封面故事：关于衰老过程的线粒体理论的实验验证
关于衰老过程的线粒体理论认为，线粒体DNA所发生的突变的积累，导致渐进性生 物能量缺乏、细胞损伤、退化并最终死亡。为验证这一理论，研究人员通过基因工 程方法使小鼠的线粒体DNA（mtDNA）聚合酶具有较差的校对活性，从而具有更大的 突变速度。这种mtDNA突变小鼠（如本期封面图片前景中所示）出现早衰迹象，在1 岁左右死亡，而正常小鼠是在2-3岁左右死亡。这表明，在mtDNA突变与衰老表现型 之间有一个因果关系，以这种小鼠为模型，将有可能设计出抵抗或延缓mtDNA突变 效应的方法来。这也许并不等于发现了一种长生不老药，但它却能告诉我们许多关 于一些衰老过程的东西。
Nature 429, 417 - 423 (27 May 2004); doi:10.1038/nature02517
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans, monkeys and rodents. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle and brain. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with ageing. We have now addressed this question experimentally by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show that the knock-in mice develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals.
人类基因组测序项目完成近半
随着第9号和第10号人类染色体准确测序和分析结果的发表，人类基因组测序项目 已完成近半。迄今已发表的人类染色体有第6、7、9、10、13、14、19、20、21、 22号染色体和Y染色体，剩下12个已编号的染色体和X染色体有待完成。 “人类基 因组项目”所收集的序列数据是按照“百慕大标准”获取的，将目标准确性定为 99.99%，即每10000个DNA碱基中不到1个错误。在一篇分析文章中，来自“斯坦福 人类基因组中心”的一个研究小组对人类基因组序列数据做了一个质量评估，他们 得出结论认为，在整个基因组中，“百慕大标准”被超过了10倍，使得每10000个 DNA碱基中不到1个错误。
Nature 429, 365 - 368 (27 May 2004); doi:10.1038/nature02390
Quality assessment of the human genome sequence
As the final sequencing of the human genome has now been completed, we present the results of the largest examination of the quality of the finished DNA sequence. The completed study covers the major contributing sequencing centres and is based on a rigorous combination of laboratory experiments and computational analysis.
黑猩猩第22号染色体完成测序
本期Nature发表了黑猩猩第22号染色体的完整序列，并将该序列与人类相应的染色 体、即第21号染色体做了比较。比较显示了伴随物种形成所发生的基因组变化及其 生物学后果，这一过程似乎比人们所预料的更为复杂。黑猩猩第22号染色体与人类 相应染色体序列相比，约1.5%发生单碱基取代，另外还有近68000个插入或删除。 这一结果足以在多数蛋白质中促成变化。
Nature 429, 382 - 388 (27 May 2004); doi:10.1038/nature02564
DNA sequence and comparative analysis of chimpanzee chromosome 22
The International Chimpanzee Chromosome 22 Consortium
Human–chimpanzee comparative genome research is essential for narrowing down genetic changes involved in the acquisition of unique human features, such as highly developed cognitive functions, bipedalism or the use of complex language. Here, we report the high-quality DNA sequence of 33.3 megabases of chimpanzee chromosome 22. By comparing the whole sequence with the human counterpart, chromosome 21, we found that 1.44% of the chromosome consists of single-base substitutions in addition to nearly 68,000 insertions or deletions. These differences are sufficient to generate changes in most of the proteins. Indeed, 83% of the 231 coding sequences, including functionally important genes, show differences at the amino acid sequence level. Furthermore, we demonstrate different expansion of particular subfamilies of retrotransposons between the lineages, suggesting different impacts of retrotranspositions on human and chimpanzee evolution. The genomic changes after speciation and their biological consequences seem more complex than originally hypothesized.
一种可用作磁记录铁电存储装置的稀土锰酸盐
多铁材料既有铁电性，又有铁磁性。最近的研究以在如数据存储系统和传感器等装 置中利用这种材料可能产生的强大磁电效应的可能性为重点。用稀土锰酸盐 TbMn2O5（最近发现该物质是一种多铁材料）所做的实验显示，该材料中在铁电性 与磁性之间有一定的相互作用，所以它可作为一种候选材料用在磁记录铁电存储装 置中。施加一个磁场，既可诱导一个高度可重复的电极化切换（导致一种巨大的磁 容效应），又可诱导产生一个永久的极化印记。
Nature 429, 392 - 395 (27 May 2004); doi:10.1038/nature02572
Electric polarization reversal and memory in a multiferroic material induced by magnetic fields
Ferroelectric and magnetic materials are a time-honoured subject of study and have led to some of the most important technological advances to date. Magnetism and ferroelectricity are involved with local spins and off-centre structural distortions, respectively. These two seemingly unrelated phenomena can coexist in certain unusual materials, termed multiferroics. Despite the possible coexistence of ferroelectricity and magnetism, a pronounced interplay between these properties has rarely been observed. This has prevented the realization of multiferroic devices offering such functionality. Here, we report a striking interplay between ferroelectricity and magnetism in the multiferroic TbMn2O5, demonstrated by a highly reproducible electric polarization reversal and permanent polarization imprint that are both actuated by an applied magnetic field. Our results point to new device applications such as magnetically recorded ferroelectric memory.
“太古代”大气中甲烷含量未必很高
在自“太古代”以来被保留下来的一些土壤（称为古土壤）中明显缺乏菱铁矿 （FeCO3）这种矿物质，这一事实导致人们猜测，当时（距今约22亿年前）甲烷一 定是最重要的温室气体。该猜测是基于这样一个假设：低含量的菱铁矿表明大气中 人们所熟悉的温室气体二氧化碳浓度相对较低，但大气中一定有高浓度的温室气体 来补偿当时较低的太阳通量。然而，“太古代”大气中富含甲烷的观点受到一些新 发现及地质证据的挑战。这些新发现表明，缺乏菱铁矿未必会限制早期地球大气中 二氧化碳浓度；地质证据表明，在整个地质历史中，巨大的菱铁矿矿床会在一定环 境条件下形成。
Nature 429, 395 - 399 (27 May 2004); doi:10.1038/nature02573
Evidence from massive siderite beds for a CO2-rich atmosphere before ~ 1.8 billion years ago
It is generally thought that, in order to compensate for lower solar flux and maintain liquid oceans on the early Earth, methane must have been an important greenhouse gas before 2.2 billion years (Gyr) ago. This is based upon a simple thermodynamic calculation that relates the absence of siderite (FeCO3) in some pre-2.2-Gyr palaeosols to atmospheric CO2 concentrations that would have been too low to have provided the necessary greenhouse effect. Using multi-dimensional thermodynamic analyses and geological evidence, we show here that the absence of siderite in palaeosols does not constrain atmospheric CO2 concentrations. Siderite is absent in many palaeosols (both pre- and post-2.2-Gyr in age) because the O2 concentrations and pH conditions in well-aerated soils have favoured the formation of ferric (Fe3+)-rich minerals, such as goethite, rather than siderite. Siderite, however, has formed throughout geological history in subsurface environments, such as euxinic seas, where anaerobic organisms created H2-rich conditions. The abundance of large, massive siderite-rich beds in pre-1.8-Gyr sedimentary sequences and their carbon isotope ratios indicate that the atmospheric CO2 concentration was more than 100 times greater than today, causing the rain and ocean waters to be more acidic than today. We therefore conclude that CO2 alone (without a significant contribution from methane) could have provided the necessary greenhouse effect to maintain liquid oceans on the early Earth.
甲壳类浮游动物为什么不能有效抑制硅藻？
海洋生态学家经常问，为什么预示海洋之春的繁茂的一层层硅藻（覆盖着硅石的单 细胞藻类）不能被甲壳类浮游动物更有效地吃掉。如果它们“有眼力”的话，将会 有足够多的东西吃，鱼类也将会有更多的食物。相反，未被吃掉的硅藻消耗了宝贵 的养分，然后沉到了海底。硅藻向海床的沉降，如同春雨一样将养分带给底栖生 物。该过程也是调节大气中二氧化碳的一个主要机制。浮游动物为什么不能成功抑 制硅藻的原因不清楚。但是现在，用桡脚类动物Calanus helgolandicus所做的饲 养实验表明，在硅藻与其捕食者之间在进行一场化学战：当被咬碎时，一些早期繁 茂的硅藻会释放毒素，杀死以硅藻为食的桡脚类的后代；这样虽然不能阻止桡脚类 继续吃硅藻，但却能影响其“兵员补充”，限制来年较早复苏的过冬者的数量。
Nature 429, 403 - 407 (27 May 2004); doi:10.1038/nature02526
The growth cycle in nutrient-rich, aquatic environments starts with a diatom bloom that ends in mass sinking of ungrazed cells and phytodetritus. The low grazing pressure on these blooms has been attributed to the inability of overwintering copepod populations to track them temporally. We tested an alternative explanation: that dominant diatom species impair the reproductive success of their grazers. We compared larval development of a common overwintering copepod fed on a ubiquitous, early-blooming diatom species with its development when fed on a typical post-bloom dinoflagellate. Development was arrested in all larvae in which both mothers and their larvae were fed the diatom diet. Mortality remained high even if larvae were switched to the dinoflagellate diet. Aldehydes, cleaved from a fatty acid precursor by enzymes activated within seconds after crushing of the cell, elicit the teratogenic effect. This insidious mechanism, which does not deter the herbivore from feeding but impairs its recruitment, will restrain the cohort size of the next generation of early-rising overwinterers. Such a transgenerational plant–herbivore interaction could explain the recurringly inefficient use of a predictable, potentially valuable food resource—the spring diatom bloom—by marine zooplankton.
捕食动物物种多样性的重要性
关于生物多样性与生态系统功能和生命延续之间联系的争论，在很大程度上忽略了 捕食者物种多样性的作用。鉴于在食物链上处于较高位置的动物灭绝危险更大的事 实，研究捕食者物种消失也是很重要的。现在，对一个沿海沼泽群落所做的一项研 究（跟踪节肢体动物捕食者、食草动物和植物的命运）表明，捕食动物物种多样性 是保持生态系统健康发展的重要因素。当捕食动物物种多样性高时，它们彼此之间 相互影响，强烈的捕食者效应得到分散。这一作用使得生态系统能够缓冲食草动物 和植物丰度的较大变化，从而保持食物链的稳定。
Nature 429, 407 - 410 (27 May 2004); doi:10.1038/nature02554
Predator diversity dampens trophic cascades
Food web complexity is thought to weaken the strength of terrestrial trophic cascades in which strong impacts of natural enemies on herbivores cascade to influence primary production indirectly. Predator diversity can enhance food web complexity because predators may feed on each other and on shared prey. In such cases, theory suggests that the impact of predation on herbivores relaxes and cascading effects on basal resources are dampened. Despite this view, no empirical studies have explicitly investigated the role of predator diversity in mediating primary productivity in a natural terrestrial system. Here we compare, in a coastal marsh community, impacts of arthropod predators on herbivores and plant productivity between a simple food web with a single predator species and a complex food web with a diverse predator assemblage. We show that enhancing predator diversity dampens enemy effects on herbivores and weakens trophic cascades. Consequently, changes in diversity at higher trophic levels can significantly alter ecosystem function in natural systems.
ALS病的基因疗法
家族性运动神经细胞疾病（更具体地说，是家族性肌萎缩侧索硬化，英文简称为 ALS）是罕见的，仅占运动神经细胞疾病病例的约5%，但仍是无法治愈的，通常在 发病后5年内导致瘫痪和死亡。现在，在一个小鼠ALS模型中，研究人员发现，涉及 肌内注射一种表达VEGF（脉管内皮生长因子）的Lentivirus病毒载体的基因疗法， 可延缓运动神经细胞退化，使存活时间延长约30%。这种类型的病毒载体可稳定一 年以上，说明重复注射也许是不必要的，从而使得VEGF基因疗法成为这种慢性病的 一种真正有希望的治疗方法。
Nature 429, 413 - 417 (27 May 2004); doi:10.1038/nature02544
VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model
Amyotrophic lateral sclerosis (ALS) causes adult-onset, progressive motor neuron degeneration in the brain and spinal cord, resulting in paralysis and death three to five years after onset in most patients. ALS is still incurable, in part because its complex aetiology remains insufficiently understood. Recent reports have indicated that reduced levels of vascular endothelial growth factor (VEGF), which is essential in angiogenesis and has also been implicated in neuroprotection, predispose mice and humans to ALS. However, the therapeutic potential of VEGF for the treatment of ALS has not previously been assessed. Here we report that a single injection of a VEGF-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene coding for the mutated G93A form of the superoxide dismutase-1 (SOD1G93A) (refs 7–10), even when treatment was only initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30 per cent without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field so far.
微型DNA计算机研制成功
由生物分子做成的计算机与电子计算机不一样，可以其本身所具有的分子形式分析 生物信息，所以将来有一天也许能够用来在患者身上诊断和治疗疾病。目前，这种 设想仍然属于科学幻想的范畴，但随着一种微型生物计算机（比一个人体细胞还要 小很多）的开发成功，我们离这一目标更靠近了一步。放在一个试管中的这一装置 可探测特定RNA分子的水平，并通过释放一种DNA分子、抑制某一特定基因的表达来 做出响应。这种计算机被编程来从与小细胞肺癌或前列腺癌相关的基因中识别和分 析mRNA。与此同时，它将以一种抗癌药物为模型获得的DNA分子释放出来。“智能 药物”应用成为现实可能还需要几十年时间，但对基因表达的这种类型的逻辑控制 也许远远用不了这么久就会在生物传感和基因工程中找到用武之地。
Nature \ 429, 423 - 429 (27 May 2004); doi:10.1038/nature02551
Nature AOP, published online 28 April 2004
An autonomous molecular computer for logical control of gene expression
Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems. Recently, simple molecular-scale autonomous programmable computers were demonstrated allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for 'logical' control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug.
