Learn how to use tools in systems biology to model metabolic interactions within microbial communities. The workshop will cover background in constrained based modeling and show applications of modelling single and multiple species.
2. What are we going to do today?
1. Motivation – Eugen
2. Introduction – Federico
3. Theory of BacArena – Eugen
4. BacArena practical – Eugen
5. Social event – Susanne
4. Jeong et al, Nature, 2011
Why I study Systems Biology
Emergence: Phenomenon in which
larger components arise through local
interactions of smaller components such
that larger components have additional
properties
Systems biology: Study of the
interactions between the components of
biological systems, and how these
interactions give rise to the function of
that system
5. Systems Biology Philosophies
Top Down
• Data driven
• Network inference
• Statistical modeling
Bottom Up
• Hypothesis driven
• Model formulation
• Model assembly
Genes Metabolites Proteins ….
Organelles Metabolism .…
Organisms .…
Ecosystem
6. Systems Biology Philosophies
Top Down
• Data driven
• Network inference
• Statistical modeling
Bottom Up
• Hypothesis driven
• Model formulation
• Model assembly
Genes Metabolites Proteins ….
Organelles Metabolism .…
Organisms .…
Ecosystem
15. In few words....
• Growth measurement and type of metabolism in a specific environment
• Strain characterisation: required media for growth
• Essential enzymes for growth
• Biotechnological applications: strain engineering
18. Biofilm Gut microbiota
http://ausubellab.mgh.harvard.edu/picturehtml/pic20.html
Zoetendal, Raes et al. (2012)
Pseudomonas aeruginosa biofilm
Biofilm microcolony formed by P. aeruginosa strain PA14
carrying GFP. Biofilms were cultivated in flow chambers under
continuous culture conditions. Analysis of biofilm spatial
structures were done using confocal scanning laser microscopy
after 9 hours of incubation.
From single organism to community modeling
21. A
B
Cr1
r2 r3
e1
e2
e3
D
e4
r4 r5
panModel
• Limited “a priori” knowledge
• No attempt to segregate reactions by strains / species
• Exploration of metabolic potential of an entire community
more then interactions between community members
Enzyme soup
24. Cumulative biomass as objective function
o Combination of the biomass functions for each species: same
abundance for each species
o Weighted combination of the biomass functions for each species on
the base of their presence in experimental active communities
o Data integration B𝑐 = 𝑋𝐵1 + YB2 … . +ZBn
Cumulative biomass
25. Simulating ecosystems: modeling bacteria communities
o Enzyme soup
Exploring community potential
No Individuals representation
o Compartmentalization
Abundances fixed and not changing
No concentrations
No time and space resolved simulation
Variable control problem
predict uptake and secretion of
metabolites with known species
abundances
predict community growth
with known uptake and secretion rates
o Agent Based modeling integration
28. BacArena – How it works
Models of
different or
same species
Integration of constrained and agent based modeling
29. BacArena – How it works
Models of
different or
same species
Movement &
Replication of
species
30. BacArena – How it works
Models of
different or
same species
Movement &
Replication of
species
Metabolite
concentration
in the Arena
31. BacArena – How it works
Models of
different or
same species
Movement &
replication of
species
Metabolite
concentration
in the Arena
Uptake &
Secretion of
metabolites
32. BacArena – How it works
Models of
different or
same species
Movement &
replication of
species
Metabolite
concentration
in the Arena
Uptake &
Secretion of
metabolites
Interactions
come from
exchange
33. BacArena – How it works
Models of
different or
same species
Movement &
replication of
species
Metabolite
concentration
in the Arena
Uptake &
Secretion of
metabolites
Interactions
come from
exchange
Metabolic
Phenotypes in
Individuals
34. BacArena – How it works
Models of
different or
same species
Movement &
replication of
species
Metabolite
concentration
in the Arena
Uptake &
Secretion of
metabolites
Interactions
come from
exchange
Metabolic
Phenotypes in
Individuals
Discrete time steps simulating spatial metabolic dynamics
35. BacArena – How it works
Models of
different or
same species
Movement &
replication of
species
Metabolite
concentration
in the Arena
Uptake &
Secretion of
metabolites
Interactions
come from
exchange
Metabolic
Phenotypes in
Individuals
Discrete time steps simulating spatial metabolic dynamics
How do I know the model
parameters?
36. Parameterize the Model with
Experimental Data
Bauer et al, in revision
Values are taken from experimental literature,
but you can also plug in your own data
37. Programming Details
• R package deposited in CRAN
• Matrix based implementation
• Modular, extendible code
• Object oriented programming
• Arena environment
• Bac species & models
• Substance metabolites
• Eval evaluate simulation
• Separate simulation & analysis
38. Programming Details
• R package deposited in CRAN
• Matrix based implementation
• Modular, extendible code
• Object oriented programming
• Arena environment
• Bac species & models
• Substance metabolites
• Eval evaluate simulation
• Separate simulation & analysis
39. Programming Details
• R package deposited in CRAN
• Matrix based implementation
• Modular, extendible code
• Object oriented programming
• Arena environment
• Bac species & models
• Substance metabolites
• Eval evaluate simulation
• Separate simulation & analysis
40. Programming Details
• R package deposited in CRAN
• Matrix based implementation
• Modular, extendible code
• Object oriented programming
• Arena environment
• Bac species & models
• Substance metabolites
• Eval evaluate simulation
• Separate simulation & analysis
41. Programming Details
• R package deposited in CRAN
• Matrix based implementation
• Modular, extendible code
• Object oriented programming
• Arena environment
• Bac species & models
• Substance metabolites
• Eval evaluate simulation
• Separate simulation & analysis
42. Now let’s start the
Demonstration
Everything will be uploaded here:
http://rsg-luxembourg.iscbsc.org/
43. Availability of BacArena
• Paper is currently under revision
• Official version is on CRAN:
• https://CRAN.R-project.org/package=BacArena
• Development version is hosted on GitHub:
• https://github.com/euba/BacArena
45. Conclusions
Metabolism of individual
cells in population
• Top down data integration
• Meta-genomic data
• Meta-transcriptomic data
• Model assumptions
• Metabolite diffusion
• Heterogeneous metabolism
From local interactions
arises complexity
46. Acknowledgments
Molecular Systems
Physiology Group:
Ines Thiele (PI)
Stefania Magnusdottir
Marouen Guebilla
Dmitry Ravcheev
Laurent Heirendt
Alberto Noronha
Federico Baldini
Almut Heinken
Maike Aurich
Christian-Albrechts-Universität Kiel:
Christoph Kaleta
Johannes Zimmermann
Thanks to the HPC facilities of the University of Luxembourg
48. More RSG Courses – Stay Tuned!
20.03. B'RAIN Company Presentation
When? Monday 20.03.2017 from 17:00 to 19:00
Where? Maison du Savoir Room 4.410
05.04. Latex Workshop
When? Monday 05.04.2017 from 17:00 to 19:00
Where? Maison du Savoir Room 4.410
12.04. Git Workshop
When? Wednesday 12.04.2017 from 17:00 to 19:00
Where? TBA