Hacking the Brain’s Security System

by Rob Mitchum

The brain is a privileged organ, afforded protections denied to all the other organs of the body. Though the circulatory system functions much the same way above and below the neck, using blood to exchange nourishment for waste with cells, the exchange is conducted under much heavier security in the central nervous system. This TSA for the brain and spinal cord is known as the blood-brain barrier, and its role is protecting the fragile, irreplaceable cells of the nervous system from external disease and the body’s own immune weapons.

While we can all be thankful for the unceasing service of the blood-brain barrier (sometimes abbreviated as BBB), many scientists are interested in figuring out how it can be breached. Many neurological diseases, including multiple sclerosis and stroke, can be attributed in part to breakdowns of the BBB. Drugs designed to treat brain disease must also find a way through the BBB’s strong defenses to get to their desired targets.

That made the blood-brain barrier the perfect subject for this year’s Chicago Symposium on Translational Neuroscience, an annual gathering of neurologists and laboratory neuroscientists from the University of Chicago Medicine and other institutions. This year, the Neuro contingent was joined by UChicago’s young Institute for Molecular Engineering in presenting the conference, underscoring that the topic is very much an engineering problem: how do you build a blood-brain barrier, and how do you selectively knock it down?

The day’s first speaker, Richard Daneman of the University of California, San Francisco, explained what the field currently knows about the unique properties of the BBB. In most of the body, the capillaries of the circulatory system are “leaky,” he said, allowing many molecules to pass between the cells and the blood through the cracks between the endothelial cells that make up the blood vessel walls. But in the BBB, those cells form a tight seal, and molecules are transported into and out of the vessels by highly selective transporters instead of passive diffusion. Daneman illustrated these defenses with an experiment where blue dye is injected into an animal, which is later dissected. While organs such as the kidney or liver take on a distinct blue hue, the brain and spinal cord remain free from the dye, which cannot penetrate the barrier.

Daneman is interested in “barriergenesis,” how the BBB is constructed during development. Previously, researchers hypothesized that brain cells called astrocytes were responsible for building the BBB. But using mice and rat models, Daneman’s laboratory determined that this defense system is already in place during embryonic stages, before astrocytes first appear. Instead, Daneman’s experiments pointed to another cell group called pericytes as critical architects of the BBB. When the genes for forming pericytes were knocked out in a mouse line, the BBB did not form its tight seal…as indicated by the appearance of blue brains after a dye injection.

Now Daneman’s lab is digging into the molecular signals that construct the BBB during development and maintain its integrity throughout life. Some of those experiments involve taking the endothelial cells that form the BBB out of their native habitat to study them on the lab bench, the subject of a talk from Eric Shusta of the University of Wisconsin – Madison. Endothelial cells only make up about one-tenth of one percent of the cells in the brain, Shusta said, and don’t form the tight seals characteristic of the BBB in the lab dish unless they are co-cultured with other neural cell types.

Shusta’s laboratory has tackled these problems using the hot prospects of laboratory science: pluripotent stem cells. When researchers in his group decided to try to differentiate stem cells into BBB-like endothelial cells, Shusta said “I thought they were a little bit crazy, but the initial experiments worked.” What’s more, with neural stem cells, the researchers could also generate other nervous system cell types that might play an important role in barriergenesis. That experimental set-up can now be used to test for the cellular factors that build the BBB and as well as assess different drugs’ ability to pass through the barrier, without the constraints of having to endlessly harvest scarce endothelial cells.

“From one rat brain we can get about 6 to 12 filters, but from one vial of stem cells, we can easily get ten thousands of filters,” Shusta said. “We think that we can keep optimizing this, and hopefully make an impact in developmental and drug screening applications.”

The clinical reasons for pursuing BBB research were described by Alexandre Prat, the head of neuroscience research at the Centre hospitalier de l’Université de Montréal (CHUM). A neurologist specializing in multiple sclerosis, Plat described how the autoimmune neurological disorder is caused in part by immune cells infiltrating the brain through gaps in the BBB. Prat’s research is focused on how these breaches occur during MS attacks, with a particular interest in cell adhesion molecules (CAMs), factors produced by the endothelial cells that act as chaperones to transport immune cells across the BBB.

The laboratory found that one particular CAM, called CD166/ALCAM, offers a promising target for preventing the immune cell infiltration associated with MS attacks. What’s more, it may avoid the rare but very serious side effect of another MS drug, natalizumab, which uses a similar strategy of blocking the passage of immune cells across the BBB. In approximately 1 out of 1,000 cases, natalizumab works too well, leaving the central nervous system open to infection by the JC virus, which can cause a fatal condition called progressive multifocal leukoencephalopathy. A new drug developed by Prat’s laboratory in cooperation with a pharmaceutical company is currently being tested as a potentially safer alternative.

Prat’s research shows how reverse engineering the complexity of the blood-brain barrier can point the way to promising clinical tools. Just as companies now hire former hackers to find the weak points in their network, scientists are looking for the cracks in the wall of the BBB, so that they can be either repaired to treat disease or exploited to deliver drugs to the brain. While nobody wants to revoke the brain’s privileged security system, it will be helpful to know the code.