Editorials
臨床試験は社会からの信頼の上に成り立っており、製薬企業は、結果の透明性を高める努力を続けるべきだ。
Data sharing will pay dividends p.131
As public pressure builds for drug companies to make more results available from clinical trials, the industry should not forget that it relies on collective goodwill to test new therapies.
doi: 10.1038/505131a
大学での暴力的犯罪を防ぐことを目指す脅威評価チームは、問題を抱える教職員や学生を危機から救う命綱にもなる。
Risk management p.131
Teams aimed at preventing violence on campus can offer a lifeline to those in crisis.
doi: 10.1038/505131b
Natureでは今年、戦争が科学研究にどう影響し、逆に科学が戦争にどう影響するかを、いくつかの記事で取り上げていく。
Conflict of interest p.132
How two world wars affected scientific research, and vice versa.
doi: 10.1038/505132a
News
イタリアのスタミナ財団が行った幹細胞治療をめぐり、懸念を裏付ける流出情報が。
Leaked files slam stem-cell therapy p.139
Disclosures and resignations reveal scientific concerns over methods of Italy’s Stamina Foundation.
doi: 10.1038/505139a
素粒子物理学分野で、査読付き論文のオープンアクセス化を実現することを目的とした国際プロジェクトが始まったが、有力誌が不参加に。
Particle-physics papers set free p.141
Tensions as open-access initiative goes live — without the field’s leading journal.
doi: 10.1038/505141a
WHOの希少疾病への取り組みに、効果が上がらないとの批判が。
Projects set to tackle neglected diseases p.142
But they do little to alter the process of drug development.
doi: 10.1038/505142a
多数の小型衛星を使って、地球をほぼリアルタイムで画像化しようという計画が。
Many eyes on Earth p.143
Swarms of small satellites set to deliver close to real-time imagery of swathes of the planet.
doi: 10.1038/505143a
中国が、研究開発費の対GDP比率で、ヨーロッパよりも上に。
China tops Europe in R&D intensity p.144
Reforms to commercial and academic research systems still needed despite reaching spending milestone, say scientists.
doi: 10.1038/505144a
News Features
コンピューター科学：学習する機械
Computer science: The learning machines p.146
膨大な量の写真、音声データを用いて「深層学習（deep learning）」をさせることで、コンピューターが真の人工知能へと次第に近付いてきている。
doi: 10.1038/505146a
職場での暴力：物騒なキャンパス
Workplace violence: Caught on campus p.150
暴力事件の発生をきっかけに、キャンパスの安全を保つための脅威評価制度を取り入れる大学が増えているが、この方式はうまく機能するだろうか。
doi: 10.1038/505150a
News & Views
フォーラム: 発生生物学：つながれたWntタンパク質
Developmental biology: Tethered wings p.162
シグナル伝達分子のWntは、組織中を拡散していくことで生物の発生を誘導すると考えられてきた。だがショウジョウバエでは、主要なWntタンパク質を移動できない状態にしてやっても、ほぼ正常な付属器を持つ個体に成長することが分かった。発生に関する我々の知識へのこの知見の関わりついて、2人の研究者が論じている。
doi: 10.1038/nature12848
電気化学：金属を使わないエネルギー貯蔵
Electrochemistry: Metal-free energy storage p.163
流動電池では、電気活性材料の溶液を電気化学セル内に流すことによってエネルギーが発生する。こうした材料は金属塩であることが多く、非金属電気活性材料は大規模エネルギー貯蔵への道を開くと考えられる。
doi: 10.1038/505163a
治療学：薬剤投与量に関する難問の追求
Therapeutics: Detective work on drug dosage p.165
患者が必要とする薬剤投与量は個々に異なるし、それに対する応答も方もさまざまである。ラットで薬剤の血中濃度を継続的に監視できるようにする汎用手法が考案され、これは患者ごとに異なる投薬量決定への道を開くものとなりそうだ。
doi: 10.1038/505165a
量子物理学：原子のSQUID
Quantum physics: An atomic SQUID p.166
超伝導量子回路は最も感度の高い磁力計の中核技術である。極低温原子気体を使ってこれに類似したデバイスが今回実現されたが、これは回転検出へ応用できる可能性がある。
doi: 10.1038/nature12846
HIV：ウイルスの侵入をかぶりつきで見る
HIV: Ringside views p.167
2つの結晶構造から、ヒトおよびサルの免疫不全ウイルスのVifとVpxというタンパク質が、細胞のタンパク質分解装置を再プログラム化することで、宿主防御網への侵入を仲介することが分かった。
doi: 10.1038/505167a
Articles
老化：生命系統樹全体にわたって見られる老化の多様性
Diversity of ageing across the tree of life p.169
Examination of demographic age trajectories for species from a wide range of taxonomic groups shows that these species have very diverse life-history patterns; mortality and reproduction vary greatly with age for both long- and short-lived species, and the relationships between ageing, mortality and reproduction are clearly complex.
doi: 10.1038/nature12789
ゲノミクス：ゾウギンザメのゲノムは、顎口類の進化を理解する上で比類ない手がかりを提供する
Elephant shark genome provides unique insights into gnathostome evolution OPEN p.174
Whole-genome analysis of the elephant shark, a cartilaginous fish, shows that it is the slowest evolving of all known vertebrates, lacks critical bone formation genes and has an unusual adaptive immune system.
doi: 10.1038/nature12826
発生生物学：膜繋留型Winglessによるパターン形成と成長の制御
Patterning and growth control by membrane-tethered Wingless p.180
Replacement of the wingless (wg) gene in Drosophila with one that expresses a membrane-tethered form of Wg results in viable flies with normally patterned appendages of nearly the right size; early wg transcription and memory of signalling ensure continued target-gene expression in the absence of Wg release, even though the spread of Wg could boost cell proliferation.
doi: 10.1038/nature12879
Letters
宇宙：金属欠乏銀河における塵の希少さ
The rarity of dust in metal-poor galaxies p.186
Galaxies observed at redshift z > 6, when the Universe was less than a billion years old, thus far very rarely show evidence of the cold dust that accompanies star formation in the local Universe, where the dust-to-gas mass ratio is around one per cent. A prototypical example is the galaxy Himiko (z = 6.6), which—a mere 840 million years after the Big Bang—is forming stars at a rate of 30–100 solar masses per year, yielding a mass assembly time of about 150 × 106 years. Himiko is thought to have a low fraction (2–3 per cent of the Sun’s) of elements heavier than helium (low metallicity), and although its gas mass cannot yet be determined its dust-to-stellar mass ratio is constrained to be less than 0.05 per cent. The local dwarf galaxy I Zwicky 18, which has a metallicity about 4 per cent that of the Sun’s and is forming stars less rapidly (assembly time about 1.6 × 109 years) than Himiko but still vigorously for its mass, is also very dust deficient and is perhaps one of the best analogues of primitive galaxies accessible to detailed study. Here we report observations of dust emission from I Zw 18, from which we determine its dust mass to be 450–1,800 solar masses, yielding a dust-to-stellar mass ratio of about 10−6 to 10−5 and a dust-to-gas mass ratio of 3.2–13 × 10−6. If I Zw 18 is a reasonable analogue of Himiko, then Himiko’s dust mass must be around 50,000 solar masses, a factor of 100 below the current upper limit. These numbers are quite uncertain, but if most high-z galaxies are more like Himiko than like the very-high-dust-mass galaxy SDSS J114816.64 + 525150.3 at z ≈ 6, which hosts a quasar, then our prospects for detecting the gas and dust inside such galaxies are much poorer than hitherto anticipated.
doi: 10.1038/nature12765
材料：ウエハースケールグラフェン膜の対面式の移動
Face-to-face transfer of wafer-scale graphene films p.190
Graphene has attracted worldwide interest since its experimental discovery, but the preparation of large-area, continuous graphene film on SiO2/Si wafers, free from growth-related morphological defects or transfer-induced cracks and folds, remains a formidable challenge. Growth of graphene by chemical vapour deposition on Cu foils has emerged as a powerful technique owing to its compatibility with industrial-scale roll-to-roll technology. However, the polycrystalline nature and microscopic roughness of Cu foils means that such roll-to-roll transferred films are not devoid of cracks and folds. High-fidelity transfer or direct growth of high-quality graphene films on arbitrary substrates is needed to enable wide-ranging applications in photonics or electronics, which include devices such as optoelectronic modulators, transistors, on-chip biosensors and tunnelling barriers. The direct growth of graphene film on an insulating substrate, such as a SiO2/Si wafer, would be useful for this purpose, but current research efforts remain grounded at the proof-of-concept stage, where only discontinuous, nanometre-sized islands can be obtained. Here we develop a face-to-face transfer method for wafer-scale graphene films that is so far the only known way to accomplish both the growth and transfer steps on one wafer. This spontaneous transfer method relies on nascent gas bubbles and capillary bridges between the graphene film and the underlying substrate during etching of the metal catalyst, which is analogous to the method used by tree frogs to remain attached to submerged leaves. In contrast to the previous wet or dry transfer results, the face-to-face transfer does not have to be done by hand and is compatible with any size and shape of substrate; this approach also enjoys the benefit of a much reduced density of transfer defects compared with the conventional transfer method. Most importantly, the direct growth and spontaneous attachment of graphene on the underlying substrate is amenable to batch processing in a semiconductor production line, and thus will speed up the technological application of graphene.
doi: 10.1038/nature12763
電気化学：無金属有機–無機水系流動電池
A metal-free organic–inorganic aqueous flow battery p.195
As the fraction of electricity generation from intermittent renewable sources—such as solar or wind—grows, the ability to store large amounts of electrical energy is of increasing importance. Solid-electrode batteries maintain discharge at peak power for far too short a time to fully regulate wind or solar power output. In contrast, flow batteries can independently scale the power (electrode area) and energy (arbitrarily large storage volume) components of the system by maintaining all of the electro-active species in fluid form. Wide-scale utilization of flow batteries is, however, limited by the abundance and cost of these materials, particularly those using redox-active metals and precious-metal electrocatalysts. Here we describe a class of energy storage materials that exploits the favourable chemical and electrochemical properties of a family of molecules known as quinones. The example we demonstrate is a metal-free flow battery based on the redox chemistry of 9,10-anthraquinone-2,7-disulphonic acid (AQDS). AQDS undergoes extremely rapid and reversible two-electron two-proton reduction on a glassy carbon electrode in sulphuric acid. An aqueous flow battery with inexpensive carbon electrodes, combining the quinone/hydroquinone couple with the Br2/Br− redox couple, yields a peak galvanic power density exceeding 0.6 W cm−2 at 1.3 A cm−2. Cycling of this quinone–bromide flow battery showed >99 per cent storage capacity retention per cycle. The organic anthraquinone species can be synthesized from inexpensive commodity chemicals. This organic approach permits tuning of important properties such as the reduction potential and solubility by adding functional groups: for example, we demonstrate that the addition of two hydroxy groups to AQDS increases the open circuit potential of the cell by 11% and we describe a pathway for further increases in cell voltage. The use of π-aromatic redox-active organic molecules instead of redox-active metals represents a new and promising direction for realizing massive electrical energy storage at greatly reduced cost.
doi: 10.1038/nature12909
化学：アリル炭素–水素結合活性化と選択的炭素–炭素結合活性化を融合する
Merging allylic carbon–hydrogen and selective carbon–carbon bond activation p.199
Since the nineteenth century, many synthetic organic chemists have focused on developing new strategies to regio-, diastereo- and enantioselectively build carbon–carbon and carbon–heteroatom bonds in a predictable and efficient manner. Ideal syntheses should use the least number of synthetic steps, with few or no functional group transformations and by-products, and maximum atom efficiency. One potentially attractive method for the synthesis of molecular skeletons that are difficult to prepare would be through the selective activation of C–H and C–C bonds, instead of the conventional construction of new C–C bonds. Here we present an approach that exploits the multifold reactivity of easily accessible substrates with a single organometallic species to furnish complex molecular scaffolds through the merging of otherwise difficult transformations: allylic C–H and selective C–C bond activations. The resulting bifunctional nucleophilic species, all of which have an all-carbon quaternary stereogenic centre, can then be selectively derivatized by the addition of two different electrophiles to obtain more complex molecular architecture from these easily available starting materials.
doi: 10.1038/nature12761
海洋：高速で拡大する下部海洋地殻由来の初生層状ハンレイ岩
Primitive layered gabbros from fast-spreading lower oceanic crust p.204
Three-quarters of the oceanic crust formed at fast-spreading ridges is composed of plutonic rocks whose mineral assemblages, textures and compositions record the history of melt transport and crystallization between the mantle and the sea floor. Despite the importance of these rocks, sampling them in situ is extremely challenging owing to the overlying dykes and lavas. This means that models for understanding the formation of the lower crust are based largely on geophysical studies and ancient analogues (ophiolites) that did not form at typical mid-ocean ridges. Here we describe cored intervals of primitive, modally layered gabbroic rocks from the lower plutonic crust formed at a fast-spreading ridge, sampled by the Integrated Ocean Drilling Program at the Hess Deep rift. Centimetre-scale, modally layered rocks, some of which have a strong layering-parallel foliation, confirm a long-held belief that such rocks are a key constituent of the lower oceanic crust formed at fast-spreading ridges. Geochemical analysis of these primitive lower plutonic rocks—in combination with previous geochemical data for shallow-level plutonic rocks, sheeted dykes and lavas—provides the most completely constrained estimate of the bulk composition of fast-spreading oceanic crust so far. Simple crystallization models using this bulk crustal composition as the parental melt accurately predict the bulk composition of both the lavas and the plutonic rocks. However, the recovered plutonic rocks show early crystallization of orthopyroxene, which is not predicted by current models of melt extraction from the mantle and mid-ocean-ridge basalt differentiation. The simplest explanation of this observation is that compositionally diverse melts are extracted from the mantle and partly crystallize before mixing to produce the more homogeneous magmas that erupt.
doi: 10.1038/nature12778
遺伝学：発生中の遺伝子発現動態への遺伝的変動の影響
The effects of genetic variation on gene expression dynamics during development p.208
The development of a multicellular organism and physiological responses require massive coordinated changes in gene expression across several cell and tissue types. Polymorphic regions of the genome that influence gene expression levels have been identified by expression quantitative trait locus (eQTL) mapping in many species, including loci that have cell-dependent, tissue-dependent and age-dependent effects. However, there has been no comprehensive characterization of how polymorphisms influence the complex dynamic patterns of gene expression that occur during development and in physiology. Here we describe an efficient experimental design to infer gene expression dynamics from single expression profiles in different genotypes, and apply it to characterize the effect of local (cis) and distant (trans) genetic variation on gene expression at high temporal resolution throughout a 12-hour period of the development of Caenorhabditis elegans. Taking dynamic variation into account identifies >50% more cis-eQTLs, including more than 900 that alter the dynamics of expression during this period. Local sequence polymorphisms extensively affect the timing, rate, magnitude and shape of expression changes. Indeed, many local sequence variants both increase and decrease gene expression, depending on the time-point profiled. Expression dynamics during this 12-hour period are also influenced extensively in trans by distal loci. In particular, several trans loci influence genes with quite diverse dynamic expression patterns, but they do so primarily during a common time interval. Trans loci can therefore act as modifiers of expression during a particular period of development. This study provides the first characterization, to our knowledge, of the effect of local and distant genetic variation on the dynamics of gene expression throughout an extensive time period. Moreover, the approach developed here should facilitate the genetic dissection of other dynamic processes, including potentially development, physiology and disease progression in humans.
doi: 10.1038/nature12772
がん：HMGA2は競合内因性RNAとして機能し、肺がんのプログレッションを促進する
HMGA2 functions as a competing endogenous RNA to promote lung cancer progression p.212
Non-small-cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide. As the majority of patients present with invasive, metastatic disease, it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma, in which it contributes to cancer progression and metastasis. Here we show that Hmga2 promotes lung cancer progression in mouse and human cells by operating as a competing endogenous RNA (ceRNA) for the let-7 microRNA (miRNA) family. Hmga2 can promote the transformation of lung cancer cells independent of protein-coding function but dependent upon the presence of let-7 sites; this occurs without changes in the levels of let-7 isoforms, suggesting that Hmga2 affects let-7 activity by altering miRNA targeting. These effects are also observed in vivo, where Hmga2 ceRNA activity drives lung cancer growth, invasion and dissemination. Integrated analysis of miRNA target prediction algorithms and metastatic lung cancer gene expression data reveals the TGF-β co-receptor Tgfbr3 (ref. 12) as a putative target of Hmga2 ceRNA function. Tgfbr3 expression is regulated by the Hmga2 ceRNA through differential recruitment to Argonaute 2 (Ago2), and TGF-β signalling driven by Tgfbr3 is important for Hmga2 to promote lung cancer progression. Finally, analysis of NSCLC-patient gene-expression data reveals that HMGA2 and TGFBR3 are coordinately regulated in NSCLC-patient material, a vital corollary to ceRNA function. Taken together, these results suggest that Hmga2 promotes lung carcinogenesis both as a protein-coding gene and as a non-coding RNA; such dual-function regulation of gene-expression networks reflects a novel means by which oncogenes promote disease progression.
doi: 10.1038/nature12785
免疫：マイコバクテリアは膜脂質を協調的に使うことでマクロファージ動員を操作する
Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids p.218
The evolutionary survival of Mycobacterium tuberculosis, the cause of human tuberculosis, depends on its ability to invade the host, replicate, and transmit infection. At its initial peripheral infection site in the distal lung airways, M. tuberculosis infects macrophages, which transport it to deeper tissues. How mycobacteria survive in these broadly microbicidal cells is an important question. Here we show in mice and zebrafish that M. tuberculosis, and its close pathogenic relative Mycobacterium marinum, preferentially recruit and infect permissive macrophages while evading microbicidal ones. This immune evasion is accomplished by using cell-surface-associated phthiocerol dimycoceroserate (PDIM) lipids to mask underlying pathogen-associated molecular patterns (PAMPs). In the absence of PDIM, these PAMPs signal a Toll-like receptor (TLR)-dependent recruitment of macrophages that produce microbicidal reactive nitrogen species. Concordantly, the related phenolic glycolipids (PGLs) promote the recruitment of permissive macrophages through a host chemokine receptor 2 (CCR2)-mediated pathway. Thus, we have identified coordinated roles for PDIM, known to be essential for mycobacterial virulence, and PGL, which (along with CCR2) is known to be associated with human tuberculosis. Our findings also suggest an explanation for the longstanding observation that M. tuberculosis initiates infection in the relatively sterile environment of the lower respiratory tract, rather than in the upper respiratory tract, where resident microflora and inhaled environmental microbes may continually recruit microbicidal macrophages through TLR-dependent signalling.
doi: 10.1038/nature12799
神経科学：脳損傷後の炎症と細胞死の経頭蓋的改善
Transcranial amelioration of inflammation and cell death after brain injury p.223
Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function. At present, no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain insights into TBI pathogenesis, we developed a novel murine closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic-receptor-dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We also show that the skull bone is permeable to small-molecular-weight compounds, and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results shed light on the acute cellular response to TBI and provide a means to locally deliver therapeutic compounds to the site of injury.
doi: 10.1038/nature12808
構造生物学：HIV-1 VifによるCBF-βおよびCUL5 E3リガーゼ複合体乗っ取りの構造的基盤
Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif p.229
The human immunodeficiency virus (HIV)-1 protein Vif has a central role in the neutralization of host innate defences by hijacking cellular proteasomal degradation pathways to subvert the antiviral activity of host restriction factors; however, the underlying mechanism by which Vif achieves this remains unclear. Here we report a crystal structure of the Vif–CBF-β–CUL5–ELOB–ELOC complex. The structure reveals that Vif, by means of two domains, organizes formation of the pentameric complex by interacting with CBF-β, CUL5 and ELOC. The larger domain (α/β domain) of Vif binds to the same side of CBF-β as RUNX1, indicating that Vif and RUNX1 are exclusive for CBF-β binding. Interactions of the smaller domain (α-domain) of Vif with ELOC and CUL5 are cooperative and mimic those of SOCS2 with the latter two proteins. A unique zinc-finger motif of Vif, which is located between the two Vif domains, makes no contacts with the other proteins but stabilizes the conformation of the α-domain, which may be important for Vif–CUL5 interaction. Together, our data reveal the structural basis for Vif hijacking of the CBF-β and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs.
doi: 10.1038/nature12884
構造生物学：細胞タンパク質分解経路のレンチウイルスによる破壊の構造的基盤
Structural basis of lentiviral subversion of a cellular protein degradation pathway p.234
Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells as well as resting CD4+ T cells by reducing the cellular deoxynucleoside 5′-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation. The molecular mechanism by which these viral proteins are able to usurp the host cell’s ubiquitination machinery to destroy the cell’s protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell’s normal protein degradation pathway to inactivate the cellular viral defence system.
doi: 10.1038/nature12815
生物工学：大型褐藻類の糖類からの人工酵母系による効率的なエタノール生産
Efficient ethanol production from brown macroalgae sugars by a synthetic yeast platform p.239
The increasing demands placed on natural resources for fuel and food production require that we explore the use of efficient, sustainable feedstocks such as brown macroalgae. The full potential of brown macroalgae as feedstocks for commercial-scale fuel ethanol production, however, requires extensive re-engineering of the alginate and mannitol catabolic pathways in the standard industrial microbe Saccharomyces cerevisiae. Here we present the discovery of an alginate monomer (4-deoxy-l-erythro-5-hexoseulose uronate, or DEHU) transporter from the alginolytic eukaryote Asteromyces cruciatus. The genomic integration and overexpression of the gene encoding this transporter, together with the necessary bacterial alginate and deregulated native mannitol catabolism genes, conferred the ability of an S. cerevisiae strain to efficiently metabolize DEHU and mannitol. When this platform was further adapted to grow on mannitol and DEHU under anaerobic conditions, it was capable of ethanol fermentation from mannitol and DEHU, achieving titres of 4.6% (v/v) (36.2 g l−1) and yields up to 83% of the maximum theoretical yield from consumed sugars. These results show that all major sugars in brown macroalgae can be used as feedstocks for biofuels and value-added renewable chemicals in a manner that is comparable to traditional arable-land-based feedstocks.
doi: 10.1038/nature12771
構造生物学：X線自由電子レーザーのデータによるタンパク質結晶のde novo構造決定
De novo protein crystal structure determination from X-ray free-electron laser data p.244
The determination of protein crystal structures is hampered by the need for macroscopic crystals. X-ray free-electron lasers (FELs) provide extremely intense pulses of femtosecond duration, which allow data collection from nanometre- to micrometre-sized crystals in a ‘diffraction-before-destruction’ approach. So far, all protein structure determinations carried out using FELs have been based on previous knowledge of related, known structures. Here we show that X-ray FEL data can be used for de novo protein structure determination, that is, without previous knowledge about the structure. Using the emerging technique of serial femtosecond crystallography, we performed single-wavelength anomalous scattering measurements on microcrystals of the well-established model system lysozyme, in complex with a lanthanide compound. Using Monte-Carlo integration, we obtained high-quality diffraction intensities from which experimental phases could be determined, resulting in an experimental electron density map good enough for automated building of the protein structure. This demonstrates the feasibility of determining novel protein structures using FELs. We anticipate that serial femtosecond crystallography will become an important tool for the structure determination of proteins that are difficult to crystallize, such as membrane proteins.
doi: 10.1038/nature12773
