For the promise of human induced pluripotent stem cells (iPSCs) to be realized, it is necessary to ask if and how efficiently they may be differentiated to functional cells of various lineages. Here, we have directly compared the neural-differentiation capacity of human iPSCs and embryonic stem cells (ESCs). We have shown that human iPSCs use the same transcriptional network to generate neuroepithelia and functionally appropriate neuronal types over the same developmental time course as hESCs in response to the same set of morphogens; however, they do it with significantly reduced efficiency and increased variability. These results were consistent across iPSC lines and independent of the set of reprogramming transgenes used to derive iPSCs as well as the presence or absence of reprogramming transgenes in iPSCs. These findings, which show a need for improving differentiation potency of iPSCs, suggest the possibility of employing human iPSCs in pathological studies, therapeutic screening, and autologous cell transplantation.

Mutation for microcephaly: Zika virus infections in humans have been known since 1947. Microcephaly and neuropathologies associated with Zika have only been reported recently, most prevalently in the Americas. Yuan et al. investigated recent stable mutations in the virus genome and engineered them into a low-virulence ancestral strain (see the Perspective by Screaton and Mongkolsapaya). A single amino acid substitution (serine to asparagine, S139N) in the viral precursor membrane protein exacerbated symptoms in pregnant mice. The reverse mutation (N139S) was less virulent. The S139N mutation arose in 2013 in French Polynesia before the virus jumped to Brazil in 2015. In vitro, this amino acid change made the virus more infectious for mouse and human neural progenitor cells and promoted apoptosis. The terrible sequelae of infection during pregnancy could thus be the result of a simple viral mutation. Science , this issue p. 933 ; see also p. 863

Specification of distinct cell types from human embryonic stem cells (hESCs) is key to the potential application of these naïve pluripotent cells in regenerative medicine. Determination of the nontarget differentiated populations, which is lacking in the field, is also crucial. Here, we show an efficient differentiation of motor neurons (∼50%) by a simple sequential application of retinoid acid and sonic hedgehog (SHH) in a chemically defined suspension culture. We also discovered that purmorphamine, a small molecule that activates the SHH pathway, could replace SHH for the generation of motor neurons. Immunocytochemical characterization indicated that cells differentiated from hESCs were nearly completely restricted to the ventral spinal progenitor fate (NKX2.2+, Irx3+, and Pax7−), with the exception of motor neurons (HB9+) and their progenitors (Olig2+). Thus, the directed neural differentiation system with small molecules, even without further purification, will facilitate basic and translational studies using human motoneurons at a minimal cost. Disclosure of potential conflicts of interest is found at the end of this article.