EZH2, which transfers methyl groups to lysine 27 of histone H3, are higher during the pro-gression of prostate cancer and other tumours. Their latest data1 are suggestive of a transcrip-tional link between cancer progression and GNMT activity, through the binding of both the androgen receptor and the oncogene ERG to the promoter sequence of the GNMT gene in tumour cells.

Unexpectedly, Sreekumar et al. not only show that sarcosine is a biomarker for prostate-cancer progression, but also provide evidence, using cells maintained in culture, for its func-tional role in regulating the features of cancer cells. They find that the addition of sarcosine to benign prostate epithelial cells promotes invasive properties in these cells, whereas lowering GNMT levels in a prostate-cancer cell line reduces its invasiveness.

By contrast, however, a previous study8 showed that mice lacking GNMT develop liver cancer with age. Moreover, in a significant proportion of human prostate cancers, GNMT undergoes a phenomenon called loss of hetero-zygosity — in which one copy of the gene is lost — and the expression of this gene was documented to decrease with prostate-cancer progression9. Reconciling these earlier findings with those of Sreekumar et al. is necessary to determine the overall significance of sarcosine levels in assessing cancer progression.

At present, the greatest value of metabo-lomic approaches seems to be for the devel-opment of non-invasive screening procedures that can be used for effective cancer diagnosis and prognosis. Notably, Sreekumar and col-leagues1 show that sarcosine levels in urine have a modest but significant predictive value for prostate-cancer diagnosis; this suggests that assessment of metabolite levels in urine might be an appropriate screening tool when applied together with examination of PSA levels and other approaches for monitoring disease pro-gression. Furthermore, the authors identify several other metabolites that are more read-ily detected in cancer and metastases than sar-cosine, although with no obvious mechanistic link to disease progression; these metabolites might therefore be more suitable for predictive screening tests.

It is not known whether metabolome changes similar to those Sreekumar et al. observe in prostate cancer occur in other tumours. It will also be of interest to learn how environmental factors such as diet (including intake of methionine — the precursor of S-ade-nosylmethionine) may affect the metabolome profile and thus the usefulness of metabolo-mic analysis in cancer screening. As a starting point, however, Sreekumar and colleagues’ observations suggest that metabolomics has a promising future in aiding cancer diagnosis and treatment. ■

Cory Abate-Shen is in the Departments of Urology and of Pathology, and Michael M. Shen is in the Departments of Medicine and of Genetics and Development, Herbert Irving Comprehensive

Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.e-mails: cabateshen@columbia.edu;mshen@columbia.edu

1. Sreekumar, A. et al. Nature 457, 910–914 (2009).2. Griffin, J. L. & Shockcor, J. P. Nature Rev. Cancer 4, 551–561

(2004).

SOLID-STATE CHEMISTRY

Boron charged under pressureJohn S. Tse

Crystal-structure prediction methods and diffraction data show that a newly discovered form of boron is partially ionic. This is the first time such a structure has been observed for any elemental solid.

The concept of atomic structure — ordered arrangements of atoms, such as the arrays found in crystalline solids — is central to an understanding of the properties of matter. The most successful technique for determin-ing crystal structures is X-ray diffraction. But this method doesn’t always work, especially for unusually complex structures, or if the resolu-tion of the technique is limited by the extreme conditions required for the crystals to exist. In these cases, an independent method for pre-dicting plausible structures is desirable to assist the interpretation of experimental diffraction patterns. Such a method is extremely difficult to realize in practice. But reporting in this issue (page 863), Oganov et al.1 demonstrate the use of first-principles calculations, in combination with diffraction data, to determine the crystal structure of a new, stable form of boron that forms at high pressure.

The theoretical prediction of crystal struc-tures has long been a challenging problem. Recently, there has been a resurgence of inter-est in applying first-principles calculations to predict structures, without having any prior information about the arrangement of atoms. These include ex nihilo approaches2 (which generate structures at random, and then use computational methods to ‘relax’ the structures into low-energy arrangements) and genetic algorithms3 (which start with a population of random structures, from which low-energy structures ‘evolve’ during subsequent rounds of changes that simulate natural selection). An exciting aspect of Oganov and colleagues’ work1 is that it used the latter approach to successfully predict a thermodynamically stable structure.

The authors’ method3 for predicting crys-tal structures builds on previous pioneering work4 that predicted the structures of clusters of atoms. The process starts with a population of randomly generated parent structures, from which offspring structures evolve in heredity and mutation operations. In heredity opera-

tions, two low-enthalpy structures are selected and sliced up, and slices from each structure are then combined to produce offspring (Fig. 1). Mutation operations create distortions to the unit cell (the fundamental repeat unit of a crystalline structure) and/or to the atomic positions of a parent structure. After several rounds of operations, the lowest-energy crystal structure should emerge.

Boron provides a tough test for the authors’ predictive method because of its chemical and structural complexity. Discovered in 1808, the original samples of boron were later found to contain only 60–80% of the element, and

Figure 1 | Heredity operations in crystal-structure prediction. Genetic algorithms are used to predict crystal structures of compounds. These involve heredity operations, whereby models of the unit cells of approximate, likely structures (parent structures) are cut into slices, and slices from different parents are combined to produce offspring structures. After several heredity and mutation operations (which generate distortions to unit cells), low-energy structures of the compound under investigation should emerge. Oganov et al.1 use genetic algorithms to determine the crystal structure of a newly identified form of boron.

Parent structures

Offspring structures

3. Spratlin, J. L., Serkova, N. J. & Eckhardt, S. G. Clin. Cancer Res. 15, 431–440 (2009).

4. Denkert, C. et al. Mol. Cancer 7, 72 (2008).5. Ippolito, J. E. et al. Proc. Natl Acad. Sci. USA 102, 9901–9906

(2005).6. Kind, T. et al. Anal. Biochem. 363, 185–195 (2007).7. Varambally, S. et al. Nature 419, 624–629 (2002).8. Martínez-Chantar, M. L. et al. Hepatology 47, 1191–1199

(2008).9. Huang, Y.-C. et al. Clin. Cancer Res. 13, 1412–1420 (2007).

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more efficient7. The mutation operation could (and should) also be improved.

Furthermore, there have been considerable successes in predictions of crystal structures that are based solely on randomly generated structures8 — the advantage of this approach being that the sampling of possible structures is completely unbiased. Such lack of bias might prevent the evolution process from predicting structures that lie in a local energy minimum of the potential energy surface that describes all the possible arrangements of atoms (rather than finding structures of the lowest possible energy).

Oganov and colleagues’ paper1 describes a crucial first step towards a truly ab initio method for predicting crystal structures. Perhaps just as importantly, it broadens our knowledge

of the possibilities for chemical bonding in elemental solids, and adds yet another chapter to the bizarre history of boron. ■

John S. Tse is in the Department of Physics and Engineering Physics, University of Saskatchewan, 116 Science Place, Saskatoon, Saskatchewan S7N 0K4, Canada.e-mail: john.tse@usask.ca

1. Oganov, A. R. et al. Nature 457, 863–867 (2009).2. Pickard, C. J. & Needs, R. J. Phys. Rev. Lett. 97, 045504 (2006).3. Oganov, A. R. & Glass, C. W. J. Chem. Phys. 124, 244704

(2006).4. Deaven, D. M. & Ho, K. M. Phys. Rev. Lett. 75, 288–291 (1995).5. Wigner, E. & Huntington, H. B. J. Chem. Phys. 3, 764–770

(1935).6. Edwards, B. & Ashcroft, N. W. Nature 388, 652–655

(1997).7. Abraham, N. L. & Probert, M. I. J. Phys. Rev. B 73, 224104

(2006).8. Pickard, C. J. & Needs, R. J. Nature Phys. 3, 473–476 (2007).

DEVELOPMENTAL BIOLOGY

Birth of the blood cellMomoko Yoshimoto and Mervin C. Yoder

Could it be that mouse fetal liver cells and adult bone-marrow blood cells originate from a subset of cells that line the blood vessels in the embryo? Several lines of evidence suggest that this is indeed the case.

During embryonic development, haemato-poietic stem cells, which give rise to blood cells, and endothelial cells, which line blood vessels, both form from the mesodermal germ-cell layer; but exactly how is debatable. On the one hand, a controversial, century-old theory proposes that both haematopoietic and endo-thelial cells arise from a mesoderm-derived common precursor called a haemangio blast. On the other hand, a younger theory proposes that haematopoietic stem cells (HSCs) form from a subset of early endo thelial cells known as haemogenic endothelium. The relationship between haemangioblasts and haemogenic endothelium has never been resolved. In this issue, however, three papers1 –3 clarify the potential relatedness and significance of these cell types.

The concept of the haemangioblast initially arose from observations that, in the chick yolk sac, a mesoderm-derived cell can give rise to both primitive red blood cells and endothelial cells. Moreover, the finding that, in the mouse yolk sac, the formation of blood islands — aggregates of blood cells and endothelium — requires the expression of specific genes such as Flk-1 provided further support for the related-ness of the two cell lineages. But the strongest evidence for the existence of haemangioblasts was obtained after the development of the BL-CFC in vitro assay. This assay allows clonal (single-cell) analysis of blast colony-forming cells (BL-CFCs), which are derived from dif-ferentiating mouse embryonic stem (ES) cells4. By definition, BL-CFCs can directly form both

haematopoietic and endothelial cells, and are therefore the closest detectable equivalent of the theoretical haemangio blasts .

When ES-cell-derived Flk-1-expressing (Flk-1+) mouse cells are grown in culture, char-acteristic BL-CFC colonies appear that consist of an aggregate of non-adherent blood cells over lying an adherent layer of endothelium. This observation, together with insights4,5 into the molecular regulation of the development and differentiation of colonies that emerge from a BL-CFC (blast colonies), has been enlightening. Nonetheless, little has become clear about the cellular events that herald the generation of blood cells from BL-CFCs.

Lancrin et al.1 (page 892) used time-lapse photography to analyse the sequence of cellular events required for the formation of mature blast colonies from cultured Flk-1+ cells. They find that these colonies form in two stages. First, after 36–48 hours of ‘plating’ Flk-1+ cells for growth in culture, the cells form tightly adherent clus-ters. Subsequently, round, non-adherent cells appear, which then proliferate to complete the formation of mature blast colonies. Among the adherent cell clusters at 48 hours, a transient cell population expressing various endothelial (but not mesodermal or BL-CFC) markers appear, displaying the potential to form haemato poietic cells. From this population, both primitive blood-cell colonies eventually form, character-ized by their expression of the embryonic ver-sion of the haemoglobin protein, together with definitive blood-cell colonies expressing adult haemoglobin.

it wasn’t until 1909 that a 99% pure sample was isolated. So far, at least 16 polymorphs (structural forms) of boron are known, yet the ground-state structure of boron is still con-troversial. Oganov et al.1 report a new form of boron that adds to this mélange — a poly-morph that is stable at high pressure (18–89 gigapascals). So what is its structure?

Working with a ‘quenched’ sample of the material (one that had been recovered to ambi-ent pressure without disrupting its structure), the authors first obtained some basic infor-mation about the unit cell of the polymorph. They then applied their prediction technique to a range of possible atomic arrangements, and successfully obtained a thermodynami-cally stable structure that reproduced the observed diffraction pattern of the material. The structure is made up of icosahedral clus-ters of 12 boron atoms (B12) and of pairs of boron atoms (B2), arranged in a cubic lattice (see Fig. 1b on page 864). It is both gratifying and exciting that the correct structure was predicted, despite its complexity.

A surprising finding is that the bonding between the B12 clusters and the B2 pairs is partially ionic, as suggested by the infrared spectrum of the polymorph and supported by the theoretical calculations. It was generally believed that the effect of pressure on a cova-lently bonded compound was to weaken the bonds, and so enhance electron mobility. For example, it was suggested5 that a simple com-pound, such as solid hydrogen (an insulator consisting of H2 molecules, in which electrons are localized within covalent bonds), would transform under extreme pressure to a metal (containing mobile, delocalized electrons). More recent experimental and theoretical results6, however, suggest that spontaneous polarization of H2 bonds might occur under pressure, so that partial charges develop on the atoms of each molecule — electrons situated in the interstitial region would leave positive charge on the atoms.

Oganov et al.1 report the first observation of an elemental solid that has some ionic struc-ture — the B12 clusters have a partial negative charge, whereas the B2 units have a partial posi-tive charge. The build-up of negative charge on the B12 cluster is stabilized by sharing the negative charge (electron) among the molecu-lar orbitals of the B12 units. This effect, com-bined with electrostatic interactions between the B2 and the B12 units, helps to stabilize the ionic complex. This picture, if correct, is differ-ent from the proposed spontaneous electronic polarization in dense hydrogen, and may be unique to boron.

Oganov and colleagues’ results prove the efficiency and reliability of their prediction technique, but there is still some room for improvement. Simply mixing and matching planar slices of parent structures in the heredity operation isn’t necessarily the best procedure for finding low-energy structures — slices that have periodic, wave-like geometries might be

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