19.8: ESC and iPSC derived organoids

Model systems have provided a wide range of insights into the processes involved in development. That said, it is immediately obvious that there are important differences – after all people are instantly distinguishable from members of closely related species and certainly look and behave differently from mice. For example, the surface layer of our brains are extensively folded (they are known as gyrencephalic) while the brain of a mouse is smooth and referred to as lissencephalic. The failure of the human brain cortex to fold is known as lissencephaly, a disorder associated with several severe neurological defects.^[621] With the advent of more and more genomic sequence data, we can identify human specific molecular (genomic) differences. Many of these sequence differences occur in regions of our DNA that regulate when and where specific genes are expressed. Sholtis & Noonan provide an example: the HACNS1 locus is an 81 basepair region that is highly conserved in various vertebrates from birds to chimpanzees; there are 13 human specific changes in this sequence that appear to alter its activity, leading to human-specific changes in the expression of nearby genes.^[622] At this point ~1000 genetic elements that are different in humans compared to other vertebrates have been identified and more are likely to emerge.^[623] Such human-specific changes can make modeling human-specific behaviors, at the cellular, tissue, organ, and organismic level, in non-human model systems problematic. It is for this reason that scientists have attempted to generate better human specific systems.

The Nobel prize winning work of Kazutoshi Takahashi and Shinya Yamanaka, who devised methods to take differentiated (somatic) human cells and reprogram them into ESC/PSC-like cells, cells known as induced pluripotent stem cells (iPSCs), represented a technical breakthrough that jump-started this field.^[624] Since then progress as been rapid. In particular, Madeline Lancaster, Jurgen Knōblich, Yoshiki Sasai, and a growing community of others have devised approaches by which such cells can be induced to form tissue specific organoids. Cerebral organoids, which produce brain-like tissues, have been used to examine developmental defects associated with microencephaly and Zika-virus infection-induced microencephaly, lissencephaly, Down’s syndrome and others. Both ES and iPS cells can be induced to differentiate into what are known as gastruloids. Gastruloids can develop anterior-posterior (head-tail), dorsal-ventral (back-belly), and left-right axes analogous to those found in human embryos.^[625] Perhaps surprisingly (and perhaps not) human organoids develop along a time-line to that observed in intact human embryos, which means that these studies can take significant amounts of time.^[626].

An ethical / moral / religious issue associated with this type of work is that, as gastruloids, assembloids, and embryoids become increasingly like natural human embryos, how they are treated becomes contentious. A similar issues involves the "excess" embryos generated in the course of in vitro fertilization protocols. These are discussion best considered in the context of non-science course.

---