scholarly journals Designing Minimal Genomes Using Whole-Cell Models

2018 ◽  
Author(s):  
Joshua Rees ◽  
Oliver Chalkley ◽  
Sophie Landon ◽  
Oliver Purcell ◽  
Lucia Marucci ◽  
...  
Keyword(s):  
In Silico ◽  
Genome Engineering ◽  
Cell Model ◽  
Mycoplasma Genitalium ◽  
Computational Design ◽  
Functional Assay ◽  
Proof Of Concept ◽  
Computational Tools ◽  
Whole Cell ◽  
Genome Design

AbstractIn the future, entire genomes tailored to specific functions and environments could be designed using computational tools. However, computational tools for genome design are currently scarce. Here we present algorithms that enable the use of design-simulate-test cycles for genome design, using genome minimisation as a proof-of-concept. Minimal genomes are ideal for this purpose as they have a simple functional assay, the cell either replicates or not. We used the first (and currently only published) whole-cell model, for the bacterium Mycoplasma genitalium. Our computational design-simulate-test cycles discovered novel in-silico minimal genomes smaller than JCVI-Syn3.0, a bacteria with, currently, the smallest genome that can be grown in pure culture. In the process, we identified 10 low essentiality genes, 18 high essentiality genes, and produced evidence for at least two Mycoplasma genitalium in-silico minimal genomes. This work brings combined computational and laboratory genome engineering a step closer.

scholarly journals Testing theoretical minimal genomes using whole-cell models

2020 ◽  
Author(s):  
Joshua Rees-Garbutt ◽  
Jake Rightmyer ◽  
Oliver Chalkley ◽  
Lucia Marucci ◽  
Claire Grierson
Keyword(s):  
In Silico ◽  
Cell Model ◽  
Mycoplasma Genitalium ◽  
Essential Genes ◽  
Cellular Division ◽  
Whole Cell ◽  
Gene Sets ◽  
Dividing Cells ◽  
Species Specific

AbstractThe minimal gene set for life has often been theorised, with at least ten produced for Mycoplasma genitalium (M. genitalium). Due to the difficulty of using M. genitalium in the lab, combined with its long replication time of 12 - 15 hours, none of these theoretical minimal genomes have been tested, even with modern techniques. The publication of the M. genitalium whole-cell model provided the first opportunity to test them, simulating the genome edits in-silico. We simulated eight minimal gene sets from the literature, finding that they produced in-silico cells that did not divide. Using knowledge from previous research, we reintroduced specific essential and low essential genes in-silico; enabling cellular division. This reinforces the need to identify species-specific low essential genes and their interactions. Any genome designs created using the currently incomplete and fragmented gene essentiality information, will very likely require in-vivo reintroductions to correct issues and produce dividing cells.

scholarly journals The genome design suite: enabling massive in-silico experiments to design genomes

2019 ◽  
Author(s):  
Oliver Chalkley ◽  
Oliver Purcell ◽  
Claire Grierson ◽  
Lucia Marucci
Keyword(s):  
In Silico ◽  
Large Scale ◽  
Computational Models ◽  
Solution Space ◽  
Mycoplasma Genitalium ◽  
Specific Model ◽  
Computer Clusters ◽  
Optimisation Algorithms ◽  
Genome Design

AbstractMotivationComputational biology is a rapidly developing field, and in-silico methods are being developed to aid the design of genomes to create cells with optimised phenotypes. Two barriers to progress are that in-silico methods are often only developed on a particular implementation of a specific model (e.g. COBRA metabolic models) and models with longer simulation time inhibit the large-scale in-silico experiments required to search the vast solution space of genome combinations.ResultsHere we present the genome design suite (PyGDS) which is a suite of Python tools to aid the development of in-silico genome design methods. PyGDS provides a framework with which to implement phenotype optimisation algorithms on computational models across computer clusters. The framework is abstract allowing it to be adapted to utilise different computer clusters, optimisation algorithms, or design goals. It implements an abstract multi-generation algorithm structure allowing algorithms to avoid maximum simulation times on clusters and enabling iterative learning in the algorithm. The initial case study will be genome reduction algorithms on a whole-cell model of Mycoplasma genitalium for a PBS/Torque cluster and a Slurm cluster.AvailabilityThe genome design suite is written in Python for Linux operating systems and is available from GitHub on a GPL open-source [email protected], [email protected], and [email protected].

scholarly journals Toward a Whole Cell Model of Mycoplasma Genitalium

2011 ◽  
Vol 100 (3) ◽  
pp. 32a ◽  
Author(s):  
Jonathan R. Karr ◽  
Jayodita C. Sanghvi ◽  
Jared M. Jacobs ◽  
Markus W. Covert
Keyword(s):  
Cell Model ◽  
Mycoplasma Genitalium ◽  
Whole Cell

scholarly journals Genome-driven cell engineering review: in vivo and in silico metabolic and genome engineering

2019 ◽  
Vol 63 (2) ◽  
pp. 267-284 ◽  
Author(s):  
Sophie Landon ◽  
Joshua Rees-Garbutt ◽  
Lucia Marucci ◽  
Claire Grierson
Keyword(s):  
Computational Models ◽  
Genome Engineering ◽  
Computational Design ◽  
Biological Research ◽  
Cellular Processes ◽  
Recent Developments ◽  
Entire Cell ◽  
Design Algorithms ◽  
Genome Design

Abstract Producing ‘designer cells’ with specific functions is potentially feasible in the near future. Recent developments, including whole-cell models, genome design algorithms and gene editing tools, have advanced the possibility of combining biological research and mathematical modelling to further understand and better design cellular processes. In this review, we will explore computational and experimental approaches used for metabolic and genome design. We will highlight the relevance of modelling in this process, and challenges associated with the generation of quantitative predictions about cell behaviour as a whole: although many cellular processes are well understood at the subsystem level, it has proved a hugely complex task to integrate separate components together to model and study an entire cell. We explore these developments, highlighting where computational design algorithms compensate for missing cellular information and underlining where computational models can complement and reduce lab experimentation. We will examine issues and illuminate the next steps for genome engineering.

scholarly journals A Whole Cell Model of Mycoplasma Genitalium Elucidates Mechanisms of Bacterial Replication

2012 ◽  
Vol 102 (3) ◽  
pp. 731a ◽  
Author(s):  
Jonathan R. Karr ◽  
Jayodita C. Sanghvi ◽  
Jared M. Jacobs ◽  
Derek N. Macklin ◽  
Markus W. Covert
Keyword(s):  
Cell Model ◽  
Mycoplasma Genitalium ◽  
Whole Cell ◽  
Bacterial Replication

Molecular Design of Peptide-Fc Fusion Drugs

2019 ◽  
Vol 20 (3) ◽  
pp. 203-208 ◽  
Author(s):  
Lin Ning ◽  
Bifang He ◽  
Peng Zhou ◽  
Ratmir Derda ◽  
Jian Huang
Keyword(s):  
Rational Design ◽  
Molecular Design ◽  
Computational Design ◽  
Fusion Technology ◽  
Computational Tools ◽  
Open Questions ◽  
Biological Therapeutics ◽  
Key Steps ◽  
Computational Resources ◽  
Tools And Methods

Background:Peptide-Fc fusion drugs, also known as peptibodies, are a category of biological therapeutics in which the Fc region of an antibody is genetically fused to a peptide of interest. However, to develop such kind of drugs is laborious and expensive. Rational design is urgently needed.Methods:We summarized the key steps in peptide-Fc fusion technology and stressed the main computational resources, tools, and methods that had been used in the rational design of peptide-Fc fusion drugs. We also raised open questions about the computer-aided molecular design of peptide-Fc.Results:The design of peptibody consists of four steps. First, identify peptide leads from native ligands, biopanning, and computational design or prediction. Second, select the proper Fc region from different classes or subclasses of immunoglobulin. Third, fuse the peptide leads and Fc together properly. At last, evaluate the immunogenicity of the constructs. At each step, there are quite a few useful resources and computational tools.Conclusion:Reviewing the molecular design of peptibody will certainly help make the transition from peptide leads to drugs on the market quicker and cheaper.

scholarly journals A Self-Assembling Whole-Cell Vaccine Antigen Presentation Platform

2018 ◽  
Vol 200 (15) ◽  
Author(s):  
Julie Liao ◽  
Daniel R. Smith ◽  
Jóhanna Brynjarsdóttir ◽  
Paula I. Watnick
Keyword(s):  
Vibrio Cholerae ◽  
Bacterial Biofilm ◽  
Cell Vaccine ◽  
Secreted Protein ◽  
Proof Of Concept ◽  
Whole Cell ◽  
Content Type ◽  
Self Assembling ◽  
Whole Cell Vaccine ◽  
Common Infection

ABSTRACTDiarrhea is the most common infection in children under the age of 5 years worldwide. In spite of this, only a few vaccines to treat infectious diarrhea exist, and many of the available vaccines are sparingly and sporadically administered. Major obstacles to the development and widespread implementation of vaccination include the ease and cost of production, distribution, and delivery. Here we present a novel, customizable, and self-assembling vaccine platform that exploits theVibrio choleraebacterial biofilm matrix for antigen presentation. We use this technology to create a proof-of-concept, live-attenuated whole-cell vaccine that is boosted by spontaneous association of a secreted protein antigen with the cell surface. Sublingual administration of this live-attenuated vaccine to mice confers protection againstV. choleraechallenge and elicits the production of antigen-specific IgA in stool. The platform presented here enables the development of antigen-boosted vaccines that are simple to produce and deliver, addressing many of the obstacles to vaccination against diarrheal diseases. This may also serve as a paradigm for the development of broadly protective biofilm-based vaccines against other mucosal infections.IMPORTANCEDiarrheal disease is the most common infection afflicting children worldwide. In resource-poor settings, these infections are correlated with cognitive delay, stunted growth, and premature death. With the development of efficacious, affordable, and easily administered vaccines, such infections could be prevented. While a major focus of research on biofilms has been their elimination, here we harness the bacterial biofilm to create a customizable platform for cost-effective, whole-cell mucosal vaccines that self-incorporate secreted protein antigens. We use this platform to develop a sublingually administered live-attenuated prototype vaccine based onVibrio cholerae. This serves not only as a proof of concept for a multivalent vaccine against common bacterial enteric pathogens but also as a paradigm for vaccines utilizing other bacterial biofilms to target mucosal infections.

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