DeeAnn Visk Ph.D. Founder and Principal Writer DeeAnn Visk Consulting

New Understandings Are Resulting in More Representational Models for Drug Discovery

Innovative ideas have spawned new techniques to tackle the challenges of treating brain disorders. Many presentations at last week’s annual meeting of the Society for Neuroscience in San Diego reflected these advances. 

Inspired by the sequencing of the human genome, the connectome is an ambitious project to find all the connections in the brain. This continuing task presents computational challenges with about 100,000 neurons and one billion synapses in a cubic millimeter of brain.  Nonetheless, computing the connectome, or mapping all the connections within the human brain is within reach. Powerful computer processors will someday allow us to determine all the connections made by every cell within the human brain.

A novel approach to viewing this data was on display at the Zeiss booth in the form of a virtual reality technology that allows users to travel through the inside of a sample of cerebral cortex.  The experience takes one inside a 3D space controlled by hand gestures, allowing one to zoom in or zoom out of the section, or rotate it in three dimensions. 

Kinetically interacting with data may provide new insights into the connectome of the brain.  Offered by arivis and Zeiss, this technology can recreate a 3D virtual reality experience from data gained by a wide range of techniques, including computer tomography, confocal microscopy, electron microscopy, and magnetic resonance imaging.

The road to drug discovery and development for brain maladies is littered with corpses of dead-end candidates. Current thinking is that previous discovery methods looking at one target with one drug in one cell type was too simplistic. Newer models that involve the use of multiple cell types within a cell culture to screen candidate compounds exemplify this. Longitudinal studies are also gaining ground with live imaging of rodent brains through transparent cut outs in their skulls. 

Using simple whole animal models can be very advantageous in terms of expense. Dr. Lifang Li at the Baylor College of Medicine described complex behavioral screens for a variety of brain conditions using Drosophila melanogaster.  This service is offered by the drug discovery core facility at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, which also has a fully automated apparatus to screen Drosophila embryos with drug candidate compounds.

Blood Brain Barrier

A unique approach to studying the blood brain barrier (BBB) is found in the microfluidics chip offered by Cedars Sinai Los Angeles and Emulate. In vivo approaches to this question are expensive; discrepancies across species can yield misleading results when applied to humans.  Problems with traditional in vitro approaches (trans-well membranes) include difficult-to-maintain-cultures. 

Emulate offers a microfluidic chip that mimics the BBB.  The side representing the brain is seeded with human neural cells; the other side representing the endothelium is seeded with human endothelial cells. A membrane through which cell processes can be sent divides the two sides. Preliminary testing shows this technique to be a good recapitulation of the human BBB.

Complex Models

Researchers at the drug discovery and development level are more aware of the strengths and shortcomings of various models used in the process, points out Dr. Patrick Sweeney, Managing Director of Charles River Discovery Services.  This level of understanding permits scientists to better evaluate the data from each approach with regards to validating new compounds. 

Charles River has responded to the needs of clients wishing to explore CNS issues with more complex models.  In addition to offering their usual selection of high quality lab animals, Charles River also has a full selection of screening models that can be employed for drug discovery and screening.

Cellular Dynamics offers a selection of several neural cell types and a model that may predict the tendency of a drug candidate to induce seizures or seizurogenicity.  Remember the cardiac problems induced by several drugs in the past 20 years?  Wouldn’t it be good to predict similar problems in neurological drug candidates before clinical trials with a cell culture model?

New ways of thinking about brain function have expanded beyond just growing multiple cell types in co-culture to looking at multiple organ systems within the body.  For example, Dr. Constantino Iadecola, director of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, has studied the effect of the gut microbiome, which modulates the immune system, on the ability of patients to recover from strokes. 

Postulating an entire new axis (microbiome-gut-brain) for connecting these seemly unrelated systems is a novel way of thinking, which is much more complex than previous models.  Dr. Iadecola envisions a future where patients at risk for a stroke could first have their gut flora modified by antibiotics before a high-risk procedure such as a neurosurgery or vascular surgery.  Additionally, clinical trials for neurological drugs could be stratified by gut microbiome.

More research by Dr. Iadecola has identified a potential mechanism by which high blood pressure could contribute to dementia.  In this model, immune cells or macrophages invade the BBB and maintain a position close to the blood vessels in the brain.  This invasion is facilitated by high blood pressure. Next the macrophages send out free radicals that damage the surrounding tissue.

This work is an example of how seemingly diverse systems, immunological and vascular, interact to impact the brain. Dr. Iadecola explained that considering how these peripheral systems affect the brain can lead to fresh approaches to treating brain maladies.

With the aging population of the United States, a better understanding of age-related brain diseases is essential to finding new treatments for these maladies.  Increased understanding of the complex processes carried out in the brain is leading to more representational models being used in the drug discovery and development. The work presented at the 2016 Society for Neuroscience conference in San Diego offers many promising new approaches to address these issues.

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