HIGH-TEMPERATURE SUPERCONDUCTIVITY Mind the pseudogap The discovery of predicted collective electronic behaviour in copper-oxide superconductors in the non-superconducting state provides clues to unlocking the 24-year-old mystery of high-temperature superconductivity. See Letter p.283 CHANDRA VARMA T he phenomenon of high-temperature superconductivity is a beautiful and well-posed scientific problem with many facets. On page 283 of this issue, Li et al. 1 report observing a special kind of intense col- lective electronic fluctuation in the most mysterious phase of matter exhibited by high- temperature superconducting copper-oxide materials (cuprates). Taken together with pre- vious experimental 2–6 and theoretical 7 work, this observation significantly narrows the range of directions likely to be fruitful in the quest to understand high-temperature super- conductivity. The authors performed their experiments in two samples of HgBa 2 CuO 4+δ , which has one of the simplest crystal structures of any of the cuprate families and is ideal for such studies. Li and colleagues’ experiments 1 pertain to the pseudogap region of the phase diagram of the cuprates (Fig. 1), a sort of precursor state to the superconducting phase that most con- densed-matter physicists regard as the Rosetta Stone for discovering the physical principles that underlie the cuprates’ behaviour. On entering the pseudogap region, at a temper- ature below T* but above the temperature below which superconductivity emerges (T c ), all cuprates’ thermodynamic and electronic- transport properties change by a large amount owing to the materials’ loss of low-energy electronic excitations. The pseudogap region is bounded on one side by a region of remarkably simple but unusual properties, which do not fit into the Fermi-liquid-type model that has been used to describe metals at low temperatures for about a hundred years. Some researchers got to grips with understanding this ‘strange-metal’ region early in the history of high-T c superconduct- ivity, by hypothesizing a quantum critical point in the dome-shaped superconductivity region of the phase diagram (Fig. 1). This point would occur at zero temperature and would involve a change in the symmetry of the materials’ electronic structure. Because T c is determined by the materials’ collective electronic excita- tions in the non-superconducting state, it is unarguable that the coupling of electrons to such excitations in the strange-metal region and their modifications in the pseudogap region lead to high-T c superconductivity. If it exists, a quantum critical point in the Figure 1 | Phase diagram of the cuprates. At very low levels of electron–hole doping, cuprates are insulating and antiferromagnetic (the materials’ neighbouring spins point in opposite directions). At increased doping levels, they become conducting, and the exact temperature and doping level determine which phase of matter they will be in. At temperatures below T c , they become superconducting, and at temperatures above T c but below T* they fall into the pseudogap phase. The boundary of the pseudogap region at low doping levels is unknown. The transition between the Fermi-liquid phase and the strange-metal phase occurs gradually (by crossover). QCP denotes the quantum critical point at which the temperature T* goes to absolute zero. Li and colleagues’ study 1 pertains to the pseudogap phase. Insulator and antiferromagnetic Superconductivity Pseudo- gap phase Strange metal Fermi liquid Doping T* T c QCP ? Temperature Crossover conditions. Both groups agree that, under conditions optimized by geneticists for growth in conventional laboratories, aneuploid cells usually divide less rapidly than cells with the normal chromosomal complement. An important distinction in the methods used to generate the aneuploid strains might explain the differences in the findings 2,7,8 . Torres et al. 7,8 engineered yeast cells with a haploid (single) set of chromosomes to carry one extra chromosome and then selected for faster growth using conventional lab condi- tions for 9–14 days — a time frame during which mutations are expected to accumulate. By contrast, Pavelka et al. analysed strains that often carried multiple aneuploid chromosomes and, importantly, minimized the number of generations before analysis. This illustrates a crucial truism of experimental genetics: you get what you select for. Pavelka and co-workers also directly address a controversy concerning the role of excess proteins in aneuploid cells. Previously, Torres et al. 7 proposed that there is a specific set of genes and proteins that are regulated in response to aneuploidy in general. In their more recent study 8 , they showed that some 20% of proteins exhibit levels that do not track with gene copy number, and that a large proportion of these proteins are members of macromolecular complexes. By contrast, other groups 9,10 have found that the levels of most proteins generally reflect changes in chromo- some copy number and that less than 5% of the proteins exhibit ‘dosage compensation’ — whereby the relative protein level is inde- pendent of gene-copy number. Pavelka et al. specifically test this hypothesis by quantitative mass spectrometry of about 2,000 proteins in each of five aneuploid strains and do not find compelling evidence for specific dosage com- pensation of protein-complex components. Overall, these studies 2,7–10 are consistent with the idea that aneuploidy is not a single, unique state and that all aneuploid strains do not share a single, common phenotype or protein profile. Rather, different aneuploid strains use differ- ent mechanisms for optimal growth under different conditions. This conclusion may be less satisfying than a single, simple answer, especially given the crucial implications for cancer cells: it remains unclear whether cancer cells divide uncontrollably because they are aneuploid and/or because they have accumulated mutations that allow them to tolerate aneuploidy. But it should be remem- bered that work on cancer cells themselves 11 suggests that not all aneuploidies are equal: aneuploidy can either promote or inhibit tumorigenesis, depending on the context. Pavelka and colleagues’ work 2 therefore supports the idea that, whereas mutations can facilitate the proliferation of aneuploid cells, aneuploidy itself can be sufficient to provide a growth advantage under a broad range of stress conditions. ■ Judith Berman is in the Department of Genetics, Cell Biology, and Development, and the Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455, USA. e-mail: jberman@umn.edu 1. http://8e.devbio.com/article.php?ch=4&id=24 2. Pavelka, N. et al. Nature 468, 321–325 (2010). 3. Duesberg, P., Li, R., Fabarius, A. & Hehlmann, R. Contrib. Microbiol. 13, 16–44 (2006). 4. Hede, K. J. Natl Cancer Inst. 97, 87–89 (2005). 5. Rancati, G. et al. Cell 135, 879–893 (2008). 6. Selmecki, A., Gerami-Nejad, M., Paulson, C., Forche, A. & Berman, J. Mol. Microbiol. 68, 624–641 (2008). 7. Torres, E. M. et al. Science 317, 916–924 (2007). 8. Torres, E. M. et al. Cell 143, 71–83 (2010). 9. Geiger, T., Cox, J. & Mann, M. 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