Welcome to our new blog series about the blood brain barrier (BBB)! In Part 1, we will give a brief history on the discovery of the BBB, as well as introduce what we know about its composition and biological functions.
The blood brain barrier or BBB is a highly regulated selective biological barrier situated at the blood to brain interface. In simple terms, the role of the BBB is to separate the brain from the rest of the body. This physical separation protects the neurons and glial cells and maintains brain homeostasis by preventing pathogens, drugs, and other potentially harmful agents (such as certain large water-soluble molecules) that may be present in circulating blood from non-selectively crossing into the extracellular fluid of the brain.
In this new series, we will explore how our current understanding of the human BBB is evolving as the industry moves forward with novel therapeutic candidates and modalities, such as adeno-asssociated virus (AAV), CAR-T, and CRISPR.
A brief history of the BBB
The BBB exists in all extant vertebrates, and it was first discovered during experiments carried out in the late 1800s by German and South African scientists Paul Ehrlich and Edwin Goldmann. Upon injecting certain water-soluble dyes into the bloodstream of mice, Ehrlich and his associate Goldmann noticed that the dyes infiltrated all mouse tissues except for the brain and the spinal cord.
Conversely, injection of the same dyes into the subarachnoid space (this is a cerebrospinal fluid (CSF)-filled compartment that harbors the major cerebral blood vessels) resulted in staining of the brain and the CSF, but not peripheral tissues. The term blood brain barrier was first coined a few years later by German neurologist Max Lewandowsky who originally gave it the German name ‘bluthirnschranke’.
Subsequent experiments by German physician Ulrich Friedemann, who also worked under Ehrlich, revealed that certain lipid-soluble dyes were able to cross the BBB by direct transport across the cerebral microvasculature. Over the following 50 years or so, and owing largely to advances in microscopy, experiments undertaken by many others revealed that the BBB is comprised of tight junctions between cerebral endothelial cells (ECs), which restrict the free movement of substances from the blood and interstitial fluid (ISF). The ISF is a fluid that surrounds the parenchymal cells of the brain and spinal cord. The history of the BBB will not be discussed further in this series but a summary can be found in a recent review (1, and references therein).
What does the BBB look like?
Despite more than a century of research, our understanding of the structure and mechanisms underlying the human BBB remains incomplete. Although beyond the immediate scope of this series, it is worth mentioning that invertebrates, such as the fruit fly species Drosophila melanogaster, which is widely used as a model organism for the BBB, possess a so-called glial blood-brain barrier comprised of perineurial and sub-perineurial glial cells (2). Indeed, most of our knowledge about the human BBB is derived through studies in non-rodent or even non-mammalian animal models as well as immortalized or tumor cell lines.
Taking the above limitations into account, let’s take a look at what we do know about BBB composition in general. Firstly, the barrier is formed by microvascular ECs that line the cerebral capillaries that penetrate the brain and spinal cord. The microvascular ECs of the BBB are distinct from the vascular ECs that line peripheral blood vessels. Unique characteristics of these BBB-borne ECs include:
- The presence of tight junctions that act as a tight seal between adjacent ECs and thereby block non-selective or free passage of water-soluble molecules between the blood and brain.
- A complete absence of fenestrations. These are round or oval-shaped window-like holes found in the cells of the blood endothelium, which allow larger molecules and proteins to travel from the blood cells into organs and tissues.
- The absence of pinocytic activity – a process whereby a cell takes in fluids along with dissolved small molecules – but presence of active transport mechanisms to permit the passage of essential molecules such as nutrients while blocking the passage of potential harmful endo- and exogenous molecules. Although the two may sound similar, pinocytosis is distinct from phagocytosis, which is a process whereby cells engulf large particles or whole cells, either as a way to acquire food or as a defense strategy.
- The presence of xenobiotic-metabolizing enzymes. The BBB harbors a range of xenobiotic-metabolizing enzymes belonging to the CYP1, CYP2 and CYP3 families of cytochrome P450 enzymes, whose activities serve as a metabolic barrier to the entry of drugs and other xenobiotics into the brain (reviewed in 3).
- Expression of CNS-specific P450 enzymes involved in maintaining brain homeostasis, e.g., CYP46A1, which converts cholesterol to 24-hydroxycholesterol, which can then penetrate the BBB.
- The BBB ETs harbours an array of efflux systems with collectively broad affinities, which actively pump compounds including drugs out of the BBB endothelium back into the bloodstream.
- Abundant expression of transferrin receptor (TfR), whose physiological function is to transport iron into the brain parenchyma (the functional tissue of the brain) to maintain iron homeostasis. TfR is exclusively expressed in the brain ECs, and in recent years, it has attracted significant attention as a potential target for brain drug delivery.
The properties and functions of the BBB are for the most part manifested in the microvascular brain endothelium, however these are also reliant upon critical interactions with mural cells, immune cells, glial cells, and neural cells, all of which interact in a structure that has become known as the neurovascular unit in recent years (4,5).
While the BBB is the major protector with respect to brain homeostasis, a blood-CSF barrier, which is formed by tight junctions between neighboring choroid plexus epithelial cells, also exists, and its role is to prevent the passive transport of molecules into and out of the brain by blocking their movement through the intercellular space between the cells.
BBB – friend and/or foe?
The human BBB is critical to our survival. Given its location and unique characteristics, it protects the brain parenchyma from inflammation and invasion by pathogens, and blocks the entry of potentially harmful endogenous blood-borne molecules, as well as drugs and other exogenous agents. The importance of the BBB is further illustrated by what happens when it becomes degraded or lost entirely, for example, in brain disorders including stroke, multiple sclerosis (MS), brain injury, and neurodegenerative disorders (6, and references therein).
While the BBB functions are critical for maintaining brain function and homeostasis, the stringency of the barrier ironically poses a massive obstacle to the pharmacological treatment of nearly all brain disorders (6).
A better understanding of the human BBB is urgently needed
The urgent need for therapies to treat brain diseases including genetic brain disorders, brain cancers, neurodegenerative diseases (e.g., Parkinson’s, Alzheimer’s, MS) and others has motivated intense efforts to alter or bypass the BBB to deliver therapeutic agents to the brain (reviewed in 7). Despite massive efforts, progress in treating brain diseases has been very slow, with one of the main reasons being poor drug penetration efficacy across the BBB.
One major contributing factor to slow progress in this area is that all drug development strategies to target the brain are heavily based upon non-human models of the BBB, leading to a disconnect between how we understand BBB biology and what is actually going on in the human BBB.
That was it for now. Stay tuned for Part 2, where we will take a look at the current landscape of BBB models used within research and drug development, and address why new and better human-relevant BBB models are urgently needed to close the gaps in our understanding of the human BBB to pave the way for new treatments for brain diseases.
References
- Menaceur C, Gosselet F, Fenart L, Saint-Pol J. The Blood-Brain Barrier, an Evolving Concept Based on Technological Advances and Cell-Cell Communications. Cells. 2021 Dec 31;11(1):133. doi: 10.3390/cells11010133. PMID: 35011695; PMCID: PMC8750298.
- Limmer S, Weiler A, Volkenhoff A, Babatz F, Klämbt C. The Drosophila blood-brain barrier: development and function of a glial endothelium. Front Neurosci. 2014 Nov 14;8:365. doi: 10.3389/fnins.2014.00365. PMID: 25452710; PMCID: PMC4231875.
- Toselli F, Dodd PR, Gillam EM. Emerging roles for brain drug-metabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs. Drug Metab Rev. 2016;48(3):379-404. doi:10.1080/03602532.2016.1221960.
- Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015 Jan 5;7(1):a020412. doi: 10.1101/cshperspect.a020412. PMID: 25561720; PMCID: PMC4292164.
- Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020 Nov 18;17(1):69. doi: 10.1186/s12987-020-00230-3. PMID: 33208141; PMCID: PMC7672931.
- Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012 Nov;32(11):1959-72. doi: 10.1038/jcbfm.2012.126. Epub 2012 Aug 29. PMID: 22929442; PMCID: PMC3494002.
- Reinhold AK, Rittner HL. Barrier function in the peripheral and central nervous system-a review. Pflugers Arch. 2017 Jan;469(1):123-134. doi: 10.1007/s00424-016-1920-8. Epub 2016 Dec 12. PMID: 27957611.
Karen O’Hanlon Cohrt is an independent Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen relocated to Denmark where she held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Karen has been a full-time science writer since 2017, and has since then held numerous contract roles in science communication and editing spanning diverse topics including diagnostics, molecular biology, and gene therapy. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for learning helps her to keep abreast of exciting research developments as they unfold. Karen is currently based in Ireland, and you can follow her on Linkedin here.
