REVIEW ARTICLE

Multilevel Causation and the Extended Synthesis

Maximiliano Martnez Maurizio Esposito

Received: 24 April 2013 / Accepted: 29 November 2013 / Published online: 27 February 2014

Konrad Lorenz Institute for Evolution and Cognition Research 2014

Abstract In this article we argue that the classicallinear

and bottom-up directedmodels of causation in biology,

and the proximate/ultimate dichotomy, are inappropriate

to capture the complexity inherent to biological processes.

We introduce a new notion of multilevel causation where

old dichotomies such as proximate/ultimate and bottom-up/

top-down are reinterpreted within a multilevel, web-like,

approach. In briefly reviewing some recent work on com-

plexity, EvoDevo, carcinogenesis, autocatalysis, compara-

tive genomics, animal regeneration, phenotypic plasticity,

and niche construction, we will argue that such reinterpre-

tation is a necessary step for the advancement of the

Extended Synthesis.

Keywords Bottom-up approach Extended Synthesis Multilevel causation Proximate/ultimate dichotomy

One of the specific and critical aims of the Extended

Synthesis program is to identify and explain the causal

forces present in developmental mechanisms that play an

essential role in the evolution of form (Pigliucci and Muller

2010). The question about the origin and causal mecha-

nisms of organismal form concerns the interface between

evolution and development. Orthodox explanations that

focus on natural selection as the only source of speciation

and morphogenesis need to be complemented with devel-

opmental, physical, and systemic explanations in order to

obtain a more adequate and complete elucidation of the

causes of biological form. To integrate these causal

mechanisms with natural selection is also a long-term goal

of the evolutionary developmental biology (EvoDevo)

research program. Two different but related concerns are

pivotal to this aim: (1) how development (broadly con-

ceived) causally influences evolution, and (2) how evolu-

tion has causal effects on development.

Of course, such concerns are not new (Reif et al. 2000;

Olsson et al. 2010; Pigliucci and Muller 2010). However,

as many scientists and philosophers have stressed in the

last decades (e.g., Hamburger 1980; Gottlieb 1992; Gilbert

et al. 1996; Love 2003, 2006; Amundson 2005), develop-

mental biology only received scanty attention in the

Modern Synthesis (MS henceforth). For most of the MSs

architects, development was not a central phenomenon to

investigate because it simply followed from the instruc-

tions contained in the genes previously selected. Certainly,

as we will argue, the wide acceptance of Mayrs famous

distinction between proximate and ultimate causes did not

help. It further enlarged the gulf between development and

evolution. Mayrs dichotomy indeed assumed that the

causal mechanism of natural selection was the ultimate

cause behind the emergence of genetic programs imple-

menting and directing development. Development was

therefore conceived as an effect, a consequence of natural

selection. However, the 19th-century developmental tradi-

tion (Esposito 2013), which attracted some now overlooked

biologists even in the 20th century (including Garstang, De

Beer, Svertsov, Schmalhausen, Waddington, Goldschmidt,

and Kuhn), is reemerging in new guises. Many contem-

porary developmental biologists are revisiting, now

armored with fascinating new observations and hypotheses,

the idea that development can have a fundamental role in

the emergence of novelties in evolution (e.g., Muller and

M. Martnez (&)Departamento de Humanidades, Universidad Autonoma

Metropolitana-Cuajimalpa, Mexico City, Mexico

e-mail: mmartinez@correo.cua.uam.mx

M. Esposito

Departamento de Filosofa, Universidad de Santiago de Chile,

Santiago, Chile

123

Biol Theory (2014) 9:209220

DOI 10.1007/s13752-014-0161-3

Newman 2003; West-Eberhard 2003). More and more

biologists, including geneticists, question the simple and

straightforward causal relation between genotype and

phenotype, i.e., genetic programs and developmental

outcomes (e.g., Noble 2013). The organism is increasingly

seen as a hierarchical system in which different levels of

organization interact in complex ways. Thus, organisms are

not the mere product of closed genetic programs, but the

result of an interactive co-determination among evolution,

development, and environment (broadly conceived), and

between higher and lower levels of biological organization.

In the light of this more complicated picture, a central

question to be addressed is: can we still inquire about these

multiple organismal co-determinations using our tradi-

tional causal models in biology? In fact, many authors have

recently pointed out the difficulty of understanding these

causal relationships using the proximate/ultimate dichot-

omy (West-Eberhard 2003; Amundson 2005; Brigandt

2007; Laubichler and Maienschein 2007; Plutynski 2008;

Laland et al. 2011; Martnez 2011; Mesoudi et al. 2013)

and the bottom-up causal model (Gilbert and Sarkar 2000;

Strohman 2000; Noble 2006), both of which are deeply

entrenched in our scientificand even in our vernacular

epistemology. We sympathize with these ideas, and argue

here that a proper causal framework appropriate to the

Extended Synthesis is required in order to build adequate

models to capture the complex causal interrelationships

that involve entities and processes at different levels of

biological organization. We will suggest that it is possi-

bleattending to theoretical and empirical research on

morphogenesis, niche construction, comparative genomics,

natural selection, autocatalytic networks, phenotypic plas-

ticity, and animal regenerationto build up a new causal

framework that better fits the integrative requirements of

the Extended Synthesis.

Laland et al. have recently argued for a revision of our

old models of causality (2011, 2013). In echoing Levins

and Lewontins (1985) old notion of dialectical biology,

Laland et al. propose a new causal model uncovering dis-

parate observations and disciplines: from EvoDevo to

niche construction, from human cooperation to cultural

evolution. For them, all these disciplines suggest forms of

causation that are irreducible to unidirectional and linear

causal processes. Phenomena related to developmental

biology and niche construction are certainly paradigmatic

examples illustrating why we need a new model they call

reciprocal causation.

In this article we share part of the proposal of Laland

et al. (2013). We agree that Mayrs old dichotomy is today

deeply problematic and a new causal model is required.

However, we think that the notion of reciprocal causa-

tion is unnecessarily limited; it only captures a part of the

biological phenomena. Even though many mechanisms

operating behind the emergence of evolutionary novelties

can be very well characterized by a model of reciprocal

causation, we think that additional forms of causal inter-

action need also to be mentioned, i.e., forms of causation

where physical constraints, genetic and non-genetic

inheritance, stochastic events, and self-organization are

considered. This is especially important in the light of

recent critiques of the model of reciprocal causation that

Dickins and Barton (2013) have made. In particular, the

authors argue that in invoking a dynamic interaction

between development and evolution, Laland et al. are

assuming what they pretend to criticize: the proximate/

ultimate distinction. Indeed, Dickins and Barton claim, two

interacting things must be logically different. If both

development and evolution remain two distinct processes

(though connected), we can still defend the idea that

development and evolution have their own causes (which

implies specific why and how questions). As a con-

sequence, Laland et al. do not replace Mayrs dichotomy,

they only make the trivial observation that there is some

kind of connection between ultimate and proximate causes

(Dickins and Barton 2013).

But the critiques of Dickins and Barton do not apply to

our multilevel causation model (MC). Indeed, MC does not

merely describe the relation between evolution and

development. We are not talking about two things in

interaction. We are talking about one process (the organ-

ism) in interaction with several other processes (including,

of course, evolution and development).1 From a more

general perspective, with MC we refer to all the processes

and interactions that are behind the origination and evo-

lution of the organismal forms (from bacteria to eukary-

otes, including dynamic entities such as super-organisms).

For this reason we propose taking MC as an ideal candidate

to be placed at the base of the causal framework men-

tioned, replacing the traditional causal concepts prevalent

in biology, and extending the notion of reciprocal causa-

tion. We also hope that placing MC as a touchstone of

integrationist causal models will help to promote a deeper

inclusion of theories of complexity in the Extended Syn-

thesis agenda.

Rethinking Causation in the Extended Synthesis

During the last decade there have been important argu-

ments calling into question the traditional causal approa-

ches to evolution and development (Gilbert and Sarkar

2000; Thierry 2005; Laland et al. 2011). Specifically, these

arguments focus on the necessity to (1) reconsider the

1 On the organism conceived as a processual entity see Woodger

(1929) and Dupre (2012).

210 M. Martnez, M. Esposito

123

dichotomy of proximate/ultimate causes, and (2) comple-

ment the bottom-up causal model with a top-down one. Let

us see what the criticisms are.

The Proximate/Ultimate Causal Dichotomy

In a well-known and very influential paper published in

1961, Mayr introduced the dichotomy between proximate

and ultimate causes to clarify the notion of causation in

biology. Mayr pointed out the separation between func-

tional biology and evolutionary biology: two areas with

their own methods, goals, and basic concepts (Mayr 1961).

Mayrs argument does not need to be restated here, but it is

worth remembering two main points: (1) Mayrs dichot-

omy has been amply accepted in biology. (2) The dichot-

omy not only had explanatory value; it also had an

undeniable ontological dimension by referring to two dif-

ferent kinds of causes that produce different types of bio-

logical results. The dichotomy separates the nature of

physiological and phylogenetic processes: their operation

and their biological consequences are independent (Mayr

1961). As Amundson (2005, p. 99) has put it: Proximate

causation involves the processes in an individuals lifetime,

and ultimate causation involves the historical origins of the

characters of an individual organism. After 1970 the

dichotomy was mainly used to refer to developmental

processes as proximate and, therefore, irrelevant to evolu-

tionary explanations (p. 212).

However, Amundson himself argues that ontogeny can

be understood as a dynamic process in a causal continuous

chain. Development can be seen as an intermediary stage in

a causal (neither dichotomous nor contrasting) continuum.

Amundsons view implies the coherent idea that the bio-

logical world is not deeply divided into two kinds of causes

(requiring two kinds of explanations); on the contrary,

biological causation in the generation and evolution of

form seems to be a complex matter that goes far beyond

such idealizations. It incorporates many entities and prop-

erties at diverse levels of organization and at different time

scales (Huang 2000; Newman 2003b; Riedl 2005; Thierry

2005; Plutynski 2008).

Amundson is not alone in criticizing Mayrs dichotomy.

From another perspective, West-Eberhard (2003, 2005) has

argued that Mayrs model is very problematic insofar as

proximate mechanisms, in many cases, produce the varia-

tion on which natural selection works: For evolutionary

biology, proximate mechanisms represent more than just

different levels of analysis of research styles. They are the

causes of the variation upon which selection acts (West-

Eberhard 2003, p. 11). Muller (2005, 2007) has pointed out

that the proximate/ultimate dichotomy stems primarily

from the impossibility of either evolution or development

separately providing a complete causal explanation of

organismal form. This explanatory limitation is prompted

by the particular interpretation of causality held so far by

each field, and rooted in the entrenched polarized image of

remote and proximate causes. Muller et al. suggest that an

alternative to the dichotomy is to consider the two cau-

salities not as opposite, but interrelated (Muller 2005;

Callebaut et al. 2007).

This is also the spirit behind Plutynskis work on

dominance. She has shown how a biologically complex

phenomenon like genetic dominance can only be explained

by taking into consideration a wider causal framework that

goes beyond the proximate/ultimate dichotomy, and

includes both top-down and bottom-up causal approaches.

According to Plutynski (2008), the discrete categories of

proximate and ultimate causes are not useful to explain

general patterns in biology, where it is necessary to

determine the interaction of multiple levels of organization

and connect different time scales. In a similar vein, Bri-

gandt (2007) has argued that such a dichotomy not only

obscures explanations of complex phenomena like evolv-

ability; it also creates unnecessary tensions (e.g., between

typological and population thinking). Thierry (2005,

p. 1182) has similarly argued that the dual proximate/

ultimate model blocks important approaches to the rela-

tionship between evolution and development: it cannot

account for the different scales of the evolutionary time and

for the epigenetic constraints that direct the changes open

to living beings.

Other alternatives recommend removing the dichotomy

altogether. Instead of considering the two causalities

entwined, one suggestion is to build a new causal frame-

work going beyond the dichotomy (Hall 2000; Amundson

2005; Laubichler and Maienschein 2007). This last view-

point, regarding the necessity of a replacement, coincides

with the position that a novel conceptual framework is

required for the Extended Synthesis.

In our opinion, this viewpoint is more fruitful than the

alternatives previously mentioned for two principal rea-

sons. First, and as the critiques of Dickins and Barton

(2013) also show, to try to solve the problems using the

same concepts of proximate and ultimate would not

help much: their usual contrasting meanings are deeply

entrenched in our biological theories and practices, and it

would be extremely difficult and probably hopeless to try

to reform them toward conciliation. It is thought that they

are opposed by nature and that they operate at different

time scales. But new lines of research show how causation

in morphogenesis and evolution is a very complex and

multifarious phenomenon, going far beyond any frame-

work that would result from just taking proximate and

ultimate causes merely as interrelated. We review some of

this work in the next sections to support the proposal of

building a new causal framework for the Extended

Multilevel Causation and the Extended Synthesis 211

123

Synthesisone that drops the concepts of proximate and

ultimate. We will also explore the possibility of taking

into account both bottom-up and top-down causalities in

the understanding of complex biological phenomena. This

suggestion gives us some clues about the starting point of

the construction of the new causal framework required for

the Extended Synthesis, and leads us to the second theme

of this section.

The Incompleteness of the Bottom-up Approach

The criticisms of reductionism and the bottom-up approach

to biological causalityfrom molecules to ecosystems

are vast and well known. One recent criticism comes from

Noble (2006): the usual reductionist bottom-up model of

causality is insufficient to explain and capture what hap-

pens in the organization and evolution of complex systems.

Noble reminds us of two fatal problems with the bottom-

up approach: computability and relevance. With regard to

the former, he says that even if it were possible to recon-

struct the chemical activity involved in the folding of a

single molecular protein (which would take months of the

most advanced computing), the molecular reconstruction of

the processes of an entire cell, which involves, say, the

interactions of 1,012 molecules, would be practically

impossible. The second fatal problem is that even if it were

possible to calculate the molecular activities of systems,

those findings would certainly be irrelevant:

Structures and processes at a higher level simply are

not visible at the molecular level. The genes and

proteins of the body do not in some way know or

reveal what they are doing in higher-level func-

tions. The assumption that they do is a strange one.

(Noble 2006, p. 78)

We can extend Nobles remarks and say that the issue is

not just a matter of explanation and of epistemological

approaches to biological phenomena; the issue is also onto-

logical. It is a fact that the complexity of biological processes

such as morphogenesis involves systemic developmental

properties that go beyond the molecular level.

Other authors also insist on the inadequacy of the bot-

tom-up approach in the epistemological, methodological,

and ontological domains. Thus Strohman (2000, p. 575)

states:

In biology, molecular reductionism has mostly dis-

tracted us from study of mesoscopic realms between

genotype and phenotype where complex organiza-

tional states exist and where, also exist networks ofregulatory proteins capable of reorganizing patterns of

gene expression, and much other emergent cellular

behavior, in a context-dependent manner.

In a similar vein, Gilbert and Sarkar (2000) argue from an

organismic perspective that bottom-up and top-down

approaches must be used to explain the complex ontology

of biological phenomena: Organicist ontology and expla-

nations would include those bottom-up considerations but

would also include the functioning of the tissue within the

organism, the functioning of the organism within its

environment (2000, p. 2).

Multilevel Causation

Given the discomfort with both the dichotomous and bot-

tom-up approaches, what are the alternatives? The point

made by Newman (2003b), Riedl (2005), Noble (2006),

Plutynski (2008), and Mitchell (2009) is worth developing.

The central idea is that we need to think in terms of a

causal model that includes multiple directions of causation,

which will allow different levels of organization and dif-

ferent time scales to be interrelated. This is not only

desirable in order to have a more complete wide-ranging

theory of the relationship among evolution, development,

and environment; it can also provide a new causal frame-

work required for the Extended Synthesis. Needless to say,

this is mandatory to grasp the biological discoveries made

in recent decades.2 Let us see what the principal virtues of

multilevel causation are.

The Concept of Multilevel Causation

A way to visualize what we mean by MC is the image of a

web of life as recently represented by Raoult et al.

Indeed, the biologists Eugene Koonin, Didier Raoult, and

coworkers have recently stated that the data accumulated in

microbial genomics, and comparative genomics more gen-

erally, demonstrate that genetic information not only flows

vertically, but also laterally (Raoult and Koonin 2012, p. 1).

If lateral transfer of informational genes is much more

widespread than previously expected, our conception of

species and our notion of the tree of life need substantial

2 Multilevel causation is fundamental in organization processes of

biological complexity: in areas of study such as complexity theory

(Kauffman 1993; Emmeche et al. 2000; Hooker 2011), niche

construction theory (Gilbert and Sarkar 2000; Laland et al. 2008),

epigenesis (Newman 2003b), paleontology (Vrba and Eldredge 1984;

Sepkoski 2008), systems biology (Palsson 2006; Trewavas 2006),

cellular autocatalysis (Moreno and Umerez 2000), neurobiology (Ellis

2009), and evolutionary theory (Campbell 1974; Mitchell 2009;

Martnez and Moya 2011), there are many advanced works about the

importance of the co-determination of bottom-up and top-down

causes. This co-determination is seen as a universal pattern of

organization (El-Hani and Queiroz 2005).

212 M. Martnez, M. Esposito

123

revisions (Merhej and Raoult 2012). In addition, if the

evolution of the genome is characterized by gene deletions

and duplications and insertions and genome rearrange-

ments (Merhej and Raoult 2012, p. 2), this means that

every genome, including the human genome, is a chimera,

i.e., a set of genes with viral, bacterial, and eukaryotic

origins. Yet, such chimerical genomes contain many genes

that do not increase the overall fitness of the organism. As a

consequence, evolution is not only about mutation and

selection, but also about stochastic processes of assortment.

Genomes are thus constituted by genes of different evolu-

tionary lines that cannot be represented by a unique tree of

life. A more complex and intricate picture is required,

which Raoult dubs the web of life (see Fig. 1).

We can use this image of the web of life for visualizing

a web-like model of causation. In fact, it can be argued that

the complex web of life, which resembles an intricate

network more than an ordered tree, mirrors the complex,

multileveled relations that we can observe at different levels

of biological organization, both diachronically and synch-

ronically. In other words, the web of life also reflects a

web of causes where physical constraints, natural selection,

environment, chance, genetic and non-genetic information

interact. Whereas the traditional tree of life can be seen as the

outcome of a unique causal line going from gene mutation

towards selection (ultimate causes), the web of life is the

result of a large assortment of causes. From this perspective,

MC would provide the conceptual framework for consider-

ing how the web of life came about, and the multiple

mechanisms producing it.

One of the main virtues of an MC approach is that it

provides a flexible framework for investigation: there are

neither principal (evolutionary) nor secondary (proximate)

causes that can be neatly distinguished, in principle at least.

There is no fixed frame in which we can a priori establish

where why and how questions are. MC uncovers

diverse types of causationlinear, reciprocal, or top-

downwithout any pretension of reducing or subsuming

one to the other. MC also fosters a pluralist cooperation

among disciplines in assuming that there are neither centers

(e.g., natural selection) nor peripheries (e.g., EvoDevo)

fixed once and for all; what is central and peripheral

changes with the growth of knowledge. In sum, MC is a

descriptive concept denoting the complex causal relations

we find across levels of biological organization.

As a very general definition, with MC we refer to all the

mechanisms of causal determination and co-determination

(i.e., feedback loops), multiply directed (bottom-up and

top-down), that occur between entities and events at dif-

ferent levels of organization, and that connect different

time scales.3

Some of these kinds of causal co-determinations will be

exemplified in the following sections.

Fig. 1 The web ofmitochondria (Merhej and

Raoult 2012)

3 It is worth mentioning that several philosophers (e.g., Kim 1998;

Craver and Bechtel 2007) call into question the notion of top-down or

downward causation, arguing that it presents important difficulties in

its conceptualization. But see Andersen et al. (2000) and Klister

(2010) for a defense of downward causations concept.

Multilevel Causation and the Extended Synthesis 213

123

Niche Construction and Multilevel Causation

Here we review some work on niche constructionin a

nutshell, the influence of the environment on the organism

and its components. Odling-Smee et al. (2003) define niche

construction as a process in which organisms change the

relation between themselves and their environment.

Organisms not only inherit an ecological niche; they also

transform that niche in each generation. What the authors

argue is that the ways organisms modify their environment

and the modalities through which the environment influ-

ences organisms fitness have important evolutionary out-

comes: Niche construction is itself an evolutionary process

that can potentially codirect and regulate natural selection

and other evolutionary processes (Odling-Smee et al.

2003, p. 133). The reciprocal feedbacks that are established

between organisms and environments defy a simple and

linear model of causation. Evolution is not a process simply

driven from gene mutation and selection, because which

genes are selected (or expressed) also depends on the con-

textual ecological niche (that previous generations of

organisms have contributed to transform).

For Gilbert and Sarkar (2000) there are two higher levels

that regulate genes: cellular cytoplasm and the environ-

ment. With regard to the latter, they mention well-known

examples such us the ant larva becoming a queen or a

worker depending on the food it is given, or a wrasse

becoming a male or a female depending on whether a male

is already in the reef (2000, p. 7). The authors regard these

kinds of influences as downward directed:

These life history strategies make up a large part of

contemporary ecology. However, the proximate

causes for most of these changes are unknown. They

represent top-down regulation wherein the upper

level (the environment) selects the phenotype rather

than the lower level (the genes). To be sure, both are

needed; but the reductionist approach of explaining

the phenotype solely from the component parts of the

lower levels will not suffice. (2000, p. 7)

They add: Whole organisms and their environmental

interactions are becoming studiable, and gene expression

patterns are being seen as being controlled both from the

bottom-up and from the top-down (2000, p. 7)

Laland et al. (2008) go deeper into the study of the

relationship between development, evolution, and envi-

ronment. They describe some remarkable examples of

niche construction and multilevel causation with ontogeny

in the wild.4 It is worth mentioning that, in general, pro-

posals of non-genetic inheritance, such as epigenetic

inheritance, niche construction/ecological inheritance, and

cultural inheritance, adopt instances of multilevel causation

in their analysis that go beyond the dichotomy of proxi-

mate/ultimate (Mesoudi et al. 2013).

Autocatalytic Networks and Multilevel Causation

Other work that incorporates multilevel causation includes

research on autocatalytic networks. The transition from

inorganic to organic chemistry is thought to involve self-

organized networks of molecular arrangements whose

properties give rise to the basic and overall characteristics

of living systems (Lee et al. 1997). Kauffmans (1993)

work on this topic is well known. But do autocatalytic

networks exhibit processes of multilevel causation? This is

proposed by Moreno and Umerez (2000) with regard to

cells: the self-organization of a fundamental system like the

cell is established through the interactions of the whole

system. The functional material that makes up the system is

fabricated within internal processes of the cell itself: the

cause of a given functional component in a cell is the

whole network of (recursive) reactions that constitute the

cell itself (Moreno and Umerez 2000, p. 110). In this way,

the whole system determines what happens to its constit-

uents, representing a case of downward causation. This top-

down determination, in conjunction with bottom-up

determination (from the constituents to the whole) in a

feedback loop, promotes order and complexity in the cell

system. Following hierarchical theory, El-Hani and Que-

iroz (2005, p. 162) define this kind of causal determination

in autocatalytic networks as the influence of the whole over

its components. The higher level of every system imposes

constraints on its parts, affecting its behavior with the

organizational pattern that the higher level determines.

Natural Selection and Multilevel Causation

Multilevel causation has also been applied to describe the

positive causal role of natural selection in the generation of

complex morphology (Campbell 1974; Ellis 2006; Mart-

nez and Moya 2011). Natural selection operating at higher

levels of organization (individual or populational) affects

the configuration of the lower (molecular or genetic) levels

of the next generation. This gives natural selection a cre-

ative causal role in morphogenesis. The point here is that

the fitness of the individuals partly determines the com-

position of the initial molecular conditions of the sub-

sequent generation(s). In other words, if an individual

succeeds in survival and reproduction, its DNA will

4 Such is the case of the female goldenrod gallfly. The proteins

contained in the saliva of the gallfly larva induce a cellular

Footnote 4 continued

proliferation on the goldenrod. A gall is formed and the larva enters in

it and continues to be protected as it feeds.

214 M. Martnez, M. Esposito

123

(ceteris paribus) be present in the next generation as the

starting point of a new individual. We see, then, a dia-

chronic feedback causal loop in action: what occurs to

entities at higher levels of organization causally affects the

entities of lower levels (in the subsequent generations),

which in turn construct new higher level entities, and so on.

Figure 2 is useful for understanding this mechanism.

The initial conditions of every life cycle are determined

in part by what happened in the previous generation (at the

organismal level). We observe, then, the causal influence of

a higher level (organismal) on a lower level (molecular).

Looking at Fig. 2, if we take the three types of arrows

(thin, thick, dashed) as a causal continuum, we realize the

influence of any past event over the future ones, connecting

different time scales (ontogenetic and phylogenetic). Any

point of the continuum is conditioned by past events, and it

will condition future ones because of the channeling effect

of downward and upward causations operating together.

Ontogeny and Multilevel Causation

Newman, Muller, and colleagues (Muller and Newman

2003; Muller and Olsson 2003; Newman 2003a, b; New-

man et al. 2006) have argued that many of the basic

morphological features of living systems are products of

generic properties that are physically inevitable (and not

encoded in the DNA). The authors study some physical

attributes of cell aggregates and tissues, such as diffusion,

differential adhesion, oscillation, and reactiondiffusion

coupling. This evidence leads them to argue that those

properties were present at the origins of body plans, acting

as causes of their form. Those properties, which persist

entrenched in the development of modern-day organisms,

were the constructional causes of basic features of organ-

ismal form, such as lumen formation, compartment for-

mation, multilayering, segmentation, and so on. Also, the

ancient cell aggregates (metazoan ancestors, 700 mya)

would have behaved like liquids and possessed elasticity,

exhibiting properties of soft matter (excitable media)

(Newman 2003a; Newman et al. 2006). Newman (2003a,

p. 223) writes:

The cells of these primitive aggregates were highly

evolved metabolically, with complex biochemical and

genetic networks; they were open and responsive to

the external environment; and they were capable of

self-organizing dynamical activities under appro-

priate circumstances. For instance, positive and neg-

ative feedback loops of chemical reactivity, when

confined to the interior of an individual cell, will often

lead to temporal oscillations in one or more chemical

component they can readily arise as self-organizingside-effects of the metabolic circuitry , ratherthan as the expression of an evolved program.

Newman et al. (2006) regard three mechanisms as most

important: (1) interactions of cell metabolism with the

physicochemical environment within and external to the

organism; (2) interactions of tissue masses with the phys-

ical environment on the basis of physical laws inherent to

condensed materials; and (3) interactions among tissues

themselves, according to an evolving set of rules:

Because the inherent physical properties, in their self-

organizing capacities, but also conditioned by exter-

nal parameters and extrinsic forces, can act as mor-

phogenetic determinants, the dynamical, constraining

and environmental aspects of developmental causa-

tion can productively be analyzed in the framework

of inherency and interaction, i.e., epigenecist.

(Newman et al. 2006, pp. 290291)

One important fact to mention here is that, as Newman has

pointed out, the descriptions in current molecular develop-

mental biology point the arrow of causation in the upward

direction only. As Newman has put it:

Fig. 2 Natural selectionbetween levels of biological

organization (from Martnez

and Moya 2011)

Multilevel Causation and the Extended Synthesis 215

123

The decoupling between genotypic and phenotypic

change in both evolution and development implies that

causality runs in both directions, not that these levels

are causally independent of each other. And because

phenotype is itself a multileveled concept with mor-

phological and biochemical aspects, determination is

actually multifarious. (Newman 2003b, p. 171)

To summarize: embryo physics follows ahistorical

generic processes of self-organization, present in all com-

plex systems (alive or not). Those epigenetic processes

were present at the very beginning of metazoans, and have

prevailed since then.

Carcinogenesis and Multilevel Causation

Here we want to mention the work of Soto and Sonnenschein

on carcinogenesis (2005). They adopt an organicist

approach instead of the usual reductionist and deterministic

genetic approach, arguing that the somatic mutation theory

(SMT), where cancer is a cellular problem caused by mutated

genes, is inadequate, so an alternative theory is required.

Tissue organization field theory (TOFT) seems appropriate at

this point, because it shows carcinogenesis as a problem of

tissue organization in a developmental process that goes

awry. How is this theoretical dichotomy related to downward

causation acting between levels of organization? In TOFT,

Soto and Sonnenschein (2005, p. 103) write, cancer is placed

in a different hierarchical level of complexity than in

SMT: (1) carcinogenesis represents a problem of tissue

organization comparable to organogenesis, and (2) prolifer-

ation is the default state of cells. The authors assert that this

new theory permits a better and more adequate definition of

the phenomenon, but it implies a switch in the usual way of

seeing living organization:

The unidirectional flow from genes to shape is being

modified to include cell movements that cause physi-

cal stress in neighboring cells inducing specific gene

expression. This causal chain, from a molecular event to

physical stress inducing the next molecular event

appears as an emergent (i.e., an increased number of

cells moving) acting as a downward cause. (p. 115)

Phenotypic Plasticity, Environment, and Ontogeny

Cor van der Weele (1999) lamented the absence of the

environment from developmental biologys textbooks. As

she argued, despite the availability of many observations and

known phenomena, developmental biology still overlooks the

centraland very often determinantrole played by envi-

ronmental parameters in the processes of morphogenesis.

From the aphids development to the butterflys seasonal

polyphenisms, from the sexual determination of echiurid to

the predator-induced polyphenisms in Daphnia cucullata (van

der Weele 1999; Gilbert 2002), all show that the environment

is much more important than commonly believed. If van der

Weele is right, the changing role of the environment in

inducing and influencing morphological traits and behavior

also implies the need to change our causal models of expla-

nation. If the old genetic framework saw genes as the starters

and inducers of a cascade of events heading directly to the

phenotype, now we need to rethink the relations among

genotype, environment, and phenotype as a triadic dynamic

network. In other words, this is an intricate web of causes and

effects where the environment can determine a specific gene

expression, and phenotypes in turn can determine the envi-

ronmental variables that may act on gene selection.

The cases of predator-induced polyphenisms are very

illustrative. They are included in the more general category

of phenotypic plasticity. Indeed, the development and

morphology of many organisms can be deeply shaped by

population density, food, temperature, sex ratios, and the

presence of predators (Gilbert 2002; West-Eberhard 2003).

It is now well known that the morphology of many rotifers

(including Daphnia) changes if development happens in the

presence of predators. For instance, Daphnia cucullata

develops a protective helmet when kairomones (compounds

released by predators) are detected in its environment.

Kairomones dramatically influence the developmental path

of Daphnia; in so doing kairomones also influence its fit-

ness. Apart from rotifers and gastropods, predator-induced

polyphenism is also present in vertebrates and social insects

(Weider and Pijanowska 1993; Passera et al. 1996; Gilbert

2002; Miyakawa et al. 2010).

Environmental causes, including seasonal and nutri-

tional polyphenism, illustrate that causation is not uni-, but

multidirectional: from genotypes to phenotypes, from the

environment to genotypes, and from phenotypes to the

environment. As Gilbert concluded in 2003, we need a

more context-dependent analysis of the causal network

operating behind the origination of organismal morphol-

ogy; we need a biology that must integrate the signals

from the genome, from the interactions between cells, and

from the environment in which the organism develops

(Gilbert 2003, p. 98). A unidirectional model of biological

causation is inadequate for grasping the interactive,

dynamic, and multilevel interactions among environment,

development, heredity, and evolution. In short, we need to

consider a multilevel model of causation.

Animal Regeneration and Morphogenetic Fields

From the celebrated studies of Hans Spemann it was clear

that the phenomena of regeneration and, more generally,

cellular differentiation and morphogenesis were not easily

216 M. Martnez, M. Esposito

123

explainable with a bottom-up model of causality. In one of

his numerous heteroplastic (interspecific) transplantation

experiments, Spemann (1919) showed that the embryo was

extremely plastic during development. The multiple rela-

tions between the parts and whole could not be easily

accommodated in a linear, upward, causal model. In fact,

only rarely were the transplanted parts strictly determined

at the beginning because, once they were implanted, their

activities changed according to the new environment. In

sum, the activities of transplanted parts always depended

on the activity of the surrounding cell system in which

these new tissues were inserted.

As Spemann illustrated (see Fig. 3), Triturus teaniatus

gastrula (a, left) has a white spot in the middle representing a

transplant of tissue taken from a Triturus cristatuss gastrula (b,

left), and vice versa. The original tissue transplanted in a (left)

would normally become epidermis, but it behaves according

to the new environment into which it is inserted, so it becomes

an eye and part of the brain (a, right). Likewise the original

tissue transplanted in b (left) would normally become the

forebrain and an eye, but in the new environment it forms

epidermis. The last figure (b, right) represents the Triturus

cristatus embryo at an advanced stage of development. Note

the black pigmented cells in the gill area (Spemann 1919,

pp. 588589; see also Hamburger 1988).

In order to explain the plastic property that embryos

exhibited during morphogenesis, Spemann assumed the

existence of a morphogenetic field that could account for

the specific direction of cellular differentiation, i.e., a limb

field produces limb tissue, an epidermis field produces

epidermis cells and so forth. Although the notion of the

morphogenetic field was partially forgotten after the 1960s

(Gilbert 1997), developmental biologists resurrected it in

the 1990s (Davidson 1993; Bolker 2000). In a recent arti-

cle, Levin defines the morphogenetic field as follows:

The quintessential property of a field model is non-

localitythe idea that the influences coming to bear

on any point in the system are not localized to that

point and that an understanding of those forces must

include information existing at other, distant regions

in the system. In a sense, the familiar morphogen

gradient is already a field model, as it refers to

changes of the prevalence of some substance across a

spatial domain, as opposed to a single concentration

level at some local spot. Cells in vivo are immersed

in a number of interpenetrating sets of signalsgra-

dients of chemicals, stresses, strains, pressures, and

electric potential. (Levin 2012, p. 2)

In revising the experiments on regeneration and regu-

lation in planaria, Levin claims that the conceptual use of

the morphogenetic field is more compatible with a top-

down perspective, based on the flow of information at

different, even distant, levels of biological organization.

Fig. 3 Spemanns heteroplastictransplantation experiments on

Newt embryos (1919,

pp. 588589)

Multilevel Causation and the Extended Synthesis 217

123

Indeed, as he notes, the process of head regeneration in

planaria prevents the formation of other heads in distal

injured sites. The cells in the posterior axis of the planaria

body behave as if they knew that a head is regenerating

on the other side. Thus, Levin continues, in order to

understand the process of regulation in the planaria body,

single cells are not the most effective units of investigation.

In a morphogenetic approach, higher levels of organization

are required and multilevel forms of causation need to be

considered. In the spirit of Spemanns old proposal, Levin

concludes that a deeper understanding of the phenomena

related to animal regeneration, embryogenesis, and cancer

requires a morphogenetic approach more compatible with a

model of downward causationa perspective that may

also have fundamental implications for our understanding

of evolution, development, and cognition.

Conclusions

The examples of multilevel causation reviewed above

comprise diverse and complex causal relations between

levels of hierarchical organization. What they show is that in

nature there are multifarious mechanisms, interactions, and

connections that permit feedback controls at both intra- and

inter-levels of organization, which can generate order and

complexity in the form and function of biological systems.

This fact has important implications for our usual theoretical

approaches to evolution and development, and calls for a

more inclusive (and non-gene-centered) perspective, like the

one proposed by the Extended Synthesis. In line with Laland

et al.s (2013) proposal, we have asserted here that it is

impossible to use our classical conceptual frameworks to

describe and understand the biological causal complexity

implied by the interface between evolution and develop-

ment. However, we consider Laland et al.s model of reci-

procal causation unnecessarily restricted.

We agree that the ubiquitous phenomena of phenotypic

plasticity offer many of the variants on which natural

selection works. We also agree that organisms often induce

changes in the environment that may increase the fitness

and alter the final selective outcomes. In general, we agree

with Laland et al. that various forms of feedbacks can be

described as reciprocal. But there are other crucial causal

relations happening among the environment, development,

and genomes that cannot be reduced to reciprocal feed-

back. Indeed, once we extend our attention from the rela-

tions between evolution and development to all the causes

working behind the origination of organic forms (from

bacteria to eukaryotes), we need to expand our models of

causation accordingly. The case illustrated by Raoult,

Koonin, and colleagues is exemplar (Merhej and Raoult

2012; Raoult and Koonin 2012). Microbial genomics

shows that evolutionary changes in bacteria are not unidi-

rectional and merely adaptive; they are often the result of

stochastic processes. In order to understand bacterias

morphological variation and evolution, a web of causes

needs to be invoked.

In addition, cellular autocatalytic networks present a

form of downward causation that is systemic rather than

exclusively linear or reciprocal. Feedback controls are only

one out of various types of partswhole relationships. The

properties of self-organization that we can observe in

whole cellular systems are essentially interactive and

characterized by ramified causality. As Moreno and

Umerez describe, the higher levels of a cellular system

impose specific constraints over the composing parts

(2000, pp. 108110). Yet, Spemanns and Levins experi-

ments demonstrate that a morphogenetic field determines

the fate of individual cells: here we have cases of down-

ward causation where reciprocal causation plays only a part

in a broader interconnected whole. Finally, the physical

generic attributes that characterize ontogenyincluding

cases of developmental constraintsare best viewed as yet

another kind of multilevel causation: inner and outer

environments, together with inherent biological properties,

all work behind the constitution of life forms.

In short, if evolution is more than mutation and adaptive

selection, and if linear or dichotomized models of causa-

tion fail in describing lifes complex networks, a wider

approach is necessaryone that includes multiple direc-

tions of causal determination between entities and events at

the diverse levels of organization and at different time

scales. It is in this sense that we advocate the necessity of

using a model based on multilevel causation in the

Extended Synthesis.

Acknowledgments We are grateful to all the members of PhiBio,Seminario de Filosofa de la Biologa UAM-C, for useful discussions.

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Multilevel Causation and the Extended SynthesisAbstractRethinking Causation in the Extended SynthesisThe Proximate/Ultimate Causal DichotomyThe Incompleteness of the Bottom-up Approach

Multilevel CausationThe Concept of Multilevel CausationNiche Construction and Multilevel CausationAutocatalytic Networks and Multilevel CausationNatural Selection and Multilevel CausationOntogeny and Multilevel CausationCarcinogenesis and Multilevel CausationPhenotypic Plasticity, Environment, and OntogenyAnimal Regeneration and Morphogenetic Fields

ConclusionsAcknowledgmentsReferences