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A Step Back In History: The Blood-Brain Barrier

The center of our nervous system, the brain, is considered the most complex organ. It can influence our body by generating and arranging patterns of muscle movement and by regulating the secretion of hormones. Evolution has guaranteed many ways to protect it from potential damage caused by external and internal body factors. First, there’s an approximately 7mm thick skull. Also, our brain is surrounded by cerebrospinal fluid that can act as a cushion and three enveloping membranes called the meninges, all working together as a defense system. An additional safeguarding element is the blood–brain barrier: while the skull, meninges and cerebrospinal fluid secure the brain from physical or external damage, the blood–brain barrier (BBB) preserve it against most blood circulating pathogens and harmful toxins that could cause infections in brain tissue and simultaneously allowing the passage of O₂ and vital nutrients.

The blood-brain barrier protects the brain from pathogens and toxins circulating in the blood. Image credit: Nature Reviews/Microbiology
The blood-brain barrier protects the brain from pathogens and toxins circulating in the blood. Image credit: Nature Reviews/Microbiology

In the early 1900’s, an outbreak of the sleeping sickness disease caused by trypanosomes on the northern side of Lake Victoria in Africa motivated German scientist Paul Ehrlich, known as the father of chemotherapy, to find a cure. For his research, he used dyes to stain animal tissue. By injecting many types of dyes into the blood circulation of adult animals, he observed that all organs were stained except the brain (and spinal cord). At the time, he reached the conclusion that the central nervous system (CNS) had low affinity to the dyes. Furthermore, while experimenting on infected mice, Ehrlich injected a dye called Trypan red. Within three days of the injection, the mice were declared cured. The celebrated success of the experiment didn’t last long, however. Several months after the injection, there was a relapse of the disease.

A few years later, his associate, scientist and surgeon Edwin E. Goldmann, performed vital staining on animals using dyes elaborated by Ehrlich while performing experiments to study tumors. He noticed that ‘trypan blue’ spread rapidly and had the lowest toxicity on the body. Goldmann also observed the same phenomenon as Ehrlich: that systemic injections of Trypan blue stained all the organs except the brain and spinal cord. When he decided to inject the dye directly into the CNS, to his surprise, the CNS was completely stained, but none of the other organs. In the year 1921, physiologist and biochemist Lina Solomonovna Stern was the first to adopt the term “blood-brain barrier.” In one of her reports, she explains, “… between blood, on the one hand, and cerebrospinal fluid, on the other, there is a special apparatus or mechanism, capable of performing a kind of screening of substances that are normally present in the blood or have entered it accidentally. We propose to call this hypothetical mechanism, which lets some substances through while slowing or completely blocking others, the Blood-Brain Barrier.”

Blood-brain barrier timeline table
Blood-brain barrier discovery timeline table. Credit: Susana Fares Mazloum

Decades later, scientist Frank Jennings, while studying the relapse of the sleeping sickness disease in mice as a continuation of Ehrlich’s work, came to the conclusion that Ehrlich’s treatment of the disease with Trypan red wasn’t successful because trypanosomes are able to cross the BBB and the dye wasn’t. In other words, Trypan red was able to eliminate the parasite from the blood, but there was a relapse because it didn’t eliminate it from the CNS, due to its inability to pass through the BBB.

Finally, during the 1960’s, scientists were able to confirm the existence, structure, and exact location of the BBB, thanks to the emergence of the electron microscope. Scientists Morris J. Karnosvski and Thomas S. Reese were the first to visualize the BBB through the microscopic lens and publish an article with the details. They observed that blood vessels are normally bounded on the inside with endothelial cells, and that these endothelial cells found in blood vessels in the brain are stuck together very tightly, consisting of tight junctions: areas in which membranes of two cells join. Along with the tight junctions, the blood brain barrier is composed of astrocytes, star-shaped brain cells that provide support, and pericytes,  cells found on the wall of blood vessels that aid in sustenance, too.

bbb
Blood Brain Barrier. Credit: C.J. Guerin, MRC Toxicology Unit / Science Source.

Now we know that the BBB is a highly selective semipermeable membrane barrier and that it’s one of the most important structures in our organism when it comes to the protection of our CNS, and it is a subject of extensive research in the combat of neurological disorders.

Bentivoglio M, Kristensson K. Tryps and trips: cell trafficking across the 100-year-old blood–brain barrier. Trends in Neurosciences. 2014;37(6):325-333. doi:10.1016/j.tins.2014.03.007.

Grigorian, Nora Andreevna. “Lina Solomonovna Stern (Shtern).” Jewish Women: A Comprehensive Historical Encyclopedia. 1 March 2009. Jewish Women’s Archive. (Viewed on July 5, 2017) <https://jwa.org/encyclopedia/article/stern-shtern-lina-solomonova>.

Jennings F.W. The brain as a source of relapsing Trypanosoma brucei infection in mice after chemotherapy. Int. J. Parasitol. 1979;9:381–384

Reese TS, Karnovsky MJ. FINE STRUCTURAL LOCALIZATION OF A BLOOD-BRAIN BARRIER TO EXOGENOUS PEROXIDASE. The Journal of Cell Biology. 1967;34(1):207-217.

Edited by: Kaylynn Crawford and Shreya Singireddy