Unlocking the mysteries of the blood-brain barrier

It might astonish you to know that, although we use our brains all the time, science knows very little about how they actually work. That is why recently, President Barack Obama announced a $100 million initiative to map the human brain.

“We can identify galaxies light-years away; we can study particles smaller than an atom; but we still haven’t unlocked the mysteries of the three pounds of matter that sits between our ears,” Obama said in a press conference on the announcement April 2.

The blood-brain barrier involves functional interactions between endothelial cells that form brain capillaries, astrocytes, and pericytes in a complex microenvironment. (Illustration by Martin Rietveld)

The blood-brain barrier involves functional interactions between endothelial cells
that form brain capillaries, astrocytes, and pericytes in a complex microenvironment. (Illustration by Martin Rietveld)

Obama’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) project will seek to discover what occurs between the 100 billion cells firing inside the brain with the goalof helping to prevent and even cure neurological diseases, such as Alzheimer’s or Parkinson’s, that affect as many as 100 million Americans.

Johns Hopkins University is at the forefront of brain science research. The Brain Science Institute (BSi) at the Johns Hopkins School of Medicine was launched to develop new multidisciplinary research teams; create cutting edge-research cores for use by all brain researchers at Hopkins; and foster translation of discoveries to treatments of brain diseases, in part, by improving our ability to partner with industry and biotechnology.

In 2012, Peter Searson, professor of materials science and engineering and director of Johns Hopkins Institute for NanoBioTechnology (INBT), joined forces with Jeffrey Rothstein MD, PhD, director of the BSi, to create the Blood-Brain Barrier Working Group. This group brings together researchers with diverse interests and expertise to address key problems associated with drug delivery, to discover the role of the blood-brain barrier (BBB) in disease, and to elucidate the structure and function of the BBB.

“The blood-brain barrier is a dynamic interface that separates the brain from the circulatory system and protects the central nervous system from potentially harmful chemicals while, at the same time, regulating transport of essential molecules and maintaining a stable environment,” Searson said. “It is formed from highly specialized endothelial cells that line the brain capillaries, which transduce signals in two directions: from the vascular system and from the brain. The structure and function of the BBB is dependent upon the complex interplay between different cell types, specifically the endothelial cells, astrocytes and pericytes, within the extracellular matrix of the brain and with the blood flow in the capillaries.”

Although the BBB serves the important purpose of tightly regulating the environment of the brain and preventing sudden changes, which the brain cannot tolerate, Searson said, “this interface also blocks the passage of drug molecules to treat disease, neurodegenerative disorders, inflammation or stroke. Unfortunately, animal models are insufficient for use in under-standing how the human blood-brain barrier functions or responds to drugs. In addition, little is known about how disease, inflammation or stroke disrupts or damages the blood-brain barrier.”

With this in mind, the BBB working group has two primary goals, Searson explained. “Our long-term goal is to build an artificial microvessel that will be the first platform that recapitulates a brain capillary in its local microenvironment. This will enable fundamental studies as well as drug discovery and the development of methods to cross the blood-brain barrier,” Searson said.

The second goal is to understand how the blood-brain barrier can be damaged or disrupted so that strategies can be developed to repair it. Injury and disease can disrupt the normal structure and function of the blood brain barrier.

Currently the BBB Working Group has 40 researchers from disciplines as diverse as anesthesiology, materials science and engineering, pharmacology and oncology. Three postdoctoral fellows and 12 pre-doctoral students are also involved. The group meets monthly and hosts expert speakers on various topics. The working group website also lists current funding opportunities to which members can apply and conferences and workshops of interest.

Membership in the working group is open to any student, faculty member or staff at Johns Hopkins University in any discipline.

Visit the Blood-Brain Barrier Working Group website here.

This article was written by Mary Spiro and appeared in the 2013 issue of Nano-Bio Magazine.

Tackling the brain’s barrier

Watch this video now. Click the image.

Much like a sentry at a border crossing, the network of tiny blood vessels surrounding the brain only allows a few important molecules in or out. Of course, there is good reason for this. The brain controls the senses, motor skills, breathing, and heart rate, as well as being the seat of thoughts and emotional experiences. Just as our tough plated skull offers a physical armor for the brain, the blood-brain barrier shields our brain from potentially harmful substances at the molecular level.

“Despite its powerful role in controlling bodily functions, the brain is extremely sensitive to chemical changes in environment,” said Peter Searson, director of Johns Hopkins Institute for NanoBioTechnology (INBT) and lead on the Blood Brain Barrier Working Group (BBBWG). The BBBWG is a collaboration between INBT and the Brain Science Institute at the Johns Hopkins School of Medicine.

Oxygen, sugars (such as glucose), and amino acids used to build proteins can enter the brain from the bloodstream with no trouble, while waste products, such as carbon dioxide, exit the brain just as easily. But for most everything else, there’s just no getting past this specialized hurdle. In fact, the blood-brain barrier protects the brain so effectively that it also prevents helpful drugs and therapeutic agents from reaching diseased areas of the brain. And because scientists know very little about the blood-brain barrier, discovering ways to overcome the blockade has been a challenge.

“We still don’t know very much about the structure and function of the blood-brain barrier,” Searson said. “Because we don’t know how the blood-brain barrier works, it presents a critical roadblock in developing treatment for diseases of the central nervous system, including Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease), Alzheimer’s, autism, brain cancer, Huntington’s disease, meningitis, Multiple Sclerosis (MS), neuro-AIDS, Parkinson’s, and stroke. Treatable brain disorders are limited to depression, schizophrenia, chronic pain, and epilepsy. If we had a better understanding of how the blood-brain barrier worked, we would be in a better position to develop treatments for many diseases of the brain,” Searson said. But he added, even with a better understanding of the blood-brain barrier, humans cannot be used to study new therapies.

One way the BBBWG plans to surmount this roadblock is by creating an artificially engineered (or simulated) blood-brain barrier. An engineered artificial blood-brain barrier would allow researchers to conduct studies that simulate trauma to or diseases of the blood-brain barrier, such as stroke, infection, or cancer.

“It would also give us insight into understanding of the role of the blood-brain barrier in aging,” said Searson. Drug discovery and the development of new therapies for central nervous system diseases would be easier with an artificial blood-brain barrier and certainly safer than animal or human testing. Such an artificial membrane could be used as a platform to screen out drugs used to treat maladies outside the brain, but which have unwanted side effects, such as drowsiness.

The creation of such a platform will require the skills of a multidisciplinary team that includes engineers, physicists, neuroscientists and clinicians working together to bring new ideas and new perspectives, Searson added, and will build on recent advances in stem cell engineering and the development of new biomaterials. Current members of the BBBWG include researchers from the departments of neuroscience, anesthesiology, psychiatry, pathology and pharmacology from the Hopkins School of Medicine and from the departments of mechanical engineering, chemical and biomolecular engineering and materials science from the Whiting School of Engineering.

One member of that multidisciplinary team is Lew Romer, MD, associate professor of Anesthesiology and Critical Care Medicine, Cell Biology, Biomedical Engineering, and Pediatrics at the Center for Cell Dynamics at the Johns Hopkins School of Medicine.

“At a cellular level, the focus here is on the adhesive interface of the neurovascular unit – the place where the microcirculation meets the complex parenchyma (or functional surface) of the brain,” Romer said. “This is a durable but delicate and highly specialized region of cell-cell interaction that is responsive to biochemical and mechanical cues.”

Romer said work on the blood-brain barrier is a “fascinating and essential frontier in cell biology and translational medicine, and one that clinicians struggle to understand and work with at the bedsides of some of our sickest and most challenging patients from the ICU’s to the Oncology clinics. Development of an in vitro blood-brain barrier model system” that could be used in molecular biology and engineering manipulations would provide investigators with a powerful window into this vital interface,” Romer added.

Visit the Blood-Brain Barrier Working Group website here.

Watch a student video about current blood-brain barrier research here.

Story by Mary Spiro first appears in the 2012 edition of Nano-Bio Magazine.