Modeling Workshop Seattle 2016

KarenLogo

May 24/25

This workshop has been designed for ocean scientists who have an interest in applying computational systems biology to their research. No prior knowledge of computational systems biology is required. Participants will learn the basics of computational systems biology and how it can be applied to biological research. The workshop will include both tutorials and hands on exercises. In addition, the workshop is an opportunity to meet other ocean scientists interested in utilizing systems biology techniques and to meet bioengineering experts who can guide you towards resources you may need for your research.

Models for the afternoon exercises

Model 1:

import tellurium as te
r = te.loada(’’’
$A -> B; vo;
B + C -> D; k1 * B * C – k2 * D;
A = 1; C = 1.5;
vo = 0.6; k1 = 0.34; k2 = 0.78;
’’’)
m = r.simulate (0, 100, 100)
r.plot()

Model 2:

import tellurium as te
r = te.loada(’’’
$S1 -> S2; k1 * S1;
S2 ->; Vm * S2/(Km + S2);
k1 = 0.4; S1 = 5;
Vm = 2; Km = 0.5;
’’’)
m = r.simulate (0, 10, 100)
r.plot()

Model 3:

import tellurium as te
r = te.loada(’’’
$S1 -> S2; k * S1;
S2 -> S3; vo;
vo = 15; k = 0.4;
S1 = 5; S2 = 50
’’’)
m = r.simulate (0, 10, 100)
r.plot()

Extension Exercise

Build a single gene cassette.

Build the following model of a single gene cassette.  Set all rate constants ki to 1.  Set Km = 0.5 and Vm = 2. Study the effect of varying the Hill coefficient (h=1,2,3,4) on the production of protein as a function of repressor level.

What is the effect of increasing k1 on protein dynamics?

GeneCassette

Room Location in Foege Building: N403
  1. Make your way to the fourth floor either via the stairwell (north entrance) or the elevator (south entrance).
  2. One the west side of the building there is a long corridor.
  3. From the stairwell, turn left and left again on to the corridor walk  until you reach N403 (near the end of the corridor on the right)
  4. From the elevator, turn to your right as you exit then  left on to the corridor
  5. Wall south a short distance to N403 on the right.
Eating Options For Lunch

eatingOptions

Downloading Software

In order to prepare for the workshop it is recommended that the following tools be installed on your laptop before arriving.

For Windows users with Windows Vista and up. Download Tellurium and start the installer.

For Mac users: Download and install the Mac OS DMG file

For further details visiting the Tellurium web site.

If you experience any problem with installing the software contact, please see our contact page.

If you are a Linux user a basic distribution, please ask on the mailing list linked above.

Registration

Registration is FREE. However in order to gauge numbers we would be grateful if interested individuals could provide the following information and forward it to Karen Parker at:

karen.parker2000 at gmail.com  (Note replace the ‘at’ with @)

Please provide in your email:
Name:
Title
Organization
Email
Cell Phone:
Research Interests
Do you require travel assistance?
Do you have any dietary restriuctions we should be aware of?

Speakers and Tutors

Jonathan Karr: Whole Cell Modeling

Jonathan is a Fellow in the Institute for Genomics & Multiscale Biology Institute at the Mount Sinai School of Medicine. His research group focuses on developing large-scale dynamical “whole-cell” models of individual cells and their applications to bioengineering and medicine. He worked on building, validating and utilizing a whole cell computational of Mycoplasma Genitalium to identify kinetic parameters and biologic functions and to elucidate how complex phenotypes arise from individual molecules and their interactions. The example demonstrates the feasibility of whole cell modeling and illustrates the benefits and challenges of both flux balance analysis and kinetic modeling techniques.

Jennifer Levering: Metabolic Reconstruction

Jennifer Levering is a Computational Systems Biologist interested in the development and application of mathematical modeling. During her PhD in the Kummer lab at Heidelberg University, Germany, she constructed and analysed dynamic as well as genome-scale stoichiometric models of the human pathogen Streptococcus pyogenes to understand similarities and differences to related lactic acid bacteria and to identify growth requirements and possible drug targets of the human pathogen. For her postdoctoral research, Jennifer joined the Palsson lab at UCSD and worked on a detailed and compartmentalized genome-scale metabolic network reconstruction as well as regulatory network inference for the marine diatom Phaeodactylum tricornutum to uncover unexpected biochemistries and to provide an important in silico template for directing future metabolic engineering efforts. After three years as a Post Doc in the Palsson lab, Jennifer joined the Zengler lab at UCSD.

Herbert Sauro: Kinetic Modeling

Herbert Sauro is an associate professor at UW. He has worked in a number of areas including control theory in metabolism as well modeling standards for systems biology and synthetic biology. He has written three textbooks on Enzyme Kinetics, modeling and linear algebra.

Teaching Assistants:

Kyle Medley: Kyle is a 3rd year graduate student at UW. He helped develop the simulator libroadrunner together with testing debugging and porting of libroadrunner to the Mac and Linux. He also does theoretical work on networks and is involved in the repoducibility of the M. genitalium whole-cell modeling project.

Kiri Choi: Kiri is a 3rd year graduate student at UW. He helped develop the Tellurium front-end and integrating the various python packages. His work now is looking at machine-learning and novel ways to build and validate cellular models.

AGENDA

TimeTues May 24Wed May 25Thursday May 25
5.30 pmFinishFinish
8.30 amIntroductionIntroduction to Kinetic Modeling, running simple examplesOptional Project Time
8.45 amPlenary Talk: Jonathan KarrIntroduction to Kinetic Modeling.
Different kinds of analyses including stochastic steady state
and sensitivity analysis.
Optional Project Time
9.45.amBreakBreakOptional Project Time
10.10 amPython Crash CourseModel exchange. Exercises: 1) Exchanging models
2) Downloading models from biomodels
Lunch
10.45 amCoffee BreakCoffee Break
11 amSetting up your computerDebugging models
Exercises: Find the errors
Why some models don't work
12.30 pmLunchLunch
1.30 pmIntroduction to constraint base modelingExercises in building metabolic and signaling networks
Where to get data, how to validate models, model fitting.
2.30 pmMetabolic reconstruction fundamentalsChemotaxis case study
3.45 pmCoffee BreakCoffee Break
4.10 pmExercises in constraints based modeilngExercises in building genetic networks

Downloadable Material:

 

Exercise files for May 24

Simulation Software Cheat Sheet

Modeling Cheat Sheet

Simulator Documentation with Lots of Examples

Introductory Slides to Simulator Software

Exercises

Plenary Lecture: Jonathan Karr

Tutors

Jennifer Levering: Zengler lab, Department of Pediatrics, UCSD,

Herbert Sauro: Department of Bioengineering, University of Washington, UW

LOCATION

The workshop will be located in the Department of Bioengineering at the University of Washington in Seattle.

William Foege Building on the UW Campus

The image below shows the location (Red Circle) of the Bioengineering department on the UW campus.  For those coming from the Airport the map also indicates the light-rail station  (red square, lower right corner) which is only a 10 minute walk to the department.

UW

ACCOMMODATION

University Inn 800-733-3855

Rooms have private baths and cost about $200 per night with taxes. Located two blocks from campus https://gc.synxis.com/rez.aspx?Hotel=40207&start=availresults&locale=en-us&arrive=&depart=&Promo=

A block of rooms have been reserved at the University Inn at a discounted rate. To book a room at the discounted rate, book the room before May 9th at 4Pm by calling Michele at 425-974-7103 between 8:30am and 5pm.  The block of rooms is reserved under the name Systems Biology workshop.

The College Inn 206-633-4441

4000 University Way NE, Seattle, Wa Located on campus. Rooms are private but do not have private baths and cost about $75 per night with taxes. http://www.collegeinnseattle.com/

DINNER

There will be a Tuesday evening group dinner at around 6:30 pm Tues at 2900 Westlake Ave North, Seattle, Wa. It is on the south side of the Fremont Bridge. It is about a 10 min drive and a pleasant 45 min walk along a bike path from the University.

TRAVEL SUPPORT AND INFORMATION

For those coming from out of town and particularly via the airport, there is a direct light-rail connection to the university campus.

FAQ

What is Computational Systems Biology?

Computational systems biology is a technique to build simulation models of biological cell functions. Flux balance Analysis (FBA) models the metabolism of an organism based on the biochemical reaction set implied by the genome.  It can represent 10 reactions or thousands of reactions. The reaction equations represent the stoichiometry of the reaction equations.   It can simulate metabolic pathway activity based on the measured nutrient input and biomass with some limitations which need to be carefully evaluated. The FBA model can also be modified based on proteomic or transcriptomic data.  Kinetic Modeling is a model based in the physics of protein interactions. Typically there are 10-100 functions considered including biochemical reactions, diffusion, binding, transcription, and translation. This technique is often used for regulatory network simulations. It can also be used to simulate signaling between organisms. When building a whole cell model the two techniques can be combined.

How much of a math background is required?

Generally only a background in algebra is required for flux balance analysis. An understanding of differential equations is helpful for kinetic modeling. Kinetic modeling utilizes a set of differential equations to build the biological system model, however the model building and simulation tools have built in math intelligence so that the user does not need to enter or solve differential equations.  If the user understands the protein to protein interactions and can characterize them, the development tool will guide the modeler to the correct differential equation to represent the interaction.  Herbert Sauro’s book on Enzyme Kinetics (see recommended reading), is an excellent book which describes the relationship between the differential equations and the characterization of protein interactions. That being said, validating a model requires a solid understanding of the assumptions, limitations and theory of the model. If you start with a small, simple model and run simulations to confirm it behaves as expected, you will avoid being overwhelmed by the complexity of the system.

What resources are available to learn more about systems biology?

Enzyme Kinetics, modeling and linear algebra:

1. Enzyme Kinetics for Systems Biology, Sauro (2012) ISBN-10: 0982477333
2. Systems Biology: Introduction to Pathway Modeling, Sauro (2014) ISBN-10: 0982477376
3. Systems Biology: Linear Algebra for Pathway Modeling, Sauro (2015) ISBN-10: 0982477392
4. Uri Alon’s intro to systems biology course.

Whole cell modelling

Karr, Jonathan R., Jayodita C. Sanghvi, et al. “A Whole-Cell Computational Model Predicts Phenotype from Genotype.Cell 150(2): 389-401.

Sanghvi, J. C., S. Regot, et al. (2013). “Accelerated discovery via a whole-cell model.Nat Meth 10(12): 1192-1195.

Constraint Based Modeling

COBRApy documentation (https://cobrapy.readthedocs.org/en/latest/)

BIGG Models (http://bigg.ucsd.edu/)

Thiele, I, and Palsson BO (2010). A protocol for generating a high-quality genome-scale metabolic reconstruction. Nature Protocols 5(1):93-121

Orth, J, Thiele, I, Palsson, BO (2010). What is flux balance analysis? Nature Biotechnology 28(3):245-248

Lewis, N, Nagarajan, H, Palsson, BO (2012). Constraining the metabolic genotype-phenotype relationship using a phylogeny of in silico methods. Nat Rev Micorbiol 10:291-305

Levering, J., J. Broddrick, et al. (2015). “Engineering of oleaginous organisms for lipid production.” Current Opinion in Biotechnology 36: 32-39.

For more advanced material:

Palsson, Bernhard; Systems Biology. Constraint-based Reconstruction and Analysis, Cambridge University press, 2015

Useful Databases:

BioModels http://www.ebi.ac.uk/biomodels-main/publmodels

Le Novère, N., B. Bornstein, et al. (2006). “BioModels Database: a free, centralized database of curated, published, quantitative kinetic models of biochemical and cellular systems.” Nucleic Acids Research 34(suppl 1): D689-D691.

SABIO-RK- Biochemical Reaction Kinetics Database

http://sabio.villa-bosch.de/

FUNDING ACKNOWLEDGEMENTS

We wish to acknowledge the generous support of Karen Parker who made this workshop possible as well as generous support from the NSF (#1355909) ABI Development Award.

KarenLogo