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27041 Systems Biology: Fall 2012

Danish title:	Introduktion til systembiologi
English title:	Introduction to systems biology
Language:	English
Point (ECTS):	5
Course type:	MSc/ BSc Eng course, Advanced Course Taught under open university

Content

Introduction to systems biology, methods and techniques, high throughput techniques including gene expression and protein-protein interaction screens. Definition of biological structures and processes as systems. Interactions and networks, graph theory, biological network analysis. Principles of mathematical modelling, first principle models versus data-driven models. Constructing qualitative models by data integration. Quantitative modeling and simulation, analysis of dynamical models. Metabolic networks and quantitative description of these. Elementary flux models. Kinetic models for enzyme catalyzed reactions and for signal transduction pathways. Pathway reconstruction.

Course Instructors

Chris Workman, PhD
Fred De Masi, PhD

Course learning objectives

A student who has met the objectives of the course will be able to:

• Describe the different approaches to systems biology.
• Describe different high-throughput experimental techniques used in systems biology.
• Construct a biological network model from interaction data.
• Calculate biological network properties using graph theory.
• Understand the function and behavior of frequent regulatory network motifs.
• Use of systematic genome-wide data together with biological networks to evaluate cellular response or other phenomena.
• Design regulatory networks with a defined input/output function.
• Estimate the significance of network models and ontologies based on high-throughput experimental data.
• Model fitness based on cost benefit analysis.
• Understand the evolution of regulatory mechanisms in context of the Demand theory of regulation.
• Determine the properties of dynamic models.

Schedule overview

Module #	Week #	Date	Module
1	12	04/09/2012	Overview and introduction
2	12	11/09/2012	Protein-protein interaction data
3	12	18/09/2012	Biological networks: Theory and applications
4	12	25/09/2012	Simple regulatory network models
5	12	02/10/2012	Dynamic regulatory network models
6	13	09/10/2012	Dynamic systems properties
7	13	23/10/2012	Temporal programs and network motifs in developmental
8	13	30/10/2012	Signaling and mixed interaction networks, gene ontologies
9	13	06/11/2012	Causal models
10	13	13/11/2012	Protein-level optimality
11	15	20/11/2012	Demand rules for gene regulation
12	15	27/11/2012	Engineering regulatory systems
13	15	04/12/2012	Review and exam prep.

04/09/2012: Module 1

Title: Overview and introduction

Schedule

09:00	-	09:30	Lecture	Introduction: lecturers, format and materials	[slides]
09:30	-	09:45	Discussion	Review Systems Biology pre-course survey	[online survey]
09:45	-	10:00		- BREAK -
10:00	-	10:20	Lecture	Review survey
10:20	-	11:00	Lecture	Motivation for Systems Biology	[slides]

Reading

• Can a biologist fix a radio? Lazebnik Y., Cancer Cell 2002 [PDF]

Objectives

1. Identify the various preconceptions of Systems Biology as a field.
2. Be able to discuss the technological advances that have created a need for more systems biology
3. Be able to discuss the trade-off between model accuracy and tractability.
4. Be able to demonstrate what is meant by ``the whole is more than the sum of its parts''.

11/09/2012: Module 2

Title: Protein-protein interaction data

Schedule

08:30	-	08:45	Lecture	Brief review of last lectures key topics
08:45	-	09:45	Lecture	Introduction to interaction data types	[slides]
09:45	-	09:50		- BREAK -
09:50	-	10:45	Exercise	Protein-protein interaction data	[exercise]
10:45	-	11:00		- BREAK -
11:00	-	11:40	Exercise	Comparative assesment of protein-protein interaction data sets	[exercise]
11:40	-	12:00	Discussion	Thoughts on protein-protein interaction data

Reading

• Studying the interactome with the yeast two-hybrid system and mass spectrometry (Causier B, Mass Spec Reviews 2004) [PDF]

• Comparative assessment of large-scale data sets of protein-protein interactions (von Mering C, et al. Nature 2002) [PDF]

• Proteome survey reveals modularity of the yeast cell machinery (Gavin et al. Nature 2006) [PDF]

• Lecture note on quality scoring of protein-protein interaction data, notes and examples [PDF]

Objectives

1. Describe two methods for measuring protein-protein interaction data
2. Draw protein-protein interaction networks from experimental data
3. Calculate quality of protein-protein interaction data generated by either yeast two-hybrid or MS
4. Discuss strength and weaknesses of the yeast two-hybrid method and MS for detecting protein-protein interaction data

18/09/2012: Module 3

Title: Biological networks: Theory and applications

Schedule

08:30	-	08:45	Lecture	Brief review of last lectures key topics
08:45	-	09:45	Lecture	Network anlaysis: topology, modules, and applications	[slides]
09:45	-	09:55		- BREAK (10min) -
09:55	-	10:55	Exercise	Network topology exercise	[exercise]
10:55	-	11:05		- BREAK (5min) -
11:05	-	12:00	Comp. Ex.	Cytoscape, topology/statistics/modules	[exercise]

Reading

• Global network properties. Barabasi& Oltvai, Nat Rev Genet 2004. [PDF]

• SnapShot: Protein-Protein Interaction Networks (Seebacher & Gavin, Nature 2011) [PDF]

Objectives

1. Be able to provide graph/network global properties. Be able to define a path in a graph/network.
2. What is meant by a scale-free network
3. Be able to determine whether a network is random or scale free based on relevant network parameters
4. Be able to calculate the clustering coefficient for a node in a network (as we defined it) and be able to describe what values are represented in the numerator and the denominator of the clustering coefficient.
5. What might a high cluster coefficient tell you about the relationship of proteins?
6. Be able to identify modules in protein-protein interaction network

25/09/2012: Module 4

Title: Simple regulatory network models

Schedule

08:30	-	08:45	Lecture	Review of last week and Cytoscape exercise
08:45	-	09:45	Lecture	Simple models of regulation	[slides]
09:45	-	09:55		- 10 min break -
09:55	-	10:45	Exercise	Problems from Chapter 2 (part 1)	[exercise]
10:45	-	11:00		- 5 min break -
11:00	-	12:00	Comp. Ex.	Regulatory networks representation	[exercise]

Reading

• An Introduction to Systems Biology, Uri Alon, Chapters 1 & 2 (pages 1-22).

Objectives

1. Basic understanding of transcriptional regulation
2. Understand how mRNA profiling (transcriptomics) is done, experimentally
3. Be able to model simple regulatory interactions
4. Be able to represent a regulatory network as a graph
5. Understanding of regulatory modules and how they are discovered

02/10/2012: Module 5, Week 39

Title: Dynamic regulatory network models

Schedule

08:30	-	08:45	Lecture	Brief review of last lectures key topics
08:45	-	09:45	Lecture	Methods for measuring regulatory interactions (ChIP and PBM)	[slides]
09:45	-	09:50		- BREAK -
09:50	-	10:50	Exercise	Problems from Chapter 2 (part 2)	[exercise]
10:50	-	12:00	Exercise	Problems from Chapter 3	[exercise]

Readings

• An Introduction to Systems Biology, Uri Alon, Chapters 3

Objectives

1. Be able to describe how protein-DNA interactions are measured
2. Explain how autoregulation can be used by a cell
3. Be able to calculate the response time for both n.a.r. and simple regulation
4. Analytically identify dynamic properties of coupled models of simple regulation (regulatory cascades)

09/10/2012: Module 6

Title: Dynamic systems properties

Schedule

08:30	-	08:45	Lecture	Brief review of last lectures key topics
08:45	-	09:40	Lecture	Boolean networks and their dynamics	[slides]
09:40	-	09:50		- 10 minute break -
09:50	-	10:20	Lecture	Feed Forward Loops (Chapter 4)
10:20	-	10:25		- BREAK -
10:25	-	12:00	Exercise	Exercises	[exercise]

Readings

• An Introduction to Systems Biology, Uri Alon, Chapter 4

Objectives

1. Be able to formulate a Boolean network abstraction
2. Explain some global properties of discrete network dynamics
3. Define the concepts of an attractor
4. Explain the dynamic properties of at least two different feed-forward motif models

23/10/2012: Module 7

Title: Temporal programs and network motifs in developmental

Schedule

08:30	-	08:45	Lecture	Review
08:45	-	09:40	Lecture	Chap 5: Temporal programs and the global structure of transcription networks Temporal programs	[slides]
09:40	-	09:50		- 10 min break -
09:50	-	10:40	Lecture	Functional Genomics and Genetic Interactions
10:40	-	10:45		- 5 min break -
10:45	-	12:00	Exercise	Problems from Chapters 5 and 6	[exercise]

Reading

• Introduction to Systems Biology by Uri Alon, Chapter 5, Chapter 6 (6.1, 6.2 only)

Objectives

1. Describe the biological functions of the single-input module (SIM)
2. Design a regulatory circuit that implements a LIFO or FIFO queue
3. Be able to propose topological generalizations of small network motifs
4. Be able to model simple feedback loops
5. Be able to list the different types of genetic interactions
6. Be able to describe how genetic interactions are measured

30/10/2012: Module 8

Title: Signaling and mixed interaction networks, gene ontologies

Schedule

08:30	-	08:45	Lecture	Brief review of last lectures key topics
08:45	-	09:50	Lecture	Signal transduction networks, Composite network motifs	[slides]
09:50	-	10:00		- 10 min break -
10:00	-	12:00	Exercise	Gene ontology exercise	[exercise]

Reading

• An Introduction to Systems Biology by Uri Alon, Chapter 6 (6.3-6.7)

• Gene ontology tutorial [CampusNet]

Objectives

1. Be able to characterize the information processing capabilities of signaling networks
2. To identify the features of a biological oscillator
3. Extract funtional information for a given gene
4. Extract genes with a specific functional information
5. Statistics for gene set function enrichment
6. Introduction to gene ontologies and the Gene Ontology consortium

06/11/2012: Module 9

Title: Causal models

Schedule

08:30	-	08:45	Lecture	Review
08:45	-	09:40	Lecture	Examples of systematic transcriptional regulatory network (TRN) inference	[slides]
09:40	-	09:45		- 5 min break -
09:45	-	10:20	Lecture	TRN functional annotation and analysis in DNA damage stress
10:20	-	10:30		- 10 min break -
10:30	-	12:00	Exercise	Exercises	[exercise] [zip data] [cys]

Readings

• (catch-up on missed reading Chapters 1-6, solution sets)

Objectives

1. Gain an overview of an integrative systems biology project involving both interaction data and system output data.
2. Be able to integrate a number of different interaction networks and filter them based on specific questions.
3. Gain an ability to solve non-trivial problems in Cytoscape

13/11/2012: Module 10

Title: Protein-level optimality

Schedule

08:30	-	08:45		Lecture and Cytoscape exercise review
08:45	-	09:40		Optimality at a single protein level	[slides]
09:40	-	09:45		- 5 min break -
09:45	-	10:30		Optimality at a single protein level, continued
10:30	-	10:40		- 10 min break -
10:40	-	12:00		finish Chapter 10
11:00	-	12:00		Exercises - Protein-level optimality	[exercise]

Readings

• Introduction to Systems Biology by Uri Alon, Chapter 10.

• (OPTIONAL) Dekel and Alon, Nature 2005 [PDF]

Objectives

1. Evaluate the fitness of an organism through cost-benefit analysis.
2. Model the fitness of an organism in terms of optimal expression levels of a protein under constant conditions.
3. Apply a cost-benefit analysis to multiple types of regulatory systems under static and dynamic conditions.
4. Explain the evolutionary significance of expression level of a protein under given environmental conditions.

20/11/2012: Module 11

Title: Demand rules for gene regulation

Schedule

08:30	-	08:45		Review of W10
08:45	-	09:45		Solutions to protein-level optimality problems
09:45	-	09:55		- 10 min break -
09:55	-	10:30		Demand rules for gene regulation	[slides]
10:30	-	10:40		- 10 min break -
10:40	-	12:00		Exercises: 11.1, 11.3, 11.4	[exercise]

Readings

• Chapter 11, An Introduction to Systems Biology by Uri Alon

Objectives

1. Explain why cells may evolve one mechanism of regulation versus another
2. Be able to describe the affects of mutations on positive and negative regulatory mechanisms
3. Understand how the demand rules change in multi-regulator systems

27/11/2012: Module 12

Title: Engineering regulatory systems

Schedule

08:30	-	08:45		Review of week 11, exercises
08:45	-	09:15		Synthetic Biology overview
09:15	-	09:25		- 10 min break -
09:25	-	10:30		Reviews on the subject (Khalil and Collins, other TBA)
10:30	-	12:00

Readings

• Synthetic biology: applications come of age, Khalil AS and Collins JJ Nat Rev Gen. 2010

Objectives

1. Describe some basic objectives of synthetic biology
2. Knowledge of biotechnology standards

04/12/2012: Module 13

Title: Review and exam prep.

Schedule

09:00	-	09:50		Exam preparation
10:00	-	12:00		Exam preparation

Readings

• TBA

Objectives

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