Tackling the brain’s barrier

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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.

INBT launches Johns Hopkins Center of Cancer Nanotechnology Excellence

Martin Pomper and Peter Searson will co-direct INBT’s new Center of Cancer Nanotechnology Excellence (Photo: Will Kirk/Homewood-JHU)

Faculty members associated with the Johns Hopkins Institute for NanoBioTechnology have received a $13.6 million five-year grant from the National Cancer Institute to establish a Center of Cancer Nanotechnology Excellence. The new Johns Hopkins center brings together a multidisciplinary team of scientists, engineers and physicians to develop nanotechnology-based diagnostic platforms and therapeutic strategies for comprehensive cancer care. Seventeen faculty members will be involved initially, with pilot projects adding more participants later.

The Johns Hopkins Center of Cancer Nanotechnology Excellence, which is part of the university’s Institute for NanoBioTechnology, is one of several NCI-supported centers launched through a funding opportunity started in 2005. According to the NCI, the program was established to create “multi-institutional hubs that integrate nanotechnology across the cancer research continuum to provide new solutions for the diagnosis and treatment of cancer.”

Peter Searson, who is the Joseph R. and Lynn C. Reynolds Professor of Materials Science and Engineering in the Whiting School of Engineering and director of the Institute for NanoBioTechnology, will serve as the center’s director. The co-director will be Martin Pomper, professor of radiology and oncology at the School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

“A unique feature of the center is the integration of research, education, training and outreach, and technology commercialization,” Searson said.

To move these new technologies toward use by physicians, a Cancer Nanomedicine Commercialization Working Group will be established and headed by John Fini, director of intellectual property for the university’s Homewood campus. This group will be responsible for managing and coordinating the translational process.

Another special feature of the center will be its Validation Core, led by Pomper, who is also associate director of the Johns Hopkins In Vivo Cellular and Molecular Imaging Center and director of the Johns Hopkins Small Animal Imaging Resource Program.

“Validation is about assuring that the experimental products and results we generate are on target and able to measure the biological effects for which they’re intended,” he said.

Searson and Pomper said the center will consist of four primary research projects.

One project will seek methods to screen bodily fluids such as blood or urine for indicators of cancer found outside of the genetic code, indicators called epigenetic markers. Led by Tza-Huei “Jeff” Wang, associate professor of mechanical engineering in the Whiting School of Engineering; Stephen Baylin, the Virginia and Daniel K. Ludwig Professor of Cancer Research in the School of Medicine; and James Herman, a professor of cancer biology in the School of Medicine, this project will use semiconductor nanocrystals, also known as quantum dots, and silica superparamagnetic particles to detect DNA methylation. Methylation adds a chemical group to the exterior of the DNA and is a biomarker frequently associated with cancer.

A second project, led by Anirban Maitra, associate professor of pathology and oncology at the School of Medicine and the Johns Hopkins Kimmel Cancer Center, will focus on curcumin, a substance found in the traditional Indian spice turmeric. In preclinical studies, curcumin has demonstrated anti-cancer properties but, because of its physical size, it is not readily taken up into the bloodstream or into tissues. Engineered curcumin nanoparticles, however, can more easily reach tumors arising in abdominal organs such as the pancreas, Maitra said. This team will try to determine whether nanocurcumin, combined with chemotherapeutic agents, could become a treatment for highly lethal cancers, such as pancreatic cancer.

Hyam Levitsky, professor of oncology at the Johns Hopkins Kimmel Cancer Center, will lead a third project, which will seek to use a noninvasive method to monitor the effectiveness of vaccines for cancer and infectious diseases.

A final project will build on the work of Justin Hanes and Craig Peacock, professors in the School of Medicine, to deliver therapies directly to small cell lung cancer tissue via mucus-penetrating nanoparticles.

All research efforts will be supported by a nanoparticle engineering core, led by Searson, which will make and characterize a variety of nanomaterials. Another core, centering on bioinformatics and data sharing, will be led by Rafael Irizarry, professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health.

Johns Hopkins Institute for NanoBioTechnology

Sidney Kimmel Comprehensive Cancer Center