KEYNOTE LECTURES

Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. We developed cortical organoids that spontaneously display periodic and regular oscillatory network events that are dependent on glutamatergic and GABAergic signaling. These nested oscillations exhibit cross-frequency coupling, proposed to coordinate neuronal computation and communication. As evidence of potential network maturation, oscillatory activity subsequently transitioned to more spatiotemporally irregular patterns, capturing features observed in preterm human electroencephalography (EEG). These results show that the development of structured network activity in the human neocortex may follow stable genetic programming, even in the absence of external or subcortical inputs. Our approach provides novel opportunities for investigating and manipulating the role of network activity in the developing human cortex. Applications for neurodevelopmental disorders and brain evolution will be discussed.

The precision of genome editing has the promise to positively impact on a wide variety of both genetic and non-genetic diseases. When genome editing is combined with the use of stem cells, a novel cell based drug with potential lifetime durability and broad biodistribution can be created. While there are now multiple different genome editing technologies, for the modification of cells outside the body, homology directed repair using the homologous recombination machinery utilizes natural cellular mechanisms and provides the greatest versatility both in terms of types of changes and types of cell types that it can applied to. This versatility does not come at a cost of decreased efficiency as high efficiencies can also be regularly achieved. In this talk, I will discuss our progress of using HDR in stem cells to address the genetic diseases of sickle cell disease, cystic fibrosis and Huntington’s disease and to address the HIV global pandemic. These diseases demonstrate how HDR can be applied to a variety of different stem cell types including hematopoietic stem cells, basal cells (the stem cells of the respiratory epithelium) and induced pluripotent stem cells.