4.5 — Organogenesis: How Each Organ Physically Forms

Your heart started as two tubes that fused into one, began beating on about day 22 before it had any chambers, and then looped, twisted and partitioned itself into four rooms while it was already pumping. It never stopped to be rebuilt. Every stage had to work well enough to keep the embryo alive while the next stage was under construction.

That constraint — remodel while running — explains most congenital heart disease, and it is the theme of this whole page. Each organ below is followed from a flat sheet or a simple tube to a working structure, and each of the commonest birth defects is named at the exact step that failed.

The heart

Day 18 to 21. Mesoderm cells form two tubes on either side of the midline. As the embryo folds side to side (Chapter 4.4), the two tubes are brought together and fuse into a single tube with an inflow end at the bottom and an outflow end at the top.

Day 22. The tube starts beating. This is the first organ to function in a human embryo, and it does so before it has chambers, valves or a divided circulation. It has to, because diffusion alone can no longer supply an embryo of this size.

Days 23 to 28: looping. The tube grows faster than the space containing it, so it buckles into an S-shape and folds to the right. Everything about the final left–right arrangement of the heart follows from which way this loop goes.

When it loops the wrong way — dextrocardia — the heart is a mirror image. In isolation it is often harmless. Combined with reversal of all the other organs (situs inversus totalis) it is usually harmless too. Combined with normal positioning of everything else, it is frequently associated with severe cardiac defects, because the heart's connections no longer match the vessels it must join.

And the reason the loop goes right at all traces back to cilia — the leftward fluid flow described in Chapter 1.5. Without working cilia the direction is decided at random, which is why about half of people with primary ciliary dyskinesia have reversed organs.

Weeks 4 to 7: partitioning. The single tube must become four chambers and two separate outflow vessels, without ever stopping.

The atrial septum grows down as one sheet that develops a hole in its middle, and then a second sheet grows down beside it overlapping the hole. The result is a flap valve — the foramen ovale — that lets blood pass from right atrium to left but not back. This is deliberate: the fetus does not use its lungs, so most blood must bypass them (Chapter 7.9).

The ventricular septum grows up from the floor and meets tissue growing down.

The outflow tract is divided by a spiral wall formed largely by neural crest cells that migrated in (Chapter 4.4), separating the single vessel into aorta and pulmonary artery, which is why they twist around each other.

Now the defects, each at its step.

Ventricular septal defect — the ventricular septum fails to close completely. The commonest congenital heart defect, about a third of all cases. Blood shunts from the higher-pressure left ventricle into the right, overloading the lungs. Small ones close spontaneously in most cases; large ones need surgical repair, and left untreated the raised lung pressure eventually becomes irreversible and the shunt reverses, which is a catastrophe called Eisenmenger syndrome.

Atrial septal defect — the flap valve fails to seal after birth. Often silent for decades and found in adulthood.

Patent ductus arteriosus — the fetal vessel connecting pulmonary artery to aorta fails to close after birth. Chapter 7.9. Closable with indometacin or ibuprofen in a premature infant, because those drugs block the prostaglandin that holds it open.

Tetralogy of Fallot — a single developmental error, the outflow septum forming too far forward, produces four consequences at once: a narrowed pulmonary outflow, a ventricular septal defect, an aorta sitting over the defect, and a thickened right ventricle from the resulting pressure. The child is blue, because deoxygenated blood is being pushed into the aorta. It is the commonest cyanotic congenital heart disease, and it is repairable surgically with excellent long-term results — the first successful operation, in 1944, essentially created paediatric cardiac surgery.

Transposition of the great arteries — the outflow septum fails to spiral, so the aorta arises from the right ventricle and the pulmonary artery from the left. This creates two separate circuits with no connection, and it is incompatible with life unless some mixing exists. It is a neonatal emergency: prostaglandin is given to keep the ductus open as a temporary connection, and definitive surgery follows within days.

The gut and its derivatives

The endoderm becomes a tube running head to tail. Then it elongates far faster than the abdomen, and everything that follows is a consequence of that.

Weeks 6 to 10: the physiological hernia. The gut becomes too long for the abdominal cavity, which is at this stage largely occupied by the liver. So the midgut loops out into the umbilical cord, rotates 270 degrees anticlockwise while it is out there, and returns during week 10, by which time the abdomen has grown.

This is normal. An ultrasound at nine weeks showing bowel in the cord is not a defect.

Malrotation happens when the rotation is incomplete, leaving the bowel anchored abnormally on a narrow stalk. It can twist on that stalk — volvulus — cutting off its own blood supply. In an infant this presents as bilious vomiting, which is always an emergency: green vomit in a newborn means obstruction below the bile duct until proven otherwise, and delay costs bowel.

Buds from the tube become organs. The liver buds off from the duodenum in week 4 and becomes the largest organ in the embryo, producing blood cells before the marrow takes over. The pancreas forms as two buds — dorsal and ventral — that rotate and fuse. When they fuse in the wrong arrangement they encircle the duodenum: annular pancreas, causing obstruction.

The lungs bud off the front of the foregut in week 4 and branch repeatedly — 23 generations of branching, finishing the airway pattern by about week 16, with alveoli continuing to be added until well after birth. Because the lung comes off the gut tube, a failure of separation leaves a connection between them: tracheo-oesophageal fistula, in which the oesophagus ends blindly and the lower part connects to the trachea. The newborn cannot swallow saliva, chokes on the first feed, and needs surgery. It is often associated with other anomalies, and the association is another neural crest and foregut story.

The thyroid begins at the back of the tongue and descends through the neck, leaving a track behind it. A remnant of that track can persist as a thyroglossal cyst — a midline neck lump that moves upward when the person sticks out their tongue, which is a diagnostic sign that only makes sense once you know where the gland came from.

The kidneys

The kidney is built three times over, and this is one of the strangest sequences in development.

Pronephros — appears in week 3, is non-functional, and degenerates within days. It is a vestige of a fish kidney.

Mesonephros — functions briefly in the embryo, then degenerates too, except that its duct system is taken over in males to become the epididymis and vas deferens.

Metanephros — the definitive kidney, forming from week 5, working from about week 10.

And it forms in the pelvis, then ascends. As it climbs, it takes new blood supply from progressively higher points on the aorta and discards the old ones.

Two failure modes follow directly. If the two developing kidneys touch as they ascend, they fuse at the lower poles into a horseshoe kidney, which then cannot rise past a large artery and stays low. It occurs in about 1 in 500 people and is usually harmless, though it raises the risk of stones and infection. If a kidney fails to ascend at all, it remains a pelvic kidney. And if an old blood vessel fails to regress, an accessory renal artery crosses the ureter and can obstruct it.

Kidney development depends on a conversation between two tissues. A ureteric bud grows out of the duct and into a mass of mesoderm; the bud induces the mesoderm to form nephrons, and the mesoderm induces the bud to branch. If either signal fails, no kidney forms.

Bilateral renal agenesis is fatal, and the reason is not the kidneys. Fetal urine is the main source of amniotic fluid from the second trimester, and amniotic fluid is what allows the lungs to develop — the fetus breathes it in and out, and the pressure is required for the airways to grow. With no kidneys there is no fluid, the lungs stay hypoplastic, and the baby dies of respiratory failure at birth. The combination, called Potter sequence, also produces characteristic flattened facial features from compression. One missing organ causing death through a completely different organ is a good demonstration of how interlinked development is.

The limbs

Limb buds appear in week 4 — arms first, legs a couple of days later, which is why arm defects from a teratogen precede leg defects by days (the thalidomide timings in Chapter 4.4).

Three axes are set by three signalling centres, and each has a matching malformation.

Proximal to distal — a ridge of thickened ectoderm at the bud's tip keeps the tissue beneath it dividing. Remove it and the limb stops growing at whatever stage it had reached, which is exactly the phocomelia pattern.

Thumb to little finger — a small group of cells at the back edge of the bud releases a gradient of signal; high concentration gives little finger, low gives thumb. Too much signal in the wrong place gives extra digits — polydactyly, one of the commonest congenital anomalies.

Front to back — patterning of which side is palm and which is back of the hand.

The hand starts as a paddle, and fingers are separated by the programmed cell death of Chapter 1.8 removing the tissue between them, in week 7 to 8. Failure gives syndactyly, fused fingers, which is repaired surgically.

The limbs also rotate, and this is why the knee bends backward relative to the elbow. The upper limb rotates laterally so the elbow points backward; the lower limb rotates medially so the knee points forward. The dermatome map of the limbs looks scrambled for the same reason — it is a straightforward segmental map that has been twisted (Chapter 11.8).

The face

The face is assembled from five separate blocks of tissue that grow toward the midline and fuse — a frontonasal prominence from above, paired maxillary prominences from the sides, and paired mandibular prominences from below. They meet and fuse between weeks 5 and 9.

Cleft lip is failure of the maxillary prominence to fuse with the medial nasal prominence, at around week 6. It is usually to one side of the midline, which is exactly where that fusion line runs — clefts are not down the centre of the lip, and that is the anatomical giveaway.

Cleft palate is a separate, later event — failure of the palatal shelves to swing up from vertical to horizontal and fuse, around weeks 8 to 12. The shelves must rise over the tongue, which is why anything that keeps the tongue high, such as a small jaw, causes cleft palate mechanically.

Together they affect about 1 in 700 births, one of the commonest congenital anomalies. They can occur separately or together, and the fact that they are different events at different weeks is why. Repair is staged — lip usually at around 3 months, palate at around 9 to 12 months — and the outcome with modern surgery and speech therapy is generally very good.

The brain

The neural tube's head end expands into three swellings — forebrain, midbrain, hindbrain — which become five, and then the enormous elaboration of the human cortex.

The tube's cavity persists as the ventricles, filled with cerebrospinal fluid. Blockage anywhere along that path causes hydrocephalus: fluid continues to be produced, cannot drain, pressure rises, and in an infant whose skull sutures are still open the head enlarges. Treatment is a shunt diverting fluid to the abdomen.

Neurons are born deep and migrate outward, layer by layer, with later-born neurons travelling past earlier ones — so the cortex is built inside out. Migration failures cause epilepsy and intellectual disability, and on a scan they appear as a cortex with the wrong number of layers or a smooth surface with no folds.

The corpus callosum, the huge bundle connecting the two hemispheres, forms between weeks 12 and 20. Failure gives agenesis of the corpus callosum, with a wide range of outcomes from near-normal to severe.

And brain development continues long after birth. Myelination proceeds through childhood and adolescence, and the prefrontal cortex — responsible for planning and impulse control — is not fully myelinated until the mid-twenties. Chapter 11.5 and Volume VI take that further.

The timeline, in one place

Week	What is happening
1	Fertilisation, cleavage, implantation
2	Two-layer disc, amniotic cavity
3	Primitive streak, three germ layers, notochord
4	Neural tube closes, heart beats, limb buds, gut tube folds
5–8	All organs formed in outline — the critical period
9–12	External genitalia distinguishable, palate fuses
13–26	Growth, brain development, lungs branch
24	Approximate limit of viability with intensive care
26–40	Growth, fat deposition, surfactant production, lung maturation

Weeks are counted differently by different people and this causes real confusion. Embryologists count from fertilisation. Obstetricians count from the first day of the last menstrual period, which is about two weeks earlier, because that is a date a woman can actually report. So an "8-week pregnancy" contains a 6-week embryo. Both are correct within their conventions, and the difference matters when reading anything about drug safety windows.

What the next page fixes

Every defect above was described at the step that failed. What has not been covered is why the step fails — what causes it, how much is genetic and how much environmental, what can be detected before birth, and what can be prevented. Chapter 4.6 covers birth defects as a subject in their own right: their causes, their frequency, screening, and the honest limits of what antenatal testing can tell you.