High-throughput On-chip Genetic/ Drug Screening Technologies for Neural Degeneration/Regeneration

Mehmet Fatih Yanik
High-Throughput Neurotechnology Group
Research Laboratory of Electronics

Neural injury and degeneration are one of the greatest medical challenges affecting humankind. Even after the expenditure of several billion dollars targeting the development of new therapies, there is still no cure for damage to the central nervous system. This is in stark contrast to the significant therapeutic advancements made in the treatment of other types of injuries/diseases. Neural degeneration and regeneration following injury are arguably the most complex biological processes involved in healing. Controlling the machinery of these processes will likely require a systems-level understanding of signaling pathways.

Microfluidic chip developed by Yanik Lab allows rapid genetic and drug studies on small animals like C. elegans. (A) The chips can capture and immobilize awake animals within seconds using automated micro-manipulations. (B) Cellular resolution images of the neural networks of these transparent animals can be recorded once the animals are immobilized. (C) The animals possess well-defined neural networks that allow a variety of studies on nervous system. (image: Mehmet Fatih Yanik, MIT).

Microfluidic chip developed by Yanik Lab allows rapid genetic and drug studies on small animals like C. elegans. (A) The chips can capture and immobilize awake animals within seconds using automated micro-manipulations. (B) Cellular resolution images of the neural networks of these transparent animals can be recorded once the animals are immobilized. (C) The animals possess well-defined neural networks that allow a variety of studies on nervous system. (image: Mehmet Fatih Yanik, MIT).

Microarray studies indicate large numbers of genes, up or down regulated, following injury, yet the roles of most of these factors still remain unknown. Elucidation of their function and interactions can lead to the discovery of novel drug targets and compounds that may be used to treat these devastating injuries by simultaneous manipulation of multiple genetic and biochemical targets. Yet, making such discoveries with existing techniques is overwhelmingly difficult.

For large-scale genetic and compound discoveries, our group develops high-throughput technologies using microfluidic and advanced optical techniques, and conducts sophisticated assays on neural degeneration and regeneration. We perform both in vitro and in vivo studies. For in vivo studies, we employ small animals such as invertebrate C. elegans and vertebrate zebrafish. Discoveries in such small-animal models have made significant impact, exemplified by the two recent Nobel prizes awarded in medicine for studies conducted on C. elegans.

To dramatically accelerate compound and genetic discoveries using such animals, we recently developed the first high-throughput on-chip small-animal screening technologies. Our chips capture and immobilize whole animals within seconds, allowing us to acquire three-dimensional sub-cellular resolution images of their nervous system. To generate precise models of neural damage for performing genetic/compound screens on injured animals, we also developed femtosecond laser microsurgery that allows sub-cellular resolution neural injury inside whole animals. For in-vitro genetic/compound screens on mouse primary neurons as well as human embryonic stem-cell derived neurons, we also developed other high-throughput technologies. These technologies may allow discovery of novel genes, drug targets, and small molecules for treatment of devastating neurological injuries and diseases. They can also be used for high-throughput discoveries in other areas of medicine.

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