Physiology restores purpose to evolutionary biology

Abstract

Life is purposefully creative in a continuous process of maintaining integrity; it adapts to counteract change. This is an ongoing, iterative process. Its actions are essentially directed to this purpose. Life exists to exist. Physiology is the study of purposeful living function. Function necessarily implies purpose. This was accepted all the way from William Harvey in the 17 th century, who identified the purpose of the heart to pump blood and so feed the organs and tissues of the body, through many 19 th and early 20 th century examples. But late 20 th century physiology was obliged to hide these ideas in shame. Teleology became the 'lady who no physiologist could do without, but who could not be acknowledged in public.' This emasculation of the discipline accelerated once the Central Dogma of molecular biology was formulated, and once physiology had become sidelined as concerned only with the disposable vehicle of evolution. This development has to be reversed. Even on the practical criterion of relevance to health care, gene-centrism has been a disaster, since prediction from elements to the whole system only rarely succeeds, whereas identifying whole system functions invariably makes testable predictions at an elemental level. ADDITIONAL KEYWORDS: biological function-Central Dogma-purpose in biology-teleology. FUNCTION IN PHYSIOLOGY Physiology is concerned with function in living organisms. It is from this study of function that teleology, the study of purpose, emerges as an equally necessary tool of analysis. We begin this paper with some examples of quantitative functional analysis in order to demonstrate how understanding the physiological functions of life leads to predictions concerning molecular and other lower-level processes, whereas the reverse is rarely true.

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Biological Journal of the Linnean Society, 2022, XX, 1–13. With 3 figures.
Physiology restores purpose to evolutionarybiology
RAYMONDNOBLE1 and DENISNOBLE2,*,
1Institute for Women’s Health, University College London, London WC1E 6AU, UK
2Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford OX1 3PT, UK
Received 26 November 2021; revised 2 April 2022; accepted for publication 8 April 2022
Life is purposefully creative in a continuous process of maintaining integrity; it adapts to counteract change. This
is an ongoing, iterative process. Its actions are essentially directed to this purpose. Life exists to exist. Physiology
is the study of purposeful living function. Function necessarily implies purpose. This was accepted all the way from
William Harvey in the 17th century, who identified the purpose of the heart to pump blood and so feed the organs and
tissues of the body, through many 19th and early 20th century examples. But late 20th century physiology was obliged
to hide these ideas in shame. Teleology became the ‘lady who no physiologist could do without, but who could not be
acknowledged in public.’ This emasculation of the discipline accelerated once the Central Dogma of molecular biology
was formulated, and once physiology had become sidelined as concerned only with the disposable vehicle of evolution.
This development has to be reversed. Even on the practical criterion of relevance to health care, gene-centrism has
been a disaster, since prediction from elements to the whole system only rarely succeeds, whereas identifying whole
system functions invariably makes testable predictions at an elemental level.
ADDITIONAL KEYWORDS: biological function – Central Dogma – purpose in biology – teleology.
FUNCTION IN PHYSIOLOGY
Physiology is concerned with function in living
organisms. It is from this study of function that
teleology, the study of purpose, emerges as an equally
necessary tool of analysis. We begin this paper with
some examples of quantitative functional analysis
in order to demonstrate how understanding the
physiological functions of life leads to predictions
concerning molecular and other lower-level processes,
whereas the reverse is rarelytrue.
The circulaTion of The blood
The function of the circulation was the object of William
Harvey’s Exercitatio Anatomica de Motu Cordis et
Sanguinis in Animalibus (On the Movement of the
Heart and Blood in Animals) in 1628 (Whitteridge,
1964). His work was the first use of quantitative
calculations to answer a functional question and is
therefore one of the origins of the quantitative systems
biological approach (Auffray & Noble, 2009). His
discovery of the function of the heart as the circulation
of the blood was already announced in a lecture he
gave in1616:
‘So it is proved that a continual movement of
the blood in a circle is caused by the beat of the
heart.’ [from Prelectiones Anatomiae Universalis,
translated by Gweneth Whitteridge (1964); see
also Keynes (1978)]
Knowing how frequently the heart beats and what
volume of blood could be pumped out during each beat
he estimated how rapidly the heart could empty the
entire volume of blood in thebody:
‘This is also clearly to be seen by any who watch
the dissection of living creatures, for not only if the
great artery be cut, but, as Galen proves, even in
man himself, if any artery even the smallest be cut,
in the space of about half an hour, the whole mass
of blood will be drained out of the whole body …’
‘By careful reckoning, of course, the quantity
of blood forced up beyond the valve by a single
compression may be estimated, and this multiplied
by a thousand gives so much blood transmitted in
this way through a single portion of the veins in a
relatively short time, that without doubt you will
be very easily convinced by the quickness of its
passage of the circulation of the blood.’
The answer in the case of a human is 30 minutes.
Harvey then proposed an answer to the question
where in the body does all this bloodgo?
applyparastyle “g//caption/p[1]” parastyle “FigCapt”
*Corresponding author. E-mail: denis.noble@dpag.ox.ac.uk
© The Author(s) 2022. Published by Oxford University Press on behalf of The Linnean Society of London.
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2 R. NOBLE and D.NOBLE
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Until Harvey, people thought that the blood ebbs
and flows back and forth as it gets pumped into the
expanding arteries, rather like the tides of the sea
ebbing back and forth on the seashore. Harvey realized
that this could not be true since he demonstrated one-
way flow of blood through the veins taking blood to
the heart. The veins have valves, so ensuring that the
blood cannot travel back to the extremities. It must
always flow towards the heart. He concluded:
‘It must therefore be concluded that the blood
in the animal body moves around in a circle
continuously, and that the action or function of the
heart is to accomplish this by pumping. This is the
only reason for the motion and beat of the heart.’
Since there is continuous one-way flow the arteries
and veins must somehow connect together. With the
naked eye Harvey could not see how that happened
so he supposed that there must be what he called
porosities in the tissues through which the blood could
flow from the tips of the arterial tree into the tips of
the venous tree. Harvey’s achievement therefore was
not only to discover the circulation of the blood, but
also to make a prediction that he himself could not
prove. It was in 1661 that Marcello Malpighi used a
light microscope to observe the flow of blood through
what we now call capillaries in the brain and other
organs (Pearce, 2007).
The principle of consTrainT
However, much as we might study the particles of
blood, what we now call cells, platelets, vesicles and
all their associated fluids and dissolved molecules,
nothing in these molecular movements would tell
you that the blood circulates. This fact was realized
by Benedict Spinoza, who communicated his idea in a
letter to The Royal Society in1665:
‘Let us imagine, with your permission, a little
worm, living in the blood, able to distinguish by
sight the particles of blood, lymph etc, and to
reflect on the manner in which each particle, on
meeting with another particle, either is repulsed,
or communicates a portion of its own motion. This
little worm would live in the blood, in the same
way as we live in a part of the universe, and would
consider each particle of blood, not as a part, but
as a whole. He would be unable to determine, how
all the parts are modified by the general nature of
blood, and are compelled by it to adapt themselves,
so as to stand in a fixed relation to one another.’
(Elwes, 1951: p.291)
There is an important lesson here: functional theories
about the workings of the cells, tissues, organs and
systems of a living organism can make micro-level
predictions that can be tested experimentally. But the
converse does not necessarily or even usually hold.
The multitudinous directions of movement of particles
will not yield conclusions about the functioning of
the whole, as we know well from thermodynamics,
where constraint of such movements by containers
generates the high-level properties of temperature,
volume and pressure, and where most of the lower-
level stochasticity is ironed out. Later in this article
we will show that biology has reached a similar
impasse in seeking to explain physiological function
in health and disease purely from measurements
of gene sequences and associations in genome-wide
association studies(GWAS).
The constraint of molecular and other micro-
components by membranes and other boundaries in
physiological systems can be readily understood with
a simple diagram (Fig. 1). Without constraint, particles
will move every which way and so disperse any
functional network they may form. Under constraint
by boundaries, functional networks may persist. Such
constraint must have developed at a very early stage
in the development of life. Boundaries are highly
functional in physiological systems (Noble etal.,
2019). Their essential membranous molecules, lipids,
do not depend on genes. Yet those molecules are also
inherited. They are also better self-replicators than
DNA. Lipids automatically insert themselves into
existing membranes.
The renal sysTem and counTer-currenT flow
Physiological studies of the kidney and renal system
illustrate the same kind of functional analysis leading
to successful predictions of micro-level components
and processes.
Unconstrained Constrained
Figure 1. Left: through random thermal motion
unconstrained particles will move in all directions. Any
functional network they may form will disperse and so
cease to be functional. Right: constraint, e.g. by a vesicular
membrane, will keep most particles contained. Afunctional
network may then survive.
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PHYSIOLOGY RESTORES PURPOSE 3
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The structure of the kidney is a compact maze,
with tiny tubes interweaving with each other, forming
pathways bending back on themselves to run to where
they came from. From a molecular-level viewpoint this
all seems pointless. Why carry fluids and molecules
dissolved in them back and forth through such long
tortuosities? Calculations using physiological high-
level insight provide the answer. From an engineering
point of view the arrangement of the renal tubules
uses the principle of counter-current flow, which
was first proposed in the kidney by Werner Kuhn
in 1951, and confirmed by Carl Gottschalk (Blythe,
1998). Engineers frequently use this principle to
construct heat exchangers and to concentrate chemical
compounds.
This principle is of functional use all over the body.
It is amazingly simple but also deeply explanatory. In
the limb extremities arteries and veins run together
side by side. The hot blood emerging from the heart
warms the cool blood coming back through the veins.
This heat exchange system conserves heat in the
body as a whole, so enabling warm-blooded organisms
to keep heat balance more easily. This balance in
turn optimizes metabolic processes, such as enzyme
reactions, so that they run at optimumlevels.
Such a mechanism is not restricted to endotherms.
For example, the vascular lining in the trachea of adult
leatherback sea turtles helps them maintain body
temperature while foraging in cold water via counter
current exchange. The trachea of adult sea turtles is
lined throughout by a continuous vascular plexus,
with longitudinally arranged, large-diameter blood
vessels lying mainly in the deeper layers of the mucosa,
with prominent cross-connections between them,
thus functioning as a counter-current arrangement,
retaining heat and maintaining body temperature.
The tubular kidney structure uses the same
counter-current principle to achieve filtering of the
blood. Waste products get concentrated while water is
conserved. Nothing in the molecular viewpoint would
provide these insights. Just like Spinoza’s particles of
blood, the organizing principles simply do not reside,
and cannot be discerned, at thatlevel.
These functional insights predict the existence of
the required selective protein transporters in the cells
lining the kidney tubules. Many of those have now
been found (e.g. Boron & Boulpaep, 2017: chapter on
the Urinary System).
homeosTasis and homeorhesis
In the 19th century Claude Bernard identified the
constancy of variables like temperature and acidity as
a form of homeostasis. He called this the constancy of
the internal environment (Bernard, 1865; Noble, 2008).
This was an important functional insight, but it is only
approximately correct. Pressures, temperatures and
many other important variables are not kept strictly
constant. Organisms are not simple thermostats. The
controlled variables hunt around their mean values
while the organism seeks to optimize its functions on
many processes at the same time. This hunting around
is a form of homeorhesis which should be clearly
distinguished from homeostasis. Organisms are open
systems and cannot be in a maintained steady state.
The idea of homeorhesis was first introduced by
Conrad Waddington [(1957: pp.32, 43, 149); see also
Pereira (2021) and Ray (2021)] and is another form
of maintaining integrity. Organisms accept a degree
of disorder in the interests of survival. There is a
continual tension between order and disorder, which
forms part of the way in which organisms harness
stochasticity (Noble & Noble, 2018). Function emerges
from this order-disorder symmetry (Noble, 2021a),
Similar emergence of function through multiple,
unpredictable, forms of DNA mutations explains
the evolutionary adaptation of the haemoglobins of
organisms to high or low altitude (Natarajan etal.,
2016).
The nerve impulse and hearT pacemaker rhyThm
emerge from high-level consTrainTs
Membranes in organisms are critical to nearly all the
control processes by which molecular-level processes
serve the interests of the organism as a whole. One
of the reasons is that the lipid bilayers are so thin
that the electric field generated across them is
enormous. They can support fields up to 10 000 volts
per cm before they break down. Such field strengths
are sufficient to cause membrane-bound proteins
to change shape depending on which way the field
works. Many transporter proteins forming channels
and carriers in cell membranes can be regulated
and so form electric switches. If the field changes, as
found during electrical events like nerve impulses,
the channels can open and close. Switching of sodium,
potassium and calcium ion channels underlies nearly
all forms of action and rhythm potentials in cells. In
turn the channels conduct ions, which changes the
membrane potential, so forming a feedback loop, the
Hodgkin Cycle. That cycle is necessary to explain
the nerve impulse (Hodgkin & Huxley, 1952). One of
us showed in 1960 that this process can also generate
heart rhythm (Noble, 1960, 1962, 2020b).
Other than relying on DNA to form the RNA
templates for the proteins involved, the fundamental
physiological processes involved are independent of
DNA. No changes in gene expression are needed on
the timescale of individual nerve impulses or heart
beats. Gene expression changes too slowly to be part
of the nerve impulse or heart rhythm generator. Nor
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4 R. NOBLE and D.NOBLE
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are there any genes for lipids. Such processes in the
lipid membranes of the nucleus are deeply involved
in the cell networks by which DNA is controlled. Cell
membranes are life’s computing power used to control
many living processes, notably including DNA where
the nuclear membrane and its channels perform a
similar controlling function. Cell membranes are
where the equivalent of IF-THEN-ELSE branching
controls are located in organisms, not in the genome.
physiological funcTion in evoluTionary
biology
All the examples we have presented so far are from
standard physiology. The Modern Synthesis claims
that those are the only examples there could be, since
that synthesis confined physiological functions to the
disposable vehicle for the transmission of genes. On
that view, physiological functions cannot influence the
evolution of genes since the Weismann Barrier was
deliberately hypothesized to exclude communication
between the soma and the germ line, an idea accepted
alike by the original synthesis (Huxley, 1942) and in
the textbooks and popularizations today [see Shapiro
& Noble (2021b) for detailed analysis].
Charles Darwin, who was a member of the
Physiological Society in the UK from its foundation
in 1876 (Sharpey-Schafer, 1927), would certainly not
have agreed. The Origin of Species (Darwin, 1859)
contains around 12 references to the inheritance of
acquired characteristics. Furthermore, he took this
idea so seriously that he proposed a physiological
process by which it could occur. In his book, The
Variation of Animals and Plants Under Domestication
(Darwin, 1868), he outlined a theory for how
physiological changes in organisms during their
lifetime could influence future generations through
their effects on the germ line cells, the future eggs
and sperm. So convinced was he that he treated his
theory of pangenesis as a ‘beloved child’ (Desmond
& Moore, 1991: p.551). This was no passing fancy.
He very much wished it to be true. At the same time,
he realized its speculative nature, since no-one had
any evidence that transmission of material, which
he called gemmules, from the soma to the germ line
could occur. 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, p.377)
‘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, p.378)
He therefore imagined his gemmules as rather like
spores. He was wrong to suppose that they were
capable of ‘reproducing a similar cell’, but correct to see
cells as ‘casting off a free gemmule’. His text only needs
revising to read ‘capable of influencing other cells’ for
his gemmules to become the extracellular vesicles of
today. His theory did not need them to reproduce, only
to influence characteristics. One is left to wonder what
Darwin would have made of viruses and the way they
cause disturbance in organisms. Would he perhaps see
these as ‘rogue gemmules’? Where else would viruses
have come from but from cells? They cannot replicate
withoutcells.
When, after Darwin’s death, Weismann proclaimed
the ‘all-sufficiency’ (allmacht) of natural selection and
the necessity for a barrier (Weismann, 1892, 1893) ,
it was difficult, if not impossible, for defenders of
Darwin’s idea to resist Weismann’s exclusion of the
inheritance of acquired characteristics.
Yet, in retrospect, we can now see that Darwin was
using a similar logic to that of William Harvey and
his ‘porosities’. The fact that we cannot directly see
something postulated by a valid scientific theory does
not, in itself, disprove the theory. It may simply mean
that the resolution with which we can see things is
not sufficiently high. Harvey’s porosities appeared just
three decades later in the light microscope detection of
capillaries. Darwin’s gemmules have had to wait much
more than a century (Liu & Chen, 2018), but we have
nevertheless found them. The evidence that DNAs,
RNAs and other molecules get transmitted from the
soma to the germ line is now clear from work in many
laboratories (Lavitrano etal., 2006; Cossetti etal., 2014;
Chen H etal., 2016; Chen Q etal., 2016; Spadafora,
2018; Skvortsova etal., 2018; Zhang etal., 2018; Noble,
2019; Bonner & Willms, 2021). Darwin’s gemmules
have become the extracellular vesicles detected by
an order of magnitude increase in the resolution of
light microscopy, brought about by detecting light
directly emitted from vesicles by fluorescent labelling
of molecules contained in the vesicles, which also
means that we know precisely what the molecules are.
Notably, they include DNAs, RNAs and transcription
factor proteins.
darwin’s physiological experimenTs wiTh
burdon sanderson and romanes
Darwin was not only one of the first Honorary Members
of the Physiological Society, he was an enthusiastic
supporter of physiological experimentation and
collaborated with the cardiac physiologist John
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PHYSIOLOGY RESTORES PURPOSE 5
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Burdon Sanderson on experiments using the Venus
fly trap (Williams, 1973) published in 1873 (Burdon
Sanderson, 1873) and with George John Romanes,
described in the history of the Society (Sharpey-
Schafer, 1927) as ‘Of all the young men who helped to
launch the Society, Romanes was unquestionably the
most brilliant.’ Romanes bravely tried to resist the
tide of Weismannism. The reasons are relevant to our
article.
For many years, Romanes worked as a physiologist in
close collaboration with Darwin in attempts to obtain
experimental evidence for the pangenesis idea from
grafting experiments in plants and animals. The full
details of that interaction over many years are to be
found in Schwartz (1995). Romanes became ‘Darwin’s
staunchest supporter at a time when Wallace ceased to
be one’ (Schwartz, 1995: p. 283). He published an article
in the Linnean Society Journal on what he called
Physiological Selection (Romanes, 1886), and became
the Secretary of the Society. In his article hewrote:
‘I became satisfied that some cause, or causes,
must have been at work in the production of
species other than that of natural selection, yet of
an equally general kind.’
Romanes’ work with Darwin was all done, of course,
without knowledge of genetics and might have
succeeded better had he lived to the early 20th century.
He died in 1894 at the age of 46, a great loss to the
cause of physiology in evolutionary biology.
The relevant knowledge of genetics came 50years
later with the work of Waddington showing genetic
assimilation during deliberate iterative selection of
acquired traits in fruit flies (Waddington, 1957). The
knowledge and facilities that Darwin and Romanes
had in the 19th century were not up to the job. They
were unaware of epigenetic control of genetics, as
introduced by Waddington (1957), and later developed
into the modern version of genome marking and
similar controls of chromosomes. And they were
also tackling the much more difficult question of
direct soma to germline communication. Even today,
with the identification of such communication via
extracellular vesicles, determining the extent to which
such transmission could underlie specific acquired
characteristics remains for further research to clarify.
Zhang etal. (2018) show an example of how this
identification can be achieved by identifyimg the RNA
transmitting metabolic inheritance. So, in a few cases
we know the functional significance of transmission of
nucleotides to the germ line. But, much more research
of this kind is needed before we can know how the
germ cells and subsequent embryonic development
interpret nucleotides transmitted from thesoma.
As for the unsuccessful inter-species grafting
experiments of Romanes and Darwin, these were
later overtaken by the spectacular discovery
of symbiogenesis (Mereschkowsky, 1910; Kozo-
Polyansky, 1924; Margulis, 1970) as a major step in
evolutionary transitions arising precisely from the
fusion of different species. Darwin and Romanes
would surely be celebrating that success in showing
how fusion between organisms could drive major
evolutionarychange.
Sadly, almost all of these important 20th century
discoveries made outside the remit of the hardened form
of the Modern Synthesis are ignored or downplayed
in the modern textbooks and popularizations of
evolutionary biology (Shapiro & Noble, 2021b).
The predicTable failure of genome sequencing
To Transform healTh care
From all these functional processes at higher
physiological levels we make a general prediction
about the genetic molecular level. With the exception
of the rare monogenetic diseases, we would not
expect knowledge of DNA sequences to be powerful
in predicting functional processes of health and
disease at higher levels of physiological organization
since, as we have shown, high level insights predict
lower level properties, but the predictive power only
rarely goes the other way. As Joyner & Prendergast
(2014) say, ‘The time has come to stop chasing Mendel’
by replacing gene-centric interpretations with
physiological understanding of complex regulatory
processes (Joyner & Pedersen, 2011).
That is precisely what the results of genome-wide
association studies (GWAS) show. For all complex
multi-factorial diseases, the associations with
particular DNA sequences are low or even negligible.
That is why many genomics scientists now accept
the plurigenic or even omnigenic (Boyle etal., 2017)
theory: most DNA sequences are involved in most or
even all functions.
Incidentally, this outcome was predicted by Julian
Huxley in his book Evolution: The Modern Synthesis
in1942:
‘…every character is dependent on a very large
(possibly all) of the genes in the hereditary
constitution: but some of these genes exert marked
differential effects upon the visible appearance.’
Huxley (1942: p. 19)
Only in the case of rare genetic diseases do we find
strong correlations, most of which we knew about
even before genome sequencing. This fact means that
there is usually a mismatch between physiological
causal role and the GWAS association score. Consider
as an example the cyclic membrane and ion channel
switch processes generating heart rhythm. Achannel
contributing 80% of the pacemaker current change
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6 R. NOBLE and D.NOBLE
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would produce less than a 20% change in frequency
when removed either by gene knock-out or by blocking
drugs (Noble etal., 1992; Noble, 2011). This kind of
mismatch is strong empirical evidence for function
in physiology since the difference is a measure of
functional robustness in the physiological control
processes. Even a zero association score cannot be
taken to mean no causal role. It could show just how
robust the control processes are. Noble & Hunter
(2020) have recently pointed the way forward out of
this impasse using the computational modelling tools
of the PHYSIOME Project. It is in this context that
we can understand, for example, how knocking out
the CLOCK gene in mice does not remove circadian
rhythm (DeBruyne etal., 2006). The more the processes
involved in circadian rhythm have become understood
the more necessary it is to understand the multi-
level physiological nature of its control (Roenneberg
& Merrow, 2005). Khalilimeybodi etal. (2020) have
used computational modelling of regulatory networks
to reveal extensive cross-talk between processes
regulating cardiac hypertrophy. Only 40 out of 170
single reaction deletions had an effect on model
accuracy.
To understand the significance of this failure of
GWAS to deliver the expected health benefits we
should recall what was promised as clinical benefits
when the Human Genome Project was launched: the
head of National Institutes of Health, Collins (1999),
claimed that human genome sequencing would leadto
…previously unimaginable insights, and from
there to the common good [including] a new
understanding of genetic contributions to human
disease and the development of rational strategies
for minimizing or preventing disease phenotypes
altogether.’
These ‘unimaginable insights’ were expected to come
within 10 to 20years after the first full sequencing of
the human genome. As we have shown, they were not
just ‘unimaginable’, from a functional physiological
viewpoint they would not have been expected to exist.
The gene-centric consensus of the late 20th century
prevented the significance of that prediction being
appreciated. Two decades of massive investment have
now been spent searching for functional explanations
and possible therapies at the wrong levels of
organization (Baverstock, 2021). As a consequence,
we have found the costs of drug development
increasing while the output of successful medications
has declined (Khanna, 2012). Analysis of failures in
drug development shows that the great majority are
in medications for complex multifactorial diseases
(Arrowsmith, 2011). Very few new targets identified by
genome sequencing have proved fruitful.
As a further result the world is unprepared for the
economic costs of aging populations (Scott & Gratton,
2020) since the great majority of funding has gone to
low-level genomic studies. Having the incorrect view of
function in physiology therefore costs money and lives.
In the case of late-stage cancers, for example, there has
been little or no significant improvement in prognosis
and lifespan since President Nixon announced the
‘War on Cancer’ 50years ago. The cause of this failure
is that aggressive and expensive chemotherapies
simply provoke rapid evolution in the cancerous
tumours (Shapiro & Noble, 2021a). Aphysiological
understanding of evolution can reveal why such rapid
evolution occurs. The slow accumulation of point
mutations cannot.
LIFE IS PURPOSEFULLY CREATIVE
The drive To live
Life is naturally and necessarily purposive. The ability
to choose has developed through the evolution oflife.
All the examples of physiological functions above
demonstrate the purpose for which organisms possess
those functions. It would be a misuse of language to
deny that those purposesexist.
Yet, how could that be true if organisms were
programmed by molecular sequences, as gene-centric
theories of evolution assume? Purpose cannot be a
property of molecular level deterministic one-way
programs. There is no sense in talking of being selfish
or altruistic if there is no choice in the matter. That
is true of programmed machines like computers that
become purposive through the agency of humans that
design them, and it would be equally true of organisms
if their development were automatically programmed.
The reality is that there are no programs in
genomes (Coen, 1999; Noble, 2016). All the IF-THEN-
ELSE branching routines that organisms use in their
abilities to choose and control necessarily involve much
more than DNA, including the role of membranes, the
components of which are not dependent on genes.
The activity of DNA is zero until it is activated by the
organism itself. As an example, when the PERIOD
gene forms part of a circadian rhythm cycle it requires
activation or inhibition to come from the cell to switch
it on and off. That includes processes outside the
nucleus, such as manufacture of the PERIOD protein,
and the role of the nuclear membrane in controlling
how rapidly molecules pass through it. That is why it
is important to note that organisms never inherit DNA
alone. They necessarily also inherit all the functions of
the fertilized egg cell, including the cell cycle processes.
Life does not exist below the level of the cell. And most
organisms on earth are still unicellular.
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PHYSIOLOGY RESTORES PURPOSE 7
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Not only do organisms inherit all the natural cell
functions, they also inherit the faculty of choice, the
ability to develop many forms of choice behaviour as
they develop and interact with their environment,
including other organisms. Purposive functions are
therefore both inherited and developed. We return to
the developed capacity to create novel ways to choose
later. First, let us consider the many transitions
through which evolution has endowed organisms
with their inherited functional capacities. Some of
those transitions are summarized in Figure 2 taken
from one of our previous publications (Noble & Noble,
2021a).
Each transition depends on the evolution of the
prior transitions. There is a ratchet effect (Hoffmann,
2012). Each time a major transition occurs, it opens
the way for the next transition. The nature of the
evolutionary process also changes. Evolution itself
evolves (Noble etal., 2014). If a process made possible
by one of the transitions can enable evolution to be
more rapid, then that newly-enabled process will
automatically dominate. That is another reason why
restricting evolution to blind natural selection cannot
be correct. Rapid radiations, such as the Cambrian
explosion, are then more easily understood (Gould &
Eldredge, 1977; Gould, 2002; Ginsburg & Jablonka,
2010, 2019). Similar insights are now proving valuable
in understanding the rapid evolutionary radiation
of genomic forms in cancerous tumours (Shapiro &
Noble, 2021a).
This process of emerging transitions is an old
idea in evolutionary biology, explored notably in
Maynard Smith & Szathmary’s (1995) book The
Major Transitions in Evolution, and more recently
in Ginsburg & Jablonka’s (2019) book The Evolution
of the Sensitive Soul. It also goes back at least to
Lamarck’s idea of ‘le pouvoir de la vie’ [the force of life
(Lamarck, 1809)]. Lamarck has been widely ridiculed
for his ideas and this one is no exception. However,
Lamarck was not a vitalist. He was firmly a materialist
(Pichot, 1994). The current idea of a ratchet process
in the development of major transitions corresponds
well to what he had in mind, which was that each
stage in the evolution of organisms created a further
way up the ladder of complexity. It is widely thought
that Lamarck also considered that the ladder concept
best represented the transformation of species with
no branching (Futuyma & Kirkpatrick, 2018: p.10).
This also is not correct. Lamarck himself changed
his mind and replaced his ladder with a tree of life
(Gould, 2000; Noble, 2020a), which was even more
detailed than that drawn by Darwin 28years later in
his Notebook B (Noble, 2019).
The concept of the enabling effect of major
evolutionary transitions does not, in itself, imply that
the transitions were inevitable. All life on earth might
one day be snuffed out by cosmic catastrophes, but
that does not remove the historical fact that the major
transitions occurred, and in a sequence of increasing
functionality. Nor is the ladder of life idea incompatible
Unformed
chemical soups
Autocatalyc
networks
RNA world
–primive
cells
DNA world –
cells with
genec memory
Symbiosis –
eukaryotes Mulcellularity Nervous
systems
Limited
associave
learning
Unlimited
associave
learning –
consciousness
Major transions in evoluon
Increasing openness
Agency: harnessing stochascity
Acve Agency:
consciousness
Figure 2. Evolution of organisms represented as a possible time sequence with major transitions (from Noble & Noble,
2021a).
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8 R. NOBLE and D.NOBLE
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with a tree of life, which itself is not incompatible with
a network of life. That is what we must now suppose
since organisms extensively exchange DNA and other
factors between themselves. The branches of the tree
communicate with each other. Each analogy, ladder,
tree and network can be viewed as useful, but partial,
metaphors. The mistake of the hardened form of the
Modern Synthesis was to insist that only one of the
metaphors was correct.
where do purposes come from?
Organisms live on the edge between order and disorder.
Unlike a crystal, DNA is not a self-replicator, nor is
its replication highly accurate unless the cell makes
it so. The disorder that arises from inaccurate copying
is itself under control and corrected by the organism.
That control can be as accurate or disordered as the
organism requires. When under stress organisms allow
greater disorder and so generate many more DNA
variants to become a treasure trove of novelty. This is
how the immune system defends the organism against
novel attacks and how organisms deal with stress
to enable their populations to evolve more rapidly.
Neo-Darwinists sometimes claim that this is just an
exception, but the evidence that such rapid changes
have occurred, including major re-organizations of
genomes, has been clear ever since the full sequencing
of the human genome was compared with that of other
species in 2001 (Lander etal., 2001; Shapiro, 2011).
Functionally important proteins, such as transcription
factors and chromatins, were shown to have evolved by
domain accretion (Shapiro, 2011; Noble, 2016: pp.200–
204; Shapiro & Noble, 2021b). It would be exceedingly
improbable that such accretion could have occurred
through the slow accumulation of small mutations
(Noble & Noble, 2017). This is one of the examples
of faster, more targeted, processes taking over from
Natural Selection through being morerapid.
We have also shown how disorder can be used
by organisms capable of purposive choice, through
exploiting stochasticity in the nervous system (Noble
& Noble, 2020). Wewrote:
‘What we have shown in this article is that
there is no difficulty from an empirical science
viewpoint in envisaging how organisms could
achieve conformity to rational actions through the
process of harnessing stochasticity. Harnessing
is a necessary causal process, as is evident also
from its role in guiding evolution (Noble, 2017;
Noble and Noble, 2017). Functional boundaries
between organisational levels mean causation up
and down are necessarily different (Noble etal.,
2019), but they do not compete for primacy. They
mesh together and are both enabling and creative.
In setting boundaries, downward causation can be
viewed more like a context, setting constraints,
purpose and goals. It is then not too difficult to
view reasons, ethics, laws and customs operating
in this way. They are socio-biological processes
influencing predisposition states in the organism.
Thinking that we need to solve how upward and
downward causation “compete” with each other is
a mistake. They mesh. Reasons are not incidental
or merely epiphenomenal; organisms create
them as contextual logic. Thus, reasons form the
contextual influences within which action occurs.’
(Noble & Noble, 2020: pp.288–289)
Levels of organization thus form a nesting relationship
with and between each other. This is illustrated in
Figure 3.
All higher levels constrain lower levels, so that the
greatest constraint is at the molecular DNA level,
while the greatest openness lies at the sociotype level.
Note though that this point should not be interpreted
to mean that constraints pass only one way between
the hierarchy of levels of organization. On the contrary,
there must be simultaneous transmission of causal
influences up and down, as shown by Noble etal.
(2019), who also discuss the differences in the forms of
causation at differentlevels.
This purposive view of life is the very antithesis of
the Modern Synthesis. It is also faithful to Darwin’s
strong wish, expressed in his physiological work with
Romanes, that his ‘beloved child’ (Desmond & Moore,
1991) could be proved in his lifetime.
Organisms inherit the faculty for purposiveness in
addition to their genomes. As Popper once put it ‘All life
is problem solving’, the English title of one of his books
(Popper, 1999). They use their agency to develop new
purposes. DNA is a toolbox in that continual search for
novelty and success in maintaining their integrity. So
also is stochasticity in the nervous system (Noble &
Noble, 2018).
IMPACT OF THE MODERN SYNTHESIS ON
PHYSIOLOGY
The Modern Synthesis in its original version,
as formulated by Julian Huxley in 1942, did not
completely exclude physiological function in the
process of evolution:
‘Contrary to the views of the Weismann School,
selection alone has been shown to be incapable
of extending the upper limit of variation …
mutation alone has been shown to be incapable of
producing directional change … the third process
of recombination is almost equally essential, not
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PHYSIOLOGY RESTORES PURPOSE 9
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only for conferring plasticity on the species and
allowing for a sufficient speed of evolutionary
change, but also for adjusting the effects of
mutations to the needs of the organism.’ (Huxley,
1942: p.29, our emphasis)
It is remarkable that even the chief spokesperson
for the original Modern Synthesis 80years ago
included the functional idea that mutations could
respond to the needs of the organism. In this text he
refers to recombination in sexual reproduction, but
the idea nevertheless contains the seeds of realizing
that other recombination processes could also ensure
that evolution proceeds much faster and in a directed
sense to meet ‘the needs of the organism’. Function in
physiology is what serves ‘the needs of the organism’.
After all, symbiogenesis (Mereschkowsky, 1910; Kozo-
Polyansky, 1924; Margulis, 1970), which could be viewed
as the ultimate in recombinant evolution since it is the
complete fusion of two very different genomes, was
one of the critically important transitions in evolution
(Fig. 2). Huxley also acknowledged the role of
hybridization in evolution (Huxley, 1942: p.147). Darwin
would have been pleased to see his ‘beloved child’ of
cross-species interaction flourish so spectacularly, and
especially so in his Galapagos finches (Bell, 2015).
It was the restrictive, hardened, form of the Modern
Synthesis that developed in the 1960s, through the
publication of Adaptation and Natural Selection
(Williams, 1966), and in the 1970s through the The
Selfish Gene (Dawkins, 1976, 2016), that finally
sealed the fate of purpose in biology (Noble & Noble,
2021b). From then on the sidelining of physiology
became complete. Physiology was henceforth viewed
as dealing solely with the disposable vehicle of the
‘real’ object of evolution, the supposedly ‘immortal’
genes. The influence of those two books was profound.
Who would choose to be focused on the ‘disposable’
vehicle, the phenotype, if it played no role whatsoever
in evolution? The subsequent dominance of molecular,
and particularly genomic, approaches left integrative
physiology with very much a back seat in biology. Many
university departments of physiology were closed or
absorbed into more general biological and medical
departments. The consequence has been that two
generations of students have now been trained with
little knowledge of physiology above that of the cell. The
study of life became subsumed to a form of chemistry.
Just how pervasive these changes were is illustrated
by the outcome of a long-running correspondence
between Max Perutz, Head of the MRC Laboratory
of Molecular Biology in Cambridge, and the logician
of science, Karl Popper, on whether biology could be
reduced to a form of chemistry (Niemann, 2014; Noble
& Noble, 2021a). That correspondence is central to the
theme of our paper since Popper gave a lecture to the
Royal Society in 1986 in which he distinguished passive
Darwinism (natural selection) from active Darwinism
(the agency of organisms in choosing other organisms
with which to mate or collaborate). In effect, Popper
was appealing to his audience to bring purpose back
into biology and, specifically, evolutionary biology. His
lecture fell on deaf ears, and it was never published. Yet
Popper was right: All Life is Problem Solving became
the title of one of his books published posthumously in
English (Popper, 1999).
Sociotype
Ecotype (niche)
Phenotype
Organ types
Tissue types
Cell types
Karyotype
DNA
Increasing openness
stniartsnocgnisaercnI
Figure 3. Levels of organization and causation in organisms (from Noble & Noble, 2021a).
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10 R. NOBLE and D.NOBLE
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Popper’s 1986 lecture never got published by The
Royal Society since he was intent on convincing
Perutz of his case (Niemann, 2014). Perutz did not
yield (Perutz, 1986). Our interpretation of the failure
of Popper’s lecture in support of active agency in
evolution to break through is that he did not have the
evidence to hand to challenge the Central Dogma of
molecular biology [now summarized in Noble (2021b)
and Shapiro & Noble (2021b)]. Some of the critical
molecular biological discoveries appeared after his
death (Noble & Noble, 2021a, b). As Huxley admits
(Huxley, 1942: p.614 in 2010 reprint), the Central
Dogma was critical in persuading the later Modern
Synthesists to harden their position. To that end,
Dawkins even invents a second Central Dogma, the
‘Central Dogma of Embryology’:
‘Oddly, my belief in the inviolability of the central
dogma is not a dogmatic one! It is based on
reason. Imust be cautious here, and distinguish
between two forms of central dogma, the central
dogma of molecular genetics and the central
dogma of embryology. The first is the one stated
by Crick: genetic information may be translated
from nucleic acid to protein, but not the other way
round.... a very good case can be made against
violating the other central dogma, the central
dogma of embryology. This is the dogma that the
macroscopic form and behaviour of an organism
may be, in some sense, coded in the genes, but the
code is irreversible. If Crick’s central dogma states
that protein may not be translated back into DNA,
the central dogma of Embryology states that
bodily form and behaviour may not be translated
back into protein.’ (Dawkins, 1982: p.174)
Dawkins’ invention of yet another ‘central dogma’
is the basis of the frequent mistake of thinking that
the Central Dogma of molecular biology is ‘a modern
version of the Weismann Barrier’ and so buttresses
the Barrier idea as absolute (see https://simple.
wikipedia.org/wiki/Central_dogma_of_molecular_
biology; accessed 26 October 2021). It cannot do so.
The central dogma of molecular biology (Crick, 1970)
is a statement about molecular level interactions; the
Weismann Barrier (Weismann, 1892) is a statement
about the isolation of germ cells. As we have shown,
vastly more is inherited by cells than their molecular
genomes. And vastly more is inherited by offspring
than their germinal DNA. In the case of mammals, the
offspring clearly inherit maternal and paternal effects
independent of their DNA (Gluckman & Hanson, 2004)
and they acquire the microbiome, containing vastly
more than their own cells’ DNA. For a more complete
deconstruction of the Central Dogma of molecular
biology see Shapiro (2011), Shapiro & Noble (2021b)
and Noble (2021b). Neither Crick’s nor Dawkins’
‘Central Dogmas’ have any place in science.
The key to understanding the demise of purposive
interpretations of physiology in the mid-20th century
is a historical fact. The deconstruction of the
Central Dogma of molecular biology had to wait for
further molecular biological discoveries in order to
understandthat:
(a) DNA cannot possibly be a self-replicator in the way
‘how crystals are formed.’ (Dawkins, 1976: p.17),
(b) there cannot, therefore, be a hard separation of
‘replicator’ and ‘vehicle’,and
(c) organisms have the ability to selectively modify
their genomes and so to influence the direction of
their evolution.
WHATNOW?
Since we now know better, what should we do aboutit?
It will require creative ingenuity to shift the culture
of biology away from the misunderstandings of the
20th century. If we date the dogmatic hardening of
the Modern Synthesis as 1970, then that misleading
culture has embedded itself for half a century. We
cannot suddenly recreate the pre-1970s culture
when integrative functional biology experienced
many golden periods of discovery. It will be for a new
generation to discover and create their own culture fit
for the challenges of the 21st century.
They will have plenty of looming signposts to warn
them what went wrong. Theirs will be a generation
that must take responsibility for the way in which
the earth’s ecosystems need rescuing, even for our
own species to survive. Theirs will be the generation
that faces the challenge of aging societies, requiring
medical science to find solutions to diseases of old age
that do not readily yield to reductionist gene-centric
solutions since those diseases are multi-factorial. Only
an integrative approach that understands those multi-
factorial interactions can possibly hope to address
those diseases.
Theirs will be a generation that can try to recover
from the damage to society that results from
reductionist models of physiology and evolution that
have metaphorically shaped ideas and models in fields
as diverse as economics, sociology, philosophy, ethics,
politics… the list goes on because no aspect of today’s
society can have escaped dogmas like ‘we are born
selfish’, ‘they [genes] created us body and mind’, ‘it’s in
their DNA’, and the myriad of other tropes of related
types that we now use almost without thinking.
Those future generations will also need to rewrite
the textbooks, not only because they see the virtue
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PHYSIOLOGY RESTORES PURPOSE 11
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of ‘let us therefore teach our children’, but also
because their politicians, economists, sociologists and
philosophers will also need to find new strategies, in
collaboration with biologists who can lead them out of
the gene-centric impasse.
We wish them all well. It is arguably a challenge the
scale of which human society has never facedbefore.
ACKNOWLEDGEMENTS
No funding sources supported this work. There are
no conflicts of interest. We thank Anthony Kenny and
Perry Marshall for valuable comments on an early
draft of this article, and an anonymous reviewer for
comments on the manuscript submitted. The article is
based on an oral presentation to the Linnean Society
under the title ‘Physiology and telos: is teleology a sin?’
(https://vimeo.com/562981272), and is a contribution
to a special issue on Teleonomy in Living Systems,
guest edited by Richard I.Vane-Wright and Peter
A.Corning, based on this Linnean Society meeting
held on 28–29 June 2021.
daTa availabiliTy
This article is based on information in the published
accessible literature.
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