The great wall of the brain: How a blue dye revealed secret

“On July 22, it is celebrated the National Day of the Calceteiro and the Portuguese Footwear and is also a mourning date for Norway (as pictured in the film 22 July). However, what brings me here today is another ephemeral: World Brain Day.

Lately, it seems that the calendar does not have enough days for so many celebrations created to generate awareness, this practical Englishism that combines awareness and awareness. Our most important organ is no exception: the diseases affecting it remain a huge social challenge and there is still much to discover. 

The brain collects information, but how does it get there? How do you learn? How do you find out? How do you generate knowledge? Today, I tell a short story that illustrates how scientific knowledge is born of a giant puzzle, patiently assembled by various players throughout generations.

If the brain is so vital it seems logical that evolution protects it. In fact, the vast majority of vertebrates (animals with backbone) have their brains shielded by a strict barrier, like beach on the Behave. To cross, one must be a tiny, fat-soluble molecule, or a microbe that has evolved strategies to overcome this obstacle. This border, which protects the brain from toxic molecules, autoimmunity and infections, is also a great “headache” when you want to develop neurological medicines. But how was the blood brain barrier discovered? The answer took almost 80 years.

The history of human knowledge is made of attempts, mistakes, observations and a hint of luck. In 1885, Paul Ehrlich, a future Nobel Prize winner, studied the absorption of chemical paints into tissues. Convinced that they could be modified to kill microbes, in 1904, he developed two dyes, deep blue and red-carmine, to combat trypanosomes, the causes of sleep sickness. He called them Trypan Blue and Trypan Red. By injecting Trypan Blue into mouse blood, all organs were quickly blue except for the brain, which remained immaculate. Ehrlich formulated a hypothesis (wrong but logical): the brain simply had no affinity for those paints.

By observing the same phenomenon with a different substance (potassium ferrocyanide), Max Lewandowsky opposed the hypothesis of lack of affinity, but it was Edwin Goldmann, Ehrlich's former student, who in 1909 visually tested the hypothesis of his mentor. Instead of injecting Trypan Blue into the blood, he did it directly into the cerebrospinal fluid that bathes the brain. Almost immediately, the brain became blue and the body remained intact, suggesting the existence of a protective barrier analogous to the placenta. Between 1918 and 1934, Lina Stern and Raymond Gautier systematically mapped the movement of substances between the blood and the central nervous system. Goldmann, Stern and Gautier's works definitely proved the existence of a physical barrier that blocked the transit between blood and the brain, to which they called the blood brain barrier.

In 1942 Friedemann realized that, unlike Trypan Blue, fat soluble dyes reached the brain. However, only in 1967, with advances in electron microscopy, Reese and Karnovsky first observed the blood brain barrier. It began to be noticed that the cells of the brain blood vessels were joined by very tight junctions, responsible for this selective permeability. However, it was not until 1981 that Stewart and Wiley sealed the debate, showing that although there were tight junctions in other organs, those in the brain were special. 

And Trypan Blue, was he able to cure sleep sickness? Yes and no. Yes, while trypanosomes navigate the bloodstream; no, from the moment they infiltrate the brain. Still, this dye was not a failure. Not only did it serve as a basis for the development of suramine, a drug that, for decades, was the first line of treatment for the early phase of sleep sickness, but it is also used daily by thousands of scientists to distinguish living from dead cells under the microscope.

It was thus, in a scientific stumbling block driven by the urgency of treating a tropical disease, that the human being discovered one of the most fascinating anatomical peculiarities of our very existence. After all, knowledge is built on long, winding paths, just like our brains.”