Methods for predicting biological activities of cellular constituents

• US 20030014232A1
• Filed: 05/21/2002
• Published: 01/16/2003
• Est. Priority Date: 05/22/2001
• Status: Abandoned Application

• Current Assignee: Entelos, Inc. (SilkRoad Inc.)
• Original Assignee: Entelos, Inc. (SilkRoad Inc.)
• Inventors: Fallon, Renee A., Paterson, Thomas S.
• Application Number:
  US10/153,847
• Publication Number:
  US 20030014232A1
• Time in Patent Office: Days
• US Class Current: 703/11
• 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

Abstract

Methods for predicting the activity of cellular constituents in a biological system are described. In particular, a method for predicting the potential biological activity of a cellular constituent for affecting a biological state is described. A method for identifying biological processes of a biological state modulated by a cellular constituent is also described. Also included is a method for predicting biological processes involved in the action of a drug.

Claims

1. A method for predicting potential biological activity of a cellular constituent for affecting a biological state S comprising:

(a) assigning a set F₀ of functions to said cellular constituent, each function of set F₀ being a modification of at least one biological process of said biological state S;

(b) adding information for one function of set F₀ to a computer model of said biological state, said computer model representing a plurality of individual biological processes associated with said biological state, at least one of said plurality of individual biological processes being a process modified by said one function of set F₀, said computer model being configured to evaluate the effect of said biological processes on said biological state;

(c) executing said computer model with said added one function of set F₀ to produce value S_x for said biological state in the presence of said added one function of set F₀;

(d) repeating steps (b) and (c) for any other functions of set F₀;

(e) comparing all of said S_x values for functions of set F₀ to an S₀ value, said S₀ value being produced by executing said computer model without any of the functions of set F₀ being added into said computer model; and

(f) identifying the functions in set F₀ having a difference in S_x value relative to S₀ as having a higher potential biological activity of said cellular constituent for affecting said biological state and identifying the functions in set F₀ having substantially no difference in S_x value relative to S₀ as having a lesser potential biological activity for affecting said biological state.

2. The method of claim 1, further comprising:

obtaining experimental information on biological activity of said cellular constituent for at least one individual biological process in said computer model;

adding said experimental information to said computer model;

re-evaluating S_X values for each of said functions of set F₀; and

using said re-evaluated S_X values to re-order, if necessary, priority of scientific investigation on functions of cellular constituents for ability to affect said biological state.

3. The method of claim 1, wherein functions of set F₀ are ordered in a subset F₁ from greatest difference in S_x values relative to S₀ to lowest difference in S_x values relative to S₀, and priority of a scientific investigation is ordered based on said ordered set.

4. The method according to claim 1, wherein said assigning a set F₀ of functions includes obtaining experimental information on biological activity of said cellular constituent and associating said experimental information with said cellular constituent.

5. The method according to claim 1, wherein said adding information for said one function of set F₀ includes assigning a fractional contribution of said one cellular constituent to at least one of said plurality of individual biological processes.

6. The method according to claim 1, wherein said cellular constituent is selected from the group consisting of polynucleotides and polypeptides.

7. A method for selecting a subset Z₁ of cellular constituents having a potential biological activity for affecting biological state S from a set Z₀ of cellular constituents, comprising:

(a) assigning a set F₀ of functions to each cellular constituent of set Z₀, each function being a modification of at least one biological process of said biological state S;

(b) adding information for one of said functions of set F₀ for one of said cellular constituents of set Z₀ to a computer model of said biological state, said computer model representing a plurality of individual biological processes associated with said biological state, at least one of said plurality of individual biological processes being a process modified by said one function of set F₀, said computer model being configured to evaluate the effect of said individual biological processes on said biological state;

(c) executing said computer model with said added one function of set F₀ of said one cellular constituent being incorporated into the computer model to produce a value S_X for said biological state in the presence of said one function of set F₀ of said one cellular constituent;

(d) repeating steps (b) and (c) for any other functions of set F₀;

(e) repeating steps (b), (c) and (d) for any other cellular constituents of set Z₀;

(f) comparing all of said S_X values for cellular constituents in set Z₀ to a S₀ value, said S₀ value being produced by executing said computer model without any of said functions of any of said cellular constituents being added into the computer model;

(g) establishing a selection characteristic for potential members of said subset Z₁, said selection characteristic being a range of differences between S_x values for cellular constituents in set Z₀ to S₀; and

(h) assigning to said subset Z₁ cellular constituents having said selection characteristic, the difference in S_x values to S₀ value being correlated to the potential biological activity of said cellular constituent for affecting said biological state.

8. The method of claim 7, further comprising:

creating a subset Z₂ of cellular constituents from said subset Z₁ of cellular constituents, said creating the subset Z₂ of cellular constituents, comprising;

(a) perturbing one of the cellular constituents of subset Z₁ in a biological assay system;

(b) executing said biological assay system in the presence of said perturbed cellular constituent to produce a set of function values, each function value FV_x of said set of function values being related to at least one function of set F₀ of said perturbed cellular constituent;

(c) repeating steps (a) and (b) for any other cellular constituents of subset Z₁;

(d) comparing each function value FV_x to a function value FV₀, the function value FV₀ being produced without perturbation of said cellular constituents in said biological assay system;

(e) establishing a selection characteristic for potential members of subset Z_2, said selection characteristic being a range of differences between FV_x and FV₀ values; and

(f) assigning to said subset Z₂ cellular constituents having said selection characteristic, the selection characteristic for potential members of subset Z₂ being correlated to the effect of the perturbation of said cellular constituent on the functions of set F₀.

9. The method of claim 7, further comprising:

obtaining experimental information on biological activity of each cellular constituent in subset Z₁ for at least one individual biological process in said computer model;

adding said experimental information to said computer model;

re-evaluating S_x values for each of said cellular constituents in subset Z₁; and

using said re-evaluated S_X values to re-order, if necessary, priority of a scientific investigation on cellular constituents in subset Z₁ for ability to affect said biological state.

10. The method of claim 7, wherein set Z₁ is an ordered set in which set members are ordered from greatest difference in S_x values relative to S₀ to lowest difference in S_x values relative to S₀, and priority of a scientific investigation is ordered based on said ordered set.

11. The method according to claim 7, wherein said assigning a set F₀ of functions includes obtaining experimental information on biological activity of said cellular constituent and associating said experimental information with said cellular constituent.

12. The method according to claim 7, wherein said adding information for said one function of set F₀ includes assigning a fractional contribution of said one cellular constituent to at least one of said plurality of individual biological processes.

13. The method according to claim 7, wherein said cellular constituents are selected from the group consisting of polynucleotides and polypeptides.

15. The method according to claim 14, wherein said assigning a function includes obtaining experimental information on biological activity of said cellular constituent and associating said experimental information with said cellular constituent.

16. The method according to claim 14, wherein said adding information for said function includes assigning a fractional contribution of said one cellular constituent to at least one of said plurality of individual biological processes.

17. The method according to claim 14, wherein said cellular constituent is selected from the group consisting of polynucleotides and polypeptides.

18. The method according to claim 14, wherein said biological assay system is selected from the group consisting of a cell-based system and an animal model.

20. The method of claim 19, further comprising:

creating a subset F₂ of functions of said cellular constituent from said subset F₁ of functions, said creating the subset F₂ of functions, comprising;

(a) perturbing said cellular constituent in a biological assay system;

(b) executing said biological assay system in the presence of said perturbed cellular constituent to produce a set of function values, each function value FV_x of said set of function values being related to one function of subset F₁;

(c) comparing each function value FV_x to a function value FV₀, the function value FV₀ being a value produced without perturbation of said cellular constituent in said biological assay system;

(d) establishing a selection characteristic for potential members of said subset F₂, said selection characteristic being a range of differences between FV_x values and FV₀ values; and

(e) assigning to said subset F₂ functions having said selection characteristic, the selection characteristic for potential members of subset F₂ being correlated to the effect of the perturbation of said cellular constituent on the functions of subset F₁.

14. A method for identifying potential biological processes of a biological state modulated by a cellular constituent comprising:

(a) assigning a function to said cellular constituent, said function being a modification of at least one biological process of said biological state;

(b) adding information for said function to a computer model of said biological state, said computer model representing a plurality of individual biological processes associated with said biological state, at least one of said plurality of individual biological processes being a process modified by said function, said computer model being configured to evaluate the effect of said biological processes on said biological state;

(c) executing said computer model so that a virtual stimulus in the presence of said function is presented to produce a response value R_x for said biological state in the presence of said function;

(d) providing a biological stimulus to a biological assay system to produce a biological response value BR_x for said biological assay system in the presence of said biological stimulus, said biological stimulus being the biological equivalent of the virtual stimulus and said biological assay system being the biological equivalent of the said biological state;

(f) establishing a selection characteristic for identifying potential biological processes of said biological state modulated by said cellular constituent, wherein said selection characteristic being a range of differences between the response value R_x and the biological response value BR_x; and

(g) identifying said biological process having said selection characteristic as a potential biological process of said biological state modulated by said cellular constituent.

19. A method for predicting potential biological activity of a cellular constituent for affecting a biological state S, comprising:

(a) assigning a set F₀ of functions to said cellular constituent, each function of set F₀ being a modification of at least one biological process of said biological state S;

(b) adding information for one function of set F₀ to a computer model of said biological state, said computer model representing a plurality of individual biological processes associated with said biological state, at least one of said plurality of individual biological processes being a process modified by said one function of set F₀, said computer model being configured to evaluate the effect of said biological processes on said biological state;

(c) executing said computer model with said added one function of set F₀ to produce value S_x for said biological state in the presence of said added one function of set F₀;

(d) repeating steps (b) and (c) for any other functions of set F₀;

(e) comparing all of said S_x values for functions of set F₀ to an S₀ value, said S₀ value being produced by executing said computer model without any of the functions of set F₀ being incorporated into said computer model;

(f) establishing a selection characteristic for potential members of a subset F₁ of set F₀, said selection characteristic being a range of differences between S_x values for functions in set F₀ to S₀; and

(g) assigning to said subset F₁ functions having said selection characteristic, the selection characteristic for potential members of subset F₁ being correlated to the potential biological activity of said cellular constituent for affecting said biological state.

21. A method for predicting potential biological activity of a cellular constituent for affecting a biological state S, the method using a computer model that represents a plurality of individual biological processes associated with said biological state, said computer model being configured to evaluate an effect of said individual biological processes on said biological state, the method comprising:

(a) assigning a set F₀ of functions to said cellular constituent, each function of set F₀ being a modification of at least one biological process of said biological state S;

(b) performing the following for each function from the set F₀;

(i) adding information for one function of set F₀ to a version of the computer model without added information for the remaining functions of set F₀, at least one of said plurality of individual biological processes being a process modified by said added one function of set F₀; and

(ii) executing said computer model with said added one function of set F₀ to produce value S_x for said biological state in the presence of said added one function of set F₀;

(c) comparing all of said S_x values for functions of set F₀ to an S₀ value, said S₀ value being produced by executing said computer model without any of the functions of set F₀ being incorporated into said computer model; and

(d) identifying the functions in set F₀ having a difference in its associated S_x value relative to S₀ as having a higher potential biological activity of said cellular constituent for affecting said biological state and identifying the functions in set F₀ having substantially no difference in S_x value relative to S₀ as having a lesser potential biological activity for affecting said biological state.