Available via license: CC BY
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Received: 23 May 2022 Accepted: 11 July 2022
DOI: 10.1113/EP090133
REVIEW ARTICLE
Modern physiology vindicates Darwin’s dream
Denis Noble
Department of Physiology, Anatomy &
Genetics, University of Oxford, Oxford, UK
Correspondence
Denis Noble, Department of Physiology,
Anatomy & Genetics Parks Road, Oxford OX1
3PT,UK.
Email: denis.noble@dpag.ox.ac.uk
Funding information
None
Handling Editor: Jeremy Ward
Abstract
Charles Darwin spent the last decade of his life collaborating with physiologists
in search of the biological processes of evolution. He viewed physiology as the
way forward in answering fundamental questions about inheritance, acquired
characteristics, and the mechanisms by which organisms could achieve their ends
and survival. He collaborated with 19th century physiologists, notably John Burdon-
Sanderson and George Romanes, in his search for the mechanisms of transgenerational
inheritance. The discovery that the genome is not isolated from the soma and the
environment, and that there is no barrier preventing somatic characteristics being
transmitted to the germline, means that Darwin’s pangenetic ideas become relevant
again. It is time for 21st century physiology to come to the rescue of evolutionary
biology. This article outlines research lines by which this could be achieved.
KEYWORDS
Charles Darwin, evolutionary biology, extracellular vesicles, George Romanes, inheritance of
acquired characteristics, John Burdon-Sanderson, pangenesis
1HISTORICAL INTRODUCTION: DARWIN’S
PHYSIOLOGICAL COLLABORATIONS
This article revisits an earlier article published in Experimental Physio-
logy nearly a decade ago (Noble, 2013) entitled ‘Physiology is rocking
the foundations of evolutionary biology’. The justification for a revisit
is that many new physiological experiments and interpretations of
genomic data have appeared. The time is ripe for a reassessment.
I begin with a largely ignored historical fact: Charles Darwin’s later
ideas on evolution inspired new physiological experimentation on the
processes that could be involved. He was also deeply involved in those
experiments. In fact, in the last decade (1872–1882) of his life, he
collaborated with three physiologists: Michael Foster, John Burdon-
Sanderson and George Romanes. These collaborations initially focused
on the physiological processes that could explain some of Darwin’s
observations on plants at his home, Down House in Kent.
He was intrigued by plants capable of catching insects, such as
Venus’ fly-trap,Dionaea muscipula. The leaves develop rows of sensitive
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© 2022 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
hairs which sense when an insect arrives on the plant. What intrigued
Darwin was the rapidity with which the convex leaves can snap
together while changing shape to become concave, so forming a cavity
within which the insect becomes trapped (Hodick & Sievers, 1988).
Plants are not generally capable of such rapid movement. The fly-trap
and similar insectivorous plants are unusual in reacting so quickly. He
worked therefore with Burdon-Sanderson to determine whether the
rapid trigger might be electrical, just as 19th century physiologists
had demonstrated rapid action potentials in nerves and muscles in
animals. Burdon-Sanderson (1873, 1888) and Burdon-Sanderson and
Page (1876) showed that the mechanism does indeed involve an action
potential (Williams, 1973,2002). Modern experiments show that
plants do this via calcium channels (Beilby, 1984; Williamson & Ashley,
1982; see Krol et al., 2006 for discussion and further references).
(Darwin did not put his name to the 1873 publication, as was his custom
generally in such collaborations.)
Burdon-Sanderson also introduced Darwin to his student at UCL,
George Romanes, which led to a collaboration of great importance to
Experimental Physiology. 2022;107:1015–1028. wileyonlinelibrary.com/journal/eph 1015
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evolutionary biology. In The Origin of Species (Darwin, 1859) Darwin
had already subscribed to the inheritance of acquired characteristics
through use and disuse, in addition to the process of natural selection.
He refers to such inheritance around 12 times in the book. In his
Introduction to the 1964 Harvard reprint of Darwin’s book (Mayr,
1964, 1982), Mayr writes:
Curiously few evolutionists have noted that, in addition
to natural selection, Darwin admits use and disuse
as an important evolutionary mechanism. In this he
is perfectly clear. For instance. .. on page 137 he
says that the reduced size of the eyes in moles and
other burrowing mammals is ‘probably due to gradual
reduction from disuse, but aided perhaps by natural
selection’. In the case of cave animals, when speaking of
the loss of eyes he says, ‘I attribute their loss wholly to
disuse’ (p. 137). On page 455 he begins unequivocally,
‘At whatever period of life disuse or selection reduces
anorgan...’.Theimportance hegivestouse or disuse is
indicated by the frequency with which he invokes this
agent of evolution in the Origin. I find references on
pages 11, 43, 134, 135, 136, 137, 447, 454, 455, 472,
479, and 480.
Nine years later, in The Variation of Animals and Plants Under
Domestication (Darwin, 1868), he speculated on the possible
mechanisms of pangenesis since he realised that, in organisms
with separate specialised germ-lines, there would need to be
communication between the soma and the germ-line for such
pangenetic inheritance to be possible. He treated his theory of
pangenesis as a ’beloved child’ (Desmond & Moore, 1991, p 551),
so this was no passing fancy. He very much wished it to be true. He
postulated the existence of tiny particles, which he called gemmules,
which could communicate from the soma to the germ-line. He wrote:
Physiologists maintain, as we have seen, that each cell,
though to a large extent dependent on others, is to a
certain extent, independent or autonomous. I go one
step further, and assume that each cell casts off a free
gemmule, which is capable of reproducing a similar cell.
(Darwin, 1868, vol. 2, pp. 377)
He fully acknowledged the speculative nature of his theory:
The existence of free gemmules is a gratuitous
assumption, yet it can hardly be seen as very
improbable, seeing that cells have the power of
multiplication through the self-division of their
contents. (Darwin, 1868, vol. 2, pp. 378)
He therefore imagined his gemmules as rather like spores. As I will
show in a later section of this article, Darwin was correct to see cells
as ‘casting off a free gemmule’, and we have had to wait for more than
New Findings
∙What is the topic of this review?
Revisiting the 2013 article ‘Physiology is rocking
the foundations of evolutionary biology’.
∙What advances does it highlight?
The discovery that the genome is not isolated from
the soma and the environment, and that there is
no barrier preventing somatic characteristics being
transmitted to the germline, means that Darwin’s
pangenetic ideas become relevant again.
a century for the resolution of microscopy of living tissues to become
great enough to visualise what I will argue are Darwin’s gemmules
(see video ‘Rediscovering the real Darwin’: https://www.youtube.com/
watch?v=H8jPyHFKU7I).
But, in orthodox 20th century evolutionary biology, Darwin’s idea
was dismissed outright since, if true, it would break a cardinal, but
unproven (see, e.g., Noble, 2016, pp. 126–128), assumption of the
Modern Synthesis, that is, the Weismann Barrier, which postulates
that the germline is isolated from influences via the organism or its
environment. It is important to note that Weismann’s idea was first
formulated after Darwin’s death in 1882 (Weismann, 1892, 1893).
Darwin therefore never had an opportunity to respond to Weismann’s
radical proposal.
Yet, the evidence shows that, had he lived to see it, Darwin would
have opposed Weismann, since Darwin treated pangenesis as his
‘beloved child’, in the sense that he put a lot of effort into trying to prove
it. This evidence is clear in his sustained collaboration with George
Romanes. Their strategy was to perform experiments in which the
tissues of different plant species were grafted together to see whether
they could communicate their presumed gemmules, and so their
characteristics, to each other, conceivably even fusing to form new
species. Had they succeeded, they would have discovereda mechanism
by which hybridisation could lead to a form of symbiogenesis.
Romanes became Darwin’s staunch defender against Weismann.
When Darwin passed away, Romanes persisted with the experiments,
and eventually published an article in the Zoological Journal of the
Linnean Society in which he proposed a theory of physiological selection
in addition to natural selection (Romanes, 1886). Romanes also became
the Secretary of the Linnean Society. But his theory of physiological
selection remained just that, an interesting and potentially ground-
breaking theory, but largely without the experimental evidence that he
and Darwin had tried hard to find. The problem was that the methods
of microscopy of the 19th century did not have the resolution required
to visualise what might have existed as the postulated gemmules.
Romanes died in 1894, at the early age of 46. Had he lived
just another few years he would have witnessed the rediscovery
of Mendel’s work on genetics and could have planned pangenesis
experiments much more likely to succeed. He might even have
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FIGURE 1 photographs of pages from the 1876 Minute Book showing that Burdon-Sanderson chaired the inaugural meeting at which T. H.
Huxley, Michael Foster and George Romanes were all present, and that Charles Darwin was elected one of the first Honorary Members
predated Waddington (1942, 1959) in his fruit fly experimentsshowing
the inheritance of an acquired characteristic. As it was, Darwin’s
dream that his young colleague might vindicate his pet theory died
with Romanes. It would take more than a century before that dream
could be fully resurrected. Unfortunately, Weismann and his imagined
Barrier, not Romanes’s and Darwin’s also-imagined gemmules, became
the basis on which the 20th century Modern Synthesis was developed.
Romanes’s and Darwin’s ‘beloved child’ was still-born.
2 DARWIN AND THE FOUNDATION OF THE
PHYSIOLOGICAL SOCIETY IN 1876
Further evidence for the close professional relations between Darwin
and the early British physiologists comes from the minutes of the
foundation meetings of The Physiological Society in 1876. The two
titans of evolutionary biology, Charles Darwin and Thomas Henry
Huxley, were foundation members. Figure 1shows that the first
meeting was chaired by Burdon-Sanderson at his London home with
Huxley, Foster and Romanes all present as founding members. The
minutes also show Charles Darwin elected to Honorary Membership
at the subsequent meeting in Romanes’s home, when the minutes were
signed by Michael Foster. When I first noticed these minutes during the
Centenary celebrations of the Society in 1976 (Noble, 1976) I imagined
that the founders simply wished to honour Charles Darwin as the
greatest naturalist of the 19th century. I did not realise that the honour
was also due to Darwin in his additional role in the science of physio-
logy itself. Darwin clearly saw physiology as an essential cornerstone
of the nuanced version of evolutionary theory that he was developing
with Romanes in his last decade.
With this historical introduction, I will now turn to the role of physio-
logy in evolutionary biology today and how it can vindicate Darwin’s
‘beloved child’. I will show how we can echo Darwin’s and Romanes’s
search for a physiological understanding of the evolutionary process
and so complete Darwin’s dream.
3PHYSIOLOGY UNDERMINES THE
FOUNDATIONS OF THE MODERN SYNTHESIS
3.1 Origin of the 2013 Experimental Physiology
article
A decade ago, in 2012, I lectured to the Congress of the Chinese
Association of Physiological Sciences in Suzhou (see video on https://
www.youtube.com/watch?v=kOKOacjdi40), which was repeated as
the President’s Lecture at the 2013 International Congress of Physio-
logical Sciences in Birmingham, UK, and subsequently published in
Experimental Physiology (Noble, 2013). That article has been highly
cited, but it, and particularly the videoed lectures on which it is based,
were also the subject of a wave of abusive critical comments on social
media and weblogs challenging all the evidence presented for physio-
logy ‘rocking the foundations of evolutionary biology’ (see 2016 video
on https://www.youtube.com/watch?v=KeVlBFX0qVc). Yet, over the
intervening decade, there has been no response published in a peer-
reviewed journal by any of the vociferous critics. So, the article still
stands and it is worth summarizing the central points. They were:
∙Selection is at the level of organisms, not genes.
∙Acquired characteristics can be inherited, as Darwin also assumed.
∙There is no replicator separate from the vehicle.
∙Genomes are not isolated from the organism and its environment.
There was sufficient evidence in 2013 to justify these points and
that they require a fundamental revision of 20th century evolutionary
theory which, incidentally, would bring it into line with Darwin’s own
later position. Selfish Gene theory (Noble, 2011) and the associated
ideas of genetic causation (Noble, 2008a) need revising. One way to
illustrate that need is to ask how the concept of the Tree of Life has
developed. As illustrated in Figure 2, the tree idea as first sketched
by Lamarck (1809) and Darwin (1837) has now become an extensive
network as much as it is a tree.
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FIGURE 2 The tree of life becomes a network. Black lines
represent the classical tree; grey lines represent the extent to which
the tree has become a network There is promiscuous exchange and
development of nucleotide sequences between unicellular life forms.
Later symbiotic fusions of cyanobacteria and proteobacteria enabled
the development of multicellular plants and animals. In multicellular
organisms, plants, animals and fungi, the exchange of nucleotide
sequences and proteins between somatic and germline cells can
influence the development of future generations. (Based on the work
of Carl Woese, who identified the Archaea, and a diagram from
Franklin Harold, In Search of Cell History, University of Chicago Press,
2014)
3.2 Species have frequently exchanged their
components during evolution
The reason the tree has become an extensive network is that organisms
have frequently exchanged their components, including nucleotide
sequences, during their evolution. Several papers and books published
recently document the details (Noble, 2021a, 2021b,2022;Shapiro,
2022a, 2022b; Shapiro & Noble 2021). Shapiro & Noble (2021)
document in detail the many experimental discoveries made over
a period of many years that fall outside the range of the M.odern
Synthesis, but are neglected or downplayed in modern textbooks and
popularisations. Out of 40 such discoveries identified and referenced,
only three are given any attention at all, and usually not accurately.
Many of these discoveries relate to the way in which species exchange,
develop and fuse their nucleotide sequences and genomes (the grey
lines in Figure 2).
Symbiogenesis (the process most relevant to Darwin’s and
Romanes’s efforts), for example, is hardly referred to at all in Futuyma
and Kirkpatrick’s (2018) standard textbook, Evolution, and its main
champion, Lynn Margulis, is not even openly acknowledged. Yet,
as Darwin would surely have recognised given its proximity to the
processes he was researching with Romanes, symbiogenesis was a
crucial evolutionary transition, creating greatly improved production
of ATP, leading to the possibility of multicellular organisms. Metazoan
life as we now know it on our planet, including humans, simply would
not have been possible without this transition. Plants developed from
fusion of cyanobacteria with eukaryote ancestors to generate what
became plastids. Alphaproteobacteria fused with urkaryotes to form
mitochondria in the eukaryotic cell line.
Darwin and Romanes were therefore correct to look for physio-
logical processes by which different species could fuse their
constituent components and properties. Today, we know that this
has happened time and again during the evolution of life on earth.
Had Romanes lived to witness the work of Mereschkowsky (1910)
and Kozo-Polyansky (1924) on the fusion processes that gave plants
their energy-producing plastids, he would have had the clue he needed:
the first indications that fusion of different species could succeed in
generating new species. The 20th century development of evolutionary
biology could have been based on Romanes’s idea of physiological
selection, meaning selection of a fusion process that resulted in new
physiological processes. Instead, we had to wait until 1971 for Lynn
Margulis (1970, 1981) to show that a similar process had generated
mitochondria in eukaryotes.
3.3 The hardening of the Modern Synthesis
Noble (2021a) complements the article with Shapiro (Shapiro & Noble,
2021) since it unravels the historical process by which orthodox
evolutionary biology became trapped in a highly restricted version
of the Modern Synthesis. The evolutionary biologist Steven J. Gould
(2002) called this historical change the ‘hardening’ of the Modern
Synthesis. That hardening has recently been analysed from a historical
perspective in Noble and Noble (2022), showing that it can be dated to
around 1963, when Julian Huxley wrote an Introduction to the second
edition of his book Evolution: The Modern Synthesis (Huxley, 1942,
2010). Huxley’s original book, the 1942 edition, was extraordinarily
broad, with a substantial number of the discoveries identified by
Shapiro and Noble (2021) acknowledged or foreseen. By contrast, the
introduction to the 1963 edition is deeply influenced by the work of
Watson and Crick on the double helix nature of DNA. Huxley writes:
I have left to the end the most important scientific event
of our times – the discovery by Watson and Crick that
the deoxyribonucleic acids – DNA for short – are the
true physical basis for life, and provide the mechanism
of heredity and evolution. Their chemical structure,
combining two elongated linear sequences in a linked
double spiral or bihelix, makes them self-reproducing,
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and ensures that they can act as a code, providing an
immense amount of genetical ’information,’ together
with occasional variations of information (mutations)
which also reproduce themselves. Linear constructions
of DNA are, of course, the primary structures in the
genetic organelles we call chromosomes. (Huxley, 1963,
p 614 in the 2010 reprint)
Thisisthesmokingguninthestory.Incommonwithmanyother
biologists at that time, Huxley was so impressed with the molecular
biological discoveries of Watson and Crick and their interpretation as
supporting the Central Dogma of molecular biology (Crick, 1958, 1970)
that he did not stop to ask the question whether it really is true that the
double helix ‘makes them self-reproducing’, nor whether they really ‘act
as a code’. Neither of Huxley’s conclusions are correct. I am certainly
not the first to point out the errors involved. Yet they are still not widely
acknowledged.
3.4 Summary of why DNA does not self-replicate
The essence of this argument can be summarized in five stages:
∙DNA cannot replicate ‘like a crystal’ (Dawkins, 1976). It is a flexible
thread wound around the chromatin proteins that can be partially
unwound when it needs to be used as a template to make RNAs and
proteins.
∙The natural error-rate of DNA replication is around 1 in 104which, in
a genome of 3 billion base pairs, would generate as many as hundreds
of thousands of errors.
∙In normal cell division those errors are then corrected by the living
cell which can reduce the error rate to just 1 in 1010.
∙.Mismatches in the double helix, and other molecular clues, are used
by the cell to enable the highly accurate error-correction process.
∙So far as we know, only the complex processes of a living cell make
this possible.
Therefore, there is no replicator separate from its vehicle. DNA
cannot replicate faithfully outside a living cell. This fact alone destroys
Selfish Gene theory as a valid scientific hypothesis (Noble & Noble,
2022b).
3.5 ‘Selfishness’ in genes is not physiologically
testable
Dawkins’s justification for calling genes ‘selfish’ is that they increase
their number in the gene pool and that this can be experimentally
counted: ‘Genes can be counted and their frequency is the measure
of their success’ (Dawkins, 2016, p 346). But this is vacuous since we
cannot use the defining characteristic of a ‘selfish’ gene, that is, success
in increasing its number in future generations, as the only experimental
prediction the theory can make. The founding definitions of a valid
theory cannot be used as experimental confirmation of the theory,
since they are necessarily true. Nor can the problem be side-stepped
by defining all genes as selfish, as I earlier wrote:
What does ‘selfish’ mean in the selfish gene story? First
we must decide whether ‘selfish’ defines a property that
is universal to all genes (or even all DNA sequences) or
whether it is a characteristic that distinguishes some
DNA sequences from others. This is not as easy as it
may seem. I suspect that the original intention was that
all genes could be represented as ‘seeking’ their own
success in the gene pool, regardless of how effective
they might be in achieving this. One reason for thinking
this is that so-called junk DNA is represented in the
selfish gene story as an arch-example of selfishness:
hitching a ride even with no function.
But on that interpretation, the demonstration that the
concept is of no utility in physiological science is trivially
easy. Interpreted in this way, a gene cannot ‘help’ being
selfish. That is simply the nature of any replicator.
But since ‘selfishness’ would not itself be a difference
between successful and unsuccessful genes (success
being defined here as increasing frequency in the gene
pool), nor between functional and non-functional genes,
there would be no cashable value whatsoever for the
idea in physiology. Physiologists study what makes
systems work. It matters to us whether something is
successful or not. Attributing selfishness to all genes
therefore leaves us with nothing we could measure to
determine whether ‘selfishness’ is a correct attribute.
As metaphor, it may work. But as a scientific hypothesis
it is empty. (Noble, 2011, p. 1010).
3.6 Physiological sensing and communication
networks control the error-correcting process
The fact that DNA is not a self-replicator is what gives living organisms
control over the error-correcting process. The immune system uses
this control to reduce error-correction in the variable part of the DNA
template for immunoglobulins and so generate millions of new DNA
sequences from which the organism selects the very few that can
work as the template for a successful antibody. The same process of
hypermutation occurs in bacteria (e.g., in reaction to antibiotics) and
in many other organisms when under stress. Organisms can therefore,
at least partly, direct their own evolution. These are the reasons
why evolution cannot be completely blind (Noble & Noble, 2017).
Organisms have the ability to feel their way forwards in difficult times,
which is when they employ hypermutation and other genetic processes
to find a way through. The process is one in which disorder, such as
random mutations, can be harnessed to serve the ordering regulatory
processes in living systems (Noble, 2016; Noble & Noble, 2018).
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Controlling the error-correcting process is a well-documented way
for organisms to react functionally since, in the immune system, it is
functionally directed for two reasons. First, the process is activated
in response to environmental challenges, and is therefore targeted
at meeting those challenges. Second, it can be targeted at specific
sequence regions in the genome (Odegard & Schatz, 2006). Under-
standing the ability for organisms to achieve such targeting depends
on unravelling the extraordinary processes by which events at the
cell surface can trigger messages travelling via the microfilaments to
specific regions of the nucleus (e.g., Ma et al., 2014; Kar et al., 2016).
So much for the idea that the genes are ‘sealed off from the outside
world’ (Dawkins, 1976). On the contrary, they are the most open to
influences from the environment (Noble & Noble, 2021). For a valuable
review of the physiological mechanisms of stress-induced evolution
see Mojica and Kueltz (2022), who list the five stress-induced changes
as: (1) mutation rates, (2) histone post-translational modifications,
(3) DNA methylation, (4) chromoanagenesis and (5) transposable
element activity.
I will return to the role of signalling via microfilaments in a later
section.
3.7 Are extracellular vesicles capable of
functioning as Darwin’s gemmules?
Extracellular vesicles (EVs) were first identified using electron micro-
scopy.Cells were found to be surrounded by a variety of what appeared
to be debris, ‘cellular dust’ (Corbel & Lorico, 2019). They are known
to be formed by cells in a variety of ways. They are called exosomes
when formed from multi-vesicular bodies in cells, ectosomes or micro-
vesicles when formed from the cell membrane, and apoptotic bodies
when released during cell death. Raposo et al. (1996) were the first
to show that exosomes could contain components that induce T cell
responses. Since then, functional properties have been found in a
wide variety of clinical conditions, summarised in Exosomes: A Clinical
Compendium (Edelstein et al., 2019). I was one of the editors of that
volume and I was surprised by the wide variety of cell types and
forms of communication that had been found in many different clinical
conditions. It was impossible to avoid an obvious question. Darwin in
1868 had written ‘each cell casts off a free gemmule, which is capable of
reproducing a similar cell’. His text only needs revising to read capable
of influencing other cells (instead of ‘reproducing a similar cell’) for his
gemmules to become the extracellular vesicles of today. After all, his
idea did not need them to reproduce, only to influence characteristics.
I therefore contributed an article myself to the book (Noble, 2019)
drawing attention to the possibility that EVs and exosomes could
function as Darwin’s supposed gemmules.
3.8 Transmission of regulatory molecules and
nucleotide sequences to the germline
Molecules capable of influencing gene regulation can be trans-
mitted to the germ cells in a variety of circumstances, including in
vitro transfers in which sperm cells act as vectors for introducing
DNA into egg cells, transmission of regulatory small RNAs from
the epididymus to epididymal spermatozoa, long distance trans-
mission from the brain to the germline, and reverse transcription of
nucleotide sequences into the genome (Cossetti et al., 2014;Chen
et al., 2016; Chen, Yan & Duan, 2016; Lavitrano et al., 1989, 2006;
Noble, 2019; Skvortsova et al., 2018; Spadafora, 2018; Zhang et al.,
2018).
Good examples of functional transmission of soma characteristics
include the work of Zhang et al. (2018) identifying the nucleotide
sequences that transmit paternally acquired metabolic disorders, and
Toke r e t al. ( 2022) showing the transgenerational inheritance of sexual
attractiveness in C. elegans viasmallRNAsandHRDE-1.Thereviewby
Skvortsova et al. (2018) is particularly valuable since it covers a very
wide field of work on transgenerational inheritance and a wide variety
of possible mechanisms.
The question now, therefore, is not whether Darwin’s idea was
correct in supposing that gemmules (aka EVs) exist, and that the soma
can influence the germline, but rather what transgenerational forms of
inheritance are actively promoted. This is a new field of research and
it is full of opportunities for physiological approaches to clarify (see
Allis et al., 2015). As physiologists we have no difficulty with accepting
the influence of parental transmission on the health and disease of
their children. Gluckman and Hanson’s book, The Fetal Matrix: Evolution,
Development and Disease (2005), showed even 17 years ago that we
already know that Darwin was correct both in accepting the existence
of parental influences in inheritance, but also in recognising the
importance of physiology in understanding the processes by which
evolution is achieved.
In view of the immense impact that the Central Dogma had on Julian
Huxley and the unnecessary hardening of the Modern Synthesis, it
is time that the diagrams of the Central Dogma should be updated
to include the physiological processes that control DNA replication,
expression and reorganisation. Figure 3does that by placing the
functional physiological networks in a central place in the chains of
causes and effects between the environment, the organism, its DNAs,
RNAs and proteins.
Figure 3also represents the extent to which feedback control
is involved in organisms, all the way from the environment to the
genome. We owe this understanding to the application of control
theory in physiology, pioneered by Claude Bernard in the 19th
century and Walter Cannon in the 20th. Bernard can therefore
be regarded as the first systems biologist (Noble, 2008b). His
work may well have been known to Darwin since the founders
of The Physiological Society in 1876 much admired Bernard.
He referred to the ‘constancy of the internal environment’, but
today we know that none of the regulated variables are strictly
constant. Organisms need to balance the regulation of one variable
against another. Organisms are not simple thermostats. Bernard’s
‘constancy of the internal environment’ has therefore been replaced
by processes that require much more complex decisions in balancing
the regulation of one controlled variable against that of many
others.
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DNA RNA PROTEIN
ENVIRONMENTAL INFLUENCES
FUNCTIONAL
NETWORKS
RNAs form parts
of networks
Networks control DNA replicaon
and error-correcng
Networks control
protein folding
Proteins form
parts of networks
Networks control
RNA replicaon
Environment influences
funconal networks
Organisms create
environment
Direct effects of e.g. radiaon on DNA
FIGURE 3 The Central Dogma of
molecular biology (bottom row of the relations
between DNA, RNA and proteins) placed in the
context of physiological control by the
functional physiological networks. Those
networks are subject to environmental
influences (black arrow) as well as contributing
to the environment (white arrow). DNA
expression and reorganisation is under control
by the functional networks (hatched arrow).
RNAs and proteins form important
components of the functional networks
(upward shaded arrows), while the functional
networks determine how protein amino acid
chains are folded (downward arrow from
networks to proteins). The physical
environment also has direct effects on DNA,
for example, through radiation breakage.
(EditedfromNoble,2021a;Figure2)
4SUMMARY OF EXPERIMENTAL FINDINGS
CONTRARY TO THE MODERN SYNTHESIS
The unravelling of the fundamental bases of the Modern Synthesis
depends on the accumulation of contrary experimental evidence by
many scientists during the last 100 years. In this section I will
briefly summarise those findings that are relevant to the diagrams
in Figures 2and 3, and indicate who was responsible for them. In
my experience many physiologists are unaware of the major changes
that are underway in evolutionary biology and why those changes are
very important for the future contributions physiology could make to
those developments. The aim of this section of my paper is to point
the way for physiologists to understand and catch up on knowledge
of these important evolutionary processes and to propose areas for
future research.
4.1 Symbiogenesis
The process by which symbiogenesis became recognised as a major
step in understanding evolutionary biology is the subject of a
shortreviewbyGray(2017). Lynn Margulis was the scientist
responsible for resurrecting an idea first proposed by Mereschkowsky
(1910) and Kozo-Polyansky (1924) for the cyanobacterial origin of
plastids (chloroplasts) in plants. Margulis (1970, 1981) identified
alphaproteobacteria as the origin of mitochondria in eukaryotes. The
evidence depends on:
a confluence of data — biochemical, molecular, and
cell biological, coupled with the characterisation in a
group of eukaryotic microbes (the jakobid flagellates)
of a gene-rich mitochondrial genome that strongly
resembles a shrunken bacterial genome — now provides
a compelling case for a single, endosymbiotic, alpha-
protobacterial origin of mitochondria. (Gray, 2017,
p 1286)
In the case of plants ‘a compelling case for an endosymbiotic
origin has always been easier to make for the plastid than for the
mitochondrion.’ Gray also points out that ‘there is clearly much more
to be discerned’ (p. 1287). This is an open invitation for physiology
and genomics to investigate these issues further. There is also the
open question: which other organelles might have originated through
symbiogenesis? Recall that the lipid membranous structures do not
depend on DNA templates. They must have had origins independent
of DNA. Furthermore, the membranous structures of eukaryotic cells
represent vast quantities of structural information which must be
inherited in addition to DNA (Noble, 2017b). Lipid membranes are also
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the true ‘crystal-like’ replicators. Lipid molecules automatically insert
themselves into membranes, which is how membranes grow between
cell replication cycles.
This is a suitable point at which to note that all attempts to draw
tree–network diagrams, such as Figure 2, are compromises. Just like
maps, they should not be confused with what they aim to represent.
We should not take even Woese’srevision as sacrosanct (Vane-Wright,
2017).
4.2 Discovery of archaea
Until the work of Carl Woese (Woese, 1967;Woese&Fox,1977)it
was generally assumed that there was a linear progression of early life
forms before the evolution of eukaryotes. Woese’s great achievements
were to identify a distinct group, the archaea, as phylogenetically
distant from bacteria, and to show that eukaryotic forms have more
biochemical properties in common with archaea than with bacteria.
These discoveries (Woese, Kandler & Wheelis, 1990) led to the three-
part early Tree of Life forming the basis of Figure 2. Woese was
trained and worked as a biophysical biochemist, the first sequence-
based phylogeneticist, but I also regard him as a brilliant physiologist.
In 2005 he published an article in Current Biology in which he wrote:
I see the question of biological organization taking two
prominent directions today. The first is the evolution
of (proteinaceous) cellular organization, which includes
sub-questions such as the evolution of the translation
apparatus and the genetic code, and the origin and nature
of the hierarchies of control that fine-tune and precisely
interrelate the panoply of cellular processes that constitute
cells. It also includes the question of the number of
different basic cell types that exist on earth today: did
all modern cells come from a single ancestral cellular
organization? (Woese, 2005, my emphasis)
He correctly saw the significance of ‘hierarchies of control that
fine-tune cellular processes’ (represented here in Figure 3), which can
be viewed as a perspective very similar to the principle of biological
relativity,that is, causation from and to all levels of organisation (Noble,
2016). His work was strongly resisted by evolutionary biologists
adhering to the Modern Synthesis (Mayr, 1998).
4.3 Discovery of natural genetic engineering
The idea of ‘natural’ genetic engineering should be uncontroversial,
yet it also has been strongly resisted. After all, what scientists now
achieve in genetically engineering organisms is frequently based on
the CRISPR techniques first discovered in prokaryotes, endowing them
with the natural biochemical processes that form their equivalent
of the immune system by generating acquired resistance to viruses
(Barrangou et al., 2007). This work led to the award of the Nobel Prize
in Chemistry to Charpentier and Doudna in 2020.
But the idea that organisms can themselves engineer changes
in their nucleotide sequences and change the organisation of their
genomes originates much earlier with the work of Barbara McClintock
who, in the 1940s and 1950s, showed that maize plants reorganise
their chromosomes when under stress. As early as the 1930s she
showed the link between chromosomal rearrangement and the
recombination of genetic traits. Julian Huxley knew about similar work
in his book Evolution: The Modern Synthesis (Huxley, 1942;seeHuxley,
2010, p. 137). Yet, when McClintock (1953) published in the journal
Genetics she was completely ignored. Three decades later (1983) she
was awarded the Nobel Prize in Physiology and Medicine. In her Nobel
lecture (McClintock, 1984) she clearly enunciated the principle that
the physiology of cellular control is the key in understanding these
phenomena.
McClintock’s mantle was then inherited by James Shapiro, a
bacterial geneticist at the University of Chicago, who demonstrated
the process of genetic engineering and reorganisation of genomes
in bacteria (Shapiro, 1992, 2011,2022a, 2022b). This major trans-
formation of the molecular biology of evolutionary processes has also
been strongly resisted by supporters of the Modern Synthesis, since
his work involves non-random and saltatory mutations as well as the
violation of the Central Dogma that protein action cannot change the
genome (and possibly because Shapiro has repeatedly described these
capacities of organisms as a form of intelligence). He is in good company
since Darwin also used ‘intelligence’ to characterise the capacities of
worms and plants (Bradley, 2020, pp. 63–67). The refusal by many
evolutionary biologists to recognise how control processes in living
systems form the basis of intelligence is a deep misunderstanding of
evolution. No-one doubts that humans and other primates show what
we naturally call intelligence. Yet their, and our, intelligent abilities
must themselves have evolved from other organisms, including single
cell organisms. Evolution has generated those processes naturally
through successive transitions, each of which enables further trans-
itions with new characteristics. Those processes are properties of living
organisms and are proper subjects for physiological research since
stochasticity in living organisms is harnessed (used) by physiological
control processes (Noble & Noble, 2018, 2022a). Shapiro’s work is now
beautifully collated in the latest edition (Shapiro, 2022a) of his book
Evolution: A View from the 21st Century.
The use of the word ‘natural’ here is comparable to the distinction
Darwin made between natural and artificial selection. In his 1859
book, Darwin invented the idea of natural selection by comparison
with deliberate (artificial) selection by humans breeding animals and
plants for desirable characteristics. But he also realised that the same
deliberation is manifest in the choices (sexual selection) made by many
organisms, including birds (Darwin, 1859;1868, vol. 2, pp. 75; 1871,
chap. 8).
4.4 The tree becomes a network
In addition to the processes of natural genetic engineering, living
organisms have been promiscuous in the exchange and reorganisation
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of nucleotide sequences. It was formerly thought that such exchange
is limited to single-cell organisms but, as discussed earlier, cells in
multicellular organisms also convey nucleotide sequences to each
other via extracellular vesicles.
Darwin is justly acknowledged for his famous ‘I Think’ tree sketch
in one of his experimental notebooks (Darwin, 1837), though it should
be more widely known that Lamarck first drew a tree of life nearly
three decades earlier in 1809 (see Gould, 2000). I doubt whether
either Darwin or Lamarck would be surprised that their 19th century
attempts to capture the evolutionary connectedness of all species
should now be supplanted by a tree–network, as in Figure 2.Both
were flexible in the light of evidence, Darwin through his gemmules
idea, leading to acknowledgement that natural selection is not the only
process in evolution, and Lamarck through abandoning his original idea
of a single ladder of life.
Yet, when the British Magazine The New Scientist published an
editorial (Anon, 2009) on this seemingly obvious and important
development, it was immediately greeted with derision (Dennett et al.,
2009): ‘First it’s false, and second, it’s inflammatory.’ Why? Because
‘Your cover was handing the creationists a golden opportunity.’
I have some sympathy for this problem since I have myself been
misrepresented by creationists. But we should be answering
misrepresentation by patiently explaining the correct interpretation.
Scientists should not be seeking to close down debate and discussion.
Incidentally, Dennett et al. accepted that the tree has now become a
network, but then downplayed the fundamental significance of inter-
species and transgenerational transmission of nucleotide sequences
and characteristics:
Of course there’s a tree; it’s just more of a banyan
than an oak at its single-celled-organism base. The
problem of horizontal gene-transfer in most non-
bacterial species is not serious enough to obscure the
branches we find by sequencing their DNA.
This is the kind of reasoning that led supporters of the hardened
version of the Modern Synthesis to strongly oppose Carl Woese’s use
of nucleotide sequencing of bacterial and other species to discover the
archaea, leading to the significance of the processes of symbiogenesis.
Playing down the significance of important discoveries hinders
adventurous research by pretending that ‘nothing much/fundamental
has changed’. Not for nothing was Carl Woese described in Science
as ‘microbiology’s scarred revolutionary’ (Morell, 1997). Furthermore,
unicellular life forms are by far the most numerous and probably
responsible alone for 1–2 billion years of evolutionary history, while
lateral transfer between cells in metazoa and plants is precisely
what enables the inheritance of Lamarckian-style use-and-disuse
characteristics in species with specialised germlines.
4.5 Communication between membrane
receptors and nuclear DNA
The discovery of the functional significance of extracellular vesicles
is not the only example in modern physiological research where
the revolution in resolution in microscopy matters. The ability to
visualise the extensive networks of fine filaments in living cells using
fluorescent marking has also provided a solution to another problem
in evolutionary biology: if organisms can manipulate their nucleotide
sequences in ways that react functionally to environmental stress, how
do nuclear components react to external influences sensed by the cell
membrane receptors? The answer is that sub-membranous changes,
for example, in ion concentrations due to the opening of ion channels,
trigger molecular messages that can travel on the molecular motors
moving along the microfilaments and so travel to specific locations in
the nucleus.
To visualise this, imagine a small protein around 1 nm in radius
located near the cell membrane. The nucleus of a small cell around
20 µm in size would therefore be around 10 µmfromthesurface
membrane. If we magnified the small protein to be around 1 cm (as it
might be sketched in a diagram), a magnification of 10 million times, the
nucleus would appear to be 100 km away, roughly the distance from
Oxford to London. For a large cell around 100 µm, such as a human
oocyte, the nucleus would appear to be 1000 km away, roughly the
distance to the far north of Scotland. The microfilaments that trans-
port the motors and their cargo are about 25 nm in diameter and, on
the same magnification would be the size of a small footpath running
the whole length of the country.
Yet accurate and targeted transport of messenger molecules over
these tiny cell ‘roadways’ has been discovered in living cells. Examples
of recent physiological studies that demonstrate this process can be
found in the papers of Ma et al. (2014)andKaretal.(2016), working
on the transmission of signals from calcium concentration changes that
control the relevant gene activity in the nucleus. The molecular motors
can achieve this transport at a speed of up to 2 µm/s. The nucleus
can therefore be reached within just a few seconds. Visualising these
processes using fluorescent markers reveals a vast trafficking system
with messenger molecules moving rapidly in all directions between the
cell and its nucleus. The work of Kar et al. (2016) is ground-breaking
in showing the dependence on two calcium compartments. Multiple
causation must surely be the norm in physiological control systems.
These studies open the way for many further physiological
investigations on how cells control their genomes, and so may make
major contributions to evolutionary biology. Barbara McClintock pre-
dicted in 1984 that the genome would be found to be: ‘an organ of
the cell, monitoring genomic activities and correcting common errors,
sensing the unusual and unexpected events, and responding to them
by restructuring the genome’ (McClintock, 1984). Physiology is now
in a position to fulfil her dream too. Discovering the cellular signalling
pathways that can regulate gene expression and proof-correcting of
DNA replication would be crucial to fulfilling that dream.
4.6 Lamarckian forms of inheritance
The French biologist Jean-Baptiste Lamarck was professor of natural
history of insects and worms at the Botanical Garden in Paris when
he published his great work on evolution, Philosophie Zoologique,in
1809. He investigated natural processes by which evolution could
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have occurred. One of these was the physiological process of use
and disuse. In modern physiology, that process is evident everywhere
in the body. Identical twins who choose different lifestyles naturally
develop different muscular structure, and physiologists have now
identified the RNAs that mediate differential expression of muscle
proteins (Bathgate et al., 2018). A crucial evolutionary question now
is whether and how those control characteristics can be transmitted
across generations. This work provides a specific goal for research on
physiological signalling, particularly because it would ideally require
identification of multiple causation pathways, since many genes are
involved in the use–disuse regulation of muscle proteins (Ahmetov and
Fedotovskaya, 2015). The association levels with individual genes are
very low.
When Lamarck wrote his book he also thought, initially, that the
process of increasing complexity of life could be represented as a
ladder of life, continuous with no branching. But, as I have already
noted, he replaced this concept with his drawing of the first Tree of Life
(Lamarck, 1809, 1994, p. 649 in 1994 reprint). Lamarck’s tree of life is
much more detailed than Darwin’s sketch.
For championing evolution by natural processes he was praised by
Darwin as ‘this justly celebrated naturalist .. . who upholds the doctrine
that all species, including man, are descended from other species’
(Darwin, 1869). But in his own time in Paris he was completely trashed
by his arch rival at the natural history museum, Georges Cuvier, who
was a serial creationist. When Neo-Darwinism grew in ascendance
in the early 20th century, based on eliminating the inheritance
of acquired characteristics from evolutionary biology, Cuvier’s
ridicule was echoed by those who developed the Modern Synthesis.
Lamarck’s reputation as ‘this justly celebrated naturalist’ has never
recovered.
Yet, there is ample evidence that Lamarck was essentially right
(Allis et al., 2015; Bateson & Gluckman, 2011; Escobar et al., 2021;
Gissis & Jablonka, 2011; Gluckman & Hanson, 2005; Gluckman et al.,
2016; Jablonka, 2016; Jablonka & Lamb, 2005, 2014;Noble,2021b;
Skvortsova et al., 2018). The demise of the Weismann Barrier, following
the discovery that regulatory nucleotide sequences developed bysoma
cells can be transmitted to the germline, resurrects the valid question:
how many such characteristics are transmitted in this way?
There are two factors standing in the way of research on this
question. The first is that few funding agencies are currently likely to
accept proposals. We must hope that will change with time as people
become more aware of the changes that are rapidly developing in the
field of evolutionary biology. The second is the multi-genic nature of
physiological control. As I have already noted in the work of Kar et al.
(2016), identifying multiple pathways of gene regulation is challenging,
but forms an essential part in unravelling the physiological control
processes involved.
4.7 Demise of gene-centrism
Gene-centric interpretations of physiology and evolution are far from
achieving their goals. One reason for this impasse is that association
studies do not reveal physiological causation (Felin et al., 2021a,
2021b). With Peter Hunter I have recently outlined how this impasse
might be negotiated (Noble & Hunter, 2020). Modelling physiological
regulatory networks could help to explain the low association scores
and identify where causation exists even when the association score is
very low. It all depends on how robust the networks are and how easily
they can switch from one pathway to another.
The details on why we need to move on from Selfish Gene theory,
as popularised by Dawkins (1976, 2016), have been published in Noble
and Noble (2022b). The Selfish Gene was a brilliant popular exposition
of Neo-Darwinism, but moving away from its simplicity is essential for
the future of physiology and evolutionary biology. Dawkins himself has
stated that ‘in some ways I would quite like to find ways to recant the
central message of The Selfish Gene. So many things are fast happening
in the world of genomics....’ (Dawkins, 2016, p 345). Indeed they are,
and I believe he can.
4.8 Function, purpose and teleology
The purposive teleological language used in some parts of this article is
deliberate. But I recognise that most scientists, including many physio-
logists, have been trained, as I was, to avoidsuch language in favour of a
passive descriptive form. I now use purposive language because I think
that the existence of purpose in organisms is a proper object of physio-
logical study, as argued in a recent article with my brother, Raymond
(Noble & Noble, 2022a). Living organisms are naturally purposive.
They must use anticipation and creativity in behaviour to survive. The
physiological processes involved must therefore have evolved. How
purposive anticipatory behaviour can be explained physiologically and
how explanations based on it can be tested empirically are the main
foci of some of our recent articles. Here I briefly summarise the main
conclusions.
1. The harnessing of stochasticity (first referred to in Noble, 2017a
and extensively developed in Noble et al., 2019; Noble & Noble,
2017, 2018,2021, 2022a,2022b) is a necessary process since, if
chance is merely experienced (the Neo-Darwinist view) rather than
used functionally, the faculty of choice is not possible. Purposive
behaviour depends on that faculty. Without it, organisms would
be automata. Purely passive descriptions of their behaviour would
then suffice.
2. Organisms capable of choice exhibit unlimited associative learning,
which is one of the empirical criteria for being able to attribute
consciousness and deliberative anticipatory action (Ginsburg &
Jablonka, 2019). Using that criterion those authors date the
evolution of this faculty as around the time of the Cambrian
Explosion, c. 500 million years ago, in which case it vastly predates
the evolution of the human species, and must be more widespread
than commonly assumed.
3. The unlimited nature of such learning also precludes representation
of organisms with agency as following specific fixed algorithms.
Fixed algorithms cannot generate behaviour dependent on the
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harnessing of stochasticity, since specific outcomes are then
necessarily unpredictable, although they may be explicable in
retrospect. The behaviour is more comparable to a game in which
the participants alter the rules as the game progresses (see also
item 6). Yet those flexible rules govern what happens.
4. The processes of choice in organisms with nervous systems may
include neuronal circuits that are subject to neural selection, as
first proposed by Gerald Edelman (1978) (and see Noble & Noble,
2021 for explanation). Edelman’s idea was summarily dismissed by
Crick (1989) as incompatible with Neo-Darwinist interpretations of
evolution, which led to its neglect. This is yet another opportunity
for physiological research, specifically neuroscience, to contribute
to evolutionary biology. It is also an example of how the Neo-
Darwinist mind-set restricts the questions that are regarded as
valid. Crick’s dismissal of Edelman’s Neuronal Selection theory was
based on the requirement of a strict separation between replicator
and vehicle. Edelman’s idea did not require that. Nor does such
separation exist, even for the genome.
5. The forms of causation differ in important ways between the
various levels of organisation in living organisms (Noble et al.,
2019). Most relevant to the question of agency and purpose, social
factors have a primary role, as explained in Noble and Noble (2021)
and in Noble and Ellis (2022). In principle, it is now possible to
understand how immaterial social factors can play the role they
must if agency is to be possible. Most importantly,it is not necessary
to resort either to Cartesian dualism or to supernatural events to
provide an explanation.
6. There is current interest in whether the development of artificial
intelligence (AI) could achieve the criteria for the equivalent
of agency in living organisms (Noble & Noble, 2019). In those
discussions Raymond and I have suggested that this may be difficult
or even impossible with silicon-based materials. To the extent
that a living organism can be compared to a computer (Bray,
2011), organisms are aqueous ‘computers’, with access to a vastly
greater degree of stochasticity at the molecular level. A significant
challenge for AI research is whether it would be necessary to
develop water-based computational systems. It took evolution
billions of years to do that. I doubt whether the achievement of
agency in AI systems is just around the corner.
The issue of agency and purpose in organisms is still strongly
disputed in evolutionary biology. However, with the exception of
agency itself, the majority of the possible research opportunities for
physiology’s future contributions to evolutionary biology outlined in
this article do not depend directly on this issue. Readers who prefer to
reject the idea of agency may still find valuable ideas for research in
what I have outlined.
5CONCLUSION
I would like to think that Charles Darwin would be delighted that,
over a century later, his links with physiology through his work with
Burdon-Sanderson and with Romanes have been spectacularly reborn.
His dream is now very much alive. It is time for physiology to come
to the rescue of evolutionary biology by providing the evidence for
the causal mechanisms of evolutionary change, which Darwin himself
believed was lacking from his theories (Bradley, 2022; see also West-
Eberhard, 2008), and which are still lacking from the standard theories
today.
ACKNOWLEDGEMENTS
This article would have been impossible without the cooperation
of many dissenters from the Modern Synthesis view of
evolution. For most of the last decade I have been privileged
to be part of THETHIRDWAYOFEVOLUTION (http://www.
thethirdwayofevolution.com/) which has become a stimulating forum
for the exchange of ideas on new (and old!) trends in evolutionary
biology. Many of the members of that forum have themselves made
ground-breaking discoveries and developed innovative ideas that have
been ignored, downplayed and often ridiculed. I am far from being the
first dissenter from the Modern Synthesis to be denigrated in this way.
It has happened to a long line of scientists, starting with Lamarck (who
was completely trashed at his own funeral, seemingly never to recover
his reputation), followed by McClintock (ignored despite winning
a Nobel Prize for mobile genetic elements in 1981), Waddington
(excluded from the founding circle of the Modern Synthesis), Margulis
(downplayed or ignored despite the great importance of symbiogenesis
in evolution), and Jablonka and Lamb who pioneered reconsideration
of Lamarck in the light of epigenetic inheritance. For a more complete
list see Shapiro and Noble (2021). I also thank my colleagues in the
International Union of Physiological Sciences for their support and
encouragement during the periods when I was Secretary-General
(1994–2001) and President (2009–2017). Some of the key lectures
on which the 2013 article in Experimental Physiology was based were
given at IUPS Congresses. I thank my brother, Raymond Noble, who, as
zoologist, neuroscientist and philosopher, has joined me in publications
in many recent articles and books. Ben Bradley, Eva Jablonka, Perry
Marshall, James Shapiro, Corrado Spadafora, Richard Tsien and
Richard Vane-Wright made valuable comments on earlier drafts. I am
grateful to Sir Anthony Kenny for innumerable discussions on some of
the more philosophical issues involved. Some sections of the article are
based on my previous publications (all cited) but in journals less likely
to be read by physiologists. This article presents the arguments from a
specifically physiological viewpoint.
During the writing of this article, Denis Noble became a Fellow of
the Linnean Society.
COMPETING INTERESTS
None.
AUTHOR CONTRIBUTIONS
Sole author.
FUNDING INFORMATION
None.
1026 NOBLE
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How to cite this article: Noble, D. (2022). Modern physiology
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