The Blood-Brain Barrier

A tightly sealed lining of the brain's blood vessels keeps toxins and germs out — and most medicines too. How it works, how it was discovered, and why drug designers wrestle with it.

In most of the body, the walls of tiny blood vessels — capillaries — have small gaps that let substances leak in and out. In the brain they are sealed. The blood-brain barrier (BBB) is this selective seal.

Discovery

In the 1880s the German scientist Paul Ehrlich injected dyes into the bloodstream of animals and found they stained almost every organ except the brain. His student Edwin Goldmann later injected dye directly into the fluid around the brain and found it stained the brain but not the rest of the body — showing a barrier between blood and brain, not a quirk of the dye.

How it is built

The barrier is formed by the endothelial cells that line brain capillaries, stitched together by tight junctions that block the gaps. They are supported by pericytes, cells wrapped around the capillaries, and by the endfeet of astrocytes. Together these form the "neurovascular unit".

Small, fat-soluble molecules such as oxygen, carbon dioxide, alcohol, caffeine and nicotine pass easily. Glucose and amino acids are carried across by dedicated transporter proteins. Large molecules — most proteins, antibodies and many drugs — are kept out, and pump proteins actively push many foreign chemicals back into the blood.

The drug-delivery problem

It is estimated that the great majority of small-molecule drugs, and virtually all large-molecule drugs, don't cross the BBB well. A classic workaround is L-dopa for Parkinson's disease: dopamine itself can't cross, but its precursor L-dopa is carried in by an amino-acid transporter and then converted to dopamine inside the brain. Researchers are developing other tricks: "Trojan horse" antibodies that hitch a ride on transport receptors, viruses engineered to cross, and focused ultrasound with microbubbles to open the barrier briefly in one spot.

Gaps by design

A few small brain regions, the circumventricular organs, lack a full barrier on purpose — so the brain can sample the blood, for instance to detect toxins and trigger vomiting, or to sense hormones.