Academic and molecular matrices: a study of the transformations of connective tissue research at the University of Manchester (1947-1996)

This paper explores the different identities adopted by connective tissue research at the University of Manchester during the second half of the 20th century. By looking at the long-term redefinition of a research programme, it sheds new light on the interactions between different and conflicting levels in the study of biomedicine, such as the local and the global, or the medical and the biological. It also addresses the gap in the literature between the first biomedical complexes after World War II and the emergence of biotechnology. Connective tissue research in Manchester emerged as a field focused on new treatments for rheumatic diseases. During the 1950s and 60s, it absorbed a number of laboratory techniques from biology, namely cell culture and electron microscopy. The transformations in scientific policy during the late 70s and the migration of Manchester researchers to the US led them to adopt recombinant DNA methods, which were borrowed from human genetics. This resulted in the emergence of cell matrix biology, a new field which had one of its reference centres in Manchester. The Manchester story shows the potential of detailed and chronologically wide local studies of patterns of work to understand the mechanisms by which new biomedical tools and institutions interact with long-standing problems and existing affiliations.     

Special issue: Cytochrome P450 structure and function: introduction

The 17th International Conference on Cytochrome P450 Biochemistry, Biophysics and Structure was held in Manchester, UK from 26-30 June 2011. This issue of FEBS J. contains review and primary research articles reflecting the breadth of science covered at this conference, and reflecting the impact of P450-related research in fields as diverse as steroid metabolism, plant biochemistry, structural biology and biotechnology.     

Joining forces in the quest for orthologs

A report of the 24th International Conference on Yeast Genetics and Molecular Biology, Manchester, UK, 19-24 July 2009.     

Yeast systems biology: modelling the winemaker's art

Yeast research represents an important nexus between fundamental and applied research. Just as fundamental yeast research transitioned from classical, reductionist strategies to whole-genome techniques, whole-genome studies are advancing to the next level of biological research, referred to as systems biology. Industries that rely on high-performing yeast, such as the wine industry, are therefore poised to reap the many benefits that systems biology can provide. This includes the promise of strain development at speeds and costs which are unobtainable using current techniques. This article reviews the current state of whole-genome techniques available to yeast researchers and outlines how these processes can be used to obtain 'systems-level' information to provide insights into winemaking.     

Predicting complex phenotype–genotype interactions to enable yeast engineering: Saccharomyces cerevisiae as a model organism and a cell factory

There is an increasing use of systems biology approaches in both “red” and “white” biotechnology in order to enable medical, medicinal, and industrial applications. The intricate links between genotype and phenotype may be explained through the use of the tools developed in systems biology, synthetic biology, and evolutionary engineering. Biomedical and biotechnological research are among the fields that could benefit most from the elucidation of this complex relationship. Researchers have studied fitness extensively to explain the phenotypic impacts of genetic variations. This elaborate network of dependencies and relationships so revealed are further complicated by the influence of environmental effects that present major challenges to our achieving an understanding of the cellular mechanisms leading to healthy or diseased phenotypes or optimized production yields. An improved comprehension of complex genotype–phenotype interactions and their accurate prediction should enable us to more effectively engineer yeast as a cell factory and to use it as a living model of human or pathogen cells in intelligent screens for new drugs. This review presents different methods and approaches undertaken toward improving our understanding and prediction of the growth phenotype of the yeast Saccharomyces cerevisiae as both a model and a production organism.     

Construction of synthetic regulatory networks in yeast

Yeast species such as Saccharomyces cerevisiae have been exploited by humans for millennia and so it is therefore unsurprising that they are attractive cells to re-engineer for industrial use. Despite many beneficial traits yeast has for synthetic biology, it currently lags behind Escherichia coli in the number of synthetic networks that have been described. While the eukaryotic nature of yeast means that its regulation is not as simple to predict as it is for E. coli, once initial considerations have been made yeast is pleasingly tractable. In this review we provide a loose guide for constructing and implementing synthetic regulatory networks in S. cerevisiae using examples from previous research to highlight available resources, specific considerations and potential future advances.     

Advancing secondary metabolite biosynthesis in yeast with synthetic biology tools

Secondary metabolites are an important source of high-value chemicals, many of which exhibit important pharmacological properties. These valuable natural products are often difficult to synthesize chemically and are commonly isolated through inefficient extractions from natural biological sources. As such, they are increasingly targeted for production by biosynthesis from engineered microorganisms. The budding yeast species Saccharomyces cerevisiae has proven to be a powerful microorganism for heterologous expression of biosynthetic pathways. S. cerevisiae's usefulness as a host organism is owed in large part to the wealth of knowledge accumulated over more than a century of intense scientific study. Yet many challenges are currently faced in engineering yeast strains for the biosynthesis of complex secondary metabolite production. However, synthetic biology is advancing the development of new tools for constructing, controlling, and optimizing complex metabolic pathways in yeast. Here, we review how the coupling between yeast biology and synthetic biology is advancing the use of S. cerevisiae as a microbial host for the construction of secondary metabolic pathways.     

Highlights from the 2010 BAS/BSCR spring meeting: New Frontiers in Cardiovascular Research

The British Atherosclerosis Society (BAS)/British Society for Cardiovascular Research (BSCR) spring meeting was held in Manchester, UK, on 7–8 June 2010. Experts in the field of systems biology, proteomics, metabolomics and miRNAs presented how these techniques can be used to discover ‘New Frontiers in Cardiovascular Research’. The conference was attended by over 150 participants, mainly from the UK. A total of 2 days of presentations and a poster session with 55 posters provided the possibility to discuss the latest research results and showed the opportunities that new techniques can offer in cardiovascular research.     

Highlights from the 2010 BAS/BSCR spring meeting: New Frontiers in Cardiovascular Research

The British Atherosclerosis Society (BAS)/British Society for Cardiovascular Research (BSCR) spring meeting was held in Manchester, UK, on 7-8 June 2010. Experts in the field of systems biology, proteomics, metabolomics and miRNAs presented how these techniques can be used to discover 'New Frontiers in Cardiovascular Research'. The conference was attended by over 150 participants, mainly from the UK. A total of 2 days of presentations and a poster session with 55 posters provided the possibility to discuss the latest research results and showed the opportunities that new techniques can offer in cardiovascular research.     

A method for plasmid purification directly from yeast

A rapid technique for purifying plasmids from yeast Saccharomyces cerevisiae is described that yields high-quality DNA suitable for bacterial transformation, yeast transformation, and direct DNA sequencing. The method requires only small culture volumes and proprietary bacterial plasmid miniprep kits that allow one to simultaneously prepare a large number of samples in a very short period of time while avoiding the use of toxic organic chemicals. Both yeast single-copy CEN/ARS and high-copy 2micro shuttle plasmids can be isolated using this method. This technique is useful for plasmid purification from yeast two-hybrid experiments as well as yeast genetics and molecular biology experiments.     

Emerging technologies in yeast genomics

The genomic revolution is undeniable: in the past year alone, the term 'genomics' was found in nearly 500 research articles, and at least 6 journals are devoted solely to genomic biology. More than just a buzzword, molecular biology has genuinely embraced genomics (the systematic, large-scale study of genomes and their functions). With its facile genetics, the budding yeast Saccharomyces cerevisiae has emerged as an important model organism in the development of many current genomic methodologies. These techniques have greatly influenced the manner in which biology is studied in yeast and in other organisms. In this review, we summarize the most promising technologies in yeast genomics.     

The winemaker's bug: From ancient wisdom to opening new vistas with frontier yeast science

The past three decades have seen a global wine glut. So far, well-intended but wasteful and expensive market-intervention has failed to drag the wine industry out of a chronic annual oversupply of roughly 15%. Can yeast research succeed where these approaches have failed by providing a means of improving wine quality, thereby making wine more appealing to consumers? To molecular biologists Saccharomyces cerevisiae is as intriguing as it is tractable. A simple unicellular eukaryote, it is an ideal model organism, enabling scientists to shed new light on some of the biggest scientific challenges such as the biology of cancer and aging. It is amenable to almost any modification that modern biology can throw at a cell, making it an ideal host for genetic manipulation, whether by the application of traditional or modern genetic techniques. To the winemaker, this yeast is integral to crafting wonderful, complex wines from simple, sugar-rich grape juice. Thus any improvements that we can make to wine, yeast fermentation performance or the sensory properties it imparts to wine will benefit winemakers and consumers. With this in mind, the application of frontier technologies, particularly the burgeoning fields of systems and synthetic biology, have much to offer in their pursuit of "novel" yeast strains to produce high quality wine. This paper discusses the nexus between yeast research and winemaking. It also addresses how winemakers and scientists face up to the challenges of consumer perceptions and opinions regarding the intervention of science and technology; the greater this intervention, the stronger the criticism that wine is no longer "natural." How can wine researchers respond to the growing number of wine commentators and consumers who feel that scientific endeavors favor wine quantity over quality and "technical sophistication, fermentation reliability and product consistency" over "artisanal variation"? This paper seeks to present yeast research in a new light and a new context, and it raises important questions about the direction of yeast research, its contribution to science and the future of winemaking.     

Timeline: Neurospora: a model of model microbes

In the 1940s, studies with Neurospora pioneered the use of microorganisms in genetic analysis and provided the foundations for biochemical genetics and molecular biology. What has happened since this orange mould was used to show that genes control metabolic reactions? How did it come to be the fungal counterpart of Drosophila? We describe its continued use during the heyday of research with Escherichia coli and yeast, and its emergence as a biological model for higher fungi.     

Timing matters

Cells are entities in space and time. Systems biology strives to understand their composition, structural organization as well as dynamic behavior under different conditions. Here, measures for dynamic properties such as characteristic times, time hierarchy and time-dependent response are reviewed. Using a number of examples from yeast and micro-organism systems biology, the importance of considering the timing in experimental and theoretical research is discussed.     

非常规酵母的分子遗传学及合成生物学研究进展

先进的合成生物学技术与传统的分子遗传学技术的结合更有助于实现酵母底盘细胞的快速改造和优化。酵母合成生物学研究最早开始于常规酵母——酿酒酵母(Saccharomyces cerevisiae),近些年来又迅速扩展至一些非常规酵母,包括巴斯德毕赤酵母(Pichiapastoris)、解脂耶氏酵母(Yarrowialipolytica)、乳酸克鲁维酵母(Kluyveromyces lactis)和多形汉逊酵母(Hansenula polymorpha)等。借助合成生物学技术与工具,目前科学家们已经成功开发出了能够高效生产生物材料、生物燃料、生物基化学品、蛋白质制剂、食品添加剂和药物等工业产品的重组非常规酵母工程菌株。本文系统总结了合成生物学工具(主要是基因组编辑工具)、合成生物学组件(主要是启动子和终止子)和相关分子遗传学方法在上述非常规酵母系统(底盘细胞)中的最新研究进展和应用情况,并讨论了其他合成生物学技术在这些非常规酵母表达系统中的潜在适用性和应用前景。这为研究人员利用合成生物学方法在这一新型非模式微生物底盘细胞中设计和构建各种高附加值工业产品的异源合成模块并最终实现目标化合物的高效生物合成提供了科学的理论指导。     

大肠杆菌和酵母表达系统的研究进展

20世纪70年代以来,分子生物学及基因组学迅猛发展,其在生物及医学领域发挥着越来越重要的作用。在发酵工业中,分子生物学技术广泛应用于菌种的遗传改造和基因工程菌株的构建,以期提高发酵产物的产量并丰富发酵产物的类型。其中,利用原核及真核表达系统进行外源基因的扩增、表达以生产蛋白疫苗、核酸疫苗和酶制剂等是近十年来发酵工业的新兴领域。本文从表达载体和宿主菌改造两方面综述近些年来大肠杆菌及酵母表达系统的新进展与新技术。     

Expression of actin mutants to study their roles in cardiomyopathy

Mutations in the human cardiac actin gene (ACTC) have been implicated in the development of hypertrophic or dilated cardiomyopathy in humans. To determine the molecular mechanism for the disease development, a system for the expression of mutant cardiac actin proteins that may be lethal to eukaryotic cells must be developed. Here, we explore some of the advantages and disadvantages of human ACTC expression in yeast and insect cells. We show that human ACTC is incapable of rescuing a yeast endogenous actin (ACT1)-knockout in yeast cells and that coexpression of human ACTC in yeast results in slower growth, making yeast an unsuitable expression system. However, we show that it is possible for yeast cells to express a polymerization-deficient ACTI mutant, thereby allowing us to examine the cell biology of this mutation in the future. Finally, mutant forms of human cardiac actin can be expressed in and purified from insect cells in a properly folded and functional form, permitting important characterization of the biochemical mechanisms responsible for cardiomyopathy development in humans. These studies allow for further research into the biochemical characteristics of previously untenable actin mutant proteins.     

Can yeast systems biology contribute to the understanding of human disease?

Saccharomyces cerevisiae is a unicellular eukaryal microorganism that has traditionally been regarded either as a model system for investigating cellular physiology or as a cell factory for biotechnological use, for example for the production of fuels and commodity chemicals such as lactate or pharmaceuticals, including human insulin and HPV vaccines. Systems biology has recently gained momentum and has successfully been used for mapping complex regulatory networks and resolving the dynamics of signal transduction pathways. So far, yeast systems biology has mainly focused on the development of new methods and concepts. There are also some examples of the application of yeast systems biology for improving biotechnological processes. We discuss here how yeast systems biology could be used in elucidating fundamental cellular principles such as those relevant for the study of molecular mechanisms underlying complex human diseases, including the metabolic syndrome and ageing.     

Yeast Systems Biology: Model Organism and Cell Factory

For thousands of years, the yeast Saccharomyces cerevisiae (S. cerevisiae) has served as a cell factory for the production of bread, beer, and wine. In more recent years, this yeast has also served as a cell factory for producing many different fuels, chemicals, food ingredients, and pharmaceuticals. S. cerevisiae, however, has also served as a very important model organism for studying eukaryal biology, and even today many new discoveries, important for the treatment of human diseases, are made using this yeast as a model organism. Here a brief review of the use of S. cerevisiae as a model organism for studying eukaryal biology, its use as a cell factory, and how advances in systems biology underpin developments in both these areas, is provided.