systems biology surabhi agarwal affiliations the examination of a biological entity as an integrated...

Systems Biology

Surabhi AgarwalAffiliations

The examination of a biological entity as an integrated system, rather than the study of its

individual characteristic reactions and components is termed as systems biology.

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1This animation consists of 2 parts:Part 1: Systems Biology ConceptsPart 2 : Modeling Biological Networks

2. Difference between system study and component study

3. Systems Biology Triangle 4. Work flow for Systems analysis

1. Analogy

http://1.bp.blogspot.com/_WyIc2oXjvmc/SKGOVUfo-uI/AAAAAAAAArA/h6BZq_t2MY8/s400/Air+car+engine+dia.jpg http://www.istockphoto.com/file_thumbview_approve/7129036/2/istockphoto_7129036-car-parts-two.jpg

Definitions of the components:Part 1: Systems Biology Concepts

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1 1. Systems biology: It is a discipline for studying organisms as a network of interacting components.

2. Genomics: The entire sequence of an organism’s hereditary information, encoded in DNA is known as the genome and their study is called genomics.

3. Transcriptomics: The study of the set of all RNA molecules, including mRNA, rRNA and tRNA, present in an organism is referred to as the transcriptomics.

4. Proteomics: The study of the entire complement of proteins expressed by the genome of an organism under specific defined conditions is known as the proteomics.

5. Model system: A simple system of networks which can be mapped to the problem under consideration and is easily computationally modeled within available technologies.

6. System: This term can be used to refer to a metabolic pathway, an organelle, a cell, a metabolic pathway, a metabolic system or an entire organism. The meaning of this term depends on the reference of the problem.

Analogy / Scenario / Action1

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4A car is formed by placing together many of its parts such as screw, tyre, engine, key, etc. If we want to gain an understanding of each of the part as a distinct entity, we will study them separately. But to get an insight into the contribution of the part in forming the car, we need to study it in context of the car. Similarly, Systems Biology is an integrated approach of understanding biological system in context of the patterns of molecular interactions present in them.

Is used to fix parts together. Features of a screw cannot describe its role. It can be used to arrange a PC an AC, a TV !??

Used to make a vehicle move faster by reducing friction due to its rotatory motion. It can be used to run a bullock cart, a cycle !!??

Used along with a lock to safeguard your belongings as one lock has one unique keo from which it can be opened. Can be used to lock your room, your suitcase !!??

Used to convert fuel energy into mechanical energy. Can be used to make several equipments operate such as Air plane, Motorbike !!??

Action Audio Narration

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Step 1.a - Two Approaches in Systems Biology

Systems is an entity which maintains its existence through a mutual interaction of its constituent parts

Systems biology research consists of the1. Identification of the Parts2.Characterization of the components. 3. Exclude the ones which are not a part of the system4. Identify the interaction of the components with each other

5. Identify the interaction of the components with the environment which modulate the parts either directly or indirectly through modulation of internal interactions

Schematic to depict the concept of Systems Biology

Follow the steps in the animation. Re-draw all figures. The text in the blue boxes on the top needs to be displayed as well as narrated. Animator needs to make sure that the blue box and the narration appears at the right step of the process as shown in the power point animation.

Systems is an entity which maintains its existence through a mutual interaction of its constituent parts. Systems biology research consists of the:1.Identification of the Parts2.Characterization of the components.3.Exclude the ones which are not a part of the system4.Identify the interaction of the components with each other5.Identify the interaction of the components with the environment which modulate the parts either directly or indirectly through modulation of internal interactions

Systems biology and the virtual physiological human Molecular Systems Biology 5: 292; published online 28 July 2009; doi:10.1038/msb.2009.51


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Step 1.b - Two Approaches in Systems Biology

SYSTEMS

PARTS

Reductionist Approach: Disintegrating the system into its component parts and studying them.

Integrative Approach: Integrating the study of individual components to form conclusions about system


Follow the steps in the animation. Re-draw all figures. The text in the blue boxes on the top needs to be displayed as well as narrated. Animator needs to ensure the order of steps and that the blue box and the narration appears at the right step of the process as shown in the power point animation.

Systems biology concepts can be understood with the help of two approaches, namely, the “Reductionist” approach and the “Integrative” approach. “Reductionist Approach” focuses on disintegrating the system into its component parts and studying them, whereas, Integrative Approach focuses on Integrating the study of individual components to form conclusions about system.

Systems biology and the virtual physiological human Molecular Systems Biology 5: 292; published online 28 July 2009; doi:10.1038/msb.2009.51

Step 2.a: Studying components


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4Description of the action

DNA binding protein

DNA Protein Product

Lipoprotein


Figures need to be re-drawn. Follow the steps exactly as shown in the animation. Animator needs to ensure the order of steps. Show the images. Depict the labeling and then remove it from display. Show the zooming effect on the molecules.

Consider a cell with its component molecules. Here we study the a “metabolic pathway” as a “biological system”. When the environment of the cell is perturbed a little, the individual components undergo unique changes, such as increase in production rate, or decrease in their amount. At this stage, due to lack of knowledge of the nature of interaction of proteins, we cannot interpret how the system gets affected

Step 2.b: Studying Systems


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But when we study the interaction of one component with the other, we can conclude, that the increase in rate if DNA binding protein leads to increase in the synthesized amount of DNA which further changes the final amount of lipo-protein produced. Thus we can see, that to study a system, we need to analyze not just the components, but their interactions therof. Th se biological systems can be:1. Protein-protein interaction networks2. Gene regulatory networks3. Protein-DNA networks4. Protein lipid interactions5. Metabolic Networks


Figures need to be re-drawn. Follow the steps exactly as shown in the animation. Animator needs to ensure the order of steps.

Step 2.c: System studies requires “omics”


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To study the systems we need to know about the components and its interactions. The data about the components comes from Genomic and Proteomic studies. The data about the molecular interactions comes from interactomics studies.

The information about the proteins comes from Proteomics data. This data can be experimental or it can be retrieved from public domain databases


Follow the animation steps. Re-create images. Animate and narrate the green boxes.

The information about the DNA complement of an organism comes from the Genomics Data. This, again, can either be retreived experimentally or from databases.

Step 3: Systems Biology Triangle


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http://controls.engin.umich.edu/wiki/images/4/45/TransitionDiagram.JPG , Biochemistry by Stryer et al., 5th edition, Biochemistry by A.L.Lehninger et al., 3rd edition

EXPERIMENT

TECHNOLOGYCOMPUTATIONAL MODELLING

THEORY

Schematic to depict the Systems Biology Triangle

Follow the animation steps. Re-create images

To study the systems we need to know about the components and its interactions. The data about the components comes from Genomic and Proteomic studies. The data about the molecular interactions comes from interactomics studies

Step 4: Work flow for Systems Biology

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Systems Biology: A Brief Overview, Hiroaki Kitano,, 1662 (2002); 295 Science

Data and Hypothesis

driven Modeling

Systems Analysis and

theory formulation

PredictionExperimental Design and

device development

Experiment Data analysis

Biological knowledge

and contradictory

issues

EXPERIMENTS COMPUTATION

Selection ofbiological significant

problem

Creation of a model for the problem which represents computable set of assumptions and hypotheses that will be subjected to experimental validation Compatibility of the model with

established experimental facts will reveal the adequacy of the assumptions made. If incompatible, the model will be modified or rejected

Systems analysis are conducted on the consistent models to make predictions for the system

From all the predictions, a small set is selected to validate them using wet-lab experiments which are designed for this purpose.

The data from the experiments is analyzed and the inadequate models are discarded

Step 5:

Action Audio Narration1

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Description of the action

Follow the animation steps. Re-create images. Show the circular image first. The two sides must be in two different colors. On the left side highlight “EXPERIMETS” with the same color as the left half of the circle. And in the right side highlight the word “COMPUTATION” in the same color as the right side of the circle. The one by one highlight the segments. The definition of the event in the segment has to be displayed in the animation s well as narrated.

Genral protocol for a systems biology experiment

A typical work flow for approaching a biological problem with a system biology perspective is:1. Selection ofbiological significant problem 2. Creation of a model for the problem which represents computable set of assumptions and hypotheses that will be subjected to experimental validation 3. Compatibility of the model with established experimental facts will reveal the adequacy of the assumptions made. If incompatible, the model will be modified or rejected4. Systems analysis are conducted on the consistent models to make predictions for the system5. From all the predictions, a small set is selected to validate them using wet-lab experiments which are designed for this purpose.6. The data from the experiments is analyzed and the inadequate models are discarded


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1 This animation consists of 2 parts:Part 1: Systems Biology ConceptsPart 2 : Modeling Biological Networks

Stoichiometric Analysis Ordinary Differential Equations

Definitions of the components:Part 2: Modeling Biological Networks

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1 1. ODE: ODE stands for Ordinary Differential Equation. It is a mathematical relation that can be used for modeling biological systems.

2. Stochiometric Model: Modelling a biological network based on its stochiometirc coefficients, reaction rates and metabolite concentrations.

3. Reaction rates: Rate of a reaction is the measure of the formation or degradation of metabolites involved in that reaction. To determine reaction rates, we need substrate concentrations at specific time intervals and values for the reaction constants.

Step 1.a - Stoichiometric Analysis


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v: Vector of Reaction rates

N: Stoichiometric MatrixS: Vector of Concentration values

http://www.ece.cmu.edu/~brunos/Lecture3.pdf

Static image Display the equation and narrate the text To model more complex networks stochiometric modeling can be used which has 3 basic components:1.The concentration of all the reactants and products in the form of a vector of Concentration values (S)2.The Stoichiometric Matrix that describes the production and consumption of each metabolite at each of individual reaction (N)3.The vector for Rate of all the reactions involved (v)Information on any two will help us in determining the third.


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GLU G6P

ATP ADP

FBP

ATP ADP

ATP

GLU

ADP

G6P

F6P

FBP

F6P

-1 -1+1

+1

0

0

0 0 0

-1

+1 0

-1 0+1

0

-1

+1

v1 v3v2

Step 1.b - Stoichiometric Analysis

Schematic to describe Stoichiomettric Model

Follow steps in animation. Re-draw all images. Write the equations in proper manner as separate Images

Let us consider first 3 reactions of glycolsis and model their stoiciometric matrix. The rows of this matrix represents each reactant and product of all the reaction in this system. The column represents individual reaction, ex- in this case, there are 3 reaction steps. So column 1 represents 1st step, column 2, second step, column third step and so on. If a particular substrate is consumed in the reaction step, we fill -1 in the matrix. If it is produced we enter +1. And if it is not involved in the reaction, we write 0. For huge systems, we continue to fill the matrix in a similar form, by breaking the entire network into individual steps.



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ATP

GLU

ADP

G6P

F6P

FBP

-1 -1+1

+1

0

0

0 0 0

-1

+1 0

-1 0+1

0

-1

+1

v1 v3v2

S = N =

v1 v3v2v =

S: Vector of Concentration values N: Stochiometric Matrix

v: Vector of Reaction rates

T

Step 1.c - Stoichiometric Analysis


Follow steps in animation. Re-draw all images. Matrix shown in the previous slide is divided into the three parts an each part is defined separately.

Here, S is matrix of concentrations of each of the reactants/substrates. N is the matrix of the stoichiometric coefficient describing the production and consumption of reactants and products. V is the matrix of rates of the 3 reactions involved. Since v matrix needs to be multiplied with N, we will transpose it such that the number of rows in v equals the number of columns in N.



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dS ──

dt

Step 1.d - Stoichiometric Analysis

N= . v

ATP

GLU

ADP

G6P

F6P

FBP

=

-1 -1+1

+1

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0 0 0

-1

+1 0

-1 0+1

0

-1

+1

. v1 v3v2

Tv1

v3

v2

3 COLUMNS

3 ROWS


Follow steps in animation. Re-draw all images. Write the equations in proper manner as separate text

The simple linear equation for modeling networks, takes the following shape in its vector form. Once such a model is constructed, if 2 variables are known, we can determine the unknown variables. The same concept of modeling systems can be applied to larger biological systems like:1.Metabolic Network2.Protein-Protein Interaction3.Gene regulatory Network



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Step 2.a - Ordinary Differential Equations - Basics

Schematic to describe ODE Model


Here we describe basic Ordinary Differential Equations (ODE) with the help of simple equations. A general ODE “da by dt is equal to f”, signifies that ‘The change in “a” during a short time interval ‘dt” is “f” times of “dt”’. In the first equation “da by dt is equal to zero”, the concentration of “a” does not change with time. In the second equation, “da by dt is equal to one”, concentrations of “a” changes by dt in time “dt”. In the third equation “da by dt is equal to minus a”, Concentrations of “a” decreases with time. The larger the initial concentration of “a”, the larger is the decrease. The “minus” sign shows the decrease in concentration.

http://tsb.mssm.edu/summerschool/images/f/f0/IntroODE.ppt

The change in “a” during a short time interval ‘dt” is “f” times of

“dt”Generalized form of an

Ordinary Differential Equation (ODE)

Concentrations of “a” changes by dt in time “dt”

Concentrations of “a” decreases with time. The larger the initial

concentration of “a”, the larger is the decrease

Concentrations of “a” does not change with time

Shows decrease in concentration

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Step 2.b – Biological Reactions to Ordinary Differential Equations


A 0

A B

A + B C

Law of Mass-Action : The rate of a reaction is proportional to the product of the concentration of the reactants

REACTANTSCONCENTRATION OF REACTANTS

“a” reduces in concentration by a value which is

proportional to its initial concentration.

The concentration of “a” reduces and “b” increase with

time by a value which is proportional to initial concentration of “a”.

The concentration of “a” and “b” reduces and “c” increase with time by a value which is

proportional to initial concentration of “a” and “b”

CONSTANTS OF PROPORTIONALITY

Step 5:

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The Law of Mass-Action says that “The rate of a reaction is proportional to the product of the concentration of the reactants”. The highlighted variables depict the position of “reactant” in the “reactions” and the position of “concentration of reactants” in the “ODEs”. The only reactant involved in first reaction is “A”. As the equation shows, “A” reduces to zero with time. From the ODE, we infer, that as the time increases, a reduces in concentration by a value which is proportional to its initial concentration.In the second reaction, “A” converts to “B” with time. From the ODE for “A”, we infer, that as the time increases, “a” reduces in concentration by a value which is proportional to its initial concentration. From the ODE for “B”, we infer, that as the time increases, “b” increases in concentration by a value which is proportional to initial concentration of “a”. In the third reaction the concentration of “a” and “b” reduces and “c” increase with time by a value which is proportional to initial concentration of “a” and “b”.


Re-draw all images. Highlight the components as shown in the slide animation. Write the equations in proper manner as separate text


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Step 2.c - Common Biological Ordinary Differential Equations

Static table Display table and read the narration Here we display a summary of common reactions and their corresponding Ordinary Differential Equations. These equations are for individual reactions. In a metabolic network, we extrapolate these reactions to cover an entire network by summating the contribution from all individual reactions within the pathway.


BIOLOGICAL REACTION RATE CONSTANT

CORRESPONDING ODE

A 0 k1

A B k2

A + B C k3

A + B A + D k4


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Glucose Glucose-6-P Fructose-6-P Fructose-1,6Bi-phosphate

ADP

ADP

2ADP

ATP

ATP

ATP + AMP

ATP ATPADP ADP

v1 v4 v5

v8

v6

v7

ATP

ADP

v3

Step 2.d - Ordinary Differential Equations

v2



In this example we construct a model for the initial steps of Glycolysis with the help of ODE models. Here you can see the reactions in glycolysis. Several reactions are accompanied by the consumption of ATP into ADP . The rate of each individual reaction is represented by a variable v. These rates are determined by reaction kinetics.


Step 2.e - Ordinary Differential Equations


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Glucose Glucose-6-P Fructose-6-P Fructose-1,6Bi-phosphate

ADP

ADP

2ADP

ATP

ATP

ATP + AMP

ATP ATPADP ADP

v1 v4 v5

v8

v6

v7

ATP

ADP

v3

v2



Now, to determine the concentration of each of the substrates at a given time, we need to account for all the reactions which involve this substrate. Thus, to determine the concentration of G6P at a given time, we need to determine its rate of production (v1) and its rate of consumption (v2 , v3). The same process when extrapolated to all the reactants and products of a metabolic pathway, we get the ODE Model for glycolysis..


Interactivity option 1.a - Assignment

Boundary/limitsInteracativity Type Options Results

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.

=

-1 1 0

A B

C

D

E

F

r1r2

r3 r5

r4

Construct a Model for a Hypothetical Network by Drag and Drop

User is supposed to drag the red blue and green tabs in their respective brackets.

The blue tabs should not be taken off from the screen as they will be used multiple times to fill a 2D matrix

The resultant Matrix is shown in the next slide. If any of the tabs have been wrongly entered, show a red cross and encircle the red tabs. Else show a green tick

-1 -1 0 0 0

1 -1 -1 0 0

0 1 1 -1 0

0 0 1 0 -1

0 0 0 1 0

0 0 0 0 1

.

Interactivity option 1.b - Result

Boundary/limitsInteracativity Type Options Results

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.=

Construct a Model for a Hypothetical Network by Drag and Drop

User is supposed to drag the red blue and green tabs in their respective brackets,.

The blue tabs should not be taken off from the screen as they will be used multiple times to fill a 2D matrix

The resultant Matrix is shown in the next slide. If any of the tabs have been wrongly entered, show a red cross and encircle the red tabs. Else show a green tick

A

B

C

D

E

F

-1

1 0

A B

C

D

E

F

r1r2

r3 r5

r4

r1

r2

r3

r4

r5

0 0 0 0

1 -1 -1 0 0

0 1 0 -1 0

0 0 1 0 -1

0 0 0 1 0

0 0 0 0 1

Questionnaire1. Which is NOT a method to model biological networks

Answers: a) ODEs b) Stoichiometric Analysis c) Half-life analysis d) All

2. Data for systems biology is obtained from

Answers: a) Experiments b) Databases c)Both d)None

3. A biological system refers to

Answers: a) A cell b)A tissue c) An organism d) All

4. Which process cannot be modelled using sytems biology?

1. Answers: a) Digestion b) Protein-Protein Interaction

c) Gene regulatory Network d) Metabolic reaction

5. Sytems biology does includes

a) Modeling networks b) Determinig reaction kinetics c) Both d) None of the Above

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Links for further readingFollowing URLs are used for animations

http://controls.engin.umich.edu/wiki/images/4/45/TransitionDiagram.JPG

Biochemistry by Stryer et al., 5th edition

Biochemistry by A.L.Lehninger et al., 3rd edition

http://1.bp.blogspot.com/_WyIc2oXjvmc/SKGOVUfo-uI/AAAAAAAAArA/h6BZq_t2MY8/s400/Air+car+engine+dia.jpg

http://www.istockphoto.com/file_thumbview_approve/7129036/2/istockphoto_7129036-car-parts-two.jpg


Systems biology and the virtual physiological human Molecular Systems Biology 5:29

http://www.ece.cmu.edu/~brunos/Lecture3

http://tsb.mssm.edu/summerschool/images/f/f0/IntroODE

http://tsb.mssm.edu/summerschool/images/f/f0/IntroODE

Links for further reading

Published Literature

1. Systems biology and the virtual physiological human. Peter Kohl & Denis Noble; Molecular Systems

Biology 5:292; 2009.

2. Biology and the systems view. Bettina Bock von Wülfingen; EMBO Rep. 10(S1): S37–S4; 2009.

3. Systems Biology: An Approach. P. Kohl, EJ Crampin, TA Quinn & D Noble; Clinical pharmacology &

Therapeutics, 88, 1, 2010.

4. The Systems Biology Graphical Notation. Nicolas Le Novère, Michael Hucka, Nicolas Le Novère4, Yukiko

Matsuoka & the SBGN Consortium; Nature Biotechnology 27, 735 – 741, 2009.

5. Hypothesis-driven omics integration. Andreas Schmid & Lars M; Nat Chem Biol. 6(7):485-7; 2010.

6. Network spreading. Nicola McCarthy; Nature Reviews Cancer.10, 80-81, 2010.

7. Visualization of omics data for systems biology. Nils Gehlenborg et al.; Nature Methods 7, S56 - S68,

2010.

8. Systems Biology: A Brief Overview. Hiroaki Kitano; Science 1:Vol. 295. no. 5560, pp. 1662 – 1664, 2002

Links for further reading

Webliography

http://www.systemsbiology.org/



Books

1. System modeling in cellular biology --- Edited by Z.Szallasi, J.Stelling, and V.Periwal

2. Systems Biology in practice --- E.Klipp, R.Herwig, A.Kowald, C.Wierling, H.Lehrach

3. Systems Biology - properties of reconstructed networks --- B.Palsson

systems biology surabhi agarwal affiliations the examination of a biological entity as an integrated...

Documents

systems biology systems

system study

systems biology concepts

systems biology triangle4

systems analysis

biological system

metabolic system

integrated system