10.

551
SYSTEMS ENGINEERING

Department of Chemical Engineering

Massachusetts institute of Technology

Spring 2011
 Part-1:

Introduction to Systems Engineering

 Section-1.1:

Objectives and Organization of 10.551

 Course Objectives
• Introduce the “Systems Approach” as a basic
paradigm for solving complex engineering
problems.
– Structured representation of engineering problems
• Objectives, Specifications, Constraints
• Models, Solutions
– Integration of material from diverse sources
• Cover a series of systems methodologies and
problem-solving procedures for typical classes
of problems
– Analysis, Synthesis, Diagnosis, Identification, Control,
Planning and Scheduling
– Graphs, Simulation, Optimization, Model-Based
Control, Models from Data, etc.
 Course Organization
Instructors:
Professors Richard Braatz, 66-372, braatz@mit.edu, and
George Stephanopoulos, 66-44, geosteph@mit.edu

Teaching Assistants:
Adekunle Adeyemo (66-060) Tel. (617) 253-0285 (adeyemo@mit.edu)
Matthew Stuber (66-363) Tel. (617) 253-6468 (stuber@mit.edu)

Time and Place of Lectures:

Room: 66-110 Mondays and Wednesdays: 11:00 – 12:30 pm

Course Web Page:

http://stellar.mit.edu/S/course/10/sp11/10.551/
 Course Organization

Reading Material:
Comprehensive notes and background articles will be distributed in
class. Students will be expected to read this material, and
homework assignments will test material in these notes not covered
in class.

Grade:
Homework (individual effort) 45%
Projects (group effort) 40%
Class Participation 15%
 Course Schedule
Part-1: Introduction to Systems Engineering

- Systems and their origin.

- Examples of problems in Systems Engineering
- The 10.551 Course: Objectives, Syllabus, Organization.

Part-2: Foundations of Systems Engineering

- Scope and Formulation of Engineering Problems
- Goals, Objectives, Specifications and Constraints
- Types of Models; Hierarchical decomposition of systems
- Types of Problems: Forward solution and inversion of models

Part-3: Structural Analysis of Systems

- Graphs and digraphs: Representation of systems
- Partitioning and Precedence Ordering of systems
- Structural analysis of modeling equations
- Structural controllability and observability of systems
- Applications to engineering problems

Part-4: Steady State Analysis of Systems

- Formulating steady-state models and simulations
- Degrees of freedom and design specifications
- The Sequential-Modular Strategy
- The Equation-Oriented Strategy
- Applications to engineering problems
 Course Schedule
Part–5: Optimization of Systems: Theory and Algorithms
- Basic concepts and definitions
- Linear programming
- Unconstrained nonlinear optimization
- Nonlinear Programming
- Combinatorial optimization
- Applications to engineering problems

Part-6: Simulation of Dynamic Systems

- Basic concepts: Systems described by ODEs and DAEs
- Formulating dynamic simulations; consistent initialization
- Numerical integration of ODEs and DAEs
- Modeling-simulation of hybrid Discrete/Continuous systems
- Applications to engineering systems

Part-7: Linear Systems Theory and Model-Based Process Control

- The nature of feedback control

- The concept of model-based control systems
- Design and analysis of model-based control systems applications

Part-8: Creating Models from Data

- Types of models created from data
- Linear and nonlinear regression
- Experimental design
- Clustering techniques
 Schedule of Assignments
Assignm. Date-out Date-due Subject

HW-1 February 2 February 14 Definition of systems and

their characteristics

HW-2 February 14 February 21 Structural analysis of systems

Project-1 February 21 March 9 Sequential-modular Steady-State

Simulation using ASPEN Plus

HW-3 March 9 March 28 Optimization

HW-4 March 28 April 6 Dynamic modeling

Project-2 April 6 April 20 Dynamic simulation using the Equation-

Oriented Simulator JACOBIAN

Project-3 April 20 May 4 Model-Predictive Control

HW-5 April 4 May 11 Models from data

Personal Statement Regarding Homework Solutions

Personal Statement
In the spirit and practice of MIT’s long-held “Honor
System”, I state that, in preparing the solution for this
problem set, I have not used material from the
homework solutions of past students or copies of
solutions provided by the instructor or the TAs in earlier
semesters.
___________________________________ Name
___________________________________ Signature

Attach signed copy of this statement with the submission of

your homework.
 Section 1.2:

What is Process Systems Engineering?

 The Scope
What is Process Systems Engineering ?

The set of activities involved in the Engineering of Systems

with Physical, Chemical, Biological Processing Operations
Types of Processing Systems
• Produce chemicals and materials
• Provide therapeutic treatment of human diseases.
• Produce energy.
• Manufacture products that enhance quality of life
• Ensure quality of the environment
The Approach of Process Systems Engineering
• The interest is on the “behavior” of the system as a whole

• The emphasis is on studying how the components of the system and

their interactions contribute to the overall “behavior” of the system
 Processing Systems and Engineering Activities
Systems Engineering Activities
Chemical Processes Synthesis of processing schemes; Simulation and analysis of performance; Optimization of performance;
Monitoring-Analysis-Diagnosis of operations; Control and Optimization of operations
Control and Safety Synthesis of control structures; synthesis of safety systems (ISIs; LOPAs); Synthesis of operating procedures;
Systems Monitoring and diagnosis of control and systems performance; Modeling and simulation of dynamic operations

Network of Batch Synthesis of networks of batch operations; Planning and Scheduling (optimal) of batch operations into multi-
Operations purpose batch chemical plants; Monitoring-Analysis-Diagnosis of batch operations for equipment faults or/and
(Batch Plants) performance degradation; Modeling and simulation of dynamic batch operations

Oil and Gas Identify fields with hydrocarbons; Identify geological structure of deposits and their amounts; Select optimal
Production Systems production strategy over the life of the field; Design production system; Inherently safe and operable production
systems; Planning and scheduling production operations; Control and optimization of operations
Air Pollution Definition of system (Components; Interactions); Model Behavior; Simulate effects of various scenaria;
Diagnose sources of increased pollution; Develop strategies for pollution control
Cardiovascular Model the entire cardiovascular system; Monitor-Analyze-Diagnose its performance; Control and/or redesign.
System

Molecules as Define molecules as systems (components; Interactions); Model physical and chemical behavior (structure-
Systems properties relationships; structure-reactivity relationships); Synthesize reactions; Generate Supra-molecular
structures; Diagnose molecular failures
Reactions as Systems Synthesis of chemical reaction networks (to achieve desired products); Select network of reactions to model
(Systems Chemistry) chemical processes (e.g. combustion); Design self-replicating reaction networks; Identify networks of reactions
as catalytic mechanisms
Biological Systems Synthesis of metabolic networks; Identification of biological processes (signal transduction pathways; gene
(Systems Biology) transcription system; gene regulation system; immunological activity; circadian rythms).

Products as Product Å Assembly of components Å Manufacturing of components Å Materials/chemicals of a component

Systems Å Production of materials/chemicals
 Examples of Systems: Continuous Chemical Processes

Cooling Water
Gas Recycle Purge
Make-up
Hydrogen
Compressor

Benzene
Fuel Cooling Water

Toluene
Steam
Feed-effluent
Feed-effluent Furnace
Reactor Cooling Water
heat exchanger
heat exchanger

Stabilizer
Stabilizer
Furnace
Quench

Steam Steam

Toluene
bank Water
bankof
ofcoolers
coolers
Cooler Flash
Flash
Steam

Cooling Water
Toluene Recycle

Toluene + Hydrogen → Benzene + Methane

2 Benzene → Diphenyl + Hydrogen

The Hydrodealkylation of Toluene Process

 Design-Oriented Engineering Activities
for Chemical Processes
1. Process Synthesis: Given a set of chemical reactions, synthesize an
economically optimal process, i.e.
– Select the type of unit operations to be used; their sizes; and interconnections among units
– Select the optimal sizes of unit operations and their optimal operating conditions
That minimize the annual operating cost.

Raw Materials Product

(known) Process (known)
? By-Products
Chemistry (known)
(known)

2. Process Analysis and Evaluation: Given a chemical process (type of unit

operations and their sizes, the units’ interconnections) and its operating conditions
(raw materials, heating and cooling resources, temperatures and pressures of all
units), compute
– The characteristics of all streams (flows, compositions, temperatures, pressures), and
– The total operating cost

Raw Processing Streams (?)

Materials Process
(known) (known) Performance (?)
(Operating Cost; Operability;
Safety; Environmental)
 Process Synthesis
Input-Output Plant Energy, Q
1 3 Purge (H2, CH4)
Toluene
I/O Plant 4
2 Product (B; 99%)
Hydrogen
By-Product (D)
5
Toluene (T) + H2 Æ Benzene + CH4
2Toluene Æ Diphenyl (D) + H2

Cooling Water

Gas Recycle Purge

Make-up
Hydrogen
Compressor
Cooling Water

Benzene
Fuel
Feed-effluent Reactor
Toluene heat exchanger
Steam Cooling Water

Stabilizer
Furnace
Quench

Steam
Steam

Toluene
Water
bank of coolers
Cooler Flash Steam

Cooling Water

Toluene Recycle
 Process Synthesis: The Methyl Acetate Process
Acetic Acid

Methanol Extractive Solvent

Distillation Methyl Recovery
Acetate (Distillation)

Catalyst Methanol
Recovery
(Distillation)
Distillation
Water
Azeotropic
Distillation Color Column
(Distillation)

Liquid
Extraction
Water
Entrainer Heavies
Recovery
Distillation
Flash Column
From: Siirola, 1996
(Distillation)

Water
 Inventing the Single Column Methyl Acetate Process

400,000,000 lb/yr
Distillation
Task G
Acetic Acid Methyl 1/5 capital investment
Extractive Acetate 1/5 energy consumption
Distillation
Task F

Catalyst of conventional plants

Reactive
Distillation
Task E

Reaction
Task A

Reactive
Distillation
Task B
Methanol

Distillation
Tasks
C and D

(Agreda and Partin, 1979)

Water
 Process Analysis and Evaluation (Simulators)

Aspen Plus®
Aspen HYSYS®

DESIGN II IPS PRO/II

Invensys Process Systems
 Operations-Oriented Engineering Activities
for Chemical Processes
1. At Early Stages of Process Design:
– Inherent Safety
– Avoidance of Effluents with Environmental Impact
– Operable and Controllable designs
• Startup; Shut-down; Change-over.

2. At Later Stages of Engineering Design

– Layout of Processing Units: Safety; Cost; Maintenance; Operability
– Piping and Instrumentation diagram designs: Safety; Control;
Operability

3. During Operations:
– Process Control
– Monitoring, Analysis, Diagnosis of Process Operations:
– Identification of Faults;
– Performance degradation: Catalyst decay; Fouling; Change of raw
materials, etc.
– Optimization of Operations
 Example of Process Synthesis: Hierarchical Synthesis
of Hydro-dealkylation of Toluene Plant to produce Benzene
Recycle Structure
Input-Output Plant Energy, Q Gas Recycle (H2, T, CH4, B) 3 Purge
1 3 Purge (H2, CH4)
Toluene 7
I/O Plant 4
2 Product (B; 99%) 1 6 4
Hydrogen Toluene Product
By-Product (D) Reaction Separation
5 2
Hydrogen Section Section 5
By-Product
Toluene (T) + H2 Æ Benzene + CH4 8
2Toluene Æ Diphenyl (D) + H2 Liquid Recycle (T, B, D)

7
3
10
The Complete Process Flowsheet 1 6
Reaction Generalized Phase
Gas Section Separation
Purge 2
Recycle 9
Hydrogen Compressor F13
4
Product
Toluene Q
Recovery
Steam-(b)
Exchanger Reactor 5
8
Furnace

Coolers Flash
Quench
Hydrogen,
Benzene Methane
Stabilizer

Toluene
Benzene

Toluene

Diphenyl
 Examples of Systems: Control Structures

FI CC
F8 FI F9
FI
Short-horizon
A Purge
Control Strategies
F1 (A, B) JI

CW2
FI XA
LI PI
D TI XB
F5 LC
F2 (D, B) A
N XC
Long-horizon
A
L XD Control Strategies
FI F7 TI Y
PC Z XE
LC
E E
XF
F3 (E, F) SC PI R
FI XG • What is the
XA
LI
PI XH intention
A F10
XB
N
TI TC
(purpose) of
XC A CW1 A XD
L
Y FI FI
N
A XE
each control
XD TC
XE
Z
E TI
L
Y XF
loop?
R LI Steam Z
F6 XG
XF
%A, %C
E
R XH
• How were
LC
FI
Control
TI
FI
F11
they selected?
F4 (A, B, C)
Product
C

x11,G , F11
Control Loops for : Stabilization of Reactor Operation

FI

F8 FI F9
FI

A Purge
F1 (A, B) JI

CW2
FI XA
PI
D TI XB
F5
F2 (D, B) A
N XC
A
L XD
FI F7 TI Y
PC Z XE
LC
E E
XF
F3 (E, F) SC PI R
FI XG
PI XH
XA
LI
XB A F10
N
XC A CW1 A XD
L N
Y FI FI A XE
XD TC
Z L
XE E TI Y XF
R Steam Z
F6 XG
XF E
R XH
FI
FI TI F11
F4 (A, B, C)
Product
C
Control Loops for : Material Inventory Control

FI

F8 FI F9
FI

A Purge
F1 (A, B) JI

CW2
FI XA
LI PI
D TI XB
F5 LC
F2 (D, B) A
N XC
A
L XD
FI F7 TI Y
Z XE
E E
XF
F3 (E, F) SC PI R
FI XG

XA XH

XB A F10
N
XC A CW1 A XD
L N
Y FI A XE
XD
Z L
XE E Y XF
R LI Steam Z
F6 XG
XF E
R XH
%A, %C
Control LC FI
FI TI F11
F4 (A, B, C)
Product
C
Control Loops for: Production Rate and Product Quality

FI

F8 FI
FI

A Purge
F1 (A, B) JI

CW2
FI XA
PI
D F5 XB
F2 (D, B) A
N XC
A
L XD Long-horizon
FI F7 TI Y Control Strategies
Z XE
E E
XF
F3 (E, F) PI R
FI XG

XA XH

XB A F10
N
A TI A XD
XC CW1
L N
Y FI FI A XE
XD
Z L
XE E Y XF
R Steam Z
XG
XF F6 E
R XH
FI
FI TI F11
F4 (A, B, C)
Product
C

x11,G , F11
 Control Loops for: Minimization of Production Cost

FI CC
F8 FI
FI
Short-horizon
A Purge
Control Strategies
F1 (A, B) JI

CW2
FI XA
PI
D TI XB
F5
F2 (D, B) A
N XC
Long-horizon
A
L XD Control Strategies
FI F7 TI Y
Z XE
E E
XF
F3 (E, F) SC PI R
FI XG

XA XH

XB A F10
N
XC A TI TC A XD
CW1
L N
Y FI FI A XE
XD
Z L
XE E Y XF
R Steam Z
F6 XG
XF E
R XH
FI
FI TI F11
F4 (A, B, C)
Product
C

x11,G , F11
 Missing Control Loops

™ Energy Inventory Control

™ Control loops ensuring that the operational

constraints of the various equipment are
satisfied.

™ Safety

™ Environmental Regulations Control

™ Operational Transition Control

 Synthesis of Control Structures

• Given
– Process with all its units, their sizes, and interconnections
– Desired operating conditions, e.g.
• Minimize total operating cost,
• Achieve desired product flowrate and composition,
• Maintain operating conditions within safe ranges, etc.
• Synthesize a set of control systems, which achieve the
desired objectives, i.e.
– Select what variables to measure in order to monitor the desired
operating objectives,
– Select what variables to manipulate in order to achieve the desired
operating objectives,
– Select the interconnections between (measurements) and
(manipulations) in order to form the control loops,
– Design the control laws, i.e. given the measurements, how much
should the manipulations change?
 MPC Impact for 13 Ethylene Plants

Starks and Arrieta, 2007

2
Broad Industrial Impact of MPC

Qin and Badgwell, 2003

3
 Examples of Systems: Safety Control Structures

Shut-Down
Valves
(1-out-of-2)
Reactor Cooler

Gas Analysis
Temperature Measurements
Measurements (2-out-of-3)
(1-out-of-2)
Safety
Circuits

- Given a Process with all its units and desired safe operating ranges
- Select
- what variables to measure and the redundancy of measurements,
- what variables to manipulate and the redundancy of the manipulations
In order to ensure safe operation in the presence of various failures.
Risk Management and Process Integrity:
Environmental Devastations and Industrial Accidents

WHEN WHERE WHAT FATALITIES

1955-80 Love Canal Health effects

from toxic chemicals
1966 Feyzin, France LPG Bleve 18
1974 Flixborough, UK Cyclohexane 28
1979 Bantry Bay, Ireland Crude 50
1982 Ocean Ranger, Canada Platform 84
1984 Mexico LPG Bleve 600+
1984 Bhopal, India Methyl isocyanate 20000+
1986 Chernobyl, USSR Nuclear powerplant 100+
1988 Piper Alpha Platform 167
1988 Norco, USA Propane FCCU 7
1989 Pasadena TX, USA Ethylene/isobutane 23

3
 Risk Management and Process Integrity
Love Canal, NY: 1955-80

800 families affected

33% chromosomal damage
56% of children born ‘74-’78
had birth defect

Flixborough,
UKCyclohexane Plant
1974
 Risk Management and Process Integrity
Bhopal, India: 1984

3,800 killed immediately

20,000+ over time.

Piper Alpha,
North Sea: 1988

167 killed
 Process Systems Engineering and Process Risk
Management

From
“React and Fix”
to
“Predict/Detect and Prevent”

Process Safety
Inherently Safer Advanced Monitoring Management
Process Designs Diagnostic, and Mitigating Through
Systems Continuous Improvement
Integrate
Process Safety • SIS: Rational instrumentation Culture
And • LOPAs: Rational protection
Control Strategies • HAZOPs: Science-based Work Processes
in early stages of design • Risk Registers: Knowledge-based
Management
 Examples of Systems: Network of Batch Operations
(Production of Intermediates for Pharmaceuticals)

Trienone
(Primary raw
M1: material) THF
CH 3MgBr

O (I) OMgBr

M2: H2O/HOAc
H2O HOMgBr
NaOAc

OMgBr OH (II)
Carbinol
(Primary
Quench: product)
CH 3MgBr H2O CH 4 HOMgBr
Gel
Break: H2 O
HOAc HOMgBr Mg ++ H 2O Br- -
OAc

SR:
H+
H2O

OH (II) By-Product (III)

- Synthesize a series of batch operations to convert TRIENONE to CARBINOL

- Allocate batch operations to a set of available equipment: Minimize total time
 Examples of Systems: Network of Batch Operations
(Production of Intermediates for Pharmaceuticals)

Trienone H2O NaOAc HOAc

Production-Related Operations Carbinol
(Primary raw (Primary product)
material) THF Dissolve Mix
Cyclohexane Cyclohexane
Trienone M2/
(I) Dissolve
Quench/
M1 Gel Flash Decant Concentrate Mix Concentrate Mix Crystallize Filter Dry II
Break/
CH3MgBr Dissolve SR L V
/Et2O V L V V
III
Cool CH4 Mg+2 Et2O (Et2O) (II) C6H12
Cool (Et2O) Br- THF THF (THF) (THF)
THF (THF) -OAc C6H12 C6H12
H2O
NaOAc

CH4 Et2O

C6H12
Et2O
Condense Distill

Distill
Condense Distill Distill
THF

THF
C6H12 THF

Evaporate Condense

C6H12
Mg+2 H2O
Br-
-OAc
Evaporate Condense Distill
NaOAc Et2O

III THF
Ancillary Operations Condense Distill (II)

THF
Examples of Systems: Atmospheric Pollution

Activities
• Define system
• Components
• Interactions
• Model Behavior
• Diagnose, e.g.
• Sources of
increased
pollution
• Control pollution,
etc.
Examples of Systems: Human Cardiovascular System

Activities
• Model
• Monitor
• Analyze
• Diagnose
• Control
• Redesign (?)
• other (?)
 Examples of Systems: Molecules as Systems

(6-amino-penicillianic acid)

Connected
Components
Activities
• Synthesize molecular (atoms through bonds)
structures Connected Components
• Model Behavior
• Physical Properties
(functional groups through bonds)
• Reactivity at various sites
• Diagnose molecular failures
• Generate reactions
 Examples of Systems: Molecules as Systems

Use Molecule’s structure to Compute physical

properties or kinetic rates
(The Group-Contribution and LFER ideas)

H O
H
C C C O H
H

Physical Property =

= Contribution from (C=C) + Contribution from (C=O) + Contribution from (O-H) + correction

 Examples of Systems: Molecules as Systems

Using Molecular Structural Components to

Generate Reactions

H O
H
C C C O H
H

R O
C C
R H
R R
C R C/O
C
C C
This does not inherit the
R R same Reactivity around
R H
the C=C double bond as
These two inherit the same Reactivity around the the “mother” group
C=C double bond as the “mother” group
 Examples of Systems: Reaction Networks

System Components: Molecules

Component Interconnections: Reactions

Activities
• Synthesize reaction pathways
C3H8 producing desired chemicals.
C2H4 H2 • Syntrhesize reaction network including
reactions with substantial rates affecting
C2H5• the modeling of a chemical process (e.g.
CH3• H• combustion)
C2H6
• Model the behavior, e.g. composition
C2H6
of all reacting species in the network.
CH4
• Control the composition of reacting
species in the network.
• Diagnose the failure of reacting
networks
• other (?)
Examples of Systems: Generating Reaction Networks
Generate all reactions, which have substantial rates, and thus
affect the modeling of a particular process
Rj(t) < Rmin(t) Rate-based termination rule

.
.
.
C 3H 8

C 2H 4 H2
C2H5•
CH3• H•
C2H6
C2H6
CH4
Expanding
Envelope of
Reaction Set
Examples of Systems: Generating Reaction Pathways

• Generate all possible reaction pathways, which lead

from given reagents to a desired product.
• Select the “optimum” reaction pathway for the
development of a production process
Available Starting Reagents

R2,2,1 R2,1 R1

. . .R 2,2,2
.
R2,2 R2
.
P
.
. . (Desired
.
. . . Product)
R2,2,m-1 R2,k-1 Rn-1 .

R2,2,m R2,k Rn
 Examples of Reaction Systems:
Identifying Catalytic Reaction Networks

C4 H10 Æ C4 H8 + H2 (Overall reaction)

Elementary Reaction Steps:

(1 Æ) C4 H10 Æ C4 H8(m) + H2
(Æ 1) C4 H8(m) + H2 Æ C4 H10 + (m)
(2 Æ) C4 H8(m) Æ C4 H8 + (m)
(Æ 2) C4 H8 + (m) Æ C4 H8(m)
(3 Æ) C4 H8(m) Æ C4 H6(m) + H2
(Æ 3) C4 H6(m) + H2 Æ C4 H8(m)
(4 Æ) C4 H6(m) Æ C4 H6 + (m)
(Æ 4) C4 H6 + (m) Æ C4 H6(m)
(5 Æ) C4 H10 + C4 H6 (m) + (m) Æ 2C4 H8 (m)
(Æ 5) 2C4 H8 (m) Æ C4 H10 + C4 H6 (m) + (m)
 Examples of Systems:
Identifying Catalytic Reaction Networks
Combinatorial Generation of Feasible Reaction Networks for the Catalytic
Dehydrogenation of Butane, using elementary steps in previous slide.

C4 H10 C4 H10 (m)

(m)
C4 H10 (m)

1 5 1 5
1 +
C4 H8(m) C4 H8(m)
C4 H8(m) Other
Structures
3 2 3 2
2

H2 H2 H2
C4 H8 C4 H8
C4 H8

C4 H6(m) C4 H6(m)

Select the most “Likely” using experimental data

Emergence of the term “Systems Chemistry”

• Catalytic and autocatalytic reaction networks

• Self-Replicating and self-reproducing chemical systems
• Dynamic combinatorial chemistry
• Emergent phenomena in molecular networks
• Information processing by molecular networks
• Complex dynamic and chaotic behavior of chemical
systems: bifurcation; chiral symmetry breaking
• Bottom up approaches to synthetic biology and chemical
evolution
• Chemical self-organization inspired by the problems of
the origin and synthesis of life
• Self-assembly and formation of supramolecular
structures
 Examples of Systems: Products as Systems

• DNA Sequencer, Batteries, Fuel Cells, OLEDs

• Example: OLED

OLED for Displays and Lighting

Cathode e-
Electron Transmission Layer Light
Hole Blocking Layer
Light-Emitting Layer
Hole Transmission Layer
Hole Injection Layer
p+
Anode (ITO,other)
Substrate (Glass, Plastic)
 Examples of Systems: Technology Supply Chain

Technology Supply Chain in the Development of Pharmaceuticals

Chips Proteomics Imaging Fluidics Structure Predictive CDU SNP

ADMET

Commercial
Gene/Target Target Lead Lead OP
Clinical and Patient
Identification Validation Identification Preclinical
Trials Mgmt

Process Development / Manufacturing

BiologyMarkers Chemistry Chem Genetics Patho- Pharmaco- Patient

Computational Biology CompChemistry pharmacology genomics Management
Examples of Systems: Biological Systems
(Emergence of a new field: “Systems Biology”)

Metabolites

DNA RNA Protein

The “Cell” is among the most

Signaling intricate and richest in diversity
Pathways systems we know
Examples of Biological Systems: DNA Transcription System

• Identification of system:
components and interactions.
• What are the proteins
triggering the expression?
• What part of the DNA
(gene) regulates the onset
of transcription?
• Modeling and analysis.
• Regulation and control of
transcription.
• Diagnosis of failures in
transcription.
• Coordination of transcription of
many genes.
Examples of Biological Systems: Gene Expression
Regulation Systems

• Identification of system:
components and interactions.
• What are the proteins
involved in gene regulation?
• What part of the DNA (gene)
regulates the onset of gene
expression?
• What is the structure of
regulation?
• Feedback,Feedforward
• Cascade, Ratio, other
• Modeling and analysis.
• Interaction of control loops.
• Diagnosis of expression failures
• Coordination of expression of
many genes.
 Examples of Biological Systems: Functional Coupling
of Gene Clusters

2 7 9 11 12 13 14 15 16 17
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29
8 10 atpA
desB fumC atpB
acs
icfA
prk
rbcL
rbcS
4 phaD1
napA desA
desD
petF
τ=2 pdhA
τ=2 fabD
bgl
22 glcD
light 18 24 26 glcF
3 psbA2 accC phaB eno
rbcR humB pdhB fda
τ=2 gpmB
τ=5 pfkA
pgi
τ=2 pgk
pykF
tktA
psaB
apcA
28 19 cpcA
ndh psbD1 cpcB
ndh rpl2
desC rps1
icd
31
gap2
ndh 6 27 20
phaA phaE 5 sll0 psbD2
ftrC phaD3 phaD2 1
acnB gltA pta
ppc 30 fbp
petB ack psaA
accD gap1 23 psbA3 25 τ=6
glgA petA ftrV
glgA psbA1 gdh
glcE 21
rplA nblA
apcB τ=
nblA
rpl1 10
τ=1
Examples of Biological Systems: Metabolic Pathways

Allosteric
Regulation
in the TCA
 Examples of Biological Systems: Metabolic Pathways
Lysine Production: gnd devB/opcA/zwf glucose-6-P
ribulose-6-P 6-P-gluconate
Over- and Under-Expressed Genes rpe rpi rbsK ribose
pgi
fructose-6-P
Glucose/Lactose Results xylulose-5-P ribose-5-P pfk
fructose-1,6-bisphosphate
tkt fba

Gene Chips: Monitor Gene expression levels sedoheptulose-7-

3-phosphoglyceraldehyde dihydroxyacetonephosphate
gap
P tpi
tal 1,3-bisphosphoglycerate
tkt pgk
3-P-glycerate
erythrose-4-P
gpm/Rv2419c/Rv3837c
2-P-glycerate
eno
phosphoenolpyruvate
pyk bioF bioA bioD bioB
pyruvate biotin
ppc pca
aceE/lpd/pdh/Rv0462
acetyl-coA
glt/citE
oxaloacetate
citrate
mdh
aceB icd
malate glyoxylate
ketogluterate
fum
aceA
Seq u en ce L5 G3 L5 G3- 2 G5 L3 G5 L3 - 2 fumarate suc/lpd
en o (CG) - 1 .5 8 27 - 1 .6 0 76 4 0 .3 4 15 6 7 0.5 17 1 8 8 succinate
sdh
f b a (CG) - 1 .0 5 7 54 - 0 .9 6 98 1 0 .0 9 19 3 4 0.1 16 3 7 5 ask aat/aspB
f b a (CG- f u l l ) - 1 .0 0 6 81 - 0.9 08 3 0 .2 4 97 3 6 0.0 12 9 7 1
glutamate
g ap (CG) - 2 .4 4 24 - 2 .4 0 65 9 1 .5 4 60 5 8 1.3 59 3 0 7
g ap (CG- f u l l ) - 2 .4 5 5 08 - 2 .4 6 38 1 1 .5 3 95 2 6 1 .3 4 3 5 aspartate
g pi (CG) - 0 .5 2 1 08 - 0 .5 9 12 1 0 .0 2 54 7 5 - 0 .04 5 3 1 asd
g pm (CG) - 1 .0 6 9 74 - 1 .0 6 01 4 - 0.0 07 7 4 0.1 61 9 6 5
dapA dapB dapD dapE dapF lysE/G
p f k (CG)
p f k (CG- f u l l )
- 0 .6 2 4 38 - 0 .6 4 25 4 1 .2 5 52 2 3 0.6 36 1 0 2
- 0 .9 1 8 85 - 0 .7 9 38 3 1 .4 9 52 5 8 1.2 61 2 6 3
aspartate semialdehyde lysine
thrA
p gk (CG) - 0 .6 5 3 85 - 0 .3 4 64 4 0 .8 8 72 8 1 0.8 32 7 7 9
p gk (CG- f u l l ) - 1 .2 3 9 35 - 0 .9 1 33 7 0 .8 9 54 7 5 1.2 26 8 0 1 thrB
p yk (CG) 0 .8 4 05 1 .1 2 7 78 8 0 .3 1 26 2 1 1.0 64 1 8 4
p yk (CG- f ul l ) - 1 .9 3 2 27 - 1 .9 4 35 6 1 .1 8 20 9 2 1 .11 0 8 8
thrC
t p i (CG) - 1 .4 6 8 36 - 1 .0 7 22 1 1 .0 8 44 2 3 1.6 42 6 2 9
t p i (CG- f u l l ) - 1 .4 4 3 74 - 1 .1 1 19 3 1 .0 8 65 7 3 1.3 56 2 8 5 threonine
Chris Roberge; PhD thesis, 2005
 Examples of Biological Systems: Metabolic Pathways

• Identify all the steps of a Metabolic Pathway of

interest, e.g. production of poly-hydroxy-alkanoates.
• Estimate carbon fluxes through the metabolic
pathway of interest and associated pathways.
– Identify rate-limiting steps on pathway of interest
– Identify yield-limiting steps on associated pathways
• Identify the allosteric regulation structures
• Modify pathways to “optimize” performance
– Over-express “favorable” enzymes.
– Knock-out “unfavorable” enzymes.
• Insert complete pathways from an other species
 Examples of Biological Systems: Signaling Pathways

Growth Factor

P
Receptor-Ligand binding
Receptor PTK Receptor PTK P
P
GRB2/Sos

Ras-GDP Ras-GTP

Signaling Raf
pathways
P
Mek Mek P

Gene
Nucleus P
induction MAPK MAPK
P

P
TF TF
Transcription
 Examples of Biological Systems: Signaling Pathways

ƒ What is the structure of the signaling pathways?

ƒ How is the information from a single ligand
transmitted to multiple targets?
ƒ How do multiple ligands affect the expression of
a single gene?
ƒ How do different cell types or conditions
influence signaling?
ƒ How do differences in dynamics play a role in
determining the “message”?
Examples of Biological Systems: Infection of a Cell with HIV

HIV is one of the most

well-studied virus.
- Receptor mediated attachment
onto cell surface.
- Co-receptor mediated entry.
- Release of mRNA.
- mRNA translation.
- Polyprotein expression.
- Cleavage into protein.
- mRNA replication.
- Assembly of structural protein
and mRNA inclusion.
- Exocytosis.

Interaction between HCV particle and cell receptor

is critical for viral sensing system and vaccine study.
How does HCV attach to cell surface and internalize?
Example of Biomedical System: Targeted Delivery
of Radionuclides to Tumors (From: Kelly Davis-Orcutt PhD Thesis)

CEA
binding

DOTA
binding

excellent safety profile in humans

chelates trivalent cations (177Lu, 90Y, 86Y, 111In, 213Bi, 225Ac)
 Example of Biomedical System: Targeted Delivery
of Radionuclides to Tumors (From: Kelly Davis-Orcutt PhD Thesis)

Does this design address

effectively the problem ?

INTEGRATED SYSTEMS APPROACH

Product Design
ƒ Selection of Antigen
ƒ Hapten
ƒ Bispecific Antibody
ƒ Clearing Agent
Therapeutic Process (Operation)
ƒ Administration of Antibody; dose, time
ƒ Administration of Clearing Agent; dose, time Clearing Agent
ƒ Administration of DOTA; dose, time
A new design element
Examples of Systems: Information System for CIM

EXTERNAL BUSINESS INFORMATION SYSTEM

ENVIRONMENT
Market END USER
Finance Marketing Accounting FUNCTIONS
Supplier Materials Supply
Distributor Decision Support , etc.
Government Management
General Planning
Finance
Accounting
PLANT PRODUCTION MANAGEMENT
Marketing
SYSTEM
Supply
Demand
Production Planning
Production Planning
Production Evaluation, etc.
Manufacturing
Engineering
Information
Flows PROCESS MONITORING ,ANALYSIS
AND CONTROL
OFFICE AUTOMATION
Distributed Control System
Advanced Control System Electronic Mail /File Schedules

FIELD OPERATIONS
Laboratory Process Utilities Storage Tanks Blending/Shipping
Example of Systems: Natural Gas and CO2
Supply Chain