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\DOI{10.5802/crbiol.202}
\datereceived{2025-10-28}
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\COI{The author does not work for, advise, own shares in, or receive
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has declared no affiliations other than their research organization.}

\begin{document}

%\dateposted{2026-02-16}

\begin{noXML}

\CDRsetmeta{articletype}{review} 

\editornote{Article submitted by invitation}
\alteditornote{Article soumis sur invitation}

\title{Development is an evolutionary phenomenon}

\alttitle{Le d\'{e}veloppement est un ph\'{e}nom\`{e}ne \'{e}volutionnaire}

\author{\firstname{Guillaume} \lastname{Lecointre}\CDRorcid{0000-0001-7282-0516}}
\address{Institut de Syst\'{e}matique, \'{E}volution et
Biodiversit\'{e}, UMR 7205 CNRS-MNHN-SU-EPHE-UA, Case Postale 24,
Mus\'{e}um National d'Histoire Naturelle, 57 rue Cuvier, 75005 Paris,
France}
\email{Guillaume.lecointre@mnhn.fr}

\keywords{\kwd{Descent with modification}
\kwd{EvoDevo}
\kwd{Genetic program}
\kwd{Natural selection}
\kwd{Ontogenesis}
\kwd{Ontophylogenesis}
\kwd{Phylogenesis}}

\altkeywords{\kwd{Descendance avec modification}
\kwd{\'{E}voD\'{e}vo}
\kwd{Programme g\'{e}n\'{e}tique}
\kwd{S\'{e}lection naturelle}
\kwd{Ontog\'{e}n\`{e}se}
\kwd{Ontophylogen\`{e}se}
\kwd{Phylogen\`{e}se}}

\dedicatory{\raggedleft This paper is dedicated to Andr\'{e}
Adoutte (1947--2002), who developed a true passion for phylogenetics
and development.\break\vspace*{1pc}}

\begin{abstract} 
EvoDevo called homeotic genes ``architect genes'' because they
``control'' ``body plans''. The first metaphor involves purposefulness
and brings finalism; the second one is cybernetic; the third one is
idealistic/platonic. These are three ways of thinking that are
incompatible with today's evolutionary theory. Using such ordering
causal factors, EvoDevo partly stayed outside biology---and evolution
as well---because in biology, order is not causal: it is a consequence
that we need to explain. Natural selection is one of the concepts
explaining the rise of apparent short-term biological order, or
regularities. We no longer need the verb ``to control'' [Nijhout, 
\textit{Prog. Biophys. Mol. Biol.}, {169--170} (2022)]. 
Since genes are controlled [Noble, \textit{Interface
Focus}, {7} (2017)], just as much as they
control, the notion of control in this context is not appropriate. It
would be better to speak of ``contribution''. \textit{Natural
selection} and \textit{descent with modification}, the two pillars of
the Darwinian approach to life [Gayon, \textit{C. R. Palevol},
{8} (2009)], are entering the soma. They are not
restricted to the functioning of the adult soma, but also to the entire
developing soma, avoiding ``adultocentrism'' [Minelli, 
\textit{Toward a Theory of Development} (2014)]. The first
pillar, natural selection within the body, anticipated by  [Roux, 
\textit{Der Kampf der Teile im Organismus: Ein Beitrag zur
Vervollst\"{a}ndigung der Mechanischen Zweckm\"{a}ssigkeitslehre}
(1881); Roux, \textit{La lutte des parties dans l'organisme} (2013)],
but occulted during the past century  [Heams, \textit{La
lutte des parties dans l'organisme} (2013b)], is now helping to
explain cancer dynamics, aging, neurogenesis, etc. With the second
pillar, it is now possible to construct the phylogeny of cells of a
single developing organism, or to perform a phylogenetic analysis of
metastases from a single patient. Ontogenesis and phylogenesis are no
more two distinct processes: \textit{natural selection} and
\textit{descent with modification} both contribute to explain both the
developing individual and its stability, as well as the regularity of
individuals of a same population from which we name species. The two
pillars of evolutionary theory---descent with modification and natural
selection---do occur within the developing organism itself and the
resulting phenomenon is ontophylogenesis  [Kupiec, 
\textit{L'ontophylogen\`{e}se. \'{E}volution des esp\`{e}ces et
d\'{e}veloppement de l'individu} (2012)], 
which is actually studied by EvoDevo. 
\end{abstract}

\begin{altabstract}
L'EvoDevo a qualifi\'{e} les g\`{e}nes hom\'{e}otiques de
\og g\`{e}nes architectes \fg parce qu'ils
\og contr\^{o}lent \fg  les \og
plans d'organisation \fg. La premi\`{e}re m\'{e}taphore est
teint\'{e}e de finalisme, la deuxi\`{e}me est cybern\'{e}tique, la
troisi\`{e}me est id\'{e}aliste/platonicienne, trois fa\c{c}ons de
penser incompatibles avec la th\'{e}orie de l'\'{e}volution actuelle.
En utilisant de tels facteurs causaux ordonnateurs, l'\'{E}voD\'{e}vo
est rest\'{e}e en partie en dehors de la biologie --- et de
l'\'{e}volution \'{e}galement --- car en biologie, l'ordre n'est pas
causal, c'est une cons\'{e}quence que nous devons expliquer. La
s\'{e}lection naturelle est l'un des concepts expliquant
l'\'{e}mergence d'un ordre biologique apparent \`{a} court terme, ou de
r\'{e}gularit\'{e}s. Nous n'avons plus besoin du verbe \og
contr\^{o}ler \fg  [Nijhout,  \textit{Prog.
Biophys. Mol. Biol.}, {169--170} (2022)]. Comme les
g\`{e}nes sont autant contr\^{o}l\'{e}s  [Noble, \textit{Interface
Focus}, {7} (2017)] qu'ils contr\^{o}lent,
la notion de contr\^{o}le \`{a} leur sujet n'est pas appropri\'{e}e. Il
vaudrait mieux parler de \og contribution \fg.
La \textit{s\'{e}lection naturelle} et la \textit{descendance avec
modification}, les deux piliers de l'approche darwinienne de la vie
[Gayon, \textit{C. R. Palevol}, {8} (2009)],
entrent dans le soma. Sans se limiter au fonctionnement du soma adulte,
ces deux concepts s'appliquent aussi \`{a} l'ensemble du soma en
d\'{e}veloppement, \'{e}vitant ainsi l' \og
adultocentrisme \fg  [Minelli, \textit{Toward a
Theory of Development} (2014)]. Le premier pilier, la
s\'{e}lection naturelle au sein du corps, anticip\'{e} par [Roux, 
\textit{Der Kampf der Teile im Organismus: Ein Beitrag zur
Vervollst\"{a}ndigung der Mechanischen Zweckm\"{a}ssigkeitslehre}
(1881); Roux, \textit{La lutte des parties dans l'organisme} (2013)], 
mais occult\'{e} au cours du si\`{e}cle dernier [Heams, 
\textit{La Lutte des Parties Dans l'organisme} (2013b)], permet
aujourd'hui de comprendre la dynamique du cancer, le vieillissement, la
neurogen\`{e}se, etc. Gr\^{a}ce au deuxi\`{e}me pilier, il est
d\'{e}sormais possible de construire la phylog\'{e}nie des cellules
d'un seul organisme en d\'{e}veloppement, ou d'effectuer une analyse
phylog\'{e}n\'{e}tique des m\'{e}tastases d'un seul patient.
L'ontogen\`{e}se et la phylogen\`{e}se ne sont plus deux processus
distincts : la s\'{e}lection naturelle et la descendance avec
modification contribuent toutes deux \`{a} expliquer \`{a} la fois le
d\'{e}veloppement de l'individu et sa stabilit\'{e}, ainsi que la
r\'{e}gularit\'{e} des individus d'une m\^{e}me population \`{a} partir
de laquelle nous nommons des \og esp\`{e}ces
\fg. Les deux piliers de la th\'{e}orie de l'\'{e}volution 
--- la descendance avec modification et la s\'{e}lection naturelle ---
se produisent au sein m\^{e}me de l'organisme en d\'{e}veloppement et
le ph\'{e}nom\`{e}ne r\'{e}sultant est l'ontophylogen\`{e}se  [Kupiec,
\textit{L'ontophylogen\`{e}se. \'{E}volution des esp\`{e}ces et
d\'{e}veloppement de l'individu} (2012)], ce qu'\'{e}tudie en
r\'{e}alit\'{e} l'\'{E}voD\'{e}vo. 
\end{altabstract}

%\input{CR-pagedemetas}

\maketitle

\twocolumngrid

\end{noXML}

\dedication{This paper is dedicated to Andr\'{e}
Adoutte (1947--2002), who developed a true passion for phylogenetics
and development.}

\xsection{}
\noindent
If we define living organisms by their abilities to reproduce, develop
and evolve, the discovery of \mbox{developmental} genes has permitted to
associate these three phenomena and incorporate them into the
evolutionary theory. However, the corresponding field of research
called ``EvoDevo'' adopted into its deserving and fruitful research
program idealistic views where order (things are at the ``right
place'') and instruction (the order to come is already written) are the
causes of biological phenomena. Genetic control, genetic program,
architect genes, phylotypic stages, body plans do ensure order. The
point we would like to raise here is that these platonic ideas have
prevented development from being fully viewed as an evolutionary
phenomenon. It seems to be useful because, although EvoDevo is not a
homogeneous field, these ideas are still in use in most of today's
Evo-Devo practitioners in their most visible papers. Last but not the
least, EvoDevo did not develop those ideas, but rather borrowed them
from the classical comparative anatomy of the early 19th century 
\citep[e.g.\ body plan, see][]{Schmitt2006} and the history of molecular
biology, rooted in Erwin Schr\"{o}dinger's \textit{What is life}
(\citeyear{Schrodinger1944}), \citep[p.~197]{FoxKeller2000,FoxKeller2002,
Morange2003,Kremer2023}.


\section{Background}


When is a theory called ``Darwinian''? Two pillars are classically
required \citep{Gayon2009}: natural selection and descent with
modification. Natural selection occurs when three conditions are met
among the entities considered (individuals, cells, viruses, behaviors,
etc.). First, these entities spontaneously vary at random. ``Random''
means (1) that we don't focus on the cause of the variation; and (2)
that the new version of the trait where variation just occurred can be
disadvantageous to the entity, or neutral or else advantageous in terms
of its transmission to other entities of the same kind. Second, this
new version is subject to transmission to other entities, whatever the
process of transmission (mitosis, infection of a cell where copies will
be produced, sexual reproduction, mimicking, learning, etc.). It is
heritability, and the spectrum of properties involved strongly widened
during the last 25 years \citep{Danchin2010,Danchin2011,Laland2015,Laland2022,
Danchin2022,Danchin2023}. Both the ``inclusive evolutionary
synthesis'' \citep{Danchin2013,Danchin2022} and the ``extended
evolutionary synthesis'' \citep{Laland2015} consider that variance
heritability with \mbox{evolutionary} effects extends far beyond DNA
sequences. At this step, if no constraining conditions are met,
frequencies of different variants will fluctuate at random in the
\mbox{illimited} population: this is called drift. In the \mbox{presence} of
constraining conditions, only variations that favor the number of its
copies among descendants will have an increasing frequency; possibly
reaching 100\% if differences among competing variants at the same
trait are maintained all along the process. Indeed, a fourth condition
has sometimes been put forward \citep[e.g.][p.\ 39]{Danchin2022}: for
natural selection to occur, heritability of the variant is required,
for sure, but it is not sufficient: there must be heritability of
differences among variants.

The second pillar is descent with modification. Traits that are shared
by entities which do not mix in any way must have been inherited from
past ancestors, dating back to the times when the new trait appeared
and increased within a single mixing population. Since then,
generations have followed each other, possibly through two diverging
genealogies leading to the two extant separated entities. Modifications
continued to occur all along the two genealogies
(\textit{modification}), explaining why entities are different today.
But they still share some traits in common (explained by descent). This
principle allows the reconstruction of phylogenies. Genealogies being
empirically inaccessible (ancestors have disappeared), the search of
ancestor-descendant relationships is an epistemological dead-end. But
global genealogies can be partly inferred through the search for
sister-group relationships, a methodology brought by 
\citet{Hennig1950,Hennig1966}. Therefore, producing a hierarchy of
shared traits among entities (under the mathematical form of a
``tree'') reflects phylogenetic relationships. In certain
circumstances, horizontal transfers or fusion of organisms seem to
challenge the form of that ``tree''; however, it does dot. We must see
the mathematical form of a ``tree'' as a tool to depict a hierarchy of
properties, or ``relationships'', even when these relationships are not
phylogenetic. Horizontal transfers can be represented using several
such trees.

Considering these general principles, it is obvious that everything
that biology has to deal with begins with \textit{variation}
({e.g.}\ with neither instructions nor order). Charles Darwin
dedicated an entire book to it \citep{Darwin1868}. It is the concept
embedded at the very core of natural selection, drift, and descent with
modification. Biology is the science of variation. Not in the sense
where one should explain the causes of each variation taken separately.
Physics and chemistry already have theories and methods to take it in
charge. Biology is biology because it focuses on the global
consequences of such variations at the population level, whatever their
individual tiniest\unskip\break causes.

\section{Where is variation when order is causal?}

 ``Genetic control'' and ``genetic program'' come from cybernetics
\citep{FoxKeller2000,FoxKeller2002,Peluffo2015}, not biology 
\citep[p.~197]{Segal2011,Heams2013a,Nijhout2022,Kremer2023}. ``Architect genes''
is a finalistic, DNA-centered metaphor \citep[p.~228]{Kremer2023}, as
used for instance in  \citet{Philippidou2013}. The notion of
``Phylotypic stage'' comes from circular reasoning \citep{Hejnol2016}
which maintains an essentialist view of animal phyla 
\citep[taxonomic realism][pp.~147--148]{Lecointre2021}. ``Body plan'' is a
platonic, idealistic concept \citep[p.~184]{Kremer2023} that should be
replaced by phylogenetic mosaics \citep{Takhtajan1959}'s and
\citet{Hennig1965,Hennig1966}'s heterobathmy of characters). These
concepts all use the notion of instruction: the order (biological
organization, regularities to come) is already written somewhere and
development is the unfolding of a program. These concepts were all
ignoring biological variation as the fundamental biological phenomenon.
\citet{Nijhout1990} diagnosed:\looseness=-1

\begin{quote}
The concepts that genes control development and morphology, that
genomes contain developmental information, and that development follows
a genetic program pervade modern thinking in molecular, developmental,
and evolutionary biology. The genome is assumed to encode higher levels
of organization. Genes and their products are seen as the causative
agents of differentiation, and controlled gene expression is seen as
the driving force of progressive change in development. The crucial
regulatory role attributed to genes is emphasized by the widespread
acceptance of the notion that a substantial number of genes are
specifically concerned with the orderly progression of events during
development. As a consequence, it is assumed that an understanding of
the mechanisms of gene regulation and of the detailed structure of the
genome are not only fundamental to an understanding of \mbox{development} but
virtually sufficient for this understanding.
\end{quote}

Several decades later, in a remarkable critical analysis of genetic
control and genetic program, \citet{Nijhout2022} confirmed:

\begin{quote}
Genes code for the sequence of nucleotides in RNA. That's it.
Everything else about an organism plays out at higher levels of
organization, where RNAs make essential but circumscribed
contributions, mostly through the production of proteins. This basic
fact has been known for a very long time and is codified as the Central
Dogma of molecular biology. Yet, research published in technical
journals regularly ascribes special properties to genes and genomes
that greatly exceed their actual mandate of coding for proteins. Among
other things, they are said regularly said to `control' various
biological parts and processes, ranging from other genes to complex
morphologies. Similarly, genes and genomes are also said to contain
`programs' and `blueprints' for cells, tissues, organs, behaviors, and
even entire organisms. These claims have been commonplace for decades
({\ldots}), yet authors who appeal to genetic control, programs, and
blueprints seldom---if ever---define what exactly they mean by these
terms. It has long been recognized that these terms are actually
metaphors that, perhaps, need no definition because they describe
processes that need no definition because they are commonly used in
day-to-day life ({\ldots}). In particular, the idea that genes control
development is now widely accepted, and often simply taken for granted.
This understanding of what genes do has regularly been called into
question, but research practices have seldom changed as a result. One
reason why criticisms of the genetic control paradigm have been
ineffective is that efforts to dethrone genes from their seat of causal
primacy have often been accompanied by calls to install some other
purported controller in their place \citep{Waggoner2015}. This simply
trades one king for another. An alternative way to approach the problem
is to reject the notions of control and master regulation entirely.
\end{quote}

Genes are partners, not ``controllers''. The ideas rejected by Nijhout
have their deep roots in the idealistic morphology of the German
nineteenth century and preformationist thinking of the seventeenth
century \citep{Tort1998}: the phenotypic order is \mbox{sufficiently}
explained by a microscopic order where the homunculus is replaced by
the ``genetic program'' \citep{Kupiec2000,Heams2013a}. The fact is,
such ideas are not compatible with evolutionary biology. In modern
biology, order does not explain anything; it is what we need to
understand based on disorder and changes at the chemical scale that
produce variations. If the explanation of the regularity of forms
between adult cats and their offspring is ``because there is a cat
genetic program'', we have explained nothing at all. 
\citet[p.~15]{Vignaux1977} already pointed out the circularity of
Lwoff's claim (\citeyear{Lwoff1969}):

\begin{quote}
La seule source d'ordre biologique est l'ordre biologique.
\end{quote}

Development is not the unfolding of a program
(\xcitealp{Heams2013a}{2013a}; \xcitealp{Moczek2014}{2014}, p.~224;
\xcitealp{Kampourakis2017}{2017}, pp.~172--173), it is a construction
\citep{Laland2015}. 

Charles \citet{Darwin1859} revolutionized biology precisely because,
with the principle of natural selection, he explained apparent order
(regularity of forms in a same species and fit between forms and
functions) from disorder (random variation), ignorantly importing
\citet[p.~15]{Maupertuis1751}'s intuitions into science. During the
twentieth century, biochemistry, molecular biology (molecular genetics
included), molecular physiology, medical research, and EvoDevo were
non-Darwinian, in that sense. These disciplines tried to explain
biological order from biological order, ignoring that natural selection
was a concept already available to explain an apparent order (or
regularity) at a given scale of space and (short) time from disorder at
a lower scale. Indeed, natural selection eliminates extreme variations,
then ending up with an impression of regularity to our eyes.
Unfortunately, the Nobel laureates Lwoff, Monod and Jacob tried to
explain macroscopic order as a consequence of a sufficient microscopic
order (instructions from a program). \citet{Mayr1961} did the same by
introducing the ``program'' and the associated concept of teleonomy to
eradicate suspicion of teleology in biology, in order to explain the
apparent purposefulness of organisms and their characteristics. In a
less sophisticated manner, \citet[p.~17]{Jacob1970} did not mention
teleonomy but confessed:


\begin{quote}
Longtemps le biologiste s'est trouv\'{e} devant la t\'{e}l\'{e}ologie
comme aupr\`{e}s d'une femme dont il ne peut se passer, mais en
compagnie de qui il ne veut pas \^{e}tre vu en public. \`{A} cette
liaison cach\'{e}e, le concept de programme donne maintenant un statut
\mbox{l\'{e}gal}.
\end{quote}


When biology makes a causative use of order (e.g.\ by using a genetic
upward causation), biology thinks outside its own theory. Put in
another way, evolution and above all, evolutionary thinking, must fully
enter the soma and its development. EvoDevo is just starting this
mutation four decades after its birth.

\section{Order and regularity: causes, or consequences?}

During the last third of the 20th century, the genetic program
accounted for the regularity and repeatability of developments. Other
processes, such as self-organization and the stabilizing effects of
intricat networks of genetic influences, have been evoked to account
for their stability \citep{Guo2021} and repeatability (i.e.\ 
robustness). Later on, robustness was better explained by homeostatic
mechanisms, which dynamically maintain forms and functions against
varying environments and genetic variation
\citep{Nijhout2019,Nijhout2025}. In developing organisms, such
homeostatic mechanisms ``make the progression of morphogenesis
relatively insensitive to genetic and environmental variation so that
the outcomes vary little, even in the presence of severe mutational and
environmental stress. Accordingly, developmental systems give the
appearance of being goal-oriented'' \citep{Nijhout2019}.

\begin{table*}
\caption{\label{tab1}Effects of Mayr's species realism, and the present
``coming back'' to the original Darwin, after
\citet{Lecointre2015a,Lecointre2015b}}
%\tabcolsep4pt
\begin{tabular}{ccccc}
\thead
Century & & What explains & What is to be explained & The given \\
\endthead
18th & Linnaeus & God & Regularity & Species\\
19th & Darwin &  Natural selection & Regularity and change &  Individuals\\
20th & Mayr &  Natural selection & Change & Species\\
21st && Natural selection & Regularity and change & Individuals
\botline
\end{tabular}
\vspace*{3pt}
\end{table*}

In parallel, natural selection was taught as a factor of change.
Natural selection was supposed to explain how a species changes over
time. To account for a repeatable developing organism, researchers did
not need a factor of change, but factors of stability and robust
repeatability. The genetic program played that role. Then, during half
a century, we were taught that the regularity of species was ensured by
the genetic program and the change of species by natural selection.
This view is a consequence of species realism, maintained, among
others, by Ernst Mayr. Mayr gave priority to understanding what a
species is, here and now in synchrony, privileging processes over
patterns, leading to its ``biological concept'' of species. Species
being the given (Table~\ref{tab1}), so one has to explain how the given
species changes. Other authors like Georges Simpson gave priority to
understanding species in diachrony, privileging patterns over
processes. The first approach tends to species realism (the given is
species), the second favors a perception of species as a linguistic
convention. In this second approach, the given being varying
individuals, then one has to explain how a species does not change:
this was Darwin's approach. Today, the theoretical phylogenetic
definition of species is a set of individuals being members of the same
genealogy as long as this genealogy is not split. If there is a split,
whatever the reason, another species name must be given to subsequent
daughter branches. Empirically speaking, a species here and now is just
a hypothesis made by taxonomists. It is the hypothesis that all known
members are parts of a same isolated genealogical lineage. This
hypothesis is supported by several criteria, the most common being
similarity and interbreeding, and is made to facilitate language and
communication. The modern phylogenetic concept of species is
nominalist: what does exist are individuals.

Going back to \citet{Darwin1859}, species are conventions aimed to name
a certain degree of similarity among individuals. What is given is not
the species itself, but individuals (Table~\ref{tab1}). This is the reason why
he could pay attention to variations among them (contrary to Linnaeus,
who explicitly neglected variation). Darwin offered a nominalist
explanation of the origin of species by asking the question: given the
variation among individuals that do interbreed, what is the cause of
similarity among individuals? Natural selection, in the short term,
explains similarity: each generation is pruned, with extreme variants
being eliminated. From the resulting similarity, we do create species
for the needs of our language. Thus, for Darwin, first of all natural
selection acts as a stabilizing factor. We just have to consider the
profound meaning of the subtitle of his main book,
The origin of species by means of
natural selection or the preservation of favoured races in the struggle
for life. The words evolution,
transformation or transmutation are absent. The word ``preservation''
is used to specify the permanence of something. Obviously, in the long
term if the environment changes, the mean form of the species will
change. But first of all, natural selection explains apparent stability
and similarity, i.e.\ regularity across individuals. In other words,
apparent order is the short-term consequence of \mbox{natural} selection.

This was neither fully understood nor taught during the last third of
the last century because the genetic program replaced natural selection
within the soma to account for its stability. 


\section{Natural selection within bodies}

For many decades, the cause of regularity and ``fine tuning'' of
somatic functioning has been thought as the result of a program. It is
time to replace the notion of program with natural selection among
cells, without excluding (1) the stabilizing effects of intricate
consequences of many genetic impulses (``genetic networks''); (2) at
certain molecular levels, self-organization; and (3) homeostatic
mechanisms \citep{Nijhout2025}. \citet{Roux1881,Roux2013} introduced natural
selection within the organism. Darwin read the book a year before his
death and declared in a letter to G.~J.~Romanes 
\citep{Heams2013c}:

\begin{quote}
As far as I can imperfectly judge, it is the most important book on
evolution which has appeared for some time. 
\end{quote}

A century later, the concept of natural selection was locally
introduced into some somatic processes described by neuroscience (e.g.\ 
Edelman's ``neural darwinism'' in 1987, and his opposition to
instructionist approaches, both in immunology and in neurocience).
Immunology has also been one of the first biological fields to move
away from instructionist schemes of explanation, as early as 1966 (e.g.\ 
Brenner and C. Milstein used random \mbox{somatic} {hypermutation} of
immunoglobulin genes to explain \mbox{immunoglobulin} diversity, G. Edelman
and J. Gally used random somatic gene recombinations as a source of
immunoglobulin diversity, MacFarlane Burnett's ``clonal selection''
being different than what we call here natural selection). Cancerology
did it soon after \citep{Nowell1976,Sonnenschein1999,Soto2005}. 
\citet{Soto2008} summarized the role of physicalism and downward
causation in developmental and cancer biology of the past century.
Above all, at the very end of the last century, two major theoretical
advances took place. First, variation (and not instruction) is at the
source of any phenomenon occurring within and among cells---already
anticipated by Edelman---was generalized when gene expression itself
began to be understood as stochastic, culminating with the 
remarkable study of Elowitz
et~al.\ \citep{Elowitz2002,Raj2008,Kupiec2013,Heams2013b}.  
Second, \citet{Kupiec1997} based his views on the fundamental stochasticity of
gene expression to propose a Darwinian theory of cell differentiation
\citep{Kupiec2014}. Today, the stochasticity of gene expression in cell
populations, i.e.\ random variation among cells, appear to have a better
explanatory power than instructionist models to understand the
development and the functioning of an organism
\citep{Kupiec2012,Noble2017}. As a result, studies of cancer and aging
now fully adopt models involving natural selection \citep{Nelson2017}
and metastasis is considered an evolutionary process
\citep{Turajlic2016}. \citet{Grajzel2020} perfectly summarized the
present state of the art by the formula: 

\begin{quote}
Cancer is a genetic disease fueled by somatic evolution. 
\end{quote}

Somatic evolution is not only for cancerous cells, but for all cells.
Among them, we find somatic variation (indeed to a very high degree
among tumoral cells), transmission (through mitosis) and constraints
(nutrients, space, etc.). These are the three fundamental conditions to
obtain natural selection of some cellular lineages over others. In the
past decade, cancer and evolution made the front pages of the most
visible journals \citep{Willyard2016} and therapies based on
evolutionary reasoning are developed and appear to be successful
\citep{Enriquez2016,Degregory2019a,Degregory2019b,Thomas2019}.

A remark should be made here about the different words ``regulation'',
``control'' and ``instruction''. A multicellular organism is a colony,
and we have to consider the fitness of the colony. In tumors, it can be
argued that cells do not evolve anymore for the benefit of the colony,
escaping coordination with their neighbors. So, this is the tumorous
cell's own fitness (reproductive potential) that predominates in cancer
cell competition, precisely because they have escaped most homeostatic
phenomena. But normal development is not a mildly managed
tumorigenesis. It is anti-tumorigenic, heavily constrained, as a whole
and as a result of organismal selection. Regulation is predominant, in
the sense that cells actively prevent the proliferation of their
neighbors. We don't have open-ended evolution as in a population within
an ecosystem. Not only that, but there is active elimination of extreme
variants (``sick cells'', see for instance \citet{Kajita2010}). One can
argue that this is because cell populations in a given organ are
strictly confined in numbers and volume at any stage of development,
allowing for the evolution and predominance of homeostatic mechanisms.
So, there is a component of ``order'' in selection at the level of the
multicellular colony that predominates over the individual fitness of
cells in the developing individual. However, here regularity could be
better designated by ``regulation'' rather than by ``control'' or
``instruction''. 

\begin{table*}
\caption{\label{tab2}From the origins of biology, reification of
species and individuals has led to separate two distinct phenomena:
phylogenesis and ontogenesis\vspace*{2pt}}
\begin{tabular}{cccc}
\thead
Reified entity & Components & What is to be explained & What explains \\
\endthead
Individuals & Cells & Ontogenesis & Genetic program\\
Species & Individuals & Phylogenesis & Descent with modification\\
None & Cells and individuals & Ontophylogenesis & \parbox[t]{5cm}{\centering Natural selection and descent with modification} \vspace*{2pt}
\botline
\end{tabular}
\tabnote{In the latter, the ``genetic program'' replaced the short-term
stabilizing effects of natural selection (and other homeostatic
mechanisms). Ontophylogenesis corrects this philosophical heritage
\citep[after][]{Lecointre2020}.}
\end{table*}

\section{Descent with modification within (developing) bodies}

It is now possible to reconstruct a phylogenetic tree of metastases
from a single patient \citep{Zhao2016}. The comparison of
transcriptomes of single cells made it possible to reconstruct the
phylogeny of tissues of a developing zebrafish
\citep{Farrell2018,Wagner2018}, or the phylogeny of tissues of the frog
\textit{Xenopus} \citep{Briggs2018}. Interestingly, the tissues that
were \mbox{traditionally} \mbox{considered} to be homogeneous in origin (endoderm,
mesoderm, ectoderm) actually are not. Surprisingly, there are several
ways to develop a vertebrate: in the frog, ectoderm is paraphyletic and
mesoderm is monophyletic, while in the zebrafish ectoderm is
\mbox{monophyletic} and mesoderm is paraphyletic (mesoderm gives birth to
endoderm). This is a strong experimental argument against the
vertebrate body plan, and the notion of ``body plan'' in general
\citep[p.~184]{Kremer2023}; the true phylogenetic reasoning invites
us to view patterns and processes as evolutionary mosaics. More
recently, the lineage tracing of human development was obtained through
the phylogenetic analysis of somatic mutations \citep{Chapman2021},
allowing to discover the hypoblastic origin of extra-embryonic mesoderm
and primitive blood. \citet{SchmidSiegert2017} could reconstruct
the phylogeny of somatic mutations in a single oak. Actually, the view
of a phylogeny reconstructed from parts of a single organism had been
initiated long ago by \citet{Fitch1970}. By defining orthologous genes
and paralogous genes among different copies within a multigenic family
(e.g.\ globin genes), he already conceived that a phylogeny of different
elements of an individual could be constructed.

\section{What EvoDevo is actually studying: ontophylogenesis}

If natural selection and descent with modification---the two pillars of
Darwinian evolution---are now fully considered as explanatory within
the developing body, then development is understood as an evolutionary
process. EvoDevo becomes EvoEvo, in a way. \citet{Moczek2012}
formulated this idea as an \mbox{epistemological} program:
``\textit{development should be nested within a theory of developmental
evolution}''.  \citet{Kupiec2009,Kupiec2012} already developed the idea
that ontogenesis and phylogenesis are two facets of the same general
process of life deployment and diversification called
\textit{ontophylogenesis} \citep{Kupiec2009,Kupiec2012}. As already
mentioned above, there is no process of cell deployment in the
individual development that is ontologically separated from the process
of deployment of a species. Ontogeny and phylogeny are a single process
of diversifying lineages of entities that are submitted to natural
selection. In the absence of any platonic invariants, like ``the
genetic program'' or ``the body plan'', and in the \mbox{absence} of
reification of species, phyla or individuals, EvoDevo would already
have achieved \citet{Moczek2012,Moczek2014}'s program of ``building a
theory of developmental evolution'', which is ontophylogenesis
(Table~\ref{tab2}).


\section{Conclusion}

By viewing development as an evolutionary phenomenon, we don't refer to
the idea of ``recapitulation'' of \'{E}tienne Serres (1786--1868),
Johann Friedrich Meckel (1781--1833) and Ernst Haeckel (1834--1919).
For these authors, developmental stages reflect the past history of
organisms and as such, are constructed as an argument in favor of
transformism, soon called ``la th\'{e}orie de l'\'{e}volution des
formes organiques'', a remarkable modern expression brought by
\citet[p.~212, 219]{Gerard1845} \citep[p.~384]{Laurent1987}. The
point here is that the developmental process involves basic phenomena
that make a given transformation an example of \textit{Darwinian
evolution}. In development, natural selection among cells is at play,
as well as homeostatic mechanisms \citep{Nijhout2025}, to \mbox{explain}
functionality, regularity and robustness. \citet{Muller2007} reviewed
how EvoDevo's results ``\textit{take evolutionary theory beyond the
boundaries of the Modern synthesis}'', which is a way of promoting
EvoDevo's scientific \mbox{fecundity,} for good reasons
\citep{Minelli2014}. But there is still a
paradox: EvoDevo continues to publish papers full of instructionist
and/or platonic metaphors. Sometimes metaphors are productive for a
certain time span, and finish to become an obstacle later
\citep{Kremer2023}. As nicely summarized by \citet{Peluffo2015}:

\begin{quote}
However, metaphors that `illuminate matters quickly and efficiently'
may dim `with time and \mbox{frequent} \textit{usage}' \citep{Wilkins2013}
until they no longer capture the complexity of the field to which they
belong.
\end{quote}

\begin{table}
\caption{\label{tab3}Replacement of cybernetic/idealistic/finalist
metaphors by pre-cybernetic, truly biological terms in order to view
genes as partners (not ``controllers'') and to make development as an
evolutionary phenomenon}
%\tabcolsep4pt
\begin{tabular}{cc}
\thead
\parbox[t]{3cm}{\centering End-20th century metaphors} & To be replaced with \vspace*{2pt}\\
\endthead
Genetic control & Genetic contribution$^{**}$\\
Architect genes & Upstream-effect genes$^{*}$\\
Genetic program & None\\
Phylotypic stages & None\\
Body plan & Phylogenetic mosaic
\botline
\end{tabular}
\tabnote{$^*$ Or homeotic genes (in the sense of \citet{Bateson1894}'s homeotic mutations).}
\tabnote{$^{**}$ Or just ``genic action'' of H.~J.~M\"{u}ller or T.~H.~Morgan.}
\end{table}

EvoDevo should fully enter evolutionary thinking, to which,
paradoxically, it contributes: contrary to \citet{Lwoff1969}, biological
order does not come from biological order. Biology is neither physics
nor chemistry. Biology is biology because its explanations do not deal
with invariants like universals and laws, but with historical singulars
and their variations \citep{Gayon2003}. To do so, EvoDevo should
abandon the platonic metaphors of body plan, phylotypic stage, and the
associated taxonomic realism, which are clearly potential sources of
methodological bias \citep{Levin2016,Hejnol2016}. They should be
replaced by words embedded within a true phylogenetic way of thinking
(Table~\ref{tab3}). The diversity of \mbox{organismal} patterns unfolds through time as
mosaics, not plans: this is what Takhtajan and Hennig called
heterobathmy of characters, and EvoDevo has already introduced
phylogeny into the soma to depict its development. EvoDevo should
abandon the instructionist notions of genetic program and genetic
control as well; natural selection and homeostatic mechanisms being
stabilizing sources. EvoDevo is the right place to unify biology. There
should not be two separate theories in biology, the one explaining the
rise of the reified individual through the unfolding of an
instructionist program, and the other explaining the rise of a reified
species through natural selection. The achievement of the EvoDevo
program should be ontophylogenesis, where descent with modification and
natural selection enter into the somatic development from egg to death.
This change is ongoing, better explaining cancers and aging, among
other phenomena occurring within consortia of cells.

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