Progress in Biophysics and Molecular Biology 165 (2021) 66e71

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Progress in Biophysics and Molecular Biology

journal homepage: www.elsevier.com/locate/pbiomolbio

Cellular Darwinism: Regulatory networks, stochasticity, and selection

in cancer development
Denis Noble
Department of Physiology, Anatomy & Genetics, University of Oxford, OX1 3PT, UK

a r t i c l e i n f o a b s t r a c t

Article history: There are strong parallels between the evolutionary origin of species within populations of organisms
Received 29 December 2020 and new concepts for the origin of cancers within cell populations in the tissues of the body. The analogy
Received in revised form is that cancers can be regarded as a new somatic species developing within the host organism. In both
8 June 2021
cases, understanding the processes involved requires a multi-scale analysis, including higher-level
Accepted 14 June 2021
control of genetic and epigenetic changes. A key to developing successful therapeutic strategies will
Available online 17 June 2021
be to identify the processes that control heterogeneity in tissues. These include processes outside the
currently dominant theory of evolution, i.e. the Modern Synthesis. Specifically, organisms can partially
Keywords:
Cancer evolution
direct both genetic and epigenetic changes through the harnessing of chance. The loci and rates of
Harnessing of chance mutation and of genome reorganisation are forms of targeted functional reorganisation of genomes. They
Harnessing of stochasticity are more likely to result in functional reorganisations compared to the slow accumulation of point
Hypermutation in evolution mutations.
Tissue heterogeneity © 2021 Elsevier Ltd. All rights reserved.
Central dogma

1. Introduction
A major theme of this Special Issue on Cancer and Evolution is
that there are strong parallels between the evolutionary origin of
species within populations of organisms and new concepts for the
origin of cancers within cell populations in the tissues of the body.
The analogy is that cancers can be regarded as a new somatic
species developing within the host organism. But how, in fact, do
new species develop?
That question is not as obvious as it may seem. Because, to fully
appreciate the parallel between the origins of cancers and the or-
igins of species, we need to turn the current popular theory of
evolution, the Modern Synthesis (Huxley, 1942; Futuyma and
Fitzpatrick, 2018; Coyne, 2009), on its head with regard to
random genetic variations. That theory, also called Neo-Darwinism,
is based on the assumption that inherited variations are always
purely random. The better survival of fitter organisms is then
attributed to natural selection, which is blind in the sense that it
does not purposefully chose which particular variants should be
generated. Variations are undirected even if evolutionary adapta-
tion appears directed. This idea was famously popularised in
Dawkins’ (1986) The Blind Watchmaker.
E-mail address: Denis.noble@dpag.ox.ac.uk.
I will show that the reverse must also be the case. Cells and
organisms can control and use the stochasticity within them, and in
their environments, so that stochasticity is harnessed (Noble, 2017).
Development and evolution then become partially directional. Or-
ganisms can influence their futures and inheritance. The organism
is therefore not just a vehicle for its genes but, together with its
ancestors, can be considered the author of its own genome
(Shapiro, 2017).
As a historical aside, this idea is closer to Darwin's (1859)
“Artificial Selection”, and his later work on “Sexual Selection”
(Darwin 1871). In both cases Darwin's meaning is real (not blind)
selection by organisms themselves. Natural selection, by contrast, is
more like a filter. The idea of selection in “Natural Selection” is
therefore metaphorical. This important distinction is very clear at
the beginning of the Origin of Species (Darwin 1859).
My conclusion will be that there are strong reasons to think that
cancerous tumours are doing something similar. The biological
mechanisms enabling them to do so exist.
2. Terminology
There has been considerable confusion over what is meant in
evolutionary biology by saying that genetic changes are or are not
random. When randomness is harnessed by higher-level functional
systems, they can be both. It then depends on the level from which

https://doi.org/10.1016/j.pbiomolbio.2021.06.007
0079-6107/© 2021 Elsevier Ltd. All rights reserved.
D. Noble
one views what is happening. It is easy to illustrate the difference
by considering what happens in the immune system, or in any
other physiological process involving guided somatic hyper-
mutation. At the hyper-mutating sites e the variable part of the
immunoglobulin sequence in the case of the immune system e the
variations will be seen as stochastic. At the supra-cellular level of
selection the very same process will be viewed as non-random
since it favours the successful cells that produce a match for the
antigen. Yet the success of those cells depends on a random process
at the molecular level. Harnessed randomness is then no longer
purely random (undirected) from the viewpoint of the organism.
The guidance can be either active or passive. As a physiologist I
would define the difference as being whether the guidance is
purely structural or whether it depends on a decision process. The
immune system clearly involves a higher-level choice between the
results thrown up by hypermutation by targeting the process to the
DNA that encodes the antibody-binding variable regions of im-
munoglobulins. Also, the somatic hypermutation process is trig-
gered only in activated B cells that have entered “germinal centers”
in lymph nodes and the spleen. It is targeted.
A good example of passive guidance would be the photosyn-
thetic process. Plants and cyanobacteria passively absorb the pho-
tons that happen to hit them, yet the resulting storage of energy is
clearly not random e it is a canalisation of the radiation energy. But
there is no active selection of photons. This difference is important
to keep in mind when applying the canalisation concept to tumour
development. A key question will be the extent to which flexible
physiological control processes are involved in cancer radiation of
cellular forms and what those might be. The answer to that ques-
tion will also be relevant to possible therapeutic approaches. If the
guidance is through active physiological control processes then we
need to understand how to work with their flexibility to nudge
those processes towards better outcomes. This idea will become
clearer when I introduce the concept of the epigenetic landscape
(Fig. 2).
A further terminological clarification is that what I usually refer
to as “physiological regulatory networks” corresponds with what
many authors call “Gene Regulatory Networks (GRNs).” I don't use
that terminology because the regulation is not by genes, it is
regulation at a higher level. The genes themselves are what are
regulated. GRN terminology sometimes seems ambiguous in rela-
tion to this distinction. The processes involved float largely free of
the genome since, as Huang (2021) argues:
“The GRN is the master system through which a genome im-
poses genome-wide constraints in gene expression, such that
despite random molecular noise, activities of gene loci are not
independent but globally coordinated. This coordination results
in recurrent gene expression patterns that are stable to
perturbations”
3. Cell selection in development
A theory of Darwinian selection amongst random variations in
populations of cells in developing tissues was first developed by
Kupiec (1983, reprinted 2020), although it had a partial precursor in
Weismann's idea of selection amongst germ-line cells (Weismann,
1896). Kupiec (2009) emphasised the role of stochasticity in cellular
development. Elsasser (1984) was also one of the early pioneers of a
non-reductionist model of cellular function leading to similar
conclusions. His approach was non-reductionist precisely because
reductionists tend to avoid stochasticity and espouse determinism.
Writing a commentary on the 2020 republication of Kupiec's
1983 paper, Andras Paldi (2020) has succinctly expressed the
67
Progress in Biophysics and Molecular Biology 165 (2021) 66e71
parallel:
“The apparently predetermined gene expression patterns that
characterise the defined cell phenotypes are the results of a
selective stabilization of some patterns through interactions
between the cells. This way of framing one of the modern bio-
logy's central questions calls for the same reasoning Charles
Darwin proposed to explain the evolution of biological species.
The idea that spontaneous variation followed by selective sta-
bilization of some of these variants can account for the emer-
gence of new cell types during ontogenesis places the evolution
of the species and cell types on the same theoretical ground.”
The emphasis is mine and it speaks for itself. Kupiec's idea is
precisely the key concept of the Cancer and Evolution comparison.
Note though that the influence is not just one way. The study of
cancer benefits from concepts developing currently in evolutionary
processes that lie outside the narrow confines of the Modern
Synthesis (Shapiro and Noble, 2021, this volume). In turn, inter-
preting tumour development, and particularly rapid metastasis, as
a rapid evolutionary radiation strongly reinforces the need to break
out from those narrow confines.
4. Harnessing of chance
By harnessing chance variations organisms canalise develop-
ment and evolution in directions that favour maintenance of their
functions. Canalisation by higher-level (meaning epigenetic, i.e.
above the genome) organisation was first described by Conrad
Waddington (1957). Moreover, as Huang (2021) also notes, the
meaning of ‘epigenetic’ here is not the modern meaning of
“epigenetic regulation by DNA methylation and covalent chromatin
marks.” It is the canalisation process, which includes transitions
between attractor states with no necessary mutations or even
changes in genome or histone marking.
The evolutionary process is therefore not completely blind. It
can be characterised as a form of feeling forwards, the one-eyed
watchmaker rather than a blind one (Noble and Noble, 2017).
Many of the physiological control processes by which organisms
achieve this kind of control are now fairly well understood. The
regulatory networks by which cells maintain their integrity effec-
tively buffer higher levels against molecular-level random varia-
tions (Noble, 2011). This process protects the organism from many
possibly deleterious effects of genomic change by developing
robustness in the functional networks, so ensuring that vital
physiological functions are maintained. Yet harnessing still permits
variation to be used when the organism needs to do so. Harnessing
of chance therefore serves a dual role in living organisms: pro-
tecting function from disorder, while also selecting and targeting
disorder at the cellular and molecular levels when they need to
create novelty.
As a bonus, this view of the relationship between regulatory
networks and the genome automatically explains the very low as-
sociation scores in Genome-wide association studies. These are so
low that it is clear that very many genes must be involved in each
phenotype. Some even go so far as to conclude that perhaps all
genes are involved in every function: now known as the omnigenic
hypothesis (Boyle et al., 2017). This is what we would expect if the
functional networks operating above the level of the genome are
integrating, as they must, the activity of all the gene products
involved. In a completely interconnected system, perturbations of
all components may produce change in overall behaviour.
This issue is of practical importance since it can be used to
distinguish between association and causality. By connecting ge-
nomics data to physiological modeling of functional processes it
D. Noble
may become possible to introduce causal interpretations of
Genome-wide association studies e GWAS (Noble and Hunter,
2020). The low association scores are not only what would be ex-
pected if the functional levels above the genome are strongly
robust, they are also the clues to establishing causality rather than
just association. As I have shown in the case of the robustness of the
cardiac rhythm generator (Noble, 2011), a highly functional
component gene or protein can show a low or even zero association
score. Even a process as central as circadian rhythm can survive the
knockout of a key gene (Debruyne et al., 2006), while studies of
yeast showed that as many as 80% of knockouts can be functionally
silent under standard growth conditions (Hillenmeyer et al., 2008).
Yet most of those knockouts were found to be functional under
conditions of nutritional stress.
Living organisms can therefore be seen as living on the
boundary between order and disorder (Noble, 2021a). Contrary to
Schro€dinger's (1943) proposal that organisms create high-level
order from molecular-level order, life resembles physics, particu-
larly thermodynamics, in creating order from disorder. I have
explained the details of this contrast with Schro€dinger's theory, and
why that theory cannot be correct, in a previous article in this
journal (Noble, 2021c). Furthermore, as already noted above,
determinism and randomness are opposites. So why do we need to
reject Schro€dinger's theory, and its subsequent inspiration for the
Central Dogma of molecular biology (Crick, 1958, 1970)?
The reason is that it is physically impossible for DNA to replicate
like a crystal (which was the metaphorical basis for Schro €dinger's
theory) since, inside a cell, it does not actually form a crystal. In
living organisms it remains at all times a thread, wound around its
mirror image to form the double helix, which is in turn wound
around the chromatin histone proteins. This thread-like character
is necessary for it to be possible for parts of the thread to become
loosened enough from the condensed attachment to the histones to
be read. The sequence is not locked up in the rigid 3-dimensional
structure of a crystal. Replication cannot therefore use the deter-
minate crystal method of self-templating. DNA is not a crystalline
self-replicator.
Schro€dinger could not have known that in 1942. He would have
had to foresee the much later discoveries on the remarkable cellular
machinery of DNA error-correcting processes that can reduce a
natural copying error rate from 1 in 104 base pairs to only 1 in 1010.
What happens then to the Central Dogma of molecular biology?
It loses its status as a general principle of one-way causation in
biology, and reverts to being a more restricted molecular biological
fact about templating: DNA sequences form templates to make
proteins, but protein sequences do not form templates for making
DNA. That is what the molecular biology showed. No more than
that.
The processes by which the organism changes its DNA do not
rely on template information. Fig. 1 illustrates that the flow of
causation then is from higher-level functional networks that can
sense when the organism is stressed in its environment and when
it can use the processes of natural genetic engineering (Shapiro,
2011 2021).
As a side-issue, if DNA does not form a crystal in living cells, how
was the crystallographic data for deducing the double helical
structure of DNA obtained? The answer in the case of Rosalind
Franklin's work, which was used by Watson and Crick, was that she
produced X-ray diffraction patterns from fibrous DNA, the famous
Photo 51 (Pederson, 2020). 3D crystals formed from DNA were not
studied until Alexander Rich's much later work on Z-DNA (Wang
et al., 1979; Ha et al., 2005; Schimmel, 2015). DNA can be made
to form 3 dimensional crystal lattices (Paukstelis et al., 2004) but
these are not the forms in which it exists in a living cell. There is a
partial exception in the case of dinoflagellates where the
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Progress in Biophysics and Molecular Biology 165 (2021) 66e71
Fig. 1. Central Dogma diagram (bottom row of causation) embedded in interactions
with the system of functional causal networks (often called GRNs). The forms of
causation in Crick's 1958 formulation are represented by the blue arrows: DNA makes
RNAs and proteins that then form the networks. All causation is upward. The 1970
reformulation after the discovery of reverse transcription is represented by the orange
arrows. The downward green arrows represent the processes of natural genetic en-
gineering in response to environmental influences (downward black arrows). Purple
arrow represents the influence of network structure on protein folding and function
(Noble, 2021b).
chromosomes exist in a liquid-crystalline state (Chow et al., 2010),
but how these organisms access and replicate their DNA is un-
known. Clearly, the liquid crystalline state must somehow permit
that.
5. Stochasticity in cell populations
Sui Huang (2009, 2013; Pisco et al., 2013; Zhou et al., 2014) and
his colleagues have demonstrated extensive stochasticity of protein
expression even in clonal cell populations. The range of expression
levels can be as much as 1000 fold different from cell to cell. Their
work also shows that the form of distribution within the population
is a population level attractor. If cells are cloned from high ex-
pressers, they initially form a population of high expressers, but
over a few days the distribution of expression reverts to the original
distribution. This is true even in populations showing bi-modal
distributions. Cells cloned from one of the two peaks initially
show the peak from which they were cloned. Over several days the
bi-modal distribution becomes re-established.
Huang uses a diagram inspired by Waddington’s (1957) original
epigenetic landscape diagram to explain his results, as shown in
Fig. 2. In the landscape representation, individual cells will shift
around amongst the various stable positions and the landscape of
their probabilities will determine the overall population distribu-
tion. The epigenetic landscape can therefore be regarded as a
thought-tool embodying the concept of harnessing the random-
ness, and canalising development towards the population attractor.
As an attractor the landscape can persist through cell divisions, just
as happens once cellular differentiation has occurred in the
developing embryo. The same genome can be used to generate
hundreds of different cell types.
What might the function of such stochasticity be? The general
function is that it permits selection amongst cells with different
gene expression profiles, just as the immune system selects
amongst cells with different hyper-mutation outcomes. The dif-
ference lies in whether the stochasticity is genetic or epigenetic. In
conditions of stress this difference may not matter. As Waddington
(1957) first showed, epigenetic changes can canalise development
over a sufficient number of generations to enable genetic assimi-
lation to occur. If rapid mutation is already occurring as a reaction
to stress, the existing genetic variability could be enough to permit
rapid genetic assimilation (see explanation of this process in Noble,
2016, pp 216e219). Speciation then begins. Possible markers for
early stage cancer might therefore depend on identifying the
relevant parts of the regulatory networks that are responsible for
D. Noble Progress in Biophysics and Molecular Biology 165 (2021) 66e71

Fig. 2. An epigenetic landscape diagram to illustrate Huang et al.‘s observation of population attractors in gene expression dynamics. (A) A projected epigenetic landscape with two
attractors [low X (LX), high X (HX)] and their sub-attractors, which contribute to heterogeneity. Each circle represents a network state (i.e. a cellular phenotype) determined by the
level of X as indicated by the position on the horizontal axis (i.e. one state space dimension, trait X, of the high-dimensional state space). The vertical axis displays the ‘potential’ V
(X). The height of the accumulation of circles reflects the density distribution as a function of X. (B) Associated flow cytometry histograms of cell population distributions with
respect to X. Subpopulation sorting can reveal the reversibility and the transition rates between the subpopulations (from Huang, 2009).

the architecture of the epigenetic landscape attractor. That is a big attractors, leads to the view that mutations are largely followers in
challenge since it will require deep understanding of the architec- cancer evolution. This also is a parallel between cancer evolution
ture and complex dynamics of cellular networks. and species evolution (West-Eberhard, 2003).
The process of genetic assimilation, guided by epigenetic

69
D. Noble
6. Tissue stochasticity in cancer and the development of drug
resistance
That is the question tackled by Zhou et al. (2014). They ask
whether the models of population genetics that have been exten-
sively developed within the framework of the Modern Synthesis
could be used. The problem is that “these models tacitly assume a
one-to-one mapping between genotype and phenotype and as-
sume random genetic mutations as the mechanism for cell
phenotype innovation.” This is a serious drawback since genome-
wide association studies have clearly falsified this assumption in
favour of multigenic or even omnigenic theories (Boyle et al., 2017).
New approaches are therefore required (Huang, 2009; Altschuler
and Wu, 2010). The requirements all fall outside the Modern Syn-
thesis framework. Zhou et al. identify the three requirements:
 Reversible state transitions: these transitions are often approxi-
mately symmetrical while mutations in the traditional model
are typically irreversible;
 Frequent state transitions: transition rate often is in the same
time scale as division time or even faster, while mutation rate
per locus is much slower than the division rate.
 Transitions are not strictly non-Lamarckian. Since they are due to
changes of gene expression and not mutations in the genome
they can be induced in a controlled (purposeful) or uncontrolled
manner while mutations are randomly directed and their rates
not easily tunable.
I agree with these requirements, but it is important to note that
the statement “mutations are randomly directed and their rates not
easily tunable” is really just an assumption of standard evolu-
tionary theory. In fact, growth conditions can influence both the
number and spectrum of mutations, and the frequencies are
exquisitely sensitive to stresses, including factors like exposure to
sunlight, as well as factors like mitotic errors. In E. coli the presence
or absence of a DNA polymerase (DNA Pol IV) can dramatically
change the mutation rate (Wagner and Nohmi, 2000).
These requirements require modeling the directed harnessing of
stochasticity as argued earlier in this article. Zhou et al. (2014)
specifically conclude “By uniting the dynamics of reversible tran-
sitions between distinct cell phenotypes with their growth rates,
we can capture the contributions for the evolution of the cell
population from both Darwinian selection and Lamarckian induc-
tion.” Detailed examples of such modeling are given in their article.
Can this approach help in clarifying the relative roles of muta-
tions and epigenetic transitions in cancer development? This is the
issue tackled in Pisco et al. (2013) who have combined quantitative
measurements and mathematical modeling to investigate possible
mechanisms of multi-drug resistance in H60 leukemic cells. The
results clearly show that the speed with which such resistance
develops is better explained by epigenetic transitions. This is
important for two reasons. First, their arguments match well with
parallel arguments in relation to evolutionary biology. Epigenetic
transitions will always enable faster change since there is no need
to wait for single mutations to slowly spread through a population.
The environmental factors that can canalise the relevant epigenetic
transitions will influence the whole population, not just single cells.
Lamarckian evolution is therefore inevitably much faster
(Burggren, 2016). In any situation in which both mechanisms can
operate, the epigenetic one will win out.
The good news is that, for the same reasons, epigenetic variation
could be more readily reversed since the changes are not neces-
sarily assimilated into the genome. Pisco et al.‘s work therefore
reveals a “new opportunity for early therapeutic intervention
against the development of drug resistance.” In a 2013 review
70
Progress in Biophysics and Molecular Biology 165 (2021) 66e71
Huang concludes:
“Of practical relevance is that recognition of the phenomenon of
drug-induced escalation of malignancy opens a new opportu-
nity for therapeutic approaches designed to stifle therapy
resistance: if development of resistance is not a Darwinian
evolutionary progress fueled by random mutations but a
response shaped by network dynamics that involves attractor
transitions, then it is mediated by the molecular signaling
pathways that, in the healthy part of the landscape, facilitate
state transitions during development but now misdirect tran-
sitions into the wrong attractors. These pathways could serve as
therapeutic targets.”
I believe this could be the game-changer in cancer treatment. If
we can nudge epigenetic landscapes in the right direction by
intervening before genomic assimilation occurs then we have the
justification for early intervention. As I hope I have made clear, this
requires abandoning the Modern Synthesis framework as the sole
model for development and evolution. Non-genetic cell plasticity
makes it impossible to explain within the limits of somatic muta-
tion theory (Shen and Clairambault, 2020). Switching to a more
productive approach to cancer therapy is urgently needed since we
are facing not only an impasse in developing successful therapies,
but also a financial one (Fojo et al., 2014).
7. The role of intercellular communication
The existence of tissue-level attractors that determine the sto-
chastic distributions in cell populations requires intercellular
communication. Can cells communicate their epigenetic states to
each other?
One of the ways in which this can be achieved is via intercellular
exchange of information within extracellular vesicles, EVs
(Edelstein et al., 2019). These contain the RNAs and other molecules
that both give a portrait of the epigenetic state of the cells from
which they come, and which can also influence the epigenetic state
of the cells that absorb them. The implications for the development
of cancers are important. Those implications are the subject of
another presentation in this issue of the journal (Bonner and
Willms, 2021).
Cells can also communicate via their electrophysiological
properties, either directly when they are electrically coupled, or via
the ion exchanges with the tissue fluid. These aspects are addressed
in another article in this Special Issue (Levin, 2021).
8. Conclusions
The main conclusion of this article is that the active role of
physiological regulatory networks (often called Gene Regulatory
Networks when they refer to intracellular regulation) can help
explain why so little advance has been made in the treatment of
late stage metastasis. Rapid evolution, of species and tumours, re-
quires more processes than the gradual accretion of point muta-
tions. Mutations are more likely to be followers of the development
of new attractor states at levels above the genome. Therapeutic
strategies would be best targeted at that level of organisation. This
conclusion is compatible with the concept of two-phased cancer
evolution, comprising a genome reorganisation mediated punctu-
ated phase and a gene-mutation mediated stepwise phase, as
outlined by Heng and Heng (2020).
Epigenetic control of genomic and evolutionary changes could
play a role in both phases, particularly if we include Waddington's
early (1957) definition of epigenetics, which was the canalisation of
genomic change by the phenotype followed by genetic
D. Noble
assimilation. The modern definition, by focusing on genome and
chromosome marking has narrowed the concept down compared
to Waddington's work. Both forms of epigenetic process must be
involved to fully understand how the physiological regulatory
networks at all levels carry out their role.
A second conclusion is that the harnessing of stochasticity may
play a major role in tumour development. Genome reorganisation
of tissues under stress would explain the rapid radiation of cell
forms in late stage cancer.
I acknowledge the previous work, more than a decade ago, by
Susan Rosenberg showing that the occurrence of random genetic
mutations may be a tightly controlled, and, in a sense, “purposeful”
response to stressful environments. She and her team presented
good evidence of stress-induced mutagenesis programs (Galhardo
et al., 2007). Rosenberg's hypothesis was that stress-inducible
mutagenesis mechanisms can “accelerate adaptive evolution in
populations specifically when organisms are maladapted to their
environments, i.e., when they are stressed, and then return ge-
nomes to low mutation rates in rare adapted mutants that thrive in
the new environment and so are stressed no longer".
Author statement
This article has not been submitted elsewhere.
No funding supported this work, and I have no conflict of in-
terest to declare.
Acknowledgements
I thank James Shapiro, Azra Raza and Sui Huang for many helpful
comments in writing this article.
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