Multicellular metabolic models and methods

• US 20060147899A1
• Filed: 07/21/2005
• Published: 07/06/2006
• Est. Priority Date: 03/29/2002
• Status: Active Grant

• Current Assignee: Genomatica Incorporated
• Original Assignee: Genomatica Incorporated
• Inventors: Schilling, Christophe H., Famili, Imandokht
• Granted Patent: US 8,949,032 B2
• Time in Patent Office: Days
• US Class Current: 435/4
• CPC Class Codes: G01N 2500/10 involving cells
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 5/00 ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
• CPC Class Codes: G16B 50/00 ICT programming tools or database systems specially adapted for bioinformatics
• CPC Class Codes: G16B 50/10 Ontologies; Annotations
• CPC Class Codes: G16C 20/30 Prediction of properties of chemical compounds, compositions or mixtures

Abstract

The invention provides a computer readable medium or media, having: (a) a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) a constraint set for said plurality of reactions for said first, second and third data structures, and (e) commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells. The first, second and third data structures also can include a plurality of data structures. Additionally provided is a method for predicting a physiological function of a multicellular organism. The method includes: (a) providing a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) providing a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) providing a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) providing a constraint set for said plurality of reactions for said first, second and third data structures; (e) providing an objective function, and (f) determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.

Claims

1. A computer readable medium or media, comprising:

(a) a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(b) a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(c) a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(d) a constraint set for said plurality of reactions for said first, second and third data structures, and

(e) commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.

2. The computer readable medium or media of claim 1, wherein said first data structure comprises a first reaction network.

3. The computer readable medium or media of claim 1, wherein said second data structure comprises a second reaction network.

4. The computer readable medium or media of claim 1, wherein said first or second data structures comprise a plurality of reaction networks.

5. The computer readable medium or media of claim 1, further comprising one or more fourth data structures and one or more fourth constraint sets, each fourth data structure relating a plurality of reactants to a plurality of reactions from a one or more third cells within a multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product.

6. The computer readable medium or media of claim 5, wherein said one or more fourth data structures comprises a plurality of data structures.

7. The computer readable medium or media of claim 6, wherein said plurality of data structures comprise a data structure for a plurality of different cells.

8. The computer readable medium or media of claim 6, wherein said plurality of data structures comprise a data structure for a plurality of different cell types.

9. The computer readable medium or media of claim 7 or 8, wherein said one or more third cells comprise at least 4 cells, 5 cells, 6 cells, 7 cells, 8 cells, 9 cells, 10 cells, 100 cells, 1000 cells, 5000 cells, 10,000 cells or more.

10. The computer readable medium or media of claim 1, wherein said first and second cells comprise eukaryotic cells.

11. The computer readable medium or media of claim 1, wherein said first and second cells comprise prokaryotic cells.

12. The computer readable medium or media of claim 10, wherein said first and second eukaryotic cells comprise cells of the same tissue or organ.

13. The computer readable medium or media of claim 10, wherein said first and second eukaryotic cells comprise cells of different tissues or organs.

14. The computer readable medium or media of claim 1, wherein at least one of said reactions is annotated to indicate an associated gene.

16. The computer readable medium or media of claim 1, wherein at least one of said reactions is a regulated reaction.

17. The computer readable medium or media of claim 16, wherein said constraint set includes a variable constraint for said regulated reaction.

18. The computer readable medium or media of claim 1, wherein said at least one intra-system reaction comprises one or more reactions performed in the hematopoietic system, urine, connective tissue, contractile system, lymphatic system, respiratory system or renal system.

19. The computer readable medium or media of claim 18, wherein said intra-system reactions comprise a reactant or reactions selected from the group consisting of a bicarbonate buffer system, an ammonia buffer system, a hormone, a signaling molecule, a vitamin, a mineral or a combination thereof.

20. The computer readable medium or media of claim 1, wherein said first or second cell is selected from a mammary gland cell, hepatocyte, white fat cell, brown fat cell, liver lipocyte, red skeletal muscle cell, white skeletal muscle cell, intermediate skeletal muscle cell, smooth muscle cell, red blood cell, adipocyte, monocyte, reticulocyte, fibroblast, neuronal cell epithelial cell or a cell set forth in Table 5.

21. The computer readable medium or media of claim 1, wherein said physiological function is selected from metabolite yield, ATP yield, biomass demand, growth, triacylglycerol storage, muscle contraction, milk secretion and oxygen transport capacity.

22. The computer readable medium or media of claim 1, wherein said data structure comprises a set of linear algebraic equations.

23. The computer readable medium or media of claim 1, wherein said commands comprise an optimization problem.

24. The computer readable medium or media of claim 1, wherein at least one reactant in said plurality of reactants or at least one reaction in said plurality of reactions is annotated with an assignment to a subsystem or compartment.

25. The computer readable medium or media of claim 24, wherein a first substrate or product in said plurality of reactions is assigned to a first compartment and a second substrate or product in said plurality of reactions is assigned to a second compartment.

15. The computer readable medium or media of 14, further comprising a gene database having information characterizing said associated gene.

26. The computer readable medium or media of claim 15, wherein a plurality of reactions is annotated to indicate a plurality of associated genes and wherein said gene database comprises information characterizing said plurality of associated genes.

27. A computer readable medium or media, comprising:

(a) a plurality of first data structures each relating a plurality of reactants to a plurality of reactions from a plurality of first cells within a multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

;

(b) a plurality of second data structures each relating a plurality of reactants to a plurality of reactions from a plurality of second cells within said multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(c) a plurality of third data structures each relating a plurality of intra-system reactants to a plurality of intra-system reactions within said multicellular organism, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(d) a constraint set for said plurality of reactions for said first, second and third data structures, and (e) commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said multicellular organism.

28. The computer readable medium or media of claim 27, wherein said first data structure comprises a first reaction network.

29. The computer readable medium or media of claim 27, wherein said second data structure comprises a second reaction network.

30. The computer readable medium or media of claim 27, wherein said first or second data structures comprise a plurality of reaction networks.

31. The computer readable medium or media of claim 27, further comprising plurality of fourth data structures and one or more fourth constraint sets, each of said plurality of fourth data structures relating a plurality of reactants to a plurality of reactions from a plurality of third cells within a multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product.

32. The computer readable medium or media of claim 31, wherein said plurality of first through fourth data structures comprise data structures for a plurality of different cells.

33. The computer readable medium or media of claim 31, wherein said plurality of first through fourth data structures comprise data structures for a plurality of different cell types.

34. The computer readable medium or media of claim 32 or 33, wherein said one or more third cells comprise at least 4 cells, 5 cells, 6 cells, 7 cells, 8 cells, 9 cells, 10 cells, 100 cells, 1000 cells, 5000 cells, 10,000 cells or more.

35. A method for predicting a physiological function of a multicellular organism, comprising:

(a) providing a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(b) providing a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(c) providing a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product;

(d) providing a constraint set for said plurality of reactions for said first, second and third data structures;

(e) providing an objective function, and

(f) determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.

36. The computer readable medium or media of claim 35, wherein said first data structure comprises a first reaction network.

37. The computer readable medium or media of claim 35, wherein said second data structure comprises a second reaction network.

38. The computer readable medium or media of claim 35, wherein said first or second data structures comprise a plurality of reaction networks.

39. The computer readable medium or media of claim 35, further comprising one or more fourth data structures and one or more fourth constraint sets, each fourth data structure relating a plurality of reactants to a plurality of reactions from a one or more third cells within a multicellular organism, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product.

40. The computer readable medium or media of claim 39, wherein said one or more fourth data structures comprises a plurality of data structures.

41. The computer readable medium or media of claim 40, wherein said plurality of data structures comprise a data structure for a plurality of different cells.

42. The computer readable medium or media of claim 40, wherein said plurality of data structures comprise a data structure for a plurality of different cell types.

43. The computer readable medium or media of claim 41 or 42, wherein said one or more third cells comprise at least 4 cells, 5 cells, 6 cells, 7 cells, 8 cells, 9 cells, 10 cells, 100 cells, 1000 cells, 5000 cells, 10,000 cells or more.

44. The computer readable medium or media of claim 35, wherein said first and second cells comprise eukaryotic cells.

45. The computer readable medium or media of claim 35, wherein said first and second cells comprise prokaryotic cells.

46. The computer readable medium or media of claim 44, wherein said first and second eukaryotic cells comprise cells of the same tissue or organ.

47. The computer readable medium or media of claim 44, wherein said first and second eukaryotic cells comprise cells of different tissues or organs.

48. The computer readable medium or media of claim 35, wherein at least one of said reactions is annotated to indicate an associated gene.

50. The computer readable medium or media of claim 35, wherein at least one of said reactions is a regulated reaction.

51. The computer readable medium or media of claim 50, wherein said constraint set includes a variable constraint for said regulated reaction.

52. The computer readable medium or media of claim 35, wherein said at least one intra-system reaction comprises one or more reactions performed in the hematopoietic system, urine, connective tissue, contractile system, lymphatic system, respiratory system or renal system.

53. The computer readable medium or media of claim 52, wherein said intra-system reactions comprise a reactant or reactions selected from the group consisting of a bicarbonate buffer system, an ammonia buffer system, a hormone, a signaling molecule, a vitamin, a mineral or a combination thereof.

54. The computer readable medium or media of claim 35, wherein said first or second cell is selected from a mammary gland cell, hepatocyte, white fat cell, brown fat cell, liver lipocyte, red skeletal muscle cell, white skeletal muscle cell, intermediate skeletal muscle cell, smooth muscle cell, red blood cell, adipocyte, monocyte, reticulocyte, fibroblast, neuronal cell epithelial cell or a cell set forth in Table 5.

55. The computer readable medium or media of claim 35, wherein said physiological function is selected from metabolite yield, ATP yield, biomass demand, growth, triacylglycerol storage, muscle contraction, milk secretion and oxygen transport capacity.

56. The computer readable medium or media of claim 35, wherein said data structure comprises a set of linear algebraic equations.

57. The computer readable medium or media of claim 35, wherein said commands comprise an optimization problem.

58. The computer readable medium or media of claim 35, wherein at least one reactant in said plurality of reactants or at least one reaction in said plurality of reactions is annotated with an assignment to a subsystem or compartment.

59. The computer readable medium or media of claim 58, wherein a first substrate or product in said plurality of reactions is assigned to a first compartment and a second substrate or product in said plurality of reactions is assigned to a second compartment.

49. The computer readable medium or media of 48, further comprising a gene database having information characterizing said associated gene.

60. The computer readable medium or media of claim 49, wherein a plurality of reactions is annotated to indicate a plurality of associated genes and wherein said gene database comprises information characterizing said plurality of associated genes.