Saturday, 28 November 2009

First-ever Blueprint of A Minimal Cell Is More Complex Than Expected

EMBL and CRG scientists reveal what a self-sufficient cell cannot do without Saturday, 28 November 2009 What are the bare essentials of life, the indispensable ingredients required to produce a cell that can survive on its own? Can we describe the molecular anatomy of a cell, and understand how an entire organism functions as a system? These are just some of the questions that scientists in a partnership between the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the Centre de Regulacio Genòmica (CRG) in Barcelona, Spain, set out to address. In three papers published back-to-back today in Science, they provide the first comprehensive picture of a minimal cell, based on an extensive quantitative study of the biology of the bacterium that causes atypical pneumonia, Mycoplasma pneumoniae. The study uncovers fascinating novelties relevant to bacterial biology and shows that even the simplest of cells is more complex than expected. Mycoplasma pneumoniae is a small, single-cell bacterium that causes atypical pneumonia in humans. It is also one of the smallest prokaryotes – organisms whose cells have no nucleus – that do not depend on a host's cellular machinery to reproduce. This is why the six research groups, which set out to characterize a minimal cell in a project headed by scientists Peer Bork, Anne-Claude Gavin and Luis Serrano, chose M. pneumoniae as a model: it is complex enough to survive on its own, but small and, theoretically, simple enough to represent a minimal cell – and to enable a global analysis. A network of research groups at EMBL's Structural and Computational Biology Unit and CRG's EMBL-CRG Systems Biology Partnership Unit approached the bacterium at three different levels. One team of scientists described M. pneumoniae's transcriptome, identifying all the RNA molecules, or transcripts, produced from its DNA, under various environmental conditions. Another defined all the metabolic reactions that occurred in it, collectively known as its metabolome, under the same conditions. A third team identified every multi-protein complex the bacterium produced, thus characterising its proteome organisation. "At all three levels, we found M. pneumoniae was more complex than we expected", says Luis Serrano, co-initiator of the project at EMBL and now head of the Systems Biology Department at CRG. When studying both its proteome and its metabolome, the scientists found many molecules were multifunctional, with metabolic enzymes catalyzing multiple reactions, and other proteins each taking part in more than one protein complex. They also found that M. pneumoniae couples biological processes in space and time, with the pieces of cellular machinery involved in two consecutive steps in a biological process often being assembled together.

Mycoplasma pneumoniae blueprint.This image represents the integration of genomic, metabolic, proteomic, structural and cellular information about Mycoplasma pneumoniae in this project: one layer of an Electron Tomography scan of a bottle-shaped M. pneumoniae cell (grey) is overlaid with a schematic representation of this bacterium's metabolism, comprising 189 enzymatic reactions, where blue indicates interactions between proteins encoded in genes from the same functional unit. Apart from these expected interactions, the scientists found that, surprisingly, many proteins are multifunctional. For instance, there were various unexpected physical interactions (yellow lines) between proteins and the subunits that form the ribosome, which is depicted as an Electron microscopy image (yellow). Credit: Takuji Yamada /EMBL.
Remarkably, the regulation of this bacterium's transcriptome is much more similar to that of eukaryotes – organisms whose cells have a nucleus – than previously thought. As in eukaryotes, a large proportion of the transcripts produced from M. pneumoniae's DNA are not translated into proteins. And although its genes are arranged in groups as is typical of bacteria, M. pneumoniae doesn't always transcribe all the genes in a group together, but can selectively express or repress individual genes within each group. Unlike that of other, larger, bacteria, M. pneumoniae's metabolism does not appear to be geared towards multiplying as quickly as possible, perhaps because of its pathogenic lifestyle. Another surprise was the fact that, although it has a very small genome, this bacterium is incredibly flexible and readily adjusts its metabolism to drastic changes in environmental conditions. This adaptability and its underlying regulatory mechanisms mean M. pneumoniae has the potential to evolve quickly, and all the above are features it also shares with other, more evolved organisms. "The key lies in these shared features", explains Anne-Claude Gavin, an EMBL group leader who headed the study of the bacterium's proteome: "Those are the things that not even the simplest organism can do without and that have remained untouched by millions of years of evolution – the bare essentials of life". This study required a wide range of expertise, to understand M. pneumoniae's molecular organisation at such different scales and integrate all the resulting information into a comprehensive picture of how the whole organism functions as a system – an approach called systems biology. "Within EMBL's Structural and Computational Biology Unit we have a unique combination of methods, and we pooled them all together for this project", says Peer Bork, joint head of the unit, co-initiator of the project, and responsible for the computational analysis. "In partnership with the CRG group we thus could build a complete overall picture based on detailed studies at very different levels." Bork was recently awarded the Royal Society and Académie des Sciences Microsoft Award for the advancement of science using computational methods. Serrano was recently awarded a European Research Council Senior grant. References: Proteome Organization in a Genome-Reduced Bacterium. Sebastian Kühner, Vera van Noort, Matthew J. Betts, Alejandra Leo-Macias, Claire Batisse, Michaela Rode, Takuji Yamada, Tobias Maier, Samuel Bader, Pedro Beltran-Alvarez, Daniel Castaño-Diez, Wei-Hua Chen, Damien Devos, Marc Güell, Tomas Norambuena, Ines Racke, Vladimir Rybin, Alexander Schmidt, Eva Yus, Ruedi Aebersold, Richard Herrmann, Bettina Böttcher, Achilleas S. Frangakis, Robert B. Russell, Luis Serrano, Peer Bork, and Anne-Claude Gavin Science 27 November 2009: 1235-1240,
DOI: 10.1126/science.1176343 Transcriptome Complexity in a Genome-Reduced Bacterium. Marc Güell, Vera van Noort, Eva Yus, Wei-Hua Chen, Justine Leigh-Bell, Konstantinos Michalodimitrakis, Takuji Yamada, Manimozhiyan Arumugam, Tobias Doerks, Sebastian Kühner, Michaela Rode, Mikita Suyama, Sabine Schmidt, Anne-Claude Gavin, Peer Bork, and Luis Serrano Science 27 November 2009: 1268-1271, DOI: 10.1126/science.1176951 Impact of Genome Reduction on Bacterial Metabolism and Its Regulation. Eva Yus, Tobias Maier, Konstantinos Michalodimitrakis, Vera van Noort, Takuji Yamada, Wei-Hua Chen, Judith A. H. Wodke, Marc Güell, Sira Martínez, Ronan Bourgeois, Sebastian Kühner, Emanuele Raineri, Ivica Letunic, Olga V. Kalinina, Michaela Rode, Richard Herrmann, Ricardo Gutiérrez-Gallego, Robert B. Russell, Anne-Claude Gavin, Peer Bork, and Luis Serrano Science 27 November 2009: 1263-1268, DOI: 10.1126/science.1177263 ......... ZenMaster
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Stem Cells Heal Lungs of Newborn Animals

Study anticipated to benefit premature babies Saturday, 28 November 2009 Dr. Bernard Thébaud lives in two very different worlds. As a specialist in the Stollery Children's Hospital's Neonatal Intensive Care Unit at the Royal Alexandra Hospital, he cares for tiny babies, many of whom struggle for breath after being born weeks before they are due. Across town, in his laboratory in the Faculty of Medicine & Dentistry at the University of Alberta, Dr. Thébaud dons a lab coat and peers into a microscope to examine the precise effect of stem cells on the lungs. Today, with his scientific research being published in the American Journal of Respiratory and Critical Care Medicine, Dr. Thébaud has made a significant leap to bridge the gap between those two worlds. An international team of scientists led by Dr. Thébaud has demonstrated for the first time that stem cells protect and repair the lungs of newborn rats. "The really exciting thing that we discovered was that stem cells are like little factories, pumping out healing factors," says Dr. Thébaud, an Alberta Heritage Foundation for Medical Research Clinical Scholar. "That healing liquid seems to boost the power of the healthy lung cells and helps them to repair the lungs." In this study, Thébaud's team simulated the conditions of prematurity – giving the newborn rats oxygen. The scientists then took stem cells, derived from bone marrow, and injected them into the rats' airways. Two weeks later, the rats treated with stem cells were able to run twice as far, and had better survival rates. When Thébaud's team looked at the lungs, they found the stem cells had repaired the lungs, and prevented further damage. "I want to congratulate Dr. Thébaud and his team. This research offers real hope for a new treatment for babies with chronic lung disease," says Dr. Roberta Ballard, professor of paediatrics, University of California, San Francisco. "In a few short years, I anticipate we will be able to take these findings and begin clinical trials with premature babies." "The dilemma we face with these tiny babies is a serious one. When they are born too early, they simply cannot breathe on their own. To save the babies' lives, we put them on a ventilator and give them oxygen, leaving many of them with chronic lung disease," says Dr. Thébaud. "Before the next decade is out I want to put a stop to this devastating disease." The research team includes physicians and scientists from Edmonton, Alberta, Tours, France, Chicago, Illinois, and Montreal, Quebec. The team is now investigating the long-term safety of using stem cells as a lung therapy. The scientists are examining rats at 3 months, and 6 months after treatment, studying the lungs, and checking their organs to rule out any risk of cancer. Dr. Thébaud's team is also exploring whether human cord blood is a better option than bone marrow stem cells in treating lung disease. "We are also studying closely the healing liquid produced by the stem cells," says Dr. Thébaud. "If that liquid can be used on its own to grow and repair the lungs, that might make the injection of stem cells unnecessary." Reference: Airway Delivery of Mesenchymal Stem Cells Prevents Arrested Alveolar Growth in Neonatal Lung Injury in Rats Timothy van Haaften, Roisin Byrne, Sebastien Bonnet, Gael Y. Rochefort, John Akabutu, Manaf Bouchentouf, Gloria J. Rey-Parra, Jacques Galipeau, Alois Haromy, Farah Eaton, Ming Chen, Kyoko Hashimoto, Doris Abley, Greg Korbutt, Stephen L. Archer, and Bernard Thébaud Am. J. Respir. Crit. Care Med. 2009; 180: 1131-1142. ......... ZenMaster

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Wednesday, 25 November 2009

Research Teams Map Genetic, Genomic Patterns in Han Chinese Population

First 'genetic map' of Han Chinese may aid search for disease susceptibility genes Wednesday, 25 November 2009 A pair of papers in the American Journal of Human Genetics today is highlighting the genetic and genomic variation present within the Han Chinese population. It is the largest ethnic population in the world. In the first of these papers, a Genome Institute of Singapore-led team developed a genetic map of the Han Chinese population by genotyping thousands of individuals from across China. This first historical genetic variation map is providing insights into Han Chinese population structure and evolutionary history — for instance, revealing North-South population structure in China. And down the road, researchers say, the results should pave the way for genome-wide association and other studies in the population. Based on genome-wide DNA variation information in over 6,000 Han Chinese samples from 10 provinces in China, this new map provides information about the population structure and evolutionary history of this group of people that can help scientists to identify subtle differences in the genetic diversity of Asian populations. Understanding these differences may aid in the design and interpretation of studies to identify genes that confer susceptibility to such common diseases as diabetes in ethnic Chinese individuals. Understanding these differences also is crucial in exploring how genes and environment interact to cause diseases. With the genetic map, the GIS scientists were able to show that the northern inhabitants of China were genetically distinguishable from those in the south, a finding that seems very consistent with the Han Chinese's historical migration pattern. The genetic map also revealed that the genetic divergence was closely correlated with the geographic map of China. This finding suggests the persistence of local co-ancestry in the country. "The genome-wide genetic variation study is a powerful tool which may be used to infer a person's ancestral origin and to study population relationships," said Liu Jianjun, Ph.D., GIS Human Genetics Group Leader. "For example, an ethnic Chinese born and bred in Singapore can still be traced back to his or her ancestral roots in China," Dr. Liu said. "By investigating the genome-wide DNA variation, we can determine whether an anonymous person is a Chinese, what the ancestral origin of this person in China may be, and sometimes which dialect group of the Han Chinese this person may belong to.” "More importantly, our study provides information for a better design of genetic studies in the search for genes that confer susceptibility to various diseases," he added. Of particular interest to people in Singapore are the findings that while the majority of Singaporean Chinese hail from Southern China as expected, some have a more northern ancestral origin. GIS Executive Director Edison Liu, M.D., said: "Genome association studies have provided significant insights into the genes involved in common disorders such as diabetes, high cholesterol, allergies, and neurological disorders, but most of this work has been done on Caucasian populations.” "More recently, Dr. Liu Jianjun from our institute has been working with his Chinese colleagues to define the genetic causes of some of these diseases in Asian populations," the GIS Executive Director added. "This work refined those tools so that the results will not be obscured by subtle differences in the genetic diversity of Asian populations. In the process, Dr. Liu has reconstructed a genetic historical map of the Chinese people as they migrated from south to north over evolutionary time." "There are definite differences in genetic architecture between populations," noted Chia Kee Seng, M.D., Head, Department of Epidemiology & Public Health, National University of Singapore (NUS), and Director, NUS-GIS Centre for Molecular Epidemiology. "We have seen this in the Singapore Genome Variation Project, a Joint NUH-GIS effort. Understanding these differences is crucial in exploring how genes and environment interact to cause diseases," he added. The research results published in American Journal of Human Genetics is part of a larger ongoing project on the genome-wide association study of diseases among the Chinese population. The project is a collaboration between GIS and several institutions and universities in China. In Jan. 2009, Nature Genetics published the findings of researchers at the GIS and Anhui Medical University, China, on psoriasis, a common chronic skin disease. In that study, led by Dr. Liu Jianjun at the GIS and Dr. Zhang Xuejun at the Anhui Medical University, the scientists discovered a genetic variant that provides protection against the development of psoriasis. The collaboration's recent discovery of over a dozen genetic risk variants for systematic lupus erythematosus (SLE) in the Chinese population was published in Nature Genetics in Oct. 2009. In a second AJHG paper, a Chinese research team genotyped more than 1,700 Han Chinese individuals from dozens of sites in China as part of another study aimed at understanding the genetic and genomic patterns within the Han Chinese population. The researchers genotyped 1,721 Han Chinese samples at about 160,000 SNPs for this paper. They collected more than 1,500 of the samples, while 44 were collected through the Human Genome Diversity Panel project and 171 were collected in Beijing and Denver as part of the HapMap project. That team detected north-south stratification similar to that reported by the Singapore-led team, though they designated three main Han Chinese clusters from northern, southern, and central parts of China. Again, individuals from the cities — in this case Beijing, Shanghai, and Guangzhou — did not represent populations that were as homogenous as those in other locations were. The researchers also found some SNPs that were strongly differentiated in different parts of the country. For instance, they reported, the frequency of SNPs in the genes FADS2 and HCP5 varied from north to south. Based on several simulated GWAS, each involving 300 cases and 300 controls, the team suggested that even the relatively subtle genetic variation within China could lead to excess false-positive associations. "Although differences in allele frequencies among Han Chinese clusters are small, our study has demonstrated the importance of accounting for population stratification in order to reduce false-positive associations," the researchers wrote. Reference: Genetic Structure of the Han Chinese Population Revealed by Genome-wide SNP Variation Jieming Chen, Houfeng Zheng, Jin-Xin Bei, Liangdan Sun, Wei-hua Jia, Tao Li, Furen Zhang, Mark Seielstad, Yi-Xin Zeng, Xuejun Zhang, Jianjun Liu The American Journal of Human Genetics, 25 November 2009, doi:10.1016/j.ajhg.2009.10.016 Genomic Dissection of Population Substructure of Han Chinese and Its Implication in Association Studies Shuhua Xu, Xianyong Yin, Shilin Li, Wenfei Jin, Haiyi Lou, Ling Yang, Xiaohong Gong, Hongyan Wang, Yiping Shen, Xuedong Pan, Yungang He, Yajun Yang, Yi Wang, Wenqing Fu, Yu An, Jiucun Wang, Jingze Tan, Ji Qian, Xiaoli Chen, Xin Zhang, Yangfei Sun, Xuejun Zhang, Bailin Wu and Li Jin The American Journal of Human Genetics, 25 November 2009, doi:10.1016/j.ajhg.2009.10.015 ......... ZenMaster

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