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 Understanding
Radiation Biology
From DNA Damage to Cancer
and Radiation Risk
 Understanding
Radiation Biology
From DNA Damage to Cancer
and Radiation Risk

K. H. Chadwick
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742

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Library of Congress Cataloging-in-Publication Data

Names: Chadwick, K. H. (Kenneth Helme), 1937- author.

Title: Understanding radiation biology : from DNA damage to cancer and radiation
risk / by Kenneth Chadwick.
Description: Boca Raton: CRC Press, [2020] | Includes bibliographical references and index.
Identifiers: LCCN 2019031202 (print) | LCCN 2019031203 (ebook) | ISBN 9780367253769
(paperback) | ISBN 9780367255152 (hardback) | ISBN 9780429288197 (ebook)
Subjects: LCSH: Radiobiology.
Classification: LCC QH543.5 .C44 2020 (print) | LCC QH543.5 (ebook) | DDC 571.4/5--dc23
LC record available at https://lccn.loc.gov/2019031202
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Visit the Taylor & Francis Web site at

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To my wife, Hilary, my daughters, Carolyn and Victoria,
and my Bichon Frisé, Bonnie
Contents
Prologue.....................................................................................................................xi
Acknowledgements................................................................................................... xv

PART I Ionising Radiation Effects

Chapter 1 The Molecular Model and DNA Double Strand Breaks.......................3

1.1 The Molecular Model Hypothesis –
The Basic Concepts....................................................................3
1.2 The Induction of DNA Double Strand Breaks...........................4
1.3 The Linear–Quadratic Function and DNA Double Strand
Breaks.........................................................................................5
1.4 The Alpha Mode of Double Strand Break Induction.................6
1.5 The Beta Mode of Double Strand Break Induction....................8
1.6 The Influence of Repair............................................................ 10
1.6.1 Single Strand Break Repair......................................... 10
1.6.2 Double Strand Break Repair....................................... 11
1.7 The Experimental Evidence for the Linear–Quadratic
Dose Response of Radiation-Induced DNA Double
Strand Breaks........................................................................... 12
1.8 Inferences, Implications and Insights....................................... 16
1.8.1 The Alpha Mode of Radiation Action......................... 18
1.8.2 The Beta Mode of Radiation Action........................... 19
1.9 Conclusions...............................................................................20

Chapter 2 The Molecular Model for Cellular Effects.......................................... 21

2.1 The Relationship of Double Strand Breaks to Cellular
Effects....................................................................................... 21
2.2 Cell Survival............................................................................. 21
2.3 Chromosomal Aberrations....................................................... 23
2.4 Mutation Frequency..................................................................24
2.5 The Linear–Quadratic Equation and Data Analysis................26
2.5.1 Survival of Synchronous Cells....................................26
2.5.2 The Influence of Different Exposure Conditions
on the Linear and Quadratic Coefficients................... 31
2.6 The Micro-Dosimetry Problem................................................34
2.7 Conclusions............................................................................... 38

vii
viii Contents

Chapter 3 The Link from Molecular Lesion to Cellular Effects......................... 41

3.1 The Correlations between DNA Double Strand Breaks
and Cellular Effects.................................................................. 41
3.2 The Correlation between DNA Double Strand Breaks
and Cell Survival...................................................................... 42
3.3 The Correlation between Chromosomal Aberration Yield
and Cell Survival...................................................................... 51
3.4 The Correlation between Mutation Frequency and
Cell Survival............................................................................. 54
3.5 An Implied Correlation............................................................ 61
3.6 Conclusions............................................................................... 63

Chapter 4 DNA Double Strand Breaks and Chromosomal Aberrations............. 65

4.1 Introduction.............................................................................. 65
4.2 Recombination Repair of DNA Double Strand
Breaks.......................................................................................66
4.3 Repair of DNA Double Strand Breaks and the
Formation of Chromosomal Aberrations................................. 68
4.4 Strong Supporting Evidence..................................................... 76
4.5 Complex Rearrangements........................................................ 78
4.6 Additional Comments............................................................... 79
4.6.1 Other Aberration Formation Theories........................ 79
4.6.2 Repetitive DNA........................................................... 79
4.6.3 Non-Homologous End Joining and Micro-
Homology-Enabled Recombination Repair................80
4.7 Telomere to Break Rejoining ................................................... 81
4.8 Mutations.................................................................................. 82
4.9 Conclusions............................................................................... 83

Chapter 5 The Effect of Dose Rate, Fractionation and Post-Irradiation Repair....... 85

5.1 Introduction.............................................................................. 85
5.2 The Repair of DNA Single Strand Breaks and the Dose
Rate Effect................................................................................ 85
5.2.1 Three Exposure Time Regions.................................... 87
5.3 Experimental Measurements of the Dose Rate Effect.............90
5.3.1 Cell Survival................................................................ 91
5.3.2 Chromosome Aberrations........................................... 93
5.3.3 Mutation Frequency....................................................94
5.4 The Effect of Dose Fractionation.............................................97
5.4.1 The Influence of Post-Irradiation Repair.................. 102
5.4.2 The Repair of DNA Single Strand Breaks
between Fractions...................................................... 102
5.4.3 Further Analytical Possibilities................................. 103
5.4.4 Other Published Data................................................ 104
Contents ix

5.5 The Effect of Post-Irradiation Repair..................................... 107

5.5.1 Cell Survival.............................................................. 107
5.5.2 Chromosome Aberrations......................................... 108
5.5.3 Mutation Frequency.................................................. 109
5.6 Conclusions............................................................................. 111

Chapter 6 Radiation Quality.............................................................................. 113

6.1 Introduction............................................................................ 113
6.2 Relative Biological Effectiveness........................................... 115
6.3 A Qualitative Appreciation of the Effect of Radiation
Quality.................................................................................... 117
6.4 A Quantitative Appreciation of the Effect of Radiation
Quality.................................................................................... 121
6.5 The Biological Effectiveness of Sparsely
Ionising Radiations................................................................. 130
6.6 Conclusions............................................................................. 132

Chapter 7 Radiation-Induced Cancer................................................................. 133

7.1 Stochastic Effect..................................................................... 133
7.2 Experimental Data.................................................................. 136
7.3 Dose Rate............................................................................... 140
7.4 Human Data............................................................................ 142
7.5 Cancer in Children and Young Adults................................... 146
7.5.1 Childhood Cancers.................................................... 147
7.5.2 Cancer in Young Adults............................................ 148
7.6 Conclusions............................................................................. 149

Chapter 8 Radiation-Induced Lethality............................................................. 151

8.1 Radiation-Induced Lethality.................................................. 151
8.2 The Effect of Dose Rate......................................................... 154
8.3 The Effect of Radiation Quality............................................. 157
8.4 Conclusions............................................................................. 159

Chapter 9 Radiological Protection..................................................................... 161

9.1 Introduction............................................................................ 161
9.2 Linear No-Threshold Concept................................................ 161
9.3 The Dose and Dose Rate Effectiveness Factor....................... 164
9.4 The Weighting Factor of Sparsely Ionising Radiation and
Dose Equivalent...................................................................... 165
9.5 A Potential Way Forward....................................................... 167
9.6 Insights into Radiological Protection Risk from Cancer
Modelling............................................................................... 168
x Contents

9.6.1 Short-Term Exposure ................................................ 170

9.6.2 Long-Term Exposure................................................. 173
9.7 Hereditary Effects.................................................................. 177
9.8 Conclusions............................................................................. 178

PART II Ultraviolet Light Effects

Chapter 10 The Molecular Model and the Cytotoxic Action of UV Light.......... 181
10.1 The Spectrum of Ultraviolet Light......................................... 181
10.2 The Cell-Killing Effect of UVA Light .................................. 182
10.3 The Molecular Model for the Action of UVB and UVC
Light....................................................................................... 186
10.4 A Quantitative Approach to the Effects of UVB and
UVC Exposure........................................................................ 187
10.5 Conclusions............................................................................. 192

PART III Genotoxicology

Chapter 11 An Assessment of the Risk of Chemical Mutagens.......................... 195

11.1 Synergism between Radiation and Chemical Agents............ 195
11.2 The Extension of the Radiation Model to Quantify
Chemical Mutagen Cytotoxicity............................................ 198
11.2.1 The Calculation of Double Strand Lesions
Proportional to Exposure.......................................... 199
11.2.2 The Calculation of Double Strand Lesions from
Pairs of Single Strand Lesions..................................200
11.2.3 Cytotoxicity............................................................... 201
11.2.4 Mutation Frequency.................................................. 201
11.2.5 Exposure to a Chemical............................................ 201
11.3 The Analysis of the Cytotoxicity of Chemical Mutagens......202
11.3.1 DNA Cross-Linking Agents......................................202
11.3.2 Mono-Functional Chemical Agents..........................204
11.4 Risk Classification.................................................................. 210
11.5 Conclusions............................................................................. 212

Epilogue................................................................................................................. 213
References.............................................................................................................. 217
Index....................................................................................................................... 233
Prologue
The aim of this book is to present a coherent, qualitative and quantitative theory of
radiation biology which has been developed and expanded over the years from the
1970s to present day. Many readers of the wide variety of separate scientific articles,
published as part of this development, will probably not realise that a comprehensive
theoretical model lies behind them, which provides in-depth understanding of radiation
biology. Consequently, I felt that it would be a useful exercise to bring together all the
current concepts and ideas arising from this model in one place, this new book.
In 1971, my colleague, Dr H. P. Leenhouts, and I were examining cell survival
curves to see if we could find any mathematical consistency in them and noticed that,
when we plotted the logarithm of survival against the square of the radiation dose,
the data invariably lay on a straight line which crossed the zero dose axis, just under
the origin of 100% cell survival (see Figure P.1).
We soon realised that a linear–quadratic dose–effect equation of the type:

( (
S = exp - p aD + bD2 ))
where (S) is cell survival, (D) is radiation dose and (a) and (b) are coefficients that
can be determined by fitting the equation to the data, provided, to our rather inex-
perienced eyes, a very good description of a large number of cell survival data pub-
lished by others in the scientific literature (see Figure P.2 for an example).
We later discovered that, in 1966, Sinclair (1966) had found, by using a computer
to fit a selection of different mathematical functions to his cell survival data, that
the linear–quadratic equation gave the optimum fit. To the best of our knowledge,
Sinclair did not follow up on this work.
Our further analysis of published data revealed that the coefficient (a) depended
strongly on radiation quality, increasing for more densely ionising radiation, and that
the coefficient (b) depended on radiation dose rate, decreasing as the exposure was
protracted. There was a good consistency in the analyses we made and the equation
offered interesting perspectives.
We then ran into a quandary. What was the basis for the linear–quadratic equa-
tion? One of us (KHC) had had some training in radiation biology and was aware
that the Classical Theory of chromosome aberration formation proposed a linear–
quadratic equation to describe the dose–effect curves of aberration yield and we
therefore spent some time debating the question, ‘Is it simply chromosome aber-
rations that give cell inactivation?’ We found ourselves going round in a circle, not
getting any further. Fortunately, the other one of us (HPL) came from the field of
nuclear physics and was not instilled with radiation biology concepts. He was able to
think outside the circle and, after considerable discussion, we concluded that, from a
purely hypothetical point of view, the double stranded nature of the DNA molecule
in the nucleus of the cell would provide a logical target and that radiation-induced
double strand breaks in the DNA could, potentially, have a linear–quadratic dose–
effect relationship.

xi
xii Prologue

FIGURE P.1 Cell survival data plotted against the square of the radiation dose. The inset
shows the detail close to 100% cell survival and the straight line crossing zero dose at 72%
cell survival.

It was only when we turned away from the Classical Theory of chromosome
aberration formation to assume that radiation-induced DNA double strand breaks
might be induced in proportion with the dose and with the dose squared and, thus, be
responsible for cell inactivation, that we were able to move forward. A whole panoply
of radiation biological phenomena which had puzzled us suddenly started to find
logical explanations and one revelation led to another. Each conclusion conjured up
a new proposition and different cellular endpoints could be traced to the same type
of lesion, correlations were predicted and found. We started to see through the mist
and gradually developed an insight into radiation biological action.
Our assumption was not, of course, without its problems. In proposing that DNA
double strand breaks were the critical radiation-induced lesion, we tied ourselves to
what was known about the DNA and double strand breaks in the cell in 1971, which
was not a great deal, and we also tied ourselves to what would be discovered about
DNA and double strand breaks from 1971 onwards.
In 1971, we were complete novices in the interpretation of radiobiological data
but, as we developed the double strand break model, we rapidly found that a clear and
novel vista was opening and our insights, while in contradiction with conventional
dogma, offered interesting perspectives. It was as if a jigsaw puzzle was being put
together bit by bit to create a complete picture and, within ten years, we had written
a book outlining the earlier part of our work (Chadwick and Leenhouts, 1981).
Prologue xiii

FIGURE P.2 The same cell survival data as shown in Figure P.1 plotted against the radia-
tion dose. The inset shows the detail close to 100% cell survival and the line is given by the
linear–quadratic equation: S = exp(-(0.12D + 0.029D2 )) .

In spite of the 1981 book, the various bits which make up the complete jigsaw
puzzle are scattered in scientific publications that are not always easily accessible
and, in any case, many post-date the 1981 book. In addition, some proposals pre-
sented in that book, such as one on the formation of chromosome aberrations and
another on radiation-induced cancer, have been superseded and we have refined and
redefined them.
The main thrust of our work has been concerned with the development of a
straightforward but flexible model to provide a comprehensive and coherent, quanti-
tative description of radiation effects. The severity of the radiation biological effect
depends on many factors which embrace the physics of energy deposition, the chem-
istry of sensitising and protective cellular environments, free radical chemistry, the
biochemistry and genetics of DNA repair, and the structure and behaviour of the
DNA target molecule in the cell cycle. In view of this, it is unlikely that any theoreti-
cal model will provide a complete explanation of all the different aspects of radia-
tion biology. However, the model we have derived does take account of the physical,
chemical and biological parameters which influence the subsequent radiation effect.
It develops a mathematical description of dose–effect relationships which can be
used to analyse and interpret experimental data, provides links between different
cellular endpoints and has predictive qualities relevant for radiological protection.
The quantitative cellular model lends itself to application in an established model of
cancer induction and has been used to interpret radiation-induced cancer in animals
xiv Prologue

and man with illuminating predictions for radiation risks. Finally, the model has
been expanded to consider the effects of ultraviolet radiation and genotoxic chemi-
cals. In all these different areas, the model gives deep insight into the basic action of
radiation at the cellular level as well as offering important predictions on genotoxic
cancer risk.
This book reviews most of our relevant publications and sets them in the broader
scope of modelling the action of all genotoxic agents. It presents some unpublished
data and analyses, and it outlines, in more detail than has been possible in individual
publications, a myriad of thoughts and considerations that the development of the
model stimulated.
Since the 1980s, the linear–quadratic equation has been widely used, both in
radiobiology and in the radiotherapy field, to analyse radiation dose effect data as
it invariably gives a good fit (Brenner 2008; Astrahan 2008; McKenna and Ahmad
2011; Franken et al. 2013; Santiago et al. 2016; Van Leeuwen et al. 2018). Although
there are several different approaches to the derivation of the equation (Lea and
Catcheside 1942; Kellerer and Rossi 1972, 1978; Chadwick and Leenhouts 1973a,
1981; Herr et al. 2015; Bodgi and Foray 2016; Bodgi et al. 2016), the analyses have
often been made without much reference to the differing interpretations offered by
the different derivations. This is unfortunate, as it is the combination of the data
analysis with a mechanistic interpretation which provides insight. I hope that this
book will lead the reader to consider the analytical application of the linear–qua-
dratic equation in terms of the molecular lesion, the DNA double strand break, pro-
posed here as the crucial lesion which leads to the wide variety of radiobiological
effects and discover an insight into, and an understanding of, the biological action
of radiation.
Acknowledgements
I wish to record the immense satisfaction that I have experienced in the friendly
but very professional interaction with all the staff at CRC Press/Taylor & Francis,
especially Kirsten Barr and Rebecca Davies, and all at Deanta Global, especially
Conor Fagan. Without their help, expertise and advice during the preparation of this
book, it would not have been possible to bring it to completion. It has been a plea-
sure to work with them. Much of the research presented here was supported by the
Euratom Radiation Research Programme of the European Commission and the Dutch
Ministries of Agriculture and of Public Health and the Environment.

K. H. Chadwick
Kendal, United Kingdom

xv
Part I
Ionising Radiation Effects
 1 The Molecular Model
and DNA Double
Strand Breaks
A detailed, parameterised linear–quadratic dose–effect equation for the induction of
DNA double strand breaks by ionising radiation is derived based on the known struc-
ture and properties of the DNA molecule in eukaryotic cells. Experimental mea-
surements of the dose–effect relationships for the induction of DNA double strand
breaks are presented, in support of the linear–quadratic dose–effect equation. The
inferences, implications and insights for radiation action which can be drawn from a
consideration of the detailed linear–quadratic equations are elaborated.

1.1 THE MOLECULAR MODEL HYPOTHESIS –

THE BASIC CONCEPTS
The molecular model used to provide a qualitative and quantitative description of
ionising radiation effects in cells is based on just two postulates:

1. The DNA double strand break is the crucial cellular lesion which may lead
to cell inactivation, chromosomal aberrations and mutations.
2. The dose–effect relationship for the induction of DNA double strand breaks
is linear–quadratic.
Everything else derives directly from these two postulates as straight-
forward consequences which depend on the structure and properties of the
DNA molecule, on the chemical surroundings of the DNA, and on the track
structure and properties of the different radiations.
A third postulate is:
3. The radiation effects induced in cells lead to the various radiation-induced
health effects.

The first postulate, that the double strand break is a critical lesion for a cell, is not con-
tentious and is generally accepted, but there are two major objections to the model.
One, which can be called the ‘micro-dosimetry problem’, concerns the probability
that two independently induced DNA single strand breaks will be close enough to
create a double strand break at radiation doses relevant for the biological effects. The
other objection, which can be called the ‘cytological problem’, concerns the produc-
tion of chromosome exchange aberrations from a single DNA double strand break.

3
4 Understanding Radiation Biology

These two objections will be addressed at the appropriate stages as the development
of the model is expanded through the book.
In this first chapter, a detailed, parameterised linear–quadratic dose–effect equa-
tion for the induction of DNA double strand breaks by ionising radiation is derived
using the known structure and properties of the DNA molecule in eukaryotic cells.
Experimental measurements of the dose–effect relationships for the induction of
DNA double strand breaks are presented confirming the linear–quadratic dose–
effect equation. The equation is then used in Chapter 2 to develop dose–effect rela-
tionships linking the number of double strand breaks to three cellular effects: cell
death, the yield of chromosomal aberrations and mutation frequency.

1.2 THE INDUCTION OF DNA DOUBLE STRAND BREAKS

There are good reasons for choosing deoxyribonucleic acid (DNA) as the impor-
tant target for radiation effects. DNA is common to all living cells and provides the
universal genetic code. It has a high molecular weight and forms the backbone of
the chromosomes which are contained in the nucleus of the cell. The DNA in a cell
controls the internal working and defines the specific activity of the cell in an organ-
ism. Any disruption of the mechanical or genetic integrity of the DNA molecule will
clearly have serious consequences for the continued normal function of a cell.
The DNA molecule has a well-defined three-dimensional structure originally
determined by Watson and Crick in 1953 (Watson and Crick 1953). Two long poly-
mer chains of alternating sugar and phosphate units are wound around each other in
the form of a double helix. The two sugar-phosphate polymer chains are linked at
each sugar unit by one of two purine–pyrimidine pairs of nucleotide bases, adenine–
thymine pairs (A–T) and guanine–cytosine pairs (G–C), and, because the dimension
of the A–T pair is the same as the dimension of the G–C pair, the two sugar-phos-
phate chains are held parallel to each other, separated by 1.2 nm, so that the structure
resembles a long, twisted, lightly coiled, rope ladder on a molecular scale. The two
sugar-phosphate strands are wound round each other to make one full turn every
3.4 nm in a right-handed spiral, which in turn is wound around a central axis so that a
major groove and a minor groove are formed. Each complete unit of base plus sugar
plus phosphate is called a nucleotide so that each strand of the DNA is a polynucleo-
tide chain. The nucleotide purine–pyrimidine pairing occurs every 0.34 nm along
the sugar-phosphate chain so that there are ten links holding the chain together for
every full turn of the spiral. The sequence of the purine (A, G) and pyrimidine (C, T)
bases along the chain forms the basis of the genetic code. The result, illustrated
in Figure 1.1, is a very long, thin molecule reaching up to 50 mm in length with a
diameter of 2 nm.
In addition to providing the basis of the genetic code, the complementary base
pairing makes it possible for the DNA molecule to replicate itself correctly dur-
ing the DNA synthesis (S) phase of the cell cycle. In DNA synthesis, the two ‘old’
strands of DNA loosen and replication starts at many replication origins, proceed-
ing in both directions along the DNA (Benbow et al. 1985; Linskens and Huberman
1990; Douglas et al. 2018). The ‘old’ strands are copied to make two ‘new’ strands
with complementary base pairing so that the two new double helices are exact copies
The Molecular Model and DNA Double Strand Breaks 5

FIGURE 1.1 A schematic representation of the DNA double helix molecule.

of the original double helix and each of the two helices has one ‘old’ strand and one
‘new’ strand (see Figure 1.2). At mitosis, the two new DNA double helices separate
into two daughter cells, each of which carries the same genetic information from the
original cell.

1.3 THE LINEAR–QUADRATIC FUNCTION AND

DNA DOUBLE STRAND BREAKS
It is not difficult to understand how a linear–quadratic dose–effect relationship for
the induction of double strand breaks, which obviously disrupt the integrity of the
DNA double helix molecule, can be derived from the interaction of radiation tracks
with the molecular structure presented in Figure 1.1. A double strand break can be
induced as a consequence of one ionising radiation track breaking both strands of the
DNA double helix, giving a yield of breaks in proportion with radiation dose (αD). A
DNA double strand break can, at least hypothetically, also result as a consequence of
the close spatial proximity of two independently induced single strand breaks, giving
6 Understanding Radiation Biology

FIGURE 1.2 A schematic diagram of the process of the replication of DNA.

a yield of double strand breaks in proportion with the square of the radiation dose
(βD2), as is illustrated in Figure 1.3.
In accordance with these two modes of radiation action, the average number (N)
of DNA double strand breaks per cell induced by a dose (D) of radiation is, in gen-
eral, given by the equation:

N = αD + βD2 . (1.1)

Figure 1.4 presents the number (N) of double strand breaks as a function of dose (D)
according to the linear–quadratic Equation 1.1, broken down into its two components
to show that the (α) coefficient represents the initial linear slope of the curve from
zero dose, and the (β) coefficient accounts for the upwards bending of the curve.
Knowledge of the structure of the DNA double helix and its properties in the cell,
as well as knowledge of the structure of ionising radiation tracks permits us, but also
obliges us, to define the (α) and (β) coefficients in considerable detail by including
parameters to cover all the different processes which can be logically considered to
be involved in the induction of strand breaks.

1.4 THE ALPHA MODE OF DOUBLE STRAND BREAK INDUCTION

A careful consideration of the alpha mode of double strand break induction shown in
Figure 1.3, intuitively leads to a detailed derivation of the (α) coefficient by taking a
series of parameters into account which influence the probability that a DNA double
strand break is induced in the passage of a single ionising particle track.
If

• n is the number of nucleotide base pairs per cell representing the amount
of DNA in the nucleus of the cell which is the target molecule. (In a human
cell, the number of nucleotide base pairs (n) is approximately 3 × 109.)
• μ is the probability per unit dose that an ionising particle passes close to a
nucleotide base. (This parameter is dependent on the flux of particle tracks,
The Molecular Model and DNA Double Strand Breaks 7

FIGURE 1.3 Schematic representation of the hypothetically possible formation of DNA

double strand breaks in two different modes of radiation action.

usually secondary electrons, generated by and dependent on the type of

incident radiation.)
• k is the probability per nucleotide base that, when an ionising particle
passes close to a nucleotide base, an energy deposition occurs which even-
tually leads to a strand break most probably as a result of radical attack.
(This parameter is dependent on the chemical environment around the
DNA and, more specifically, on the radical scavenging in the nucleus of
the cell.)
• Ω is the probability that when the ionising particle passes close to the ‘first’
strand it also passes close to the ‘second’ strand. (This parameter clearly
depends on the spatial energy deposition pattern along the particle track
and, thus, on the type of incident radiation, as well as the particular three-
dimensional structure of the DNA molecule, especially the 1.2 nm distance
between the two sugar-phosphate strands.)

So that

• Ωk represents the probability per ‘first’ strand break that the ‘second’
strand is broken in the passage of the same ionising particle by a second
energy deposition and radical attack. (The implication is that the energy
8 Understanding Radiation Biology

700

600

500
Yield of Double Strand Breaks

400 αD + βD2

300

200
αD

100

0
0 2 4 6 8 10 12
Dose

FIGURE 1.4 The yield of DNA double strand breaks (arbitrary units) as a function of dose
according to Equation 1.1.

depositions have to be close to each strand and that two radicals, one
for each strand break are involved. Prise et al. [1993, 1999] have demon-
strated that the double strand break originates from two radicals.)

Then, the (α0) coefficient can be derived as

a 0 = 2nmkWk (1.2)

where the factor 2 merely indicates that either strand can be ‘first’, and the number
(N1) of DNA double strand breaks induced in the alpha mode of radiation action by
a dose (D) is given by:

N1 = a 0 D = 2nmkWkD. (1.3)

1.5 THE BETA MODE OF DOUBLE STRAND BREAK INDUCTION

A similar consideration of the beta mode of double strand break induction, shown
on the right of Figure 1.3, leads to a detailed derivation of the (β) term by taking a
series of parameters into account. These parameters influence the probability that a
DNA double strand break is induced as a consequence of the close proximity of two
independently induced single strand breaks. The derivation follows from the previ-
ous reasoning, making use of the same parameters.
The Molecular Model and DNA Double Strand Breaks 9

If

• (1 – Ω) is the probability that when the ionising particle passes close to the
‘first’ strand, it does not pass close to the ‘second’ strand

and

• Ω(1 – k) is the probability that when the ionising particle passes close to the
‘first’ strand, it also passes close to the ‘second’ strand but does not give an
energy deposition leading to a break in the ‘second’ strand

then

• (1 – Ω) + Ω (1 – k ) = 1 – Ωk, is the total probability per ‘first’ strand break

that the ‘second’ strand is not broken in the passage of the same ionising
particle.

As

• nμk is the probability per cell per unit dose that a break occurs in the ‘first’ strand,

then

• 2nmk (1 – Wk ) represents the probability per cell per unit dose that a single
strand break occurs in the ‘first’ strand but that it is not accompanied by a
break in the ‘second’ complementary strand in the passage of the same particle.

Again, the factor 2 merely indicates that each strand can be ‘first’.
These ‘first’ single strand breaks can be converted into a double strand break if a
‘second’ single strand break is induced in the complementary strand of the DNA as
a result of an energy deposition event caused by a different ionising particle in the
neighbourhood of the ‘first’ single strand break before it has been repaired.
So, if

• n1 is the number of nucleotide bases opposite the ‘first’ single strand break
within which a ‘second’ break will convert the ‘first’ single strand break to
a double strand break,

then

• n1μ1k1 represents the probability per unit dose per ‘first’ single strand break
that a ‘second’ break is induced in the passage of a separate ionising par-
ticle, and the number (N2) of double strand breaks induced in this mode of
radiation action is given by:

N 2 = b¥ D2 = 2nmk(1 - W k) n1 m1k1 (D2 / 2) (1.4)

10 Understanding Radiation Biology

where the coefficient (β∞ ) is the maximum value of the quadratic coefficient after an
acute exposure when there is no repair of the ‘first’ single strand breaks.
The term (D2/2) arises because, although the number of ‘first’ single strand breaks
is proportional to dose (D), the ‘second’ single strand break can only be made when
the ‘first’ is already present so that, on the average, the probability for the ‘second’
break is proportional to one-half of the dose (D/2).
A distinction has been made between the parameters (μk) involved in the induc-
tion of the ‘first’ breaks and the parameters (μ1k1) involved in the induction of the
‘second’ breaks because it is not certain that the same mechanism (radical species)
is involved in this second mode of radiation action. This point is important as it
impacts on the contentious nature of the quadratic term of the linear–quadratic equa-
tion that has been derived for the induction of DNA double strand breaks.
Consequently, the total number (NT) of DNA double strand breaks induced by a
dose (D) of radiation is given by the sum of Equations 1.3 and 1.4, though it has to be
noted that no account has yet been taken of repair processes:

N T = a 0 D + b¥ D2 = 2nmkWkD + nmk(1 - W k) n1 m1k1D2 . (1.5)

1.6 THE INFLUENCE OF REPAIR

The repair of both DNA single strand breaks and DNA double strand breaks can
influence the number of double strand breaks which are induced and remain biologi-
cally effective. Both repair processes depend on the metabolic activity of the cell,
the cell stage and the time available for repair. The repair of single strand breaks is
efficient and error-free because the nucleotide bases on the undamaged DNA strand
can be used by the repair enzymes to reconstruct the broken strand, according to the
complementary base-pairing rules. The repair of double strand breaks, a process that
was barely hinted at when the model was first derived in the early 1970s (Chadwick
and Leenhouts 1973a), is now thought to be achieved via two main pathways, non-
homologous end joining (NHEJ) and homologous recombination (HR) and, although
both processes may restore the mechanical integrity of the DNA, the genetic integ-
rity of the DNA may not be completely restored. This means that the repair of DNA
double strand breaks cannot be guaranteed to be error-free.

1.6.1 Single Strand Break Repair

Further consideration of the two modes of double strand break induction reveals that
the two energy deposition events from the same particle track in the alpha mode must
occur simultaneously so that there will not be any exposure time–related effects on
this mode of radiation action. However, the two energy deposition events from two
different particle tracks in the beta mode are not necessarily simultaneous. Thus,
when the time between the ‘first’ single strand break and the ‘second’ break is
long enough, the ‘first’ break can be repaired correctly before the ‘second’ break is
induced. This single strand break repair affects the beta mode of double strand break
induction and in a sub-acute exposure can lead to a reduction of the (β) coefficient
although the (α) coefficient is unaffected.
The Molecular Model and DNA Double Strand Breaks 11

If

• f1 is defined as the proportion of ‘first’ single strand breaks which are not
repaired before the ‘second’ break converts it to a double strand break,

then the quadratic term for the number of DNA double strand breaks becomes:

f1N 2 = f1b¥ D2 = f1nmk(1 - W k) n1 m1k1D2 (1.6)

and the number (N0) of initially induced DNA double strand breaks is given by:

N 0 = α 0 D + β0 D2 = 2nµkΩkD + f1nµk(1 − Ω k) n1 µ1k1D2 . (1.7)

The parameter (f1) can have values between 0 (full repair) and 1 (no repair).
It is important to note that, in the model, the ‘second’ single strand break converts
the ‘first’ single strand break to a double strand break at the moment that the ‘second’
break occurs.

1.6.2 Double Strand Break Repair

There is no reason to assume a priori that the processes involved in the repair of
DNA double strand breaks can distinguish between those induced in the alpha mode
or in the beta mode of radiation action and therefore this repair is included as follows:
If

• f0 is the proportion of double strand breaks which are not repaired and
remain biologically effective,

then the number of induced and effective double strand breaks (N) is given by:

(
N = f0 N 0 = ( f0 2nmkWkD ) + f0f1nmk 1 - Wk ) n1 m1k1D2 ) (1.8)

and

N = αD + βD2 . (1.1)

The parameter (f0) may have values between zero and one and depends on the meta-
bolic activity of the cell and on the time between the induction of the double strand
breaks and the moment when they become biologically effective, which is suspected
to be at the first mitosis following exposure. It seems highly unlikely that all the
double strand breaks will be perfectly repaired and that (f0) will be zero. There may
be situations or cell types where none of the double strand breaks are repaired when
(f0) would be one, so in general, (f0) is expected to have a value less than unity.
The repair parameters (f1) and (f0) are assumed to have constant values within
an experiment and be independent of the radiation doses applied. There is some
12 Understanding Radiation Biology

evidence for this as Dugle and Gillespie (1975) have reported that, in Chinese ham-
ster cells, there was no difference in the repair rate constant for DNA single strand
breaks in the dose range from 40 to 400 Gy (Gray is the unit of radiation dose). In
the case of DNA double strand breaks, Corry and Cole (1973) found no change in
repair in Chinese hamster ovary cells up to 500 Gy, and Resnick and Martin (1976)
reported that a similar proportion of breaks were repaired in yeast cells in the dose
range from 250 to 1000 Gy.
Equation 1.8 provides a detailed elaboration of the (α) and (β) coefficients of
Equation 1.1 using information on the DNA helix molecular target, the double strand
break lesion and the track structure of radiation.

1.7 THE EXPERIMENTAL EVIDENCE FOR THE LINEAR–

QUADRATIC DOSE RESPONSE OF RADIATION-
INDUCED DNA DOUBLE STRAND BREAKS
Although the accurate measurement of DNA single strand breaks was well estab-
lished when the model was developed in 1973, the measurement of DNA double
strand breaks at doses relevant for radiation biology was not possible until the 1980s.
The first indication of a quadratic component in the dose–effect for the induction
of DNA double strand breaks was found by Dugle, Gillespie and Chapman (Dugle
et al. 1976) using the measurement of both DNA single strand breaks by alkaline
gradient sedimentation and DNA double strand breaks by neutral gradient sedimen-
tation in quite heavily irradiated cells after incubation for repair. Dugle, Gillespie
and Chapman found that after incubation for repair there were two residual single
strand breaks for every residual double strand break at each dose. They also showed
that both the residual single and double strand breaks were directly related to the
square of the radiation dose. Figure 1.5 presents their strand break data redrawn as
a function of dose in order to emphasize the curvature of the relationship between
DNA double strand breaks and radiation dose. The radiation doses are indeed well
beyond the range which is of interest for cellular radiation biology but the curvature
of the dose response found for the induction of DNA double strand breaks is sig-
nificant and Dugle, Gillespie and Chapman concluded that the coefficient for double
strand breaks, induced by two independent particle events, is large enough to support
the model developed in Sections 1.1 to 1.6.
In 1982, Dikomey (1982) used a similar experimental strategy to that of Dugle
et al. (1976) measuring residual DNA single strand breaks after a one hour repair
period post exposure, assuming that the single strand break measurement was a reli-
able measurement of DNA double strand breaks. Dikomey was able to measure the
DNA double strand breaks in this way at doses which were relevant for cellular
radiation biology and used three different X-ray and hyperthermia treatments of
Chinese hamster ovary (CHO) cells. In all three cases, a linear–quadratic relation-
ship between the number of DNA double strand breaks and X-ray dose was found as
shown in Figure 1.6.
In the mid-1980s, it became possible to measure DNA double strand breaks
directly at radiation doses relevant to cellular radiation biology using neutral gradi-
ent filter elution techniques. In 1985, Radford in Australia, was the first to publish a
Another random document with
no related content on Scribd:
 § 12
George was distressed.
He and Catherine were slowly walking to Bishop’s Stortford
railway station. The Viking expression had left his features; the
motor-cap and goggles and overalls and gloves were tied up in a
brown-paper parcel which he carried under his arm. Also, his face
was very dirty.
Terrible things had happened to him.
A couple of policemen had taken his full name and address, and
made copious entries in notebooks.
Mr. H. Bullock had sworn vividly. In trying to estimate the extent
of damage to his front wheel George had tactlessly turned the full
glare of the acetylene lamp upon the horse’s eye. The horse had
hitherto been uncertain whether the situation justified panic flight or
not; now he decided swiftly in the affirmative. He rushed forward
precipitately, and in less than a dozen yards had smashed off the
wheel of the cart against a pillar-box. The cart sagged despairingly,
and streams of bilious lemonade poured through the flooring. Mr.
Bullock’s language became terrific.
And then one of the policemen had said: “By the way, got your
licence?”
George had blushed (though the fact that he was already a deep
red disguised the phenomenon).
“I’m afraid—I—I must have left it at home,” he stammered weakly,
diving into his inside pocket and fishing amongst letters and papers.
Yet both Catherine and the policeman knew in that moment that
he had not got a licence at all. Something in his voice told them.
And what is more, George knew that both the policeman and
Catherine were aware that he had not got a licence at all. Something
in their eyes told him.
 And then George had wilted under the vivid abuse of Mr. H.
Bullock. Spectators called out monotonously: “You were on the
wrong side of ’im.” “You was goin’ too fast.” “You didn’t orter ’ave
come nippin’ in like thet.” “On the kerb ’e was, a minute before—
don’t know ’ow to drive, ’e don’t.” “Didn’t orter be trusted, them soit of
cheps.” “Swervin’ abart like anythink: shouldn’ be surprised if he’s
drunk.”
And a fierce clergyman in a three-inch collar floored George with
the remark: “You ought to be in jail, my man. You are a pest to
society.”
And then George had to push the battered machine into a garage
(which was fortunately at hand), and pay exorbitantly for leaving it
there. The garage proprietor was subtly sarcastic to George.
Then George came back to parley with the policemen. The crowd
became hostile. George rather unwisely began to divest himself of
his motoring garments. Facetiousness prevailed. Catherine was the
subject of much speculation.
“I wouldn’t trust myself to ’im no more,” remarked a bystander.
And another wanted to know if her mother knew she was out. (It was
in the days of that popular song.)
“’E’s a-tryin’ to murder you, that’s wot ’e is,” said a sour-faced
spectator. “’E’s found another gal, an’ wants ter git rid of you.”
And an elderly man with a bizarre sense of humour said: “You
look out for yerself, my gal; ’e won’t ’ave no money ter marry you on
w’en ’e’s pide ’is fines.”
George caught the sally, and the whole phantasmagoria of the
police-court flashed across his mind. Also the fact that this trip to
Cambridge was likely to leave him with very little, if any money at
all....

§ 13
 And now, on the slope leading up to the railway station, George
was distressed. He was physically and mentally unmanned. He
could not speak without a tremor. He seemed so physically
enfeebled that she took his arm and asked him to lean on her. All at
once she realized the extraordinary fact that of the two she was
infinitely the stronger. With all his self-confidence and arrogance and
aplomb, he was nothing but a pathetic weakling.
The hostility of the crowd had made her vaguely sympathetic with
him. She had watched him being browbeaten by policemen and by
the owner of the cart, and a strange protective instinct surged up in
her. She wanted to stick up for him, to plant herself definitely on his
side. She felt she was bound to champion him in adversity. She
thought: “I’m with him, and I must look after him. He’s my man, and
I’ve got to protect him.”
All the long walk to the station was saturated in this atmosphere
of tense sympathy and anxious protection.
“We shall catch the 10.20,” he said. “There’s heaps of time. We
shall have over an hour to wait.”
“That’ll be all right,” she said comprehensively.
On the station platform they paced up and down many times in
absolute silence. The moon was gorgeously radiant, flinging the
goods yard opposite into blotches of light and shadow. The red
lamps of the signals quavered ineffectually.
“You know it’s awfully lucky you weren’t hurt,” he said at last.
She nodded. Pause.
Then he broke out: “You know, really, I’m most awfully sorry——”
“Oh, don’t bother about that,” she said lightly. “It wasn’t your fault.
You couldn’t help it.”
(Yet she knew it was his fault, and that he could have helped it.
She also knew that he had no licence.)
And then a strange thing happened.
 They were in the shadow of a doorway. He suddenly put his two
arms on her shoulders and kissed her passionately on the lips. Her
hair was blowing behind her like a trail of flame. He kissed her again
with deepening intensity. And then her face, upturned to his, dropped
convulsively forward. Her eyes were closed with a great mist, and
her hair fell over his hands and hid them from view. There was
something terrible in the fierceness with which he bent down and,
because he could not kiss her face, kissed her fire-burnished hair.
And as he did so again and again she began to cry very softly. His
hands could feel the sobs which shook her frame. And he was
thrilled, electrified....
“My God!” he whispered....
... Then with a quick movement she drew back. The tears in her
eyes were shining like pearls, and her face was white—quite white.
Passion was in every limb of her.
“That’s enough,” she said almost curtly, but it was all that she
could trust herself to say. For she was overwhelmed, swept out of
her depth by this sudden tide.
And all the way to Liverpool Street, with George sitting in the
corner opposite to her, her mind and soul were running mad riot....
“Good-bye,” he said later, at the gate of No. 14, Gifford Road,
and from the inflexion of his voice she perceived that their relations
had undergone a subtle change....
She watched him as he disappeared round the corner. On a
sudden impulse she raced after him and caught him up.
“George!” she said.
“Yes?”
“Will you be summoned, d’you think?”
“Oh, certainly.”
“Well—I thought I’d tell you ... if you’re short of money through it
... I’ve got some.... I can lend it to you ... if you’re short, that is....”
 “It’s awfully good of you,” he replied. Yet she knew he was
thinking of something else.... Her running back to him had reopened
the problem of farewell. He was debating: “Shall I kiss her again?”
And she was wondering if he would. In a way she hoped not. There
would be something cold-blooded in it if he did it too frequently. It
would lack the fire, the spontaneity, the glorious impulse of that
moment at Bishop’s Stortford railway station. It would assuredly be
banal after what had happened. She was slightly afraid. She wished
she had not run back to him. Nervousness assailed her.
“Good-night!” she cried, and fled back along Gifford Road.
Behind her she heard his voice echoing her farewell and the sound
of his footsteps beginning along the deserted highway. It was nearly
two a.m....
Undressing in the tiny attic bedroom she discovered a dark bruise
on her right shoulder. It must have been where he lurched sideways
against her just after the collision. She had not felt it. She had not
known anything about it....
 CHAPTER XI
THE SECOND TRANT EPISODE
§1
IT was November.
They had been engaged three months. Three months it was
since a certain winedark evening when, in the shadows of the heavy
trees on the Ridgeway, he had suddenly said:
“I suppose we are engaged?”
“Are we?”
“Well, I think it’ll be all right.... I told my father, and he didn’t
object.... Will you come to tea on Sunday?”
She perceived that their relations had entered on a new phase.
“If you like,” she said.
And he had kissed her good-bye that evening.
The Sunday had been nerve-racking. She felt she was on show.
Many years it was since she had entered the Trants’ house. In those
early days she had come in as Helen’s school friend, and nobody
had taken much notice of her. Mr. Trant had chattered amiable
trivialities and chaffed her about her red hair. Now all was immensely
different. She was George’s fiancée. She had to be treated with
deference. Mr. Trant discussed the weather and gardening and (to
the utmost extent of his capabilities) music. Mrs. Trant was effusively
embarrassed. Helen was rather frigid. After tea they went into the
drawing-room. Catherine and Mrs. Trant sat for some time together
on the couch turning over the pages of a photograph album with
careful enthusiasm. In it were portrayed the Trant family in various
stages of development—the Trant family when it had anybody
distinguished to stay with it for the week-end; the Trant family at the
door of its house, on Llandudno Pier, at Chamounix, on the
promenade deck of a P. and O. liner, and in other less idyllic
positions; the Trant family taking tea on the lawn, picnicking in
Epping Forest, about to set out for a motor spin, skating on the
Connaught Waters at Chingford, playing tennis (a) on its own grass
court, (b) on its own rubble court; the Trant family in fancy dress,
evening dress, riding dress, Alpine dress, and every other kind of
dress—in short, the Trant family in every conceivable phase of its
existence. Also the Trant family individually, collectively, and in
permutations and combinations. With studious politeness Catherine
enquired from time to time as to the identity of the various strangers
who obtruded themselves upon the Trant arena. Here were Sir Miles
Coppull (the American camphor king, holding a tennis-racket
jauntily); the Rev. R. P. Cole (President of the Baptist Association);
the Rev. St. Eves Bruce, M.A., D.D. (headmaster of George’s old
public school), beaming on Helen, by the way; not to mention groups
of fierce old gentlemen whom Mrs. Trant lumped collectively as
“some of Dad’s directors.” ...
Catherine thought: “Some day I shall be amongst all that lot...”
George suggested she should play a piano solo, and she tried a
Beethoven symphony movement. But she was unaccountably
nervous, and a valuable but rather gimcrack china and ivory model
of the Taj Mahal at Agra which was placed on top of the closed
sound-board would rattle whenever she played the chord of E flat or
its inversions.
When she stopped playing Mr. Trant said: “Let me see, is that
Beethoven?” (He pronounced the first syllable to rhyme with “see”
and the second with “grove.”)
“Yes.”
“Charming little thing,” he said vaguely....
Catherine was glad when the advent of chapel time brought the
business to a conclusion. For it was business. She could see that.
She was being sized up. When she had gone they would discuss
her. They were reckoning her up. They were not surprised at her
nervousness. They expected it. They were speculating upon her
possibilities as a daughter-in-law....
There was only one thing perhaps which did not occur to them, or
which, if it did, received less attention than it deserved.
Catherine was reckoning them up. She was keenly critical of
everything they said and did. And when Mr. Trant, shaking hands
with her at the door, said: “You must come again for a musical
evening some time, and give us some more Beethoven,” Catherine
replied:
“Oh yes, I should be delighted. I’m awfully fond of Beethoven,
aren’t you?”
But she pronounced it “Bait-hoaffen.”
There was just the merest possible suggestion of rebuke, of self-
assurance, of superiority in that....

§2
And now all these things were stale by three months.
By this time she had got used to having tea on Sundays at the
Trants’ house. She was so much at home there that she could say:
“Oh, do you mind if I shift this Taj Mahal thing while I play? It rattles
so.” After a little while they learned her fancies, and had it always
removed when she came.
And she was used to George. Everything of him she now knew.
His hopes, his dreams, his peculiarities, his vices and virtues, the
colours of all his neckties—all had been exhaustively explored during
the course of many a hundred hours together. He kissed her now
every time they met—he expended much ingenuity in arranging
times and places suitable for the ritual. Sometimes, after he had
seen her home from the theatre, his kisses were hurried,
stereotyped, perfunctory, as purely a matter of routine as putting two
pennies into the machine and drawing out a tube ticket. On other
occasions, as for instance when they strolled through country lanes
at dusk, she could sense the imminence of his kisses long before
they came. When they turned down Cubitt Lane towards the Forest
at twilight it was tacitly comprehended between them: “We are going
in here to be sentimental....” When they returned the mutual
understanding was: “We have been sentimental. That ought to last
us for some time....”
People deliberately left them alone together. They looked at the
two of them as if they were or ought to be bliss personified. They
seemed to assume that an engaged couple desires every available
moment for love-making. At meal times, for example, it was always
contrived that George should be next to Catherine. Once when Mr.
and Mrs. Trant had made the excuse that they would stroll round the
garden, Catherine, noticing that Helen was about to follow
unobtrusively, said sharply:
“Please don’t go, Helen. I want you to try over a few songs.”
Catherine wondered if Helen understood.
The fact was, being engaged was deadly monotonous. It had no
excitement, no novelty. Everything was known, expected, unravelled.
When she met George at a concert she did not think: “I wonder if he
has come here on my account.” She knew beyond all question that
he had. When at some social function she saw him chatting amongst
his male friends she did not think: “Will he come up and speak to me
or not?” She knew that his very presence there was probably on her
account, and that he would leave his male friends at the first
available opportunity. And when they had ices at a tiny table in some
retiring alcove it was not possible to think: “How funny we should
both have met like this! How curious that we should be alone here!”
For she knew that the whole thing had been premeditated, that the
alcove itself had probably been left attractively vacant for their
especial benefit. There was no point, no thrill, no expectancy in
asking the question: “Is it really me he comes to all these places
for?”
 He had declared his passion in unequivocal terms that left
nothing to be desired. That was just it: there was nothing left to be
desired. She would rather he had been ambiguous about it. And
occasionally the awful thought came to her: “If this is being engaged,
what must it be like to be married? ...”
Life was so placid, so wearyingly similar day after day, evening
after evening. Every night he met her at the stage-door of the theatre
and escorted her home. Every night he raised his hat and said
“Good evening!” Every night he took her music-case off her, and they
walked arm-in-arm down the High Street. Their conversation was
always either woefully sterile or spuriously brilliant. On the rare
occasions when they had anything particular to talk about they
lingered at the corner of Gifford Road. But she could not confide in
him. To tell him of her dreams and ambitions would be like asking for
a pomegranate and being given a gaudily decorated cabbage. Their
conversations were therefore excessively trivial: she retailed
theatrical and musical gossip, or, if the hour were very late and she
were tired, as frequently happened, she replied in weary
monosyllables to his enquiries. She found her mind becoming
obsessed with hundreds of insignificant facts which by dint of
constant repetition he had impressed upon her. She knew the
names, histories, characters, and family particulars of all the men
who worked with him in the stuffy little basement of the accountant’s
office in Leadenhall Street. She knew the complicated tangle of
rivalries and jealousies that went on there—how Mr. Smallwood did
this and Mr. Teake did that, and how Mr. Mainwaring (pronounced
Mannering) frequently lost his temper. She knew all the minutiae of
George’s daily work and existence, the restaurant he frequented for
lunch, the train he caught on the way home, the men he met day
after day in the restaurant and on the trains. Nothing of him was
there which she did not know....
Yet it was all so terribly, so tragically dull. Even his brilliance
palled. His brilliance was simply an extensive repertoire of smart
sayings culled from the works of Ibsen, Shaw, Chesterton, etc. In
three months she had heard them all. Moreover, he had begun to
repeat some of them.
 Out of a forlorn craving for incident she quarrelled with him from
time to time. His genuine sorrow at the estrangement and his
passionate reconciliation afterwards thrilled her once or twice, but
after a few repetitions became stale like the rest. Undoubtedly he
was in love with her.
And she?

§3
Doubtless one of the reasons why George’s engagement to
Catherine was not opposed very vigorously by the Trants was
Catherine’s startlingly rapid musical development, which seemed to
prophesy a future in which anything might be expected. Ever since
that Conservative Club concert Catherine had been playing regularly
in public and acquiring a considerable local reputation. Occasional
guineas and two guineas came her way, and at the opening of the
winter season she found herself with as many engagements as she
could manage. And at a local musical festival she had come out on
top in the professional pianoforte entries. A gold medal and a good
deal of newspaper prominence were the visible and immediate
results of this. Afterwards came the welcome discovery that she was
in demand. A concert organizer offered her five pounds for a couple
of solos. An enterprising and newly established photographer
photographed her gratis and exhibited a much embellished side view
(with a rather fine hair exhibition) in his window. And she ceased to
play at church socials....
Every Saturday afternoon she went to Verreker for lessons.
Though she disliked him personally, she was compelled to admit the
excellence of his teaching. He spared her no criticism, however
severe, and when he commended her work, which was rare, she
knew he meant it. If a good teacher, he was also an irritating one. He
selected her pieces, insisted on her learning those and no others,
expected from her a good deal more than it seemed possible for her
to give, and treated her generally as a rebellious child. He was
always asking her when she was going to resign her position at the
theatre. She would never be even a moderate pianist as long as she
was there, he said.
The time came when it was of financial benefit to her to resign.
She did so, and expected him to be very pleased with her. But he
merely said:
“H’m! I suppose you waited till it paid you to.”
This was so true that she had no reply ready.
He never disguised from her the fact that, however seemingly
she might be advancing on the road to fame and success, she would
never become more than a second-rate virtuoso.
“The front rank of the second-raters is as high as you’ll ever get,”
he said. But that did not hurt her now.
What did hurt her was once when he said: “You have one
abominable habit. You pose with your hair. I should recommend you
to have it cut off, then you won’t have it to think about so much.”
“Oh, should you?” she replied angrily. “I should be sensible to cut
it off, shouldn’t I, seeing it’s the only good-looking part of me!”
She hadn’t meant to say that. It slipped out.
“Is it?” he said, and for a single fatuous second she had a wild
idea that he was going to pay her a magnificent compliment. But he
added: “I mean—it never struck me as particularly good-looking. But
then I’m no judge of hair—only of music.”
She could discern in every inflection of his voice latent hostility.
There was no doubt he disliked her intensely. Latterly, too, she had
become increasingly conscious of a mysteriously antagonistic
atmosphere when he was with her. It reacted on her playing, causing
her at times to give deplorable exhibitions. It was not nervousness. It
was something in him that was always mutely hostile to something in
her. The sensation, at first interesting, became extraordinarily
irksome after a while. Once, when a poor performance of one of
Chopin’s Ballades had evoked sarcasm and abuse almost beyond
endurance, she suddenly left the music-stool and stood facing him
with her back to the instrument.
 “It’s no good,” she cried vehemently. “It’s not my fault. I’ve never
played as bad as that in my life. It’s you. I can’t play when you’re
present. Don’t know—can’t explain it, but it is so.”
He looked surprised.
“Very strange,” he said reflectively—“and unfortunate.”
She had expected him to be witheringly sarcastic. But he took it
with urbane philosophy.
“Well,” he said, “I suppose if you feel like that it can’t be helped.
We shall simply have to make the best of it.”
Which was irritatingly logical....

§4
In the Trant household the musical evening was an institution.
Rarely a month passed by unhonoured by one of these functions.
Commencing at seven or thereabouts on a Saturday evening, they
lasted till past midnight. They possessed a regular clientele of
attenders, as well as a floating population of outsiders who had
never been before and who (from more reasons, perhaps, than one)
might never come again. The drawing-room at “Highfield” was large,
but it never comfortably held the miscellaneous crowd that
assembled in it on the occasion of these musical evenings. In winter
you were either unbearably hot (near the fire) or unbearably cold
(near the window), and in summer, without exception, you were
always unbearably hot. Moreover, you were so close to your
neighbour on the overcrowded settee that you could see the
perspiration draining into her eyebrows. From a dim vista obscured
by cigarette smoke there came the sound of something or other,
indescribably vague and futile, a drawing-room ballad sung by a
squeaky contralto, a violin solo by Dvořák, or a pompous Beethovian
hum on the piano. However beautiful and forceful might be the
music, it was always vague and futile to you, because you were
watching your neighbour’s eyebrows act as a sponge to the down-
trickling perspiration.... Always in these musical evenings there was
banality. Always beauty was obscured by bathos. And could you
ever forget the gymnastic evolutions of a settleful of musical
enthusiasts balancing cups of steaming hot coffee on their knees? ...
The day before Christmas Day was a Saturday. For Christmas
Eve a musical evening had been arranged—a musical evening that,
out of deference to the season, was to surpass all previous
undertakings of the kind. Catherine was invited, and would, of
course, be one of the principal performers. In virtue of her intimate
relation to George she had come early in the afternoon and stayed to
tea. Her usual weekly lesson from Verreker was cancelled for this
particular week, probably owing to Christmas. So she would be able
to spend the entire evening at “Highfield.” She was in buoyant spirits,
chiefly owing to her rapidly advancing fame as a pianist. She had the
feeling that her presence at the Trants’ musical evening was an act
almost of condescension on her part, and it pleased her that the
Trants treated her as if this were so. She would undoubtedly be, in
music-hall parlance, the star turn of the evening. People, unknown
aspirants after musical fame, would point her out as one who had
already arrived at the sacred portals. She knew also that Mrs. Trant
had been sending round messages to friends that ran more or less
after this style: “You simply must come to our musical evening on
Christmas Eve! It is going to be an awfully big affair, and we have got
Cathie Weston coming down to play—you know, the girl who——”
The whole business tickled Catherine’s vanity.
In the interval between tea and seven o’clock she superintended
the arrangement of the piano in the drawing-room, taking care that
the light from an electric hand-lamp close by should shine
advantageously on her hair while she was playing. She decided that
she would play one of the Chopin Etudes....

§5
At a quarter past seven the room was full. According to custom
visitors introduced themselves to one another, the crowd being
altogether too large for ceremonious introductions. Late-comers
came in quietly and unostentatiously, sitting down where they could
and nodding casually to people they knew. The lighting was
æsthetically dim, being afforded by a few heavily-shaded electric
hand-lamps scattered promiscuously on tables and book-cases.
Every available corner was occupied by extra chairs brought in from
other parts of the house, and the central arena in front of the
fireplace was a dumping-ground for music-cases, ’cellos, violins, etc.
Catherine occupied a roomy arm-chair next to the fire, and was
conscious that she was being looked at attentively. A red-shaded
lamp on the end of the mantel-piece threw her hair into soft radiance,
but its effect on her eyes was so dazzling as to throw all around her
into an impenetrable dimness in which she could discern nothing but
the vague suggestion of persons and things. George sat next to her,
and from time to time passed remarks to which she replied
vivaciously, conscious that every movement of her head brought into
prominence the splendour of her hair. (Of late she had been paying
considerable attention to her hair: a visit to a West End coiffurist had
produced startling results.)
The evening crawled monotonously on. Log after log of crackling
pine was placed on the open fire-grate; song followed song, violin,
’cello, mandoline each had its turn; a girl recited “The Dandy Fifth” in
a way that was neither better nor worse than what Catherine felt she
could have done herself, and Mr. Trant’s deep voice could be heard
constantly above the periodic applause: “Charming little thing that.”
“Is that one of Bach’s?” (pronounced “Back’s”). “Very pretty, isn’t it?
Rather nice words, don’t you think?”
The order of performance was not definite. Catherine did not
know when she might be asked. Of course, she had not a trace of
nervousness. She had lost that completely now after constant
appearances on public concert platforms. And this was only a
drawing-room affair: there were no musical critics frowning in the
front row, there was probably nobody in the room who would know if
she played a false note. Besides, she would not play a false note,
She smiled contemptuously as she heard the applause evoked by a
timid rendering of a drawing-room ballad. She had an unmitigated
contempt for these drawing-room ballads. Her theatrical experience
had given her an intense hatred of cheap sentimental music of the
kind sold in music shops at one-and-sixpence a copy. The particular
song that had just been sung was of this class: its title was
monosyllabic, and its music composed with an eye to vamping the
accompaniment....
“That’s a nice little thing,” said Mr. Trant. “I don’t believe I’ve
heard it before, either.... Reminds me of something, though ... I can’t
think what....” Then in the blurred distance she could discern Mrs.
Trant’s white frocked form travelling swiftly across the room and
engaging in conversation with somebody unseen.
“Oh, please,” she heard, “please do! Everybody would be so
glad. Helen, do persuade him. Really——”
The rest was drowned in the tuning of a violin.
Then Mrs. Trant, returning to her seat, whispering to her
husband, getting up, standing with her back to the corner of the
piano, and announcing:
“We are now to have a pianoforte solo”—impressive pause;
Catherine guessed what was coming—“by Mr. Ray Verreker!”
Catherine had guessed wrong....

§6
But it was his presence there which startled her. Why was he at
such a gathering? She knew his stormy contempt for the kind of
musical suburbinanity that flourished in Upton Rising: it was his
boast that he never attended a local concert and never would.
“Suburbinanity”—that was his own word for it. She knew his fierce
hatred of the kind of things that had been going on for over an hour
—that particular violin piece by Dvořák, for instance, was anathema
to him. She knew also his passionate intolerance of mediocrity of
any kind. She could imagine his sensations when listening to that
girl’s rendering of “The Dandy Fifth.” The puzzle was, why had he
come? He knew the kind of thing it would be. He must have known
the inevitable ingredients of a suburban musical evening. And yet he
had come. He had conquered his detestation for social gatherings of
this kind so far as to come. It was rather extraordinary, completely
uncharacteristic of him.
To Catherine, always the egoist, came the thought: “Has he come
here because he knew I should be here?” Yet even a second thought
dismissed that idea as unwarrantly absurd. That would be rather an
additional reason for his staying away. For every Saturday that she
visited him convinced her more and more that he despised her and
her ways.
And she also thought: “Will the effect of his being present make
me play badly?” She did not know in the least whether it would or
not, for the circumstances were so completely different from what
they were at “Claremont.” Here she might possibly be able to forget
he was in the same room with her. Certainly he would not be at her
elbow, turning over the music pages with gestures that conveyed to
her perfectly the sensations of disgust that he was experiencing....
But he was playing. Her surprised speculations were immediately
cut short by the sound of the piano. She could see his fingers
travelling magically over the keys and his strange, grotesque face
looking vacantly over the top of the instrument. He looked different
from usual. It was probably the unaccustomed angle from which she
was watching him, for his features, perfectly unsymmetrical,
presented an astonishing variety of aspects.... She suddenly forgot
to look at him. Something that he played had thrilled her. A swift
chord, passing into a strange, uncouth melody set all her nerves
tingling. What was this piece? ... He went on through swirling
cascades of arpeggios in the right hand, falling octaves, crashing
chords, and then, once again, this strange uncouth melody, the
same, but subtly altered. Tremendous, passionately barbaric, was
this thing that he was playing. It seized hold of her as if it had
suddenly given the answer to all her wants and desires: it stretched
out clear and limitless over the furthest horizon she had ever
glimpsed; it held all the magic of the stars. And far ahead, further
than she had ever dared to look before, lay the long reaches of
boundless, illimitable passion ... passion ... passion ... that was what
it was.... Her hands twitched convulsively on the sides of the chair.
She was caught in a great tide; it was sweeping her further and
further outward and onward; she wanted to cry out but could not.
Tears were in her eyes, but they would not fall. And for the first time
that evening she forgot the pose of her head and hair....
Applause was to her the waking from a dream. They were
applauding. A fierce storm of contempt for them overtook her,
because she knew they had not heard and seen and felt what she
had heard and seen and felt. Their applause was banal, atrociously
common-place. Even in mere volume it did not exceed that which
had been accorded to the song with the monosyllabic title or to “The
Dandy Fifth.” And Catherine, vaguely annoyed that there was any
applause at all, was also vaguely angry that it had been so
indiscriminating. She did not applaud herself, but she heard George
clapping almost in her left ear, and she shot a curious glance at him.
She was thinking: “How much of it has meant anything at all to you?”
And then she heard Mr. Trant’s deep, suave voice: “What did you
say that was? Peculiar piece, but awfully pretty.”
Verreker mentioned a title she could not hear. George had
apparently caught something. He whispered to her in spasms:
“Jeux—something or other, I think he said. French, I suppose.
Modern French. Debussy school, you know. Oh, it’s ‘Jeux d’Eaux.’ I
heard him say it again. ‘Jeux d’Eaux,’ that’s what it is.... One of
Ravel’s things, you know.” ...

§7
Verreker returned to his seat. There followed a baritone song of
the rollicking variety, a ’cello solo, and then Mrs. Trant called for a
“pianoforte solo by Miss Catherine Weston.”
Catherine rose languidly, and picked her way amongst the violins
and music-stands to the piano. She screwed the stool an inch or so
higher (it being a point of honour with her always to make some
alteration, however slight, in the seating accommodation provided for
her), then she lowered the music-rest and slid it back as far as it
would go. Her first piece was to be the “Butterfly” Study in G flat
(Chopin), so she gently ran her hands arpeggio-wise along the tonic
and inversions of G flat. Having done this she paused, chafed her
fingers delicately, and tossed her head. The lamp at her side shone
on her magnificent hair, throwing her face and bust into severe
profile. It was then that she noticed a slight commotion in the far
corner of the room. A man was disengaging himself from the closely-
wedged throng and proceeding to the doorway. As he passed the
fireplace the flames flickered brightly round a log of wood just placed
on the fire. Catherine in a swift glance saw that it was Verreker....
Carefully he wound his way to the door and passed out.
Catherine flushed Her hands commenced to play, but her whole
being was tingling with anger. She was conscious that everybody in
the room had noticed his ostentatious withdrawal and was drawing
conclusions from it. Everybody knew she took lessons from him. His
going out of the room at that moment was nothing less than a
deliberate insult offered to her in front of everybody. In the half-
shadows round the piano she could see the faces of Mr. and Mrs.
Trant, both rather bewildered.... Her fingers were moving
automatically; before she properly realized she was playing a solo
they had stopped. Cloudily she grasped the fact that the “Butterfly”
Study had come to an end. Applause floated in, and she found
herself walking back to her seat. Applause thinned and subsided;
Mrs. Trant said something, and there began the tuning of a couple of
violins with much unnecessary prodding of notes on the piano.
George was saying something to her, but she was not listening. The
door opened and Verreker re-entered. He sat down unostentatiously
in a chair close by and his face was hidden by shadows. The piano
tinkled into the opening of a Haydn Concerto.... And Catherine
thought: “That was really a horrid thing to do. I believe it is the
nastiest trick I ever saw. I expected rudeness, but somehow not that
—at any rate, not in public.” She was primarily angry, but in her
anger there was more than a tinge of disappointment....
She hated him. The fact that it was his teaching that had brought
her success was swamped utterly in this petty insult he had seen fit
to offer her in public. Once the idea did strike her: perhaps it was just
coincidence that he went out while I was playing. But instinct told her
that his withdrawal was deliberate, part of a planned scheme to
humiliate her. And she kept piercing the shadows where he sat with
a venomous greenish glint in her eyes, until she reflected that even if
she could not see him, he could very likely see her. At this she
flushed hotly and turned away. The evening crept towards midnight.
Coffee was handed round. There was a momentary respite from
music after the conclusion of the Hadyn Concerto, and conversation
swelled into a murmurous hum all over the room. She lit a cigarette
and puffed out smoke languidly. George went to the music cabinet
and brought out some Ravel music. She scanned it perfunctorily; as
a matter of fact she had but a vague idea of what it was like by
looking at it. “Pavane pour un Enfant Défunt,” it was called; the first
few pages looked charmingly simple. George could not find “Jeux
d’Eaux.” Possibly he had not got a copy. But all this modern music
was frightfully interesting. Had she heard César Franck’s Violin
Sonata—the famous one? Or Scriabin’s Eleven Preludes? Or
Debussy’s “L’Après-midi d’une Faune”? Of course, futurist music
was merely the development of what other composers had led the
way to. Some of Chopin’s Ballades and Preludes, for instance, gave
one the impression that if he had lived a century later he might have
been furiously modern. And of course Tchaikovsky. In fact——
Catherine listened patiently, putting in an occasional “Yes” and
“Of course” and “I daresay.” Her one thought was: “I have been
publicly insulted.” And George did not pass even the frontiers of her
mind save when she reflected casually: “Considering what a lot
George knows, it’s rather queer he should be so remarkably
uninteresting at times....”

§8
It was nearly one on Christmas morning when the party broke up.
Catherine was waiting in the hall for George. He had gone to help
somebody to find his or her music-case. Most of the company had
gone; some were going, with much loud chattering on the doorstep