The brain: a concept in flux

Oné R. Pagán
royalsocietypublishing.org/journal/rstb
Department of Biology, West Chester University, West Chester, PA 19383, USA
ORP, 0000-0001-8232-7346

Review
Cite this article: Pagán OR. 2019 The brain: a
concept in flux. Phil. Trans. R. Soc. B 374:
20180383.
http://dx.doi.org/10.1098/rstb.2018.0383
Accepted: 8 March 2019
One contribution of 15 to a theme issue ‘Liquid
brains, solid brains: How distributed cognitive
architectures process information’.
Subject Areas:
neuroscience, behaviour, cognition
Keywords:
brain, vertebrates, invertebrates, planaria,
nervous system, plants
One of the most important aspects of the scientific endeavour is the definition
of specific concepts as precisely as possible. However, it is also important not
to lose sight of two facts: (i) we divide the study of nature into manageable
parts in order to better understand it owing to our limited cognitive capacities
and (ii) definitions are inherently arbitrary and heavily influenced by cultural
norms, language, the current political climate, and even personal preferences,
among many other factors. As a consequence of these facts, clear-cut defi-
nitions, despite their evident importance, are oftentimes quite difficult to
formulate. One of the most illustrative examples about the difficulty of articu-
lating precise scientific definitions is trying to define the concept of a brain.
Even though the current thinking about the brain is beginning to take into
account a variety of organisms, a vertebrocentric bias still tends to dominate
the scientific discourse about this concept. Here I will briefly explore the evol-
ution of our ‘thoughts about the brain’, highlighting the difficulty of
constructing a universally (or even a generally) accepted formal definition
of it and using planarians as one of the earliest examples of organisms pro-
posed to possess a ‘traditional’, vertebrate-style brain. I also suggest that
the time is right to attempt to expand our view of what a brain is, going
beyond exclusively structural and taxa-specific criteria. Thus, I propose a
classification that could represent a starting point in an effort to expand
our current definitions of the brain, hopefully to help initiate conversations
leading to changes of perspective on how we think about this concept.
This article is part of the theme issue ‘Liquid brains, solid brains: How
distributed cognitive architectures process information’.

Author for correspondence:

Oné R. Pagán The difference in mind between man and the higher animals, great as it is, certainly is
e-mail: opagan@wcupa.edu one of degree and not of kind.
—Charles Darwin
To extend our understanding of neural function to the most complex human physio-
logical and psychological activities, it is essential that we first generate a clear and
accurate view of the structure of the relevant centers, and of the human brain itself,
so that the basic plan—the overview—can be grasped in the blink of an eye.
—Santiago Ramón y Cajal

1. Definitions
A built-in aspect of the scientific outlook is that we scientists are enthusiastic nit-
pickers, who oftentimes take pleasure in finding small inconsistencies and
exceptions that will lead to reconsiderations and even in some cases complete
reformulations of established scientific definitions. As we define, refine, reconsi-
der and reformulate the ideas pertaining to a particular concept, we have a good
chance of gaining profound insights that we would not be able to obtain other-
wise. The fluidity of definitions is their main strength, because this flexibility is
one of the most important factors that allow science to grow. An excellent
example of this conceptual refinement is the process of trying to define the brain.

2. The idea of a brain

It stands to reason that ancient humans must have had an acute—albeit indir-
ect—understanding of the importance of the brain, as it is undoubtable that

& 2019 The Author(s) Published by the Royal Society. All rights reserved.
such knowledge would give our ancestors a survival advan-
tage. For example, they would have been acutely aware that a
head injury would be the surest way to kill an animal or an
enemy. It also stands to reason that they would have
known of the specific effects of injuries on particular parts
of their own heads. Alas, any practical knowledge on this
matter that our ancestors might have accumulated over the
millennia was lost until humans began to leave written
records. It is widely believed that the first written repository
of such knowledge came to us via the ancient Egyptians.
Probably the earliest explicit reference to the human brain
is found in an unnamed papyrus from about 6000 years
ago [1], however, the best-known early instance of a written
record about the human brain and what happens to it
when disturbed is found in the Edwin Smith Papyrus. This is
a 3500 year old document (likely a copy from an earlier
source) usually recognized as the first formal text on
trauma medicine [2]. This papyrus described in detail injuries
caused by industrial accidents or as a consequence of battle,
and established the first written example of treatment priori-
ties (i.e. by classifying the injuries as ‘treatable’, ‘probably
treatable’ or ‘untreatable’), articulating the basics of modern
medical triage protocols. Most importantly for the purposes
of this review, in this papyrus we also find what is probably
the first written word explicitly meaning ‘brain’ (figure 1).
This document also describes, among many other types of
injuries, the undesirable effects of head injuries. Strangely,
despite their evident knowledge of the importance of the
integrity of the brain in terms of bodily function, the ancient
Egyptians did not seem to consider the brain worthy of pres-
ervation during their burial practices, as opposed to the heart,
which was carefully preserved in mummification procedures
(for a more detailed exposition of this topic please see [3],
chapter 4). Over time, our knowledge—as well as the
interpretation of such knowledge—about the human brain
evolved into Aristotle’s dual brain concept, which defined
the brain as consisting of the encephalon (or proper brain)
and parencephalon (roughly, the cerebellum). An implicit
assumption of Aristotle’s view is that brains were part of
the anatomy of vertebrate animals. Thus, historically, the
way we thought of the brain and nervous system—not sur-
prisingly owing to Aristotle’s influence—was in the light of
vertebrate organisms.
3. To define a brain
Thinking about the brain from the ‘vertebrocentric’ point of
view [4] dictated the early discourse about its nature. This
frame of mind was the basis of the formulation of several theo-
ries of brain architecture [5,6] which described the vertebrate
brain in purely structural terms. The eventual sophistication
of anatomical knowledge gave rise to the idea of segmental
organization, which divided the brain into 10 structurally
discrete parts: cerebral cortex, basal ganglia, thalamus,
hypothalamus, tectum, tegmentum, pons, medulla, cerebel-
lum and the spinal cord [5,6]. The segmental organization
concept was refined by studying the ontogenetic (develop-
mental) origin of the aforementioned parts alongside their
phylogenetic (evolutionary) history. At this developmental/
evolutionary point, this integration explicitly acknowledged
the importance of ‘lower organisms’ in this story and conse-
quently, neuroscientists began to cautiously wander away
2
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Figure 1. Possibly the earliest known instance of the word brain in a written
language: Ancient Egyptian hieroglyphics. As modified from Pagán [3].
Illustration by Alexis G. Pagán.
Phil. Trans. R. Soc. B 374: 20180383
from a pure vertebrocentric view. Eventually, with the
advent of the molecular biology revolution, genomics began
to provide unique molecular insights into the above classifi-
cations. It is important to point out that since these theories
were purely based on structural properties, they did not
touch upon the function of such structures or upon any emer-
gent properties (consciousness as a premier example) that
might arise when these parts worked together. The study of
such integration would come later as part of the study of
the brain as a complex system.
At the point in time when scientists initiated the first
efforts to systematically define a brain, functional consider-
ations began to be taken into account in a more prominent
way. In this sense, a brain was defined as an organ acting
as the control hub of the nervous system in animals display-
ing cephalization. This definition implied that a brain must be
located within the head of the animal. Further along, this
definition was refined by stating that the brain is the organ
tasked with the generation of processes like memory, motiv-
ation, thought and consciousness. As usually occurs in
science, this refinement generated more questions; a case in
point: consciousness. Defining consciousness is as diffi-
cult—likely even more difficult—as defining the term
‘brain’ itself. Alas, consciousness is a topic beyond the
scope of this review.
4. An early effort to define the brain beyond the
vertebrate paradigm
Approximately in the mid-twentieth century, neuroscientists
began to think about the brain out of the proverbial
‘animal-centric’ box. More recently, as a result of certain
interesting discoveries, some scholars are tentatively includ-
ing microorganisms and plants in their thoughts about the
brain, a trend that as we shall see, is currently under intense
debate.
As we discussed, the original approach to answer the
question ‘What is a brain?’ was built on three main aspects:
(i) a purely structural approach, (ii) a vertebrocentric perspec-
tive, and (iii) a precise identification of what kind of
vertebrate we would be referring to. Soon enough, scientists
expanded their thoughts about the brain by including func-
tion in light of structural features and information about
developmental and evolutionary origins. Probably one of
the first explicit efforts that tried to come up with a wide
enough definition of a ‘brain’ in order to be useful to a variety
of scientists appeared in the paper: ‘What is a brain and who
said so?’, a semi-satirical yet remarkably well-thought paper
published in 1986 in the British Medical Journal by the late
Dr Martin George Netsky [7]. In this paper Dr Netsky pre-
sented an insightful and quite entertaining examination of
the multiple meanings that the word ‘brain’ can take, and I
believe that its main message is still valid today, at least in
principle. The main thesis of Dr Netsky’s paper was to
make the point that articulating a comprehensive, purely
structural definition of a ‘brain’ is bound to be rather difficult
or even impossible, at least in a way universally accepted by
the general scientific community. In these lines, Dr Netsky
proposed that a proper definition of a brain would include
aspects of structure and function integrated with mechanistic
explanations of how a brain would generate its multiple func-
tions. Some of these functions include but are not limited to,
the detection of environmental signals, the processing and
interpretation of these signals in order to generate behaviours
(ideally, from an evolutionary perspective, these behaviours
would enhance the survival chances of an individual).
Finally, other functional aspects of a brain must include learn-
ing and memory processes in order to make use of the
interpretation of such signals to better cope with future
environmental challenges. Additionally, Dr Netsky stated
that any proposed definition of the term ‘brain’ should address
questions like whether brain convolutions are essential to its
function (in fact, they are not; many vertebrate species lack
brain convolutions with no apparent disadvantages; case in
point: birds).
As a self-professed lexicophile (a dictionary enthusiast),
Dr Netsky explored a plethora of published definitions of a
brain and found all of them lacking, since these definitions
overwhelmingly focused on purely anatomical criteria. In
his words, all of these structurally-oriented definitions
merely described ‘. . . a dead brain’.
Dr Netsky’s idea emphasized that a working knowledge
of the differences between ganglia and nuclei in a neurobio-
logical context is absolutely necessary in order to truly
understand the brain. Nervous systems are assemblages com-
posed of collections of neurons that work closely with each
other to perform specific functions. A group of closely
located/interacting nerve cells is arbitrarily defined as a
ganglion ( plural: ganglia) when it is located outside of a cen-
tral nervous system and as a nucleus ( plural: nuclei) when
located within the central nervous system. The distinction
between ganglia and nuclei is not absolute and is therefore
a source of some confusion, since neuroanatomists came up
with the ganglia and nuclei designations long after some
parts of the human brain were named and described. For
example, there are parts of the mammalian central nervous
system like the aforementioned basal ganglia that are
involved in important functions such as motor control and
motor learning, executive functions like impulse control
and mental flexibility, as well as the generation of emotions,
among many other functions [8–10]. Since the basal ganglia
are located within the confines of the central nervous
system, technically, they should be called basal nuclei (and
they are increasingly called that in recent works).
It is evident that one of the main influences on Dr Netsky’s
ideas about the brain was his interest on the evolution of ner-
vous systems. In fact, Dr Netsky and a colleague, Dr Harvey
B. Sarnat, wrote one of the seminal books on this topic [11].
According to Dr Netsky the ‘origin story’ of his ‘What is a
brain and who said so?’ paper began when he and Dr 3
Sarnat submitted a review paper exploring some ideas on
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the evolution of the human brain. They proposed that the
aforementioned delineation of a clear distinction between a
ganglion and a proper brain is essential to formalize a
proper definition. Basically, they argued against the—at the
time—standard designation of invertebrate central nervous
tissue structures as ‘cephalic ganglia’. This designation is
still sometimes used even though all available evidence indi-
cates that such nerve conglomerates serve as the control
centre of the organism; in other words, an actual, bona fide,
brain. Sarnat and Netsky’s point of contention was that a
ganglion and a brain are fundamentally distinct entities,
meaning that a ganglion, however large, can never develop-
Phil. Trans. R. Soc. B 374: 20180383
mentally transition into a brain. In these lines, they could
not find any examples of this transition; in every example
that they explored, a ganglion seems to remain a ganglion
however big it would get. Their chosen example to illustrate
the point was the well-known fact that certain dinosaur
species displayed an enlarged lumbosacral ganglion, which
actually was several times larger than the actual dinosaurian
brain (this ganglion was colloquially called a second brain).
They—I think correctly—argued that it was highly unlikely
that this ‘hyperdeveloped’ dinosaurial ganglion endowed
the organism with additional cognitive abilities. Upon sub-
mission, their paper was peer-reviewed by several
invertebrate zoologists who oddly enough, took emphatic
exception to the idea of an ‘invertebrate brain’, and in no
uncertain terms advised Drs Netsky and Sarnat to abandon
the concept of an invertebrate brain. Happily, they did not,
and their paper was eventually published [12].
In the end, in his 1986 review paper Dr Netsky proposed
the following definition, explicitly referring to vertebrate
brains:
. . .that part of the central nervous system in the skull; connected
to the spinal cord; the seat of sense, motion, thought, and of
human speech; comprising two contiguous hemispheres con-
nected by commissures; a cortex of neurons, the gray matter,
surrounds both white matter and various subcortical neuronal
clusters. [7, p. 1672].
Nonetheless, in a subsequent paper, Sarnat & Netsky [12]
listed a series of structural and functional characteristics
between ganglia and brains that established them as funda-
mentally distinct entities. In the end they concluded that: (i)
no known animal possesses a cephalic ganglion, (ii) develop-
mentally, the human brain does not start as a ganglion, and
(iii) therefore, a ganglion never becomes an actual brain.
Thus, a crucial point would be to estimate when the brain
as an established structure appears within the context of
the evolutionary history of animals [13].
5. The first brain
Planarians (figure 2) include several hundred non-parasitic
flatworm species belonging to the phylum Platyhelminthes.
These organisms are broadly classified according to their
habitat; planarians occupy freshwater, marine, and terrestrial
ecological niches [14]. The best-understood group of these
worms is the freshwater type, particularly the ones belonging
to the family Dugesiidae, which includes the genera Girardia,
Dugesia and Schmidtea, comprising more than one
hundred formally described species [15]. The most striking
characteristic of many of these planarian species is their
remarkable capacity for regeneration [16,17]. As an example

Phagocata
gracilis
Girardia
tigrina
Figure 2. Representative planarian species, as indicated. The scale bar rep-
resents a length of 1 cm. (Online version in colour.)
of their regeneration abilities, one of the species most adept at
this process, Girardia dorotocephala, only requires a fragment of
about 0.08 mm3, the equivalent of approximately 10 000 cells,
to achieve complete body regeneration [18–20]. As if this fact
was not remarkable enough, the regeneration capabilities of
some planarian species include the complete and correct recon-
stitution of their nervous tissue, including their brain [21–24].
It is difficult to overstate the potential relevance of these organ-
isms’ regenerative abilities for the possible development of
medical treatments for neurological diseases and injures. Inter-
estingly, there is also mounting evidence that decapitated
planarians that regenerate their heads partially retain some
learned habits or training acquired prior to the decapitation
event, a fact that is particularly relevant to the exploration of
where memories are stored in an organism [25–27].
In the process of developing their ideas about the brain,
Sarnat and Netsky proposed as a working hypothesis that the
planarian brain could be seen as a precursor of the human
brain. In other words, they essentially proposed that the planar-
ian brain was the first evolutionary example of a vertebrate-
style brain. They were very careful to explicitly state that
there was no evidence that planarians were in a direct line lead-
ing to vertebrates, and rightly so, since today we know that they
actually are not. Nonetheless, the planarian and vertebrate
brains at the very least represent a curious example of conver-
gent evolution. Eventually, the planarian brain evolved into
an important model in the neurosciences. Additionally, it has
been recently acknowledged that the usefulness of planarians
in biomedical research goes beyond developmental biology
and regeneration. Planarians are being developed as an
animal model in the pharmacological sciences with exciting
results especially in light of neuropharmacology and the
pharmacology of abused drugs [28–31].
Even though planarians are not in the direct line leading
to chordates, their nervous system exhibits remarkable simi-
larities to vertebrate nervous systems. These parallels range
from their molecular characteristics all the way to morpho-
logical features. For example, virtually all described
flatworms species, including planarians, make use of many
of the same neurotransmitter systems as vertebrates do
4
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Phil. Trans. R. Soc. B 374: 20180383
Figure 3. A simplified representation of the D. japonica brain, showing its
nine pairs of nerve extensions. As modified from Pagán [3]. Illustration by
Alexis G. Pagán.
[28,31]. Planarian nerve cells also display a fair degree of
synaptic complexity in terms of the number and concen-
tration of different neurotransmitters within their synaptic
vesicles, as well as neuronal morphology that is more remi-
niscent of vertebrates than invertebrates [12,13]. A
particularly curious aspect of the planarian neuronal architec-
ture is the presence of dendritic spines. These structures are
widely distributed throughout the animal kingdom but are
most commonly found in vertebrate organisms [32,33].
Dendritic spines are important regulators of synaptic func-
tion, especially neuronal plasticity and memory formation
[34 –36]. Interestingly, even though the most common type
of invertebrate dendritic spines are the ones found in insects,
the planarian dendritic spines are more similar to the ones
found in vertebrate organisms [12,13,37].
The idea of the planarian brain as an anatomical forerun-
ner of the vertebrate brain relies heavily on gross anatomical
features. First, the typical planarian brain consists of two
distinct sections, which is strongly reminiscent of the well-
known dual vertebrate brain structure with its well-defined
lobes. Moreover, these lobes display projections that seem
analogous to vertebrate cranial nerves. The best characterized
planarian species in this regard, Dugesia japonica [38], pos-
sesses nine such pairs of nerve extensions (figure 3). In
contrast with the vertebrate nervous system in which a
single spinal cord connects to the two brain hemispheres, pla-
narians have two nerve cords, one from each lobe.
Interestingly, the planarian nerve cords are connected by
additional nerve fibres, giving them their characteristic
ladder-like appearance (figure 4; for an extended discussion
of the planarian nervous system please see [3], chapter 9).
6. The—real—first brain (s)
The point of view stating that the planarian brain is a true
representative of what ‘the first brain’ must have looked like
is an interesting starting point to try to gain insights on ver-
tebrate nervous systems. However, it must be pointed out
that planarians are not the most basal animals [39,40], meaning
that they cannot be the absolute first example of a brain,
broadly defined. Current ideas about the phylogeny of animals
are also in flux; this field is undergoing a minor controversy in
specialized circles. In brief, traditionally, sponges were widely
considered as the most primitive animals, defined in part by

Figure 4. Side-by-side comparison of the human and planarian central ner-
vous systems. The bar represents approximately 1 m for the drawing of a
human and 1 cm for the planarian diagram. As modified from Pagán [3].
Illustrations by Alexis G. Pagán.
the lack of an unambiguously recognizable nervous system
[41,42]. However, there is convincing evidence indicating that
the phylogenetic lineages leading to sponges and other ‘primi-
tive’ animals did possess an actual nervous system that was lost
along the course of evolution [43]. All animals possess an
unambiguously recognizable nervous system, with the poss-
ible exception of sponges. Sponges are filter feeders;
however, there are some notable exceptions: at least four
species of carnivorous sponges actively capture prey in a way
curiously reminiscent of certain carnivorous plants [44]. Preda-
tion in these sponge species appeared to have evolved only
once and it is not clear whether these sponges possess bona
fide nerve cells. However, some lines of evidence indicate the
presence of relatively sophisticated sensory cells in certain
sponge species, as well as complex gene networks related to
sensory functions in these organisms [42,45].
More recently, molecular data seems to indicate that cte-
nophores ( jellyfish-like active predatory organisms) and
sponges are ‘equally basal’, which as a first approximation
is unlikely owing to the marked differences in their morpho-
logical and physiological complexity [46]. Recent reviews of
the evidence for each position (i.e. sponges first, ctenophores
first, or both equally basal) expresses the idea that even
though both positions are plausible, there is no conclusive
evidence to make a concrete ruling on this matter [47–49].
Clearly, additional data is needed to figure out the most
likely candidate of an Urmetazoan (the last common ancestor
of all metazoans)-like animal, and therefore the question
about the first ‘true’ brain is still an open one. Regardless of
the type of animal that ends being the best candidate for an
Urmetazoan-like organism, the reality is that there are
many organisms that do not possess an obvious ‘brain’ yet
are nonetheless capable of performing many of the functions
traditionally attributed to this interesting organ.
A fair working definition of a brain is ‘the control centre of
a biological system’. Planarians (see above) represent some of
the earliest organisms displaying cephalization and bilateral 5
symmetry, a property which is directly related to a centralized
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nervous system and therefore, by definition, planarians have
an obvious control centre [50]. However, let us not forget
that there are many organisms that have a nervous system
but no obvious centralization. These types of organisms not
only survive but are also quite successful. At any rate, the fun-
damental unit of every nervous system known so far is the
neuron. Interestingly, it seems that the evolutionary origin
of neurons—an event that happened approximately 500
million years ago—coincided with the initiation of hostilities
between animal species for nutritional purposes. In other
words, neurons appeared shortly before animals began
pursuing and eating each other [51]. Incidentally, this infor-
Phil. Trans. R. Soc. B 374: 20180383
mation will likely play a role in the sponges-ctenophores
controversy (see above), as ctenophores are true preda-
tors, a characterization that tends to indicate a relatively
sophisticated nervous system.
It seems that the simplest organisms that evolved ‘true’
nervous systems are the cnidarians (hydra, jellyfish, and
related organisms; [52 –54]). The lack of cephalization dis-
played in the architecture of the nervous systems of
cnidarians seems to be a direct outcome of their radial sym-
metry [54]. An interesting particularity of the cnidarian
nervous system is that ganglia are conspicuously absent
[55]. This fact is consistent with the current consensus
suggesting that the appearance of ganglia is a hallmark of
nervous system centralization, as opposed to the distributed
nervous systems in cnidarians and related organisms [55].
The most numerous type of animals on earth, the arthro-
pods, display a ganglia-based nervous system, controlled by a
brain (which is sometimes still denoted as a cephalic ganglion),
with a series of ganglia alongside a ventral (as opposed as the
vertebrate dorsal) nerve cord. The presence of ganglia con-
nected by nerve tissue in arthropods is consistent with the
segmented nature of their body architecture [56]. Then there
is the remarkable nervous system of the cephalopods (octo-
puses, squid, etc.). These animals are undoubtedly the most
intelligent of all invertebrates. They show a significant degree
of functional convergent evolution with the nervous system of
vertebrates [57]. However, structurally, the vertebrate and
cephalopod brains look nothing alike, and in fact, it has been
established that they do not share a monophyletic origin [52,53].
These are just a few examples of the best-known, non-
vertebrate animal brains. In this issue, you will read about
examples of organisms that show rather atypical systems
capable of performing many, if not all of the activities that
a ‘traditional’ brain can. In the particular example of organ-
isms lacking an evident centralized nervous system, some
scholars have proposed to speak of ‘aneural cognition’ or
‘headless thinking’ [58]. These entities do undoubtedly
expand how we think about brains. Let us briefly explore
some representative examples of such organisms.
7. Thinking plants
Plants are one of the most curious examples of organisms
displaying brain-like functions. This is an admittedly contro-
versial assertion, since plants do not possess any kind of
centralized organs to speak of, let alone even the inkling of
a nervous system, at least at the macroscopic level. The
Greek philosopher Aristotle classified plants as ‘insensitive’
beings as a criterion to separate plants from animals. Due
to Aristotle’s fame and prestige, just as his views on the brain,
his views on the nature of plants prevailed for centuries. He
famously stated: ‘LIFE is found in animals and plants. But in
animals it is patent and obvious, whereas in plants it is
hidden and not clear.’ In essence, Aristotle was not even
sure whether plants were alive.
It was not until the 1800s that the scientific consensus about
plants began shifting in favour of plants as ‘sensitive’ beings
(that is, unambiguously living entities). It is well-known that
in the 1880s Charles Darwin and his son, Francis, produced
groundbreaking studies on plant behavior [59,60]. However,
it seems that this trend formally began in 1876 with Dr William
Lauder Lindsay (1829–1880), a Scottish physician and amateur
botanist, who published a paper titled ‘Mind in Plants’ in (of all
places) a psychiatric journal [61]. In ‘Mind in Plants’, Lindsey
told the story of his interest in whether the ‘attributes of
mind’ were present in plants in addition to animals. After a
thorough exploration of the idea, he surprised himself when
he was unable to find an unambiguous demarcation between
the ‘plant mind’ and the ‘animal mind’. He extrapolated his
findings to the idea that he would neither be able to find such
a clear distinction between ‘animal minds’ and ‘human
minds’. One of the immediate consequences of his conclusions
was that from then on, plants were considered to display true
behaviour. Along the pursuit of this line of thought, a minor
detail came up: in animals, behaviour is a direct result of the
activity of a nervous system, a system that is conspicuously
absent from plants. This ‘minor detail’ did not deter a cadre
of innovative, truly out-of-the-box thinkers, who began talking
about the ‘nervous life of plants’. This emerging trend led to the
notion that scientists could begin talking about the neuroscience
of plants or as it is better known, plant neurobiology.
To say that the concept of plant neurobiology proved con-
troversial is an understatement. One of the main challenges
that this field encountered was that plant neurobiology propo-
nents chose to use certain terms that were the traditional
purview of classical (animal-based) neurobiology as meta-
phors (and to be clear, plant neurobiology advocates
explicitly stated that they were metaphors, no doubt about
that). All appropriate disclaimers notwithstanding, fiercely
-territorial as scientists are, some classical neurobiologists
took exception to the use of ‘neurobiology’ as applied to
plants, and in all fairness, it is not hard to understand why.
To begin with, plants have no ‘nerves’ to speak of. Also,
‘neurobiology’ and ‘behaviour’ are words that are (until very
recently) invariably associated with animals. The situation
was further compounded when plant neurobiology enthu-
siasts began to use terms like ‘intelligence’, ‘mind’, ‘memory’,
‘cognition’ and ‘brain’, in the context of plant biology. The
debates about the use of these words as applied to plants
became as heated as scientific debates can be, and perhaps a
little more than that. Human emotions, though ostensibly not
actually running the scientific show, do strongly influence
the debate for sure. The arguments that the phrase ‘plant neu-
robiology’ helped initiate are perfect examples of this fact. Just
to give you a taste of how the discourse is taking place, on the
advocate’s side, there are published papers like ‘The mind of
plants: thinking the unthinkable’ [62] and ‘Plants learn and
remember: let’s get used to it.’ [63]. On the detractor’s side,
there are titles like ‘Plant neurobiology: no brain, no gain?’
[64] as well as the (rather unkind) ‘Plant neurobiology: intelli-
gent plants or stupid studies?’ [65]. Even in light of all the
disagreements that plant neurobiology as a field of study
triggers in its detractors, the undeniable reality is that plants 6
do display behaviour. They also seem to be able to display
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phenomena very much like memory and learning, and without
a doubt, they do react to their environment. These are uncon-
tested facts that virtually everyone in the scientific
community accepts; I know of no exceptions. A thorough dis-
cussion of how this field came to be is outside the scope of this
review, but there are a few excellent articles that explore this
story in detail [66–70]. One thing is for sure, these are exciting
times for the brain sciences and I fully anticipate significant
breakthroughs in the near future.
The final examples of atypical brain-like function that I
will briefly mention here will illustrate the notion that to
functionally redefine the brain as a single, static, and macro-
Phil. Trans. R. Soc. B 374: 20180383
scopic structure is a near impossible proposition. Some of
these examples are explored in much more detail in other
articles in this issue.
8. Sociomicrobiology
Probably one of the most striking examples of atypical brains
includes the activities of a variety of bacterial species. Many
of these bacteria were known to display social behaviour
before they were thought to have brain-like properties.
Early biologists described complex macroscopic structures
that they called ‘fruiting bodies’, which were recognized as
being bacterial colonies since the early 1980s [71,72]. In the
1970s, researchers described behaviours of certain myxobac-
teria (colloquially called slime bacteria, not to be confused
with slime moulds, of which we will talk further along)
that were correctly interpreted as an early example of coop-
erative behaviour. In a nutshell, these bacteria coordinate
predation. As an example, the myxobacterium Chondromyces
crocatus has the ability of forming large colonies that travel
together through soil in the form of an amoeboid body a
couple of millimetres long. Upon encountering prey, the
colony releases a coordinated ejection of digestive enzymes
from individual bacterial cells, eventually digesting their
target (reviewed in [73,74]). For a while after this discovery,
the observation of apparent cooperative bacterial behaviour
was merely considered a biological curiosity, no more than
that. However, beginning in the 1990s it became apparent
that bacterial cooperation is a much more widespread occur-
rence. The discovery of multiple examples of this
phenomenon gave rise to a new field: sociomicrobiology
(reviewed in [75]; a less technical exploration of sociomicro-
biology is included in [76, pp. 156–161]). This discipline
was created in great part in response to the recognition of
the phenomenon of quorum sensing, which describes bac-
terial communication phenomena that seem to be related to
the pathogenic nature of many bacterial species (reviewed
in [77,78]). This fact has many public health implications.
Quorum sensing disruption is currently investigated as a
possible target to develop new classes of antibiotics [79,80].
Remarkably, recent developments indicate that bacterial com-
munities rely on electrochemical processes for communication
purposes, just as nerve cells do [81–83]. Moreover, one of the
most exciting developments in this area is the discovery that
bacteria can communicate with each other via ion channels,
in a manner quite similar to how nerve cells communicate
[83]. Surprisingly, this kind of communication can occur
between different bacterial species [81,82].
 A second example of sociomicrobiology is the case of cer-
tain eukaryotes including several species of social amoebas
colloquially called slime moulds. Their colonies are made of
individual amoeba-like organisms that were recognized as
distinct species as late as the nineteenth century [84,85]. The
two best-known genera of slime moulds are Dictyostelium
and Physarum, which are represented by several extant species.
In general, slime moulds live as unicellular, independent
amoeboid organisms when there are enough quantities of
nutrients available. During harsher environmental conditions,
the individual cells organize themselves into a macroscopic
‘slug’ whose cells show division of labour, including the gener-
ation of structures formed by cells destined not to reproduce.
Interestingly, there is a fundamental difference between
Dictyostelium and Physarum in terms of their collective behav-
iour. Dictyostelium’s cells retain their individual identity
within the colony, just like a multicellular animal. In contrast,
Physarum’s individual amoebae fuse into a single mass, form-
ing an acellular slug [86,87]. When in colony form, the slime
moulds are able to cooperate to solve problems like navigating
through a maze [88–90]. Also, they are able to solve more com-
plex problems like evaluating a variety of food sources to
achieve optimal nutrition [91]. Additionally, slime moulds dis-
play neuronal-like habituation [92], and are even able to
transfer learned behaviours through cell fusion [93]. The
notion of ‘proto-brains’ formed by individual bacterial or
amoeboid cells is something that was unthinkable until very
recently. Slime moulds are currently studied in terms of their
‘proto-cognitive’ abilities [94–96].
In summary, the fact is that certain types of social bacteria
seem capable of performing some of the currently accepted
brain functions. Examples of these are the perception of
environmental signals and their analysis and interpretation
( particularly when related to nutrients), as well as the coordi-
nation between individuals in order to acquire such nutrients.
Also, eukaryotes like slime moulds are able to perform the
aforementioned activities and they take it one step further,
namely by engaging in learning and memory processes and
on the generation of true division of labour, including the
apparent sacrifice of certain individuals for the sake of the
community and even the loss of individual cellular identity
when in the macroscopic form. Moreover, we already saw
that the signalling mechanisms between single-celled individ-
uals in prokaryotic and eukaryotic colonies are closely
reminiscent of signalling mechanisms traditionally associated
with nerve cells, and that at least in the case of the slime
moulds scientists are beginning to speak of ‘proto-cognitive’
behaviours. Taken together, all these facts at the very least
argue for the characterization of the behaviour of social bac-
teria and slime moulds as brain-like. It seems that the study
of these organisms illustrate an example of the research direc-
tions that could lead to a fundamental redefinition of what a
brain is.
I would like to finish this section with some thoughts that
I expressed a few years ago about slime moulds and social
bacteria (from [3, pp. 152]):
Another rather interesting trait of slime molds and related organ-
isms is that they are capable of rather impressive feats
traditionally thought to be limited to ‘higher’ animals. These
include behaviors like problem-solving skills and the ability to
learn. Amazingly, they also display the ability to anticipate
environmental changes based on prior experience. Still, just like
bacteria, the amoeba-like cells in slime molds do not possess an
actual animal-like nervous system. If we think about it, from 7
our admittedly biased perspective, the absence of a nervous
system makes the behavioral repertoire of bacteria and slime
royalsocietypublishing.org/journal/rstb
molds even more astonishing. Curious creature as I am, this
makes me ask myself, wouldn’t it be interesting to find out
whether bacterial populations have some form of self-awareness?
Would it be possible at some fundamental level that slime molds,
well, wonder?
9. Superorganisms
A particularly intriguing phenomenon relevant to the
exploration of the concept of a brain is the phenomenon of
collective behaviour in superorganisms. Here we will find a
series of eusocial organisms like the usual suspects, such as
ants, termites and bees, but also organisms that we would
Phil. Trans. R. Soc. B 374: 20180383
not think of as eusocial, like certain mammals (the naked
mole-rat; [97]) and even an eusocial type of worm (an as
yet undescribed parasitic flatworm belonging to the
Himasthla genus; [98,99]). Eusocial animals represent a par-
ticularly interesting example of atypical, ‘collective’ brains,
because each individual possesses a brain of its own yet the
interacting individuals generate emergent behaviours.
The comparison of superorganisms with brains was pro-
posed as early as the 1990s ([100], reviewed in [101]; [102];
reviewed in nautil.us/issue/23/dominoes/ants-swarm-like-
brains-think-rp). Also, a series of predictions about how the
comparison between entities like ant nests and brains can
throw light into the latter’s fundamental processes [103]. Over-
all, these authors list a series of parallels between ant colonies
and brains (this comparison can obviously be extrapolated to
other types of superorganisms, i.e. bees, termites, etc.). Some
of the most relevant parallels in terms of this review are:
— The overall activities of ant colonies and brains are gener-
ated by the multiple interactions of numerous subunits
displaying various degrees of independence (nerve cells,
versus independent animals).
— Each of the aforementioned subunits is unaware of the
single, larger entity that is generated with their actions,
and their collective behaviour can be likened to distribu-
ted and parallel processes.
— Their collective behaviour generates phenomena that
result from multiple individual actions at the level of
the subunit (a neuron fires or does not fire; an ant
moves away or towards the nest).
— Collectively, the above actions result in emergent phenom-
ena like memory and decision making among others.
— Neither brains nor ant colonies possess an obvious control
centre or any evident hierarchical chain of command.
— Just as any two brains are distinct by virtue of the differ-
ent ways in which their nerve cells interact, any two ant
colonies will behave in their own, idiosyncratic way; in
other words, they display individuality.
10. A proposal to expand the conceptual idea of
a brain
In the spirit of the question raised by Dr Netsky [7], if we ask
ourselves ‘What is a brain?’, we can say that a brain can be
thought of in terms of ‘a wide variety of physical substrates
capable of generating the functions of a brain’. Additionally,
once we establish this definition about a brain, if we ask
ourselves ‘Who says so?’, we could say that the answer
is ‘the scientists working on the specific fields that study these
various physical substrates’. There is a specific purpose for
my choice of expressing the above statements in tautological
form. Virtually any and all definitions that we can offer about
the brain are by necessity, arbitrary (although it is clear that
some definitions will be more precise than others). The unde-
niable reality is that at the end of the day, nature does not care
about how we choose to characterize it. Nature is; it is that
simple. Our definitions are for our exclusive and explicit
benefit. As biology is a science of exceptions, we can period-
ically redefine a particular concept and there is a real
possibility that we will discover a previously undescribed
class of organisms that will be the proverbial exception that
proves the rule. This being said, this constant delineation of
definitions is largely responsible for the progress of science
and is still the best strategy we have to date.
Another hard fact is that the human brain, with its
approximately 86 billion nerve cells with thousands of con-
nections between each other, and about as many glial cells
as neurons [104] seems to possess a series of abilities in
common with many evidently simpler systems. In a general
article titled ‘Thinking about the brain’, the late Dr Francis
Crick speculated on the best tools to study the workings of
the brain—in its vertebrocentric meaning—including higher
functions like perception, conception, imagination, volition
and emotion (and here I would humbly add consciousness).
He presciently stated that: ‘It would not be too surprising if
the proper theoretical tool for approaching such problems
turned out to be communication theory.’ [105, p. 219].
I believe that Dr Crick’s assertion will be proven right
sooner rather than later. Communication theory must be
one of the fundamental disciplines that will help us under-
stand what brains are and how they work. As a first
approximation, a systematic, all- (or at least most-) encom-
passing definition of a brain could be that a brain seems to
be an assemblage of independent yet closely related units.
These independent units can be individuals in a superorgan-
ism, nerve cells organized into a ‘traditional brain’, amoebas
in slime moulds, or bacteria in a biofilm, among other
examples. These interacting units communicate with each
other in various ways that nonetheless result in similar emer-
gent phenomena that we collectively group as aspects of
behaviour, memory, and other cognition-related processes.
Although in many cases the units of a brain are within the
same organism (i.e. neurons in a human brain), in many
other cases these units are independent (again, think bacteria,
slime moulds and individual ants), a fact consistent with the
concept of ‘fluid-’ or ‘liquid-like’ entities.
And what about plants? What do we do about plants?
Plants represent an especially difficult challenge in light of
the fundamental differences between them and animal
species that possess or generate nervous-system-like activities
and serve as control centres of an individual. No plant dis-
plays any indication of obvious centralized control systems.
It would be interesting to observe the development of a theor-
etical framework of plants using abilities traditionally within
the purview of brain-like systems.
It seems clear that the multiple ways in which a variety of
organisms have evolved the capacity to generate phenomena
that we unambiguously recognize as ‘brain-like’ prevents the
formulation of an all-encompassing definition. Based on this
idea, I propose an organizational scheme (figure 5) in an
effort to offer a systematic classification of the various possible
versions of a brain. It is to be noted that I intend for this scheme 8
to be a mere starting point, by necessity subject to modification
royalsocietypublishing.org/journal/rstb
as the field progresses. Also, the fact that I chose representative
examples of selected organisms to illustrate the particular brain
‘type’ does not preclude the possibility of including other
organisms. Finally, I only include living natural organisms in
this scheme, although it is clear that artificial entities are and
will continue to be discussed as possible brain candidates,
especially in light of current technological trends.
11. Proposed classification of brain types
This classification system represents a first approximation in
Phil. Trans. R. Soc. B 374: 20180383
an effort to expand the conceptual idea of a brain. In this
approximation, I do not include criteria like intelligence,
thinking, reasoning, and other so-called cerebral higher func-
tions, although I arbitrarily use evidence of cognitive
processes to differentiate between multicellular vertebrate
and invertebrate brains.
(a) Type 0: No brains
This classification represent organisms that live indepen-
dently, namely single-celled organisms displaying evident
behaviour but no evidence of collective or cooperative be-
haviour at the current state of knowledge. Organisms of
this type would include organisms like paramecia and
other protists, whose membrane are excitable in the neuronal
sense and use this property to generate behaviour [109]. Also
included in this group are solitary bacterial species, which
also display true behaviour as well as some neuron-like
characteristics [110].
(b) Type 1: Facultative brains
Single-celled organisms showing collective behaviour (i.e.
‘proto social’ traits). These types of organisms are capable of
forming cell conglomerates that closely approximate the cri-
teria for multicellularity; these conglomerates usually arise
under challenging environmental conditions (i.e. scarcity of
nutritional resources). When in their ‘pseudo-multicellular’
form, these organisms display a variety of functional charac-
teristics closely reminiscent of traditional brain processes
(memory, ability to solve problems, cooperative behaviour,
etc.). In this classification we would include social bacteria,
slime moulds (see above) and yeast; interestingly, these latter
organisms are being proposed as models to study neuronal
behaviour [111].
(c) Type 2: ‘True’ brains—invertebrates
This includes one of the traditional conceptual views of a
brain. This classification includes the brains of multicellular
organisms that at the present state of the field unmistakably
display behaviour albeit with no concrete evidence of ‘cogni-
tive’ processes. Generally belonging to ‘lower organisms’,
these types of brains are neuron-based, with the exception
of plants, which at the moment remain controversial
members of this group (see above).
(d) Type 3: ‘True’ brains—vertebrates
This is the ‘classical’ conceptual view of a brain, namely,
vertebrate brains. This type of brain is present in multicellular,
 type 0 type 1 type 2 type 3 type 4 9

royalsocietypublishing.org/journal/rstb
no brains facultative true brains: true brains: brains within
brains invertebrates vertebrates brains

single-celled single-celled ‘non-cognitive’ ‘cognitive’ superorganisms

organisms; organisms; multicellular multicellular
non-social social organisms organisms
Figure 5. Proposed classification of brain types (see text). It is clear that some refinement is needed; for example, please note that cephalopods display undeniably
higher cognitive capacities than many vertebrate species [52,53,57,106,107], and as we saw previously, sponges are multicellular but do not show clear evidence of
neuronal processes [41,42,45]. A speculative, yet intriguing possibility is that this classification system might represent a starting point to develop neurobiological
theories related to astrobiological research, as scientists are beginning to talk about possible nervous systems elsewhere in the universe [108].

Phil. Trans. R. Soc. B 374: 20180383

‘higher’ organisms with clear evidence of cognitive processes.
These types of organisms may or may not display cooperative
behaviour, but exclude eusocial organisms.
(e) Type 4: Brains within brains—superorganisms
This includes multicellular organisms displaying true eusoci-
ality. This classification includes organisms possessing
‘traditional’ nervous systems generating higher functions
upon their interaction, thus, ‘brains within brains’. Eusocial
organisms traditionally include the social insects (i.e. bees,
ants, termites, etc.) among other types of organisms. Some
authors argue that humans might belong in this category,
but the general scientific consensus argues against this idea.
12. Concluding remarks
By studying the integration of the behaviour of individual
components, from single cells to whole organisms, there is
the potential of discovering general principles that might
govern the emergence of what we currently call a ‘brain’.
There are certain entities that stretch almost to the absolute
limit what we would think of as a brain. For example, viruses
are biologically evolving entities that to my knowledge have
never been characterized as possessing brain-like behaviour.
However, quite surprisingly, certain bacteriophages are able
to detect bacterial biofilm-modulating signals [112] and use
these signals to influence quorum sensing activities in their
bacterial hosts. Moreover, certain viruses are capable of com-
municating with each other in order to actually coordinate
strategies to infect bacterial hosts. This is a phenomenon that
was hypothesized as early as the 1940s (reviewed in [113]),
and formally reported in 2017 [114]. One of the main ideas dis-
cussed here is that communication between independent
living entities is a characteristic of a brain. To state that a
virus population displays brain-like characteristics will cer-
tainly prove controversial, and certainly more work on this
idea is warranted. As an example of these efforts, viruses are
currently thought of as complex adaptive systems [115]; this
point of view will certainly initiate interesting conversations
and speculations on whether the behaviour of communicating
viruses qualify as an example of brain-like functions.
Perhaps a brain is best described not as an actual physical
object, but as an emergent process whose individual struc-
tural components are subject to biological evolution and
may possess physical independence in order to collectively
generate aspects of behaviour. In other words, the brain can
be seen as a rather fluid or liquid entity. There is little
doubt that much more work is necessary to begin to under-
stand and apply these new concepts. An exciting fact about
this effort is that it is bound to generate stimulating new
ways for us to understand the brain in its multiple incarna-
tions; perhaps even ideas that our own brains have never
pondered before.
Data accessibility. This article has no additional data.
Competing interests. I declare that I have no competing interests.
Funding. I received no funding for this study.
Acknowledgements. I wish to thank Dr Eric Sweet, a colleague and friend
at the Department of Biology of West Chester University, for insight-
ful and useful comments. I wish to express my deep appreciation to
Dr Ricard Solé, Dr Melanie Moses and Dr Stephanie Forrest, organi-
zers of the working group ‘Liquid brains, solid brains’ held at the
Santa Fe Institute 4– 5 December, 2017. My heartfelt thanks go to
Dr Ricard Solé for inviting me to participate in the working group;
this was a quite unexpected honour. I also gratefully acknowledge
the support of my research programme by the Department of Biology
and the College of Science and Mathematics, West Chester Univer-
sity. I also thank my brother, Mr Alexis G. Pagán for figures 1, 3
and 4. Sections of this review include expanded selections from my
book The First Brain: The Neuroscience of Planarians (2014) Oxford Uni-
versity Press.

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