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Introduction
Complexus 2006;3:211–216 DOI: 10.1159/000095881
Received: March 3, 2006
Accepted after revision: June 28, 2006
Published online: September 21, 2006
Wings for Flying,
Lymphocytes for Defense:
Spandrels, Exaptation and
Specific Immunity
Gustavo C. Ramos a
Nelson M. Vaz c
Kay Saalfeld b
a
Departamento de Farmacologia and b Departamento de Ecologia e Zoologia, UFSC,
Florianópolis, Brazil
c
Departamento de Bioquímica e Imunologia, UFMG, Belo Horizonte, Brazil
Key Words
Evolution Immunology Adaptation Exaptation Spandrels
Abstract
The evolution of the immune system of jawed vertebrates with its vast array of
clonally expressed lymphocyte receptors is usually viewed as optimized for the
defense of the organism. There is a clear association between neo-Darwinism,
the dominant view in current biology, and the usual description of immunological activity as adaptive immunity. Herein, using the concepts of spandrels
and exaptation created by Gould and coworkers, we review data from comparative immunology and claim that the immune system was not formed as a
system optimized for the defense of the organism, but rather may be viewed as
a spandrel, a consequence of processes not originally linked to interactions with
foreign materials.
Copyright © 2006 S. Karger AG, Basel
Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2006 S. Karger AG, Basel
1424–8492/06/0034–0211
$23.50/0
Accessible online at:
www.karger.com/cpu
Gustavo Campos Ramos, Departamento de Farmacologia,
Centro de Ciências Biológicas, Bloco ‘D’, Caixa Postal 476,
Universidade Federal de Santa Catarina,
Trindade, Florianópolis, SC 88049-900 (Brazil)
Tel. +55 48 3331 9491, ext. 216, Fax +55 48 3337 5479
E-Mail ramosgc@farmaco.ufsc.br
Over the last century, a way of seeing
the world based on neo-Darwinism became so strong that it is now considered
as a fact and an a priori condition for biological thinking. This way of seeing the
world, based on adaptations and functions, which was called the adaptationist
program by Gould and Lewontin [1], has
guided the conduction of biological and
medical research and teaching, and oriented whole branches of medical endeavor. Modern immunology is a good example of this influence [2].
From the late 1950s, immunology has
been based on and corroborated by neoDarwinian concepts, which it also helps
to support. In neo-Darwinian (Burnetian) immunology [3], an ‘immune
system’, the main function of which is the
defense of the organism, is viewed as a
pool of isolated lymphocyte clones unconnected from each other and from
body components. This approach has
been very important in understanding
many features of immunological phenomena, but many others remain unsolved, such as autoimmunity.
Herein, we propose that, due to the
strong association between neo-Darwinism and Burnetian immunology, important alterations in immunological thinking require the uprooting of its neo-Darwinian fundaments. In attempting to do
this, we apply to immunology concepts
and metaphors proposed by Gould and
coauthors [1, 4] that contradict the adaptationist program. The main implication
of this initiative is to suggest the adoption
of research programs based on the structure and organization of living systems
rather than on their functions or their
ability to compete, as is currently the
norm.
The Adaptationist Program
The adaptationist program assumes
that the organism, in its changes, follows chan ges in its medium and that
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ORIGINAL RESEARCH PAPER
212
seen in neo-Darwinism. For example,
El-Hani and Emmeche [8] say:
‘Change arises out of an external process of
sorting (natural selection) and, according to this
point of view, assumptions about causal agency
within organisms are unnecessary. Selection becomes merely an external force. Mutation is the
inner force that creates variation, but this force
is random and, thus, without connections to the
needs of the organism and its functions. The organism becomes a passive meeting point of forces alien to the very organism. The irony is that
the organism becomes irrelevant to evolutionary
biology, merely a medium where the outer selective force meets with the inner producer of variation. This may bring along a tendency to reify
the living organism as a mere passive thing.’
For the majority of scientists, neoDarwinism (the synthetic theory of evolution) is consolidated as a fact and is the
only way to contemplate living systems.
However, the theory has serious problems. In brief:
ism and its form are generated, rather
than simply with the constitution of a
particular kind of molecules. This consideration becomes clear in the words of
Waddington [see 11]: ‘Changes in genotypes only have ostensible effects in evolution if they bring with them alterations
in the epigenetic processes by which phenotypes come into being; the kinds of
change possible in the adult form of an
animal are limited to the possible alterations in the epigenetic system by which it
is produced.’
(2) Biological Information Is Not
Specified neither Solely in Nucleic
Acid Structure nor in Any Other
Component of Biological Systems
Kimura [9] demonstrated in his neutralist theory that the relation between
genotype and phenotype is wider than it
was assumed by the neo-Darwinist tradition, by showing that molecular evolution and the evolution of form are separate phenomena. For example, mutation
rates of different species are rather constant according to the molecule studied
and the time range. Species that are considered as living fossils (e.g., sharks), and
which, therefore, should carry fewer mutations (since they changed less over
time), display mutation rates very similar
to any other species, when certain loci are
studied [9].
Furthermore, this problem regarding
genotype/phenotype relation has also
been extensively discussed by developmental biologists [10–12]. An important
aspect of developmental approaches is
the preoccupation with how the organ-
In neo-Darwinism, all biological information is assumed to be specified in
the genes. Thus, studying evolution
would amount to understanding the
fluctuation of genotypic frequencies in
populations throughout their lives.
These ideas have been extensively discussed by many authors [see 13, for a
lucid summary]. A well-known example
which contradicts genetic determinism
is the experience of Kollar and Fisher
[14], which deals with hen’s teeth. Birds
are toothless and it is generally agreed
that they do not have genes for teeth.
However, experiments in which grafts of
chick epithelium combined with mouse
molar mesenchyme produced a variety
of dental structures. In other words, the
formation of teeth is not determined
only by the nuclear content, but rather
depends on the developmental context
[discussed in 15]. Oyama [12] also presents important reflections concerning
this issue. This author points out that an
organism’s nature – the characteristics
that define it at a given time – is not a
genetic program or plan causing development, but a product of development.
Thus, Oyama [12] argues that nature is
not transmitted, but constructed, and
what passes from one generation to the
Complexus 2006;3:211–216
Exaptive Immunity
(1) The Genotype/Phenotype
Relation Is neither Simple nor
Direct
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natural selection determines practically
all organic forms, functions and behaviors. The organism becomes a set of individualized structures (traits), each
one of which performs actions that were
optimized by natural selection, with a
specific function [1]. This teleological,
functionalist view focuses mainly on
understanding function; the structure
and organization of living systems becomes a secondary issue. Gould and Lewontin [1] and Gould and Vrba [4] challenged this dominant adaptationist
(functionalist) program by introducing
two new concepts: spandrels and exaptation, to indicate ‘characters which are
constructed and are useful in virtue of
their internal organization and structure, rather than by a process of natural
selection’.
A clear example of exaptation is the
relation between feathers, wings and
flying. Bird feathers and wings have always been seen as adapted for flying.
Obviously, they make flying possible,
but since feathers were already present
in nonflying small theropod dinosaurs
[5], possibly involved in thermal insulation, they can no longer be seen as adaptations for flying. The relation between wings and flying in insects also
appears to be exapted from aquatic surface skimming [6].
The importance of the concepts of exaptation and spandrels is in indicating
that the adaptationist program may explain some evolutionary patterns but is
neither sufficient, nor necessary to the
understanding of evolutionary processes [7].
By being generated at random and either activated and expanded by external
antigens (immunity), or inhibited (suppressed, regulated) by body components (natural tolerance), the ‘immune
system’ has no predictable form (organization) of its own and becomes a passive meeting point of external forces.
This is exactly the way the organism is
Ramos /Vaz /Saalfeld
Complexus 2006;3:211–216
(3) In General, Evolution Is neither
Slow nor Gradual
Eldredge and Gould [16] in their theory of punctuated equilibrium stress that
evolution of form is neither slow nor
gradual. They argue that evolution includes long periods of stasis, with few
morphological changes (in spite of constant mutation rates), which are interrupted by short periods of intense morphological change, which are ‘punctual’
on a geologic time scale. This is supported by the fossil record, in which there are
virtually no intermediary forms between
species [reviewed by Gould and Eldredge,
17]. If evolution were a slow and gradual
process of transformations, the fossil record should be expected to contain innumerable intermediate species.
Gould’s Approach: The
Spandrels of San Marco and
Exaptations
According to Gould [18], the differentiation between an adaptive and an exaptive characteristic can be made based on
the historic order of emergence of a certain characteristic and then one may observe whether its current utility arose together with the historic origin or a posteriori. Utility arising a posteriori signals
an exaptation. Therefore, this inference
can be made based on the fossil record in
a phylogenic context. We suggest that
comparative immunology offers other
examples of exaptation.
Comparative Immunology
In comparative immunology, critical
points in the development of the immune
system are: the emergence of the MHC
(major histocompatibility complex), and
of molecules containing variable regions
generated somatically: immunoglobulins (BCR or Ig) and T cell receptors
(TCR) and also of a unique process of receptor diversification [19]. Both BCRs
and TCRs are formed in somatic processes of rearrangement of two or three gene
segments, which transcribe variable (V),
junctional (J) and diversity (D) regions,
which are then joined to a constant (C)
region. In this process, variations may
also occur on the exact point of section of
the genetic elements, creating further diversity. Moreover, extra nucleotides are
added in the junctions of genetic elements, generating the so-called N regions. These processes of gene rearrangement and the subsequent process of polypeptide chain pairing to form the
complete receptors are potentially able to
generate an immense diversity of clonally expressed receptors individually expressed on lymphocytes [20].
In the processes of gene rearrangement, two recombinases known as recombination activating gene (RAG),
RAG1 and RAG2, play a crucial role.
These two enzymes are found only in
jawed vertebrates and their emergence in
phylogeny coincides with that of adaptive
213
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In what is now a classic paper on discussions about evolution, Gould and
Lewontin [1] used an example from architecture to demonstrate the preponderance of structural features over functional interpretations. Inverted triangular structures may result from building
arches to support the ceiling. In the Saint
Mark’s Basilica, in Venice, these inverted
triangles are covered with mosaic figures
so elaborate and harmonious that one
may be led to believe that these works of
art are the reason for the surrounding architecture. However, there is an inversion
in this reasoning. The primary construction plan of the building included, but
did not aim at, the generation of large inverted triangles which were later decorated with colorful mosaics: the triangles
inevitably arose from building the supporting arches.
In architecture and art these structures that arise a posteriori are called
spandrels, i.e., a spandrel is a structure
that is formed as a consequence of previous architectonic structures, and not as
the primary intention. Gould and Lewontin [1] suggested that spandrels may
be used as metaphors for biological structures, that is things that ‘design the physical properties – form, position, constitution and number – which must arise as
inevitable consequences of primary reasons or alterations in complex structures’.
A few years later, Gould and Vrba [4]
introduced another new concept into
evolutionary biology, exaptation, which
is related to the concept of spandrels and
which provokes a reevaluation on the
use of the term adaptation. These authors argue that the word adaptation has
a clear teleologic connotation: ad + aptus – in the direction of an aptitude. Inside the neo-Darwinian perspective,
this teleology is explicable by the selective pressures that guide evolution in
the direction of the fittest. However, to
see every useful trait as ‘adapted’ reinforces the adaptationist program and
hinders the consideration of other possibilities. Therefore, Gould and Vrba [4]
separate ‘adaptation’ – those characteristics built by selection for a defined
function – from exaptation – those
characteristics which are not built by selection, but are useful for their effects.
The major implication of the term exaptation is to refute the functionalism essential in biological thinking. Gould
and Vrba [4] end their paper on exaptation stating that the time and frequency
of observed exaptations will confirm
whether this term will become relevant.
The identification and discussion of
examples of exaptation in immunology
will have the double meaning of subsidizing the importance of the concept of
spandrels and to uproot the strong association between immunology and
neo-Darwinism.
next is an entire developmental system,
not only genes.
214
transfer, a nondirected form of evolution,
has proven to be a wider phenomenon,
leading Brosius [23] to put forward the
idea that ‘Genomes were forged by massive bombardments with retroelements
and retrosequences.’ Among the several
characteristics of mammalian organisms
acquired by horizontal transfer, one of
the most dramatic is that related to syncytin, an important mediator in mammalian placenta morphogenesis, which
was identified as a retroviral envelope
protein [24].
Another interesting issue is the regulation of the expression of RAG genes.
The gene responsible for the activation of
these recombinases was found in Amphioxus (Cephalochordata), a member of a
close group of organisms that received
the microbial genes [25]. Unless it is assumed that these genes were already ‘predicting and waiting’ for the insertion of a
viral gene, it seems quite clear that this
loop of gene activation also represents an
exaptive phenomenon, devoid of intentionality (directionality).
This exaptation of viral integrases into
recombinases in vertebrate organisms
seems to coincide with an important period in the evolution of adaptive immunity. The emergence of adaptive immunity is intriguing because instead of a
slow and gradual evolution, it arose ‘as a
big bang’ [26]. In the words of Bartl et al.
[20]: ‘In conclusion, at this time adaptive
immunity appears to have evolved ‘‘with
a bang’’ or all at once in an ancestor of the
jawed vertebrates with all components
appearing out of nowhere.’
This sudden emergence, as well as
many data from comparative biology of
immune systems, seem to demonstrate
two aspects: first, that this is an exaptive
condition; second, that it is an outstanding example of Gould and Eldredge’s
punctuated equilibrium. To argue in favor of this punctual event in the genesis
of the immune system, we must examine
the time scales on which these processes
took place. The first vertebrates appeared
approximately at 525 million years ago. It
is estimated that those organisms had no
lymphocytes, nor any functional component of adaptive immunity [19]. At about
450 million years ago, there was a separation of taxa forming the jawless (Agnatha) and the jawed (Gnatostomatha)
vertebrates. Living representatives of Agnatha are the lampreys, which have no
lymphocytes, but have recently been
shown to generate a diversified repertoire of receptors based on lysine repeats
[27, 28]. On the other hand, all the living
jawed vertebrates, including cartilaginous fish (sharks, rays and kin), bony fish
and other groups that evolved from them,
display an adaptive immune system.
Thus, it is assumed that the lymphocytic
system must have arisen at a point after
the split between jawless and jawed fish.
Also, as the system is present in cartilaginous and bony fish, it is accepted it was
formed before this separation. And this
is the curious thing: the period between
the formation of jaws and the separation
between cartilaginous and bony fish is
extremely short (punctual, in geologic
time units) and presents no intermediate
forms. Furthermore, after its inception,
approximately 450 million years ago, the
system remained practically unaltered,
corresponding to a period of stasis, as
posited in the theory of punctuated equilibrium.
It is not our purpose to describe in detail the evolution of the immune system,
but rather to emphasize that this evolution was not driven by selective pressures, and the immune system was not
formed as a system optimized for the defense of anti-infectious the organism.
The suggestion of a nondirective exaptive
emergence of the process of diversification of lymphocyte receptors implies that
immunological defense is an exaptation
that corroborates the theory of punctuated equilibrium. Rinkevich [29] also refutes the idea of a pathogen-directed
Complexus 2006;3:211–216
Exaptive Immunity
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immunity. In spite of many efforts, it has
been impossible to find phylogenetic relations between these recombinases with
other molecules present in ancestor animal lineages, as would be necessary to
indicate a slow and gradual process culminating in the current processes of gene
rearrangement. The genes coding for
these recombinases seem to have been
acquired by horizontal transmission –
directly from the genome of a microorganism or a virus to the genome of a
jawed ancestor vertebrate [21]. The main
facts corroborating this hypothesis are:
(1) Despite many attempts, molecules
showing homology to RAG1 and RAG2
have not been found in multicellular organisms out of the group of jawed vertebrates.
(2) Microbial integrases and integration host factors present high homology
to RAG1 and RAG2, respectively.
(3) These RAG genes resemble those
of microbes in lacking introns.
(4) The spacer segment between RAG
1 and RAG 2 contains defective pieces of
retroposons.
(5) Constructs consisting of RAG1 and
RAG2 may act as transposons [22].
These data strongly suggest an exaptive character in the evolution of the process of lymphocyte clonal receptor diversification. In other words, these genes
were not initially adapted to optimize
host defense mechanisms: they originated in the context of a different structural
dynamics, derived from a microorganism or a virus, participating in nonimmunological processes, such as the integration of viral DNA to the genome of
other cells. In a fortuitous punctual moment of evolution, these genes were integrated into the genome of a jawed ancestor vertebrate and this became part of the
evolution of its genome. This is quite different from imagining selective pressures in the generation of a diversified
repertoire of receptors aimed at antiinfectious defense. Horizontal genetic
Ramos /Vaz /Saalfeld
Concluding Remarks
There is a series of exaptive events in
the evolution of the immunological activity which are not consistent with the
idea of a system adapted for defensive
functions of the organism. Therefore, it is
misleading to present anti-infectious defense as the main reason guiding the evolution of immune systems. We argue that
immunological defense is a possible result of what takes place, not a mechanism
driving what takes place – a commentary
that says nothing about the systems involved in its generation, or, in the words
of Atlan and Cohen [34]: ‘danger, like
self-nonself, is a human’s teleological interpretation of what evolution ought to
be doing’. Accepting that this is so opens
the possibility for different questions and
approaches in immunology, and argues
for the rupture of the conceptual knot between immunology and neo-Darwinism
(functionalism). Data from comparative
immunology support the idea of an exaptive (non-pathogen-instructed) phylogenic drift of the lymphocytic system instead of an evolution adapted for defensive functions. Furthermore, seeing the
immune network as a spandrel allows us
to focus the attention on the organization
and structure of the immune system and
its insertion in the organism. Although
an alternative theory is not proposed, the
application of Gould’s terminology to immunology, as in evolutionary biology, demands abandoning the functionalist notions of neo-Darwinism.
Acknowledgments
We are grateful for having received suggestions from and having discussed central aspects
of this manuscript with Dr. Jorge Mpodozis,
Dr. Francisco Botelho and Dr. Evelyn Fox Keller.
This study was supported by the CNPq-Brasil
grant 30.5043/2003-0 to N. Vaz.
Complexus 2006;3:211–216
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