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Surabhi Agarwal Affiliations

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1 Surabhi Agarwal Affiliations
Systems Biology 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. Title of the concept Surabhi Agarwal Affiliations

2 1 Master Layout 2 3 4 5 This animation consists of 2 parts:
Part 1: Systems Biology Concepts Part 2 : Modeling Biological Networks 2 1. Analogy 2. Difference between system study and component study 3 4 3. Systems Biology Triangle 4. Work flow for Systems analysis 5

3 Definitions of the components: Part 1: Systems Biology Concepts
Systems biology: It is a discipline for studying organisms as a network of interacting components. Genomics: The entire sequence of an organism’s hereditary information, encoded in DNA is known as the genome and their study is called genomics. 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. 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. Model system: A simple system of networks which can be mapped to the problem under consideration and is easily computationally modeled within available technologies. 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. 2 3 4 5

4 Analogy / Scenario / Action
1 Analogy / Scenario / Action Used to convert fuel energy into mechanical energy. Can be used to make several equipments operate such as Air plane, Motorbike !!?? 2 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 !!?? 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 !?? 3 A 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. 4 5

5 3 1 2 4 5 Step 1.a - Two Approaches in Systems Biology
Systems biology research consists of the 1. Identification of the Parts 2.Characterization of the components. 4. 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 3. Exclude the ones which are not a part of the system Systems is an entity which maintains its existence through a mutual interaction of its constituent parts 1 2 3 4 Action Description of the action Audio Narration 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: Identification of the Parts Characterization of the components. Exclude the ones which are not a part of the system Identify the interaction of the components with each other Identify the interaction of the components with the environment which modulate the parts either directly or indirectly through modulation of internal interactions 5 Systems biology and the virtual physiological human Molecular Systems Biology 5: 292; published online 28 July 2009; doi: /msb

6 3 1 2 4 5 Step 1.b - Two Approaches in Systems Biology SYSTEMS PARTS
Integrative Approach: Integrating the study of individual components to form conclusions about system Reductionist Approach: Disintegrating the system into its component parts and studying them. PARTS 4 Action Description of the action Audio Narration 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 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. 5 Systems biology and the virtual physiological human Molecular Systems Biology 5: 292; published online 28 July 2009; doi: /msb

7 Step 2.a: Studying components
1 2 Protein Product DNA 3 DNA binding protein Lipoprotein 4 Action Description of the action Audio Narration Schematic to depict the concept of Systems Biology 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 5

8 Step 2.b: Studying Systems
1 2 3 4 Action Description of the action Audio Narration Schematic to depict the concept of Systems Biology Figures need to be re-drawn. Follow the steps exactly as shown in the animation. Animator needs to ensure the order of steps. 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 networks 2. Gene regulatory networks 3. Protein-DNA networks 4. Protein lipid interactions 5. Metabolic Networks 5

9 Step 2.c: System studies requires “omics”
1 2 3 The information about the proteins comes from Proteomics data. This data can be experimental or it can be retrieved from public domain databases The information about the DNA complement of an organism comes from the Genomics Data. This, again, can either be retreived experimentally or from databases. 4 Action Description of the action Audio Narration Schematic to depict the concept of Systems Biology Follow the animation steps. Re-create images. Animate and narrate the green boxes. 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. 5

10 Step 3: Systems Biology Triangle
1 EXPERIMENT 2 3 COMPUTATIONAL MODELLING TECHNOLOGY THEORY 4 Action Description of the action Audio Narration 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 5 , Biochemistry by Stryer et al., 5th edition, Biochemistry by A.L.Lehninger et al., 3rd edition

11 Step 4: Work flow for Systems Biology
1 Creation of a model for the problem which represents computable set of assumptions and hypotheses that will be subjected to experimental validation Selection of biological significant problem EXPERIMENTS COMPUTATION 2 Biological knowledge and contradictory issues Data and Hypothesis driven Modeling 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 The data from the experiments is analyzed and the inadequate models are discarded Systems analysis are conducted on the consistent models to make predictions for the system 3 Experiment Data analysis Systems Analysis and theory formulation From all the predictions, a small set is selected to validate them using wet-lab experiments which are designed for this purpose. Experimental Design and device development Prediction 4 5 Systems Biology: A Brief Overview, Hiroaki Kitano,, 1662 (2002); 295 Science

12 3 1 2 4 5 Step 5: Action Description of the action Audio Narration
Genral protocol for a systems biology experiment 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. A typical work flow for approaching a biological problem with a system biology perspective is: 1. Selection of biological 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 rejected 4. Systems analysis are conducted on the consistent models to make predictions for the system 5. 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 2 3 4 5 Systems Biology: A Brief Overview, Hiroaki Kitano,, 1662 (2002); 295 Science

13 Stoichiometric Analysis Ordinary Differential Equations
Master Layout 1 This animation consists of 2 parts: Part 1: Systems Biology Concepts Part 2 : Modeling Biological Networks 2 3 4 Stoichiometric Analysis Ordinary Differential Equations 5

14 Definitions of the components: Part 2: Modeling Biological Networks
1 ODE: ODE stands for Ordinary Differential Equation. It is a mathematical relation that can be used for modeling biological systems. Stochiometric Model: Modelling a biological network based on its stochiometirc coefficients, reaction rates and metabolite concentrations. 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. 2 3 4 5

15 Step 1.a - Stoichiometric Analysis
2 S: Vector of Concentration values N: Stoichiometric Matrix v: Vector of Reaction rates 3 Action Description of the action Audio Narration Static image Display the equation and narrate the text To model more complex networks stochiometric modeling can be used which has 3 basic components: The concentration of all the reactants and products in the form of a vector of Concentration values (S) The Stoichiometric Matrix that describes the production and consumption of each metabolite at each of individual reaction (N) The vector for Rate of all the reactions involved (v) Information on any two will help us in determining the third. 4 5

16 Step 1.b - Stoichiometric Analysis
ATP ADP ATP ADP v3 v1 v2 G6P F6P FBP GLU 2 ATP -1 -1 GLU -1 3 ADP +1 +1 G6P +1 -1 F6P +1 -1 FBP +1 4 Action Description of the action Audio Narration 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. Schematic to describe Stoichiomettric Model Follow steps in animation. Re-draw all images. Write the equations in proper manner as separate Images 5

17 Step 1.c - Stoichiometric Analysis
S: Vector of Concentration values N: Stochiometric Matrix v1 v2 v3 2 ATP -1 -1 GLU -1 ADP +1 +1 N = S = 3 G6P +1 -1 F6P +1 -1 FBP +1 v: Vector of Reaction rates T v = v1 v2 v3 4 Action Description of the action Audio Narration Schematic to describe Stoichiomettric Model 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. 5

18 Step 1.d - Stoichiometric Analysis
── dt . = N v 2 -1 -1 ATP -1 GLU v1 . T = +1 +1 ADP 3 v1 v2 v2 v3 3 ROWS +1 -1 G6P v3 +1 -1 F6P +1 FBP 4 3 COLUMNS Action Description of the action Audio Narration Schematic to describe Stoichiomettric Model 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: Metabolic Network Protein-Protein Interaction Gene regulatory Network 5

19 3 1 2 4 5 Step 2.a - Ordinary Differential Equations - Basics Action
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” does not change with time 2 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 3 Shows decrease in concentration 4 Action Description of the action Audio Narration Schematic to describe ODE Model Follow steps in animation. Re-draw all images. Write the equations in proper manner as separate text 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. 5

20 CONCENTRATION OF REACTANTS CONSTANTS OF PROPORTIONALITY
Step 2.b – Biological Reactions to Ordinary Differential Equations 1 Law of Mass-Action : The rate of a reaction is proportional to the product of the concentration of the reactants A 2 A B “a” reduces in concentration by a value which is proportional to its initial concentration. 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” 3 The concentration of “a” reduces and “b” increase with time by a value which is proportional to initial concentration of “a”. A + B C 4 5 CONCENTRATION OF REACTANTS CONSTANTS OF PROPORTIONALITY REACTANTS

21 3 1 2 4 5 Step 5: Action Description of the action Audio Narration
Schematic to describe ODE Model 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 2 3 4 5 Systems Biology: A Brief Overview, Hiroaki Kitano,, 1662 (2002); 295 Science

22 3 1 2 4 5 Step 2.c - Common Biological Ordinary Differential Equations
BIOLOGICAL REACTION RATE CONSTANT CORRESPONDING ODE A k1 A B k2 A + B C k3 A + B A + D k4 2 3 4 Action Description of the action Audio Narration 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. 5

23 3 Step 2.d - Ordinary Differential Equations 1 2 4 5 v2 v1 v4 v3 v5 v6
ADP v2 ATP ADP ATP ADP v1 ATP v4 v3 v5 2 Glucose Glucose-6-P Fructose-6-P Fructose-1,6 Bi-phosphate v6 ADP ATP 3 v7 ATP ADP v8 ATP + AMP 2ADP 4 Action Description of the action Audio Narration Schematic to describe ODE Model Follow steps in animation. Re-draw all images. Write the equations in proper manner as separate text 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. 5

24 Step 2.e - Ordinary Differential Equations
1 ADP v2 ATP ADP ATP ADP v1 ATP v4 v3 v5 Glucose Glucose-6-P Fructose-6-P Fructose-1,6 Bi-phosphate 2 v6 ADP ATP 3 v7 ATP ADP v8 ATP + AMP 2ADP 4 Action Description of the action Audio Narration Schematic to describe ODE Model Follow steps in animation. Re-draw all images. Write the equations in proper manner as separate text 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.. 5

25 Interactivity option 1.a - Assignment
-1 r1 A B r5 r3 D F 2 -1 -1 1 -1 -1 3 1 1 -1 . . = 1 -1 1 4 1 Interacativity Type Options Boundary/limits Results 5 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

26 Interactivity option 1.b - Result
r1 A B r5 r3 D F 2 -1 A r1 1 -1 -1 B r2 3 . C 1 -1 r3 = D 1 -1 r4 E 1 r5 4 F 1 Interacativity Type Options Boundary/limits Results 5 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 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 The blue tabs should not be taken off from the screen as they will be used multiple times to fill a 2D matrix

27 Questionnaire 1 1. 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? 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 2 3 4 5

28 Links for further reading
Following URLs are used for animations Biochemistry by Stryer et al., 5th edition Biochemistry by A.L.Lehninger et al., 3rd edition uI/AAAAAAAAArA/h6BZq_t2MY8/s400/Air+car+engine+dia.jpg two.jpg Systems Biology: A Brief Overview, Hiroaki Kitano,, 1662 (2002); 295 Science Systems biology and the virtual physiological human Molecular Systems Biology 5:29

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

30 Links for further reading
Webliography 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


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