RESUMEN
Recent advances in synthetic biology have paved the way for new cellular therapies, using cells capable of autonomously treating chronic diseases. These cells integrate a set of genes functioning in a closed-loop synthetic circuit, delivering a therapeutic effector in response to a specific pathological signal. While promising in mice, these therapies face clinical challenges related to safety and feasibility of in vivo implementation. The latest generations of synthetic circuits aim to address these issues through advanced bioengineering strategies outlined in this article.
Title: Les circuits synthétiques de gènes fonctionnant en boucle fermée - Concept et dernières avancées. Abstract: Les progrès récents de la biologie synthétique ont ouvert la voie à de nouvelles thérapies fondées sur des cellules rendues aptes à produire de manière autonome des substrats afin de traiter des maladies chroniques. Ces cellules modifiées intègrent un ensemble de gènes fonctionnant en circuit synthétique à boucle fermée, qui permettent de délivrer un effecteur thérapeutique en réponse à un signal pathologique déterminé. Bien que prometteuses chez la souris, ces thérapies font face à des obstacles cliniques liés à leur sûreté et à leur implémentation in vivo. Les dernières générations de circuits synthétiques cherchent à résoudre ces problèmes grâce à des stratégies de bioingénierie avancées, que nous présentons dans cet article.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Redes Reguladoras de Genes , Genes Sintéticos , Biología Sintética , Humanos , Animales , Biología Sintética/métodos , Biología Sintética/tendencias , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Ratones , Terapia Genética/métodos , Terapia Genética/tendenciasRESUMEN
Synthetic biology is a rapidly emerging field with broad underlying applications in health, industry, agriculture, or environment, enabling sustainable solutions for unmet needs of modern society. With the very recent addition of artificial intelligence (AI) approaches, this field is now growing at a rate that can help reach the envisioned goals of bio-based society within the next few decades. Integrating AI with plant-based technologies, such as protein engineering, phytochemicals production, plant system engineering, or microbiome engineering, potentially disruptive applications have already been reported. These include enzymatic synthesis of new-to-nature molecules, bioelectricity generation, or biomass applications as construction material. Thus, in the not-so-distant future, synthetic biologists will help attain the overarching goal of a sustainable yet efficient production system for every aspect of society.
Asunto(s)
Inteligencia Artificial , Biología Sintética , Biología Sintética/métodos , Biología Sintética/tendencias , Biotecnología/tendencias , Biotecnología/métodos , Plantas/metabolismo , HumanosRESUMEN
Killer yeasts secrete protein toxins that are selectively lethal to other yeast and filamentous fungi. These exhibit exceptional genetic and functional diversity, and have several biotechnological applications. However, despite decades of research, several limitations hinder their widespread adoption. In this perspective we contend that technical advances in synthetic biology present an unprecedented opportunity to unlock the full potential of yeast killer systems across a spectrum of applications. By leveraging these new technologies, engineered killer toxins may emerge as a pivotal new tool to address antifungal resistance and food security. Finally, we speculate on the biotechnological potential of re-engineering host double-stranded (ds) RNA mycoviruses, from which many toxins derive, as a safe and noninfectious system to produce designer RNA.
Asunto(s)
Biología Sintética , Biología Sintética/métodos , Biología Sintética/tendencias , Levaduras/genética , Levaduras/metabolismo , Biotecnología/tendencias , Biotecnología/métodos , Factores Asesinos de Levadura/genética , Factores Asesinos de Levadura/metabolismo , Hongos/genética , Hongos/metabolismoRESUMEN
The COVID-19 pandemic has thrust RNA as a platform for drug development into the spotlight. However, identifying promising drug candidates is challenging. With advances in synthetic biology and artificial intelligence (AI) models, we can overcome this hurdle, transforming drug development and ushering in a new era in the pharmaceutical industry.
Asunto(s)
Inteligencia Artificial , Desarrollo de Medicamentos , Biología Sintética , Biología Sintética/métodos , Biología Sintética/tendencias , Desarrollo de Medicamentos/métodos , Humanos , COVID-19/virología , SARS-CoV-2/genética , SARS-CoV-2/efectos de los fármacos , Tratamiento Farmacológico de COVID-19 , PandemiasRESUMEN
Three billion years of evolution has produced a tremendous diversity of protein molecules1, but the full potential of proteins is likely to be much greater. Accessing this potential has been challenging for both computation and experiments because the space of possible protein molecules is much larger than the space of those likely to have functions. Here we introduce Chroma, a generative model for proteins and protein complexes that can directly sample novel protein structures and sequences, and that can be conditioned to steer the generative process towards desired properties and functions. To enable this, we introduce a diffusion process that respects the conformational statistics of polymer ensembles, an efficient neural architecture for molecular systems that enables long-range reasoning with sub-quadratic scaling, layers for efficiently synthesizing three-dimensional structures of proteins from predicted inter-residue geometries and a general low-temperature sampling algorithm for diffusion models. Chroma achieves protein design as Bayesian inference under external constraints, which can involve symmetries, substructure, shape, semantics and even natural-language prompts. The experimental characterization of 310 proteins shows that sampling from Chroma results in proteins that are highly expressed, fold and have favourable biophysical properties. The crystal structures of two designed proteins exhibit atomistic agreement with Chroma samples (a backbone root-mean-square deviation of around 1.0 Å). With this unified approach to protein design, we hope to accelerate the programming of protein matter to benefit human health, materials science and synthetic biology.
Asunto(s)
Algoritmos , Simulación por Computador , Conformación Proteica , Proteínas , Humanos , Teorema de Bayes , Evolución Molecular Dirigida , Aprendizaje Automático , Modelos Moleculares , Pliegue de Proteína , Proteínas/química , Proteínas/metabolismo , Semántica , Biología Sintética/métodos , Biología Sintética/tendenciasAsunto(s)
Código Genético , Ingeniería de Proteínas , Proteínas , Investigadores , Biología Sintética , Código Genético/genética , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Biología Sintética/métodos , Biología Sintética/tendencias , Ingeniería de Proteínas/métodos , Ingeniería de Proteínas/tendenciasAsunto(s)
Embrión de Mamíferos , Embriología , Ratones , Biología Sintética , Animales , Embrión de Mamíferos/citología , Embrión de Mamíferos/embriología , Embriología/métodos , Embriología/tendencias , Femenino , Masculino , Ratones/embriología , Óvulo , Espermatozoides , Biología Sintética/métodos , Biología Sintética/tendenciasRESUMEN
Epidemic diseases and antibiotic resistance are urgent threats to global health, and human is confronted with an unprecedented dilemma to conquer them by expediting development of new natural product related drugs. C-nucleoside antibiotics, a remarkable group of microbial natural products with diverse biological activities, feature a heterocycle base linked with a ribosyl moiety via an unusual C-glycosidic bond, and have played significant roles in healthcare and for plant protection. Elucidating how nature biosynthesizes such a group of antibiotics has provided the basis for engineered biosynthesis as well as targeted genome mining of more C-nucleoside antibiotics towards improved properties. In this review, we mainly summarize the recent advances on the biosynthesis of C-nucleoside antibiotics, and we also tentatively discuss the future developments on rationally accessing C-nucleoside diversities in a more efficient and economical way via synthetic biology strategies.
Asunto(s)
Actinobacteria/metabolismo , Antibacterianos/biosíntesis , Nucleósidos/biosíntesis , Biología Sintética/métodos , Actinobacteria/genética , Productos Biológicos/química , Streptomyces/genética , Streptomyces/metabolismo , Biología Sintética/tendenciasRESUMEN
Recent advances in biomolecular engineering have led to novel cancer immunotherapies with sophisticated programmed functions, including chimeric antigen receptor (CAR) T cells that bind tumor-associated antigens (TAA) to direct coordinated immune responses. Extensive engineering efforts have been made to program not only CAR specificity, but also downstream pathways that activate molecular responses. Collectively, these efforts can be conceptualized as an immunotherapy circuit: TAAs bind the CAR as input signals; intracellular signaling cascades process the binding interactions into transcriptional and translational events; and those events program effector output functions. More simply, this sequence may be abstracted as input, processing, and output. In this review, we discuss the increasingly complex scene of synthetic-biology solutions in cancer immunotherapy and summarize recent work within the framework of immunotherapy circuits. In doing so, a toolbox of basic modular circuits may be established as a foundation upon which sophisticated solutions can be constructed to meet more complex problems.See related article on p. 5.
Asunto(s)
Inmunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéutico , Antígenos de Neoplasias/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Humanos , Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Biología Sintética/tendencias , Linfocitos T/inmunologíaRESUMEN
Employing concepts from physics, chemistry and bioengineering, 'learning-by-building' approaches are becoming increasingly popular in the life sciences, especially with researchers who are attempting to engineer cellular life from scratch. The SynCell2020/21 conference brought together researchers from different disciplines to highlight progress in this field, including areas where synthetic cells are having socioeconomic and technological impact. Conference participants also identified the challenges involved in designing, manipulating and creating synthetic cells with hierarchical organization and function. A key conclusion is the need to build an international and interdisciplinary research community through enhanced communication, resource-sharing, and educational initiatives.
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Células Artificiales , Bioingeniería/métodos , Bioingeniería/estadística & datos numéricos , Bioingeniería/tendencias , Colaboración Intersectorial , Orgánulos/fisiología , Biología Sintética/tendencias , Predicción , HumanosRESUMEN
Synthetic biology has the potential to transform cell- and gene-based therapies for a variety of diseases. Sophisticated tools are now available for both eukaryotic and prokaryotic cells to engineer cells to selectively achieve therapeutic effects in response to one or more disease-related signals, thus sparing healthy tissue from potentially cytotoxic effects. This report summarizes the Keystone eSymposium "Synthetic Biology: At the Crossroads of Genetic Engineering and Human Therapeutics," which took place on May 3 and 4, 2021. Given that several therapies engineered using synthetic biology have entered clinical trials, there was a clear need for a synthetic biology symposium that emphasizes the therapeutic applications of synthetic biology as opposed to the technical aspects. Presenters discussed the use of synthetic biology to improve T cell, gene, and viral therapies, to engineer probiotics, and to expand upon existing modalities and functions of cell-based therapies.
Asunto(s)
Congresos como Asunto/tendencias , Ingeniería Genética/tendencias , Terapia Genética/tendencias , Informe de Investigación , Biología Sintética/tendencias , Animales , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Marcación de Gen/métodos , Marcación de Gen/tendencias , Ingeniería Genética/métodos , Terapia Genética/métodos , Humanos , Células Asesinas Naturales/inmunología , Aprendizaje Automático/tendencias , Biología Sintética/métodos , Linfocitos T/inmunologíaRESUMEN
The steadfast advance of the synthetic biology field has enabled scientists to use genetically engineered cells, instead of small molecules or biologics, as the basis for the development of novel therapeutics. Cells endowed with synthetic gene circuits can control the localization, timing and dosage of therapeutic activities in response to specific disease biomarkers and thus represent a powerful new weapon in the fight against disease. Here, we conceptualize how synthetic biology approaches can be applied to programme living cells with therapeutic functions and discuss the advantages that they offer over conventional therapies in terms of flexibility, specificity and predictability, as well as challenges for their development. We present notable advances in the creation of engineered cells that harbour synthetic gene circuits capable of biological sensing and computation of signals derived from intracellular or extracellular biomarkers. We categorize and describe these developments based on the cell scaffold (human or microbial) and the site at which the engineered cell exerts its therapeutic function within its human host. The design of cell-based therapeutics with synthetic biology is a rapidly growing strategy in medicine that holds great promise for the development of effective treatments for a wide variety of human diseases.
Asunto(s)
Ingeniería Celular/métodos , Ingeniería Genética/mortalidad , Biología Sintética , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Redes Reguladoras de Genes , Ingeniería Genética/métodos , Humanos , Biología Sintética/métodos , Biología Sintética/tendenciasRESUMEN
Cell-free synthetic biology is a rapidly developing biotechnology with the potential to solve the world's biggest problems; however, this promise also has implications for global biosecurity and biosafety. Given the current situation of COVID-19 and its economic impact, capitalizing on the potential of cell-free synthetic biology from an economic, biosafety, and biosecurity perspective contributes to our preparedness for the next pandemic, and urges the development of appropriate policies and regulations, together with the necessary mitigation technologies. Proactive involvement from scientists is necessary to avoid misconceptions and assist in the policymaking process.
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COVID-19/terapia , Biología Sintética/economía , Biología Sintética/legislación & jurisprudencia , Materiales Biocompatibles , Tecnología Biomédica , Bioaseguramiento , Biotecnología , Sistema Libre de Células , Difusión de Innovaciones , Política de Salud , Humanos , Seguridad , Biología Sintética/tendenciasRESUMEN
The field of synthetic biology is increasingly being positioned as a key driver of a more sustainable, bio-based economy, and has seen rapid industry growth over the past 15 years. In this paper we undertake an exploratory investigation of the relationship between sustainability and synthetic biology, identifying and analyzing sustainability-related language on the public websites of 24, US-based synthetic biology companies. We observe that sustainability is a visible part of the self-presentation of the nascent synthetic biology industry, explicitly mentioned by 18 of the 24 companies. The dominant framing of sustainability on these company websites emphasizes environmental gains and "free-market" approaches to sustainability, with little explicit mention of social dimensions of sustainability such as access, justice or intergenerational equity. Furthermore, the model of sustainability presented focuses on incremental transition towards environmental sustainability through direct substitution of products and processes using bioengineered alternatives (n = 16 companies), with no change in societal consumption or policy frameworks required in order to see sustainability gains. One-third of the companies analyzed (n = 8) mention "nature" on their websites, variously framing it as a resource to be managed or as a source of inspiration; whether the latter signals a potentially more complex relationship with nature than advanced free-market models of sustainability remains to be seen. As the synthetic biology industry begins to grow in size and visibility, we suggest this is an opportune time for the community to engage in explicit deliberation about its approach to sustainability.
Asunto(s)
Comercio , Conservación de los Recursos Energéticos , Desarrollo Sostenible , Biología Sintética/organización & administración , Biología Sintética/tendencias , Bioingeniería/métodos , Ambiente , Humanos , Industrias , Internet , Liderazgo , Proyectos Piloto , Política Pública , Estados UnidosRESUMEN
Recent developments in synthetic biology may bring the bottom-up generation of a synthetic cell within reach. A key feature of a living synthetic cell is a functional cell cycle, in which DNA replication and segregation as well as cell growth and division are well integrated. Here, we describe different approaches to recreate these processes in a synthetic cell, based on natural systems and/or synthetic alternatives. Although some individual machineries have recently been established, their integration and control in a synthetic cell cycle remain to be addressed. In this Perspective, we discuss potential paths towards an integrated synthetic cell cycle.
Asunto(s)
Células Artificiales , Mimetismo Biológico/genética , Ciclo Celular/genética , Replicación del ADN/genética , Modelos Genéticos , Biología Sintética/métodos , Bacteriófagos/genética , Escherichia coli/genética , Biosíntesis de Proteínas/genética , Biología Sintética/tendencias , Transcripción Genética/genéticaRESUMEN
Archaeal membrane lipids are structurally different from bacterial and eukaryotic membrane lipids, but little is known about the enzymes involved in their synthesis. In a recent study, Exterkate et al. identified and characterized a cardiolipin synthase from the archaeon Methanospirillum hungatei. This enzyme can synthesize archaeal, bacterial, and mixed archaeal/bacterial cardiolipin species from a wide variety of substrates, some of which are not even naturally occurring. This discovery could revolutionize synthetic lipid biology, being used to construct a variety of lipids with nonnatural head groups and mixed archaeal/bacterial hydrophobic chains.
Asunto(s)
Archaea/genética , Lípidos de la Membrana/genética , Proteínas de la Membrana/genética , Methanospirillum/enzimología , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Archaea/química , Archaea/enzimología , Bacterias/enzimología , Lípidos de la Membrana/química , Proteínas de la Membrana/química , Methanospirillum/metabolismo , Biología Sintética/tendencias , Transferasas (Grupos de Otros Fosfatos Sustitutos)/químicaRESUMEN
Spontaneous tumor regression following bacterial infection has been observed for hundreds of years. These observations along with anecdotal medical findings in 1890s led to the development of Coley's "toxins," consisting of killed Streptococcus pyogenes and Serratia marcescens bacteria, as the first cancer immunotherapy. The use of this approach, however, was not widely accepted at the time especially after the introduction of radiation therapy as a treatment for cancer in the early 1900s. Over the last 30-40 years there has been renewed interest in the use of bacteria to treat human solid tumors. This is based on the observation that various nonpathogenic anaerobic bacteria can infiltrate and replicate within solid tumors when given intravenously. Bacteria tested as potential anticancer agents include the Gram-positive obligate anaerobes Bifidobacterium and Clostridium, as well as the gram-negative facultative anaerobe Salmonella. Recent advances in synthetic biology and clinical success in cancer immunotherapy provide renewed momentum for developing bacteria-based cancer immunotherapy for cancer treatment and should allow greater potential for the development of novel therapeutic approaches for this devastating disease.
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Terapia Biológica/métodos , Neoplasias/terapia , Interferencia de ARN , Biología Sintética/métodos , Animales , Línea Celular Tumoral , Ensayos Clínicos Fase I como Asunto , Neoplasias del Colon/microbiología , Neoplasias del Colon/terapia , Escherichia coli/genética , Escherichia coli/fisiología , Femenino , Vectores Genéticos/genética , Vectores Genéticos/uso terapéutico , Humanos , Inmunoterapia/métodos , Inmunoterapia/tendencias , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias/microbiología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Inducción de Remisión , Salmonella typhimurium/genética , Salmonella typhimurium/fisiología , Especificidad de la Especie , Organismos Libres de Patógenos Específicos , Biología Sintética/tendencias , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Their biochemical versatility and biotechnological importance make actinomycete bacteria attractive targets for ambitious genetic engineering using the toolkit of synthetic biology. But their complex biology also poses unique challenges. This mini review discusses some of the recent advances in synthetic biology approaches from an actinomycete perspective and presents examples of their application to the rational improvement of industrially relevant strains.