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Of all the medical care that will have to be rationed during the Covid-19 pandemic, the most problematic will be mechanical ventilation. One strategy for avoiding debilitating distress over these decisions is to use a triage committee to buffer bedside clinicians.

The field of stem-cell biology has been catapulted forward by the startling development of reprogramming technology. The ability to restore pluripotency to somatic cells through the ectopic co-expression of reprogramming factors has created powerful new opportunities for modelling human diseases and offers hope for personalized regenerative cell therapies. While the field is racing ahead, some researchers are pausing to evaluate whether induced pluripotent stem cells are indeed the true equivalents of embryonic stem cells and whether subtle differences between these types of cell might affect their research applications and therapeutic potential.

Key Points There are marked differences in the in vitro differentiation capacity of pluripotent stem cell lines, including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. These differences currently limit their possible application in the clinic and as a research tool. The molecular underpinnings of these functional differences are unclear. In some cases, the differences can be ameliorated by altering culture conditions by adding or removing specific growth factors and/or signalling molecules. Pluripotent stem cells derived using the same method have highly similar gene expression profiles, yet can exhibit functional differences. This suggests that genetic or epigenetic changes are silent in the pluripotent state. Most genetic differences between founder and reprogrammed cells seem to pre-exist in a minor population of the founder cells. Epigenetic differences between ES cells and iPS cells are both residual (that is, they maintain the same epigenetic state as their respective founder cell type) and aberrant (that is, resembling neither ES cells nor founder cells), and both types of differences may have an impact on the in vitro differentiation process. It remains unclear whether gene expression heterogeneity within a clonal pluripotent stem cell line is a crucial feature of pluripotency, and whether this gene expression heterogeneity is associated with functional differences between different pluripotent cell lines. Pluripotent stem cell lines differ in their capacity to differentiate into desired cell types in vitro . Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within single clones. Characterizing such variations is important for the use of pluripotent stem cells in disease modelling and developmental processes and for their applications in regenerative medicine. Pluripotent stem cells constitute a platform to model disease and developmental processes and can potentially be used in regenerative medicine. However, not all pluripotent cell lines are equal in their capacity to differentiate into desired cell types in vitro . Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within clones. These genetic and epigenetic variations could 'lock' the pluripotency network resulting in residual pluripotent cells or alter the signalling response of developmental pathways leading to lineage bias. The molecular contributors to functional variability and heterogeneity in both embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are only beginning to emerge, yet they are crucial to the future of the stem cell field.

The U.S. biotechnology and pharmaceutical industries arguably lead the world in innovation while operating under stringent regulations set by the Food and Drug Administration (FDA). Although flexible pathways exist to accelerate the development or approval of treatments for serious illnesses or unmet medical needs, regulatory systems around the globe are under assault from forces seeking to relax rigorous, time-honored standards of safety and efficacy. Recent regulatory revisions in Japan allow regenerative medicine products to be marketed on the basis of only preliminary evidence of safety and reduced thresholds for determining therapeutic efficacy. In the United States, the 21st Century Cures . . .

Stem cells are but one class of the myriad types of cells within an organism. With potential to self-renew and capacity to differentiate, stem cells play essential roles at multiple stages of development. In the early embryo, pluripotent stem cells represent progenitors for all tissues while later in development, tissue-restricted stem cells give rise to cells with highly specialized functions. As best understood in the blood, skin and gut, stem cells are the seeds that sustain tissue homeostasis and regeneration, while in other tissues like the muscle, liver, kidney and lung, various stem or progenitor cells play facultative roles in tissue repair and response to injury. Here, I will provide a brief perspective on the evolving notion of cellular identity and how reprogramming and transcription factor-mediated conversions of one cell type into another have fundamentally altered our assumptions about the stability of cell identity, with profound long-term implications for biomedical research and regenerative medicine.

MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked posttranscriptionally in embryonic stem cells, embryonal carcinoma cells, and primary tumors. Here we show that Lin28, a developmentally regulated RNA binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we found that Lin28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin28 as a negative regulator of miRNA biogenesis and suggest that Lin28 may play a central role in blocking miRNA-mediated differentiation in stem cells and in certain cancers.

A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed Genome engineering technology offers unparalleled potential for modifying human and nonhuman genomes. In humans, it holds the promise of curing genetic disease, while in other organisms it provides methods to reshape the biosphere for the benefit of the environment and human societies. However, with such enormous opportunities come unknown risks to human health and well-being. In January, a group of interested stakeholders met in Napa, California ( 1 ), to discuss the scientific, medical, legal, and ethical implications of these new prospects for genome biology. The goal was to initiate an informed discussion of the uses of genome engineering technology, and to identify those areas where action is essential to prepare for future developments. The meeting identified immediate steps to take toward ensuring that the application of genome engineering technology is performed safely and ethically.

Human diseases such as heart failure, diabetes, neurodegenerative disorders, and many others result from the deficiency or dysfunction of critical cell types. Strategies for therapeutic tissue repair or regeneration require the in vitro manufacture of clinically relevant quantities of defined cell types. In addition to transplantation therapy, the generation of otherwise inaccessible cells also permits disease modeling, toxicology testing and drug discovery in vitro. In this review, we discuss current strategies to manipulate the identity of abundant and accessible cells by dif- ferentiation from an induced pluripotent state or direct conversion between differentiated states. We contrast these approaches with recent advances employing partial reprogramming to facilitate lineage switching, and discuss the mechanisms underlying the engineering of cell fate. Finally, we address the current limitations of the field and how the resulting cell types can be assessed to ensure the production of medically relevant populations.

Patient-derived pluripotent stem cells (PSCs) hold promise in the treatment of injury and disease. An ever-increasing number of specific cell types can be generated from PSCs, but technical challenges remain in applying these cells in the clinic. Fox et al. review the challenges in attaining this goal. These include gene modification, cell rejection, and delivery and localization issues involved in transplantation of cells for the treatment of diabetes and disorders of the blood, liver, heart, and brain. Science , this issue 10.1126/science.1247391 Pluripotent stem cells (PSCs) directed to various cell fates holds promise as source material for treating numerous disorders. The availability of precisely differentiated PSC-derived cells will dramatically affect blood component and hematopoietic stem cell therapies and should facilitate treatment of diabetes, some forms of liver disease and neurologic disorders, retinal diseases, and possibly heart disease. Although an unlimited supply of specific cell types is needed, other barriers must be overcome. This review of the state of cell therapies highlights important challenges. Successful cell transplantation will require optimizing the best cell type and site for engraftment, overcoming limitations to cell migration and tissue integration, and occasionally needing to control immunologic reactivity, as well as a number of other challenges. Collaboration among scientists, clinicians, and industry is critical for generating new stem cell–based therapies.

Pluripotent stem cells (PSCs) are capable of dynamic interconversion between distinct substates; however, the regulatory circuits specifying these states and enabling transitions between them are not well understood. Here we set out to characterize transcriptional heterogeneity in mouse PSCs by single-cell expression profiling under different chemical and genetic perturbations. Signalling factors and developmental regulators show highly variable expression, with expression states for some variable genes heritable through multiple cell divisions. Expression variability and population heterogeneity can be influenced by perturbation of signalling pathways and chromatin regulators. Notably, either removal of mature microRNAs or pharmacological blockage of signalling pathways drives PSCs into a low-noise ground state characterized by a reconfigured pluripotency network, enhanced self-renewal and a distinct chromatin state, an effect mediated by opposing microRNA families acting on the Myc / Lin28 /let-7 axis. These data provide insight into the nature of transcriptional heterogeneity in PSCs. This study uses single-cell expression profiling of pluripotent stem cells after various perturbations, and uncovers a high degree of variability that can be inherited through cell divisions—modulating microRNA or external signalling pathways induces a ground state with reduced gene expression heterogeneity and a distinct chromatin profile. Gene expression variation in pluripotency Although it is recognized that pluripotent stem cells switch dynamically between distinct substates, the gene regulatory networks specifying the states and governing transitions between them are not well defined. Using single-cell expression profiling of mouse pluripotent stem cells subjected to chemical and genetic perturbations, George Daley and colleagues establish how transcriptional networks are dynamically reconfigured to drive distinct states of pluripotency. They observe a high degree of variability that can be inherited through cell divisions and find that modulating microRNA or external signalling pathways lowers the heterogeneity in gene expression and induces a distinct epigenetic state.