The future of metabolic engineering and synthetic biology: Towards a systematic practice

Industrial biotechnology promises to revolutionize conventional chemical manufacturing in the years ahead, largely owing to the excellent progress in our ability to re-engineer cellular metabolism. However, most successes of metabolic engineering have been confined to over-producing natively synthesized metabolites in E. coli and S. cerevisiae. A major reason for this development has been the descent of metabolic engineering, particularly secondary metabolic engineering, to a collection of demonstrations rather than a systematic practice with generalizable tools. Synthetic biology, a more recent development, faces similar criticisms. Herein, we attempt to lay down a framework around which bioreaction engineering can systematize itself just like chemical reaction engineering. Central to this undertaking is a new approach to engineering secondary metabolism known as ‘multivariate modular metabolic engineering’ (MMME), whose novelty lies in its assessment and elimination of regulatory and pathway bottlenecks by re-defining the metabolic network as a collection of distinct modules. After introducing the core principles of MMME, we shall then present a number of recent developments in secondary metabolic engineering that could potentially serve as its facilitators. It is hoped that the ever-declining costs of de novo gene synthesis; the improved use of bioinformatic tools to mine, sort and analyze biological data; and the increasing sensitivity and sophistication of investigational tools will make the maturation of microbial metabolic engineering an autocatalytic process. Encouraged by these advances, research groups across the world would take up the challenge of secondary metabolite production in simple hosts with renewed vigor, thereby adding to the range of products synthesized using metabolic engineering.National Institutes of Health (U.S.) (1-R01-GM085323-01A1)Special Research Funds BOF (BOF08/PDO/014)Research Foundation Flanders (FWO-Vlaandern V.4.174.10.N.01

Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Practical reflexivity as a heuristic for theorizing technological change

The historicist turn in modern intellectual history, spurred by the Kubnian revolution, succeeded in showing the contingent nature of theorizing and knowledge claims. This occurred because the dualism of theory/observation, empirical/normative, fact/value, and prescriptive/descriptive was undermined in scientific practice. This paper discusses retention of the normative by using the concept of practical reflexivity as a heuristic to bridge the divide by claiming that theorizing and explaining are still possible, despite the fussiness of the referent and the messiness of categories such as theory, observation and meta-theory. Using the case of technology transfer in the `'Green Revolution'' in Indian agriculture, this paper explains technological change as essentially knowledge change. (C) 1997 Elsevier Science Ltd

Mapping technological trajectories of the Green Revolution and the Gene Revolution from modernization to globalization

10.1016/S0048-7333(02)00106-3Research Policy326971-990REPY

Contentions and contradictions of tourism as development option: the case of Kerala, India

Although the state of Kerala in India has been regarded as a `model of development', its achievements may be unravelling thanks to a host of internal and external problems. The government and the bureaucracy now project tourism as `an engine of growth'-an excellent source of foreign exchange and employment-to revive the local economy. Opposition to large-scale tourism projects by environmental and labour activists is often dealt with through undemocratic means. This article points to a less than sanguine role for tourism in the local economy and the dynamics that work to exaggerate tourism's share in the economy in an emerging context of governmental failure, political crisis and interest group consolidation. Lessons are drawn to revisit the debate on tourism and development

Industrial development and the dynamics of innovation in Hong Kong

10.1504/IJTM.2004.004276International Journal of Technology Management274369-392IJTM