A Synthetic Optogenetic Transcription Device Enhances Blood-Glucose Homeostasis in Mice

Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, Basel, Switzerland.
Science (Impact Factor: 33.61). 06/2011; 332(6037):1565-8. DOI: 10.1126/science.1203535
Source: PubMed


Synthetic biology has advanced the design of genetic devices that can be used to reprogram metabolic activities in mammalian cells. By functionally linking the signal transduction of melanopsin to the control circuit of the nuclear factor of activated T cells, we have designed a synthetic signaling cascade enabling light-inducible transgene expression in different cell lines grown in culture or bioreactors or implanted into mice. In animals harboring intraperitoneal hollow-fiber or subcutaneous implants containing light-inducible transgenic cells, the serum levels of the human glycoprotein secreted alkaline phosphatase could be remote-controlled with fiber optics or transdermally regulated through direct illumination. Light-controlled expression of the glucagon-like peptide 1 was able to attenuate glycemic excursions in type II diabetic mice. Synthetic light-pulse-transcription converters may have applications in therapeutics and protein expression technology.

91 Reads
  • Source
    • "Globally research in the synthetic biology and its application are on high priority (Na et al. 2013; Ausländer and Fussenegger 2013; Soma et al. 2014). Synthetic circuits sense signals and process a coordinated therapeutic output such as control of cancer (Culler et al. 2010; Nissim and Bar-Ziv 2010), T cell population controllers (Chen et al. 2010), blue-light-triggered glucose homeostasis for cure of diabetes (Ye et al. 2011) and artificial insemination (Kemmer et al. 2011). Recently, applications of synthetic biology towards production of valuables such as drugs, fuels, antibiotics and therapeutics or novel circuits with desired functions have gained more scientific attention. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The genome engineering toolkit has expanded significantly in recent years, allowing us to study the functions of genes in cellular networks and assist in overproduction of proteins, drugs, chemicals and biofuels. Multiplex automated genome engineering (MAGE) has been recently developed and gained more scientific interest towards strain engineering. MAGE is a simple, rapid and efficient tool for manipulating genes simultaneously in multiple loci, assigning genetic codes and integrating non-natural amino acids. MAGE can be further expanded towards the engineering of fast, robust and over-producing strains for chemicals, drugs and biofuels at industrial scales.
    Systems and Synthetic Biology 11/2015; DOI:10.1007/s11693-015-9184-8
  • Source
    • "The capsules may, for example, not be impervious over time, possibly exposing the engineered cells to the patients' immune system. Furthermore , the current version of the circuits are operated in standard tissue culture cells originally derived from cultures of human embryonic kidney cells transformed with sheared adenovirus 5 DNA (HEK-293 cells) (Kemmer et al. 2010; Ye et al. 2011). These cells have several chromosomal abnormalities and share other features with human cancer cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent progress in synthetic biology (SynBio) has enabled the development of novel therapeutic opportunities for the treatment of human disease. In the near future, first-in-human trials (FIH) will be indicated. FIH trials mark a key milestone in the translation of medical SynBio applications into clinical practice. Fostered by uncertainty of possible adverse events for trial participants, a variety of ethical concerns emerge with regards to SynBio FIH trials, including 'risk' minimization. These concerns are associated with any FIH trial, however, due to the novelty of the approach, they become more pronounced for medical applications of emerging technologies (emTech) like SynBio. To minimize potential harm for trial participants, scholars, guidelines, regulations and policy makers alike suggest using 'risk assessment' as evaluation tool for such trials. Conversely, in the context of emTech FIH trials, we believe it to be at least questionable to contextualize uncertainty of potential adverse events as 'risk' and apply traditional risk assessment methods. Hence, this issue needs to be discussed to enable alterations of the evaluation process before the translational phase of SynBio applications begins. In this paper, we will take the opportunity to start the debate and highlight how a misunderstanding of the concept of risk, and the possibilities and limitations of risk assessment, respectively, might impair decision-making by the relevant regulatory authorities and research ethics committees, and discuss possible solutions to tackle the issue.
    Medicine Health Care and Philosophy 08/2015; DOI:10.1007/s11019-015-9660-7 · 0.91 Impact Factor
    • "Furthermore, the authors demonstrated dose-dependent tuning of expression levels as well as spatially controlled gene expression and applied the system in a mouse model of diabetes for the light-triggered production of therapeutic insulin. An alternative design for blue light-inducible gene expression used the human photopigment melanopsin to induce calcium influx and finally tapped into the endogenous factor of activated T cell (NFAT) pathway to activate expression from a NFAT-specific reporter construct (Ye et al., 2011a). This setup yielded a 20-fold induction of gene expression in HEK-293 cells, and the authors applied the system in a pilot bioproduction process and to treat diabetic mice by the light-induced production of the glucagon-like protein 1 from implanted cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Molecular switches that are controlled by chemicals have evolved as central research instruments in mammalian cell biology. However, these tools are limited in terms of their spatiotemporal resolution due to freely-diffusing inducers. These limitations have recently been addressed by the development of optogenetic, genetically encoded and light-responsive tools that can be controlled with the unprecedented spatiotemporal precision of light. In this article, we first provide a brief overview of currently available optogenetic tools that have been designed to control diverse cellular processes. Then, we focus on recent developments in light-controlled gene expression technologies and provide the reader with a guideline for choosing the most suitable gene expression system.
    Biological Chemistry 08/2014; DOI:10.1515/hsz-2014-0199 · 3.27 Impact Factor
Show more

Similar Publications