Mutation Research 454 (2000) 89–109
Current Issues in Mutagenesis and Carcinogenesis No. 98
Radiation-induced genomic instability: a paradigm-breaking
phenomenon and its relevance to environmentally induced cancer
Keith Baverstock
WHO Regional Office for Europe, Project Office, Laippatie 4, 00880 Helsinki, Finland
Accepted 1 August 2000
Abstract
The existing paradigm governing radiobiology which is fundamental to the estimation of environmental radiation risk,
cannot explain the phenomena of radiation induced genomic instability and the bystander effect. Both effects can, however,
be understood in terms of the dynamical genome concept, qualitatively described herein. The dynamical genome concept may
find further application in better understanding other aspects of biology, most notably the cancer process in general and the
consequences of genetic modification. © 2000 Elsevier Science B.V. All rights reserved.
Keywords: Attractor; Cancer; Dynamical genome; Genomic instability; Radiation
1. Radiation-induced genomic instability and the
bystander effect
Since early in the 1990s there has been increasing
recognition of the importance of two related phenom-
ena that challenge the paradigm under which the bio-
logical effects of ionising radiation are conventionally
interpreted. These phenomena are radiation-induced
genomic instability (RIGI) and the “bystander effect”
[1]. In 1992, Kadhim et al. [2] reported the occur-
rence of non-clonal aberrations in bone marrow cells
in culture after irradiation by the traversal per cell of
on average 0.5, 1 or 2, alpha-particles. As alpha parti-
cles are a radiation of low penetration and high linear
energy transfer (LET), the dose received by individual
cells is high (of the order of up to 0.5 Gy depending
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E-mail address: keith.baverstock@who.fi (K. Baverstock).
on the diameter of the cell traversed). For an average
of 1 alpha particle per cell, 63% of cells will receive
one or more traversals and 37% no traversals at all.
Thus, the cells surviving the irradiation treatment will
be constituted from the un-irradiated cells (i.e. no al-
pha particle traversals) and those surviving the traver-
sal of the alpha-particles (of the order of 10–20% of
the traversed population). These “surviving” cells were
grown, in vitro, as discrete colonies for several gener-
ations and then scored for cytogenetic aberrations. Of
the surviving cells 40–60% had karyotypic abnormal-
ities, but not all cells in a colony exhibited the abnor-
malities and up to 50% of scored metaphases carried
non-identical abnormalities, i.e. they were non-clonal.
These results were interpreted as indicating that radi-
ation related effects could arise, de novo, several gen-
erations after the generation in which the radiation
damage was inflicted. This phenomenon of a delayed
response to irradiation is characteristic of RIGI.
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90 K. Baverstock / Mutation Research 454 (2000) 89–109
That the phenomenon is not an artefact of in vitro
growth is demonstrated by the fact that when bone
marrow cells from male mice were irradiated in vitro
and then implanted into female mice, genomic insta-
bility was seen in the male cells of the female bone
marrow [3].
A problem with the interpretation of the Kadhim
experiment was that it appeared that a higher propor-
tion of colonies were exhibiting non-clonal aberrations
than were expected to have survived the traversal of
an alpha-particle, if the expected survival rate for a
single traversal of an alpha particle of about 10–20%
was correct. This problem was resolved in an exper-
iment in which about 50% of the cells were shielded
from alpha-particles by a wire grid [4]. Survival, with
increasing numbers of alpha particle passages per cell,
was seen to level off at about 50%, but the induction
of non-clonal aberrations was independent of the pres-
ence of the grid. Clearly, cells not being traversed by
an alpha particle were exhibiting the non-clonal aber-
rations. This effect is known as the bystander effect.
Thus, this single experimental system, investigating
the effects of low traversal numbers of alpha par-
ticles through bone marrow cells, was instrumental
in revealing two, hither to, apparently unrecognised
effects of ionising radiation, which seemed to deny
two of the basic dogmas of radiobiology, namely,
that damage inflicted on DNA by ionising radiation
would, if it survived the first cell division after irradi-
ation, be replicated in all subsequent daughters of that
cell, and that directly inflicted damage to the genomic
DNA was an essential requirement for a biological
effect.
In retrospect, the literature shows that past results
have demonstrated a number of phenomena related
to RIGI, but they were not recognised for what they
were, indeed, sometimes they have been dismissed
as aberrant results. Morgan et al. [5] have reviewed
the literature in detail, identifying effects that should
broadly be classified under the term RIGI, although a
strict definition of this term is still lacking. The effects
include delayed lethal mutations (these affect colony
size in clonogenic survival experiments), delayed
apoptosis, non-clonal aberrations, enhanced mutabil-
ity and micro-nucleus generation. All these endpoints
are characterised by delayed expression by up to sev-
eral tens of generations and are readily induced by
radiation in the systems in which they occur.
More recently, Nagasawa and Little [6] have re-
ported results showing unexpectedly high levels of
mutation in cells subject to low levels of alpha par-
ticle irradiation in which few of the cells are actually
irradiated. They conclude that un-irradiated cells are
showing mutational damage through the bystander
effect. Subsequently, Little [7] has reported on the
nature of the mutations arising from the “bystander”
process, termed delayed mutation, in relation to those
induced “directly” by ionising energy deposition.
Delayed mutations tend to be “point mutations” in-
volving a single base pair, whereas direct mutations
more often involve deletions of substantial segments
of the gene. This qualitative difference is particu-
larly interesting, as it has been recognised for some
time that radiation has a tendency to induce deletions
of substantial segments of a gene, in comparison to
“spontaneous” mutations, which are usually “point”
mutations. However, as pointed out by Thacker et
al. [8], small (point) mutations are also induced by
radiation and may be responsible for some biological
effects. It is interesting to speculate whether these
mutations are directly induced or a bystander effect.
That it is damage to nuclear DNA that potentiates
RIGI is adduced from experiments in which the Auger
emitter, 125I, is introduced into different locations in
the cell, namely, attached to the plasma membrane, or
internalised into the cell, but not attached to the nuclear
DNA, or covalently bonded to nuclear DNA. Only in
the last case was genomic instability observed [9]. The
Auger process results in a cascade of low energy and,
therefore, short range, electrons, on radioactive decay.
Typically for 125I in the condensed phase some 20
electrons [10] are released with ranges predominantly
of the order of a few nanometres [11], of the order of
a few diameters of the DNA duplex. Thus, it is only
in the case that 125I is covalently bonded to DNA,
that damage to DNA is caused with a high degree of
efficiency.
Although most observations of RIGI are in in vitro
systems, Baverstock and Sankaranarayanan [12] drew
attention to the relevance to genomic instability of
the experiments of Lüning et al. [13] in which male
mice were injected with 239Pu citrate and mated with
un-irradiated female mice. A proportion of the Pu salt
becomes located in the testes from where, on radioac-
tive decay producing a 5 MeV alpha particle, it can
irradiate the spermatogonial cells. The object of the