Please cite
Res.: Gene
ARTICLE IN PRESSGModelMUTGEN-401918; No.of Pages9
Mutation Research xxx (2010) xxx–xxx
Contents lists available at ScienceDirect
Mutation Research/Genetic Toxicology and
Environmental Mutagenesis
journa l homepage: www.e lsev ier .com/ locate /gentox
Communi ty address : www.e lsev ier .co
Towards a unifying theory of late stochastic effec
Keith Bav a,∗ b,1
a Department o 1 Kuop
b Radiation Gro Cance
a r t i c l
Article history:
Received 6 Ma
Received in re
29 September
Accepted 3 Oc
Available onlin
Keywords:
Attractor
Ionizing radiat
Stochastic effe
Epigenetic inh
Genetic effects
asis
has so
non-t
stim
ende
pe B
actin
type.
cell a
n inh
alth
of vie
ntal l
single causal framework that has the potential to be extended to the effects of the other environmental
agents damaging to health.
© 2010 Elsevier B.V. All rights reserved.
1. Introdu
In the 19
X-rays were
of fruit flies
get theory t
responsible
[1]. Target t
cal radiobio
It connects
interactions
the biologic
is that one
ture of a mo
functionalit
Since 19
quently the
the late sto
Abbreviatio
rules of engag
locus.
∗ Correspon
E-mail add
1 Present ad
1383-5718/$ –
doi:10.1016/j.this article in press as: K. Baverstock, A.V. Karotki, Towards a unifying theory of late stochastic effects of ionizing radiation, Mutat.
t. Toxicol. Environ. Mutagen. (2010), doi:10.1016/j.mrgentox.2010.11.003
ction
30s Müller and Timofeeff-Ressovsky demonstrated that
capable of causing heritable changes in the offspring
. Their colleagues, Zimmer and Delbruck employed tar-
o estimate the physical size of the cellular component
for transmitting the change induced by the radiation
heory has since provided the underpinning for classi-
logy, first being applied in the work of Crowther [2].
the loss of the biological activity with the number of
of ionizing radiation in a particular volume (target) of
al material. An important assumption of target theory
primary random ionization leads to a change in struc-
lecular component of the target, thus causing an altered
y [3].
53, with the discovery of the DNA structure and subse-
genetic code, radiobiological dogma has assumed that
chastic effects of radiation, initially thought to be only
ns: ICRP, International Commission on Radiological Protection; RoE,
ement; SMT, somatic mutation theory; TRDL, tandem repeat DNA
ding author. Tel.: +358 9 727 5710.
ress: keith.baverstock@uef.fi (K. Baverstock).
dress: Schmittenackerstrasse 12, 8304 Wallisellen, Switzerland.
cancers and hereditary disease, were the result of mutations in the
genomic DNA: the specific sequences of the code that were relevant
to the endpoint being studied were the target for radiation effects.
For single-genehereditary conditionsobeyingMendelian rules, this
dogma is confirmed by the specific-locus tests in mice [4,5], but
for cancer the hypothesis remains unproven. Subsequently, non-
cancer diseases, e.g., circulatory disease, have been added to the late
effects caused by radiation exposure as a result of epidemiological
information from the survivors of the atomic bombings in Japan
[6] and from radiotherapy patients [7]. In addition, the inheritance
of mini-satellite mutations induced in humans [8–10], potentially
mirrored by the inheritance of mutations in TDRL induced in mice
[11,12], have been observed. These mutations are produced at rates
in excess of those normally found for DNA sequence mutations.
However, their connection to health detriment has yet to be estab-
lished.
In 1992 the phenomenon of genomic instability in the clonal
descendants of haemopoetic cells, showing a high level of non-
clonal chromosomal aberrations was uncovered [13]. At the same
time the bystander effect in the Chinese hamster ovary cells was
described, manifesting itself as an unexpectedly high percent-
age (30%) of cells with sister chromatid exchange, when only
1% of the cell nuclei were estimated to have been the target
for alpha-particle passages [14]. To compare: genomic instability
describes the delayed radiation effects in the irradiated cell and
its progeny, whereas the bystander effect describes the response
see front matter © 2010 Elsevier B.V. All rights reserved.
mrgentox.2010.11.003erstock , Andrei V. Karotki
f Environmental Science, University of Eastern Finland, Kuopio Campus, PL 1627, 7021
up, International Agency for Research on Cancer, International Agency for Research on
e i n f o
y 2010
vised form
2010
tober 2010
e xxx
ion
cts
eritance
a b s t r a c t
The traditionally accepted biological b
hereditary disease), i.e. target theory,
non-cancer disease and the so-called
creating uncertainty in radiation risk e
effects through two distinct and indep
other essentially epigenetic, termed ty
by a dynamic attractor and radiation
adoption of a variant attractor/pheno
can lead to the inheritance of variant
quite distinct from classical Mendelia
radiation-induced somatic human he
disease, are discussed from the point
This approach unifies at a fundamem/locate /mutres
ts of ionizing radiation
io, Finland
r, 150 Cours A. Thomas, 69372 Lyon, France
for the late stochastic effects of ionizing radiation (cancer and
far been unable to accommodate the more recent findings of
argeted effects, genomic instability and bystander effect, thus
ation. We propose that ionizing radiation can give rise to these
nt routes, one essentially genetic, termed here type A, and the
. Type B processes entail envisaging phenotype as represented
g as an agent that stresses cellular processes leading to the
Evidence from the literature indicates that type B processes
ttractors and mediate a category of trans-generational effects
erited disease, which is type A. The causal relationships for
detriment, i.e., cancer and non-cancer (e.g., cardiovascular)
w of the proposed classification.
evel the heritable and late somatic effects of radiation into a

Please cite
Res.: Gene
ARTICLE IN PRESSGModelMUTGEN-401918; No.of Pages9
2 K. Baverstock, A.V. Karotki / Mutation Research xxx (2010) xxx–xxx
Fig. 1. Presen nals a
upon it. Enviro issue
with dashed li highly
bio-molecules
of non-irra
radiation. B
dose effect
of effect is s
mutational
logical end
with a spec
targeted”. T
find a new
between sp
the consequ
The poss
tic effects o
and non-ca
radiation ca
specific mu
organization
respond to
2. Materials
2.1. Envisagin
The pheno
attention in c
cal mechanics
However, in b
organization t
the diseases i
protein confor
environment.
evolutionary s
of peptides to
associated wit
ease, Alzheim
proposed that
ruption of orga
should not be
major psychia
different level
that underlie
the late effect
material of the
two categories
zing ra
of a fe
chem
he sam
ent b
. In t
we w
conse
resid
ness w
rmody
is driv
odyna
itiona
and
correc
ateri
ng how
riptio
plasttation of the cell in a tissue, as a system built on interaction between genome sig
nmental signals are presented as composed of the signaling from the interacting t
ne). All these signals influence and regulate the cell attractor, which is a dynamic,
(see Supplementary material for details).
diated cells to the targeting of a neighbouring cell by
oth effects are thought to be important, in terms of
, at low doses. For genomic instability the magnitude
uch that based on target theory it cannot be caused by
damage to specific gene sequences related to the bio-
point [15]. Due to the absence of a causal connection
ific cellular target these effects have been termed “non-
herefore, an intensive search is currently underway to
paradigm that does not rely solely on a relationship
ecific gene mutations and biological effects, to underpin
ences of exposure to ionizing radiation [16].
ible basis for such a unified theory of the late stochas-
f ionizing radiation, covering hereditary disease, cancer
ncer disease is explored herein. It is argued that while
n act to cause health damage through the mediation of
tational damage there is a second process in which the
al, rather than the material, properties of the living cell
Ioni
volumes
cally and
within t
consequ
organism
unit and
and the
that cell
its open
only the
sense: it
a therm
Trad
mutable
Despite
ing the m
explaini
of transc
both thethis article in press as: K. Baverstock, A.V. Karotki, Towards a unifying the
t. Toxicol. Environ. Mutagen. (2010), doi:10.1016/j.mrgentox.2010.11.003
the deposition of energy from ionizing radiation.
and methods (model)
g the cell as an open system and the classification of radiation effects
menon of order or organization per se has received relatively little
onventional scientific thought, the concept of entropy and statisti-
and then in a probabilistic context, being almost the only examples.
iology some diseases can be seen as attributable more to failures in
han to damage to the substance of the cell/organism. One can take
nvolving protein mis-folding as an example. It is known that the
mational landscape can be very broad and defined by the protein
The conformational substrates adopted by a protein are a result of the
election of states that are needed for protein function [17]. Failure
adopt the proper conformation or to be processed appropriately is
h many human pathologies [18], for example Creutzfeldt-Jakob dis-
er’s disease, Parkinson’s disease, and cystic fibrosis [19]. It has been
mental retardation associated with in utero irradiation is due to dis-
nizational processes of the brain in antenatal development [20]. This
surprising as altered neuronal organization is also found in several
tric disorders [21]. Therefore, changes in biological organization at
s, from molecular to the organism, may be crucial to the processes
radiation-induced disease more generally. In fact we will show that
s of ionizing radiation, in addition to being caused by damage to the
cell, can also be caused by organizational events. We will relate these
to Aristotle’s material and efficient causes, respectively [22].
manifested in
it ignores the
non-targeted
by viewing the
tem) in which
phenotype is
fied by enviro
environment a
the genotype.
This dynam
[15,27–30]. Th
states in their
with a degree
context a quas
shown that ra
cycle attracto
organization i
systems [33] a
tion for morph
of self-organiz
tion, chromos
major cellular
as a prerequis
An attract
between dyna
encoded in the
represented b
[37]. The attrand environmental signals in terms of the primary normal influences
attractors and the signals outside of the surrounding tissue (marked
interconnected, and open system of all the cellular components and
diation gives rise to sub-cellular energy-deposition events, initially in
w nanometers in diameter, which are generally fully resolved, physi-
ically, in the time scale of seconds to minutes after energy deposition,
e cell. In the longer time frame and in multi-cellular organisms, the
iological processes will involve other cells and other tissues in the
his paper the cell is chosen to serve as the primary organizational
ill consider the processes that take place within a cell to change it
quences of those changes for the system (tissue/organism) in which
es. Another important feature of the cell as an organizational unit is
hen it itself is viewed as a system. Each individual cell is open not
namically, in respect of its nutrients, for example, but also in a wider
en by influences from its environment. Here we treat the cell as such
mically open system [23,24].
lly the cell is presented in biology as a semi-autonomous carrier of
heritable elements, genes, which define its phenotypic properties.
tly depicting genomic DNA as the receptacle of information defin-
al components of the cell, this model does not allow much scope for
organizational information is stored and processed, except in terms
nal regulation via chromatin marking. This view also does not explain
icity and simultaneous robustness of the cellular phenotype, which isory of late stochastic effects of ionizing radiation, Mutat.
the processes of ontogeny [25] and cell differentiation [26]. Moreover,
openness of the cell and fails to give a satisfactory explanation of the
effects of radiation. We assert that these problems can be overcome
cell as an operational dynamic component of a tissue/organism (sys-
it resides. An important feature of such a vision is that the cellular
derived from the interacting network of active gene products, modi-
nmental signals, including those from other cells, from the physical
nd the changes in levels of DNA transcription products prescribed by
Such interacting networks are termed attractors (Fig. 1).
ic and highly interconnected intracellular network is self-organized
e stable states of the dynamic systems are called attractors because
immediate vicinity drain into them, thus endowing the stable state
of robustness or resilience to perturbation. Cellular phenotype (in this
i-stable state of a cell) is represented by such attractors. Kauffman has
ndomly constructed Boolean networks exhibit self-organized state
rs under a specific range of conditions of connectivity [31,32]. Self-
s commonplace in far-from-equilibrium (thermodynamically open)
nd self-organization was established by Alan Turing as the explana-
ogenesis [34]. Recent biological discoveries confirm the importance
ation and pattern formation for basic cellular events, like DNA replica-
ome segregation, microtubule assembly and even organization of the
organelles [35]. The phenomenon of self-organization can be regarded
ite for the emergence of biological functions.
or can be seen as the manifestation of multiple dynamic steady states
mic modes of a dynamical system, in this case the active gene products
genomic DNA of the cell. Evidence consistent with phenotype being
y attractors has been found in bacteria [36] and in mammalian cells
ctors may possess a high degree of robustness against perturbation