MICHAEL SENDTNER A major goal for biomedical researchers has been to repair damaged cells and tissues by reinitiating the body’s devel- opmental mechanisms. In this respect, the use of embryonic stem cells — and of induced pluripotent stem cells, which are generated by reprogramming differentiated adult cells — has seemed promising. But these cells come with various problems, including ethical con- cerns, and potential tumorigenicity and rejec- tion by the host immune system. Three papers in this issue 1–3 describe the direct conversion of neurons from skin fibroblast cells. There is hope, although no compelling evidence, that neurons generated in this way might be superior to those generated from induced pluripotent stem cells, thereby sidestepping the problems of using such cells 4 . The conversion of mouse fibroblasts into neurons was reported last year 5 . The same team (Pang et al. 1 , page 220) now find, how- ever, that introducing the same three tran- scription factors (Brn2, Ascl1/Mash1 and Myt1l) used in their original study into human fibroblasts is not sufficient to convert the cells into functional neurons; the resulting cells are immature, and even after 3 weeks in culture do not become functional, as judged by meas- urements of action potentials. Nonetheless, the authors show that the efficiency of human fibroblast conversion into neurons is enhanced by including an extra transcription factor, NeuroD1, a member of the bHLH family. Caiazzo et al. 2 (page 224) also set out to con- vert human fibroblasts into a specific type of neuron, in this case neurons of the midbrain that secrete the neurotransmitter dopamine. Starting their study in mice, they tested the efficiency of mixtures of transcription fac- tors (combinations of Ascl1, Brn2, Myt1l and others) in the conversion process. The win- ning combination was that of Ascl1, Nurr1 and Lmx1a; Brn2 and Myt1l did not lead to dopa- mine-secreting neurons. The authors provide evidence that the conversion route was direct, and that the resulting neurons were function- ally surprisingly similar to primary dopamin- ergic neurons isolated from the brain. What’s more, when the converted dopaminergic cells were grafted into neonatal mouse brains, they became integrated and were functional. Caiazzo and colleagues then applied their method to human fibroblasts, including those from patients with Parkinson’s disease, a neurodegenerative disorder in which dopa- minergic neurons are damaged. The conver- sion efficiency of adult human fibroblasts was 10–20-fold lower than that of their mouse equivalents, and the resulting cells were less mature. This discrepancy points to species differences between mice and humans 2 . The authors’ observations fit well with those of REGENERATIVE MEDICINE Bespoke cells for the human brain Human skin cells have been directly converted into neurons, an achievement that could lead to the cell-based treatment of neurodegenerative disorders. But the road ahead remains long and tortuous. S L ., .  . Surprisingly, Kai et al. find that a reduction in the fossil-fuel methane source is not com- patible with these measurements, and that the isotope record can be explained only by a reduction in the microbial sources in the Northern Hemisphere. A drying trend in northern wetlands could have contributed to this finding 6 , but the authors convinc- ingly show that methane emissions from rice agriculture, particularly in China, must also have decreased. Their conclusion is based on changes in agricultural practices: new high- yield rice species, together with greater appli- cation of fertilizer, require shorter inundation periods, making substantial water savings and reducing methane emissions. Can these conflicting inferences on the recent slow-down of global methane growth be reconciled? Because of the limited data coverage and simplistic analysis assumptions of the two studies 1,2 , there are considerable uncertainties in the deduced methane-source variations, but the different scenarios are plausible and com- patible with their respective observations. The challenge now is to bring the different lines of evidence together, perhaps by using a more advanced modelling framework and improved bottom-up inventory information on the vari- ous methane-source categories. More extended observations will help too — particularly the mapping of atmospheric methane concentra- tion by current and upcoming satellite missions. These studies 1,2 illustrate the importance of high-precision, long-term observations of methane concentration and isotope com- position, and of auxiliary trace gases such as ethane, in distinguishing between the contributions from different sources. But more insight is needed to solve the enigma of the recent methane budget if the evolution of this important greenhouse gas over the twenty-first century is to be predicted. ■ Martin Heimann is at the Max Planck Institute for Biogeochemistry, 07701 Jena, Germany. e-mail: martin.heimann@bgc-jena.mpg.de 1. Kai, F. M., Tyler, S. C., Randerson, J. T. & Blake, D. R. Nature 476, 194–197 (2011). 2. Aydin, M. et al. Nature 476, 198–201 (2011). 3. Dlugokencky, E. J. et al. Geophys. Res. Lett. 36, L18803; http://dx.doi.org/10.1029/2009GL039780 (2009). 4. Schneising, O. et al. Atmos. Chem. Phys. 9, 443–465 (2009). 5. Bousquet, P. et al. Nature 443, 439–443 (2006). 6. Jung, M. et al. Nature 467, 951–954 (2010).  another team 6 that recently reported the direct conversion of human fibroblasts into dopa- minergic cells using a different combination of transcription factors. Yoo et al. 3 (page 228) approached the search for a suitable conversion method from a differ- ent angle. They show that combined expres- sion of miR-9/9* and miR-124 — two members of a class of short regulatory RNA sequences called microRNAs (miRNAs) — is sufficient to convert human fibroblasts into neurons. Again, the conversion process was greatly enhanced by the introduction of another bHLH-family transcription factor, NeuroD2. And increased expression of Ascl1 and Myt1l further increased the conversion efficiency of neonatal human fibroblasts: about 80% of the resulting neurons showed action-potential- like activity. As in the other two studies, Yoo and colleagues write that adult fibroblasts were less amenable to conversion. Several common themes emerge. The stud- ies 1–3 highlight the importance of the bHLH- family transcription factors and the role of miRNAs in the conversion process. Moreover, they all show that the conversion of mouse and human fibroblasts into neurons requires different protocols, and that conversion of fibroblasts from adult or aged individuals is much less productive than that of embryonic or neonatal fibroblasts. The essential role of NeuroD1 and NeuroD2 for efficient conversion correlates well with the crucial part played by these two transcription factors in neuron differentiation during normal brain development, and their reduced expres- sion as neurogenesis decreases during ageing 7,8 . A relevant question is whether the degree of methylation of the genomic region contain- ing the genes for these transcription factors is higher in human than in mouse fibroblasts and increases during ageing, thereby resulting in their reduced expression. DNA methylation is a crucial regulator of gene expression. How miR-9/9* and miR-124 substitute for Brn2 — and possibly for Ascl1 and Myt1l — in 158 | NATURE | VOL 476 | 11 AUGUST 2011 NEWS & VIEWS RESEARCH © 2011 Macmillan Publishers Limited. All rights reserved