Engineered Neuronal Networks as Drug Screening Platforms
Hybrid Neuronal Systems Laboratory
One of the central problems in drug development is that most of the highly effective drugs frequently fail in clinical human tests because: 1) They were developed for a single molecular target not taking into account the complexity of the disease process; 2) They were developed using animal models which are not necessarily valid for particular diseases in humans.
In order to offer an alternative to conventional drug development methods, our Hybrid Neuronal Systems Laboratory utilizes a group of cutting-edge scientific methods to create functional neuronal circuits. This permits the evaluation of drugs using a functional in vitro disease model with human neurons. Within our laboratory it is now possible to take living neurons, lay them in patterns on a Petri dish in the lab (see Figure 1A), and keep them alive for up to three months. Then, utilizing advanced extracellular electrophysiological techniques it is possible to directly interface silicone chips with the neurons to record the patterns of electrical activity (see Figure 1E). Therefore, it is possible to use these engineered functional networks for high-throughput drug screening.
For example, in one of our NIH-funded projects we are developing neuronal circuits from hippocampal cells to study drug effects on synaptic transmission and long-term potentiation, a cellular mechanism of memory storage. These test systems could be extremely useful for the development of novel cognitive enhancing drugs or to create an in vitro functional model of Alzheimer's disease.
Figures 1. In vivo test system to model Alzheimer's disease with design, implementation and electrophysiological characterization of engineered two-cell and multiple-cell hippocampal networks.
In another NIH-funded project we are developing a functional in vitro test system for the systematic study of the factors enhancing functional integration of stem cell-derived motoneurons in the spinal cord in Amyotrophic Lateral Sclerosis (ALS). ALS, also known as Lou Gehrig's disease, has no known cure or drug treatment. Eventually all ALS patients become immobilized through the degeneration of motoneurons, severely limiting all movements. Research in the Hybrid Neuronal Systems Laboratory focuses on the creation of an in vitro model of the stretch reflex arc (see Figure 2) utilizing cultured and patterned dorsal root ganglion, muscle and motoneurons known to be impacted by ALS. This line of research shows promise of addressing a troubling lack of treatment options for these patients.
Figures 2. In vivo test system for ALS utilizing patterned skeletal muscle and equipment developed to integrate muscle with silicon cantilevers for force measurements.