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Trypan blue dye (1913)

Paul Ehrlich was a German bacteriologist who earned his doctorate in the staining of tissues to make them more visible under a microscope. In 1885, he observed that the water soluble dyes did not stain the brain or cerebrospinal fluid when injected into the peripheral circulation of dead animals but happily stained all other organs of the body. Ehrlich initially put it down to the brain simply not taking up the dye because of differences in binding affinities between the brain and the rest of the body.

His student Edwin Goldman, however, showed in 1913 that when he injected the dye trypan blue into the cerebrospinal fluid of animals’ brain directly it did manage to turn the brain blue, but not the rest of the body. This gave rise to the notion that there was strict compartmentalisation between the brain and the rest of the circulatory system, with some kind of protective barrier between the two.

The term “blood-brain barrier” was in fact first coined by fellow German neurologist Max Lewandowsky as early as 1900 when he called it by the German word, “bluthirnschranke”. But no-one at that time knew what this barrier was. It was not until the invention of the high-powered electron microscope, more than 50 years later, that the true nature of the barrier was revealed in the form of especially tight junctions between the endothelial cells that form a protective membrane between the brain and the circulatory system that supplies it with oxygen and nutrients.

The blood-brain barrier is highly selective in terms of what it allows into the brain from the circulatory system, to prevent or limit the entry of neurotoxins and many pathogens. Many antibodies are too large to cross the blood brain barrier under normal circumstances. This led to the idea that the brain is “immune privileged”, meaning that is protected against the immune system by the barrier, although the barrier becomes more permeable to the immune system during inflammation

It is now understood that immune cells, such as T-cells and macrophages, can pass across the blood-brain barrier, especially when it is inflamed. Once inflamed, the blood-brain barrier’s defences are lowered, allowing antibiotics and the phagocytes of the immune system to pass through. But an inflamed blood-brain barrier also permits the entry of potentially dangerous elements into the brain. The blood-brain barrier is now believed to play a role in the development or onset of many serious illnesses, such as meningitis, epilepsy and Alzheimer’s.