Production Management: New Lessons from Biology

James E. Metherall, Ph.D., M.B.A.

Associate Professor of Human Genetics

University of Utah

Major Points1) Metabolic Regulation is an Extremely Complex

Operations Management Problem

1) Data Collection is NOT the Problem

1) Data Analysis is the Problem: Attempting to Understand Metabolic Regulation Through Simulation

1) Sharing Tools and Concepts: Beginning the Discussion

Enzyme: Glucokinase (2.7.1.1)

Enzymatic Transformations

Substrate Product

Simplifi ed View of Metabolic Pathways

Sigma-Aldrich

Simplified View of Metabolic Pathways

Sigma-Aldrich

Glossary of TermsProduction MetabolismTransformation Process Reaction

Raw Material Precursor/Substrate

Inline Inventory Intermediate

Product Product

Workstation Enzyme

Tool Cofactor

Workstation Blueprint Gene

Workgroup Multienzyme Complex

Organizational Layout Subcellular Compartmentation

Transport Transport

Outsourcing Dining

Operations Management Metabolic Regulation

Simplified View of Metabolic Pathways

Sigma-Aldrich

Major Points1) Metabolic Regulation is an Extremely Complex

Operations Management Problem

1) Data Collection is NOT the Problem

1) Data Analysis is the Problem: Attempting to Understand Metabolic Regulation Through Simulation

1) Sharing Tools and Concepts: Beginning the Discussion

Gene Expression: Making Enzymes

Transcription Translation

Gene DNA

mRNA Enzyme

Transcription

Gene DNA

On

Off

Gene Expression Microarrays

Hybridize Synthetic Probe

mRNA

Annealed

ExtendFlourescentNucleotides

Polymerase

**

**

*************

Destroy mRNA ** * ***** *

* * **

** * ****

* ** * **

** * ****

* ** * **

Microchip

Hybridize

Photolithography

www.affymetrix.com

Affymetrix Chips

www.affymetrix.com

Affymetrix Gene Chip System

www.affymetrix.com

Affymetrix Results

www.affymetrix.com

Gene Expression: Making Enzymes

Transcription Translation

Gene DNA

mRNA Enzyme

Transcription

Gene DNA

On

Off

Simplified View of Metabolic Pathways

Sigma-Aldrich

Major Points1) Metabolic Regulation is an Extremely Complex

Operations Management Problem

1) Data Collection is NOT the Problem

1) Data Analysis is the Problem: Attempting to Understand Metabolic Regulation Through Simulation

1) Sharing Tools and Concepts: Beginning the Discussion

HierarchicalClustering

Regulation of Cellular Cholesterol Metabolism

Acetyl CoA + Acetoacetyl CoA

HMG CoA

Mevalonate

CholesterolLDL

HMG CoAReductase

LDLReceptor

7-DHC

Acetyl CoA + Acetoacetyl CoA

HMG CoA

Mevalonate

CholesterolLDL

HMG CoAReductase

LDLReceptor

Transcriptional

7-DHC

Regulation of Cellular Cholesterol Metabolism

Sterol-Regulated GenesRab GGP TransferaseHMG CoA SynthaseCyclin B1Proteosome Subunit XRibosomal Subunit S19b-Amyloid PrecursorNADP TranshydrogenaseCOX-2Acetyl CoA CarboxylaseLDL ReceptorCdc2-related ProteinLeguainRibosomal Subunit L18AFerritin Heavy ChainDisinigrinFPP SynthaseStearoyl DesaturaseRibosomal Subunit L37G3P Acyl-transferaseMLN64 (STar-related)

CalmodulinDermatanCullin 3HMG CoA ReductaseMerF1 ATPase Subunit 6Ribosomal Subunit S247-DHC ReductaseF1 ATPase Subunit dIPP IsomeraseSqualene SynthaseUbiquinone OxidoreductaseLysosomal LipaseElectron Transfer FlavoproteinFatty Acid SynthaseNonsense-mediated Decay ProteinActivin Type BCox-3Squalene EpoxidaseStearoyl DesaturaseCathepsin L

Regulation of Cellular Cholesterol Metabolism

Acetyl CoA + Acetoacetyl CoA

HMG CoA

Mevalonate

CholesterolLDL

HMG CoAReductase

LDLReceptor

Rate Limiting

7-DHC

Acetyl CoA + Acetoacetyl CoA

HMG CoA

Mevalonate

CholesterolLDL

HMG CoAReductase

LDLReceptor

7-DHC

Multivalent Control

A I C

L

Si Sa

N

E1 EN

EL

Ex

nuc

mRNAaa

Simulating Cholesterol Homeostasis

0

10000

20000

30000

40000

0 400 800 1200 1600

Time (sec)

[L]

- LDL

+ LDL

Simulating Homeostasis

Multivalent Control Maintains Intermediate Concentrations

[I3]ss [I10]ss Model - LDL + LDL - LDL + LDL

steady state concentration (arbitrary units)

Rate limiting 124 0 183 0 Multivalent 989 999 800 929

0

5000

10000

0 25 50 75 100

Time

[C] s

s6

A. Regulatory Oscillations

h = 8

7

Regulatory Oscillations

Metabolic Simulation: GUI

Metabolic Simulation: Toolbox

Metabolic Simulation: GUI

Metabolic Simulation: Architecture1) Relational Database

– All Model and Simulation Parameters – All Result Data

2) Computational Strategy– Multithreaded

• Reactions Calculate their own Propensities and “Fire” Themselves• Metabolites Inform Dependent Reactions of Changes

– Distributed (Screen Saver) • Look Up Simulation To Run from Database• Run Simulation• Return Data to Database

3) Hardware– Processors

• Dual Core CPU: 2 Cores, 4 Threads• GPU: 240 Cores; >1000 Threads

– GPU Development Tools - NVIDIA Cuda• Windows, Mac, Linux• Direct Calls - Visual Basic, C, C#, C++, Java • Free, Open Source Development

– GPU Servers• Desktop Monitors Flicker• 960 Cores, 4000 Threads per 1U Unit

Major Points1) Metabolic Regulation is an Extremely Complex

Operations Management Problem

1) Data Collection is NOT the Problem

1) Data Analysis is the Problem: Attempting to Understand Metabolic Regulation Through Simulation

1) Sharing Tools and Concepts: Beginning the Discussion

Summary1) Production Management and Metabolism Share the

Same Goal• Satisfy Demand• Efficiently Convert Raw Materials into Products• Series of Transformations

2) Both Processes Must be Efficient: They are Subject to the Law of Survival-of-the-Fittest

• Efficiencies are Necessary to Ensure Survival of the Organization and Organism, Respectively

3) While Operation Managers Strive to Create Efficient Processes, Biologists Strive to Understand Efficient Processes

• Share Tools and Concepts• Can Metabolic Regulation Instruct Production Management

Practice?• Why not emulate what evolution has perfected?• Why not emulate what God has created?

Production Management: New Lessons from BiologyMajor PointsEnzymatic TransformationsSlide 4Slide 5Glossary of TermsSlide 7Slide 8Gene Expression: Making EnzymesGene Expression MicroarraysPhotolithographyAffymetrix ChipsAffymetrix Gene Chip SystemAffymetrix ResultsSlide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Metabolic Simulation: GUIMetabolic Simulation: ToolboxSlide 29Metabolic Simulation: ArchitectureSlide 31Summary