Market-driven strategies and the design of flexible production systems: evidence from the electronics industry

Links the concept of market-driven business strategies with the design of production systems. It draws upon the case of a firm which, during the last decade, changed its strategy from being “technology led” to “market driven”. The research, based on interdisciplinary fieldwork involving long-term participant observation, investigated the factors which contribute to the successful design and implementation of flexible production systems in electronics assembly. These investigations were conducted in collaboration with a major computer manufacturer, with other electronics firms being studied for comparison. The research identified a number of strategies and actions seen as crucial to the development of efficient flexible production systems, namely: effective integration of subsystems, development of appropriate controls and performance measures, compatibility between production system design and organization structure, and the development of a climate conducive to organizational change. Overall, the analysis suggests that in the electronics industry there exists an extremely high degree of environmental complexity and turbulence. This serves to shape the strategic, technical and social structures that are developed to match this complexity, examples of which are niche marketing, flexible manufacturing and employee harmonization.

Novel strategies to improve recombinant membrane protein production in yeast

Approximately 60% of pharmaceuticals target membrane proteins; 30% of the human genome codes for membrane proteins yet they represent less than 1% of known unique crystal structures deposited in the Protein Data Bank (PDB), with 50% of structures derived from recombinant membrane proteins having been synthesized in yeasts. G protein-coupled receptors (GPCRs) are an important class of membrane proteins that are not naturally abundant in their native membranes. Unfortunately their recombinant synthesis often suffers from low yields; moreover, function may be lost during extraction and purification from cell membranes, impeding research aimed at structural and functional determination. We therefore devised two novel strategies to improve functional yields of recombinant membrane proteins in the yeast Saccharomyces cerevisiae. We used human adenosine A2A receptor (hA2AR) as a model GPRC since it is functionally and structurally well characterised.In the first strategy, we investigated whether it is possible to provide yeast cells with a selective advantage (SA) in producing the fusion protein hA2AR-Ura3p when grown in medium lacking uracil; Ura3p is a decarboxylase that catalyzes the sixth enzymatic step in the de novo biosynthesis of pyrimidines, generating uridine monophosphate. The first transformant (H1) selected using the SA strategy gave high total yields of hA2AR-Ura3p, but low functional yields as determined by radio-ligand binding, leading to the discovery that the majority of the hA2AR-Ura3p had been internalized to the vacuole. The yeast deletion strain spt3Δ is thought to have slower translation rates and improved folding capabilities compared to wild-type cells and was therefore utilised for the SA strategy to generate a second transformant, SU1, which gave higher functional yields than H1. Subsequently hA2AR-Ura3p from H1 was solubilised with n-dodecyl-β-D-maltoside and cholesteryl hemisuccinate, which yielded functional hA2AR-Ura3p at the highest yield of all approaches used. The second strategy involved using knowledge of translational processes to improve recombinant protein synthesis to increase functional yield. Modification of existing expression vectors with an internal ribosome entry site (IRES) inserted into the 5ˊ untranslated region (UTR) of the gene encoding hA2AR was employed to circumvent regulatory controls on recombinant synthesis in the yeast host cell. The mechanisms involved were investigated through the use of yeast deletion strains and drugs that cause translation inhibition, which is known to improve protein folding and yield. The data highlight the potential to use deletion strains to increase IRES-mediated expression of recombinant hA2AR. Overall, the data presented in this thesis provide mechanistic insights into two novel strategies that can increase functional membrane protein yields in the eukaryotic microbe, S. cerevisiae.

Playing catch-up with China:challenges and strategies for smaller developing countries

This paper considers how smaller developing countries can compete with China by examining the cases of two such countries; Mauritius and Morocco. In order to supplement their more traditional extractive and agro-based industries they have developed important textile and apparel sectors, supplying principally the EU. However, the textile industries in both countries have recently come under intense competitive pressure from China with its much lower production costs and huge capacity. This paper compares and contrasts the conditions under which Mauritius and Morocco have developed their textile industries as well as exploring the challenges they now face from China and the ways in which they have reacted to them. It also examines the wider industrial policy of both countries and the extent to which they have acquired the capability to meet the threats that now face them. Some specific strategies and actions are also described and evaluated with a view to providing advice and guidance for other smaller developing countries that face similar challenges in these and other industries.

Translation strategies and cross-cultural contraints : a case study of the translation of advertising texts

Since the transfer of a message between two cultures very frequently takes place through the medium of a written text qua communicative event, it would seem useful to attempt to ascertain whether there is any kind of pattern in the use of strategies for the effective interlingual transfer of this message. Awareness of potentially successful strategies, within the constraints of context, text type, intended TL function and TL reader profile will enhance quality and cost-effectiveness (time, effort, financial costs) in the production of the target text. Through contrastive analysis of pairs of advertising texts, SL and TL, French and English, this study will attempt to identify the nature of some recurring choices made by different translators in the attempt to recreate ST information in the TL in such a manner as to reproduce as closely as possible the informative, persuasive and affective functions of the text as advertising material. Whilst recurrence may be seen to be significant in terms of illustrating tendencies with regard to the solution of problems of translation, this would not necessarily be taken as confirmation of the existence of pre-determined or prescriptive rules. These tendencies could, however, be taken as a guide to potential solutions to certain kinds of context-bound and text-type specific problem. Analysis of translated text-pairs taken from the field of advertising should produce examples of constraints posed by the need to select the content, tone and form of the Target Text, in order to ensure maximum efficacy of persuasive effect and to ensure the desired outcome, as determined by the Source Text function. When evaluating the success of a translated advertising text, constraints could be defined in terms of the culture-specific references or assumptions on which a Source Text may build in order to achieve its intended communicative function within the target community.

Evaluating design implementation strategies using enterprise simulation

Concurrent engineering and design for manufacture and assembly strategies have become pervasive in use in a wide array of industrial settings. These strategies have generally focused on product and process design issues based on capability concerns. The strategies have been historically justified using cost savings calculations focusing on easily quantifiable costs such as raw material savings or manufacturing or assembly operations no longer required. It is argued herein that neither the focus of the strategies nor the means of justification are adequate. Product and process design strategies should include both capability and capacity concerns and justification procedures should include the financial effects that the product and process changes would have on the entire company. The authors of this paper take this more holistic view of the problem and examine an innovative new design strategy using a comprehensive enterprise simulation tool. The results indicate that both the design strategy and the simulator show promise for further industrial use. © 2001 Elsevier Science B.V. All rights reserved.

Mapping the yeast host cell response to recombinant membrane protein production:relieving the biological bottlenecks

Understanding the structures and functions of membrane proteins is an active area of research within bioscience. Membrane proteins are key players in essential cellular processes such as the uptake of nutrients, the export of waste products, and the way in which cells communicate with their environment. It is therefore not surprising that membrane proteins are targeted by over half of all prescription drugs. Since most membrane proteins are not abundant in their native membranes, it is necessary to produce them in recombinant host cells to enable further structural and functional studies. Unfortunately, achieving the required yields of functional recombinant membrane proteins is still a bottleneck in contemporary bioscience. This has highlighted the need for defined and rational optimization strategies based upon experimental observation rather than relying on trial and error. We have published a transcriptome and subsequent genetic analysis that has identified genes implicated in high-yielding yeast cells. These results have highlighted a role for alterations to a cell's protein synthetic capacity in the production of high yields of recombinant membrane protein: paradoxically, reduced protein synthesis favors higher yields. These results highlight a potential bottleneck at the protein folding or translocation stage of protein production.

Supply chain strategies for competitive manufacture

Few people would argue that there is one single solution to the design of a manufacturing supply chain. Relatively recent concepts such as strategic outsourcing and partnership sourcing are extremely valuable to some manufacturing organisations. This paper presents the findings of a comprehensive survey of manufacturing sourcing practices in the UK. This study has set out to understand current and intended practices that manufacturing companies have with their key suppliers, and also the decision processes and circumstances that have caused these relationships to occur.

A consideration of modelling techniques that can be used to evaluate manufacturing strategies

Practising engineers frequently seek to understand what the effects of various manufacturing strategies will be on the performance of their production facilities. In this situation a computer model can help to provide insight and form predictions about future manufacturing system performance. Various types of modelling methods exist and each provide models that have distinct characteristics. This paper presents a review of popular modelling techniques and, based on the results of a structured experimental study, summarises their capabilities to support the evaluation of manufacturing strategies.

Which factors drive firm survival within an industry boundary over time?:the UK onshore oil and gas production industry 1984-1999

This thesis looks at the UK onshore oil and gas production industry and follows the history of a population of firms over a fifteen-year period following the industry's renaissance. It examines the linkage between firm survival, selection pressures and adaptation responses at the firm level, especially the role of discretionary adaptation, specifically exploration and exploitation strategies.Taking a Realist approach and using quantitative and qualitative methods for triangulation on a new data base derived from archival data, as well as informant interviews, it tests seven hypotheses' about post-entry survival of firms. The quantitative findings suggest that firm survival within this industry is linked to discretionary adaptation, when measured at the firm level, and to a mixture of selection and adaptation forces when measured for each firm for each individual year. The qualitative research suggests that selection factors dominate. This difference in views is unresolved. However the small, sparse population and the nature of the oil and gas industry compared with other common research contexts such as manufacturing or service firms suggests the results be treated with caution as befits a preliminary investigation. The major findings include limited support for the theory that the external environment is the major determinant of firm survival, though environment components affect firms differentially; resolution of apparent literature differences relating to the sequencing of exploration and exploitation and potential tangible evidence of coevolution. The research also finds that, though selection may be considered important by industry players, discretionary adaptation appears to play the key role, and that the key survival drivers for thispopulation are intra-industry ties, exploitation experience and a learning/experience component. Selection has a place, however, in determining the life-cycle of the firm returning to be a key survival driver at certain ages of the firm inside the industry boundary.

Strategies for sustaining manufacturing competitiveness:case studies of Australian firms

This study investigates the strategies adopted by Australian manufacturing firms to sustain their local production and competitiveness, including during the period of the recent global financial crisis. Six Australian manufacturing organisations in different sectors were selected and analysed using the market-based and resource-based views, and components of the DRAMA framework. The findings highlight several factors and company efforts to sustain manufacturing operations. These organisations pursued a range of manufacturing strategies to enable distinctive offerings in the marketplace and used various ways to differentiate themselves. This was possible through the portfolio of capabilities that determine their continued production and business performance over the period. This study provides important lessons for managers in manufacturing organisations and demonstrates how differing capabilities and strategies of firms can impact the competitiveness of local production, not only in times of economic crisis but also in the long run to sustainable competitiveness in the future.

The relationship between internationalisation and innovation:internationalisation strategies, foreign firms', patenting behaviour and FDI spillovers

This thesis aims to contribute to the understanding of the relationships between internationalisation and innovation. Based on large comprehensive firm level data from China, this thesis comprises of three empirical chapters examining internationalisation from different aspects. Specifically, the first empirical work studies how firms internationalise. It links the choice of firms’ internationalisation strategies with firm characteristics. Additionally, it re-examines the stepwise internationalisation theory by distinguishing different foreign direct investment (FDI) motives. It proposes two pecking orders of firm performance in internationalisation strategies. The second empirical study investigates what kind of innovation activities internationalised firms do. It analyses the factors that drive foreign firms to patent in an emerging host country context. It stresses the importance of the intellectual property rights protection aspect of business environment at regional level in promoting patents, the role of industry dependence on external finance in shaping foreign firms’ patenting behaviour, as well as links foreign firms’ patent production with FDI motivation. The third empirical research examines the effect of internationalisation by examining the links between inward FDI and domestic innovation in a host country. It specifically examines technology spillovers from inward FDI through the direct lens of innovation (captured by grant patents), instead of adopting the indirect productivity approach widely employed by the literature. Distinguishing different types of innovation, it provides direct evidence of heterogeneous innovation spillovers from FDI.

Outsourcing decisions:the case of parallel production

Purpose – The purpose of this paper is to investigate an underexplored aspect of outsourcing involving a mixed strategy in which parallel production is continued in-house at the same time as outsourcing occurs. Design/methodology/approach – The study applied a multiple case study approach and drew on qualitative data collected through in-depth interviews with wood product manufacturing companies. Findings – The paper posits that there should be a variety of mixed strategies between the two governance forms of “make” or “buy.” In order to address how companies should consider the extent to which they outsource, the analysis was structured around two ends of a continuum: in-house dominance or outsourcing dominance. With an in-house-dominant strategy, outsourcing complements an organization's own production to optimize capacity utilization and outsource less cost-efficient production, or is used as a tool to learn how to outsource. With an outsourcing-dominant strategy, in-house production helps maintain complementary competencies and avoids lock-in risk. Research limitations/implications – This paper takes initial steps toward an exploration of different mixed strategies. Additional research is required to understand the costs of different mixed strategies compared with insourcing and outsourcing, and to study parallel production from a supplier viewpoint. Practical implications – This paper suggests that managers should think twice before rushing to a “me too” outsourcing strategy in which in-house capacities are completely closed. It is important to take a dynamic view of outsourcing that maintains a mixed strategy as an option, particularly in situations that involve an underdeveloped supplier market and/or as a way to develop resources over the long term. Originality/value – The concept of combining both “make” and “buy” is not new. However, little if any research has focussed explicitly on exploring the variety of different types of mixed strategies that exist on the continuum between insourcing and outsourcing.

Editorial overview:new protein production tools for structural biology

Full text: The idea of producing proteins from recombinant DNA hatched almost half a century ago. In his PhD thesis, Peter Lobban foresaw the prospect of inserting foreign DNA (from any source, including mammalian cells) into the genome of a λ phage in order to detect and recover protein products from Escherichia coli [ 1 and 2]. Only a few years later, in 1977, Herbert Boyer and his colleagues succeeded in the first ever expression of a peptide-coding gene in E. coli — they produced recombinant somatostatin [ 3] followed shortly after by human insulin. The field has advanced enormously since those early days and today recombinant proteins have become indispensable in advancing research and development in all fields of the life sciences. Structural biology, in particular, has benefitted tremendously from recombinant protein biotechnology, and an overwhelming proportion of the entries in the Protein Data Bank (PDB) are based on heterologously expressed proteins. Nonetheless, synthesizing, purifying and stabilizing recombinant proteins can still be thoroughly challenging. For example, the soluble proteome is organized to a large part into multicomponent complexes (in humans often comprising ten or more subunits), posing critical challenges for recombinant production. A third of all proteins in cells are located in the membrane, and pose special challenges that require a more bespoke approach. Recent advances may now mean that even these most recalcitrant of proteins could become tenable structural biology targets on a more routine basis. In this special issue, we examine progress in key areas that suggests this is indeed the case. Our first contribution examines the importance of understanding quality control in the host cell during recombinant protein production, and pays particular attention to the synthesis of recombinant membrane proteins. A major challenge faced by any host cell factory is the balance it must strike between its own requirements for growth and the fact that its cellular machinery has essentially been hijacked by an expression construct. In this context, Bill and von der Haar examine emerging insights into the role of the dependent pathways of translation and protein folding in defining high-yielding recombinant membrane protein production experiments for the common prokaryotic and eukaryotic expression hosts. Rather than acting as isolated entities, many membrane proteins form complexes to carry out their functions. To understand their biological mechanisms, it is essential to study the molecular structure of the intact membrane protein assemblies. Recombinant production of membrane protein complexes is still a formidable, at times insurmountable, challenge. In these cases, extraction from natural sources is the only option to prepare samples for structural and functional studies. Zorman and co-workers, in our second contribution, provide an overview of recent advances in the production of multi-subunit membrane protein complexes and highlight recent achievements in membrane protein structural research brought about by state-of-the-art near-atomic resolution cryo-electron microscopy techniques. E. coli has been the dominant host cell for recombinant protein production. Nonetheless, eukaryotic expression systems, including yeasts, insect cells and mammalian cells, are increasingly gaining prominence in the field. The yeast species Pichia pastoris, is a well-established recombinant expression system for a number of applications, including the production of a range of different membrane proteins. Byrne reviews high-resolution structures that have been determined using this methylotroph as an expression host. Although it is not yet clear why P. pastoris is suited to producing such a wide range of membrane proteins, its ease of use and the availability of diverse tools that can be readily implemented in standard bioscience laboratories mean that it is likely to become an increasingly popular option in structural biology pipelines. The contribution by Columbus concludes the membrane protein section of this volume. In her overview of post-expression strategies, Columbus surveys the four most common biochemical approaches for the structural investigation of membrane proteins. Limited proteolysis has successfully aided structure determination of membrane proteins in many cases. Deglycosylation of membrane proteins following production and purification analysis has also facilitated membrane protein structure analysis. Moreover, chemical modifications, such as lysine methylation and cysteine alkylation, have proven their worth to facilitate crystallization of membrane proteins, as well as NMR investigations of membrane protein conformational sampling. Together these approaches have greatly facilitated the structure determination of more than 40 membrane proteins to date. It may be an advantage to produce a target protein in mammalian cells, especially if authentic post-translational modifications such as glycosylation are required for proper activity. Chinese Hamster Ovary (CHO) cells and Human Embryonic Kidney (HEK) 293 cell lines have emerged as excellent hosts for heterologous production. The generation of stable cell-lines is often an aspiration for synthesizing proteins expressed in mammalian cells, in particular if high volumetric yields are to be achieved. In his report, Buessow surveys recent structures of proteins produced using stable mammalian cells and summarizes both well-established and novel approaches to facilitate stable cell-line generation for structural biology applications. The ambition of many biologists is to observe a protein's structure in the native environment of the cell itself. Until recently, this seemed to be more of a dream than a reality. Advances in nuclear magnetic resonance (NMR) spectroscopy techniques, however, have now made possible the observation of mechanistic events at the molecular level of protein structure. Smith and colleagues, in an exciting contribution, review emerging ‘in-cell NMR’ techniques that demonstrate the potential to monitor biological activities by NMR in real time in native physiological environments. A current drawback of NMR as a structure determination tool derives from size limitations of the molecule under investigation and the structures of large proteins and their complexes are therefore typically intractable by NMR. A solution to this challenge is the use of selective isotope labeling of the target protein, which results in a marked reduction of the complexity of NMR spectra and allows dynamic processes even in very large proteins and even ribosomes to be investigated. Kerfah and co-workers introduce methyl-specific isotopic labeling as a molecular tool-box, and review its applications to the solution NMR analysis of large proteins. Tyagi and Lemke next examine single-molecule FRET and crosslinking following the co-translational incorporation of non-canonical amino acids (ncAAs); the goal here is to move beyond static snap-shots of proteins and their complexes and to observe them as dynamic entities. The encoding of ncAAs through codon-suppression technology allows biomolecules to be investigated with diverse structural biology methods. In their article, Tyagi and Lemke discuss these approaches and speculate on the design of improved host organisms for ‘integrative structural biology research’. Our volume concludes with two contributions that resolve particular bottlenecks in the protein structure determination pipeline. The contribution by Crepin and co-workers introduces the concept of polyproteins in contemporary structural biology. Polyproteins are widespread in nature. They represent long polypeptide chains in which individual smaller proteins with different biological function are covalently linked together. Highly specific proteases then tailor the polyprotein into its constituent proteins. Many viruses use polyproteins as a means of organizing their proteome. The concept of polyproteins has now been exploited successfully to produce hitherto inaccessible recombinant protein complexes. For instance, by means of a self-processing synthetic polyprotein, the influenza polymerase, a high-value drug target that had remained elusive for decades, has been produced, and its high-resolution structure determined. In the contribution by Desmyter and co-workers, a further, often imposing, bottleneck in high-resolution protein structure determination is addressed: The requirement to form stable three-dimensional crystal lattices that diffract incident X-ray radiation to high resolution. Nanobodies have proven to be uniquely useful as crystallization chaperones, to coax challenging targets into suitable crystal lattices. Desmyter and co-workers review the generation of nanobodies by immunization, and highlight the application of this powerful technology to the crystallography of important protein specimens including G protein-coupled receptors (GPCRs). Recombinant protein production has come a long way since Peter Lobban's hypothesis in the late 1960s, with recombinant proteins now a dominant force in structural biology. The contributions in this volume showcase an impressive array of inventive approaches that are being developed and implemented, ever increasing the scope of recombinant technology to facilitate the determination of elusive protein structures. Powerful new methods from synthetic biology are further accelerating progress. Structure determination is now reaching into the living cell with the ultimate goal of observing functional molecular architectures in action in their native physiological environment. We anticipate that even the most challenging protein assemblies will be tackled by recombinant technology in the near future.