Vanderbilt-led team to develop 'microbrain' to improve drug testing

July 24, 2012

Take a millionth of a human brain and squeeze it into a special chamber the size of a mustard seed. Link it to a second chamber filled with cerebral spinal fluid and thread both of them with artificial blood vessels in order to create a microenvironment that makes the neurons and other brain cells behave as if they were in a living brain. Then surround the chambers with a battery of sensors that monitor how the cells respond when exposed to minute quantities of dietary toxins, disease organisms or new drugs under development.

Creating such a "microbrain bioreactor" is the challenge of a new $2.1 million research grant awarded to an interdisciplinary team of researchers from Vanderbilt University, Vanderbilt University Medical Center, the Cleveland Clinic and Meharry Medical College. The award is one of 17 that are being issued by the National Center for Advancing Translational Sciences at the National Institutes of Health as part of a $70 million "Tissue Chip for Drug Testing" program. The five-year program is a cooperative effort on the part of NIH, the Defense Advanced Research Projects Agency and the FDA.

The reason for microfabricating organ simulators containing small populations of human cells - generally known as organ-on-a-chip technology - is to bridge the formidable gaps that exist between the tools that researchers currently use to develop new drugs - cell cultures and animal and human testing. These gaps not only add substantially to the difficulty and expense of developing new drugs but also contribute to the large number of experimental drugs that aren't effective or have unacceptable side effects when they are finally tested on people.

The brain is a particularly difficult target for drug development because it is surrounded by three barriers that protect it from molecular or cellular intruders. The most formidable of these is the blood-brain barrier (BBB). It surrounds the blood vessels that service the brain and allows the passage of compounds that the brain needs while simultaneously blocking the passage of other types of molecules, both foreign and domestic. The two other barriers protect the neurons from contaminants in the cerebral spinal fluid and protect the cerebral spinal fluid from contaminants in the blood. Not only do these barriers block potentially harmful molecules, neuroscientists have also discovered that they occasionally alter the chemistry of some of the compounds that they let through.

"Given the differences in cellular biology in the brains of rodents and humans, development of a brain model that contains neurons and all three barriers between blood, brain and cerebral spinal fluid, using entirely human cells, will represent a fundamental advance in and of itself," said John Wikswo, the Gordon A. Cain University Professor and director of the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE), who is orchestrating the multidisciplinary effort.

Wikswo and his collaborators argue that this new type of brain model should provide new insights into how the brain receives, modifies and is affected by drugs and disease agents. By replicating the forms of chemical communication and molecular trafficking that take place in the human brain, the device will allow them to test the effectiveness of various drug and nutritional therapies designed to prevent both acute injuries like strokes and chronic diseases like obesity and epilepsy, as well as uncovering the potential adverse effects of experimental drugs.

The basic microbrain bioreactor involves the integration of several technologies that have been developed and tested independently:

Once the microbrain bioreactor has been developed and tested, a team headed by Scott Daniels, assistant professor of pharmacology and director of drug metabolism and pharmacokinetics at the Vanderbilt Center for Neurosciences Drug Discovery, will collaborate with the Cleveland Clinic Foundation group to validate the chip technology by testing it with a number of clinically approved and experimental compounds that vary in their ability to penetrate the central nervous system. Daniels noted that "the brain-on-a-chip technology could enable the accurate prediction of human brain penetration by small molecule therapeutics and therefore bridge a critical translational gap in the drug discovery arena."

Another group, headed by Associate Professor of Medicine Kevin Niswender, will be applying the new device to study the biology of stroke and the role that the brain plays in obesity. The system will allow his group to ask fundamental questions about how dietary macronutrients and inflammatory signals influence the various components present in the brain. Assistant Professor of Molecular Physiology and Biophysics Kate Ellacot will employ the system to understand how glial cells interact with neurons in the context of inflammation in obesity. In addition, the Cleveland Clinic has a large collection of samples from patients with these and other conditions. They will put cells from selected patients in the bioreactors and quantify how they respond to different treatments. "The ability to apply these precious samples entrusted to us by patients to a platform where we can literally measure hundreds of parameters is a dream come true," said team member BethAnn McLaughlin, assistant professor of neurology and member of the Vanderbilt Kennedy Center. "We have enormous challenges in developing therapeutics to protect the brain from injury and this is a profound unmet need. Not a single drug has passed FDA approval to protect the brain from stroke, and we only have one that breaks up clots. We need to do better."
-end-
Visit Research News @ Vanderbilt for more research news from Vanderbilt. [Media Note: Vanderbilt has a 24/7 TV and radio studio with a dedicated fiber optic line and ISDN line. Use of the TV studio with Vanderbilt experts is free, except for reserving fiber time.]

Vanderbilt University

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.