, immune recognition
   ┌──┼──┼───┼──┼─────────────────────────────────────────────────┐
   │ ○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○ │ polar
   │ ║║║║║║║║║║▓║║║║║║║║║║║║║║║║║▓║║║║║║║║║║║║║║║║║║▓║║║║║║║║║║║ │ heads
   │ ║║║║║║║║║║▓║║║║║║║║║║║║║║║║║▓║║║║║║║║║║║║║║║║║║▓║║║║║║║║║║║ │ 7-8 nm
   │ ○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○ │ total
   └────────────────────────────────────────────────────────────────┘
   CYTOSOL   (K+ 140 · Na+ 12 · Cl- 4 · free Ca2+ 0.0001 mEq/L)
      ▓ = CHOLESTEROL (~1 per 2 phospholipids) — the FLUIDITY BUFFER

   ══ THE SIX FUNCTIONAL CLASSES OF MEMBRANE PROTEIN ═══════════════════

   1 CHANNEL       ╔═╗   a water-filled pore; ions pass DOWN gradient
                   ║ ║   gated by voltage, ligand, or stretch
                   ╚═╝   ex: CFTR (Cl-), aquaporin, Na+ voltage-gated

   2 CARRIER       ╔═╗   binds solute, CHANGES SHAPE, releases it
                   ║◄►║  saturable; has a Tmax
                   ╚═╝   ex: GLUT4 (glucose), SGLT2 (Na+/glucose)

   3 PUMP          ╔═╗   a carrier that SPENDS ATP to move solute
                   ║ATP  UPHILL against its gradient
                   ╚═╝   ex: Na+/K+ ATPase, Ca2+ ATPase, H+/K+ ATPase

   4 RECEPTOR      ╔═╗   binds a signal outside; changes shape;
                   ║ ⌇║  triggers an event inside. Does NOT transport.
                   ╚═╝   ex: insulin receptor, beta-1 adrenergic receptor

   5 ENZYME        ╔═╗   catalyses a reaction at the membrane surface
                   ║ E║  ex: adenylate cyclase, brush-border lactase
                   ╚═╝

   6 ANCHOR /      ╔═╗   links cytoskeleton inside to matrix or to the
     CELL-ID       ║ ▓║  neighbouring cell outside; or carries identity
                   ╚═╝   ex: integrin, cadherin, MHC glycoprotein

   ══ WHY THE INTERIOR IS THE BARRIER ══════════════════════════════════
     The middle 3 nm is pure hydrocarbon — an oil film.
     CROSSES UNAIDED:  O2 · CO2 · N2 · steroid hormones · fatty acids
                       urea and ethanol (small, slightly polar)
     CANNOT CROSS:     Na+ K+ Ca2+ Cl- · glucose · amino acids · ATP
                       water (mostly — needs aquaporins to be fast)
     → Everything the cell must control is something that CANNOT cross
       on its own. The barrier is what makes regulation possible.

The six functional classes of membrane protein

Membrane proteins are classified structurally as integral (embedded in the bilayer; transmembrane if they span it) or peripheral (attached to one surface). Functionally there are six classes, and every one of them appears somewhere in Amara's story.

Cholesterol and the glycocalyx

Cholesterol makes up 20–25% of membrane lipid by number and acts as a fluidity buffer (Chapter 2, Figure 2.6): at 37 °C its rigid ring system restrains fatty acid tails and makes the membrane less fluid, while at low temperature the same rings prevent tails from crystallizing into a solid. One molecule, opposite effects, because it interferes with whatever the tails were about to do.

The glycocalyx is the carbohydrate coat on the outer face — sugar chains of glycoproteins and glycolipids. It is the cell's identity document. ABO blood groups are glycocalyx sugars; sperm recognize eggs through it; leukocytes roll along inflamed endothelium by binding it; and the immune system's self/non-self decision is read here.

3.3 Passive Transport

Passive transport requires no energy from the cell. The energy is already stored in the gradient. Four mechanisms.

Simple diffusion

Molecules in solution move constantly and randomly. Where concentration is uneven, random motion produces net movement from high to low — diffusion — and it continues until the gradient is gone. The rate rises with the steepness of the gradient, with temperature, and with membrane surface area, and falls with molecular size and with distance.

Distance is the constraint that shapes anatomy. Diffusion time rises with the square of distance: a molecule crosses 1 µm in about 0.5 ms, 10 µm in 50 ms, and 1 mm in about 8 minutes. This is why no cell in the body is more than about 100 µm from a capillary, why alveolar walls are 0.2–0.6 µm thick, and why an organism larger than a millimetre requires a circulatory system at all. Diffusion is superb over cellular distances and useless over anatomical ones.

Only nonpolar or very small molecules diffuse through the bilayer directly: O₂, CO₂, N₂, steroid hormones, fatty acids, and — more slowly — urea and ethanol.

Facilitated diffusion

Polar solutes need help. In facilitated diffusion a channel or carrier provides a route, but the movement is still down the gradient and still costs the cell nothing.

The distinction between the two protein types matters clinically:

• Channels are pores. They are fast (10⁶–10⁸ ions/s), selective by size and charge, and gated — opened by voltage, by a ligand, or by mechanical stretch.
• Carriers bind their solute and undergo a conformational change. They are far slower (10²–10⁴/s) and saturable: once every carrier is occupied, adding more solute cannot increase transport. That ceiling is the transport maximum (Tm), and it explains glycosuria. The renal Tm for glucose is reached at a plasma glucose near 180–200 mg/dL. Amara's is 212, which means glucose is appearing in her urine right now — not because her kidney is damaged, but because her carriers are saturated.

Osmosis and tonicity

Osmosis is the diffusion of water across a selectively permeable membrane, from where water is more concentrated (fewer solutes) to where it is less concentrated (more solutes). Water crosses membranes slowly on its own and rapidly through aquaporins.

Two terms are constantly confused and must be separated:

• Osmolarity counts all dissolved particles per litre. It is a property of a solution measured in a beaker.
• Tonicity counts only the particles that cannot cross the membrane — the effective osmoles. It is a property of a solution with respect to a particular cell, and it is what predicts whether the cell will swell or shrink.

The difference is not pedantic. A 5% dextrose solution is roughly iso-osmotic to plasma when it enters the vein, but glucose is taken up by cells and metabolized, so the solution behaves as if it were pure water within minutes. Iso-osmotic in the bag; hypotonic in the body.

   TONICITY — ONE RED CELL, THREE SOLUTIONS
   ══════════════════════════════════════════════════════════════════════
   The cell's interior is ~290 mOsm/kg and is held constant.
   Everything below depends on what is OUTSIDE.

  ISOTONIC  ~290 mOsm      HYPOTONIC  <280        HYPERTONIC  >310
  ────────────────────     ─────────────────      ────────────────────
   outside = inside         outside < inside       outside > inside
   NO net water movement    water moves IN         water moves OUT

        ╭───────╮              ╭─────────╮              ╭─────╮
       │  ╭───╮  │            │           │            │ ╱╲ ╱╲ │
       │  ╰───╯  │            │           │            │ ╲╱ ╲╱ │
        ╰───────╯              ╰─────────╯              ╰─────╯
      normal biconcave        SWELLS → bursts         SHRINKS, spiky
        7.5 um disc           = HEMOLYSIS             = CRENATION

   CLINICAL FLUID:          CLINICAL FLUID:          CLINICAL FLUID:
   0.9% NaCl (154 mEq/L     0.45% NaCl (half-        3% NaCl (513 mEq/L
     Na+, 154 Cl-,            normal saline,           Na+, 1026 mOsm/L)
     308 mOsm/L)              154 mOsm/L)            7.5% NaCl, 25% albumin
   Lactated Ringer's        5% dextrose in water     mannitol 20%
     (273 mOsm/L)             (iso-osmotic in the
                              BAG, hypotonic in
   USE: volume replacement    the BODY once the      USE: pull water OUT of
   Stays in the EXTRA-        glucose is burned)     swollen cells — cerebral
   cellular fluid; ~1/4                              oedema, raised intra-
   remains intravascular    USE: free-water deficit,   cranial pressure,
                              hypernatraemia          severe hyponatraemia

   DANGER: large volumes    DANGER: HEMOLYSIS if     DANGER: fluid overload;
   of saline cause a        given fast; CEREBRAL     osmotic demyelination if
   hyperchloraemic          OEDEMA — brain cells     hyponatraemia is
   metabolic acidosis       swell inside a rigid     corrected faster than
   (Ch. 31)                 skull                    ~8-10 mEq/L per 24 h

   ══ WHY THE BRAIN IS THE ORGAN THAT KILLS YOU ════════════════════════
   Every other tissue can swell into surrounding space. The brain is
   sealed in bone. A 5% increase in brain water raises intracranial
   pressure enough to herniate the brainstem. This is why plasma
   sodium is corrected SLOWLY, in both directions.

Filtration

Filtration is bulk flow of fluid and solutes through a membrane driven by hydrostatic pressure rather than by concentration. Everything small enough to pass goes together, in proportion to how much fluid moves. It is how capillaries deliver fluid to tissue and how the glomerulus makes 180 litres of filtrate a day (Chapter 26).

Note the contrast that defines it: diffusion is selective and concentration-driven; filtration is non-selective and pressure-driven. A capillary does both at once.

3.4 Active Transport

Active transport moves a solute against its electrochemical gradient, which cannot happen spontaneously. Energy must be supplied. In primary active transport the protein hydrolyses ATP itself; in secondary active transport it borrows the gradient another pump has already built.

Primary active transport: the sodium–potassium ATPase

This one protein deserves more attention than any other in the chapter. It is present in the plasma membrane of every animal cell, it consumes 20–30% of a resting cell's ATP — and up to 70% in a neuron — and almost every process in Chapters 9, 11, 26, and 31 is ultimately powered by it.

Its job is to maintain the two gradients listed in Figure 3.1: potassium high inside, sodium high outside. It does this by exporting 3 Na⁺ and importing 2 K⁺ per ATP hydrolysed.

   THE Na+/K+ ATPase — ONE CYCLE, SIX STEPS, THREE CONSEQUENCES
   ══════════════════════════════════════════════════════════════════════
                    OUTSIDE   Na+ 140    K+ 4  (mEq/L)
   ─────────────────────────────────────────────────────────────────────
                    INSIDE    Na+ 12     K+ 140

   STEP 1  Pump opens INWARD. Three Na+ binding sites are exposed to
           the cytosol and have HIGH affinity for Na+.
              ╔═════╗
              ║ ▼▼▼ ║  ← 3 Na+ from cytosol bind
              ╚═════╝

   STEP 2  ATP binds. The terminal phosphate is transferred to the
           pump itself — the pump is PHOSPHORYLATED.
              ATP → ADP + P-pump

   STEP 3  Phosphorylation forces a CONFORMATIONAL CHANGE.
           The pump now opens OUTWARD, and its Na+ sites have
           switched to LOW affinity.
              ╔═════╗
              ║ ▲▲▲ ║  ← 3 Na+ released into extracellular fluid
              ╚═════╝    AGAINST a 12-fold gradient

   STEP 4  In the outward-facing shape, two K+ sites now have
           HIGH affinity. Two K+ bind from outside.
              ╔═════╗
              ║  ▼▼ ║  ← 2 K+ bind
              ╚═════╝

   STEP 5  K+ binding triggers DEPHOSPHORYLATION — the phosphate
           leaves the pump.

   STEP 6  The pump snaps back to the inward-facing shape; K+ sites
           become LOW affinity; 2 K+ are released into the cytosol
           AGAINST a 35-fold gradient.  → back to STEP 1.
              ╔═════╗
              ║  ▲▲ ║   ~100 cycles per second per pump
              ╚═════╝   ~1 million pumps per cell

   ══ THE MECHANISM IN ONE SENTENCE ════════════════════════════════════
   Phosphorylation and dephosphorylation flip the pump between two
   shapes whose binding sites face opposite directions AND have
   opposite affinities — so each ion is picked up where it is scarce
   and dropped where it is abundant.

   ══ THREE CONSEQUENCES, ALL ESSENTIAL ════════════════════════════════
   1 CHEMICAL GRADIENTS   Na+ out, K+ in. These are the stored energy
                          that secondary transport spends (SGLT, NCX,
                          NHE) and that action potentials discharge.
   2 ELECTRICAL GRADIENT  3 out for 2 in = net +1 charge exported per
                          cycle. Directly contributes ~3-5 mV of the
                          resting potential; INDIRECTLY sets all of it
                          by maintaining the K+ gradient. (§3.5)
   3 CELL VOLUME          Cells are full of impermeant protein anions
                          that would draw water in relentlessly. By
                          continuously exporting Na+, the pump makes
                          Na+ behave as an EXTRACELLULAR solute and
                          balances the osmotic load.
                          → STOP THE PUMP AND THE CELL SWELLS.
                            This is the first step of necrosis (§3.8).

Secondary active transport

The Na⁺ gradient built by the pump is stored energy, like water behind a dam. Secondary active transport proteins let Na⁺ run downhill and use the released energy to drag a second solute uphill. No ATP is hydrolysed by these proteins — but the transport is active, because the ATP was spent earlier by the pump.

• Symport (cotransport): both solutes move in the same direction. SGLT1 in the intestine and SGLT2 in the proximal tubule carry Na⁺ and glucose inward together, which is how glucose is absorbed and reabsorbed against its own gradient. The SGLT2 inhibitors now used in diabetes and heart failure block exactly this protein, forcing glucose into the urine.
• Antiport (countertransport): the solutes move in opposite directions. The Na⁺/Ca²⁺ exchanger uses inward Na⁺ to expel Ca²⁺; the Na⁺/H⁺ exchanger uses it to expel protons and defend intracellular pH.

Note the dependency chain, because it is where several drugs and several diseases act: ATP → Na⁺/K⁺ ATPase → Na⁺ gradient → glucose absorption, calcium expulsion, pH regulation, amino acid uptake. Break the first link and all of the others fail together.

Vesicular transport

Large particles and bulk fluid cross by membrane deformation rather than through a protein.

Receptor-mediated endocytosis is the selective one, and it is the direct link back to Chapter 2. An LDL particle bearing apoB-100 binds the LDL receptor; receptors gather in a clathrin-coated pit; the pit invaginates and pinches off; the vesicle fuses with an endosome; falling pH releases the ligand; the receptor is recycled to the surface and the LDL is delivered to a lysosome, where the cholesteryl esters are hydrolysed and free cholesterol enters the cell.

The regulation is the elegant part: when intracellular cholesterol is adequate, the cell reduces LDL receptor synthesis. This is exactly the loop statins exploit — lower hepatocyte cholesterol, and the cell displays more receptors and clears more LDL from plasma. Familial hypercholesterolaemia is the same loop broken: a defective LDL receptor means plasma LDL cannot be cleared, and untreated homozygotes may have LDL above 500 mg/dL with coronary disease in childhood.

3.5 Membrane Potential

Everything in §3.3 and §3.4 converges here. A cell that separates charge across a thin insulator is a battery, and every cell in the body is one.

The resting membrane potential is the voltage across the plasma membrane of an unstimulated cell, measured as inside relative to outside. It ranges from about −20 mV in erythrocytes to −70 mV in neurons and −90 mV in cardiac and skeletal muscle. It exists because of three facts stacked together.

Fact 1 — the gradients exist. The Na⁺/K⁺ ATPase has spent ATP to put K⁺ inside and Na⁺ outside (Figure 3.3). Inside the cell there are also large, impermeant, negatively charged proteins and phosphates that cannot leave at all.

Fact 2 — the membrane is selectively permeable. At rest, the membrane contains many open potassium leak channels and very few open sodium channels — it is roughly 25–100 times more permeable to K⁺ than to Na⁺.

Fact 3 — potassium leaves, and its charge is left behind. K⁺ diffuses down its steep concentration gradient, out of the cell. Each ion that leaves carries a positive charge with it, but the impermeant anions cannot follow. The interior becomes progressively negative, and that negativity begins to pull K⁺ back. Equilibrium arrives when the electrical pull inward exactly balances the chemical push outward. For potassium alone, that balance point — the equilibrium potential, given by the Nernst equation — is about −90 mV.

A real cell rests slightly less negative than that (−70 mV in a neuron) because a small inward sodium leak partly offsets it, and the Na⁺/K⁺ ATPase contributes a further 3–5 mV directly by exporting net positive charge.

   THE ORIGIN OF THE RESTING MEMBRANE POTENTIAL
   ══════════════════════════════════════════════════════════════════════
   OUTSIDE       Na+ 140      K+ 4       Cl- 105     Ca2+ 2.4   (mEq/L)
   ┌───────────────────────────────────────────────────────────────────┐
   │  ⇣Na+ leak    ⇡ K+ LEAK CHANNELS       ╔═══════╗  Na+/K+ ATPase  │
   │  (few open)     (MANY open)            ║3Na+ ▲ ║  spends ATP to  │
   │                                        ║2K+  ▼ ║  rebuild both   │
   │   - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  │ ← inner
   └───────────────────────────────────────────────────────────────────┘   face
   INSIDE        Na+ 12      K+ 140      Cl- 4     free Ca2+ 0.0001
                 + large IMPERMEANT protein and phosphate ANIONS (A-)

   ══ THE ARGUMENT IN FOUR STEPS ═══════════════════════════════════════
   1  K+ is 35x more concentrated inside  → it diffuses OUT
   2  A- cannot follow                    → each K+ leaves a charge behind
   3  Inside becomes NEGATIVE             → the negativity pulls K+ back
   4  Balance point = EQUILIBRIUM POTENTIAL for K+ ≈ -90 mV

   ══ WHY A REAL NEURON SITS AT -70 mV, NOT -90 ════════════════════════
      E(K+)   = -90 mV   membrane is MOSTLY permeable to K+ → dominates
      E(Na+)  = +60 mV   small inward leak drags the value up
      pump    =  -3 mV   exports net +1 charge per cycle
      ─────────────────────────────────────────────────────────────
      RESTING  ≈ -70 mV  = a weighted average, dominated by whichever
                           ion the membrane is currently permeable to

   ══ THE PRINCIPLE THAT RUNS THE NERVOUS SYSTEM ═══════════════════════
   Membrane potential is NOT set by the gradients alone. It is set by
   WHICH CHANNELS ARE OPEN. The gradients are a standing battery; a
   gated channel is a switch.
        open more Na+ channels  → potential moves toward +60 mV
                                  = DEPOLARIZATION → action potential
        open more K+ channels   → potential moves toward -90 mV
                                  = HYPERPOLARIZATION
   → Chapter 11 is this paragraph, developed.

   ══ WHY PLASMA POTASSIUM IS THE MOST LETHAL ELECTROLYTE ══════════════
   The K+ gradient sets the resting potential, and plasma K+ is the
   SMALL number in that ratio (140 inside vs 4 outside). Doubling
   plasma K+ from 4 to 8 halves the ratio and depolarizes every
   excitable cell in the body toward threshold — then past it, into
   inexcitability. Amara's K+ of 4.1 is normal. Watch it in Ch. 31.

3.6 Cytoplasm and Organelles

Cytoplasm is everything between the plasma membrane and the nucleus: the cytosol (the aqueous gel), the organelles, and inclusions (stored glycogen granules, lipid droplets, pigments). Organelles are compartments, and compartmentalization is the point — it lets one cell run incompatible chemistries a few nanometres apart.

   THE COMPOSITE CELL — STRUCTURE REASONED INTO FUNCTION
   ══════════════════════════════════════════════════════════════════════
   ┌────────────────── PLASMA MEMBRANE (7-8 nm) ──────────────────────┐
   │  ⌇⌇ glycocalyx ⌇⌇                        ╭─── MICROVILLI ───╮    │
   │                                          │ ┃┃┃┃┃┃┃┃┃┃┃┃┃┃┃ │    │
   │   ╭────── NUCLEUS ──────╮                ╰─ 20x surface area ╯   │
   │   │  ╔═══════════════╗  │  ← nuclear envelope: TWO membranes,    │
   │   │  ║  NUCLEOLUS    ║  │    perforated by NUCLEAR PORES that    │
   │   │  ║  makes rRNA   ║  │    gate all traffic in and out         │
   │   │  ╚═══════════════╝  │                                        │
   │   │  chromatin =        │      ╭──── ROUGH ER ────╮              │
   │   │  DNA + histones     │══════│ ●●●●●●●●●●●●●●●● │  ● ribosomes │
   │   ╰─────────┬───────────╯      │ ●●●●●●●●●●●●●●●● │  studding it │
   │             │                  ╰────────┬─────────╯              │
   │   FREE RIBOSOMES ●●●                    │ vesicles               │
   │   (proteins that STAY                   ▼                        │
   │    in the cytosol)              ╭─── GOLGI ────╮                 │
   │                                 │ ═══════════  │ cis face in     │
   │   ╭─── SMOOTH ER ───╮           │ ═══════════  │ trans face out  │
   │   │ no ribosomes    │           │ ═══════════  │ sorts, tags,    │
   │   │ lipid + steroid │           ╰──┬────┬───┬──╯ glycosylates    │
   │   │ synthesis;      │              │    │   │                    │
   │   │ P450 detox;     │              ▼    ▼   ▼                    │
   │   │ Ca2+ store      │       secretory  LYSO- membrane            │
   │   ╰─────────────────╯        vesicle   SOME   protein            │
   │                                       ╭────╮  → exocytosis       │
   │   ╭── MITOCHONDRION ──╮               │pH 5│                     │
   │   │ ╔═══════════════╗ │               │ 50+│ acid hydrolases     │
   │   │ ║ ╱╲╱╲╱╲ CRISTAE║ │               │enz.│ digest anything     │
   │   │ ║ inner membrane║ │               ╰────╯ ITS OWN MEMBRANE
   │   │ ║ folded to     ║ │                      IS THE SAFETY       │
   │   │ ║ multiply area ║ │                                          │
   │   │ ╚═══════════════╝ │      ╭─ PEROXISOME ─╮  ╭─ PROTEASOME ─╮  │
   │   │ own DNA, own      │      │ H2O2 -> H2O  │  │ barrel that   │  │
   │   │ ribosomes,        │      │ catalase;    │  │ shreds UBIQ-  │  │
   │   │ MATERNAL only     │      │ long-chain   │  │ UITIN-tagged  │  │
   │   ╰───────────────────╯      │ fatty acids  │  │ proteins      │  │
   │                              ╰──────────────╯  ╰───────────────╯  │
   │   CYTOSKELETON, three sizes:                                     │
   │    MICROFILAMENT  7 nm   actin      shape, crawling, cytokinesis │
   │    INTERMEDIATE  10 nm   keratin/   TENSILE STRENGTH; resists    │
   │                          desmin     pulling. Anchors desmosomes  │
   │    MICROTUBULE   25 nm   tubulin    tracks for motors; spindle;  │
   │                                     core of cilia and flagella   │
   │   CENTROSOME ✥ two centrioles at right angles → organizes the    │
   │              spindle in mitosis; nucleates cilia                 │
   └──────────────────────────────────────────────────────────────────┘
   ══ THE SECRETORY PATHWAY, IN ORDER ══════════════════════════════════
   nucleus → mRNA → ribosome ON ROUGH ER → protein enters ER lumen →
   folded, glycosylated → vesicle → GOLGI cis → medial → trans (sorted
   and tagged) → vesicle → (a) secretory granule → EXOCYTOSIS
                                (b) LYSOSOME    (c) plasma membrane

The organelles, reasoned from structure

3.7 The Nucleus and the Flow of Genetic Information

The nucleus is the cell's instruction archive. Most human cells have one; skeletal muscle fibres have hundreds; mature erythrocytes have none, which is why they cannot repair themselves and why their lifespan is fixed at 120 days (Chapter 2).

Three components:

• The nuclear envelope is two membranes, the outer continuous with rough ER. It is perforated by 3,000–4,000 nuclear pore complexes, each a gated channel roughly 100 nm across. Small molecules diffuse through; anything larger than about 40 kDa requires a signal sequence and an escort. The envelope is not a wall but a customs post, and controlling what enters is a major mechanism of gene regulation.
• The nucleolus is a dense, non-membrane-bound region where ribosomal RNA is transcribed and ribosomal subunits assembled. A prominent nucleolus means a cell making a great deal of protein — which is why it is a feature pathologists look for in rapidly dividing tumours.
• Chromatin is DNA wound around histone proteins. Two metres of DNA fit into a 6 µm nucleus by wrapping 147 base pairs around each histone octamer to form a nucleosome, then coiling the resulting beads-on-a-string into thicker fibres. Loosely packed euchromatin is accessible and being transcribed; densely packed heterochromatin is silenced. Packing is not just storage — it is a regulatory mechanism, and Chapter 29 develops it.

From gene to protein, in outline

Two steps, one in each compartment. Transcription: RNA polymerase copies one gene's DNA sequence into messenger RNA inside the nucleus; the transcript is processed — introns removed, ends capped — and exported through a nuclear pore. Translation: a ribosome reads the mRNA in triplets called codons, and transfer RNAs deliver the corresponding amino acid for each, building the polypeptide N-terminus first.

The consequences are worth stating even at this outline level. The genetic code is a code for primary structure only — and Chapter 2 established that primary structure determines everything above it. The gene specifies a sequence; the sequence folds itself. And because ribosomes on rough ER deliver their product into the ER lumen while free ribosomes deliver into cytosol, a short signal sequence at the protein's N-terminus decides its entire destination. Chapter 29 gives the full treatment.

3.8 The Cell Cycle, Mitosis, and Two Ways to Die

The cell cycle

   THE CELL CYCLE — AND WHERE THE BRAKES ARE
   ══════════════════════════════════════════════════════════════════════

                        ╭──────── M PHASE ────────╮
                        │   MITOSIS + CYTOKINESIS │  ~1 hour
                        │   P-M-A-T                │
                        ╰────────┬─────────────────╯
              M CHECKPOINT ✥     │        ╱
              are all chromo-    │       ╱  ← G1 CHECKPOINT ✥ (RESTRICTION
              somes attached     ▼      ╱      POINT) the MAIN decision:
              to the spindle?  ╭──────╮╱       size? nutrients? growth
                               │  G2  │        signals? DNA damage?
       G2 CHECKPOINT ✥         │ 2-5h │        p53 acts HERE
       is DNA replication      ╰───┬──╯    ╭──────────╮
       complete and undamaged?     │       │    G1    │ 8-12 h (variable;
       p53 acts HERE               │       │  GROWTH  │ THIS is the phase
                              ╭────┴───╮   │          │ whose length differs
                              │   S    │◄──╯          │ between cell types)
                              │ 6-8 h  │   ╰────┬─────╯
                              │ DNA    │        │
                              │ COPIED │        ▼  cells that stop dividing
                              ╰────────╯   ╭─────────────╮
                                           │     G0      │  QUIESCENT
        INTERPHASE = G1 + S + G2           │             │  neurons and
        ≈ 90% of the cycle                 │ may re-enter│  cardiomyocytes
                                           │  or never   │  enter and NEVER
                                           ╰─────────────╯  leave

   ══ MITOSIS, FOUR PHASES ═════════════════════════════════════════════
   PROPHASE     chromatin condenses into visible chromosomes, each
                already TWO sister chromatids; nuclear envelope breaks
                down; centrosomes separate and build the spindle
   METAPHASE    chromosomes align on the METAPHASE PLATE, each attached
                to both poles. The M checkpoint holds here until every
                kinetochore is attached
   ANAPHASE     sister chromatids are pulled apart to opposite poles
   TELOPHASE    chromosomes decondense; two nuclear envelopes reform
   CYTOKINESIS  an actin ring contracts, pinching the cell in two

   ══ THREE PROLIFERATIVE CATEGORIES ═══════════════════════════════════
   LABILE     divide continuously      epidermis, gut lining, marrow
                                       → injury heals by REGENERATION
   STABLE     G0, but re-enter if      liver, kidney tubule, fibroblast
              stimulated               → substantial regeneration possible
   PERMANENT  G0 permanently           NEURON, CARDIOMYOCYTE, skeletal
                                       muscle fibre
                                       → injury heals by SCAR, not by
                                         replacement.  ← Amara's heart

Checkpoints are the control system. At each, the cycle halts until a condition is verified. The key regulator is the p53 protein, which detects DNA damage and either arrests the cycle for repair or, if damage is irreparable, triggers apoptosis. Because p53 stands at the junction between "repair it" and "destroy it," it is mutated in roughly half of all human cancers — a point §3.9 returns to.

Two ways for a cell to die

This is the section that answers Amara's case.

   APOPTOSIS vs NECROSIS — TWO DEATHS, ONE CRITICAL DIFFERENCE
   ══════════════════════════════════════════════════════════════════════
                    APOPTOSIS                    NECROSIS
   ─────────────────────────────────────────────────────────────────────
   NATURE          programmed, regulated       uncontrolled injury
                   "cellular suicide"          "cellular murder"
   TRIGGER         developmental signal,       ischaemia, toxin, trauma,
                   DNA damage, loss of         extreme heat/cold,
                   survival signal, p53        infection, complement
   ATP REQUIRED?   YES — it is an ACTIVE,      NO — it is what happens
                   energy-consuming process    WHEN ATP RUNS OUT
   SCALE           SINGLE cells, scattered     SHEETS of contiguous cells
                                               (a whole perfusion territory)

   ══ THE SEQUENCE, SIDE BY SIDE ═══════════════════════════════════════
   APOPTOSIS                        NECROSIS
   1 caspase cascade activated      1 ATP falls → Na+/K+ ATPase STOPS
   2 cell SHRINKS                   2 Na+ accumulates inside
   3 chromatin condenses; DNA cut   3 water follows → CELL SWELLS
     into regular fragments         4 Ca2+ can no longer be expelled;
   4 membrane BLEBS but stays         cytosolic Ca2+ rises 1000-fold
     INTACT throughout              5 Ca2+ activates phospholipases and
   5 phosphatidylserine flips to      proteases → membrane digested
     the OUTER leaflet = "eat me"   6 MEMBRANE RUPTURES
   6 cell breaks into sealed        7 CYTOSOLIC CONTENTS SPILL INTO THE
     apoptotic bodies                 INTERSTITIUM AND THEN THE BLOOD
   7 macrophage engulfs them        8 lysosomes rupture, digesting the
     BEFORE anything leaks            remains and neighbouring cells

   ══ THE CONSEQUENCE THAT MATTERS CLINICALLY ══════════════════════════
   APOPTOSIS  ┌──────────────┐   contents never reach the extra-
              │ sealed       │   cellular space
              │ packages     │   → NO INFLAMMATION
              │ eaten intact │   → NO ENZYME OR PROTEIN IN BLOOD
              └──────────────┘   → NOTHING TO MEASURE

   NECROSIS   ┌ ─ ─ ─ ─ ─ ─ ┐   ▓ troponin ▓ CK-MB ▓ myoglobin ▓ K+
              ╎ RUPTURED    ╎ → spill out → interstitium → lymph and
              ╎             ╎   capillaries → SYSTEMIC BLOOD
              └ ─ ─ ─ ─ ─ ─ ┘ → DAMPs released → neutrophils recruited
                              → INFLAMMATION → later, SCAR (Ch. 4)

   ══ WHY IT TAKES HOURS — AMARA'S TROPONIN CURVE ══════════════════════
   07:40  artery occludes.        ATP falls within SECONDS; contraction
                                  stops within ~60 s. Cells are stunned,
                                  not yet dead. NOTHING in the blood.
   ~08:00 (20-30 min) irreversible injury begins in the worst-perfused
          subendocardium and spreads outward as a WAVEFRONT
   08:45  cytosolic free troponin from the earliest cells reaches blood
          → 0.09 ng/mL   (barely above 0.04)
   11:45  more cells rupture; STRUCTURAL troponin now unbinding from
          the myofilaments → 0.71 ng/mL
   14:30  wavefront still advancing; structural pool still releasing
          → 2.4 ng/mL and RISING
   FOUR delays stack: (1) time to irreversible injury, (2) the spreading
   wavefront, (3) 6-8% of troponin is free in cytosol and released early
   while 92-94% is BOUND to myofilaments and released slowly as they are
   degraded, (4) transit through interstitium and LYMPH to the blood.

Apoptosis is a controlled demolition. A cascade of proteases called caspases dismantles the cell from within, in a specific order, while the plasma membrane is held intact. The cell packages itself into sealed vesicles, displays a phosphatidylserine "eat me" flag on its outer leaflet (recall from §3.2 that this lipid normally faces only inward), and is consumed by a macrophage. Nothing leaks. It is how a tadpole loses a tail, how the webbing between fetal fingers is removed, how 10 billion of your own cells are retired every day, and how a lymphocyte that recognizes self is eliminated.

Necrosis is not a programme. It is the physical consequence of running out of ATP, and the sequence follows directly from §3.4 and §3.5: pumps stop, sodium and water enter, the cell swells, calcium floods in and activates degradative enzymes, and the membrane fails mechanically. Because the membrane fails, everything inside comes out.

That last sentence is the answer to Amara's second question, and it is why a blood test can detect the death of cells you cannot see.

3.9 Advanced Topic · Cellular Ageing, Telomeres, and Cancer as a Cell-Cycle Disease

The Hayflick limit and telomeres

In 1961 Leonard Hayflick showed that normal human cells in culture divide a limited number of times — about 40–60 — and then stop permanently. They do not die; they enter replicative senescence, remaining metabolically active but never dividing again.

The mechanism is a consequence of how DNA is copied. DNA polymerase cannot replicate the extreme end of a linear chromosome, so a little is lost with every division — the end-replication problem. Chromosome ends carry telomeres, repeats of the sequence TTAGGG that are disposable buffer: about 10,000 base pairs at birth, shortening by 50–200 base pairs per division. When a telomere becomes critically short, the cell interprets the exposed end as a double-strand break, p53 is activated, and the cycle arrests permanently.

The enzyme telomerase rebuilds telomeres. It is active in germ cells, in embryonic stem cells, and at low levels in some adult stem cells — and it is silenced in ordinary somatic cells. That silencing is not an oversight. A cell that could divide indefinitely is a cell that could accumulate mutations indefinitely, and the telomere clock is a tumour-suppressing mechanism that limits how many divisions any lineage can make before it must stop.

Cancer as a cell-cycle disease

Cancer is the failure of the control system in Figure 3.6. It requires the accumulation of mutations in several classes of gene, because single failures are ordinarily caught.

Three features of this table explain the clinical behaviour of cancer. It is multi-step — typically five to eight independent events — which is why incidence rises so steeply with age, since time is what accumulates mutations. It is clonal: every cell in a tumour descends from one cell that acquired the first change, which is why tumours are genetically distinctive and why targeted drugs can work. And because the last two rows disable the mechanisms that would otherwise remove the cell, cancer is best understood not as cells growing too fast — many tumour cells divide more slowly than intestinal crypt cells — but as cells failing to stop and failing to die.

Note the connection back to §3.8. p53 stands at the junction between "arrest and repair" and "trigger apoptosis." Losing p53 does not merely remove a brake; it removes the mechanism that would have deleted the cell for having lost the brake. That is why it is the most commonly mutated gene in human cancer, and why its nickname is the guardian of the genome.

Chapter Summary

§3.1 The cell theory holds that the cell is the unit of structure and function, that organism activity is aggregated cell activity, and that all cells arise from pre-existing cells. Roughly 37 trillion cells of about 200 types vary enormously in size, shape, and lifespan, and the variation is never arbitrary — cells exposed to damage are replaced rapidly, while cells whose function lies in accumulated connections are not replaced at all. Cardiomyocytes belong to the second group.

§3.2 The plasma membrane is a fluid mosaic: a 7–8 nm phospholipid bilayer, asymmetric between its leaflets, with cholesterol as a fluidity buffer, a glycocalyx of identity sugars outside, and proteins in six functional classes — channel, carrier, pump, receptor, enzyme, and anchor. The hydrocarbon interior admits only small nonpolar molecules, so everything the cell must regulate is something that cannot cross unaided.

§3.3 Passive transport spends no cellular energy. Diffusion is fast over micrometres and useless over millimetres, which is why no cell sits more than 100 µm from a capillary. Channels are fast and gated; carriers are slower and saturable, which is why Amara spills glucose into her urine at 212 mg/dL. Osmolarity counts all particles; tonicity counts only those that cannot cross, and tonicity is what predicts whether a cell swells or shrinks. Filtration is pressure-driven and non-selective.

§3.4 Primary active transport hydrolyses ATP directly. The Na⁺/K⁺ ATPase exports 3 Na⁺ and imports 2 K⁺ per ATP by flipping between two conformations with opposite site orientations and opposite affinities, consuming 20–30% of cellular ATP and maintaining the chemical gradients, the electrical gradient, and cell volume. Secondary active transport spends the Na⁺ gradient rather than ATP, by symport (SGLT) or antiport (Na⁺/Ca²⁺, Na⁺/H⁺). Vesicular transport handles bulk cargo, and receptor-mediated endocytosis is how LDL enters a cell.

§3.5 The resting membrane potential arises from ion gradients built by the pump, impermeant intracellular anions, and a membrane far more permeable to K⁺ than to Na⁺. It is not fixed by the gradients but by which channels are open, which is the principle the entire nervous system runs on.

§3.6 Organelles are compartments that let one cell run incompatible chemistries side by side. Cristae multiply mitochondrial membrane area; rough ER folds and checks exported proteins; smooth ER handles lipids, drugs, and calcium; the Golgi is a directional sorting line; lysosomes digest at pH 5 behind their own membrane; proteasomes destroy individually tagged proteins; and the three cytoskeletal filament sizes provide shape, tension, and transport. Organelle abundance is a readable statement of a cell's job.

§3.7 The nuclear envelope is a gated customs post; chromatin packing is itself a regulatory mechanism; and the genetic code specifies primary structure only — everything above it follows by self-assembly.

§3.8 The cell cycle runs G1 → S → G2 → M with checkpoints at each junction, policed largely by p53. Tissues are labile, stable, or permanent, and permanent tissues heal by scar. Apoptosis is an ATP-requiring programme that keeps the membrane intact and releases nothing; necrosis is what happens when ATP runs out, and it ruptures the membrane and spills the cytosol. That difference is why Amara has a measurable troponin.

§3.9 Telomere shortening imposes a division limit that suppresses tumours at the cost of renewal capacity, and senescent cells actively secrete an inflammatory programme. Cancer is a multi-step, clonal failure of cell-cycle control in which cells fail to stop and fail to die.

Case File 3 · Resolution

Question 1 — What is troponin doing inside a cardiac muscle cell, and what keeps it there?

Troponin is a complex of three proteins bound to the thin filament of the contractile apparatus, spaced at regular intervals along it (Chapter 2, §2.9). Troponin T binds tropomyosin, troponin I inhibits the actin–myosin interaction at rest, and troponin C binds calcium. When calcium is released into the cytosol, troponin C binds it, the complex changes shape, tropomyosin shifts on the filament, and myosin can engage actin. Troponin is the switch that converts a calcium signal into a contraction, and Chapter 9 develops the mechanism in full.

What keeps it inside is simply the plasma membrane (§3.2) — plus the fact that it has nowhere else to go. Troponin is not a secreted protein. It is made on free ribosomes in the cytosol, carries no signal sequence, never enters the ER or Golgi, and is therefore never packaged into a vesicle (§3.6, §3.7). There is no exocytotic pathway that could export it even if the cell wanted to. About 92–94% of it is bound to the myofilaments as a structural component, and the remaining 6–8% floats free in the cytosol.

So an intact cardiomyocyte cannot release troponin. Not "does not" — cannot. That is what makes the test meaningful.

Question 2 — What must have happened for troponin to be in her blood?

Cardiomyocytes must have physically ruptured. Given the answer above, there is no other route.

The sequence is necrosis (§3.8), and every step follows from earlier sections of this chapter. Her coronary artery occluded, so oxygen delivery to a territory of myocardium stopped. Within seconds, mitochondrial ATP production collapsed — and a cardiomyocyte has essentially no anaerobic reserve (§3.1). Within about sixty seconds, contraction ceased, because contraction is the largest ATP consumer. The Na⁺/K⁺ ATPase slowed and stopped (§3.4), so sodium accumulated inside; water followed it osmotically, because the impermeant intracellular anions were no longer being offset (§3.5), and the cells swelled. The Ca²⁺ ATPase and the Na⁺/Ca²⁺ exchanger failed for the same reasons, and cytosolic free calcium — normally held near 0.0001 mEq/L — rose a thousandfold. That calcium activated phospholipases and proteases which digested the phospholipid bilayer itself, a self-assembled structure with no covalent framework to resist (Chapter 2).

The membrane ruptured, and the cytosol emptied into the interstitium: troponin, creatine kinase, myoglobin, potassium, lactate. Her supporting labs confirm the same event through four different molecules — CK-MB 22 ng/mL, myoglobin 180 ng/mL, and a white cell count of 12.8 × 10⁹/L, because the spilled contents are damage-associated molecular patterns that recruit neutrophils (Chapter 20).

Contrast this with apoptosis, which is happening in Amara's body right now in thousands of cells and produces no measurable marker whatever, because an apoptotic cell keeps its membrane sealed until a macrophage has swallowed it whole. Cells die by apoptosis constantly and silently. The reason a blood test can detect a myocardial infarction is precisely that ischaemic death is messy.

Question 3 — Why did the rise take six hours?

Four separate delays stack, and none of them is the "time for the cell to die."

1. Time to irreversible injury. Occlusion at 07:40 did not kill anything instantly. Reversibly injured myocardium is stunned, not dead; the cells stop contracting within a minute but retain membrane integrity for roughly 20–30 minutes. Restore flow inside that window and most survive — which is the entire justification for emergency reperfusion.
2. A spreading wavefront. Death does not occur simultaneously across the territory. It begins in the subendocardium, the layer furthest from the epicardial coronary vessels and compressed hardest during systole, and advances outward toward the epicardium over several hours. At any moment only part of the territory is releasing its contents, and new cells keep joining. Her troponin was still rising at 14:30 because the wavefront was still advancing.
3. Two pools with different release kinetics. The 6–8% of troponin that is free in the cytosol escapes quickly through a ruptured membrane and accounts for the early, modest rise to 0.09 ng/mL. The 92–94% that is structurally bound to the myofilaments can only be released as those filaments are proteolytically degraded, which takes many hours to days. That bound pool is what drives the climb to 2.4 and beyond, and it is why troponin stays elevated for 7–10 days after an infarct while myoglobin — small, entirely cytosolic — peaks and clears within hours.
4. Transit time. Released protein must diffuse through interstitial fluid, enter cardiac lymphatics and capillaries, and be carried to a peripheral vein before it can be sampled. That alone adds a further delay.

The clinical consequence is the reason for serial sampling. A single troponin drawn at 08:45 — 0.09, barely abnormal — could not distinguish an evolving infarction from chronic low-grade release. The rise from 0.09 to 0.71 to 2.4 is the diagnosis, because a rising and falling pattern means cells are dying now. Amara's first troponin was nearly normal not because little muscle was dying, but because it was too early for the muscle that was dying to have finished telling anyone.

Systems Integration Case File · Entry 3

Review

Level 1 · Recall

3.1 Which structure is responsible for the plasma membrane's role as a barrier to ions?

a) the glycocalyx    b) integral proteins    c) the hydrophobic interior of the bilayer    d) cholesterol

3.2 The Na⁺/K⁺ ATPase moves:

a) 2 Na⁺ out and 3 K⁺ in    b) 3 Na⁺ out and 2 K⁺ in    c) 3 Na⁺ in and 2 K⁺ out    d) equal numbers of both

3.3 A cell placed in a hypertonic solution will:

a) swell and lyse    b) shrink    c) remain unchanged    d) increase its metabolic rate

3.4 Which organelle contains its own DNA?

a) lysosome    b) Golgi apparatus    c) mitochondrion    d) peroxisome

3.5 Rough endoplasmic reticulum is distinguished from smooth ER by the presence of:

a) cristae    b) ribosomes    c) acid hydrolases    d) catalase

3.6 DNA replication occurs during which phase of the cell cycle?

a) G1    b) S    c) G2    d) M

3.7 Which of the following is characteristic of apoptosis but not of necrosis?

a) cell swelling    b) membrane rupture    c) an inflammatory response    d) ATP consumption

3.8 Amara's glycosuria at a plasma glucose of 212 mg/dL is best explained by:

a) kidney damage    b) saturation of carrier proteins    c) increased filtration pressure    d) failure of the Na⁺/K⁺ ATPase

Level 2 · Comprehension

3.9 Explain why the Na⁺/K⁺ ATPase is described as maintaining cell volume, and predict what happens to a cell when it stops.

3.10 Distinguish osmolarity from tonicity, and explain why 5% dextrose and 0.9% saline behave so differently despite similar osmolarities.

3.11 A pathologist looks at an unlabelled electron micrograph showing a cell almost filled with rough ER and a very large Golgi. What kind of cell is this likely to be, and what general principle are you applying?

Level 3 · Clinical Application

3.12 A patient with heart failure takes digoxin and is started on a thiazide diuretic. Two weeks later she develops nausea, visual disturbance, and a dangerous arrhythmia. Her potassium is 2.9 mEq/L. Explain the mechanism completely.

3.13 A newborn fails to pass meconium, and by six months has poor weight gain, greasy stools, and recurrent chest infections. Sweat chloride is 96 mmol/L. Explain how one protein defect produces all four findings.

3.14 A patient arrives 90 minutes after chest pain onset with a normal troponin. The registrar wants to discharge her. Using this chapter, explain why that is unsafe.

Level 4 · Integration and Synthesis

3.15 Construct the complete causal chain from "coronary artery occludes at 07:40" to "troponin 2.4 ng/mL at 14:30," naming every cellular structure involved in order, and identify the point at which the injury becomes irreversible and why.

3.16 Argue for or against: "A cell that could not die would be an advantage." Use apoptosis, telomeres, and cancer.

Concept Map to Complete

Copy this onto blank paper and fill every bracket from memory.

                       MEMBRANE TRANSPORT
                              │
              ┌───────────────┴───────────────┐
         [ __________ ]                  [ __________ ]
         no ATP used                     ATP used
              │                                │
      ┌───────┼────────┬─────────┐      ┌──────┴───────┐
   simple  facilitated  [ _____ ] filtr [ _______ ]  [ _______ ]
   diffu-  diffusion    (water)   ation  ATP used     Na+ gradient
   sion        │                          DIRECTLY    used instead
      │    ┌───┴────┐                        │             │
   crosses │        │                    example:      symport ex:
   [ ____ ]│     [ ______ ]              [ _________ ] [ ______ ]
   examples:      saturable →            3 [ __ ] out  antiport ex:
   [ __ ][ __ ]   [ ______ ]             2 [ __ ] in   [ ______ ]
                                              │
                              ┌───────────────┼──────────────┐
                        gradients        [ ______ ]     cell VOLUME
                        for 2ndary       potential            │
                        transport             │          stop the pump →
                                        rest = [ ___ ] mV  cell [ ______ ]
                                                              │
                                                        first step of
                                                        [ __________ ]
                                                              │
                                            ┌─────────────────┴──────────┐
                                       [ _________ ]              [ _________ ]
                                       membrane INTACT            membrane RUPTURES
                                       needs [ ___ ]              needs no [ ___ ]
                                       inflammation? [ __ ]       inflammation? [ __ ]
                                       measurable in blood?       measurable? [ __ ]
                                       [ __ ]                     → TROPONIN

Lab / Self-Exploration

1. Watch osmosis. Put one raw egg in vinegar for 48 hours to dissolve the shell, leaving the membrane intact. Weigh it. Place it in distilled water for 12 hours and reweigh; then in concentrated syrup for 12 hours and reweigh. Plot the three masses and label each solution as hypotonic or hypertonic relative to the egg.
2. Estimate a diffusion distance. Drop food colouring into a still glass of water and time how long it takes to travel 1 cm without stirring. Then calculate how long it would take to cross a 0.5 µm alveolar membrane, given that diffusion time scales with the square of distance. Use the result to explain why you have a circulatory system.
3. Find a transport maximum in your own life. Look up the renal threshold for glucose (180–200 mg/dL) and explain, in two sentences, why a person with a plasma glucose of 150 has no glucose in the urine while Amara at 212 does — without using the word "damage."
4. Read a nutrition label as a cell would. Find a sports drink and calculate its osmolarity roughly, treating each gram of sugar per 100 mL as ~55 mOsm/L and each mEq of sodium as 1 mOsm/L. Is it hypotonic, isotonic, or hypertonic to plasma at 290 mOsm/kg? Predict how that affects gastric emptying and absorption rate.
5. Reason from an organelle. For each of the following, name the dominant organelle you would expect and justify it in one sentence: a sebaceous gland cell, a neutrophil, an adrenal cortical cell, a mature red blood cell.
6. Track your own cell turnover. Estimate how many of the cells in your body today were also there one year ago, using these lifespans: gut lining 4 days, skin 30 days, red cells 120 days, neurons and cardiomyocytes lifelong. Which tissues are, in a real sense, not the same tissue they were last year?

Key Terms

Next: Chapter 4 · Tissues — where the cells that survived Amara's infarction are organized into the four fabric types of the body, and where the scar that replaces her dead myocardium is built.