Nature的編輯們票選出2008年最佳的論文，其中與生技方面相關的論文節錄如下：
Artificial enzymesKemp elimination catalysts by computational enzyme design
運用電腦演算設計方法設計出來的人工酶可以製造出更高催化效率的酵素
D. Röthlisberger et al. Nature 453, 190–195 (8 May 2008)
This example of computational protein design is a major step towards the goal of designing artificial enzymes to catalyse reactions beyond the repertoire of natural biocatalysts. Potential enzymes comprising about 200 amino acids were synthesized and the best, at removing a proton from carbon, underwent 'directed evolution' to make them even better. The design strategy, which mobilizes the power of many thousands of home computers via the Rosetta@home project, is generally applicable.
Abstract:
The design of new enzymes for reactions not catalysed by naturally occurring biocatalysts is a challenge for protein engineering and is a critical test of our understanding of enzyme catalysis. Here we describe the computational design of eight enzymes that use two different catalytic motifs to catalyse the Kemp elimination—a model reaction for proton transfer from carbon—with measured rate enhancements of up to 105 and multiple turnovers. Mutational analysis confirms that catalysis depends on the computationally designed active sites, and a high-resolution crystal structure suggests that the designs have close to atomic accuracy. Application of in vitro evolution to enhance the computational designs produced a >200-fold increase in k cat/K m (k cat/K m of 2,600 M-1s-1 and k cat/k uncat of >106). These results demonstrate the power of combining computational protein design with directed evolution for creating new enzymes, and we anticipate the creation of a wide range of useful new catalysts in the future.
http://www.nature.com/nature/journal/v453/n7192/abs/nature06879.html
Micro-engineered local field control for high-sensitivity multispectral MRI
MRI造影中加入透過微製程技術作出不同光譜標誌的奈米粒子，可以在磁共振的射頻光譜中被區別出來，進而轉化為不同的顏色顯示，這種富含資訊的彩色MRI造影將成為未來的新潮流。
G Zabow , S Dodd , J Moreland & A Koretsky
Nature 453, 1058–1063 (19 June 2008)
MRI scans are one of the big success stories of medical diagnostics. This clever piece of microengineering could refine the technique by adding 'colour'. It uses tiny injectable metallic microstructures to respond to a range of radiofrequency signals that can be displayed as different colours. There's more work to be done — finding a less toxic metal than the nickel used initially for a start — but information-rich colour MRI scans are now a distinct possibility.
Abstract:
In recent years, biotechnology and biomedical research have benefited from the introduction of a variety of specialized nanoparticles whose well-defined, optically distinguishable signatures enable simultaneous tracking of numerous biological indicators. Unfortunately, equivalent multiplexing capabilities are largely absent in the field of magnetic resonance imaging (MRI). Comparable magnetic-resonance labels have generally been limited to relatively simple chemically synthesized superparamagnetic microparticles that are, to a large extent, indistinguishable from one another. Here we show how it is instead possible to use a top-down microfabrication approach to effectively encode distinguishable spectral signatures into the geometry of magnetic microstructures. Although based on different physical principles from those of optically probed nanoparticles, these geometrically defined magnetic microstructures permit a multiplexing functionality in the magnetic resonance radio-frequency spectrum that is in many ways analogous to that permitted by quantum dots in the optical spectrum. Additionally, in situ modification of particle geometries may facilitate radio-frequency probing of various local physiological variables.
http://www.nature.com/nature/journal/v453/n7198/abs/nature07048.html
Enter the 'adipomyocyte'
PRDM16 controls a brown fat/skeletal muscle switch
科學家驚訝的發現棕色脂肪細胞與骨骼肌細胞擁具有相同的來源，而白色脂肪細胞則是另一完全獨立的起源，而其中PRDM16蛋白質則是調控轉變為肌肉或棕色脂肪之間細胞命運的開關，對於治療肥胖深具潛力。
P Seale et al. Nature 454, 961–967 (21 August 2008)
This was a surprise. Brown fat cells, the ones that burn calories to generate body heat, were found to share a common origin with skeletal muscle cells. White fat cells, the energy stores, have a quite separate origin. The zinc-finger protein PRDM16 is a powerful regulator of the cell fate switch between muscle and brown fat, so may have therapeutic potential in obesity.
Abstract:
Brown fat can increase energy expenditure and protect against obesity through a specialized program of uncoupled respiration. Here we show by in vivo fate mapping that brown, but not white, fat cells arise from precursors that express Myf5, a gene previously thought to be expressed only in the myogenic lineage. We also demonstrate that the transcriptional regulator PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16) controls a bidirectional cell fate switch between skeletal myoblasts and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of PRDM16 in myoblasts induces their differentiation into brown fat cells. PRDM16 stimulates brown adipogenesis by binding to PPAR- (peroxisome-proliferator-activated receptor- ) and activating its transcriptional function. Finally, Prdm16-deficient brown fat displays an abnormal morphology, reduced thermogenic gene expression and elevated expression of muscle-specific genes. Taken together, these data indicate that PRDM16 specifies the brown fat lineage from a progenitor that expresses myoblast markers and is not involved in white adipogenesis.
http://www.nature.com/nature/journal/v454/n7207/abs/nature07182.html
Cell biology revisited
Frequency-modulated nuclear localization bursts coordinate gene regulation
系統生物學完全改變了我們所認知熟悉的細胞過程。傳統生物化學認為細胞對環境變化作出反應時，是以全有或全無的方式向細胞核發送調節蛋白來啟動標的基因。而這篇論文中顯示了在酵母細胞中從細胞質向細胞核的轉移是爆發式的，其爆發的頻率(而非強度)是隨細胞外的信號強弱而改變，進而維持其標的基因的表現。
L Cai , C K Dalal & M B Elowitz Nature 455, 485–490 (25 September 2008)
Here's an example of how systems biology can completely change the way we think about a familiar cellular process. Traditional biochemistry pictured cells as responding to environmental changes by sending regulatory proteins to the nucleus in an all-or-none fashion to activate target genes. This Article, combining cutting-edge single-cell imaging, cellular noise biophysics and computational modelling, reveals that translocation from cytoplasm to cell nucleus in the yeast cell occurs in bursts. The frequency — but not amplitude — of these bursts varies in response to extracellular signals, maintaining the relative rates of expression among target genes despite their varying absolute levels.
Abstract:
In yeast, the transcription factor Crz1 is dephosphorylated and translocates into the nucleus in response to extracellular calcium. Here we show, using time-lapse microscopy, that Crz1 exhibits short bursts of nuclear localization (typically lasting 2 min) that occur stochastically in individual cells and propagate to the expression of downstream genes. Strikingly, calcium concentration controls the frequency, but not the duration, of localization bursts. Using an analytic model, we also show that this frequency modulation of bursts ensures proportional expression of multiple target genes across a wide dynamic range of expression levels, independent of promoter characteristics. We experimentally confirm this theory with natural and synthetic Crz1 target promoters. Another stress-response transcription factor, Msn2, exhibits similar, but largely uncorrelated, localization bursts under calcium stress suggesting that frequency-modulation regulation of localization bursts may be a general control strategy used by the cell to coordinate multi-gene responses to external signals.
http://www.nature.com/nature/journal/v455/n7212/abs/nature07292.html
Turn on the insulin
In vivo reprogramming of adult pancreatic exocrine cells to -cells
不同的策略可逆轉已分化成熟的細胞，使其變成類似胚胎細胞具有再生能力，從而進行新的功能。科學家用包含3種轉錄因子的“雞尾酒”方法處理糖尿病小鼠，可將成熟胰腺外分泌細胞重新轉變為類似胰臟beta細胞而使其產生胰島素。
Q Zho , J Brown , A Kanarek, J Rajagopal & D A Melton Nature 455, 627–632 (2 October 2008)
Various strategies exist to 'dedifferentiate' mature cells to a state where they resemble an embryonic cell with the potential to regenerate to perform a new function. Here though, there is no 'in-between' stage: mature exocrine pancreatic cells in live diabetic mice were reprogrammed to produce insulin by exposure to a cocktail of three transcription factors.Abstract:One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble -cells. The induced -cells are indistinguishable from endogenous islet -cells in size, shape and ultrastructure. They express genes essential for -cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.
http://www.nature.com/nature/journal/v455/n7213/abs/nature07314.html
Crossing the membrane
Structure of a complex of the ATPase SecA and the protein-translocation channel
科學家結晶出細菌的ATPase SecA與蛋白跨膜通道的複合體並解出該結構，並進一步揭示了蛋白質穿越細胞膜的一些細節。
J Zimmer, Y Nam & T A Rapoport Nature 455, 936–943 (16 October 2008)
The determination of the crystal structure of a complex between a single bacterial protein conducting channel and the SecA motor that powers the protein across the cell membrane was an impressive technical feat. And — with two other papers in this issue tackling the mechanisms involved — it revealed some of the details about how proteins make their way through the cell membrane.
Abstract:
Most proteins are secreted from bacteria by the interaction of the cytoplasmic SecA ATPase with a membrane channel, formed by the heterotrimeric SecY complex. Here we report the crystal structure of SecA bound to the SecY complex, with a maximum resolution of 4.5 ångström (Å), obtained for components from Thermotoga maritima. One copy of SecA in an intermediate state of ATP hydrolysis is bound to one molecule of the SecY complex. Both partners undergo important conformational changes on interaction. The polypeptide-cross-linking domain of SecA makes a large conformational change that could capture the translocation substrate in a 'clamp'. Polypeptide movement through the SecY channel could be achieved by the motion of a 'two-helix finger' of SecA inside the cytoplasmic funnel of SecY, and by the coordinated tightening and widening of SecA's clamp above the SecY pore. SecA binding generates a 'window' at the lateral gate of the SecY channel and it displaces the plug domain, preparing the channel for signal sequence binding and channel opening.
http://www.nature.com/nature/journal/v455/n7215/abs/nature07335.html
基因定序現在只需花費幾個月和數千美元即可完成。這一組文章包括了幾篇標誌性的論文—在原本已發表的3組人類基因組定序外再加入對非洲優魯巴人和中國漢族人的基因組定序，另外也加入白血病患者的基因組測序與對進入個人化基因組圖譜的新世紀做探討。
Feats of DNA sequencing that once took many years and millions of dollars can now be achieved in just months and for several thousand dollars. The 6 November issue included these landmark papers — genome sequences of Yoruba African and Han Chinese individuals — to be added to the three personal genomes already published (those of Craig Venter, Jim Watson and the NIH reference sequence). Also in this issue is the genome sequence of a patient with leukaemia and a series of features on what the new era of personal genomics has in store for us.
Accurate whole human genome sequencing using reversible terminator chemistry
D R Bentley et al. Nature 456, 53–59 (6 November 2008)
Abstract:
DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400–800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30 average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.
http://www.nature.com/nature/journal/v456/n7218/abs/nature07517.html
The diploid genome sequence of an Asian individual
J Wang et al. Nature 456, 60–65 (6 November 2008)
Abstract:
Here we present the first diploid genome sequence of an Asian individual. The genome was sequenced to 36-fold average coverage using massively parallel sequencing technology. We aligned the short reads onto the NCBI human reference genome to 99.97% coverage, and guided by the reference genome, we used uniquely mapped reads to assemble a high-quality consensus sequence for 92% of the Asian individual's genome. We identified approximately 3 million single-nucleotide polymorphisms (SNPs) inside this region, of which 13.6% were not in the dbSNP database. Genotyping analysis showed that SNP identification had high accuracy and consistency, indicating the high sequence quality of this assembly. We also carried out heterozygote phasing and haplotype prediction against HapMap CHB and JPT haplotypes (Chinese and Japanese, respectively), sequence comparison with the two available individual genomes (J. D. Watson and J. C. Venter), and structural variation identification. These variations were considered for their potential biological impact. Our sequence data and analyses demonstrate the potential usefulness of next-generation sequencing technologies for personal genomics.
http://www.nature.com/nature/journal/v456/n7218/abs/nature07484.html