Modified FBA in a production network

Patent metadata

Field	Value
Publication number	US-11508459-B2
Application number	US-201815885463-A
Country	US
Kind code	B2
Filing date	Jan 31, 2018
Priority date	Jan 31, 2018
Publication date	Nov 22, 2022
Grant date	Nov 22, 2022

Abstract

A method for matching production of FBA metabolism to supply and demand within a larger production network is described herein. An objective function of FBA metabolism is modified to include an upstream supply generated in upstream sub-units, as well as a downstream demand generated within downstream sub-units in the production network. FBA metabolism and the upstream and downstream sub-units are iteratively solved with updated initial conditions, producing a time series solution to the production network.

First claim

What is claimed is:

1. A method for simulating an outcome of a cell process of at least one cell in a production network, the method comprising:
receiving an initial state dataset based on initial net demand for a plurality of molecules in a plurality of sub-units representing production and consumption of molecules external to a flux balance analysis (FBA) system, wherein multiple sub-units of the plurality of sub-units represent transcription, translation, cellular communication, cellular respiration, cellular reproduction, or cellular transport;
calculating an initial solution flux dataset by evaluating the FBA system based on a stoichiometric matrix and an objective function, the objective function based on a difference between a first target value for each molecule of the plurality of molecules and a first proportional flux contribution of each molecule of the plurality of molecules, wherein the first target value is included in a set of initial target values calculated based on the initial state dataset;
receiving a subsequent net demand for the plurality of molecules from initial solutions to the plurality of sub-units;
calculating a subsequent state dataset for the plurality of molecules in the plurality of sub-units based on the initial state dataset, the initial solution flux dataset, and the subsequent net demand;
updating the objective function, the updated objective function based on a difference between a second target value for each molecule of the plurality of molecules and a second proportional flux contribution of each molecule of the plurality of molecules, wherein the second target value is included in a set of subsequent target values calculated based on the subsequent state dataset;
calculating a subsequent solution flux dataset by evaluating the FBA system with the updated objective function; and
determining the outcome of the cell process of the at least one cell, the determining includes calculating a difference between the subsequent solution flux dataset and the initial solution flux dataset, wherein the outcome of the cell process corresponds to an estimation of a growth rate of the at least one cell, and wherein an accuracy of the updated objective function is determined based on a comparison of the estimation of the growth rate of the at least one cell to an actual growth rate of the at least one cell.

2. The method of claim 1 , wherein:
the initial state dataset includes a set of initial molecule concentrations of the plurality of molecules; and
the initial net demand for the plurality of molecules comprises:
an initial rate of supply in a first sub-unit representing production upstream from metabolism; and
an initial rate of demand in a second sub-unit representing consumption downstream from metabolism.

3. The method of claim 2 , wherein the set of initial molecule concentrations of the plurality of molecules comprises:
a total concentration of each of the plurality of molecules in the plurality of sub-units; and
a cushion concentration representing a reserve concentration of each of the plurality of molecules.

4. The method of claim 1 , wherein the initial state dataset further includes:
a set of intrinsic rate parameters for each of the plurality of molecules, wherein the set of intrinsic rate parameters represents a biological ability of the cell to adjust the subsequent solution flux dataset to the subsequent net demand for the plurality of molecules.

5. The method of claim 4 , wherein the set of intrinsic rate parameters for each of the plurality of molecules includes at least one of: a proportional rate limit, an integral rate limit, and a derivative rate limit.

6. The method of claim 1 , wherein calculating the initial solution flux dataset by evaluating the FBA system based on the stoichiometric matrix and the objective function limited by the initial state dataset further comprises:
maximizing the objective function limited by the initial state dataset within a constraint of the stoichiometric matrix to determine a maximum growth rate.

7. The method of claim 1 , wherein the initial solution flux dataset comprises:
a set of input fluxes representing in part an initial rate of supply in a first set of sub-units representing production and consumption upstream from metabolism; and
a set of output fluxes representing in part an initial rate of demand in a second set of sub-units representing production and consumption downstream from metabolism.

8. The method of claim 1 , wherein the initial net demand for the plurality of molecules in the plurality of sub-units representing production and consumption of molecules external to the FBA system is determined by at least one of: a Monte Carlo method, solving a set of ordinary differential equations (ODEs), and solving a set of partial differential equations (PDEs).

9. The method of claim 1 , wherein:
the initial state dataset is associated with a first time;
the subsequent state dataset is associated with a subsequent time; and
the difference between the subsequent solution flux dataset and the initial solution flux dataset represents metabolic production over a time interval between the first time and the subsequent time.

10. The method of claim 1 , further comprising:
calculating the subsequent solution flux dataset by evaluating the FBA system with the updated objective function limited by the subsequent state dataset until a change in a growth rate of the cell reaches a threshold.

11. The method of claim 10 , wherein the threshold is associated with homeostasis of the cell.

12. A non-transitory computer readable storage medium containing computer program code executable on a processor for causing the processor to perform operations for simulating an outcome of a cell process of at least one cell in a production network, the operations comprising:
receiving an initial state dataset based on initial net demand for a plurality of molecules in a plurality of sub-units representing production and consumption of molecules external to a flux balance analysis (FBA) system, wherein multiple sub-units of the plurality of sub-units represent transcription, translation, cellular communication, cellular respiration, cellular reproduction, or cellular transport;
calculating an initial solution flux dataset by evaluating the FBA system based on a stoichiometric matrix and an objective function, the objective function based on a difference between a first target value for each molecule of the plurality of molecules and a first proportional flux contribution of each molecule of the plurality of molecules, wherein the first target value is included in a set of initial target values calculated based on the initial state dataset;
receiving a subsequent net demand for the plurality of molecules from initial solutions to the plurality of sub-units;
calculating a subsequent state dataset for the plurality of molecules in the plurality of sub- units based on the initial state dataset, the initial solution flux dataset and the subsequent net demand;
updating the objective function, the updated objective function based on a difference between a second target value for each molecule of the plurality of molecules and a second proportional flux contribution of each molecule of the plurality of molecules, wherein the second target value is included in a set of subsequent target values calculated based on the subsequent state dataset;
calculating a subsequent solution flux dataset by evaluating the FBA system with the updated objective function; and
determining the outcome of the cell process of the at least one cell, the determining includes calculating a difference between the subsequent s

Assignees

• X Dev Llc

Inventors

• Russo Frank

Classifications

• G16B5/00 Primary

  ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks · CPC title

• G06F17/16

  Matrix or vector computation {, e.g. matrix-matrix or matrix-vector multiplication, matrix factorization (matrix transposition G06F7/78)} · CPC title

• G06F2111/10

  Numerical modelling · CPC title