BioSystems 178 (2019) 16–24

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BioSystems
journal homepage: www.elsevier.com/locate/biosystems

Quantum biology and human carcinogenesis T

Michael Bordonaro
Geisinger Commonwealth School of Medicine, 525 Pine Street, Scranton, PA 18509, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Quantum-mediated effects have been observed in biological systems. We have previously discussed basis-de-
Cancer pendent quantum selection as a mechanism for directed adaptive mutation, a process in which selective pressure
Quantum mechanics specifically induces mutation in those genes involved in the adaptive response. Tumor progression in cancer
Density matrix easily lends itself to the adaptive evolutionary perspective, as the Darwinian combination of heritable variations
Decoherence
together with selection of the better proliferating variants are believed to play a major role in multistep carci-
Adaptive mutation
Wnt signaling
nogenesis. Adaptive mutation may play a role in carcinogenesis; accordingly, we propose that the principles of
quantum biology are involved in directed adaptive mutation processes that promote tumor formation. In this
paper, we discuss the intersection between quantum mechanics, biology, adaptive evolution, and cancer, and
present general models by which adaptive mutation may influence neoplastic initiation and progression. As a
potential theoretical and experimental model, we use colorectal cancer. Our model of “quantum cancer” suggests
experiments to evaluate directed adaptive mutation in tumorigenesis, and may have important implications for
cancer therapeutics.

1. Directed adaptive mutation: a quantum phenomenon?
In this paper, biological mutations are defined as “Darwinian” when
they are random, independent of selection pressure. While this defini-
tion likely describes most mutations, adaptive mutation may also con-
tribute to genetic variability in changing environments. In adaptive
mutation the genetic change does not exist prior to the selective pres-
sure; instead, the presence and type of selection influences the fre-
quency and character of the mutation event. Evidence for adaptive
mutation exists for both bacteria and yeast, and possibly for prostate
cancer cells; researchers believe that adaptive mutation contributes to
the evolution of microbial pathogenesis, cancer, and drug resistance,
and may become a focus of novel therapeutic interventions (Bielas
et al., 2006; Cairns et al., 1988; Cairns and Foster, 1991; Foster, 2007;
Foster and Cairns, 1992; Hall, 1990, 1991a, 1991b, 1992a, 1992b,
1995, 1997, 1998a, 1998b, 1999, 2003; Hara et al., 2005; Karpinets
and Foy, 2004, 2005; Karpinets et al., 2006; Kugelberg et al., 2006;
Rosenberg, 2001). Thus, this manuscript evaluates the possibility of
directed adaptive mutation in carcinogenesis. We distinguish between
three types of mutation: (a) random (Darwinian) mutations that are
independent of selective pressure; (b) undirected adaptive mutations,
which arise when selective pressure induces a general increase in the
mutation rate; and (c) directed adaptive mutations, which arise when
selective pressures induce targeted mutations that specifically influence
the adaptive response. In this paper, we focus on directed adaptive
mutation, mediated by quantum mechanical effects, as a potential
factor contributing to carcinogenesis.
Similarities exist between adaptive mutation in bacteria or yeast
and processes that contribute to the development of cancer. This is
particularly true with respect to the evolution of mutation-driven
cancer “virulence” during neoplastic progression, as well as the devel-
opment of resistance to therapy (Hara et al., 2005; Karpinets and Foy,
2004, 2005; Karpinets et al., 2006). While certain cancers exhibit an
increase in the frequency of random mutations of several orders of
magnitude compared to normal tissue (Bielas et al., 2006), there are
examples of human cancers that do not exhibit an increased mutation
rate (Hall, 1995). Of interest is the possible role played by adaptive
mutation in the development of resistance to the androgen receptor
antagonist bicalutamide in prostate cancer cells (Hara et al., 2005).
Here, the undirected “mutator phenotype” mechanism has been in-
voked, with evidence that LNCap prostate cancer cells respond to a
bicalutamide challenge by upregulating expression of error-prone DNA
polymerases, while downregulating expression of mismatch repair
(MMR) proteins, resulting in an overall increased mutation rate (Hara
et al., 2005). Several hypotheses have been postulated to explain un-
directed adaptive mutation. These include: replication and re-
combination systems, slow repair of mismatched bases, mutagenic
transcription, and gene amplification/duplication (reviewed in
Rosenberg, 2001). The most cited potential mechanism for undirected
adaptive mutation is induction of a transient hypermutagenic “mutator

E-mail address: mbordonaro@som.geisinger.edu.

https://doi.org/10.1016/j.biosystems.2019.01.010
Received 13 December 2018; Received in revised form 21 January 2019; Accepted 25 January 2019
Available online 26 January 2019
0303-2647/ © 2019 Elsevier B.V. All rights reserved.
M. Bordonaro
phenotype,” in which the mutation frequency is increased by up to
several orders of magnitude (Foster, 2007; Hall, 1991a; Kugelberg
et al., 2006).
In contrast, directed adaptive mutation is a process in which se-
lective pressure specifically induces mutation in those genes whose
products are responsible for mediating the adaptive response. We pro-
pose that directed adaptive mutation is component of the cell’s ability
to adapt to a changing environment. This form of targeted adaptive
mutation would not be associated with a generalized increase in the
mutation rate, and therefore would not exhibit the mutator phenotype.
Therefore, alternative mechanisms need to be hypothesized and eval-
uated to explain directed adaptive mutation. We have proposed a
general model of directed adaptive mutation (Ogryzko, 1997, 2008;
Bordonaro and Ogrzko, 2013) which is summarized as follows. A di-
rected mutation that enables, e.g., cell growth will occur only (a) in an
environment suitable for cell growth, and (b) only after exposure to that
specific environment. The same growth-promoting mutation would not
occur in an environment that promotes, e.g., cellular quiescence or
apoptosis. Therefore, each specific microenvironment would be corre-
lated with a specific set of potential cell states (e.g., wild-type or mutant
DNA sequences). These mutations do not occur randomly; instead, the
cellular microenvironment selects the possible spectrum of cell states
possible in that environment. Subsequently, an irreversible change in
the state of the cell (e.g., proliferation or death) establishes the mutant
state as that which is observed, “fixing” the cell state as an observable.
According to our model, quantum coherence contributes to the devel-
opment of directed adaptive mutations through a process we call “basis-
dependent (quantum) selection.”
2. Quantum biology and adaptive mutation: density matrix and
fluctuation well trapping
Quantum mechanisms may mediate directed adaptive mutation
(Ogryzko, 1997, 2008; Bordonaro and Ogrzko, 2013), and may play a
role in directed evolution (Melkikh and Khrennikov, 2016). In our
basis-dependent model of directed adaptive mutation, biological
quantum superposition is context-dependent, and exists only during the
change of environmental conditions. Since there is no requirement to
maintain quantum coherence for some arbitrary period, past criticisms
(Seife, 2000; Tegmark, 2000) of quantum biology (e.g., “biological
systems are too warm and complex to maintain quantum coherence”)
are not relevant for the specific model proposed here. Further, re-
gardless of how the problem of coherence vs. decoherence is ap-
proached in our hypothesis, we note that quantum coherent effects
have been observed in biological systems, including systems at room
temperature (reviewed in Lambert et al., 2013). However, the role of
quantum effects in adaptive mutation has not been established. We will
summarize the arguments, made in greater detail previously
(Bordonaro and Ogrzko, 2013) for basis-dependent selection, before
considering cell death and neoplasia from a quantum biological per-
spective.
The density matrix formalism can be utilized to apply quantum
mechanical principles to biological states. The density operator de-
scription is most appropriate for biological systems, since such systems
are large and complex; further, their environment cannot be exactly
controlled, as compared to prepared pure quantum states involving,
e.g., individual photons, electrons, protons, neutrons, etc. A density
matrix describing a physical system, such as a cell state, can be envi-
sioned, for the sake of simple illustration for the “layman,” as a table
with a matching number of rows and columns. The basis of a density
matrix represents the alternative states of the system represented by the
matrix, and these states label the rows and columns of the density
matrix table. The cells of the table can be divided into two categories.
First, we term “diagonal elements” those cells in which the labels of the
rows and columns are the same. Second, off-diagonal elements” de-
scribe those elements in which the rows and columns have different
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BioSystems 178 (2019) 16–24
labels. Thus, in a theoretical matrix containing ten rows and ten col-
umns, the diagonal elements would be those describing the contents of,
e.g., cell of row 1, column 1; cell of row 2, column 2…reaching the cell
of row 10, column 10; forming a diagonal set of states. All the other
possible cell states (e.g., cell of row x, column not-x) would describe the
off-diagonal elements.
The diagonal terms correlate with the probability of finding the
system in a particular basis state. In contrast, the off-diagonal terms
describe interference between different basis states. Thus, the presence
of off-diagonal terms means that the system is in superposition relative
to the chosen basis (Bordonaro and Ogrzko, 2013). With respect to the
density matrix, decoherence refers to disappearance of the off-diagonal
terms as the system becomes irreversibly linked to the environment.
Given that the states of the system that survive decoherence are the
preferred basis states, decoherence must be a basis-dependent phe-
nomenon. For example, a diagonal density matrix can always be de-
scribed in a different basis, and, if so, off-diagonal terms will reappear,
as the original preferred states are represented in the new basis.
Therefore, in this new basis, we will observe interference between
states (i.e., superposition) and these off-diagonal terms will naturally
disappear via the coevolution of the system with its environment (i.e.,
decoherence). This is of direct relevance to the biological situation of
adaption, since a change in basis is analogous to a change in the en-
vironment. These events – change in basis, generation of off-diagonal
terms in the cellular density matrix, decoherence via coupling to the
environment, followed by “collapse” to a defined observed state – can
describe the process of a cell’s adaption to a novel environment
(Bordonaro and Ogrzko, 2013). Thus, this form of quantum selection is
termed “basis-dependent selection” since the preferred states of the
system, and the presence or absence of superposition (off-diagonal
terms of the density matrix), are dependent upon the chosen basis.
The process described above is analogous to the concept of “fluc-
tuation well trapping,” in which a specific quantum state is “captured”
or “fixed” through an irreversible interaction with the environment
(Ogryzko, 1997, 2008; Bordonaro and Ogrzko, 2013). First, assume that
a cell can be in states A1 or A2; each state represents the phenotypic
consequences of particular gene sequences. In environment B1, the two
states A1 and A2 cannot be distinguished; however, the state of the cell
can be represented as a superposition of A1/A2 in anticipation of a
change to a new environment B2. In other words, in environment B1 the
state of the cell can be viewed as “fluctuating” between the two alter-
native states A1 or A2. However, in the new environment B2, cell states
A1 and A2 can be distinguished, since B2 allows for cells in state A2 to
proliferate and undergo clonal cell expansion, while cells in state A1
remain quiescent. The change from a quiescent cell in environment B1
to clonal expansion in environment B2 represents an irreversible change
that “traps” cell state A2. Therefore, if several cells were originally in
environment B1, after the switch to environment B2 an increasing
number of cells with state A2 will be observed, as these are the cells
whose state is “trapped” or “fixed” through clonal expansion. If, after
the change in environment, cells can be in either state A1 or A2 and if
only those cells in state A2 grow, then over time, only cell colonies
characterized as state A2 will be observed.
There is an essential difference between this scheme and regular
Darwinian selection. In adaptive mutation, selection is implicated at
two different steps in two different time scales (shorter and longer).
First, in our model, selection acts to generate the “virtual population” -
i.e., the spectrum of different alternatives (i.e., elements of the new
basis), that are allowed in the new environment. Second, selection also
results in choosing certain “best fit” elements out of this virtual popu-
lation. The first step corresponds to the shorter time scale, and the
second step to the longer time scale, although as we shall see the two
steps are in fact inseparable. One way to formalize the interplay be-
tween these two modes of selection is the notion of “self-reproduction
in imaginary time” (Ogryzko, 1997, 2008; Bordonaro and Ogrzko,
2013). In this description, the two steps of selection process are present,
M. Bordonaro
now in the form of an opposition between reproduction in imaginary
time versus reproduction in real time. A quiescent cell is described as
reproducing in imaginary time, since at this shorter time scale one can
neglect exchange with the environment; hence, the intracellular dy-
namics can be approximated by unitary evolution. Reproduction in real
time (e.g., after an adaptive mutation) corresponds to a longer time
scale; thus, the switch from the starving cell state to the reproducing
cell state can be described as Wick rotation, from imaginary time to real
time (which are orthogonal to each other). The nonseparability be-
tween the two time scales is manifested by the fact that the conditions
of measurement (i.e., what happens in real time) determine how one
must represent the state of the cell before the measurement, i.e., while
it is “reproducing in imaginary time” Namely, the change to different
environmental conditions will lead to the same state of the quiescent
cell expanded in a different basis. The basis-dependent superposition is
observed as a definitive mutation after a change in the microenviron-
ment allows mutant cells to undergo an irreversible change; e.g., pro-
liferation or apoptosis. The difference between this scheme (described
by operator formalism) and Darwinian mutation, is shown in Fig. 1.
To summarize, as per basis-dependent selection: the practical
manifestation of gene sequence variants is dependent upon the en-
vironment. Therefore, we assume an environment in which cells can
grow if they have gene variant “X” – a variant that would require
mutation (e.g. from base tautomerism due to proton tunneling). In any
other environment, cells with gene variant X would not grow.
Importantly, many other gene variants would be irrelevant to cell
growth in this environment. Cells with gene variant X will be observed
only if those cells survive and proliferate. Therefore, cells with X,
generated by quantum effects at the gene sequence will be observed,
and observed only in the “permissive” environment. If the gene variant
does not occur, the cell would not proliferate. The environment “traps”
the gene variant – hence, “fluctuation well trapping” – through the
physical manifestation of the survival and proliferation of the cell that
has that variant. With respect other possible variants, they may not be
observed if those variants do not contribute to cell survival.
All possible gene variants and consequent cell states reproduce in
imaginary time (Bordonaro and Ogrzko, 2013). But only those gene
variants that confer an adaptive advantage in a given environment are
observed; as reproduction in real time. Otherwise, such cells would not
be observed and we would not be able to isolate DNA from the cell with
the relevant mutation. The mutation is directed because the production
of the adaptive mutation is not due to a non-specific increase in the
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BioSystems 178 (2019) 16–24
Fig. 1. Differences between random “Darwninian” (A) and
quantum-mediated directed adaptive (B) mutation. (A) Mutations
are random and typically pre-exist selective pressure. Cells with
different DNA sequences at the relevant allele may have different
survival rates in varying environments, which “selects” the most
“fit” cell-sequence configuration by favoring its replication. In the
figure shown, the “black” cell containing a mutated version of the
relevant gene is more able to survive in the particular environ-
ment, increasing the frequency of cells containing this DNA se-
quence. (B) In a quantum-mediated adaptive mutation event, the
possible outcomes are directly influenced by the environment. An
Operator “X” working on the state space of the system selects
possibilities “X” or “not X” as possible outcomes, and the actual
outcome of X vs. not X is random. Similarly, a different Operator,
“Y,” selects “Y” or “not Y” as possible outcomes and the Y/not Y
outcome can be random. Here, “X” and “Y” may represent dif-
ferent gene mutations, and “not X” and “not Y” represent the re-
spective wild-types. Operators are measurables of the system such
as proliferation or apoptosis in particular environments.
Therefore, in (A), randomness occurs from the beginning of the
process, in that the mutational choices for the possible outcomes is
random, but the choice of outcome (growth or not) is selected by
the environment. In (B), the mutational choice of outcome (X or
Y) is selected by the environment, and the outcome of X/not X or
Y/not Y is random.
mutation rate, but rather the idea is that the environment determines
the potential state space of gene variants (and cell phenotypes) and only
those are subject to decoherence and measurement (however defined).
3. Base tautomerism
A simple example of how quantum mechanical effects can be
manifested in adaptive mutation is through base tautomerism (super-
position of base isomers), which result in base substitution mutation.
For example, given a change in basis (a change in the cellular micro-
environment), the density matrix of a cell can contain off-diagonal
terms representing interference between cell states in which keto or
enol forms of guanine are at a given position in a gene sequence. Enol
guanine can base-pair with thymine (or uracil in RNA transcription),
introducing mutation. The same principle can occur with, e.g., amino
and imino forms of cytosine, with the imino form base-pairing with
adenine. If we assume that the mutant gene sequence in question codes
for a product that allows for the cell to proliferate in the relevant en-
vironmental conditions, adaptive mutants G > A and C > T will be
observed.
This hypothesis is supported by W.G. Cooper’s analysis of T4 bac-
teriophage mutation data (Cooper, 2009, 2011; 2012). Cooper identi-
fied G and C bases as particularly sensitive to proton tunneling, re-
sulting in a lowest-energy state consisting of a linear combination (i.e.,
superposition) of G-C isomers (Cooper, 2009, 2011; 2012). PCR ana-
lysis, which has been used to probe DNA quantum superposition in vitro
(Bieberich, 2000), also supports our proposed mechanism. A study of
the effects of primer-template mismatch determined that G-T and C-A
mismatches minimally affect PCR amplification efficiency; other types
of base pair mismatch diminish amplification to a far greater extent
(Stadhouders et al., 2010). This suggests that base tautomerism allows
G-T and C-A mismatches to be sufficiently energetically stable to not
significantly diminish amplification efficiency. PCR amplification in
vitro is analogous to DNA replication and RNA transcription in vivo;
Successful PCR amplification is a “potential well” “capturing” base
tautomerism (enol G and imino C) that results from the linear combi-
nation of G-C isomers (Cooper, 2009, 2011; 2012). These mismatches
will result in the G > A and C > T base substitutions that are con-
sistent with our hypothesis (Ogryzko, 1997, 2008; Bordonaro and
Ogrzko, 2013) and which were identified by Cooper (Cooper, 2009,
2011; 2012). Importantly, these G > A and C > T base substitutions
are represented among mutations leading to colorectal cancer, as will
M. Bordonaro
be discussed in Section 5.
The generalized theory of basis-dependent selection environment
(Ogryzko, 1997, 2008; Bordonaro and Ogrzko, 2013) involves more
than just base tautomerism, and extends to all correlations of altered
gene expression and associated cellular phenotypes that are constrained
by the environment. However, we stress that the findings of Cooper
(2009; 2011; 2012) and Brieberich (2000) clearly establish a physical
mechanism for the generation of gene variants underlying basis-de-
pendent selection (i.e., proton tunneling leading to superposition of
isomers, resulting in mutation via base tautomerism). Therefore, even if
other proposed mechanisms require validation, already established
mechanisms would minimally provide the physical basis for the pro-
posed hypothetical mechanism.
4. Carcinogenesis and mutation, general considerations
Cancer can be understood as an adaptation process. It therefore
comes as no surprise that the “Darwinian” mechanism (i.e., natural
selection of randomly generated mutations) has been applied to the
description of tumor progression (Nowak et al., 2002; Gatenby and
Vincent, 2003; Kimmel, 2010). However, the possibility of adaptive
mutation in carcinogenesis should also be considered. It has long been
established that multiple mutations contribute to the development of
cancer. This notion was first formulated in Knudson’s “two hit hy-
pothesis” (Knudson, 1971), and later it has been argued that the typical
cancer contains at least four (Loeb, 1991) or five (Stein, 1991) driver
gene mutations facilitating tumor growth. Moreover, a significant
portion of human cancers likely contain more than nine relevant driver
mutations (Hollstein et al., 1991). The usual expectation is that these
mutations and their selection occur in a consecutive manner. However,
it has never experimentally confirmed whether two pertinent values:
(a) the levels of “fitness” increase, caused by the mutation, and (b) the
costs of selection, required for the “adaptive” changes to be fixed in the
heterogeneous population of cancer cells, match the reality met in the
confines of a host organism. Thus, a potential problem with multistep
carcinogenesis is that the odds that all the multiple mutations will occur
in the same lineage is low, and in theory, tumors should never be de-
tected (Hall, 1995; Loeb, 1991; Stein, 1991). Of course, an additional
factor that could be at work in multistep carcinogenesis is enhanced
mutation rates, i.e., the early mutations that occur in human cancers
result in a mutator phenotype (Loeb, 1991; Jackson and Loeb, 1998).
However, there are examples of human cancers that do not exhibit an
increased mutation rate (reviewed in Hall, 1995). The strict Darwinian
scheme of multistep carcinogenesis may be putting too many require-
ments on the possible mutation rates, selection pressures and cell
generation numbers required to explain tumor appearance and sub-
sequent progression. On the other hand, quantum selectionism proposes
more subtle links between cell variability and selection conditions
(Fig. 1), and does not pose such strict constraints on the values of these
parameters.
With respect to basis-dependent selection and fluctuation well-
trapping, one intriguing potential model to explore is the effect of
wounding on tumor promotion. For example, there is an association
between wounding and the mobilization of hair stem cells in carcino-
genesis (Wong and Reiter, 2011). One simple model whereby wounding
can induce cancer would be through the loss of contact inhibition,
which would normally repress uncontrolled cell growth and prevent the
amplification of certain virtual pro-proliferative mutations. Assuming a
“quantum selectionist” mechanism for mutation generation, wounding
would remove the constraint of contact inhibition, allowing for the
amplification of mutations through the clonal expansion of cells pos-
sessing the relevant mutation (Fig. 2).
In relation to the model discussed in Section 2, the loss of contact
inhibition due to wounding represents the shift from an environment
not permissive for cell growth (E1) to one that allows for cell growth in
the presence of the appropriate cell state (E2). Using the density matrix
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BioSystems 178 (2019) 16–24
formalism, the change in environment due to wounding is analogous to
a basis transformation. Thus, the old preferred states of the cell before
wounding can be expressed in terms of the new basis (post-wounding
cell environment), resulting in the appearance of off-diagonal terms.
These off-diagonal terms, representing interference between states in
the new basis, may include superposition of states leading to un-
controlled cell growth. Decoherence will eliminate these off-diagonal
terms, leaving a new set of preferred states for the new basis, including
cell states characterized by gene sequence mutations allowing for
growth in the absence of contact inhibition (i.e., post-wounding).
Fluctuation well trapping will result in the observation of cell growth of
those cells containing the appropriate pro-proliferative mutation, as
described above.
Another issue relevant for oncology is programmed cell death.
Although adaptive mutation has traditionally been invoked to explain
cell proliferation, we extend the scope of the fluctuation trapping
model, applying it to mutations that cause cell death as well (Bordonaro
and Ogrzko, 2013). Our main argument is that, like proliferation, cell
death is also an irreversible process. Therefore, the mutations that favor
cell death could also be a subject of fluctuation well trapping in ap-
propriate environmental conditions. Then, like quantum measurement
and adaptation, apoptosis and other cell-death decisions can be also
described by operator formalism (Fig. 1). Accordingly, quantum
biology predicts that, like mutations beneficial for cell growth, the rate
of mutations or epigenetic alterations leading to apoptosis and other
forms of cell death can be affected by environmental changes. There are
obvious implications for cancer in this scenario, since apoptosis often
results from the imbalance in cell cycle regulation that accompanies
cancer development. In addition, many anticancer drugs work by in-
ducing apoptosis (and other forms of cell death).
5. Colorectal cancer as a model
We consider colorectal cancer as a particularly useful model for the
analysis of the adaptive mutation-cancer paradigm, since this disease is
predominantly derived from well characterized mutations in defined
cell signaling pathways. In addition, both neoplasia and prevention are
influenced by specific changes in the cellular environment, such as diet
(reviewed in Bordonaro et al., 2008; Lazarova and Bordonaro, 2012).
Most cases of colorectal cancer are initiated by mutations in the Wnt
signaling pathway, resulting in deregulated Wnt activity (Korinek et al.,
1997). The most common Wnt pathway mutation is of the APC gene.
Truncated APC proteins are no longer capable of efficiently repressing
the levels of transcriptionally active beta-catenin, resulting in deregu-
lated Wnt signaling. Thus, inappropriate constitutive Wnt signaling,
within a specific range of transcriptional activity, results in neoplasia
(Albuquerque et al., 2002; Korinek et al., 1997). Many mutations in
APC have been characterized. A typical spectrum of APC mutations
(point mutations, deletions, and insertions) was observed in The
Netherlands Cohort Study (Luchtenborg et al., 2004); a total of 978
mutations were detected in 665 sporadic CRC patients. Of these gene
abnormalities, 833 were point mutations, 126 were deletions, and 19
were insertions. Among the point mutations, the large majority were
transitions, with G > A and C > T being particularly well re-
presented; this is consistent with the quantum mechanical analysis of
T4 bacteriophage mutation data (Cooper, 2009, 2011, 2012), and fits
with a basis-dependent quantum selection method influencing base
tautomerism (Bordonaro and Ogrzko, 2013).
An interesting and useful feature of APC mutations is the broad
spectrum of the phenotypic consequences that they can have. Mutations
resulting in very high levels of Wnt activity induce programmed cell
death rather than uncontrolled proliferation, while APC mutations that
result in moderate levels of Wnt activity drive proliferation and neo-
plastic transformation (Albuquerque et al., 2002). Further, treatment of
Wnt positive neoplastic cells with histone deacetylase inhibitors such as
butyrate, a breakdown product of dietary fiber, hyperactivate Wnt
M. Bordonaro
activity and induce apoptosis (Bordonaro et al., 1999, 2007; Lazarova
et al., 2004). Therefore, definite correlations have been documented
between the type of APC mutation, levels of Wnt activity, environ-
mental factors, and the physiological outcome for the colonic cell
(Lazarova and Bordonaro, 2012).
The “just right” hypothesis of APC mutation in colorectal cancer
(Albuquerque et al., 2002) is particularly intriguing considering the
possibilities for adaptive mutation in neoplasia. This hypothesis starts
with the fact that there is a spectrum of possible mutation states (in-
cluding deletion) for the two APC alleles of a given cell. Each set of APC
sequence combinations is associated with associated phenotypic out-
comes in specific potential cellular microenvironments. The neoplastic
“read-out” of “just right” mutation is deregulated cell proliferation,
fixing the mutations as the adaptive response through clonal expansion
of the cell containing the mutations. Quantum-mediated adaptive mu-
tation is particularly relevant for explaining the “just right” distribution
of the mutation hit of the second APC allele. Thus, in our model, the
characteristics of the original APC mutation contributes to the overall
cell state that influence the induction of the “correct” mutation of the
second allele.
A related example considers the role of tyrosine 654 phosphoryla-
tion of beta-catenin on Wnt signaling and intestinal tumorigenesis (van
Veelen et al., 2011). Activation of receptor tyrosine kinases (RTKs) by
overexpression, mutation, or growth factor release in the cellular mi-
croenvironment results in tyrosine 654 phosphorylation of beta-ca-
tenin, enhancing Wnt signaling and potentiating intestinal tumorigen-
esis (van Veelen et al., 2011). Importantly, tyrosine 654
phosphorylation of beta-catenin can synergize with APC mutation to
enhance intestinal tumorigenesis; this likely occurs by increasing Wnt
activity within the range of pro-proliferative levels of Wnt signaling.
Therefore, the presence of activated RTKs, in the context of a cellular
milieu favoring cell growth as an adaptive outcome, may favor (or
“induce”) specific sets of pro-proliferative APC mutations, above and
beyond what would be expected from random Darwinian processes.
However, in another cellular microenvironment, one in which un-
controlled growth is not an optimal adaptive outcome for cell, the
presence of activated RTKs would not favor pro-proliferative APC mu-
tations, but may favor genetic changes correlated to, e.g., quiescence or
apoptosis.
Therefore, quantum-mediated APC mutation can be viewed as
analogous to fluctuation well trapping (Fig. 3). We can also represent
the process of quantum-mediated adaptive APC mutation using the
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BioSystems 178 (2019) 16–24
Fig. 2. Contact inhibition and the amplification of virtual mutants
in cancer. (A) An example of general carcinogenesis induced by an
environmental trigger such as loss of contact inhibition. At left,
there is a wild-type cell “WT” and three examples of cells with
virtual mutations associated with the ability for continuous, un-
controlled proliferation. With maintenance of contact inhibition
(top), the mutations cannot be amplified, since the environment
will not allow clonal expansion. However, with wounding, wound
healing, and the loss of contact inhibition (bottom), clonal ex-
pansion can occur, resulting in amplification of mutations al-
lowing uncontrolled growth. Neoplasia results, and this can be
viewed as an “adaptive mutation” to the wound environment. (B)
For large bowel neoplasia, there can be several virtual mutations
of the APC gene, one of which (black filled circle) results in a
moderate level of Wnt signaling consistent with uncontrolled
proliferation. Thus, mutation can be amplified via clonal expan-
sion of the cellular microenvironment allows for proliferation of
cells containing this mutation. Examples can include in-
flammatory bowel disease, dietary changes, mutations in other
signaling pathways, etc. Only in particular environmental con-
texts are specific pro-proliferative virtual mutations amplified and
observed; “induced” or adaptive mutation leading to carcinogen-
esis.
density matrix formalism (Fig. 4), analogous to our general model of
directed adaptive mutation as a quantum biological phenomenon
(Bordonaro and Ogrzko, 2013).
cancer well trapping model. (A) In Environment 1 (Basis 1), no cell
growth is possible regardless of the mutational state of the relevant
gene; here represented by APC. The environment therefore cannot
distinguish between the wild-type and mutant APC states, which, with
their associated cell types, can remain in superposition in this basis. The
“mutation well” is irrelevant in this environment. (B) A change to
Environment 2 (Basis 2) produces a situation that allows outgrowth of
“black” cells containing the “correct” APC mutation that allows cell
growth. The environment therefore allows us to distinguish different
APC gene sequences and their associated states. Cells that randomly
happen to have their DNA sequence in the correct APC format will
grow, amplifying and fixing the mutation/mutated cell phenotype. In
other cells, the APC gene (and cell phenotype) will remain in super-
position and each time the gene sequence/phenotype is in the “correct”
configuration, this configuration will be “trapped” in the “mutation
well” by cell outgrowth and amplification/fixation of the mutation/
mutated cell phenotype.
Building upon Fig. 4, and using a density matrix model for illus-
tration, we start with a situation in which the colonic cells exhibit a set
of preferred states in one given environment E0; thus we have a diag-
onalized matrix (mixture of states with no superposition:
ρ= 1/2 |Σ1 > < Σ1 | + 1/2 |Σ2 > < Σ2 | = 1/2 (10 01)
The preferred states here can represent APC gene sequences and
associated cell phenotypes (e.g., normal regulation of Wnt signaling and
normal regulation of cell proliferation).
If the cells are placed in a pro-proliferative and carcinogenic en-
vironment E1, then the old preferred states have to be written in the
basis of this new environment; thus:
( )
ρ= 1/ √2 |Ψ > < Ψ | = 1/2 1 1
1 1
We now have off-diagonal terms representing superpositions, as the
cells are exploring the state space in this new environment. We can
consider these off-diagonal terms to be superpositions of APC gene
variant states (physically generated e.g., by quantum proton tunneling
leading to base tautomerism) and correlated states of the cell.
Decoherence then eliminates the off-diagonal terms, thus:
M. Bordonaro BioSystems 178 (2019) 16–24

Fig. 3. A cancer well trapping model. (A) In Environment 1

(Basis 1), no cell growth is possible regardless of the muta-
tional state of the relevant gene; here represented by APC. The
environment therefore cannot distinguish between the wild-
type and mutant APC states, which, with their associated cell
types, can remain in superposition in this basis. The “mutation
well” is irrelevant in this environment. (B) A change to
Environment 2 (Basis 2) produces a situation that allows
outgrowth of “black” cells containing the “correct” APC mu-
tation that allows cell growth. The environment therefore al-
lows us to distinguish different APC gene sequences and their
associated states. Cells that randomly happen to have their
DNA sequence in the correct APC format will grow, amplifying
and fixing the mutation/mutated cell phenotype. In other
cells, the APC gene (and cell phenotype) will remain in su-
perposition and each time the gene sequence/phenotype is in
the “correct” configuration, this configuration will be
“trapped” in the “mutation well” by cell outgrowth and am-
plification/fixation of the mutation/mutated cell phenotype.

Fig. 4. Basis-dependent selection of APC mutations.

(A) Top left. Colonic cell in environment E0 re-
presented by a diagonal density matrix showing pre-
ferred cell states with particular DNA sequences (D).
E0 can be considered an environment that does not
promote either cell growth or cell death. Right. To
describe the adaption of the cell to new environment
E1, we represent the same state shown in top left in the
basis of preferred state of environment E1 (top right) or
E2 (bottom right). E1 is an environment that promotes
cell growth, while E2 is an environment that promotes
cell death. Note that representing the original state in
the new basis for E1 or for E2 results in off-diagonal
terms in the cellular density matrix, which represent
interference between basis states. For E1, the old states
are written in terms of the cell growth basis, with
terms representing cell states with APC gene sequences
that may be associated with cell growth (AGn). For E2,
the old states can be written in terms of the cell death
basis, with terms representing cell states with APC
gene sequences that may be associated with cell death
(ADn). Despite the fact that the original state can be
represented in a new basis, it remains stable as long as the cell is in E0. (B) Top and bottom. After the cell is placed in the new environment E1 or E2, decoherence
results in the disappearance of the off-diagonal terms. We are left with the preferred states of the new basis for E1 (cell growth) or E2 (cell death). (C) The collapse
(reduction) chooses one of the states (far right). This can lead to uncontrolled cell growth resulting from an APC mutation characterized by moderate levels of Wnt
signaling (|Ψ >) in E1 or an APC mutation resulting in apoptosis due to extremely high levels of Wnt signaling in E2 (|Φ >).

ρ= 1/2 |Ψ1 > < Ψ1 | + 1/2 |Ψ2 > < Ψ2 | = 1/2 (10 01) Decoherence would lead to a mixed state, with pro-apoptotic APC
gene variants:
So, in the new environment E1 we have new preferred states of the
APC gene, which can be compatible with unregulated Wnt signaling
ρ= 1/2 |Φ1 > < Φ1 | + 1/2 |Φ2 > < Φ2 | = 1/2 (10 01)
and cell growth. After “measurement” we have one observed state,
Finally, in the end, we observe an apoptotic cell with an APC gene
which can be a neoplastic cell with a growth-inducing APC gene var-
variant and Wnt signaling consistent with apoptosis:
iant:

ρ= 1 |Ψ > < Ψ | = (10 00) ρ= 1|Φ > < Φ| = (10 00)

The broad spectrum of various APC mutations, observed in colon
What if the cells was placed in environment E2 instead, an en-
cancer, and the variety of documented outcomes from their interaction
vironnement more conducive to apoptosis? We would then write the
with different environmental (or intracellular conditions), may prove to
original preferred basis states in the new basis thus:
be a fertile resource for experimental systems used to detect the ap-
ρ= 1/ √2 |Φ > < Φ| = 1/2 1 1
1 1 ( ) pearance of mutations in a directed/adaptive fashion, causing either
cell proliferation or apoptosis. We would like to emphasize a crucial

21
M. Bordonaro
point. Spontaneous, random mutations that occur independently of
changes in the environment and selective pressures (“Darwinian”) will
always remain an important source of genetic variation contributing to
carcinogenesis. What we propose is that in addition to standard, clas-
sical mechanisms, adaptive mutation may also play a role, particularly
in those cases in which a mutation can cause a radical alteration in cell
fate in a rapidly changing environment. Therefore, a combination of
“Darwinian” and adaptive mutation may contribute to the highly
complex and multi-variable nature of biological systems.
To summarize: the APC example underscores the utility of colorectal
cancer as a model system for consideration of adaptive mutation in
neoplasia. Notably, the same concepts can be eventually applied to
virtually any other cancer characterized by well-defined mutations that
allow adaptive advantages in certain cellular microenvironments. It is
likely that as we learn more about neoplasia, and the heterogeneity of
cell types within the tumor, as well as the role of selective pressures in
initiation, progression, and metastasis, other examples similar to the
APC model will come to our attention.
Therefore, the task is to understand: first, whether the adaptive
mutations phenomenon exists; and second, what could be its quanti-
tative contribution, compared to the standard Darwinian mechanism.
6. Experimental approaches and implications for prevention/
treatment
In this section, we will describe some potential experimental models
to test the predictions of Quantum Biology in the field of oncology.
They mostly concern the evaluation of adaptive mutations in the con-
text of cell proliferation or apoptosis.
We will describe a general experimental scheme to accomplish this
task. First, by performing a fluctuation test (reviewed in Rosenberg,
2001), it should be possible to determine whether a genetic variation A
was generated in the cell population before the application of selective
conditions B1. If a deviation from the Luria-Delbruck distribution is
observed, the next task is to rule out as a mechanism increased muta-
tional variability (e.g., mutator phenotype) due to the stress induced by
selection condition B1. The cells should be left for a prescribed amount
of time in a condition B2 that does not allow proliferation even if the
mutation A has occurred. The accumulation of the mutation A in these
conditions can be monitored directly by DNA extraction, PCR analysis,
and sequencing. Second, like the basis-dependent selection and well-
trapping scheme outlined in Section 2, we can formalize an experi-
mental approach in terms of two conditions that constrain cell growth.
The first constraint (“A”) is associated with the state of a gene (or an
epigenetic variation) that we would like to follow; and it is lifted when
a mutation occurs (A1 transforms to A2) and thus cells start to pro-
liferate. The second condition (“B”) corresponds to the state of the cell
environment that constraints the cell growth regardless of whether the
constraint A is lifted or not. We assume that environment B1 will not
allow cell growth regardless of the cell state, while environment B2 will
allow growth of state A2. Thus, only one combination of states A and B
(namely, A2 + B2) can lead to cell proliferation.
A general model to evaluate basis-dependent selection in non-neo-
plastic, non-human mammalian cells, using proliferation of mouse
embryonic fibroblast cells, was previously outlined (Bordonaro et al.,
2014). How one can apply this experimental design more specifically to
the oncology context and do so in a manner generally applicable to
different cell states, including apoptosis? We will therefore briefly re-
view what could be done for two types of relevant mutations in human
cancer cells: proliferation-inducing and cell death-inducing mutations.
First, the mutation that corresponds to the transition from A1 to A2
could be an activation of an oncogene or inactivation of a tumor sup-
pressor gene, and it would allow for cell proliferation in certain con-
ditions, but not in others. The state of environment B2 could be pre-
sence of some exogenous factor, such as a growth factor and/or cell
signaling ligand. This scenario can be compared to that in which the
22
BioSystems 178 (2019) 16–24
same mutation occurs in a context that cannot lead to cell proliferation
(e.g., absence of growth factor/ligand). If the frequency of the mutation
is higher in the first instance, this would suggest a contribution of di-
rected adaptive mutation. Potential experimental scenarios involving
colorectal cancer could focus on APC mutation (first constraint) and
alterations in the environment (second constraint; e.g., presence of
HDACis, chemotherapeutic agents, cell crowding/growth factor deple-
tion, etc.) that would change the adaptive fitness of varying APC gene
sequence-Wnt signaling correlations. One could then evaluate the fre-
quencies of different forms of APC sequence alterations according to
“Darwinian” or adaptive mutation models, using the general scheme
described above.
Second, for apoptosis-inducing mutations, the technical challenge is
to determine their frequency, given that the cells are not expected to
survive, i.e., cannot be selected for further analysis. Here, one can take
advantage of the fact that dead cells lyse and release their DNA to the
supernatant. Therefore, one should be able to measure the rate of ap-
pearance of such mutations by quantitative PCR (specific for the mu-
tation) by analyzing DNA purified from the conditioned cell medium. In
parallel, one could also measure the presence of such mutations in the
DNA of remaining living cells. By adding the two frequencies together,
one can estimate the overall frequency of mutations in one type of
environmental conditions (those that trap mutations causing cell death,
e.g., B2). The next step would be to compare this mutation frequency
with the value obtained in the same manner from the same cells, but in
the environmental conditions (e.g., B1) that do not favor pro-apoptotic
mutations. If the fluctuation trapping paradigm holds for pro-apoptotic
mutations, one would expect the mutation frequency to be higher in the
former set of environmental conditions, as compared to the latter set of
conditions that reflect the baseline of random mutation.
With respect to the evaluation of pro-proliferative vs. pro-apoptotic
mutations associated with cancer, a starting point would be APC mu-
tations, which can influence Wnt signaling, depending upon context, to
a degree consistent with either proliferation or apoptosis Albuquerque
et al., 2002; Bordonaro et al., 2008). Environmental conditions influ-
encing the neoplastic process in conjunction with mutation include, but
are not limited to: dietary factors (such as butyrate), autocrine and/or
paracrine growth factors, inflammation, contact inhibition or the lack
thereof, exposure to carcinogens, and changes in gene expression due to
genetic and/or epigenetic changes of other genes, in the relevant cell or
in surrounding cells.
With its potential to change dramatically our view on cancer, it is
intriguing to ask what new possibilities Quantum Biology would sug-
gest for cancer management? For example, given the more direct con-
nection between environment and genetic changes than is granted by
the Darwinian perspective, could there be more possibilities to mod-
ulate and affect the outcomes of cellular “proliferation or quiescence or
death” decisions? Could, for example, by choosing a “correct” en-
vironment, cells be more directly guided towards less tumorigenic
outcomes? Could in other words, mutations leading to cancer be pre-
vented by modulating the environment? Or, if these mutations have
already happened, could we force these cells to undergo apoptosis by
inducing additional mutations or other changes? To the extent that
adaptive mutation plays a role in mammalian cell physiology and in
carcinogenesis (which needs to be empirically determined), altering cell
phenotype through such mechanisms would be a rapid and direct ap-
proach to achieve therapeutic objectives, in addition to the slower
processes involving selection of pre-existing random mutations. An es-
timation of the relative quantitative contribution of adaptive mutation
mechanism would be essential to predict the efficacy of such ap-
proaches.
The new perspective brought by the adaptive mutations mechanism
could also force us to reevaluate certain drug-based therapeutic antic-
ancer strategies. The fluctuation well trapping model requires that cells
have sufficient time to explore the space of possibilities (Ogryzko, 1997,
2008; Bordonaro and Ogrzko, 2013). Thus, to prevent such a
M. Bordonaro
mechanism from occurring, it would be important to use cytotoxic
methods to kill cells quickly. This is because drugs that induce cell-cycle
arrest or other, slower-acting anti-cancer cell treatments would be more
conducive to counter-productive adaptive mutation for resistance.
Further, many preventative approaches, including some dietary inter-
ventions, are relatively slow-acting and, therefore, would likely be more
prone to the appearance of adaptive mutations for resistance. Con-
versely, using adaptive mutation through the fluctuation well trapping
model to promote clinically favorable mutations (e.g., ones causing
differentiation and/or apoptosis) is better achieved through longer-
duration treatments and exposures that would allow cells to explore the
adaptive possibilities. This is a “double-edged sword” in that the same
conditions that allow for “negative” adaptive mutation would also be
best for “positive,” clinically helpful, adaptive mutation. This balance
between positive vs. negative adaptive mutation underscores the im-
portance of selecting the proper environments and treatment regimens
to irreversibly trap the helpful outcomes, without creating the context
in which cellular exploration of clinically negative outcomes is favored.
7. Conclusion
There is an urgent need to understand whether directed adaptive
mutation plays a role in carcinogenesis as well as in the development of
resistance to anticancer therapies. This can have significant implica-
tions for cancer prevention and treatment. In fact, the directed adaptive
mutation paradigm may be particularly relevant for cancer, a disease
characterized by correlations between environmental factors, genetic
changes in defined signaling pathways, and fundamental phenotypic
outcomes. In addition to theory, we present a general outline of ex-
periments to observe adaptive mutation events in mammalian cells, and
further describe how these approaches could be applied to human
cancer. Potential discoveries derived from such experiments will lead to
methodologically more challenging biophysical studies aimed at di-
rectly identifying quantum mechanical processes involved in adaptive
mutation and tumorigenesis. Ultimately, this knowledge can be used to
more effectively prevent, diagnose, and/or treat cancer and other
human disorders.
Funding
This work was supported by The Geisinger Commonwealth School
of Medicine. This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements
Dr. Vasily Ogryzko made important contributions to the ideas un-
derlying this work; unfortunately, Dr. Ogryzko passed away while this
manuscript was in its earliest draft phases. The completed manuscript is
dedicated to his memory.
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