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ONLINE COLLECTION: Focus article "The Gene: An Appraisal"

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Introduction to: Online issue of the Journal with a Focus Article, "The Gene: An Appraisal", by Keith Baverstock. The issue contains, in addition an Editorial by Denis Noble, seven commentaries by other gene experts, and a response to criticisms by Baverstock. Baverstock argues that genes should not be thought of as regulating cellular production; instead, the cellular phenotype, a gene product interactome, regulates the cell, itself, and expresses the cell’s characteristics, suggesting that an appropriate metaphor is a brain. There is no one-way process from genes to phenotype as the current molecular genetic paradigm envisages. The contemporary error dates a century back to Wilhelm Johannsen’s proposed ‘genotype conception’ which underpins population genetics and heredity today. In fact, the prior Francis Galton’s statistically based ancestral law of inheritance is closer to the truth. The Editorial summarizes the commentaries, all supporting the main thrust of Baverstock’s case, whereas, from the many invited to comment no response was received from senior scientists using the Genome-Wide Association (GWA) methodology. Since the articles in this issue of the Journal were published, the case has been supported by the discovery that polygenic scores based on GWA fail to predict major diseases, including cardiovascular disease and cancer. Despite spending some US$8 billion by NIMH, no gene responsible for schizophrenia has been identified either. The Editorial speaks out forcefully on the disturbing silence from those leading GWA studies, pointing to the large amount of funding consigned and the very little delivered, of clinical and public health value. Denis Noble
ONLINE COLLECTION
The Gene: An Appraisal
by
Keith Baverstock
Edited by
Denis Noble
Introduction
Online issue of the Journal with a Focus Article, The Gene: An Appraisal, by
Keith Baverstock. The issue contains, in addition an Editorial by Denis Noble,
seven commentaries by other gene experts, and a response to criticisms by
Baverstock. Baverstock argues that genes should not be thought of as regulating
cellular production; instead, the cellular phenotype, a gene product interactome,
regulates the cell, itself, and expresses the cell’s characteristics, suggesting that
an appropriate metaphor is a brain. There is no one-way process from genes to
phenotype as the current molecular genetic paradigm envisages. The
contemporary error dates a century back to Wilhelm Johannsen’s proposed
‘genotype conception’ which underpins population genetics and heredity today.
In fact, the prior Francis Galton’s statistically based ancestral law of inheritance
is closer to the truth. The Editorial summarizes the commentaries, all supporting
the main thrust of Baverstock’s case, whereas, from the many invited to
comment no response was received from senior scientists using the Genome-
Wide Association (GWA) methodology. Since the articles in this issue of the
Journal were published, the case has been supported by the discovery that
polygenic scores based on GWA fail to predict major diseases, including
cardiovascular disease and cancer. Despite spending some US$8 billion by
NIMH, no gene responsible for schizophrenia has been identified either. The
Editorial speaks out forcefully on the disturbing silence from those leading
GWA studies, pointing to the large amount of funding consigned and the very
little delivered, of clinical and public health value.
Denis Noble
EDITORIAL
Editorial for Online Collection —
The Gene: An Appraisal
by
Denis Noble
Progress in Biophysics and Molecular Biology 187 (2024) 1–4
Available online 3 January 2024
0079-6107/© 2024 Elsevier Ltd. All rights reserved.
Editorial for online collection The gene: An appraisal
1. Introduction
This editorial introduces an on-line Special Collection of articles
centred on an appraisal of the idea of geneby one of the journal Board
members, Keith Baverstock.
The Collection is timely, since it has come together soon after pub-
lication of an important and rigorous test of the predictive utility of
polygenic scores, showing a disappointing predictive utility (Hingorani
et al., 2023).
I will return to the signicance of that study after introducing the
Collection.
1.1. A one-sided complete silence from defenders of genome sequencing
Keith Baverstocks article, The Gene: An Appraisal (Baverstock,
2023a), is important since it argues that genome sequencing has
generally found very low association scores for most genes in relation to
the main multifactorial diseases that are resistant to a gene-centric
analysis. Inevitably, that fact is also connected with the second fact,
that very few strategies for curing such diseases have emerged from the
results of genome sequencing. This is so despite the promise that, within
a decade, such cures would automatically emerge from the human
genome project (Collins, 1999). It is hard to see how anyone can fault
those two conclusions. Yet, as I will now explain, the journal has
received no answer whatsoever from the genomics community leaders.
An Editor-in-Chief of a journal is in a privileged position. The ben-
ets include viewing the scientic community and its arguments
through an attempt, at least, to stand back above those arguments in
order to carry conviction as a relatively neutral judge. The buck stops
here. In consequence an Editor is often faced with difcult decisions.
But, sometimes, remaining neutral is almost impossible. In writing
this Editorial I cannot remain neutral. The reason is fundamental to any
journal that prides itself on encouraging live and sometimes erce
debate. The Editors role is to try to get opinions and arguments across
the spectrum of views and interpretations.
There is no lack of such a spectrum in the case of debate about genes
and their roles and effects. Opinions vary all the way from genes for
everythingto genes for nothing(Ball, 2014); from genes created us
body and mind (Dawkins, 1976, p. 26) to genes are followers of
phenotype changes (Schwander & Weimar, 2011; Noble and Phillips,
2023).
When I received Keith Baverstocks article I therefore acted as any
Editor should: take a long view, solicit reactions from a wide spectrum of
known opinion and expertise, then sit back and wait for the debate to
happen. I therefore invited commentaries from around 15 scientists who
I judged would be broadly favourable to the article, while obviously
having their own criticisms from their particular standpoint. I also
invited around 15 who, from their previous work, would be expected to
be strongly opposed to the main thrust of the article, and some who
might be in between. An overall total of 45 were invited.
Two years later, in response, the journal has received 7 articles from
the rst and third group of invitees, but none whatsoever from the second.
Those invitees included leading geneticists and genomics people. Why
the silence? Surely, the responsibility for the huge investments of time,
money and people in genome-wide association research carries with it a
responsibility for openness to criticism and questions since that funding
is provided by society itself, via governments, businesses or charities.
Furthermore, in the case of genetics and genomics research the stakes
are very high indeed. These areas of medical research receive the lions
share of funding. Why then, over two decades since the rst publications
on sequencing human, and other, complete genomes, do we see so few
health benets that could begin to justify the huge investment that has
been made?
Faced with a crisis of ill-health amongst the growing populations of
the elderly, with multifactorial diseases notoriously unyielding to ge-
netic interpretations, why do we continue to insist that genomics
research holds the answer when the association scores with such dis-
eases are often so abysmally low? Anyway, the association scores
themselves are not a correct indication of the quantitative causal role of
genes in those disease states since physiological networks are good at
buffering changes at the molecular level (Noble and Hunter, 2020). As
that article states, quantitative physiology is ready to come to the rescue
of genomics research. Physiology measures causation, and it is often
very different from association. Even a zero association score cannot
prove no causal role. That is the major difculty with Genome Wide
Association scores and it has not been addressed.
I believe this one-sided silence from those responsible for managing
the huge investments involved reects badly on the scientic commu-
nity. It is not in the long-term interest of science itself, for science
ourishes on active debate and engagement. In the end, large scale
mistakes in prioritising research will become evident. It is better that we
should learn what mistakes have been made earlier rather than later.
Genome-wide association research has given us masses of data but is
presented, even by its own advocates, as independent of theory: A
hypothesis is a liability! (Yanai and Lercher, 2020, 2021). On the
contrary, without a theoretical guide to what to expect, we have no way
to judge the signicance of a piece of data. Accumulating data without
interpretation is scientic ‘stamp collecting‘ (Felin et al., 2021a, 2021b),
a risky abandonment of thought in biological research.
All the commentaries on The Gene: an Appraisalwe have received
Contents lists available at ScienceDirect
Progress in Biophysics and Molecular Biology
journal homepage: www.elsevier.com/locate/pbiomolbio
https://doi.org/10.1016/j.pbiomolbio.2024.01.001
Progress in Biophysics and Molecular Biology 187 (2024) 1–4
2
and published represent a strong endorsement for the journal in
encouraging debate on the issue. For, while the commentaries are
broadly supportive of the original article, they all make valuable points,
supportive or critical, that extend what I take to be Baverstocks
intentions.
As Editor in Chief for this collection of articles, I have now waited for
nearly three years since the original invitations were sent. That is
already too long. The journal is therefore proceeding to publish the
Collection as it now is. The debate remains one-sided, but that is not the
fault of this journal.
This Editorial will be more detailed than usual since the collection of
articles is not being published as a separate volume but rather as an on-
line collection. It will help readers of the collection if I summarize the
main points of the commentaries. I begin by summarising the com-
mentaries, all of which are already available online.
1.2. The genetic control paradigm
McKenna et al. (2022) write under the title The genetic control
paradigm in biology: What we say, and what we are entitled to mean
which clearly identies the thrust of the commentary. How, in any
process that consists in an interaction, in this case between phenotypes
and genotypes, can we say that one is in control of the other? One way to
answer that question is to note that the environment can never act
directly on genes in an adaptive way, since the only direct effect of the
environment on DNA is radiation and similar damage, causing breakage
and the need for repair. All adaptive change must, surely, therefore arise
via the phenotype which is in continuous interaction with the environ-
ment, including that of other organisms. Furthermore:
mutations can have a very large effect at the molecular level, but
that effect is cancelled out or buffered by evolved homeostatic and
robustness mechanisms in biochemistry, development and physi-
ology. Cryptic genetic variation is most easily detected, documented
and quantied in human diseases where genes that are characterised
as risk factors for a disease by genetic epidemiologists have been well
studied (Nijhout et al., 2015, 2018). Cryptic genetic variation will
not be ‘seenby selection until a mutation or an environmental signal
disrupts one of the stabilising mechanisms.(P. 90)
This is precisely the process that my research team found over 30
years ago in the case of the pacemaker rhythm of the heart (Noble,
2021). There is overwhelming evidence that most regulatory physio-
logical networks are robust in this way. In the few cases where they are
not, the outcome is one or other of the rare outlier genetic diseases. I
cannot understand why there should still be any doubt about this. Yet,
genomics research still looks for summing up all the small association
scores to estimate overall genetic causation, usually called the polygenic
risk score. It cannot be stated too rmly, this is nonsense. In complex
interactive systems the effects are necessarily not additive.
The authors are equally rm on the use of phrases like genetic
programs:
authors who appeal to genetic control, programs, and blueprints
seldom if ever dene what exactly they mean by these terms.(P 90)
This is necessarily so, since no-one has ever identied the equivalent
of IF-THEN-ELSE clauses in genome sequences. It is more than 40 years
since Monod and Jacob coined the phrase genetic program. It is high
time the phrase should be relegated as highly misleading. All the
important conditional processes in biological systems occur at higher
levels of organisation than the genome.
The authors identify one of the key misunderstandings as the search
for a master controller of what is happening:
Looking for a primitive causal controller in an automobile is a fools
errand. Cars are mechanical systems made-up of mutually dependent
parts. Various components might be more or less important, but none
are truly in control of the vehicles overall functionality. Something
similar can be said of organisms. Their genes, or more properly, their
gene products, play a role in many important processes, but they are
not in control of anything.(P. 91)
This is the sense in which some go so far as to say that there are no
genes for anything and it is reected in the modern view from geno-
mics research favouring what is called the omnigenic hypothesis (Boyle
et al., 2017). What is needed now is that genomics research takes seri-
ously the need to understand the regulatory networks in organisms that
enable genes to have any effects at all.
1.3. Interpretation of Johanssons gene
Nils Roll-Hansen (2022) writes under the title A special role for the
genotype. He declares his difference from Baverstock very early in his
article.
Contrary to Baverstock I hold that even if the gene has become
blurred the distinction between genotype and phenotype remains a
foundation stone of genetics.(P. 82)
He then proceeds to a deeply scholarly analysis of Johanssens ideas
on the genotype-phenotype duality, taking issue with Baverstock on
several aspects of his article, the essence of which is that Johanssons
work cannot be accurately understood simply from his publication in
German in 1909. He concludes his analysis of Johanssen:
Johanssen was by no means alone in his criticism of chromosome
theory and Neo-Darwinism. He shared a holistic approach typical of
German genetics and evolutionary studies in the 1920s and 1930s.
(P 87)
His concluding section is the most critical of the commentaries on
Baverstock, where he rejects the idea that the zygote knows what it
will develop into independently of its genotype.
1.4. Phenotype knowledge of what?
Ken Richardson (2021) responds under the title Genes and Knowl-
edge, where he asks the question knowledge of what?and promises
some grounds for optimism.
The key to his contributions lies in the question:
What rules or rules of engagementas KB calls them might
enable organisms to anticipate rapidly changing, constantly novel
states in dynamically complex environments?(P. 13)
A second key is
Robert Rosen (mentioned by KB) offered a rigorous mathematical
treatise on such anticipatory systemsin biology. Properties emerge
from the deep statistical relations in networks that transcend those of
independent components ..living things dont just change their
statein response to certain conditions; they also change the rules
by which they do so.(p. 13)
Life then is rather like a chess game in which the players change the
rules. That includes the denition of how living organisms became
systems:
When environmental change wrought on one component induced
compensatory changes in another, or even changes that anticipated,
nullied or amplied a future change, they became systems. System
integrity over continual environmental change , at least for some
period of time, is what most distinguished them from non-living
molecular mixtures.(P. 14)
This is one of the most helpful denition of systems that I have
come across. The consequence is that living forms existed before genes
they must have been learning, knowledge-forming, networks
D. Noble
Progress in Biophysics and Molecular Biology 187 (2024) 1–4
3
from the start .phenotypes arrived before genes.
The egg includes transcription factors, promoters , enhancers, and
a rich milieu of RNAs , other proteins, fats, sugars, vitamins, metal
salts, and so on. Then the sperm adds its own cargo, as well as some
polarity to the ovum. In addition, epigenetic markers on offsprings
genes, inuencing how those gens should be used on the basis of
parental experience.
I believe that statement should act as a stark warning to gene-centred
theories of biology. The sheer complexity of egg and sperm need to be
understood. So also do Richardsons comments on metabolism:
The same logic applies to the metabolism of the cell the program
of instructions comes, not from the nucleus, but rather from the
metabolic structures of the host cytoplasm.(P. 14)
He concludes on a high note:
That understanding completely reverses Dawkinss prioritisation of
(stable) genes over (changeable) phenotypes.
1.5. Cellular and organismal agency
Frantisek Baluska and Arthur Reber (2021) agree with Baverstocks
article and suggest that
follow-up research needs to focus on the sensory and electrophysi-
ology of the excitable plasma membrane which constitutes, not only
a physical smartbarrier for the cells interior, but also allows living
cells to maintain their life processes which generate and maintain
ordered cellular structures. (P. 161).
Importantly, they note that
First cells evolved from hypothetical proto-cells. It can be specu-
lated that these proto-cells were devoid of DNA-based digital mem-
ory and relied solely on the structural memory of their limiting
membranes.(P. 161)
I agree. We can see strong evidence for that speculation in the fact
that the energy factories, the mitochondria, of modern eukaryotic cells
rely on their membrane potential to function. Indeed, the mitochondrial
potential regulates the speed of the Krebs cycle and its ATP production
(Lane, 2022, p 244, 280284). Bacteria (from which the mitochondria
evolved) die by short-circuiting their electrical potential. Life depends
on Hodgkin Cycles (the interaction between membrane voltage and
protein function) everywhere (Noble 2022).
They conclude:
Cellular membranes with associated cytoskeleton represent the
primary source of the cellular agency.(P. 161)
1.6. Role of non-genetic sources of bimolecular order
Ildefonso I. De la Fuente (2021) presents a short overview of the
main non-genetic sources of bimolecular order and complexity that
underline the molecular dynamics and functionality of cells.He points
to several types of organisation in living organisms that are involved.
These include:
Dissipative self-organisation, which generates highly ordered dynamic
structures far from equilibrium, and rst proposed by Ilya Prigogine in
1977. Practically all metabolite concentrations in cells present complex
oscillations and/or non-equilibrium quasi-steady states.
Molecular information processing. An essential characteristic of the
biochemistry of life is that enzymes shape modular dissipative networks,
which perform fundamental relatively autonomous activities with spe-
cic and coherent catalytic patterns.
Systemic molecular turnover, which is the process by which all cellular
components, including structural components are continually being
renewed and controlled.
Epigenetic memory that governs the inheritance of previously ac-
quired new functional characteristics. This biochemical mechanism also
represents a huge amount of molecular information not contained in
DNA sequences.
He maintains that enzymes not genes are the essential molecular
actors of the functional architecture of life.
This commentary is rather longer than the others, running to 18
pages. It contains a valuable reference list and will form a good resource
for students and researchers interested in this eld.
1.7. From information to physics to biology
Giuseppe Longo (2023), at the Centre Cavailles in Paris, is a math-
ematician who has contributed, together with others at the Centre, in
many ways to the development of the analysis of complexity in living
systems. He agrees that Baverstocks article highlights many aspects of
the gene-centred approach that have clearly failed to deliver what was
promised, including a deeper understanding of living systems, and
practical clinical applications that would cure many multi-factorial
disease states. He poses the question what was meant, and always
has been, by decodingthe genome. In general, if you have an encoded
message . As a sequence of signs, decoding means its translation
into a language and context that is completely meaningful to the intel-
ligent agent or the (biological) structure using it. Baverstock illustrates
how far we are from this, that is, from associating, in general, and not in
a few special cases, DNA sequence information into the functional in-
formation that informs the phenotype.
His main criticism of the article is that Baverstock continues to use
informational language. Longo himself has criticised the conse-
quences of a terminology borrowed from other sciences. The problem
this creates is that one imports a Laplacian structure of determination
as Turing and Schroedinger explicitly acknowledge. Longo shows that
this ignores the multidimensionality of organisms. He pleads that we
should avoid treating material ows and their gradients as informa-
tionsince this by-passed dimensions, materiality .historicity that
is all what matters in the analysis off life.
A key section of Longos commentary deals with the history of
physics and physicalism in biology to show how we have been misled. In
contradiction with some of the other commentaries, Longo maintains
that an organism is not a self-organising system. It does not emerge
spontaneously and necessarily under certain boundary conditions. This
arises because of the essential historicity of living organisms. This is
what we would like to add to Nobles biological relativity, the non-
locality of parameters or of causal dependence: at least one of the
pertinent parameters that allows/governs the new observable (the heart
in embryogenesis, wings in evolution .) depends on the entire new
global structure that did not exist before.
1.8. Phenotypes and agency
Steven Rose (2023) argues that the last half century of research has
steadily chipped away at such a reductionist, unilinear trajectory, and
not only because of the unexpected result of the Lenski experiment
which he quotes. He is not, as it might appear from the paper, a lone
heretical voice.
I think Rose is correct. There really is now a growing community of
New Trends scientists who, to varying degrees, dissent from the
Modern Synthesis and gene-centric neo-Darwinism. I believe there is
real hope that the 21st century will see the rebirth of a more biological
theory of biology. By that I mean treating living systems as having
certain characteristics, such as purposiveness and agency as denitive of
life, rather than as requiring reductive physical and chemical explana-
tions. Purposive explanations are more predictive about lower-level
processes than the other way round (Noble and Noble, 2022, 2023).
Rose writes Baverstocks connement of the term [cellular pheno-
type] to the cellular level is at once too broad and too restricted: the
D. Noble
Progress in Biophysics and Molecular Biology 187 (2024) 1–4
4
main ‘elements of biology are expressed at several levels of
complexity.Later he continues These levels increasing complexity are
not just epistemological constructs but are ontologically and irreducibly
distinct, as spelled out by Joseph Needham in the 1930s.
In concluding, he writes Phenotypes are simultaneously thing and
process; the value of reductionist approaches is that they uncover
thingyness; the value of process thinking is that it reinserts the ‘thing
into the dynamic self-organising complexity of the living world. Baver-
stocks de-emphasising genes in favour of cells, I suggest, ts well within
this larger theoretical framework.
1.9. Replies to the commentaries
Baverstock, 2023b careful reaction to the commentaries echoes my
own interpretation of the present situation. If there existed a simple
reply to the central case of the original article, can anyone doubt that at
least some of those on the other side of the debate would have penned it?
Silence sometimes speaks loudest.
But this is not just an arcane academic argument between scientists.
Society faces a health crisis (Yuille and Ollier, 2021), with an economic
fall-out that will dwarf current preparations for health care (Scott and
Gratton, 2020). If this was a war, which in a sense it is, the troops and
battleships would already have been restrategised to meet the urgent
task in hand, to tackle the complexity of the diseases that threaten to
bring collapse to our national health systems. The nations with the
largest imbalance of aged to young populations are the richest nations in
the world, soon to be joined by the rapidly developing nations. Is it not
the highest priority now to prepare effectively for a looming crisis? The
pandemic has been bad enough. The challenge of longevity combined
with intractable diseases is threatening to be even worse. The very
viability of health services around the world is at stake.
1.10. Clinical Trial of the polygenic score catalog
My editorial returns to where it began: with the assessment of the
performance of polygenic risk scores in screening, prediction and risk
stratication, recently published by Hingorani et al. (2023). That study
used the same criteria of assessment as for a Clinical Trial. It is sufcient
to give the last word to their overall conclusion which showed:
poor performance of polygenic risk scores in population screening,
individual risk prediction, and population risk stratication.The
wide scope and analytical approach of our study might help to
resolve the debate on the value of polygenic risk scores, and avoid
unjustied expectations about their role in the prediction and pre-
vention of disease.(P. 31)
The widely promised health benets of genome sequencing have
simply failed to materialise. We now need a careful rethink of priorities
since it is clear that meeting the looming challenge of ageing populations
manifesting diseases that are notoriously resistant to genetic explana-
tions will require resources to be devoted to higher-level studies of the
causes of health and disease (Yuille and Ollier, 2021). Looking at the
genome level is about as useful as studying the pixels in a message,
rather than the message itself. The logic of living systems is not to be
found at the level of genes.
1.11. Coda
Although the journal is bringing this debate to a form of completion
in publishing this on-line collection, the door remains open to anyone
who wishes to respond to submit a stand-alone article. The central issues
are not going to go away. The invitation to the genomics community to
justify their position remains open.
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Yanai, I., Lercher, M., 2020. A hypothesis is a liability. Genome Biol. 21, 231, 2020.
Yanai, I., Lercher, M., 2021. The data-hypothesis conversation. Genome Biol. 22, 58.
https://doi.org/10.1186/s13059-021-02277-3.
Yuille, M., Ollier, B., 2021. Saving Sick Britain: Why We Need the ‘Health Society.
Manchester University Press.
Denis Noble
Department of Physiology, Anatomy & Genetics, University of Oxford, UK
E-mail address: denis.noble@dpag.ox.ac.uk.
D. Noble
1
Foreword
The idea of an Online Collection was proposed by Prof Denis Noble, Editor-in-
Chief of Progress in Biophysics and Molecular Biology (PBMB) when it was
discovered that the paper The Gene: An Appraisal, (The Gene) accepted for
publication in PBMB in May 2021 had been corrupted in the publisher’s
proofing software and was unreadable beyond the first third. Some 45
invitations were issued to researchers cited in the paper, the work of about 15 of
which I had criticised in The Gene. In October 2021, Elsevier agreed to an
Online Collection comprised of the corrected version of The Gene, an editorial,
the commentaries, and a response to criticisms. The deadline for submission of
commentaries was September 2021 and by the end of the year, five had been
submitted. I was, however, aware that Prof Giuseppe Longo had submitted
commentary, and it was not among the five. His paper was submitted on 20
October 2021 and accepted on 16 December 2022, i.e., the paper was ‘lost’ in
Elsevier’s submission system for more than a year. Similarly, Prof Stephen
Rose’s paper was submitted on 7 October 2021 was also lost in the system until
6 January 2023. Thus, a project that could have been completed in a little over
six months had taken 18 months due to Elsevier’s incompetence. However, the
problem did not end there, because at the beginning of 2023 Elsevier reneged on
their promise to produce a corrected version of The Gene, claiming that it would
be illegal to do so. Elsevier maintained this position until 9 October 2023, when
I emailed Elsevier’s CEO, Ms. Kumsal Bayazit. After consideration by an
ethical committee, Elsevier agreed and produced a corrigendum. It then took
until 20 December 2023 before a citable version of the paper was available,
leaving the way clear for me to submit my paper titled Responses to
Commentaries, which had been ready in January 2023. Incredibly, it then took
until 7 February 2024 before the proofs of that paper were available to me, and
until mid-March before the final version was published. The final step in the
publication of the Online Collection was taken by Elsevier on 3 April when it
posted it on the journal’s website as a link to a list of papers that are mostly
unavailable to the reader. Denis Noble has confirmed that this is regarded by
Elsevier as the finished project.
2
Elsevier has demonstrated that it holds its editors, authors, and readers in
contempt by maintaining that editors and authors should accept that it is
legitimate for a publisher to publish in their names corrupted and unreadable
texts. One wonders what Elsevier thinks the purpose of publishing is. Perhaps it
is simply the money it produces. I would point out that The Gene produced nine
papers that would not otherwise have been submitted to Elsevier and so it has
gained financially from the publication of The Gene.
My purpose in agreeing to the issuing of invitations to submit commentaries
was to open up the issues raised in The Gene to the widest possible discussion.
Elsevier, through its incompetence, or intention to subvert (that cannot be ruled
out), has made that outcome less likely and, thus, has done a disservice to
science.
Three years on from the initial publication of The Gene, I stand by the central
claim that the primary functional element in the cell is not the gene/genotype
but the cellular phenotype, represented by the process of gene product
interaction, in today’s terminology, a gene product interactome. Where heredity
is concerned, this interactome is directly inherited by offspring, in agreement
with the statistical/biometric approach to heredity taken by Galton and Pearson,
in the form of the Law of Ancestral Heredity, vehemently opposed by
Johannsen. Thus, more than 100 years on from that Law, discussion of its
relevance to biology is overdue.
Keith Baverstock
2 June 2014
FOCUS ARTICLE
The Gene: An Appraisal
by
Keith Baverstock
May 2021
Progress in Biophysics and Molecular Biology 186 (2024) e73–e88
Available online 2 December 2023
0079-6107/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
The Gene: An appraisal
Keith Baverstock
Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio Campus, Kuopio, Finland
ABSTRACT
The gene can be described as the foundational concept of modern biology. As such, it has spilled over into daily discourse, yet it is acknowledged among biologists to
be ill-dened. Here, following a short history of the gene, I analyse critically its role in inheritance, evolution, development, and morphogenesis. Wilhelm
Johannsens genotype-conception, formulated in 1910, has been adopted as the foundation stone of genetics, giving the gene a higher degree of prominence than is
justied by the evidence. An analysis of the results of the Long-Term Evolution Experiment (LTEE) with E. coli bacteria, grown over 60,000 generations, does not
support spontaneous gene mutation as the source of variance for natural selection. From this it follows that the gene is not Mendels unit of inheritance: that must be
Johannsens transmission-conception at the gamete phenotype level, a form of inheritance that Johannsen did not consider. Alternatively, I contend that biology
viewed on the bases of thermodynamics, complex system dynamics, and self-organisation, provides a new framework for the foundations of biology. In this
framework, the gene plays a passive role as a vital information store: it is the phenotype that plays the active role in inheritance, evolution, development, and
morphogenesis.
1. Introduction
At present, much of biology is regarded as being governed, or
regulated, by the genes in the genotype. From the level of the single cell,
through organisms and how they develop, evolve, and function, the gene
has been assigned a central role. The term is even common in discourse
about aspects of human life. It is, in short, considered vital to under-
standing how life works. The phenotype, on the other hand, plays barely
a supporting role in understanding the life process. I am proposing that
the evidence demands the reversal of this relationship. In the early
1500s, Nicolaus Copernicus proposed reversing the positions of the Sun
and the Earth, yielding the heliocentric solar system. Astronomy was
simplied, and 1500 years of Ptolemaic astronomy were consigned to
history. Newtons laws of motion were subsequently understood to
govern the planets. I propose that the evidence dictates that the
phenotype is the governor and regulator of the cell, which is the basic
‘building blockof the organism. What can ow from this, I contend, is
biology governed by thermodynamics and complex system dynamics
and a simpler and more intuitive understanding of what life is.
My metaphor for the cellular phenotype is a brain, and for the gene, a
provider of building materials, the gene products. The phenotype
‘drives and regulates the cell and the genes in the nucleus house the
information for the phenotype to build and operate the cell (Nijhout
1990). Karl Popper asserts that brains and cells can acquire knowledge
(Niemann 2014)
1
and I propose that the seat of that knowledge in the
cell is the phenotype located in the cytoplasm.
The need for a re-thinking of biology is urgent. Huge resources are
directed to the search for the genes that cause human disease. Rare
inherited disease traits are often associated with a specic gene abnor-
mality, but they affect only a few percent of the human disease burden:
in this context genetics is clinically useful. Common, or so-called poly-
genic disease traits, potentially affecting everyone, have not yet yielded,
in a clinically useable way. The reason is that genes are not responsible
for common disease traits.
Explanations in science should be simple, not complicated: in his
book, Back to Reality (Annila 2020), Finnish physicist Arto Annila,
constantly emphasises simplicity in explaining even the most apparently
intractable aspects of physics.
2
I believe the laws governing biology can
be simple too, at least once some counter-intuitive aspects have been
grasped.
3
DOI of original article: https://doi.org/10.1016/j.pbiomolbio.2021.04.005.
E-mail addresses: keith.baverstock@uef., keith@kbaverstock.org.
1
See Appendix A for full text of Poppers Medawar Lecture to the Royal Society in 1986.
2
For example, the nature of time, t: the energy, E, of a light quantum is Plancks constant, h, divided by the frequency, f, of the light. I.e., E =h/f. Therefore, h =E
x t, where f =1/t. Time is, therefore, embodied in light quanta along with energy. This is unfamiliar because it is historically not how time has been viewed: it is
simple but counterintuitive. On the other hand, Newtons laws of motion, formulated in 1687, are both simple and intuitive.
3
Unfortunately, the concept of the gene is so embedded into biological thought, and even common discourse that it now constitutes intuition. The arguments
presented here, thus, appear to be counterintuitive.
Contents lists available at ScienceDirect
Progress in Biophysics and Molecular Biology
journal homepage: www.elsevier.com/locate/pbiomolbio
https://doi.org/10.1016/j.pbiomolbio.2023.11.001
Progress in Biophysics and Molecular Biology 186 (2024) e73–e88
e74
2. A short history of the gene
In February 1865, Gregor Mendel, Abbot of the monastery in Brno,
now in the Czech Republic, introduced, in a lecture, what we now know
as the gene, calling it an ‘element. He stressed the particulate nature
(thingness, or ‘Istikeit) of elements,
4
having noted that, in the process of
inheritance they retained their unitary nature, rather than blending one
with another, as Darwin had assumed.
In 1910, Danish biologist, Wilhelm Johannsen, coined the term
‘genein a lecture, published as a paper in 1911 (Johannsen 1911).
5
He
also coined the terms genotype and phenotype for what Mendel had
called ‘characters. The gene quickly entered the scientic discourse of
the time as the ‘unit of inheritanceand it ‘tradedunder this guise for 50
or more years.
In 1944, Austrian physicist Erwin Schr¨
odinger published his 1943
lecture in Dublin, What is Life?, (Schr¨
odinger 1944). His naïve physi-
cists ideas about organisms looked at from a quantum mechanical
perspective, yielded the conclusion that the hereditary material must be
a solid, he called it an ‘aperiodic crystal.
From around 1960, Petter Portin and Adam Wilkins (Portin and
Wilkins 2017), report that the gene started to be viewed as a dened
string of nucleobases that coded for a polypeptide: it was a material
thing. This transformation was driven by the discovery of the structure of
deoxyribonucleic acid (DNA) in 1953 by Francis Crick, James Watson,
Rosalind Franklin, and Maurice Wilkins. Crick went on in 1958 to pro-
pose how proteins (more properly peptides) which yielded the pheno-
type, were coded in the genes DNA sequence (Crick 1958). In 1970,
Crick proposed the Central Dogma (which stipulated that information in
the DNA owed to the protein and not the reverse) and the sequence
hypothesis, which stipulated that the sequence of the amino acids in a
peptide determined the native and biologically active structure of the
folded protein (Crick 1970). These developments in the 1950s/60s have
determined how the gene has been perceived for the following 50 years:
molecular genetics was born.
The prospect of sequencing the whole human genome was on the
horizon by the early 1980s. Cricks assertion
6
that the ‘secret of lifelay
in the DNA that constituted the genes, made in the Eagle pub in Cam-
bridge in February 1953, became increasingly convincing to biologists
and the public alike. That ‘secretwould be revealed in the sequence of
the human genome.
7
The Human Genome Project (HGP), aimed to sequence the 3 billion
bases in the human genome, commenced on 1 October 1, 990
8
with a
grant of three billion US$ from the US Congress. Initially headed by
James Watson, it was brought to its conclusion in 2003 by Francis
Collins, now the Director of the National Institutes of Health in Wash-
ington. In 2001, when sequencing was sufciently advanced to
announce preliminary results,
9
the human genome turned out to contain
far fewer genes than the ‘one gene: one polypeptide hypothesis
10
pre-
dicted. Palaeontologist, Stephen Jay Gould, wrote in the New York Times
under the heading Humbled by the Genomes Mysteries
11
:
The general estimate [of the number of genes] for Homo sapiens … ….
had stood at well over 100,000, with a more precise gure of 142,634
widely advertised and considered well within the range of reasonable
expectation. Homo sapiens possesses between 30,000 and 40,000 genes,
with the nal tally almost sure to lie nearer the lower gure.
Indeed, the nal gure lies between 20,000 and 25,000 protein-
coding genes
12
: the HGP represented a major collision between ge-
netics and reality.
According to Portin and Wilkins (2017), since the sequencing,
several other problems have emerged with the concept of the gene: some
gene sequences are not clearly delineated; the sequence of exons
13
in the
gene is not necessarily reproduced at translation; a gene sequence may
not be contiguous along the chromosome, and a given gene in one cell
type may function differently in another. In short, the gene has proved
extremely difcult to dene concisely. This matters when the aim is to
predict the phenotype from the genotype: which was the rationale for
the HGP.
14
However, was that even a realistic aim? Take for example the
Abbreviations
2nd law second law of thermodynamics
EEA Equal environments assumption
GWA Genome-wide association
HGP Human Genome Project
IA model Independent Attractor model
LTEE Long-term evolution experiment
MS Modern Synthesis
PGS Polygenic score (sometimes termed polygenic risk
score, or PRS)
RoE Rules of engagement
SNP Single nucleotide polymorphism
4
Robert Olby in Mendel, Mendelism and Genetics. http://www.mendelweb.
org/MWolby.html. (accessed 23.02.2021).
5
This landmark paper was reprinted in 2014: Johannsen, W. (2014). The
genotype conception of heredity. 1911. Int J Epidemiol 43(4): 9891000. In
this paper references are made to the original version.
6
http://news.bbc.co.uk/2/hi/science/nature/2804545.stm (accessed
23.02.2021).
7
Lewontin says: “… the great panjandrum of DNA himself, James Dewy
Watson, explains in an essay in the collection edited by Kevles and Hood that
he doesnt want to miss out on learning how life works and Gilbert predicts
that there will be a change in our philosophical understanding of ourselves. :
Lewontin, R. C. (1992). The doctrine of DNA: Biology as Ideology. London,
England, Penguin Books Ltd. p63.
8
https://en.wikipedia.org/wiki/Human_Genome_Project (accessed
23.02.2021).
9
The ofcial completion date of the HGP was 14 April 2003 but a pre-
liminary report was released in February 2001 to coincide with the birthday of
Charles Darwin: Lander, E. S., L. M. Linton, B. Birren, C. Nusbaum, M. C. Zody
et al. (2001). Initial sequencing and analysis of the human genome. Nature
409(6822): 860921.
10
By Archibald Garrod around 1900.
11
https://www.nytimes.com/2001/02/19/opinion/humbled-by-the-genome
-s-mysteries.html (accessed 23.02.2021).
12
https://www.sciencedaily.com/terms/human_genome.htm (accessed
23.02.2021).
13
The string of bases that comprise a gene is divided into exons, sections
which code for gene products and introns, which are non-coding intervening
sequences of bases.
14
See: Lewontin, R. C. (1992). The doctrine of DNA: Biology as Ideology.
London, England, Penguin Books Ltd. In the chapter headed The Dream of the
Human Genome (pp 6183) Lewontin ridicules the then much heralded idea
that the sequence of the genome would tell us about the human condition and
locate on the human chromosomes all the defective genes that plague us noting
that some mutant genes (that for cystic brosis, for example) had already been
located, isolated, and sequenced. A decade ago, Lewontin might have felt
entirely vindicated. On 27 July 2010, Craig Venter, the entrepreneur who
competed with the HGP to sequence the human genome, was interviewed by
Der Spiegel under the title We have learned nothing from the Genome. Since
then, with the development of the technique of genome wide association
(GWA), there has been a massive upsurge in genetic studies of common disease
and behavioural traits. Despite this, Lewontin remains vindicated: as I will
argue, this decade of intense research activity has not advanced our under-
standing of the causes of common disease and behavioural traits.
K. Baverstock
Progress in Biophysics and Molecular Biology 186 (2024) e73–e88
e75
DSCAM gene found in Drosophila: it can produce 38,016
15
different
peptides, (Black 2000), more than the number of genes in the human
genome. According to the dogma, each peptide may fold into a different
protein performing a discretely different biological function.
Despite the lack of clarity over the concept of the gene, and the
unexpectedly low number of genes found by the HGP, genetic research
has forged ahead in recent decades.
Traits (Mendels characters and Johannsens phenotypes) are clas-
sied as either monogenic (Mendelian) or polygenic. Monogenic traits,
for example, the ower colour that Mendel investigated in pea plants,
have been the sole basis for experimental genetics since the time of
Mendel, according to American geneticist Richard Lewontin (1974).
Rare inherited diseases such as Huntingdons disease (there are thought
to be ~10,000
16
), affecting less than 8% of the population, are often
monogenic traits.
Rare diseases have long been diagnosed using classical genetic
techniques, but success has been limited. With the benet of knowing
the human genome sequence, improvements were expected. The ge-
nomes of 85,000 UK National Health Service (NHS) patients, the ma-
jority with undiagnosed rare diseases, have been sequenced in the
‘100,000 Genomes Project. Launched in 2012,
17
with sequencing
completed in 2018,
18
few results have been published. The project
website
19
says it has provided diagnoses in 2025% of the cases.
Using the genome wide association (GWA) technique
20
and the
human genome sequence, polygenic traits (common diseases and
behavioural conditions) have allegedly been characterised by tens to
hundreds of single nucleotide polymorphisms (SNPs)
21
at nearly as
many loci (genes), each of very small effect. This is occurring in pop-
ulations of thousands to hundreds of thousands of individuals carrying
the trait. Furthermore, the total of these effects does not add up to the
expected total genetic risks (or variances) of the diseases.
22
The differ-
ence is what is known as the ‘missing heritability(Manolio et al., 2009;
Eichler et al., 2010; Chaufan and Joseph 2013, Blanco-Gomez et al.,
2016): it is currently a major problem at the root of the genetics of
common disease and behavioural traits.
GWA data per se are, therefore, of no clinical utility. It is, however,
claimed that summing up the SNPs into a so-called polygenic score
(PGS)
23
is of diagnostic value (Plomin 2018)
24
: however, this may
resolve the problem of many small effects at numerous loci, but it leaves
the problem that the PGS can only apply to a small fraction of the total
genetic variance. The clinical utility of PGSs has yet to be proven.
Genes have been the ‘material currency of biology for 155 years.
They are centrally invoked to explain inheritance, evolution, develop-
ment, and morphogenesis: they have become icons of biological
thought, such that it is heretical that their prominence should be chal-
lenged. Yet, they are far from well-dened, and knowing their sequences
has not, so far, advanced our understanding of the most important
challenge to human health, namely common disease.
3. How Mendels elements became genes
Now I want to look in more detail at how Johannsen dened the
gene. Mendels 1865 paper lay unrecognised until 1900 when the Dutch
biologist, Hugo de Vries, discovered it and re-published it. It could then
be integrated with Darwins ideas on evolution through natural selec-
tion, as laid out in On the Origin of Species, which had been published in
1859 (Darwin and Kebler 1859).
The foundation stones of todays biology had been laid.
In the earliest years of the 20th Century, inheritance, or heredity,
was the primary problem of the day in biology. Johannsen was opposed
to the use of the above terms when applied in biology: he claimed that
their everyday use, in terms of the transmission of wealth from one
generation to the next, were misleading metaphors for biology.
25
The
dominant theory of inheritance was Francis Galtons regression law.
26
Johannsen called it the ‘transmission-conception and regarded it as
wrong: it supported Lamarckism
27
and Darwins pangenesis concept,
28
15
The DSCAM gene has a total length of 61 kb (61,000 base pairs) and is
divided into 24 exons. Four of those exons occur with up to 48 alternative se-
quences. Taking all the viable combinations of alternative splicings of the exons
and alternative sequences contributing to the mRNA that can be transcribed
from the gene, more than 38,000 peptides, and, therefore, proteins, can be
translated.
16
https://www.who.int/genomics/public/geneticdiseases/en/index2.html
(accessed 23.02.2021).
17
https://www.sciencemag.org/news/2012/12/uk-unveils-plan-sequence-
whole-genomes-100000-patients (accessed 23.02.2021).
18
https://www.genomicsengland.co.uk/the-uk-has-sequenced-100000-wh
ole-genomes-in-the-nhs/(accessed 23.02.2021).
19
https://www.genomicsengland.co.uk/about-genomics-england/the-100000
-genomes-project/(accessed 23.02.2021).
20
https://en.wikipedia.org/wiki/Genome-wide_association_study (accessed
23.02.2021).
21
https://en.wikipedia.org/wiki/Single-nucleotide_polymorphism (accessed
23.02.2021).
22
Typically, common diseases, at the population level, are thought to be be-
tween 10 and 70% due to genetic causes. These estimates are determined from
family or twin studies. In GWA studies, typically between 5 and 15% of this risk
is accounted for. The difference, or ‘missing heritability, therefore, ranges up to
several 10s of percentage points.
23
https://en.wikipedia.org/wiki/Polygenic_score (accessed 23.02.2021).
24
See Chapter 12 The DNA fortune teller.
25
In his 1911 paper Johannsen writes: The view of natural inheritance as
realised by an act of transmission, viz., the transmission of the parents (or ances-
tors) personal qualities to the progeny, is the most naive and oldest conception of
heredity. We nd it clearly developed by Hippocrates, who suggested that the
different parts of the body may produce substances which join in the sexual organs,
where reproductive matter is formed.: Johannsen, W. (1911). The Genotype
Cconception of Heredity.American Naturalist 45: 129159. Johannsens main
concern appears to be avoiding the inheritance of acquired characteristics. He
goes on: The personal qualities of any individual organism do not at all cause the
qualities of its offspring; but the qualities of both ancestor and descendant are in quite
the same manner determined by the nature of the sexual substancesi.e., the
gametesfrom which they have developed. Personal qualities are then the reactions
of the gametes joining to form a zygote; but the nature of the gametes is not deter-
mined by the personal qualities of the parents or ancestors in question. This is the
modern view of heredity. Further on he says: The genotype-conception, as I
have called the modern view of heredity, differs not only from the old trans-
mission-conception as above mentioned, but it differs also from the related hypo-
thetical views of Galton, Weismann and others, who with more or less effectiveness
tried to expel the transmission-idea, having thus the great merit of breaking the
ground for the setting in of more unprejudiced inquiries. Galton, in his admirable little
paper of 1875, and Weismann, in his long series of fascinating but dialectic publi-
cations, have suggested that the elements responsible for inheritance (the elements of
Galtons stirp or of Weismanns Keimplasma) involve the different organs or
tissue-groups of the individual developing from the zygote in question. And Weismann
has furthermore built up an elaborate hypothesis of heredity, suggesting that discrete
particles of the chromosomes are bearers of special organizing functions in the
mechanism of ontogenesis, a chromatin-particle in the nucleus of a gamete being in
some way the representative of an organ or a group of tissues. Thus, Johannsen
was aware of the Weismann barrier whereby the germ cells are ‘insulatedfrom
the rest of the organism and that the gametes do not carry ‘personal qualities,
yet he does not consider the gamete phenotypes, only their genotypes, as
Mendels ‘units of inheritance.
26
According to Galton, an individuals traits were transmitted from their
parents (50%), their grandparents (25%), their great grandparents (12.5%), and
so on, with ever diminishing importance, because of the increasing number of
ancestors, within whom the traits were distributed.
27
Jean Baptiste Lamarck was a highly regarded French biologist who died in
1829. He became the professor of Zoology when the Mus´
eum national dHis-
toire naturelle opened in Paris in 1793. He advocated the idea that qualities
gained during a lifetime could be passed on to future generations. This is called
the inheritance of acquired characteristics.
28
https://en.wikipedia.org/wiki/Pangenesis.
K. Baverstock
Progress in Biophysics and Molecular Biology 186 (2024) e73–e88
e76
both of which implied the inheritance of acquired characteristics.
Johannsen ran an experiment with self-fertilising bean plants (a so-
called ‘pure line breeding programme)
29
and recorded the dimensions
of the beans produced over two growing seasons. Bean sizes were
distributed according to a normal distribution, but different pure lines
differed slightly in the size range of the beans they produced. Johannsen
categorised these lines as ‘genotypes and the process of inheritance
through the genotype he called the genotype-conception (Johannsen
1911). He found no evidence of ancestral inuences in his
experiments
30
.
Nils Roll-Hansen (2014) says of Johannsens presentation of his
genotype-conception at the lecture in 1910, published in 1911:
This lecture summed up his experimental and theoretical achievements,
including a sharp analysis of the concepts of ‘genotypeand ‘gene. … ….
Genotype is the basic concept in Johannsens 1910 lecture. The stability
of the genotype is what makes a science of heredity possible. The concept
of ‘geneis derivative. It represents an experimentally identiable differ-
ence between genotypes
Thus, Johannsens work must be credited as the basis for modern
genetics and the understanding of inheritance, and the longstanding
theory of evolution, the Modern Synthesis (MS),
31
since inheritance is an
essential component of evolution.
The American geneticist, T. H. Morgan, writing in 1917 under the
title The Theory of the Gene(Morgan 1917), defended Mendelism and
conrmed the location of genes in chromosomes. Mendels laws of in-
heritance, based on experiments with pea plants and Johannsens
genotype-concept, were converted into a theory using primarily the
concepts of 1) two alleles (versions) per gene, each being capable of
being dominant or recessive, and 2) the phenomenon of epistasis.
32
Morgan concedes:
It has been said that by assuming enough genetic factors you can explain
anything. This is true; and it is the greatest danger of the factorial pro-
cedure. If, for example, whenever one fails to account for a result he in-
troduces another factor to take care of what he cannot explain he is not
proving anything except that he is ingenious or only naïve. (Morgan
1917).
Those simple concepts give considerable interpretative latitude and
they have been progressively added to over the years in a manner that is
perhaps not unlike epicycles in Ptolemaic astronomy. Nevertheless,
genetics today is regarded as a successful and sophisticated scientic
discipline. Indeed, on the 20th anniversary of the release of the draft
human genome sequence in 2001, the journal Nature proclaimed, A
wealth of discovery built on the Human Genome Project (Gates et al.,
2021). The authors point out that as there is no world without the HGP it
is impossible to say how much progress it represents but it is nonetheless
clear that the HGPs catalogue [of protein-coding genes] catalysed the
continuing genetic revolution.
There are, however, features of genetics that should have given
pause for thought.
First, likenesses between siblings, or those between parents and their
offspring, which we know empirically to exist, cannot be explained
intuitively in terms of the above concepts (see below).
Second, the physicist Max Delbrück dened genetics in 1935 as:
. a far-reaching, logically closed, strict science. It is quantitative
without making use of the physical measurement system.
33
(Tim-
of´
eeff-Ressovsky et al., 1935).
Delbrück acknowledges that genetics, unlike chemistry, is not based
on a more fundamental physics, from where it would be possible to
judge and test hypotheses. Thus, there is no more fundamental level
against which to judge the genotype-conception: it is simply a theoret-
ical model for which there is some support.
Third, in 1958 Francis Crick (1958) published his thoughts on how
the information coded in the gene sequences informed the phenotype.
Information coded in the base sequence needed to be transformed into
information in the form of the molecular structure of a protein, the
supposed biologically active mo