The document discusses various approaches for visualizing metabolic models and networks. It describes how metabolic models are complex mathematical representations of biochemical reactions in cells. It outlines challenges in visualizing large genome-scale models and introduces the concept of zooming user interfaces that allow semantic decomposition of models into modular views at different levels of detail. The document highlights Mimoza, a web-based tool that provides automated multi-level semantic zooming of metabolic models.

1. Visualisation of metabolic data
Anna Zhukova 1
1Institut Pasteur
Bioinformatics and Biostatistics Hub
C3BI, USR 3756 IP CNRS
Paris, France
March 3, 2016
Anna Zhukova Metabolic visualisation March 3, 2016 1 / 22

2. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

3. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Model exchange formats
[Hucka et al., 2003]
XML-like
[Lloyd et al., 2004]
XML-like
[Demir et al., 2010]
OWL ontology
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

4. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Model exchange formats
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

5. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Model exchange formats
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

6. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Model exchange formats
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

7. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Model exchange formats
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

8. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Model visualization formats
[Le Nov`ere et al., 2009]
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

9. Metabolic modelling
Metabolic models are mathematical de-
scriptions of biochemical reactions between
molecules in a cell.
Repositories
[Li et al., 2010]
379 Models annotated with metabolic
process
[Kanehisa et al., 2012]
Pathways
[Alc´antara et al., 2012]
Reactions
Anna Zhukova Metabolic visualisation March 3, 2016 2 / 22

10. Size of metabolic models
Pathway-scale – up to hundreds of reactions
Genome-scale (GSM) – thousands of reactions
98 Bacteria, 39 Eukaryota, 6 Archaea
[systemsbiology.ucsd.edu/InSilicoOrganisms/OtherOrganisms]
E. coli [Smallbone, 2013] – 2 168 reactions
S. cerevisiae [Aung et al., 2013] – 2 352 reactions
H. sapiens [Thiele et al., 2013] – 7 440 reactions
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11. Genome-scale models are complicated
Anna Zhukova Metabolic visualisation March 3, 2016 4 / 22

12. Genome-scale models are complicated
Anna Zhukova Metabolic visualisation March 3, 2016 4 / 22

13. Organisation and visualisation of metabolic models
Scale-free networks: fraction of nodes with k connections P(k) ∼ k−γ
, where
typically 2 < γ < 3 [Jeong et al., 2000].
Few hub metabolites, common for most networks:
H+
, H2O, O2, phosphate, ADP, ATP, NADP, NAD+
, etc. (∼ 5%)
Anna Zhukova Metabolic visualisation March 3, 2016 5 / 22

14. Organisation and visualisation of metabolic models
Scale-free networks: fraction of nodes with k connections P(k) ∼ k−γ
, where
typically 2 < γ < 3 [Jeong et al., 2000].
Few hub metabolites, common for most networks:
H+
, H2O, O2, phosphate, ADP, ATP, NADP, NAD+
, etc. (∼ 5%)
– need to be multiplicated
Anna Zhukova Metabolic visualisation March 3, 2016 5 / 22

15. Organisation and visualisation of metabolic models
Scale-free networks: fraction of nodes with k connections P(k) ∼ k−γ
, where
typically 2 < γ < 3 [Jeong et al., 2000].
Few hub metabolites, common for most networks:
H+
, H2O, O2, phosphate, ADP, ATP, NADP, NAD+
, etc. (∼ 5%)
– need to be multiplicated
Nested compartments
mitochondrion ⊂ mitochondrion membrane ⊂ cytoplasm
Anna Zhukova Metabolic visualisation March 3, 2016 5 / 22

16. Organisation and visualisation of metabolic models
Scale-free networks: fraction of nodes with k connections P(k) ∼ k−γ
, where
typically 2 < γ < 3 [Jeong et al., 2000].
Few hub metabolites, common for most networks:
H+
, H2O, O2, phosphate, ADP, ATP, NADP, NAD+
, etc. (∼ 5%)
– need to be multiplicated
Nested compartments
mitochondrion ⊂ mitochondrion membrane ⊂ cytoplasm
– ’cellular component’ in the Gene Ontology [Ashburner et al., 2000]
Anna Zhukova Metabolic visualisation March 3, 2016 5 / 22

17. Organisation and visualisation of metabolic models
Scale-free networks: fraction of nodes with k connections P(k) ∼ k−γ
, where
typically 2 < γ < 3 [Jeong et al., 2000].
Few hub metabolites, common for most networks:
H+
, H2O, O2, phosphate, ADP, ATP, NADP, NAD+
, etc. (∼ 5%)
– need to be multiplicated
Nested compartments
mitochondrion ⊂ mitochondrion membrane ⊂ cytoplasm
– ’cellular component’ in the Gene Ontology [Ashburner et al., 2000]
Cycles/cascades..
TCA cycle
Glycolysis
Anna Zhukova Metabolic visualisation March 3, 2016 5 / 22

18. Organisation and visualisation of metabolic models
Scale-free networks: fraction of nodes with k connections P(k) ∼ k−γ
, where
typically 2 < γ < 3 [Jeong et al., 2000].
Few hub metabolites, common for most networks:
H+
, H2O, O2, phosphate, ADP, ATP, NADP, NAD+
, etc. (∼ 5%)
– need to be multiplicated
Nested compartments
mitochondrion ⊂ mitochondrion membrane ⊂ cytoplasm
– ’cellular component’ in the Gene Ontology [Ashburner et al., 2000]
Cycles/cascades..
TCA cycle – circular layout
Glycolysis – hierarchical layout
Anna Zhukova Metabolic visualisation March 3, 2016 5 / 22

19. Anna Zhukova Metabolic visualisation March 3, 2016 6 / 22

20. I wanna see a pathway!
KEGG
[Kanehisa et al., 2012]
WikiPathways
[Kutmon et al., 2015]
TCA cycle
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21. I wanna see a pathway!
KEGG
[Kanehisa et al., 2012]
WikiPathways
[Kutmon et al., 2015]
TCA cycle
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22. Anna Zhukova Metabolic visualisation March 3, 2016 8 / 22

23. I wanna see my small model!
Desktop tools
Cytoscape
[Cline et al., 2007]
CellDesigner
[Funahashi et al., 2008]
VANTED
[Rohn et al., 2012]
Web-based tools
JWS online
[Olivier and Snoep, 2004]
MetDraw
[Jensen et al., 2014]
Mimoza
[Zhukova and Sher-
man, 2015]
TCA cycle [Nazaret et al., 2008]
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24. I wanna see my small model!
Desktop tools
Cytoscape
[Cline et al., 2007]
CellDesigner
[Funahashi et al., 2008]
VANTED
[Rohn et al., 2012]
Web-based tools
JWS online
[Olivier and Snoep, 2004]
MetDraw
[Jensen et al., 2014]
Mimoza
[Zhukova and Sher-
man, 2015]
TCA cycle [Nazaret et al., 2008]
Anna Zhukova Metabolic visualisation March 3, 2016 9 / 22

25. I wanna see my small model!
Desktop tools
Cytoscape
[Cline et al., 2007]
CellDesigner
[Funahashi et al., 2008]
VANTED
[Rohn et al., 2012]
Web-based tools
JWS online
[Olivier and Snoep, 2004]
MetDraw
[Jensen et al., 2014]
Mimoza
[Zhukova and Sher-
man, 2015]
TCA cycle [Nazaret et al., 2008]
Anna Zhukova Metabolic visualisation March 3, 2016 9 / 22

26. I wanna see my small model!
Desktop tools
Cytoscape
[Cline et al., 2007]
CellDesigner
[Funahashi et al., 2008]
VANTED
[Rohn et al., 2012]
Web-based tools
JWS online
[Olivier and Snoep, 2004]
MetDraw
[Jensen et al., 2014]
Mimoza
[Zhukova and Sher-
man, 2015]
TCA cycle [Nazaret et al., 2008]
Anna Zhukova Metabolic visualisation March 3, 2016 9 / 22

27. I wanna see my small model!
Desktop tools
Cytoscape
[Cline et al., 2007]
CellDesigner
[Funahashi et al., 2008]
VANTED
[Rohn et al., 2012]
Web-based tools
JWS online
[Olivier and Snoep, 2004]
MetDraw
[Jensen et al., 2014]
Mimoza
[Zhukova and Sher-
man, 2015]
TCA cycle [Nazaret et al., 2008]
Anna Zhukova Metabolic visualisation March 3, 2016 9 / 22

28. I wanna see my small model!
Desktop tools
Cytoscape
[Cline et al., 2007]
CellDesigner
[Funahashi et al., 2008]
VANTED
[Rohn et al., 2012]
Web-based tools
JWS online
[Olivier and Snoep, 2004]
MetDraw
[Jensen et al., 2014]
Mimoza
[Zhukova and Sher-
man, 2015]
TCA cycle [Nazaret et al., 2008]
Anna Zhukova Metabolic visualisation March 3, 2016 9 / 22

29. Anna Zhukova Metabolic visualisation March 3, 2016 10 / 22

30. I wanna see my huge model! Classical approach?
Desktop tools?
CellDesigner
[Funahashi et al., 2008]
Web-based tools?
MetDraw
[Jensen et al., 2014]
S. cerevisiae [Aung et al., 2013]
Anna Zhukova Metabolic visualisation March 3, 2016 11 / 22

31. I wanna see my huge model! Classical approach?
Desktop tools?
CellDesigner
[Funahashi et al., 2008]
Web-based tools?
MetDraw
[Jensen et al., 2014]
S. cerevisiae [Aung et al., 2013]
Anna Zhukova Metabolic visualisation March 3, 2016 11 / 22

32. Genome-scale models are complicated
Anna Zhukova Metabolic visualisation March 3, 2016 12 / 22

33. Zooming User Interface (ZUI)
Zoom
geometric zoom
semantic zoom
Anna Zhukova Metabolic visualisation March 3, 2016 13 / 22

34. Zooming User Interface (ZUI)
Zoom
geometric zoom
semantic zoom
Anna Zhukova Metabolic visualisation March 3, 2016 13 / 22

35. Zooming User Interface (ZUI)
Zoom
geometric zoom
semantic zoom
Anna Zhukova Metabolic visualisation March 3, 2016 13 / 22

36. Zooming User Interface (ZUI)
Zoom
geometric zoom
semantic zoom
Decomposition into modules
compartments
pathways
similar elements
Anna Zhukova Metabolic visualisation March 3, 2016 13 / 22

37. Mimoza [mimoza.bordeaux.inria.fr]
3-levels of semantic zoom:
1 full model
2 generalized view
3 compartment view
user’s model as input
fully automatic
Anna Zhukova Metabolic visualisation March 3, 2016 14 / 22

38. Mimoza [mimoza.bordeaux.inria.fr]
3-levels of semantic zoom:
1 full model
2 generalized view
3 compartment view
user’s model as input
fully automatic
Anna Zhukova Metabolic visualisation March 3, 2016 14 / 22

39. Mimoza [mimoza.bordeaux.inria.fr]
3-levels of semantic zoom:
1 full model
2 generalized view
3 compartment view
user’s model as input
fully automatic
Anna Zhukova Metabolic visualisation March 3, 2016 14 / 22

40. Mimoza [mimoza.bordeaux.inria.fr]
3-levels of semantic zoom:
1 full model
2 generalized view
3 compartment view
user’s model as input
fully automatic
Anna Zhukova Metabolic visualisation March 3, 2016 15 / 22

41. NaviCell [Kuperstein et al., 2013]
• large maps of molecular interactions
:) user’s model as input
:( layout is not automatic, user has to:
1 create a map in CellDesigner
2 export as an image
3 produce intermediate views in a graphical designer
4 (optionally) split the map into submaps
Anna Zhukova Metabolic visualisation March 3, 2016 16 / 22

42. Anna Zhukova Metabolic visualisation March 3, 2016 17 / 22

43. Genome Projector [Arakawa et al., 2009]
• zoomable genome map with multiple views
• 320 bacterial genomes
• based on Roche Biochemical Pathway wall chart
• overlay layers to highlight organism-specific reactions
:( only geometric zooming
Anna Zhukova Metabolic visualisation March 3, 2016 18 / 22

44. Cellular Overview [Latendresse et al., 2011]
• maps of organisms in BioCyc [Caspi et al., 2012]
• pathway-oriented
:( no compartments
:( only geometric zooming
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45. Reactome pathway browser [Croft et al., 2013]
• manually curated pathways for 19 organisms
• pathway-oriented
:) two semantic zoom levels:
1 general representation of organism’s pathways
2 detailed pathway submaps
:) compartments
Anna Zhukova Metabolic visualisation March 3, 2016 20 / 22

46. Escher [Zachary et al., 2015]
• manually curated pathways for human, S.cerevisiae, and E.coli
:) user can edit layout and add data
:( only geometric zoom
:( limited selection of pathways
Anna Zhukova Metabolic visualisation March 3, 2016 21 / 22

47. And the winner is...
Manual layout
Anna Zhukova Metabolic visualisation March 3, 2016 22 / 22

48. And the winner is...
Manual layout ZUI
Anna Zhukova Metabolic visualisation March 3, 2016 22 / 22

49. And the winner is...
Manual layout ZUI
Thank you for your attention!
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