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1.
Sci Eng Ethics ; 29(2): 9, 2023 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-36882674

RESUMO

Synthetic biologists design and engineer organisms for a better and more sustainable future. While the manifold prospects are encouraging, concerns about the uncertain risks of genome editing affect public opinion as well as local regulations. As a consequence, biosafety and associated concepts, such as the Safe-by-design framework and genetic safeguard technologies, have gained notoriety and occupy a central position in the conversation about genetically modified organisms. Yet, as regulatory interest and academic research in genetic safeguard technologies advance, the implementation in industrial biotechnology, a sector that is already employing engineered microorganisms, lags behind. The main goal of this work is to explore the utilization of genetic safeguard technologies for designing biosafety in industrial biotechnology. Based on our results, we posit that biosafety is a case of a changing value, by means of further specification of how to realize biosafety. Our investigation is inspired by the Value Sensitive Design framework, to investigate scientific and technological choices in their appropriate social context. Our findings discuss stakeholder norms for biosafety, reasonings about genetic safeguards, and how these impact the practice of designing for biosafety. We show that tensions between stakeholders occur at the level of norms, and that prior stakeholder alignment is crucial for value specification to happen in practice. Finally, we elaborate in different reasonings about genetic safeguards for biosafety and conclude that, in absence of a common multi-stakeholder effort, the differences in informal biosafety norms and the disparity in biosafety thinking could end up leading to design requirements for compliance instead of for safety.


Assuntos
Biotecnologia , Contenção de Riscos Biológicos , Humanos , Comunicação , Engenharia , Fenbendazol
2.
BMC Microbiol ; 21(1): 9, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407113

RESUMO

BACKGROUND: Pseudomonas putida KT2440 is a metabolically versatile, HV1-certified, genetically accessible, and thus interesting microbial chassis for biotechnological applications. However, its obligate aerobic nature hampers production of oxygen sensitive products and drives up costs in large scale fermentation. The inability to perform anaerobic fermentation has been attributed to insufficient ATP production and an inability to produce pyrimidines under these conditions. Addressing these bottlenecks enabled growth under micro-oxic conditions but does not lead to growth or survival under anoxic conditions. RESULTS: Here, a data-driven approach was used to develop a rational design for a P. putida KT2440 derivative strain capable of anaerobic respiration. To come to the design, data derived from a genome comparison of 1628 Pseudomonas strains was combined with genome-scale metabolic modelling simulations and a transcriptome dataset of 47 samples representing 14 environmental conditions from the facultative anaerobe Pseudomonas aeruginosa. CONCLUSIONS: The results indicate that the implementation of anaerobic respiration in P. putida KT2440 would require at least 49 additional genes of known function, at least 8 genes encoding proteins of unknown function, and 3 externally added vitamins.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Engenharia Metabólica/métodos , Pseudomonas putida/crescimento & desenvolvimento , Anaerobiose , Simulação por Computador , Bases de Dados Genéticas , Fermentação , Perfilação da Expressão Gênica , Viabilidade Microbiana , Pseudomonas putida/genética , Pseudomonas putida/metabolismo , Pirimidinas/metabolismo
3.
Microb Cell Fact ; 18(1): 179, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640713

RESUMO

BACKGROUND: Pseudomonas putida is a metabolically versatile, genetically accessible, and stress-robust species with outstanding potential to be used as a workhorse for industrial applications. While industry recognises the importance of robustness under micro-oxic conditions for a stable production process, the obligate aerobic nature of P. putida, attributed to its inability to produce sufficient ATP and maintain its redox balance without molecular oxygen, severely limits its use for biotechnology applications. RESULTS: Here, a combination of genome-scale metabolic modelling and comparative genomics is used to pinpoint essential [Formula: see text]-dependent processes. These explain the inability of the strain to grow under anoxic conditions: a deficient ATP generation and an inability to synthesize essential metabolites. Based on this, several P. putida recombinant strains were constructed harbouring acetate kinase from Escherichia coli for ATP production, and a class I dihydroorotate dehydrogenase and a class III anaerobic ribonucleotide triphosphate reductase from Lactobacillus lactis for the synthesis of essential metabolites. Initial computational designs were fine-tuned by means of adaptive laboratory evolution. CONCLUSIONS: We demonstrated the value of combining in silico approaches, experimental validation and adaptive laboratory evolution for microbial design by making the strictly aerobic Pseudomonas putida able to grow under micro-oxic conditions.


Assuntos
Proteínas de Bactérias/genética , Microrganismos Geneticamente Modificados , Oxigênio/metabolismo , Pseudomonas putida , Acetato Quinase/genética , Acetato Quinase/metabolismo , Anaerobiose , Proteínas de Bactérias/metabolismo , Di-Hidro-Orotato Desidrogenase , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Genômica , Lactobacillus/enzimologia , Lactobacillus/metabolismo , Engenharia Metabólica , Microrganismos Geneticamente Modificados/genética , Microrganismos Geneticamente Modificados/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Pseudomonas putida/genética , Pseudomonas putida/metabolismo , Ribonucleotídeo Redutases/genética , Ribonucleotídeo Redutases/metabolismo
4.
Methods Cell Biol ; 183: 51-113, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38548421

RESUMO

Glioblastoma (GBM) remains an orphan cancer disease with poor outcome. Novel treatment strategies are needed. Immunotherapy has several modes of action. The addition of active specific immunotherapy with dendritic cell vaccines resulted in improved overall survival of patients. Integration of DC vaccination within the first-line combined treatment became a challenge, and immunogenic cell death immunotherapy during chemotherapy was introduced. We used a retrospective analysis using real world data to evaluate the complex combined treatment, which included individualized multimodal immunotherapy during and after standard of care, and which required adaptations during treatment, and found a further improvement of overall survival. We also discuss the use of real world data as evidence. Novel strategies to move the field of individualized multimodal immunotherapy forward for GBM patients are reviewed.


Assuntos
Neoplasias Encefálicas , Vacinas Anticâncer , Glioblastoma , Vírus Oncolíticos , Humanos , Glioblastoma/terapia , Vírus Oncolíticos/genética , Neoplasias Encefálicas/terapia , Estudos Retrospectivos , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/metabolismo
5.
Biomedicines ; 11(7)2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37509433

RESUMO

The fundamental aim of healthcare is to improve overall health of the population by providing state-of-the-art healthcare for individuals at an affordable cost. The foundation for this system is largely referred to as "evidence-based medicine". Too often, evidence-based medicine is based solely on so-called "best research evidence", collected through randomized controlled trials while disregarding clinical expertise and patient expectations. As healthcare gravitates towards personalized and individualized medicine, such external clinical (research) evidence can inform, but never replace, individual clinical expertise. This applies in particular to orphan diseases, for which clinical trials are methodologically particularly problematic, and evidence derived from them is often questionable. Evidence-based medicine constitutes a complex process to allow doctors and patients to select the best possible solutions for each individual based on rapidly developing new therapeutic directions. This requires a revisit of the foundations of evidence-based medicine. A proposition as to how to manage evidence-based data in individualized immune-oncology is presented here.

6.
Trends Biotechnol ; 39(12): 1240-1242, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34024649

RESUMO

Few biotechnology innovations make it through the Valley of Death to markets. Based on our experience with academia, technology transfer offices, and industry, we provide insights into differences in operating levels, how to best traverse the Valley of Death, and ways to foster more innovation towards market implementation.


Assuntos
Biotecnologia , Transferência de Tecnologia , Difusão de Inovações , Humanos , Indústrias
7.
Microb Biotechnol ; 12(5): 845-848, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31199068

RESUMO

Pseudomonas putida is rapidly becoming a workhorse for industrial production due to its metabolic versatility, genetic accessibility and stress-resistance properties. The P. putida strain KT2440 is often described as Generally Regarded as Safe, or GRAS, indicating the strain is safe to use as food additive. This description is incorrect. P. putida KT2440 is classified by the FDA as HV1 certified, indicating it is safe to use in a P1 or ML1 environment.


Assuntos
Microbiologia de Alimentos/normas , Inocuidade dos Alimentos/métodos , Microbiologia Industrial/normas , Pseudomonas putida/patogenicidade , Microbiologia de Alimentos/métodos , Microbiologia Industrial/métodos , Pseudomonas putida/crescimento & desenvolvimento , Pseudomonas putida/metabolismo , Estados Unidos , United States Food and Drug Administration
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