IP Library Granted Patent US 8,612,160
Granted Patent B2
US 8,612,160 · App. 12/618,915 · Granted Dec 17, 2013

Identifying biological response pathways

Inventors: Ernest Fraenkel (Cambridge, MA); Shao-Shan Carol Huang (Cambridge, MA); David R. Karger (Cambridge, MA); Laura Riva (Cambridge, MA); Esti Yeger-Lotem (Misgav, IL)
Assignee: Massachusetts Institute of Technology
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Quick Facts
Patent No.
US 8,612,160
App. No.
12/618,915
Granted
Dec 17, 2013
Kind
B2
Abstract

A method for identifying a mechanism associated with a cellular response includes identifying molecules participating in the cellular response; accessing a database containing information characterizing molecular interactions; determining pathways connecting the identified molecules participating in the cellular response; and solving an optimization problem that includes determining a subset of the molecules and interactions having a minimum aggregate cost. The pathways include, nodes, each representing a molecule, and edges, each connecting a respective pair of nodes and representing an interaction between a respective pair of molecules represented by the respective pair of nodes. Nodes from a subset of nodes represent molecules identified as participating in the cellular response.

Claims (11)

1. A method for updating a computer-readable data storage medium with the aid of a particular microprocessor tied to said computer-readable data storage medium, said data storage medium containing interaction data, said interaction data being representative of interactions within a cell, said method comprising: providing said microprocessor with a global measurement of activity in a cell, causing said microprocessor to retrieve, from a database stored on a computer-readable medium, said interaction data, said interaction data including data representative of a subset of interactions within the cell, each of said interactions being consistent with said global measurement, causing said microprocessor to determine an aggregate cost for each of said interactions, causing said microprocessor to determine which of said interactions from said subset of interactions has a minimum aggregate cost, causing said microprocessor to provide output representative of said minimum cost interaction, and causing said output to be stored in said computer-readable data storage medium, and representing said data from said database as an interactome, said interactome having nodes representing molecules, and edges connecting pairs of said nodes, each edge representing an interaction between molecules represented by said nodes, wherein causing said microprocessor to determine which of said signaling pathways from said subset of signaling pathways has a minimum aggregate cost comprises solving a prize-collecting Steiner tree problem associated with said interactome to identify said pathways.

2. The method of claim 1 , wherein each node is weighted by a node cost representing an anticipated performance of a molecule associated with said node during a signaling event, and wherein each edge is weighted by an edge cost representing a reliability of an interaction between molecules connected by said edge.

3. A method for operating a machine for identifying a mechanism associated with a cellular response with the aid of a digital computer, the method comprising identifying molecules participating in the cellular response, causing the computer to access a database containing information characterizing molecular interactions, causing the computer to determine pathways connecting the identified molecules participating in the cellular response, wherein the pathways include a plurality of nodes, each node representing a molecule, and a plurality of edges, each edge connecting a respective pair of nodes and representing an interaction between a respective pair of molecules represented by the respective pair of nodes, wherein the plurality of nodes includes a subset of nodes that represent molecules identified as participating in the cellular response, and causing said computer to solve an optimization problem that includes determining a subset of the molecules and interactions having a minimum aggregate cost, wherein causing said microprocessor to solve an optimization problem includes identifying one subset of the originally identified nodes as an input subset containing input nodes and a separate subset of the originally identified nodes as an output subset containing output nodes, identifying a source node representing a source of flow, identifying a destination node representing a destination of flow, associating a quantity of flow with the source of flow, associating each edge with a cost value, and forming an objective function for said optimization problem based on the cost values of the edges connecting the input and output nodes and the quantity of flow traversing these edges from the source node to the destination node.

4. The method of claim 3 , wherein causing said microprocessor to determine pathways connecting the identified molecules participating in the cellular response includes numerically processing data representing the network of potential interactions to determine a sub-network of nodes and edges representative of a response pathway between the input and the output.

5. The method of claim 3 , wherein identifying molecules participating in a cellular response includes identifying one or more proteins selected from the group consisting of phosphorylated proteins, proteins encoded by a gene that, when deleted, causes a change in an organism's phenotype, and proteins that are present in an amount that changes during a cellular response.

6. The method of claim 3 , wherein the cellular response is a signaling event and wherein the destination node represents a target gene of the signaling event.

7. The method of claim 6 , further comprising identifying the destination node according to measurements of differential gene expression associated with the signaling event.

8. The method of claim 3 , wherein the pathways further include one or more intermediate nodes between the source node and the destination node.

9. The method of claim 3 , wherein identifying molecules participating in the cellular response comprises identifying molecules selected from the group consisting of proteins, mRNAs, DNA sequences, and protein-protein complexes.

10. The method of claim 3 , wherein each edge is associated with a value that represents a degree of interaction between respective molecules represented by the pair of nodes connected by the edge.

11. The method of claim 3 , wherein the cellular response is selected from the group consisting of a signaling event, a metabolic event, and a phenotypic response to a stimulus.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 25, 2010
From: FRAENKEL, ERNEST; HUANG, SHAO-SHAN CAROL; KARGER, DAVID R.; RIVA, LAURA; YEGER-LOTEM, ESTI
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 024593/0378 →
CONFIRMATORY LICENSE Recorded Apr 15, 2010
From: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 024235/0601 →
Continuity (2)
Provisional Application 61114783 · Nov 14, 2008
Related Publication 20100250143A1 · Sep 30, 2010