Biological Reaction Engineering:

Dynamic Modeling Fundamentals with

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Biological Reaction Engineering
Biological Reaction Engineering

Dynamic Modeling Fundamentals With 80 Interactive

Simulation Examples

Elmar Heinzle
Irving J. Dunn
John Ingham
Jiří E. Přenosil

Third, Completely Revised and Enlarged Edition

Authors All books published by WILEY-VCH are carefully
produced. Nevertheless, authors, editors, and
Elmar Heinzle publisher do not warrant the information contained
Biochemical Engineering in these books, including this book, to be free of
Saarland University errors. Readers are advised to keep in mind that
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66123 Saarbrücken other items may inadvertently be inaccurate.
Germany
Library of Congress Card No.:
Irving J. Dunn applied for
Department of Chemistry and
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United Kingdom
© 2021 WILEY-VCH GmbH, Boschstr. 12, 69469
Jiří E. Přenosil Weinheim, Germany
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Print ISBN: 978-3-527-32524-5

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 v

Contents

Preface xiii
Acknowledgments xxi
Nomenclature for Part I xxiii
List of Simulation Examples xxviii

Part I Principles of Bioreactor Modeling 1

1 Modeling Principles 3
1.1 Fundamentals of Modeling 3
1.1.1 Use of Models for Understanding, Design, and Optimization of
Bioreactors 3
1.1.2 General Aspects of the Modeling Approach 4
1.1.3 General Modeling Procedure 6
1.1.4 Simulation Tools 8
1.1.5 Teaching Applications 8
1.2 Development and Meaning of Dynamic Differential Balances 9
1.2.1 Derivation of a Balance Equation Using Rates 11
1.2.2 Computer Solution 12
1.3 Formulation of Mass Balance Equations 13
1.3.1 Types of Mass Balance Equations 13
1.3.2 Balancing Procedure 15
1.3.2.1 Case A: Continuous Stirred Tank Bioreactor 15
1.3.2.2 Case B: Tubular Reactor 16
1.3.2.3 Case C: River with Eddy Current 16
1.3.3 Total Mass Balances 23
1.3.4 Component Balances for Reacting Systems 24
1.3.4.1 Case A: Constant Volume Continuous Stirred Tank Reactor 25
1.3.4.2 Case B: Semicontinuous Reactor with Volume Change 26
1.3.4.3 Case C: Steady-state Oxygen Balancing in Fermentation 27
1.3.4.4 Case D: Inert Gas Balance to Calculate Flow Rates 28
1.4 Additional Relationships 29
1.4.1 Stoichiometry and Metabolite and Elemental Balancing 29
vi Contents

1.4.1.1 Simple Stoichiometry 29

1.4.1.2 Metabolic Network Stoichiometry: Metabolite Balancing 30
1.4.1.3 Elemental Balancing 31
1.4.2 Yield Coefficients 33
1.4.2.1 Mass Yield Coefficients 33
1.4.2.2 Selectivity 34
1.4.2.3 Energy Yield Coefficients 34
1.5 Thermodynamics and Equilibrium Relationships 35
1.5.1 Reaction Enthalpy 35
1.5.2 Chemical Equilibrium 35
1.5.3 Receptor Binding 35
1.5.4 Case A: Calculation of pH with an Ion Charge Balance 36
1.6 Energy Balancing for Bioreactors 38
1.6.1 Accumulation Term 39
1.6.2 Flow Term 39
1.6.3 Water Evaporation Term 40
1.6.4 Heat Transfer Term 41
1.6.5 Reaction Heat Term 41
1.6.6 Case B: Determining Heat Production Rate of a Batch Fermentation 42
1.6.7 Case C: Determining Heat Transfer Area or Cooling Water
Temperature 42
1.7 Time Constants 43
1.7.1 Derivation from Differential Equations 44
1.7.2 Derivation from Capacity and Rate 45

2 Basic Bioreactor Concepts 47

2.1 Information for Bioreactor Modeling 47
2.2 Bioreactor Operation 48
2.2.1 Batch Operation 48
2.2.2 Semicontinuous or Fed-batch Operation 50
2.2.3 Continuous Operation 51
2.2.4 Summary and Comparison of Bioreactors 54

3 Biological Kinetics 57
3.1 Enzyme Kinetics 58
3.1.1 Reaction Equilibrium 58
3.1.2 Michaelis–Menten Equation 58
3.1.3 Other Enzyme Kinetic Models 61
3.1.3.1 Double Michaelis–Menten Kinetics 62
3.1.3.2 Inhibition 62
3.1.3.3 Substrate Inhibition 63
3.1.3.4 Allosteric Kinetics 64
3.1.3.5 Temperature and pH Influence 64
3.1.4 Enzyme Deactivation 65
3.2 Simple Microbial Kinetics 65
 Contents vii

3.2.1 Basic Growth Kinetics 65

3.2.2 Cell Death and Sterilization 67
3.2.3 Specific Rates 67
3.2.4 Monod Growth Kinetics 68
3.2.5 Substrate Inhibition of Growth 69
3.2.6 Product Inhibition 70
3.2.7 Other Expressions for Specific Growth Rate 70
3.2.8 Substrate Uptake Kinetics 71
3.2.9 Substrate Uptake in Wastewater Systems 72
3.2.10 Product Formation 72
3.3 Interacting (Micro-)organisms 72
3.3.1 Case A: Modeling of Mutualism Kinetics 75
3.3.2 Case B: Kinetics of Anaerobic Degradation 76
3.4 Structured Kinetic Models 77
3.4.1 Types of Structured Kinetic Models 77
3.4.2 Examples of Simple Structured Models 78
3.4.2.1 Case C: Modeling Growth and Synthesis of Poly-β-hydroxybutyric Acid
(PHB) 79
3.4.2.2 Case D: Modeling of Sustained Oscillations in Continuous Baker’s Yeast
Culture 80
3.4.2.3 Case E: Growth and Product Formation of an Oxygen-Sensitive Bacillus
subtilis Culture 81
3.4.3 Modeling of Metabolic Networks 84
3.4.3.1 Case F: Dynamic Kinetic Model for Describing Metabolic Fluxes
Secondary Metabolite Synthesis Pathway 85
3.4.3.2 Case G: Modeling the Dynamics of Mammalian Cell Cultivation in
Fed-batch Cultures 88

4 Basic Bioreactor Modeling 91

4.1 General Balances for Tank-type Biological Reactors 91
4.1.1 The Batch Fermenter 92
4.1.2 The Chemostat 93
4.1.3 The Fed-batch Fermenter 96
4.1.4 Biomass Productivity 97
4.1.5 Case A: Continuous Fermentation with Biomass Recycle 98
4.1.6 Case B: Enzymatic Tanks-in-series Bioreactor System 100
4.2 Modeling Tubular Plug Flow Bioreactors 102
4.2.1 Steady-state Balancing 102
4.2.2 Unsteady-state Balancing for Tubular Bioreactors 103

5 Mass Transfer 105

5.1 Mass Transfer in Biological Reactors 105
5.1.1 Gas Absorption with Bioreaction in Liquid Phase 105
5.1.2 Liquid–Liquid Extraction with Bioreaction in One Phase 105
5.1.3 Surface Biocatalysis 105
viii Contents

5.1.4 Diffusion and Reaction in Porous Biocatalyst 106

5.2 Interphase Gas–Liquid Mass Transfer 106
5.3 General Oxygen Balances for Gas–Liquid Transfer 109
5.3.1 Application of Oxygen Balances 111
5.3.1.1 Case A: Steady-state Gas Balance to Determine the Biological Uptake
Rate 111
5.3.1.2 Case B: Determination of kL a Using a Chemical or Biochemical Reaction
Consuming Oxygen 111
5.3.1.3 Case C: Determination of kL a by a Dynamic Method 112
5.3.1.4 Case D: Determination of Oxygen Uptake Rates by a Dynamic
Method 113
5.3.1.5 Case E: Steady-state Liquid Balancing to Determine Oxygen Uptake
Rate 114
5.3.1.6 Case F: Steady-state Deoxygenated Feed Method for kL a 115
5.3.1.7 Case G: Biological Oxidation in an Aerated Tank 115
5.3.1.8 Case H: Modeling Nitrification in a Fluidized Bed Biofilm Reactor 117
5.4 Models for Oxygen Transfer in Large-scale Bioreactors 120
5.4.1 Case A: Model for Oxygen Gradients in a Bubble Column
Bioreactor 122
5.4.2 Case B: Model for a Multiple Impeller Fermenter 123

6 Diffusion and Biological Reaction in Immobilized Biocatalyst

Systems 127
6.1 External Mass Transfer 128
6.2 Internal Diffusion and Reaction Within Biocatalysts 130
6.2.1 Derivation of Finite Difference Model for Diffusion–Reaction Flat Plate
Systems 132
6.2.2 Finite Difference Model for Diffusion–Reaction in a Sphere 135
6.2.3 Dimensionless Parameters from Diffusion–Reaction Models 136
6.2.4 The Effectiveness Factor Concept 137
6.2.5 Case A: Estimation of Oxygen Diffusion Effects in a Biofilm 138
6.2.6 Case B: Complex Diffusion–Reaction Processes (Biofilm
Nitrification) 138

7 Automatic Bioprocess Control Fundamentals 143

7.1 Elements of Feedback Control 144
7.2 Measurement of Process Variables 144
7.2.1 Sensors Used in Biotechnology 145
7.2.2 Calculated Measured Variables 146
7.2.3 Dynamic Characteristics of Measurement 146
7.3 Types of Controller Action 147
7.3.1 On–Off Control 147
7.3.2 Proportional (P) Controller 147
7.3.3 Proportional–Integral (PI) Controller 148
7.3.4 Proportional–Integral–Derivative (PID) Controller 149
 Contents ix

7.4 Controller Tuning 150

7.4.1 Trial and Error Method 151
7.4.2 Ziegler–Nichols Method 151
7.4.3 Ultimate Gain Method 152
7.4.4 Error Integrals for Characterization of Controller Performance 152
7.5 Advanced Control Strategies 153
7.5.1 Cascade Control 153
7.5.2 Feed-forward Control 153
7.5.3 Adaptive Control 154
7.5.4 Other Types of Advanced Control 155
7.6 Application Strategies of Bioprocess Control 155

8 Basic Cell and Bioreactor Models 159

8.1 Basic Cell Balances 160
8.2 The Link of the Cell Balances to a Bioreactor 162
8.2.1 Continuous Well-Mixed Stirred-tank Bioreactor (Chemostat) 162
8.2.2 Batch Bioreactor 164
8.2.3 Case A: Checking for Metabolic Steady State in a Batch Culture 164
8.2.4 Case B: Compartmented Cell and Bioreactor Modeling 165
8.3 Organism Modeling 168
8.3.1 Case C: Bioreactor and Human-body Model for Toxicity Prediction 169

References Part I and Recommended Textbooks and References for

Further Reading 173

Part II Dynamic Bioprocess Modeling and Simulation

Examples Using the Berkeley Madonna Simulation
Language 187

9 Dynamic Bioprocess Modeling Examples 189

9.1 Modeling a Roman Fountain 190
9.2 Modeling a Lake 191
9.3 Modeling a Mammalian Cell Recirculation Reactor with External
Aeration 192
9.4 Modeling Protein Synthesis and Secretion in a Eukaryotic Cell 193
9.5 Modeling a Liver Sinusoid 194

10 Simulation Examples of Biological Reaction Processes Using

Berkeley Madonna 197

10.1 Introductory Simulation Examples 199

10.1.1 Batch Fermentation (BATFERM) 199
10.1.2 Chemostat Fermentation (CHEMO) 204
10.1.3 Fed-batch Fermentation (FEDBAT) 208
10.1.4 Introductory Exercises in Bioreactor Model Building 212
x Contents

10.2 Batch Reactors 229

10.2.1 Kinetics of Enzyme Action (MMKINET) 229
10.2.2 Lineweaver–Burk Plot (LINEWEAV) 231
10.2.3 Oligosaccharide Production in Enzymatic Lactose Hydrolysis
(OLIGO) 234
10.2.4 Batch Heat Sterilization (BATSTER) 237
10.2.5 Growth of the Coronavirus (CORONADYN) 242

10.3 Fed-batch Reactors 247

10.3.1 Variable Volume Fermentation (VARVOL and VARVOLD) 247
10.3.2 Penicillin Fermentation Using Elemental Balancing (PENFERM) 252
10.3.3 Ethanol Fed-batch Diauxic Fermentation (ETHFERM) 260
10.3.4 Repeated Fed-batch Culture (REPFED) 264
10.3.5 Repeated Medium Replacement Culture (REPLCUL) 267
10.3.6 Penicillin Production in a Fed-batch Fermenter (PENOXY) 270

10.4 Continuous Reactors 275

10.4.1 Steady-state Chemostat (CHEMOSTA) 275
10.4.2 Continuous Culture with Inhibitory Substrate (CONINHIB) 278
10.4.3 Nitrification in Activated Sludge Process (ACTNITR) 283
10.4.4 Tubular Enzyme Reactor (ENZTUBE) 287
10.4.5 Dual Substrate Limitation (DUAL) 290
10.4.6 Two-stage Chemostat with Additional Stream (TWOSTAGE) 294
10.4.7 Two-stage Culture with Product Inhibition (STAGED) 298
10.4.8 Fluidized Bed Recycle Reactor (FBR) 301
10.4.9 Nitrification in a Fluidized Bed Reactor (NITBED) 305
10.4.10 Continuous Enzymatic Reactor (ENZCON) 310
10.4.11 Reactor Cascade with Deactivating Enzyme (DEACTENZ) 313
10.4.12 Continuous Production of PHB in a Two-tank Reactor Process
(PHBTWO) 317
10.4.13 Dichloromethane in a Biofilm Fluidized Sand Bed (DCMDEG) 321

10.5 Oxygen Uptake Systems 329

10.5.1 Aeration of a Tank Reactor for Enzymatic Oxidation (OXENZ) 329
10.5.2 Gas and Liquid Oxygen Dynamics in a Continuous Fermenter
(INHIB) 332
10.5.3 Batch Nitrification with Oxygen Transfer (NITRIF) 337
10.5.4 Oxygen Uptake and Aeration Dynamics (OXDYN) 340
10.5.5 KLADYN, KLAFIT, and ELECTFIT: Dynamic Oxygen Electrode Method
for K L a 343
10.5.6 Biofiltration Column for Removing Two Inhibitory Substrates
(BIOFILTDYN) 349
10.5.7 Optical Sensing of Dissolved Oxygen in Microtiter Plates (TITERDYN
and TITERBIO) 354
 Contents xi

10.6 Diffusion Systems 361

10.6.1 Double Substrate Biofilm Reaction (BIOFILM) 361
10.6.2 Steady-state Split Boundary Solution (ENZSPLIT) 366
10.6.3 Dynamic Porous Diffusion and Reaction (ENZDYN) 369
10.6.4 Oxygen Diffusion in Animal Cell Sphere (CELLDIFFBEAD) 374
10.6.5 Oxygen Diffusion to a Single Cell or Cell Aggregate
(CELLDIFFCYL) 378
10.6.6 Immobilized Biofilm in a Nitrification Column System
(NITBEDFILM) 385

10.7 Controlled Reactors 393

10.7.1 Feedback Control of a Water Heater (TEMPCONT) 393
10.7.2 Temperature Control of Fermentation (FERMTEMP) 397
10.7.3 Turbidostat Response (TURBCON) 402
10.7.4 Control of a Continuous Bioreactor with Inhibitory Substrate
(CONTCON) 405
10.7.5 Adaptive Control of Dissolved Oxygen at Low Levels in Batch Culture
(ADAPTOXCONT) 410

10.8 Membrane and Cell Retention Reactors 419

10.8.1 Cell Retention Membrane Reactor (MEMINH) 419
10.8.2 Fermentation with Pervaporation (PERVAPSUB) 422
10.8.3 Two-stage Fermentor with Cell Recycle for Continuous Production of
Lactic Acid (LACMEMRECYC) 430
10.8.4 Tubular Hollow Fiber Enzyme Reactor Module for Lactose Hydrolysis
(LACREACT) 435
10.8.5 Immobilized Animal Cells in a Fluidized Bed Reactor
(ANIMALIMMOB) 441

10.9 Multi-organism Systems 447

10.9.1 Two Bacteria with Opposite Substrate Preferences (COMMENSA) 447
10.9.2 Competitive Assimilation and Commensalism (COMPASM) 452
10.9.3 Stability of Recombinant Microorganisms (PLASMID) 456
10.9.4 Predator–Prey Population Dynamics (MIXPOP) 461
10.9.5 Competition Between Organisms (TWOONE) 465
10.9.6 Competition Between Two Microorganisms for an Inhibitory Substrate
in a Biofilm (FILMPOP) 468
10.9.7 Model for Anaerobic Reactor Activity Measurement (ANAEMEAS) 473
10.9.8 Dynamics of an Epidemic Using the SIR Model (SIRDYN and
SIRDYNDIM) 479

10.10 Structured and Metabolic Network Models 487

10.10.1 Oscillations in Continuous Yeast Culture (YEASTOSC) 487
10.10.2 Structured Model for PHB Production (PHB) 492
10.10.3 Mammalian Cell Cycle Control (MAMMCELLCYCLE) 496
xii Contents

10.10.4 Metabolic Dynamics in Secondary Metabolite Fluxes in Potato Tubers

(POTATO) 500
10.10.5 Structured Model of the Production of Acetoin and Butanediol
(SUBTILIS) 505
10.10.6 Dynamics of Cultivation of CHO for the Production of Monoclonal
Antibodies (CHOMAB) 509

Appendix A Using the Berkeley Madonna Language and Accessing the

Simulation Examples: A Short Guide 519
A.1. Computer Requirements 519
A.2. Downloading Simulation Examples and the Berkeley Madonna
Program for this Book 519
A.3. Running Programs 520

Index 521
 xiii

Preface

Our goal in this textbook is to teach, through modeling and simulation, the quan-
titative description of bioreaction processes to scientists and engineers. In working
through the many simulation examples, you, the reader, will learn to apply material
and energy balances to describe the dynamics of a variety of bioreactors and other
biological systems. For your efforts, you will be rewarded with a greater understand-
ing of the dynamics of biological processes. The many example applications will help
you to gain confidence in modeling, and you will find that the simulation language
used, Berkeley Madonna, is a powerful tool for developing your own simulation
models. Your new abilities will be valuable for designing experiments, for extract-
ing kinetic data from experiments, in designing and optimizing biological reaction
systems, and for developing bioreactor control strategies.
This book is based on our successful course, “Biological Reaction Engineering,”
which has been held annually in the Swiss mountain resort of Braunwald for many
years and which is now known, throughout international biotechnology circles as
the “Braunwald Course.” This course has been continued with a modified direction
and is now called “Biosystems Engineering: Bioreactor and Cell Factories.” Alto-
gether the course has been held for 40 years. The newer course continues using
the book but putting more emphasis on modeling cellular systems and their reac-
tor environment. This third edition provides an excellent basis for teaching systems
biology principles. More details on the course can be found at our website: http://
www.braunwald-bioengineering.de.
Modeling is often unfamiliar to biologists and chemists, who nevertheless need
modeling techniques in their work. The general field of biochemical reaction
engineering is one that requires a very close interdisciplinary interaction between
applied microbiologists, biologists, biochemists, biochemical engineers, engineers,
bioinformaticians, and managers; a large degree of collaboration and mutual
understanding is therefore important. Microbiologists, molecular biologists, and
biochemists often lack the formal training needed to analyze laboratory kinetic
data in its most meaningful sense, and they may sometimes experience difficulty
in participating in engineering design decisions and in communicating with engi-
neers. These are exactly the types of activity required in the multidisciplinary field
of biotechnology. Chemical engineering’s greatest strength is its well-developed
xiv Preface

modeling concepts, based on material and energy balances, combined with kinetics
of reactions and of mass and energy transfer.
Biochemical engineering is a discipline closely related to conventional chemical
engineering in that it attempts to apply physical principles to the solution of biologi-
cal problems. This approach may be applied to the measurement and interpretation
of laboratory kinetic data, to metabolic network modeling, e.g. for metabolic flux
analysis or metabolic network design, or to the design of large-scale fermentation,
enzymatic or waste treatment processes. The necessary interdisciplinary cooper-
ation requires the biological scientists and chemical engineers involved to have
at least a partial understanding of each other’s fields. The purpose of this book
is to provide the mathematical tools necessary for the quantitative analysis of
biological kinetics and related biological process phenomena. More generally, the
mathematical modeling methods presented here are intended to lead to a greater
understanding of how the biological reaction systems are influenced by process
conditions.
Engineering science depends heavily on the use of applied theory, quantitative
correlations, and mathematics, and it is often difficult for all of us (not only the
biological scientist) to surmount the mathematical barrier, which is posed by engi-
neering. A mistake, often made, is to confuse “mathematics” with the engineering
modeling approach. In modeling, an attempt is made to analyze a real and possi-
bly very complex situation into a simplified and understandable physical analog.
This physical model may contain many subsystems, all of which still make physi-
cal sense, but which now can be formulated with mathematical equations. These
equations can be handled automatically by the computer. Thus, the engineer and
the biologist are freed from the difficulties of mathematical solution and can tackle
complex problems that were impossible to solve before. Models, however, still have
to be formulated and one of the most important tools of the biochemical engineer,
in this operation, is the setting up of material and energy balance equations. The
step of extracting a physical model from a complex real situation is actually the most
important and most difficult, though mostly not sufficiently treated in textbooks. It
requires a thorough understanding of physical, chemical, and biological principles
combined with a certain amount of phantasy and creativity. It may not be easy for the
biologist or biochemist to fully appreciate the importance of differential equations,
but material balance equations are not so difficult to understand, since the first law
of conservation, namely that matter can neither be created nor destroyed, is funda-
mental to all science. Material balances, when combined with kinetic rate equations,
to form simple mathematical models, can be used with very great effect as a means
of planning, conducting, and analyzing experiments. Models are especially impor-
tant as a means of obtaining a better understanding of process phenomena. A ratio-
nal and stringent approach to experimentation and design requires a considerable
knowledge of the system, which can really only be achieved using a mathematical
model. Such a model will also assist in understanding, thereby reducing costly and
time-consuming experimental work. This book attempts to demonstrate this by way
of the many detailed examples that are based on the extended scientific experience of
 Preface xv

the authors. Many of the more complex examples are often taken from our scientific
publications.
The contribution made to biotechnology by the biochemical engineering modeling
approach is especially important because the basic procedure can be developed from
a few fundamental principles. A special aim of this book is to demonstrate that you
do not have to be an engineer to learn modeling and simulation. The basic concepts
of the material balance, combined with biological and enzyme kinetics, are easily
applied to describe the behavior of well-stirred tank and tubular fermenters, mixed
culture dynamics, interphase gas–liquid mass transfer, internal biofilm diffusional
limitations, and metabolic or signaling network dynamics, as demonstrated in the
computer examples supplied with this book. Such models, when solved interactively
by computer simulation, become much more understandable to non-engineers.
The Berkeley Madonna simulation language, used for the examples in this book, is
especially suitable because of its sophisticated computing power, interactive facility,
and ease of programming. The use of this digital simulation programming language
makes it possible for the reader, student and teacher, to experiment directly with
the model, in the classroom or at the desk. In this way, it is possible to immediately
determine the influence of changing various operating parameters on the bioreactor
performance – a real learning experience.
The simulation examples serve to enforce the learning process in a very effective
manner and also provide hands-on confidence in the use of a simulation language.
The readers can program their own examples, by formulating new material balance
equations or by modifying an existing example to a new set of circumstances. Thus,
by working directly at the computer, the no-longer-passive reader can experiment
directly on the bioreaction system in a very interactive way by changing parameters
and learning about their probable influence in a real situation. Because of the speed
of solution, a true degree of interaction is possible with Berkeley Madonna, allow-
ing parameters to be changed easily. Plotting the variables in any configuration is
easy during a run, and the results from multiple runs can be plotted together for
comparison. Other useful features include data fitting and optimization.
In our experience, modeling and digital simulation has proven itself to be
absolutely the most effective way of introducing and reinforcing new concepts that
involve multiple interactions. The thinking process is ultimately stimulated to the
point of solid understanding. In short, modeling makes you think!

Organization of the Book

The book is divided into two parts: a presentation of the background theory in Part
I and the modeling and computer simulation exercises in Part II. The function of
the text in Part I is to provide the basic theory required to fully understand and to
make full use of the computer examples and simulation exercises. Numerous case
studies provide illustration to the theory. Part II constitutes the main part of this
book. New in this third edition are a few modeling examples that help the reader to
train the ability of setting up a model and writing the necessary balance equations.
These models can then directly be transferred to a full simulation model. Solutions
xvi Preface

are provided on the Wiley websites. The simulation examples in Part II provide an
excellent instructional and self-learning tool. Each of the more than 80 examples
is self-contained, including a model description, model equations, exercises, com-
puter program listing, nomenclature and references. The examples are found on
the Wiley websites: https://www.wiley-vch.de/ISBN978-3-527-32524-5 and https://
www.wiley.com/go/heinzle. The exercises range from simple parameter-changing
investigations to suggestions for writing a new program. The combined book thus
represents a synthesis of basic theory, modeling exercises, and computer-based sim-
ulation examples.
Quite apart from the educational value of the text, the introduction and use of
the Berkeley Madonna software provides the reader with the considerable practi-
cal advantage of a differential equation solution package. A screenshot guide con-
cerning the use of the software is found on the Wiley websites. Free demo versions
can be downloaded from the Berkeley Madonna website (www.berkeleymadonna
.com). These unlicensed demo versions allow running all examples that are avail-
able on Wiley websites only. Full versions can be bought there and would allow more
functionality concerning program modifications and cut and paste functions. More
details about Berkeley Madonna and useful computer platforms are briefly described
in the Appendix, and more information is provided on the Wiley websites. The Help
menu of Berkeley Madonna is very useful, and manuals can be downloaded from
their website.
Part I: “Principles of Bioreactor Modeling” covers the basic theory necessary for
understanding the computer simulation examples. This section presents the basic
concepts of material balancing, and their combination with kinetic relationships, to
establish simple biological reactor models, carefully presented in a way that should
be understandable to biologists. In fact, engineers may also find this rigorous presen-
tation of balancing to be valuable. In order to achieve this aim, the main emphasis
of the text is placed on an understanding of the physical meaning and significance
of each term in the model equations. The aim in presenting the relevant theory is
thus not to be exhaustive, but simply to provide a basic introduction to the theory
required for a proper understanding of the modeling methodology.
Chapter 1 deals with the basic concepts of modeling, the basic principles, develop-
ment and significance of differential balances, and the formulation of material and
energy balance relationships. Additional relationships are introduced: stoichiome-
try, elemental balancing, and the yield coefficient concept. Equilibrium relationships
focus on reaction equilibrium and acid-base equilibria for varying pH systems. Time
constants are introduced to assist in the order-of-magnitude analysis. Emphasis is
given to physical understanding.
Chapter 2 introduces the varied operational characteristics of the various types of
bioreactors and their differing modes of operation, with the aim of giving a qualita-
tive insight into the quantitative behavior of the computer simulation examples.
Chapter 3, on the other hand, presents enzyme and microbial kinetics. A particular
feature of the kinetic treatment is the emphasis on the use of more complex models
with interacting microorganisms and with a structured description of the cellular
behavior. Such models require much more consideration to the biology of the system
 Preface xvii

during the modeling procedure, but despite their added complexity can nevertheless
also be solved with relative ease. All these models can be combined with the various
kinds of bioreactor systems. They serve as a reminder that biological reactions are
really infinitely complex.
Chapter 4 is used to derive general material balance equations, covering the many
types of fermentation tank reactors, including tubular reactors. These generalized
equations are then simplified to show their application to the differing modes of
stirred tank bioreactor operation, discussed previously and illustrated by the simu-
lation examples.
Chapter 5 explains the basic theory of interfacial mass transfer as applied to fer-
mentation systems and shows how equations for rates of mass transfer can be com-
bined with material balances, for both liquid and gas phases. A particular extension
of this approach is the combination of transfer rate and material balance equations
to models of increased geometrical complexity, as represented by large-scale air-lift
and multiple impeller fermenters.
Chapter 6 treats the cases of external diffusion to a solid surface and internal
diffusion combined with biochemical reaction, with practical application to immo-
bilized biocatalyst and biofilm systems. Emphasized here is the conceptual ease
of handling a complex reaction in a solid biocatalyst matrix. The resulting sets of
tractable differential difference equations are solved by simulation techniques in
several examples.
Chapter 7 describes the importance of control and summarizes control strategies
used for bioreaction processes. Here the fundamentals of feedback control systems
and their characteristic responses are discussed. This material forms the basis for
performing the many recommended control exercises in the simulation examples.
It also will allow the reader and simulator to develop his own control models and
simulation programs.
Chapter 8 provides a brief introduction of modeling and simulation techniques
applied to cells, tissues, and organisms.
Part II: “Dynamic Bioprocess Modeling, Dynamic Bioprocess Simulation
Examples and the Berkeley Madonna Simulation Language,” comprises Chapter 9,
with some introductory modeling exercises. Solutions for the introductory modeling
exercises are provided on the Wiley websites: https://www.wiley-vch.de/ISBN978-
3-527-32524-5 and https://www.wiley.com/go/heinzle. Chapter 10 contains the
many computer simulation examples and also an Appendix, which gives the instruc-
tions for using Berkeley Madonna (www.berkeleymadonna.com). Each example
in Chapter 10 includes a description of its physical system, the model equations,
that were developed in Part I, and a list of suggested exercises. The programs are
also found on the Wiley websites. These example exercises can be carried out for
the reader to explore the model system in detail, and it is suggested that work on
the computer exercises be done in close reference to the model equations and their
physical meaning, as described in the text. The exercises, however, are provided
simply as an idea for what might be done and are by no means mandatory or
restrictive. Working through a particular example will often suggest an interesting
variation, such as a control loop, which can then be programmed and inserted. The
xviii Preface

examples cover a wide range of application and can easily be extended by reference
to the literature. They are robust and are well tested by a variety of undergraduate
and graduate students and also by more than 500 participants who have previously
attended the Braunwald course. In tackling the exercises, we hope you would soon
come to share our conviction that, besides being very useful, computer simulation
is also fun to do.
For the third edition, the text was thoroughly revised and some of our earlier,
less relevant material was omitted. The nomenclature was completely revised,
especially using “C” as symbol for concentration and “r” for rate throughout the
book, following a suggestion of our friend Matthias Reuss from the University of
Stuttgart. We also thank him and Christoph Wittmann from the Saarland University
for their extended discussion on the content of this book and the presentation of
simulation examples. In addition, a number of new examples resulting mainly from
the authors’ latest research and teaching work were added including some examples
of modeling the current coronavirus pandemic. There was also an opportunity in
this new edition to eliminate most of the past errors and to avoid new ones as much
as possible. Chapter 1 “Modeling Principles” was enriched with an introduction
of metabolic network principles and the concept of time constants. In Chapter 3
“Biological Kinetics,” the modeling of metabolic networks is addressed and linked
to some recent case studies. In Chapter 6 “Diffusion and Biological Reaction for
Immobilized Biocatalyst Systems,” finite differencing is also applied to spherical
geometry, e.g. gaining importance for the quantitative description of spheroids of
animal or human cells applied in drug and toxicity testing. Chapter 7 “Automatic
Process Control Fundamentals” has now a new section of the measurement of pro-
cess variables that is also important for modeling control of bioreactors realistically.
The tuning of controller using simulation is also more emphasized by introducing
the application of integral error criteria. A whole new chapter is introduced,
Chapter 8 “Basic Cell and Bioreactor Models,” which addresses the basic balancing
for describing metabolic network systems in cells and cell compartments, which
are then combined with different types of bioreactors and bioreactor operation.
This chapter also links to physiologically based pharmacokinetic (PBPK), the PBPK
modeling and simulation, and its application to modern drug efficacy and toxicity
testing.
Part II is extended with a leading Chapter 9 that focuses on the structuring of
dynamic simulation problems and making the first often most difficult steps in set-
ting up a model, defining useful balance regions and their interconnections. Chapter
10 is the largest and most outstanding chapter of the book because it contains numer-
ous simulation examples, including new introductory exercise examples in bioreac-
tor model building (Section 10.1.4). Some are relatively simple and others extend to
more complex systems, e.g. for dynamic metabolic flux analysis. All examples are
completely revised and use the nomenclature as introduced in Part I to make an eas-
ier switch between parts. All simulation examples are freely available, can be easily
downloaded from the Wiley websites, and can be directly run even with freely avail-
able download versions of Berkeley Madonna both for Windows and macOS; buying
a license will enable full functionality. A special, reduced license fee is offered for
 Preface xix

the buyers of our book (https://www.BerkeleyMadonna.com/Biological_Reaction_

Engineering).
Our book has a number of special characteristics. It will be obvious, in reading it
through, that we concentrate only on those topics of biological reaction engineering
that lend themselves to modeling and simulation and do not attempt to cover the
area completely. Our own research work is used to illustrate theoretical points, from
which many simulation examples are drawn. Part I begins with the definition of sym-
bols generally used here and ends with a list of suggested books for supplementary
reading, together with the list of cited references. Additionally, the nomenclature for
each simulation example is provided separately, though mostly following the general
nomenclature as introduced in the first part of the book.
We are confident that the book will be useful to all life scientists wishing to obtain
an understanding of biochemical engineering, as well as to chemical and biochem-
ical engineers wanting to sharpen their modeling skills and wishing to gain a better
understanding of biochemical process phenomena. We also see our book as an excel-
lent introduction to modeling in the framework of emerging fields of systems biology
and biosystems engineering. We hope that teachers with an interest in modeling
will find this to be a valuable textbook for undergraduate and graduate biochemical
engineering and biotechnological courses.
 xxi

Acknowledgments

A major acknowledgment should be made to the excellent pioneering texts of Franks

(1967 and 1972) and also of Luyben (1973), for inspiring our interest in digital sim-
ulation. We are especially grateful to our students and to the past-participants of the
Braunwald course, for their assistance in the continuing development of the course
and of the material presented in this book. Continual stimulus and assistance have
also been given by our doctoral candidates, especially at the Chemical Engineering
Department, ETH-Zurich, and from students of the Saarland University. The major-
ity of the simulation examples in the book are taken from our own research at the
ETH or Saarland University, as noted throughout the references.
We acknowledge the editing support by Zhipei Du, Luu Loi, and Duy Nguyen, all
students of the Saarland University. We are grateful to and have great respect for the
developers of Berkeley Madonna and hope that this new version of the book will be
useful in drawing attention to this wonderful simulation language.
In particular, the authors are sincerely thankful to Professor John R. Bourne for
his support and for the freedom that he gave us for our work throughout the years
at the ETH.
 xxiii

Nomenclature for Part I

Symbols (Units)

A area (m2 )
a constant in logistic equation (1/s)
A magnitude of controller input signal (various)
a specific area (m2 /m3 )
b constant in logistic equation (m3 /kg s)
b constant in Luedeking–Piret relation (1/s)
B magnitude of controller output signal (various)
C concentration (kg/m3 , kmol/m3 )
cP heat capacity (kJ/kg K, kJ/mol K)
CPR carbon dioxide production rate (mol/s)
d differential operator and diameter (–, m)
D diffusivity (m2 /s)
D dilution rate (1/s)
DM dry mass of cells (kg)
DO dissolved oxygen (g/m3 , % air sat.)
E elemental composition matrix
Ea activation energy (kJ/mol K)
F flow rate (m3 /s)
f frequency in the ultimate gain method (1/s)
G gas flow rate (m3 )
H henry’s law constant (bar m3 /kg)
hi partial molar enthalpy (kJ/mol)
IAE integral absolute error (various)
ISE integral square error (various)
ITAE integral time-weighted absolute error (various)
j diffusional mass flux (kg/m2 s, mol/m2 s)
J total diffusional mass flux (kg/s and mol/s)
J total transfer rate (kg/s and mol/s)
k constant (various)
K equilibrium constant (various)
K mass transfer coefficient (1/s)
xxiv Nomenclature for Part I

KD acid–base dissociation constant (–)

kG a gas film mass transfer coefficient (1/s)
KI inhibition constant (kg/m3 and kmol/m3 )
kL a liquid film mass transfer coefficient (1/s)
KM Michaelis–Menten constant (kg/m3 and kmol/m3 )
KP proportional controller gain constant (various)
KS Monod saturation coefficient (kg/m3 )
KW dissociation constant of water
L length (m)
m maintenance coefficient (1/s)
M mass flux (kg/m2 s)
M mass (kg or mol)
N molar flow rate (mol/s)
n number of moles (–)
n reaction order (–)
OUR oxygen uptake rate (mol/s and kg/s)
P output control signal (various)
p pressure (Pa, bar)
pi partial pressure of I (bar)
q specific rate (kg/kg biomass s)
r heat flow (kJ/m3 s)
R ideal gas constant (bar m3 /K mol)
R radius (m)
r reaction rate (kg /m3 s, kmol/m3 s)
R recycle flow rate (m3 /s)
ri reaction rate of component i (kg i/m3 s)
r i/j reaction rate of component i to j (kg/m3 s, kmol/m3 s)
RQ respiration quotient (mol CO2 /mol O2 )
rX growth rate (kg biomass/m3 s)
S selectivity (–)
S slope of process reaction curve (various)
T temperature (∘ C or K)
t time (h, min and s)
Tr transfer rate (mol/m3 s)
U heat transfer coefficient (kJ/m2 K s)
v flow velocity (m/s)
V volume (m3 )
VCD viable cell density (cells/m3 )
vm maximum reaction rate (kmol/m3 s)
w mass fraction (–)
W wastage stream flow rate (m3 /s)
x mass fraction
y mol fraction in gas (–)
Y process output value (various)
Y yield coefficient (kg/kg)
 Nomenclature for Part I xxv

Y i/j yield of i from j (kg i/kg j, mol i/mol j)

Z length variable (m)

Greek
Δ difference operator (–)
ΔG Gibb’s free reaction enthalpy (kJ/mol)
ΔH enthalpy change (kJ/mol or kJ/kg)
Φ Thiele modulus (–)
Σ summation operator (–)
𝛼 rate coefficient (various)
𝛽 rate coefficient (various)
𝛿 concentration difference quantity (kg/m3 )
𝜀 controller error (various)
𝜀 elasticity coefficient (–)
𝜂 effectiveness factor (–)
𝜇 specific growth rate (1/s)
𝜇m maximum growth rate (1/s)
𝜈 stoichiometric coefficient (–)
𝜌 density (kg/m3 )
𝜏 residence time (s, min, or h)
𝜏 time constant (s)
𝜕 partial differential operator (–)
Note: In all cases time can be specified in s, min, or h, in special cases also d.

Indices
– bar above symbol refers to dimensionless variable
* refers to equilibrium concentration
0 refers to initial, inlet, external, and zero order
1 refers to time t1 , outlet, component 1, tank 1, and first order
1, 2, ..., n refers to stream, volume elements, and stages
2 refers to tank 2, time t2 , and component 2
a refers to ambient, heating, or cooling temperature
A− refers to anions
A refers to component A, anions, and bulk
Ac refers to acetoin and acetoin formation
aer refers to aerobic
agit refers to agitation
anaer refers to anaerobic
app refers to apparent
ATP refers to ATP
ATP/X refers to consumption ATP for biomass formation
xxvi Nomenclature for Part I

avg refers to average

B refers to component B, base, backmixing, and surface position
Bu refers to butanediol
C refers to cell
C refers to combustion
C refers to coolant
c refers to critical
CO2 refers to carbon dioxide
D refers to diffusion
d refers to deactivation and death
D refers to derivative control
D refers to dissociation
DO refers to dissolved oxygen
E refers to electrode
E refers to enzyme
E refers to ethanol
eq refers to equilibrium
ES refers to enzyme–substrate complex
evap refers to evaporation
F refers to feed
f refers to final
F refers to formation
G refers to gas and to cellular compartment
H+ refers to hydrogen ions
hp refers to heat production
ht refers to heat transfer
H2 O refers to water
i general index, refers to component i and to interface
I refers to inhibitor
I refers to integral control
I refers to integral control
inert refers to inert component
J refers to jacket
K refers to cellular compartment
K+ refers to cations
L refers to liquid
L refers to lag
L refers to ligand
m refers to maximum
M refers to metabolite
max refers to maximum
mt refers to mass transfer
n refers to tank number
NH4 refers to ammonium
NO2 refers to nitrite
 Nomenclature for Part I xxvii

NO3 refers to nitrate

O and O2 refer to oxygen
obs refers to observed
P refers to particle
P refers to product
P refers to proportional control
P refers to protein
PA refers to product A
PB refers to product B
Q refers to heat
Q/O2 refers to heat–oxygen ratio
Q/S refers to heat–substrate ratio
q refers to reaction heat
r refers to reaction
R refers to reactor
R refers to recycle stream
R refers to residual biomass
S refers to substrate and surface
sat refers to saturation
set refers to set point
SL refers to liquid film at solid interface
Sn refers to substrate n
tot refers to total
X refers to biomass
X/i refers to biomass–component i ratio
X/S refers to biomass–substrate ratio
Z refers to difference between cations and ions
xxviii

List of Simulation Examples

BATFERM Batch Fermentation (10.1.1)
CHEMO Chemostat Fermentation (10.1.2)
FEDBAT Fed-Batch Fermentation (10.1.3)
Various Introductory Exercises in Bioreactor Model
Building (10.1.4)
MMKINET Kinetics of Enzyme Action (10.2.1)
LINEWEAV Lineweaver–Burk Plot (10.2.2)
OLIGO Oligosaccharide Production in Lactose Hydrolysis
(10.2.3)
BATSTER Batch Heat Sterilization (10.2.4)
CORONADYN Growth of the Coronavirus (10.2.4)
VARVOL Variable Volume Fermentation (10.3.1)
VARVOLD Variable Volume Fermentation (10.3.1)
PENFERM Penicillin Fermentation Using Elemental Balancing
(10.3.2)
ETHFERM Ethanol Fed-batch Diauxic Fermentation (10.3.3)
REPFED Repeated Fed-batch Culture (10.3.4)
REPLCUL Repeated Medium Replacement Culture (10.3.5)
PENOXY Penicillin Production in a Fed-batch Fermenter (10.3.6)
CHEMOSTA Steady-state Chemostat (10.4.1)
CONINHIB Continuous Culture with Inhibitory Substrate (10.4.2)
ACTNITR Nitrification in Activated Sludge Process (10.4.3)
ENZTUBE Tubular Enzyme Reactor (10.4.4)
DUAL Dual Substrate Limitation (10.4.5)
TWOSTAGE Two-stage Chemostat with Additional Stream (10.4.6)
STAGED Two-stage Culture with Product Inhibition (10.4.7)
FBR Fluidized Bed Recycle Reactor (10.4.8)
NITBED Nitrification in a Fluidized Bed Reactor (10.4.9)
ENZCON Continuous Enzymatic Reactor (10.4.10)
DEACTENZ Reactor Cascade with Deactivating Enzyme (10.4.11)
PHBTWO Production of PHB in a Two-tank Reactor Process
(10.4.12)
DCMDEG Dichloromethane in a Biofilm Fluidized Sand Bed
(10.4.13)
 List of Simulation Examples xxix

OXENZ Aeration of a Tank Reactor for Enzymatic Oxidation

(10.5.1)
INHIB Gas and Liquid Oxygen Dynamics in Fermenter (10.5.2)
NITRIF Batch Nitrification with Oxygen Transfer (10.5.3)
OXDYN Oxygen Uptake and Aeration Dynamics (10.5.4)
KLADYN Dynamic KLa Methods (10.5.5)
KLAFIT Dynamic KLa Methods (10.5.5)
ELECTFIT Dynamic KLa Methods (10.5.5)
BIOFILTDYN Biofiltration Column for Two Inhibitory Substrates
(10.5.6)
TITERDYN Optical Sensing in Microtiter Plates (10.5.7)
TITERBIO Optical Sensing in Microtiter Plates (10.5.7)
BIOFILM Double Substrate Biofilm Reaction (10.6.1)
ENZSPLIT Steady-state Split Boundary Solution (10.6.2)
ENZDYN Dynamic Porous Diffusion and Reaction (10.6.3)
CELLDIFFBEAD Oxygen Diffusion in Animal Cells (10.6.4)
CELLDIFFCYL Oxygen Diffusion to a Single Cell or Cell Aggregate
(10.6.5)
NITBEDFILM Immobilized Biofilm in a Nitrification Column (10.6.6)
TEMPCONT Feedback Control of a Water Heater (10.7.1)
FERMTEMP Temperature Control of Fermentation (10.7.2)
TURBCON Turbidostat Response (10.7.3)
CONTCON Feed Rate Control of Inhibitory Substrate (10.7.4)
ADAPTOXCONT Adaptive Control of Dissolved Oxygen (10.7.5)
MEMINH Cell Retention Membrane Reactor (10.8.1)
PERVAPSUB Fermentation with Pervaporation (10.8.2)
LACMEMRECYC Two Stage Fermentor with Cell Recycle (10.8.3)
LACREACT Hollow Fiber Enzyme Reactor for Lactose Hydrolysis
(10.8.4)
ANIMALIMMOB Animal Cells in a Fluidized Bed Reactor (10.8.5)
COMMENSA Bacteria with Opposite Substrate Preferences (10.9.1)
COMPASM Competitive Assimilation and Commensalism (10.9.2)
PLASMID Stability of Recombinant Microorganisms (10.9.3)
MIXPOP Predator–Prey Population Dynamics (10.9.4)
TWOONE Competition Between Organisms (10.9.5)
FILMPOP Competition for an Inhibitory Substrate in a Biofilm
(10.9.6)
ANAEMEAS Model for Anaerobic Reactor Activity Measurement
(10.9.7)
SIRDYN Dynamics of an Epidemic Using the SIR Model (10.9.8)
SIRDYNDIM Dynamics of an Epidemic Using the SIR Model (10.9.8)
YEASTOSC Oscillations in Continuous Yeast Culture (10.10.1)
PHB Structured Model for PHB Production (10.10.2)
MAMMCELLCYCLE Mammalian Cell Cycle Control (10.10.3 )
xxx List of Simulation Examples

POTATO Metabolic Fluxes in Secondary Metabolism in Potato

(10.10.4)
SUBTILIS Structured Model of the Production of Acetoin and
Butanediol (10.10.5)
CHOMAB Production of Monoclonal Antibodies by CHO Cells
(10.10.6)
 1

Part I

Principles of Bioreactor Modeling

 3

Modeling Principles

1.1 Fundamentals of Modeling

1.1.1 Use of Models for Understanding, Design, and Optimization of

Bioreactors
Any system used for carrying out bioreactions, from single enzymatic reactions to
complex multicellular reaction systems, requires a containment called a bioreactor.
The performance of a bioreactor may conventionally be investigated almost entirely
empirically. In this approach, the bioreactor behavior would be studied under prac-
tically all combinations of possible operating conditions. The results would then
be expressed as a series of input–output correlations, from which the performance
could be determined. This empirical procedure can be carried out in a routine man-
ner and requires relatively little thought concerning the actual details of the process.
While this might seem to be rather convenient, the procedure has actually disad-
vantages, since very little real understanding of the process would be obtained. Also
very many costly experiments would be required in order to obtain correlations that
would cover every process eventuality.
Compared to this, the modeling approach attempts to describe both actual and
probable bioreactor performances, by means of a well-established theory. Described
in mathematical terms, a working model for the process is established. In carrying
out a modeling task, the modeler is forced to consider the nature of all the important
parameters of the process, their effect on the process, and how each parameter must
be defined in quantitative terms. The modeler must identify the important variables
and their separate effects, which may have a highly interactive combined effect on
the overall process performance. Thus, the very act of modeling is one that forces a
better understanding of the process, since all the relevant theory must be critically
assessed. In addition, the task of formulating theory into terms of mathematical
equations is also very beneficial in that it forces a clear formulation of basic
concepts.
Once formulated, the model can be solved, and the predicted behavior can be com-
pared with experimental data. Any differences in performance may then be used
to further redefine or refine the model until a good agreement is obtained. Once
the model is established, it can then be used, with reasonable confidence, to predict
Biological Reaction Engineering: Dynamic Modeling Fundamentals With 80 Interactive Simulation Examples,
Third Edition. Elmar Heinzle, Irving J. Dunn, John Ingham, and Jǐrı́ E. P̌renosil.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
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 In addition to the above resolution, the General Assembly of
Virginia “appealed to the other states, in the confidence that they
would concur with that commonwealth, that the acts aforesaid [the
alien and sedition laws] are unconstitutional, and that the necessary
and proper measures would be taken by each for co-operating with
Virginia in maintaining unimpaired the authorities, rights, and
liberties reserved to the states respectively, or to the people.”
The legislatures of several of the New England States, having,
contrary to the expectation of the legislature of Virginia, expressed
their dissent from these doctrines, the subject came up again for
consideration during the session of 1799, 1800, when it was referred
to a select committee, by whom was made that celebrated report
which is familiarly known as “Madison’s Report,” and which deserves
to last as long as the constitution itself. In that report, which was
subsequently adopted by the legislature, the whole subject was
deliberately re-examined, and the objections urged against the
Virginia doctrines carefully considered. The result was, that the
legislature of Virginia reaffirmed all the principles laid down in the
resolutions of 1798, and issued to the world that admirable report
which has stamped the character of Mr. Madison as the preserver of
that constitution which he had contributed so largely to create and
establish. I will here quote from Mr. Madison’s report one or two
passages which bear more immediately on the point in controversy.
“The resolutions, having taken this view of the federal compact,
proceed to infer ‘that in case of a deliberate, palpable, and dangerous
exercise of other powers the states who are parties thereto have the
right, and are in duty bound, to interpose for arresting the progress
of the evil, and for maintaining, within their respective limits, the
authorities, rights, and liberties appertaining to them.’”
“It appears to your committee to be a plain principle, founded in common sense,
illustrated by common practice, and essential to the nature of compacts, that,
where resort can be had to no tribunal superior to the authority of the parties, the
parties themselves must be the rightful judges in the last resort, whether the
bargain made has been pursued or violated. The constitution of the United States
was formed by the sanction of the states, given by each in its sovereign capacity. It
adds to the stability and dignity, as well as to the authority, of the constitution, that
it rests upon this legitimate and solid foundation. The states, then, being the
parties to the constitutional compact, and in their sovereign capacity, it follows of
necessity that there can be no tribunal above their authority, to decide, in the last
resort, whether the compact made by them be violated, and consequently that, as
the parties to it, they must decide, in the last resort, such questions as may be of
sufficient magnitude to require their interposition.”
“The resolution has guarded against any misapprehension of its object by
expressly requiring for such an interposition ‘the case of a deliberate, palpable, and
dangerous breach of the constitution, by the exercise of powers not granted by it.’
It must be a case, not of a light and transient nature, but of a nature dangerous to
the great purposes for which the constitution was established.
“But the resolution has done more than guard against misconstructions, by
expressly referring to cases of a deliberate, palpable, and dangerous nature. It
specifies the object of the interposition, which it contemplates, to be solely that of
arresting the progress of the evil of usurpation, and of maintaining the authorities,
rights, and liberties appertaining to the states, as parties to the constitution.
“From this view of the resolution, it would seem inconceivable that it can incur
any just disapprobation from those who, laying aside all momentary impressions,
and recollecting the genuine source and object of the federal constitution, shall
candidly and accurately interpret the meaning of the General Assembly. If the
deliberate exercise of dangerous powers, palpably withheld by the constitution,
could not justify the parties to it in interposing even so far as to arrest the progress
of the evil, and thereby to preserve the constitution itself, as well as to provide for
the safety of the parties to it, there would be an end to all relief from usurped
power, and a direct subversion of the rights specified or recognized under all the
state constitutions, as well as a plain denial of the fundamental principles on which
our independence itself was declared.”
But, sir, our authorities do not stop here. The state of Kentucky
responded to Virginia, and on the 10th of November, 1798, adopted
those celebrated resolutions, well known to have been penned by the
author of the Declaration of American Independence. In those
resolutions, the legislature of Kentucky declare, “that the
government created by this compact was not made the exclusive or
final judge of the extent of the powers delegated to itself, since that
would have made its discretion, and not the constitution, the
measure of its powers; but that, as in all other cases of compact
among parties having no common judge, each party has an equal
right to judge, for itself, as well of infractions as of the mode and
measure of redress.”
At the ensuing session of the legislature, the subject was re-
examined, and on the 14th of November, 1799, the resolutions of the
preceding year were deliberately reaffirmed, and it was, among other
things, solemnly declared,—
“That, if those who administer the general government be permitted to
transgress the limits fixed by that compact, by a total disregard to the special
delegations of power therein contained, an annihilation of the state governments,
and the erection upon their ruins of a general consolidated government, will be the
inevitable consequence. That the principles of construction contended for by
sundry of the state legislatures, that the general government is the exclusive judge
of the extent of the powers delegated to it, stop nothing short of despotism; since
the discretion of those who administer the government, and not the constitution,
would be the measure of their powers. That the several states who formed that
instrument, being sovereign and independent, have the unquestionable right to
judge of its infraction, and that a nullification, by those sovereignties, of all
unauthorized acts done under color of that instrument, is the rightful remedy.”
Time and experience confirmed Mr. Jefferson’s opinion on this all
important point. In the year 1821, he expressed himself in this
emphatic manner: “It is a fatal heresy to suppose that either our state
governments are superior to the federal, or the federal to the state;
neither is authorized literally to decide which belongs to itself or its
copartner in government; in differences of opinion, between their
different sets of public servants, the appeal is to neither, but to their
employers peaceably assembled by their representatives in
convention.” The opinion of Mr. Jefferson on this subject has been so
repeatedly and so solemnly expressed, that they may be said to have
been the most fixed and settled convictions of his mind.
In the protest prepared by him for the legislature of Virginia, in
December, 1825, in respect to the powers exercised by the federal
government in relation to the tariff and internal improvements,
which he declares to be “usurpations of the powers retained by the
states, mere interpolations into the compact, and direct infractions of
it,” he solemnly reasserts all the principles of the Virginia
Resolutions of ’98, protests against “these acts of the federal branch
of the government as null and void, and declares that, although
Virginia would consider a dissolution of the Union as among the
greatest calamities that could befall them, yet it is not the greatest.
There is one yet greater—submission to a government of unlimited
powers. It is only when the hope of this shall become absolutely
desperate, that further forbearance could not be indulged.”
In his letter to Mr. Giles, written about the same time, he says,—
“I see as you do, and with the deepest affliction, the rapid strides with which the
federal branch of our government is advancing towards the usurpation of all the
rights reserved to the states, and the consolidation in itself of all powers, foreign
and domestic, and that too by constructions which leave no limits to their powers,
&c. Under the power to regulate commerce, they assume, indefinitely, that also
over agriculture and manufactures, &c. Under the authority to establish post roads,
they claim that of cutting down mountains for the construction of roads, and
digging canals, &c. And what is our resource for the preservation of the
constitution? Reason and argument? You might as well reason and argue with the
marble columns encircling them, &c. Are we then to stand to our arms with the
hot-headed Georgian? No; [and I say no, and South Carolina has said no;] that
must be the last resource. We must have patience and long endurance with our
brethren, &c., and separate from our companions only when the sole alternatives
left are a dissolution of our Union with them, or submission. Between these two
evils, when we must make a choice, there can be no hesitation.”
Such, sir, are the high and imposing authorities in support of “The
Carolina doctrine,” which is, in fact, the doctrine of the Virginia
Resolutions of 1798.
Sir, at that day the whole country was divided on this very
question. It formed the line of demarcation between the federal and
republican parties; and the great political revolution which then took
place turned upon the very questions involved in these resolutions.
That question was decided by the people, and by that decision the
constitution was, in the emphatic language of Mr. Jefferson, “saved
at its last gasp.” I should suppose, sir, it would require more self-
respect than any gentleman here would be willing to assume, to treat
lightly doctrines derived from such high resources. Resting on
authority like this, I will ask gentlemen whether South Carolina has
not manifested a high regard for the Union, when, under a tyranny
ten times more grievous than the alien and sedition laws, she has
hitherto gone no further than to petition, remonstrate, and to
solemnly protest against a series of measures which she believes to
be wholly unconstitutional and utterly destructive of her interests.
Sir, South Carolina has not gone one step further than Mr. Jefferson
himself was disposed to go, in relation to the present subject of our
present complaints—not a step further than the statesman from New
England was disposed to go, under similar circumstances; no further
than the senator from Massachusetts himself once considered as
within “the limits of a constitutional opposition.” The doctrine that it
is the right of a state to judge of the violations of the constitution on
the part of the federal government, and to protect her citizens from
the operations of unconstitutional laws, was held by the enlightened
citizens of Boston, who assembled in Faneuil Hall, on the 25th of
January, 1809. They state, in that celebrated memorial, that “they
looked only to the state legislature, who were competent to devise
relief against the unconstitutional acts of the general government.
That your power (say they) is adequate to that object, is evident from
the organization of the confederacy.”
A distinguished senator from one of the New England States, (Mr.
Hillhouse,) in a speech delivered here, on a bill for enforcing the
embargo, declared, “I feel myself bound in conscience to declare,
(lest the blood of those who shall fall in the execution of this measure
shall be on my head,) that I consider this to be an act which directs a
mortal blow at the liberties of my country—an act containing
unconstitutional provisions, to which the people are not bound to
submit, and to which, in my opinion, they will not submit.”
And the senator from Massachusetts himself, in a speech delivered
on the same subject in the other house, said, “This opposition is
constitutional and legal; it is also conscientious. It rests on settled
and sober conviction, that such policy is destructive to the interests
of the people, and dangerous to the being of government. The
experience of every day confirms these sentiments. Men who act
from such motives are not to be discouraged by trifling obstacles, nor
awed by any dangers. They know the limit of constitutional
opposition; up to that limit, at their own discretion, they will walk,
and walk fearlessly.” How “the being of the government” was to be
endangered by “constitutional opposition” to the embargo, I leave
the gentleman to explain.
Thus it will be seen, Mr. President, that the South Carolina
doctrine is the republican doctrine of ’98—that it was promulgated
by the fathers of the faith—that it was maintained by Virginia and
Kentucky in the worst of times—that it constituted the very pivot on
which the political revolution of that day turned—that it embraces
the very principles, the triumph of which, at that time, saved the
constitution at its last gasp, and which New England statesmen were
not unwilling to adopt, when they believed themselves to be the
victims of unconstitutional legislation. Sir, as to the doctrine that the
federal government is the exclusive judge of the extent as well as the
limitations of its powers, it seems to me to be utterly subversive of
the sovereignty and independence of the states. It makes but little
difference, in my estimation, whether Congress or the Supreme
Court are invested with this power. If the federal government, in all,
or any, of its departments, is to prescribe the limits of its own
authority, and the states are bound to submit to the decision, and are
not to be allowed to examine and decide for themselves, when the
barriers of the constitution shall be overleaped, this is practically “a
government without limitation of powers.” The states are at once
reduced to mere petty corporations, and the people are entirely at
your mercy. I have but one word more to add. In all the efforts that
have been made by South Carolina to resist the unconstitutional laws
which Congress has extended over them, she has kept steadily in
view the preservation of the Union, by the only means by which she
believes it can be long preserved—a firm, manly, and steady
resistance against usurpation. The measures of the federal
government have, it is true, prostrated her interests, and will soon
involve the whole south in irretrievable ruin. But even this evil, great
as it is, is not the chief ground of our complaints. It is the principle
involved in the contest—a principle which, substituting the discretion
of Congress for the limitations of the constitution, brings the states
and the people to the feet of the federal government, and leaves them
nothing they can call their own. Sir, if the measures of the federal
government were less oppressive, we should still strive against this
usurpation. The south is acting on a principle she has always held
sacred—resistance to unauthorized taxation. These, sir, are the
principles which induced the immortal Hampden to resist the
payment of a tax of twenty shillings. Would twenty shillings have
ruined his fortune? No! but the payment of half twenty shillings, on
the principle on which it was demanded, would have made him a
slave. Sir, if acting on these high motives—if animated by that ardent
love of liberty which has always been the most prominent trait in the
southern character—we should be hurried beyond the bounds of a
cold and calculating prudence, who is there, with one noble and
generous sentiment in his bosom, that would not be disposed, in the
language of Burke, to exclaim, “You must pardon something to the
spirit of liberty?”
 Webster’s Great Reply to Hayne,

In which he “Expounds the Constitution,” delivered in Senate,

January 26, 1830.
Following Mr. Hayne in the debate, Mr. Webster addressed the
Senate as follows:—
Mr. President: When the mariner has been tossed, for many days,
in thick weather, and on an unknown sea, he naturally avails himself
of the first pause in the storm, the earliest glance of the sun, to take
his latitude, and ascertain how far the elements have driven him
from his true course. Let us imitate this prudence, and before we
float farther, refer to the point from which we departed, that we may
at least be able to conjecture where we now are. I ask for the reading
of the resolution.
[The Secretary read the resolution as follows:
“Resolved, That the committee on public lands be instructed to inquire and
report the quantity of the public lands remaining unsold within each state and
territory, and whether it be expedient to limit, for a certain period, the sales of the
public lands to such lands only as have heretofore been offered for sale, and are
now subject to entry at the minimum price. And, also, whether the office of
surveyor general, and some of the land offices, may not be abolished without
detriment to the public interest; or whether it be expedient to adopt measures to
hasten the sales, and extend more rapidly the surveys of the public lands.”]
We have thus heard, sir, what the resolution is, which is actually
before us for consideration; and it will readily occur to every one that
it is almost the only subject about which something has not been said
in the speech, running through two days, by which the Senate has
been now entertained by the gentleman from South Carolina. Every
topic in the wide range of our public affairs, whether past or present,
—every thing, general or local, whether belonging to national politics
or party politics,—seems to have attracted more or less of the
honorable member’s attention, save only the resolution before us. He
has spoken of every thing but the public lands. They have escaped his
notice. To that subject, in all his excursions, he has not paid even the
cold respect of a passing glance.
When this debate, sir, was to be resumed, on Thursday morning, it
so happened that it would have been convenient for me to be
elsewhere. The honorable member, however, did not incline to put
off the discussion to another day. He had a shot, he said, to return,
and he wished to discharge it. That shot, sir, which it was kind thus
to inform us was coming, that we might stand out of the way, or
prepare ourselves to fall before it, and die with decency, has now
been received. Under all advantages, and with expectation awakened
by the tone which preceded it, it has been discharged, and has spent
its force. It may become me to say no more of its effect than that, if
nobody is found, after all, either killed or wounded by it, it is not the
first time in the history of human affairs that the vigor and success of
the war have not quite come up to the lofty and sounding phrase of
the manifesto.
The gentleman, sir, in declining to postpone the debate, told the
Senate, with the emphasis of his hand upon his heart, that there was
something rankling here, which he wished to relieve. [Mr. Hayne
rose and disclaimed having used the word rankling.] It would not,
Mr. President, be safe for the honorable member to appeal to those
around him, upon the question whether he did, in fact, make use of
that word. But he may have been unconscious of it. At any rate, it is
enough that he disclaims it. But still, with or without the use of that
particular word, he had yet something here, he said, of which he
wished to rid himself by an immediate reply. In this respect, sir, I
have a great advantage over the honorable gentleman. There is
nothing here, sir, which gives me the slightest uneasiness; neither
fear, nor anger, nor that which is sometimes more troublesome than
either, the consciousness of having been in the wrong. There is
nothing either originating here, or now received here, by the
gentleman’s shot. Nothing original, for I had not the slightest feeling
of disrespect or unkindness towards the honorable member. Some
passages, it is true, had occurred, since our acquaintance in this
body, which I could have wished might have been otherwise; but I
had used philosophy, and forgotten them. When the honorable
member rose, in his first speech, I paid him the respect of attentive
listening; and when he sat down, though surprised, and I must say
even astonished, at some of his opinions, nothing was farther from
my intention than to commence any personal warfare; and through
the whole of the few remarks I made in answer, I avoided, studiously
and carefully, every thing which I thought possible to be construed
into disrespect. And, sir, while there is thus nothing originating here,
which I wished at any time, or now wish to discharge, I must repeat,
also, that nothing has been received here which rankles, or in any
way gives me annoyance. I will not accuse the honorable member of
violating the rules of civilized war—I will not say that he poisoned his
arrows. But whether his shafts were, or were not, dipped in that
which would have caused rankling if they had reached, there was not,
as it happened, quite strength enough in the bow to bring them to
their mark. If he wishes now to find those shafts, he must look for
them elsewhere; they will not be found fixed and quivering in the
object at which they were aimed.

The honorable member complained that I had slept on his speech.

I must have slept on it, or not slept at all. The moment the honorable
member sat down, his friend from Missouri arose, and, with much
honeyed commendation of the speech, suggested that the
impressions which it had produced were too charming and delightful
to be disturbed by other sentiments or other sounds, and proposed
that the Senate should adjourn. Would it have been quite amiable in
me, sir, to interrupt this excellent good feeling? Must I not have been
absolutely malicious, if I could have thrust myself forward to destroy
sensations thus pleasing? Was it not much better and kinder, both to
sleep upon them myself, and to allow others, also, the pleasure of
sleeping upon them? But if it be meant, by sleeping upon his speech,
that I took time to prepare a reply to it, it is quite a mistake; owing to
other engagements, I could not employ even the interval between the
adjournment of the Senate and its meeting the next morning in
attention to the subject of this debate. Nevertheless, sir, the mere
matter of fact is undoubtedly true—I did sleep on the gentleman’s
speech, and slept soundly. And I slept equally well on his speech of
yesterday, to which I am now replying. It is quite possible that, in
this respect, also, I possess some advantage over the honorable
member, attributable, doubtless, to a cooler temperament on my
part; for in truth I slept upon his speeches remarkably well. But the
gentleman inquires why he was made the object of such a reply. Why
was he singled out? If an attack had been made on the east, he, he
assures us, did not begin it—it was the gentleman from Missouri. Sir,
I answered the gentleman’s speech, because I happened to hear it;
and because, also, I choose to give an answer to that speech, which, if
unanswered, I thought most likely to produce injurious impressions.
I did not stop to inquire who was the original drawer of the bill. I
found a responsible endorser before me, and it was my purpose to
hold him liable, and to bring him to his just responsibility without
delay. But, sir, this interrogatory of the honorable member was only
introductory to another. He proceeded to ask me whether I had
turned upon him in this debate from the consciousness that I should
find an overmatch if I ventured on a contest with his friend from
Missouri. If, sir, the honorable member, ex gratia modestiæ, had
chosen thus to defer to his friend, and to pay him a compliment,
without intentional disparagement to others, it would have been
quite according to the friendly courtesies of debate, and not at all
ungrateful to my own feelings. I am not one of those, sir, who esteem
any tribute of regard, whether light and occasional, or more serious
and deliberate, which may be bestowed on others, as so much
unjustly withholden from themselves. But the tone and manner of
the gentleman’s question, forbid me thus to interpret it. I am not at
liberty to consider it as nothing more than a civility to his friend. It
had an air of taunt and disparagement, a little of the loftiness of
asserted superiority, which does not allow me to pass it over without
notice. It was put as a question for me to answer, and so put as if it
were difficult for me to answer, whether I deemed the member from
Missouri an overmatch for myself in debate here. It seems to me, sir,
that is extraordinary language, and an extraordinary tone for the
discussions of this body.
Matches and overmatches? Those terms are more applicable
elsewhere than here, and fitter for other assemblies than this. Sir, the
gentleman seems to forget where and what we are. This is a Senate; a
Senate of equals; of men of individual honor and personal character,
and of absolute independence. We know no masters; we
acknowledge no dictators. This is a hall of mutual consultation and
discussion, not an arena for the exhibition of champions. I offer
myself, sir, as a match for no man; I throw the challenge of debate at
no man’s feet. But, then, sir, since the honorable member has put the
question in a manner that calls for an answer. I will give him an
answer; and I tell him that, holding myself to be the humblest of the
members here, I yet know nothing in the arm of his friend from
Missouri, either alone or when aided by the arm of his friend from
South Carolina, that need deter even me from espousing whatever
opinions I may choose to espouse, from debating whenever I may
choose to debate, or from speaking whatever I may see fit to say on
the floor of the Senate. Sir, when uttered as matter of commendation
or compliment, I should dissent from nothing which the honorable
member might say of his friend. Still less do I put forth any
pretensions of my own. But when put to me as a matter of taunt, I
throw it back, and say to the gentleman that he could possibly say
nothing less likely than such a comparison to wound my pride of
personal character. The anger of its tone rescued the remark from
intentional irony, which otherwise, probably, would have been its
general acceptation. But, sir, if it be imagined that by this mutual
quotation and commendation; if it be supposed that, by casting the
characters of the drama, assigning to each his part,—to one the
attack, to another the cry of onset,—or if it be thought that by a loud
and empty vaunt of anticipated victory any laurels are to be won
here; if it be imagined, especially, that any or all these things will
shake any purpose of mine, I can tell the honorable member, once for
all, that he is greatly mistaken, and that he is dealing with one of
whose temper and character he has yet much to learn. Sir, I shall not
allow myself, on this occasion—I hope on no occasion—to be
betrayed into any loss of temper; but if provoked, as I trust I never
shall allow myself to be, into crimination and recrimination, the
honorable member may, perhaps, find that in that contest there will
be blows to take as well as blows to give; that others can state
comparisons as significant, at least, as his own; and that his impunity
may, perhaps, demand of him whatever powers of taunt and sarcasm
he may possess. I commend him to a prudent husbandry of his
resources.
But, sir, the coalition! The coalition! Aye, “the murdered
coalition!” The gentleman asks if I were led or frighted into this
debate by the spectre of the coalition. “Was it the ghost of the
murdered coalition,” he exclaims, “which haunted the member from
Massachusetts, and which, like the ghost of Banquo, would never
down?” “The murdered coalition!” Sir, this charge of a coalition, in
reference to the late administration, is not original with the
honorable member. It did not spring up in the Senate. Whether as a
fact, as an argument, or as an embellishment, it is all borrowed. He
adopts it, indeed, from a very low origin, and a still lower present
condition. It is one of the thousand calumnies with which the press
teemed during an excited political canvass. It was a charge of which
there was not only no proof or probability, but which was, in itself,
wholly impossible to be true. No man of common information ever
believed a syllable of it. Yet it was of that class of falsehoods which,
by continued repetition through all the organs of detraction and
abuse, are capable of misleading those who are already far misled,
and of further fanning passion already kindling into flame. Doubtless
it served its day, and, in a greater or less degree, the end designed by
it. Having done that, it has sunk into the general mass of stale and
loathed calumnies. It is the very castoff slough of a polluted and
shameless press. Incapable of further mischief, it lies in the sewer
lifeless and despised. It is not now, sir, in the power of the honorable
member to give it dignity or decency, by attempting to elevate it, and
to introduce it into the Senate. He cannot change it from what it is—
an object of general disgust and scorn. On the contrary, the contact,
if he choose to touch it, is more likely to drag him down, down, to the
place where it lies itself.
But, sir, the honorable member was not, for other reasons, entirely
happy in his allusion to the story of Banquo’s murder and Banquo’s
ghost. It was not, I think, the friends, but the enemies of the
murdered Banquo, at whose bidding his spirit would not down. The
honorable gentleman is fresh in his reading of the English classics,
and can put me right if I am wrong; but according to my poor
recollection, it was at those who had begun with caresses, and ended
with foul and treacherous murder, that the gory locks were shaken.
The ghost of Banquo, like that of Hamlet, was an honest ghost. It
disturbed no innocent man. It knew where its appearance would
strike terror, and who would cry out. A ghost! It made itself visible in
the right quarter, and compelled the guilty, and the conscience-
smitten, and none others, to start, with,
“Prithee, see there! behold!—look! lo!
If I stand here, I saw him!”

Their eyeballs were seared—was it not so, sir?—who had thought

to shield themselves by concealing their own hand and laying the
imputation of the crime on a low and hireling agency in wickedness;
who had vainly attempted to stifle the workings of their own coward
consciences, by circulating, through white lips and chattering teeth,
“Thou canst not say I did it!” I have misread the great poet, if it was
those who had no way partaken in the deed of the death, who either
found that they were, or feared that they should be, pushed from
their stools by the ghost of the slain, or who cried out to a spectre
created by their own fears, and their own remorse, “Avaunt! and quit
our sight!”
There is another particular, sir, in which the honorable member’s
quick perception of resemblances might, I should think, have seen
something in the story of Banquo, making it not altogether a subject
of the most pleasant contemplation. Those who murdered Banquo,
what did they win by it? Substantial good? Permanent power? Or
disappointment, rather, and sore mortification—dust and ashes—the
common fate of vaulting ambition overleaping itself? Did not even-
handed justice, ere long, commend the poisoned chalice to their own
lips? Did they not soon find that for another they had “filed their
mind?” that their ambition though apparently for the moment
successful, had but put a barren sceptre in their grasp? Aye, sir,—
“A barren sceptre in their gripe,
Thence to be wrenched by an unlineal hand,
No son of theirs succeeding.”

Sir, I need pursue the allusion no further. I leave the honorable

gentleman to run it out at his leisure, and to derive from it all the
gratification it is calculated to administer. If he finds himself pleased
with the associations, and prepared to be quite satisfied, though the
parallel should be entirely completed, I had almost said I am
satisfied also—but that I shall think of. Yes, sir, I will think of that.
In the course of my observations the other day, Mr. President, I
paid a passing tribute of respect to a very worthy man, Mr. Dane, of
Massachusetts. It so happened that he drew the ordinance of 1787 for
the government of the Northwestern Territory. A man of so much
ability, and so little pretence; of so great a capacity to do good, and so
unmixed a disposition to do it for its own sake; a gentleman who
acted an important part, forty years ago, in a measure the influence
of which is still deeply felt in the very matter which was the subject of
debate, might, I thought, receive from me a commendatory
recognition.
But the honorable gentleman was inclined to be facetious on the
subject. He was rather disposed to make it a matter of ridicule that I
had introduced into the debate the name of one Nathan Dane, of
whom he assures us he had never before heard. Sir, if the honorable
member had never before heard of Mr. Dane, I am sorry for it. It
shows him less acquainted with the public men of the country than I
had supposed. Let me tell him, however, that a sneer from him at the
mention of the name of Mr. Dane is in bad taste. It may well be a
high mark of ambition, sir, either with the honorable gentleman or
myself, to accomplish as much to make our names known to
advantage, and remembered with gratitude, as Mr. Dane has
accomplished. But the truth is, sir, I suspect that Mr. Dane lives a
little too far north. He is of Massachusetts, and too near the north
star to be reached by the honorable gentleman’s telescope. If his
sphere had happened to range south of Mason and Dixon’s line, he
might, probably, have come within the scope of his vision!
 I spoke, sir, of the ordinance of 1787, which prohibited slavery in
all future times northwest of the Ohio, as a measure of great wisdom
and foresight, and one which had been attended with highly
beneficial and permanent consequences. I suppose that on this point
no two gentlemen in the Senate could entertain different opinions.
But the simple expression of this sentiment has led the gentleman,
not only into a labored defence of slavery in the abstract, and on
principle, but also into a warm accusation against me, as having
attacked the system of slavery now existing in the Southern States.
For all this there was not the slightest foundation in anything said or
intimated by me. I did not utter a single word which any ingenuity
could torture into an attack on the slavery of the South. I said only
that it was highly wise and useful in legislating for the northwestern
country, while it was yet a wilderness, to prohibit the introduction of
slaves; and added, that I presumed, in the neighboring state of
Kentucky, there was no reflecting and intelligent gentleman who
would doubt that, if the same prohibition had been extended, at the
same early period, over that commonwealth, her strength and
population would, at this day, have been far greater than they are. If
these opinions be thought doubtful, they are, nevertheless, I trust,
neither extraordinary nor disrespectful. They attack nobody and
menace nobody. And yet, sir, the gentleman’s optics have discovered,
even in the mere expression of this sentiment, what he calls the very
spirit of the Missouri question! He represents me as making an
attack on the whole south, and manifesting a spirit which would
interfere with and disturb their domestic condition. Sir, this injustice
no otherwise surprises me than as it is done here, and done without
the slightest pretence of ground for it. I say it only surprises me as
being done here; for I know full well that it is and has been the
settled policy of some persons in the south, for years, to represent
the people of the north as disposed to interfere with them in their
own exclusive and peculiar concerns. This is a delicate and sensitive
point in southern feeling; and of late years it has always been
touched, and generally with effect, whenever the object has been to
unite the whole south against northern men or northern measures.
This feeling, always carefully kept alive, and maintained at too
intense a heat to admit discrimination or reflection, is a lever of great
power in our political machine. It moves vast bodies, and gives to
them one and the same direction. But the feeling is without adequate
cause, and the suspicion which exists wholly groundless. There is
not, and never has been, a disposition in the north to interfere with
these interests of the south. Such interference has never been
supposed to be within the power of the government, nor has it been
in any way attempted. It has always been regarded as a matter of
domestic policy, left with the states themselves, and with which the
federal government had nothing to do. Certainly, sir, I am, and ever
had been, of that opinion. The gentleman, indeed, argues that slavery
in the abstract is no evil. Most assuredly I need not say I differ with
him altogether and most widely on that point. I regard domestic
slavery as one of the greatest evils, both moral and political. But,
though it be a malady, and whether it be curable, and if so, by what
means; or, on the other hand, whether it be the culnus immedicabile
of the social system, I leave it to those whose right and duty it is to
inquire and to decide. And this I believe, sir, is, and uniformly has
been, the sentiment of the north. Let us look a little at the history of
this matter.
When the present constitution was submitted for the ratification of
the people, there were those who imagined that the powers of the
government which it proposed to establish might, perhaps, in some
possible mode, be exerted in measures tending to the abolition of
slavery. This suggestion would, of course, attract much attention in
the southern conventions. In that of Virginia, Governor Randolph
said:—
“I hope there is none here, who, considering the subject in the
calm light of philosophy, will make an objection dishonorable to
Virginia—that, at the moment they are securing the rights of their
citizens, an objection is started, that there is a spark of hope that
those unfortunate men now held in bondage may, by the operation of
the general government, be made free.”
At the very first Congress, petitions on the subject were presented,
if I mistake not, from different states. The Pennsylvania Society for
promoting the Abolition of Slavery, took a lead, and laid before
Congress a memorial, praying Congress to promote the abolition by
such powers as it possessed. This memorial was referred, in the
House of Representatives, to a select committee, consisting of Mr.
Foster, of New Hampshire, Mr. Gerry, of Massachusetts, Mr.
Huntington, of Connecticut, Mr. Lawrence, of New York, Mr.
Dickinson, of New Jersey, Mr. Hartley, of Pennsylvania, and Mr.
Parker, of Virginia; all of them, sir, as you will observe, northern
men, but the last. This committee made a report, which was
committed to a committee of the whole house, and there considered
and discussed on several days; and being amended, although in no
material respect, it was made to express three distinct propositions
on the subjects of slavery and the slave trade. First, in the words of
the constitution, that Congress could not, prior to the year 1808,
prohibit the migration or importation of such persons as any of the
states then existing should think proper to admit. Second, that
Congress had authority to restrain the citizens of the United States
from carrying on the African slave trade for the purpose of supplying
foreign countries. On this proposition, our early laws against those
who engage in that traffic are founded. The third proposition, and
that which bears on the present question, was expressed in the
following terms:—
“Resolved, That Congress have no authority to interfere in the emancipation of
slaves, or of the treatment of them in any of the states; it remaining with the
several states alone to provide rules and regulations therein, which humanity and
true policy may require.”
This resolution received the sanction of the House of
Representatives so early as March, 1790. And, now, sir, the
honorable member will allow me to remind him, that not only were
the select committee who reported the resolution, with a single
exception, all northern men, but also that of the members then
composing the House of Representatives, a large majority, I believe
nearly two-thirds, were northern men also.
The house agreed to insert these resolutions in its journal; and,
from that day to this, it has never been maintained or contended that
Congress had any authority to regulate or interfere with the
condition of slaves in the several states. No northern gentleman, to
my knowledge, has moved any such question in either house of
Congress.
The fears of the south, whatever fears they might have entertained,
were allayed and quieted by this early decision; and so remained, till
they were excited afresh, without cause, but for collateral and
indirect purposes. When it became necessary, or was thought so, by
some political persons, to find an unvarying ground for the exclusion
of northern men from confidence and from lead in the affairs of the
republic, then, and not till then, the cry was raised, and the feeling
industriously excited, that the influence of northern men in the
public councils would endanger the relation of master and slave. For
myself, I claim no other merit, than that this gross and enormous
injustice towards the whole north has not wrought upon me to
change my opinions, or my political conduct. I hope I am above
violating my principles, even under the smart of injury and false
imputations. Unjust suspicions and undeserved reproach, whatever
pain I may experience from them, will not induce me, I trust,
nevertheless, to overstep the limits of constitutional duty, or to
encroach on the rights of others. The domestic slavery of the south I
leave where I find it—in the hands of their own governments. It is
their affair, not mine. Nor do I complain of the peculiar effect which
the magnitude of that population has had in the distribution of
power under this federal government. We know, sir, that the
representation of the states in the other house is not equal. We know
that great advantage, in that respect, is enjoyed by the slaveholding
states; and we know, too, that the intended equivalent for that
advantage—that is to say, the imposition of direct taxes in the same
ratio—has become merely nominal; the habit of the government
being almost invariably to collect its revenues from other sources,
and in other modes. Nevertheless, I do not complain; nor would I
countenance any movement to alter this arrangement of
representation. It is the original bargain, the compact—let it stand;
let the advantage of it be fully enjoyed. The Union itself is too full of
benefit to be hazarded in propositions for changing its original basis.
I go for the constitution as it is, and for the Union as it is. But I am
resolved not to submit, in silence, to accusations, either against
myself individually, or against the north, wholly unfounded and
unjust—accusations which impute to us a disposition to evade the
constitutional compact, and to extend the power of the government
over the internal laws and domestic condition of the states. All such
accusations, wherever and whenever made, all insinuations of the
existence of any such purposes, I know and feel to be groundless and
injurious. And we must confide in southern gentlemen themselves;
we must trust to those whose integrity of heart and magnanimity of
feeling will lead them to a desire to maintain and disseminate truth,
and who possess the means of its diffusion with the southern public;
we must leave it to them to disabuse that public of its prejudices. But,
in the mean time, for my own part, I shall continue to act justly,
whether those towards whom justice is exercised receive it with
candor or with contumely.
Having had occasion to recur to the ordinance of 1787, in order to
defend myself against the inferences which the honorable member
has chosen to draw from my former observations on that subject, I
am not willing now entirely to take leave of it without another
remark. It need hardly be said, that that paper expresses just
sentiments on the great subject of civil and religious liberty. Such
sentiments were common, and abound in all our state papers of that
day. But this ordinance did that which was not so common, and
which is not, even now, universal; that is, it set forth and declared, as
a high and binding duty of government itself, to encourage schools
and advance the means of education; on the plain reason that
religion, morality and knowledge are necessary to good government,
and to the happiness of mankind. One observation further. The
important provision incorporated into the constitution of the United
States, and several of those of the states, and recently, as we have
seen, adopted into the reformed constitution of Virginia, restraining
legislative power, in questions of private right, and from impairing
the obligation of contracts, is first introduced and established, as far
as I am informed, as matter of express written constitutional law, in
this ordinance of 1787. And I must add, also, in regard to the author
of the ordinance, who has not had the happiness to attract the
gentleman’s notice heretofore, nor to avoid his sarcasm now, that he
was chairman of that select committee of the old Congress, whose
report first expressed the strong sense of that body, that the old
confederation was not adequate to the exigencies of the country, and
recommending to the states to send delegates to the convention
which formed the present constitution.
An attempt has been made to transfer from the north to the south
the honor of this exclusion of slavery from the Northwestern
territory. The journal, without argument or comment, refutes such
attempt. The session of Virginia was made March, 1784. On the 19th
of April following, a committee, consisting of Messrs. Jefferson,
Chase and Howell, reported a plan for a temporary government of
the territory, in which was this article: “That after the year 1800,
there should be neither slavery nor involuntary servitude in any of
the said states, otherwise than in punishment of crimes, whereof the
party shall have been convicted.” Mr. Speight, of North Carolina,
moved to strike out this paragraph. The question was put according
to the form then practiced: “Shall, these words stand, as part of the
plan?” &c. New Hampshire, Massachusetts, Rhode Island,
Connecticut, New York, New Jersey and Pennsylvania—seven states
—voted in the affirmative; Maryland, Virginia and South Carolina, in
the negative. North Carolina was divided. As the consent of nine
states was necessary, the words could not stand, and were struck out
accordingly. Mr. Jefferson voted for the clause, but was overruled by
his colleagues.
In March of the next year (1785) Mr. King, of Massachusetts,
seconded by Mr. Ellery, of Rhode Island, proposed the formerly
rejected article, with this addition: “And that this regulation shall be
an article of compact, and remain a fundamental principle of the
constitution between the thirteen original states and each of the
states described in the resolve,” &c. On this clause, which provided
the adequate and thorough security, the eight Northern States, at
that time, voted affirmatively, and the four Southern States
negatively. The votes of nine states were not yet obtained, and thus
the provision was again rejected by the Southern States. The
perseverance of the north held out, and two years afterwards the
object was attained. It is no derogation from the credit, whatever that
may be, of drawing the ordinance, that its principles had before been
prepared and discussed, in the form of resolutions. If one should
reason in that way, what would become of the distinguished honor of
the author of the declaration of Independence? There is not a
sentiment in that paper which had not been voted and resolved in
the assemblies, and other popular bodies in the country, over and
over again.
But the honorable member has now found out that this gentleman,
Mr. Dane, was a member of the Hartford Convention. However
uninformed the honorable member may be of characters and
occurrences at the north, it would seem that he has at his elbows, on
this occasion, some highminded and lofty spirit, some magnanimous
and true-hearted monitor, possessing the means of local knowledge,
and ready to supply the honorable member with every thing, down