Article

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

ABSTRACT

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.

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    • "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. "
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    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.
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    • "We envisioned applying this method to cutting-edge synthetic biology approaches, known as prosthetic gene networks, developed for the treatment of systemic metabolic disorders (Auslander et al., 2014a; Rossger et al., 2013b) such as autoimmune diseases (Ye et al., 2011). Prosthetic gene networks have been validated in vitro and in vivo using available mouse models (Rossger et al., 2013a; Ye et al., 2011). However, two major drawbacks in using animal models indicate the need for novel, innovative approaches: the lack of appropriate "
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    ABSTRACT: Encapsulated designer cells implanted into mice are currently used to validate the efficacy of therapeutic gene networks for the diagnosis and treatment of various human diseases in preclinical research. Because many human conditions cannot be adequately replicated by animal models, complementary and alternative procedures to test future treatment strategies are required. Here we describe a novel approach utilizing an ex vivo human whole-blood culture system to validate synthetic biology-inspired designer cell-based treatment strategies. The viability and functionality of transgenic mammalian designer cells co-cultured with primary human immune cells were characterized. We demonstrated that transgenic mammalian designer cells required adequate insulation from the human blood microenvironment to maintain viability and functionality. The biomaterial alginate-(poly-L-lysine)-alginate used to encapsulate the transgenic designer cells did neither affect the viability of primary granulocytes and lymphocytes nor the functionality of lymphocytes. Additionally, alginate-encapsulated transgenic designer cells remained responsive to the release of the pro-inflammatory cytokine tumor necrosis factor (TNF) from the whole-blood culture upon exposure to bacterial lipopolysaccharide (LPS). TNF diffused into the alginate capsules, bound to the specific TNF receptors on the transgenic designer cells' surface and triggered the expression of the reporter gene SEAP (human placental secreted alkaline phosphatase) that was rewired to the TNF-specific signaling cascade. Human whole-blood culture systems can therefore be considered as valuable complementary assays to animal models for the validation of synthetic circuits in genetically modified mammalian cells and may speed up preclinical research in a world of personalized medicine. This article is protected by copyright. All rights reserved.
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    • "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. "
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    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.
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