Please cite
(2010), do
ARTICLE IN PRESSGModelMUT-10892; No.of Pages4
Mutation Research xxx (2010) xxx–xxx
Contents lists available at ScienceDirect
Mutation Research/Fundamental and Molecular
Mechanisms of Mutagenesis
journa l homepage: www.e lsev ier .com/ locate /molmut
Communi ty address : www.e lsev ier .co
Why d gy
Keith Bav
Department of Kuopi
a r t i c l
Article history:
Available onlin
Keywords:
Genomic insta
Dynamic attra
Evolution
Epigenetics
Radiation risk
New paradigm
ntal e
iolog
s exis
cent
y age
i to ac
ct to o
e a tra
r dam
enoty
a sep
A ef
1. Introdu
From a radiobiological perspective the reason a new paradigm is
needed is the experimental observation of “non-targeted effects”,
most notably genomic instability [1] and the bystander effect [2].
These have defied explanation for more than a decade in terms of
the conven
ory, where
Firstly, radi
in terms of
on the degr
approximat
bystander e
cell (see [3]
mental reas
effects can
alterations,
lated or org
human gen
number of
of gene pro
While it is c
gene produ
not known
in any spec
on the und
E-mail add
n se
tral Dogma, and this is now seen not to be the case. This constitutes
a crisis, in the Kuhnian [5] sense, for the paradigm based on the
Central Dogma and this has implications for radiobiology, which is
similarly based.
A new paradigm for radiobiology, in addition to explaining both
0027-5107/$ –
doi:10.1016/j.this article in press as: K. Baverstock, Why do we need a new paradigm in radiobiology? Mutat. Res.: Fundam. Mol. Mech. Mutagen.
i:10.1016/j.mrfmmm.2010.01.003
tional paradigm for radiobiology based on target the-
the target is generally taken to be the genomic DNA.
ation induced genomic instability cannot be understood
the targeting of specific genes and target theory (based
ee of effect in relation to dose) suggests that the target
es to the size of the nucleus. Secondly, in the case of the
ffect, no radiation is absorbed in the DNA of the affected
for a fuller account). There is, however, a more funda-
on, namely that in a wider biological perspective these
be described as “epigenetic”, that is, not due to genetic
but rather to how the gene products in the cell are regu-
anised to produce phenotype. Since the sequencing the
ome was completed in 2001 it has been clear that the
coding sequences is significantly less than the number
ducts known to be produced by the human genome [4].
lear that “alternative splicing” of exons is how several
cts are generated from a single coding sequence what is
is how the cell decides which is the appropriate product
ific circumstance. Genome sequencing was undertaken
erstanding that there was a deterministic relationship
ress: keith.baverstock@uef.fi.
the newly identified effects [1,2] and the established effects in
radiobiology should provide a theoretical underpinning for radio-
biology. In addition it should be consistent with any new paradigm
developed to govern biology in general.
1.1. Proposal for a new paradigm
In recent developments in cell and molecular biological research
there has been a clear trend towards recognising two features of
biology, namely, increasing complexity [6,7] and indeterminism
[8–10] in the regulation of the cell in its normal state. For exam-
ple, transcription now appears to depend collectively on multiple
factors including; DNA/chromatin marking, location of the tran-
scribed locus in the nucleus, location of nucleosomes in relation to
the initiation sites of transcription, as well as the usual upstream
transcription initiators. Often these dependences are complex in
themselves. In disease states such as carcinogenesis it is no longer
possible to see the process as being driven by a few key mutations
[11] but rather it has to be viewed as having multiple pathways of
development [12–14].
In an attempt to understand the way in which radiation was
able to induce genomic instability Baverstock [15] suggested that
phenotype might usefully be represented by a dynamic attrac-
see front matter © 2010 Elsevier B.V. All rights reserved.
mrfmmm.2010.01.003o we need a new paradigm in radiobiolo
erstock
Environmental Science, University of Eastern Finland, Kuopio Campus, PL 1627, 70211
e i n f o
e xxx
bility
ctor
a b s t r a c t
Over the past 20 or so years experime
standing, of both biology and radiob
within a framework that encompasse
or epigenetic, features of the cell. In re
a potential organisational or regulator
robustness provides a modus operand
When radiation deposition events a
cell of an established species and caus
are unrelated to any specific molecula
of evolutionarily acquired stability (g
termed type B events and give rise to
conventional effects of radiation, type
ction betweem/locate /mutres
?
o, Finland
vidence, which questions the fundamentals of some 50 years
y has accrued. In order to accommodate this new evidence
ting knowledge, attention has to be paid to the organisational
years the high dimensional dynamic attractor has emerged as
nt that represents phenotype. It is argued here that its limited
count for stress induced genomic instability.
vercome the robustness of a normal or “home” attractor in the
nsition to a variant attractor or phenotype, the consequences
age to the genomic DNA. Rather they correspond to the loss
pic replicative integrity) and robustness. Such processes are
arate category of effects and risk to those associated with the
fects. How type B risks might be assessed is discussed.
© 2010 Elsevier B.V. All rights reserved.
quence and biological function, as stipulated in the Cen-

Please cite in r
(2010), do
ARTICLE IN PRESSGModelMUT-10892; No.of Pages4
2 K. Baverstock / Mutation Research xxx (2010) xxx–xxx
tor embedded in a multidimensional state space defined by the
relevant genes. Genomic instability would then be seen as an
example of an unscheduled transition between attractors, i.e., one
that unlike differentiation, was a stochastic event. Since 2005
there have been a number of reports addressing the attractor con-
cept in bacteria [16], yeast [17,18] and mammalian cells [19,20]
where experimental evidence that attractors represent phenotype
is claimed.
further dev
instability a
cant feature
life.
An impo
attached to
ucts from w
exhibit sele
stability (in
tance to en
to the susta
A numb
a new para
genetic (gen
as independ
context to
tion that y
robustness,
established
replicate its
are indepen
In radio
routes by w
thus, poten
gene codin
to genetic d
damage beh
dependent
matings. Sim
to underlie
as direct as
modus oper
change and
However, a
by which s
damage det
initial phen
DNA damag
products en
type) out of
variant attr
had been su
ularly stabi
(a) less stab
type and mo
variant attr
in which m
cells it may
latter case
generations
modified Ro
It appears fr
is transmitt
in some wa
1 Dubrova g
meeting.
and is thus not diluted with subsequent matings, distinguishing the
process from type A processes.
1.2. How does the paradigm of epigenetic effects of radiation
exposure en
Biologic
whe
may
ntly
stic t
ty o
sible
solv
sult
tate/
r-ph
ctio
ne p
ne p
at a
hang
s the
abili
abili
igra
sent
pro
r an
“hom
, tha
le, in
atial
ant.
mo
e pr
troph
ts tr
isited
utcom
crite
or m
e of
ively
a res
t to
will
varia
as to
assoc
t the
seem
der e
e ou
divid
nent
the t
isea
be ac
tions
ile th
ising
tion.this article in press as: K. Baverstock, Why do we need a new paradigm
i:10.1016/j.mrfmmm.2010.01.003
Baverstock and Rönkkö [21] have now formalised and
eloped the concept in the context of explaining genomic
nd they identify genomic instability as a very signifi-
of biology which is highly relevant to the evolution of
rtant feature of the attractor concept is the importance
rules of engagement (RoE) between active gene prod-
hich the attractor emerges. In the model [21] the RoE
ctable variation. Particularly important is selection for
tegrity of genotype replication) and robustness (resis-
vironmentally induced attractor transitions), both vital
inability of a species.
er of features of the model indicate that it represents
digm in both biology and radiobiology. For example,
otype) and epigenetic (RoE) information are regarded
ently sourced, with the genetic information providing
a highly non-linear process of gene product interac-
ields a cell state (attractor/phenotype) with limited
but which, through evolutionary conditioning of an
species, has been optimised for its ability to correctly
genome. In reproduction both sources of information
dently inherited by the zygote.
biology, therefore, there appear to be two separate
hich radiation exposure which can lead to effects and
tially, disease outcomes. Mutational damage to the
g sequences of germ cells can be inherited and lead
isorders in the F1 and subsequent generations. Such
aves according to Mendelian rules and typically is not
on the gender of the parent. It is diluted with successive
ilar mutational damage in somatic cells is postulated
carcinogenesis although the evidence is by no means
it is for germ cells. This is the conventional (genetic)
andi by which ionising radiation induces phenotypic
risks from this source will be labelled ‘type A’ risk [22].
nother process (leading to what is termed ‘type B’ risk)
tresses on the cell’s normal organised processes, e.g.,
ection and repair, cell cycle arrest, etc., can initiate an
otypic change epigenetically, that is, without specific
e. This is brought about by forcing one or more gene
gaged in the prevailing attractor (representing pheno-
its permitted range (see [21] for detail) thus causing a
actor/phenotype to be adopted. As the exited attractor
bject to evolutionary conditioning to optimise partic-
lity and robustness, the variant attractor is likely to be,
le and (b) less robust. Thus, it will be a mutator pheno-
re prone to stress leading to further migration between
actors. In somatic cells this is postulated to be one way
alignancy can be initiated and progressed, and in germ
constitute the initial step in a speciation event. In the
the modified phenotype can be transmitted to future
but only through the germ line of one gender if the
E are to become established in a breeding population.
om studies in humans [23]1 that it is the male line that
ed. Thus, in the zygote the female phenotype (attractor)
y adopts the dynamics of the male phenotype (attractor)
ave further evidence on this point during his presentation at the NOTE
model
tor, as
sufficie
stocha
sionali
irrever
may re
as a re
nant s
mutato
the fun
ing ge
new ge
change
typic c
Thu
are
• prob
• prob
i.e., m
repre
The
stresso
nal or
of RoE
examp
and sp
import
system
the gen
in neu
produc
been v
final o
The
attract
or mor
a relat
vokes
that ac
feature
vidual
arises
space
disrup
ple, it
bystan
cell, th
tral. In
compo
tion of
other d
has to
aberra
Wh
priorit
evaluaadiobiology? Mutat. Res.: Fundam. Mol. Mech. Mutagen.
able determination of type B risk?
al effects can arise from an epigenetic event under this
n an established and conditioned, i.e., “home”, attrac-
be found in the cells of an established species, is
perturbed by some extrinsic stress that it makes a
ransition to a variant attractor. Given the high dimen-
f the attractor this transition is highly likely to be
. This initial step is not per se a health effect but it
e into a health effect, as for example in somatic cells
of further migration between attractors, until a malig-
phenotype is attained [15]. Furthermore, the probable
enotype nature of the variant attractor may either limit
ns the resultant phenotype can perform by eliminat-
roducts or endow it with new functions by creating
roducts through mutation. In other words phenotypic
genetic level can be stimulated by epigenetic pheno-
e.
parameters of concern where type B risk is concerned
ty of the initial transition to a variant attractor
ty that the initial transition will lead to a disease state,
tion into a domain of state space associated phenotypes
ing disease.
bability of the initial transition depends in part on the
d in part on the properties associated with the origi-
e” attractor. These are contingent on the inherited set
t is, are subject to variation between individuals. For
the case of ionising radiation as a stressor, event size
distribution of damage caused in the cell may well be
The “direction” in the multidimensional state space the
ves when ejected from the attractor may be related to
oduct that was perturbed (drug induced differentiation
ils has been shown to be drug dependent in terms of
anscribed [19] which indicates which attractors have
during the process) and predispose the cell to certain
es, for example, malignancy.
rion for an initial attractor transition, according to the
odel, is the induction of an out of range condition for one
the constituent active gene products [21]. This may be
common event at the cellular level but one which pro-
ponse from the community of other cells in the tissue
effectively eliminate aberrant cells. This “community”
be contingent on the RoE and thus also subject to indi-
tion.Alternatively, if a variant cell survives, thequestion
whether it has the potential to reach a domain of state
iated with disease or whether its aberrant nature will
properties of the tissue in which it lives. For exam-
s that there is little or no evidence to suggest that the
ffect is other than disruptive signalling by a stressed
tcome of which may be detrimental, beneficial or neu-
ual cells in a tissue might be regarded as the dynamic
s of an attractor that sustains the proper form and func-
issue and thus the contention that malignancy [24] and
se states are tissue responses can be supported but it
cepted that those responses are firmly rooted in cellular
.
is complexity seems daunting a start can be made on
stressors and setting up a framework for ‘type B’ risk
The most probable gene products associated with ion-