Team:NTU-Taida/Project/Introduction

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==Complex Adaptive BioSystems==
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==Introduction==
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Human bodies are highly fluctuating complex systems. They detect and integrate the clues from changing environments and their own internal states, making numerous responses after delicate computation and regulation. Traditional routes of drug administration includes '''oral intake''' or '''intravenous injection''' may be too simplified to promptly fit the real-time condition of the body states. In addition, the frequent and repetitive intake of drugs may be annoying, and sometimes the invasive processes are suffering, bringing inconvenience to our daily lives. Medical instruments or electrical monitors can instantaneously detect and response to some specific physiological or pathological parameters, but they are usually too heavy and bulky to carry, which restrict the mobility of patients while using it. Therefore we aim to program the intestinal microbes to build our novel '''smart drug delivery systems—PEPDEX'''.  
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<p style="text-indent: 2em;">We seek to bridge the fields of synthetic biology and pharmacology to provide a revolutionary way of drug delivery called '''PEPDEX''', the '''ultimate delivery system of peptides'''. Peptides bind to specific receptors and regulate many physiological processes. For instance, peptide-based hormones such as insulin, growth hormone, and ACTH coordinate many physiological functions, including energy metabolism and stress responses. Peptides have long been widely used in pharmacology to treat certain diseases. With a better understanding of diseases, peptide-based drugs can now be applied in many disease modalities (except for hormonal supply), such as neurology, and immunology. Structurally, peptide-based drugs have many benefits. First, they can be processed and modified to bind seamlessly to specific receptors with complex 3D structures, which may not be accessible to small molecule drugs. Second, when applied in immunology, synthetic peptides can be used to mimic epitopes presented to antigen-presenting cells. Modified synthetic peptides show great efficacy in the induction of cognate CD4 T-cells, which is required for therapeutic activity against infectious diseases, and, in particular, cancer. In our project this year, we demonstrate the PEPDEX system as a '''mind-altering bacterium''' which can deliver neuropeptide GLP-1 directly into circulation and act on the central nervous systems, modulating the eating behavior and protecting the cognitive function of brians as well. Based on the connection and interaction between '''complex adaptive biosystems''', we extend the essence of '''brain-gut-microbiota axis''' and tailor a living, communicable bacterium that mooderate and dance with human health.
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</p>
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There are around \(10^{13}\) to \(10^{14}\) microorganisms inhabiting in our gastrointestinal tracts, more than 10 times that of the total number of cells in human bodies. They consist of more than 1000 species, and contain 150 times as many genes as our genomes. Colonizing soon after our birth, these microbes comprise a huge community and closely interact with their hosts, having great influence on our '''immune systems''', '''endocrine''', '''metabolic states''', and even '''nervous systems''', from birth to death, from health to illness. They seem to be tiny natural machines that can be utilize, for carriage of the blueprint of our design and can function adaptively and communicably inside our bodies. Weaving into the fabric of the complexity and adaptability of these intestinal microbial communities, we can achieve desirable medical goals, in our case, production and delivery of peptide drugs. Operation and customization of these '''complex adaptive biosystems''' will be an inevitable trend towards the development of systems biology and synthetic bio-techniques.
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==Structure of PEPDEX==
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Our PepdEx system consists of 5 conceptual parts, the '''sensor''', the '''effector''', the '''main circuit''', the '''stability module''', and the '''safety module'''.
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[[FIle:NTU-Taida-Project-Structure.png|600px|center]]
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==Peptide-Based Therapies==
 
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==Bacteria and Immune System==
 
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==Bacteria and Nervous System==
 
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The novel conceptual model '''“Brain-Gut Axis”''' has received emerging attention recently. Lots of studies showing evidence that intestinal microbiota have profound impacts on our nervous systems blossom during this 5~10 years. They interact with each other bidirectionally via various pathways. These include '''neuroendocrine''' (hypothalamus-pituitary-adrenal axis), '''immune systems''' (neuromodulating cytokines), '''enteric nervous systems''' and '''autonomic nervous systems''' (vagus nerve). Gut microbes produce substance such as '''tryptophan-related metabolites kynurenic acid''', '''short chain fatty acids''', and '''neurometabolites''' GABA, noradrenalin, and dopamine that potentially target to and influence functions of our central nervous systems. In the process of neurodevelopment, they modulate the expression level of many critical genes, such as '''brain-derived neurotropic factor (BDNF)''', '''NMDA receptors''' or '''5-HT receptors''' and communicate with brain regions like striatum, hippocampus, amygdale, hypothalamus, and cingulated gyrus. It has long been known that the colonization of gut flora is related to the stress response of the hosts, changing their states of '''anxiety''' and '''exploratory behavior'''. Diseases such as '''inflammatory bowel diseases (IBS)''' and '''multiple sclerosis (MS)''' are also documented to be associated with intestinal microorganisms. New focus has been greatly put on many neuropsychiatric diseases, for instance, '''autism spectrum disorders (ASD)''', '''depression''', '''anxiety disorders''', and '''schizophrenia'''.
 
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[[FIle:NTU-Taida-Project-brain_gut_axis.png|700px|thumb|center|Diagram of brain-gut axis]]
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<html>
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<ul>
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  <li><b>Sensor</b><br/>
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According to different effects of peptides, modes of delivery, and ways of triggering, we can have different sensor modules. The triggering mechanisms can be <b>physical/chemical properties</b> (temperature, pH value), <b>innate biomolecules</b> (cytokines, hormones, neurotransmitters, surface antigens), or <b>external signals for artificial induction</b> (arabinose, antibiotics). The ways how these triggering factors change and interact with our sensors determine the time points and reactive duration of our systems.
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</li><br/>
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==Reference==
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<li><b>Effector</b><br/>
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<ol>
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Various peptide-based drugs of different therapeutic effect can be designed and incorporated into the effector part of PepdEx. They are synthesized and secreted by the bacteria using different signal sequences that target to endogenous secretion systems of bacteria. Examples are short peptides that serve as <b>cancer vaccines</b>, <b>desensitizing apitopes</b> for anti-allgery, or <b>hormone analogues</b>.
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<li>Collins SM, ''et al.'' (2012) The interplay between the intestinal microbiota and the brain. ''Nature Reviews Microbiology.'' AOP, published online 24 September 2012, 1-8.</li>
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</li><br/>
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<li>Cryan JF, ''et al.'' (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. ''NatureReviews Neuroscience'' '''13''': 701-712.</li>
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<li>Rhee SH, ''et al.'' (2009) Principles and clinical implications of the brain–gut–enteric microbiota axis. ''Nature Rev. Gastroenterol. Hepatol.'' '''6''', 306–314.</li>
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<li><b>Main circuit</b><br/>
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<li>Neufeld KM, ''et al.'' (2010) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–264.</li>
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The main circuit is the heart of our PepdEx. It performs sophisticated computational tasks, comprising elements serve as filters, gates, and switches. The structures and logical designs determine the mode of delivery. Three basic modes are <b>constitutive</b> (for maintenance of constant concentration), <b>oscillating</b> (for mimic of pulsatile hormone release or repetitive boosts in vaccination), and <b>inducible</b> (for quick sensing-reactive response) delivery. Modules of <b>quorum sensing</b> can be incorporated for synchronization or population recruitment in order to amplify the response. Via <b>systemic analysis and fine adjustment of different parameters</b> inside the circuits, we are able to regulate the strength, response time, and duration of the peptide delivery.
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<li>Bercik, P. ''et al.'' (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609.</li>
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</li><br/>
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<li>Lyte M, ''et al.'' (2006) Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol. Behav. 89, 350–357.</li>
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<li>Bravo, J. A. ''et al.'' (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055.</li>
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<li><b>Stability</b><br/>
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<li>Wall, R. ''et al.'' (2012)Contrasting effects of Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 on the composition of murine brain fatty acids and gut microbiota. Am. J. Clin. Nutr. 95, 1278–1287.</li>
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In a system with large amounts of artificial gene circuits inside the bacteria, the issues of stability rise due to <b>segregational instabilities</b>, <b>multimer catastrophe</b>, and <b>burden effect</b> of the plasmids. These may lead to death or populational imbalance of these bacteria inside the intestinal environment. Modules containing <b>partition system</b>, <b>multimer resolution system</b>, and <b>toxin-antitoxin system</b> are designed to solve these problems respectively, in order to maintain the stability of our PepdEx system.  
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<li>Tillisch, K. ''et al.'' (2012) Modulation of the brain–gut axis after 4 week intervention with a probiotic fermented dairy product. Gastroenterology 142, S-115.</li>
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</li><br/>
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<li>Mayer EA. (2011) Gut feelings: the emerging biology of gut–brain communication. Nature Rev. Neurosci. 12, 453–466.</li>
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<li>Freestone PP, ''et al.'' (2008) Microbial endocrinology: how stress influences susceptibility to infection. Trends Microbiol. 16, 55–64.</li>
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<li><b>Safety</b><br/>
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<li>Kaper JB, ''et al.'' (2005). Bacterial cell to cell signaling in the gastrointestinal tract. Infect. Immun. 73, 3197–3209.</li>
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Serious concerning the safety problems of our engineered bacteria inside the human bodies or in the environments, we delineate ways to prevent the undesirable growth and colonization of these bacteria. A safety module with a <b>thermal sensor</b> coupling with an <b>oxygen sensor</b> and <b>toxin-antitoxin system</b> is sketched to kill those who unintentional escape from the intestines. Besides, <b>traditional antibiotics use</b> followed by <b>fecal microbiota transplantation</b> rescues the hosts from overwhelming colonization of these bacteria and any unwanted effects and helps to rebuild the normal microbial composition.
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<li>Neufeld KM, ''et al.'' (2011). Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–264.</li>
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</li><br/>
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<li>Heijtz RD, ''et al.'' (2011) Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052.</li>
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<li>Gareau MG, ''et al.'' (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60, 307–317.</li>
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</ul>
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<li>Desbonnet L, ''et al.'' (2010) Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179–1188.</li>
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</html>
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<li>Lyte M. (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays 33, 574–581.</li>
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<li>Derecki, N. C. ''et al.'' (2010) Regulation of learning and memory by meningeal immunity: a key role for IL 4. J. Exp. Med. 207, 1067–1080.</li>
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<li>Lyte M, ''et al.'' (2011) Stress at the intestinal surface: catecholamines and mucosa– bacteria interactions. Cell Tissue Res. 2431, 23–32..</li>
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<li>Lee Y K, ''et al.'' (2011) Proinflammatory T cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622.</li>
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<li>Berer, K. ''et al.'' (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541.</li>
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<li>Juárez I, ''et al.'' (2008) Ontogeny of altered dendritic morphology in the rat prefrontal cortex, hippocampus, and nucleus accumbens following cesarean delivery and birth anoxia. J. Comp. Neurol. 507, 1734–1747.</li>
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</ol>
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Latest revision as of 23:56, 26 October 2012

Contents

NTU-Taida

Introduction

Introduction

Introduction

We seek to bridge the fields of synthetic biology and pharmacology to provide a revolutionary way of drug delivery called PEPDEX, the ultimate delivery system of peptides. Peptides bind to specific receptors and regulate many physiological processes. For instance, peptide-based hormones such as insulin, growth hormone, and ACTH coordinate many physiological functions, including energy metabolism and stress responses. Peptides have long been widely used in pharmacology to treat certain diseases. With a better understanding of diseases, peptide-based drugs can now be applied in many disease modalities (except for hormonal supply), such as neurology, and immunology. Structurally, peptide-based drugs have many benefits. First, they can be processed and modified to bind seamlessly to specific receptors with complex 3D structures, which may not be accessible to small molecule drugs. Second, when applied in immunology, synthetic peptides can be used to mimic epitopes presented to antigen-presenting cells. Modified synthetic peptides show great efficacy in the induction of cognate CD4 T-cells, which is required for therapeutic activity against infectious diseases, and, in particular, cancer. In our project this year, we demonstrate the PEPDEX system as a mind-altering bacterium which can deliver neuropeptide GLP-1 directly into circulation and act on the central nervous systems, modulating the eating behavior and protecting the cognitive function of brians as well. Based on the connection and interaction between complex adaptive biosystems, we extend the essence of brain-gut-microbiota axis and tailor a living, communicable bacterium that mooderate and dance with human health.

Structure of PEPDEX

Our PepdEx system consists of 5 conceptual parts, the sensor, the effector, the main circuit, the stability module, and the safety module.

NTU-Taida-Project-Structure.png


  • Sensor
    According to different effects of peptides, modes of delivery, and ways of triggering, we can have different sensor modules. The triggering mechanisms can be physical/chemical properties (temperature, pH value), innate biomolecules (cytokines, hormones, neurotransmitters, surface antigens), or external signals for artificial induction (arabinose, antibiotics). The ways how these triggering factors change and interact with our sensors determine the time points and reactive duration of our systems.

  • Effector
    Various peptide-based drugs of different therapeutic effect can be designed and incorporated into the effector part of PepdEx. They are synthesized and secreted by the bacteria using different signal sequences that target to endogenous secretion systems of bacteria. Examples are short peptides that serve as cancer vaccines, desensitizing apitopes for anti-allgery, or hormone analogues.

  • Main circuit
    The main circuit is the heart of our PepdEx. It performs sophisticated computational tasks, comprising elements serve as filters, gates, and switches. The structures and logical designs determine the mode of delivery. Three basic modes are constitutive (for maintenance of constant concentration), oscillating (for mimic of pulsatile hormone release or repetitive boosts in vaccination), and inducible (for quick sensing-reactive response) delivery. Modules of quorum sensing can be incorporated for synchronization or population recruitment in order to amplify the response. Via systemic analysis and fine adjustment of different parameters inside the circuits, we are able to regulate the strength, response time, and duration of the peptide delivery.

  • Stability
    In a system with large amounts of artificial gene circuits inside the bacteria, the issues of stability rise due to segregational instabilities, multimer catastrophe, and burden effect of the plasmids. These may lead to death or populational imbalance of these bacteria inside the intestinal environment. Modules containing partition system, multimer resolution system, and toxin-antitoxin system are designed to solve these problems respectively, in order to maintain the stability of our PepdEx system.

  • Safety
    Serious concerning the safety problems of our engineered bacteria inside the human bodies or in the environments, we delineate ways to prevent the undesirable growth and colonization of these bacteria. A safety module with a thermal sensor coupling with an oxygen sensor and toxin-antitoxin system is sketched to kill those who unintentional escape from the intestines. Besides, traditional antibiotics use followed by fecal microbiota transplantation rescues the hosts from overwhelming colonization of these bacteria and any unwanted effects and helps to rebuild the normal microbial composition.

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