Theory in Biosciences (2018) 137:117–131
https://doi.org/10.1007/s12064-018-0265-6
ORIGINAL ARTICLE
Systems biology of eukaryotic superorganisms and the holobiont
concept
Ulrich Kutschera1,2
Received: 17 January 2018 / Accepted: 5 June 2018 / Published online: 14 June 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
The founders of modern biology (Jean Lamarck, Charles Darwin, August Weismann etc.) were organismic life scientists
who attempted to understand the morphology and evolution of living beings as a whole (i.e., the phenotype). However, with
the emergence of the study of animal and plant physiology in the nineteenth century, this “holistic view” of the living world
changed and was ultimately replaced by a reductionistic perspective. Here, I summarize the history of systems biology, i.e.,
the modern approach to understand living beings as integrative organisms, from genotype to phenotype. It is documented
that the physiologists Claude Bernard and Julius Sachs, who studied humans and plants, respectively, were early pioneers
of this discipline, which was formally founded 50 years ago. In 1968, two influential monographs, authored by Ludwig von
Bertalanffy and Mihajlo D. Mesarović, were published, wherein a “systems theory of biology” was outlined. Definitions of
systems biology are presented with reference to metabolic or cell signaling networks, analyzed via genomics, proteomics,
and other methods, combined with computer simulations/mathematical modeling. Then, key insights of this discipline with
respect to epiphytic microbes (Methylobacterium sp.) and simple bacteria (Mycoplasma sp.) are described. The principles of
homeostasis, molecular systems energetics, gnotobiology, and holobionts (i.e., complexities of host–microbiota interactions)
are outlined, and the significance of systems biology for evolutionary theories is addressed. Based on the microbe—Homo
sapiens—symbiosis, it is concluded that human biology and health should be interpreted in light of a view of the biomedical
sciences that is based on the holobiont concept.
Keywords Evolution · Holobiont · Systems biology · Reductionism · Superorganism
Introduction
Biology, the science of living systems (organisms), both past
and present, emerged as a distinct discipline with the work of
the French naturalist Jean Lamarck (1744–1829). In one of
his numerous monographs, Lamarck (1815) used the word
“biology” to denote the scientific study of living organisms.
Later, he became one of the founders of animal taxonomy,
as well as the emerging evolutionary sciences (Mayr 1984;
Höxtermann and Hilger 2007; Kutschera 2011).
Lamarck, and other eminent nineteenth-century biologists, such as Charles Darwin (1809–1882), Alfred Russel
* Ulrich Kutschera
kut@uni‑kassel.de
1
The Systems Biology Group Inc, 374 California Avenue,
Palo Alto, CA 94306, USA
2
Institute of Biology, University of Kassel, 34132 Kassel,
Germany
Wallace (1823–1913), August Weismann (1834–1914),
and Ernst Haeckel (1834–1919), studied entire organisms
(animals, plants, microbes). Hence, these pioneers used an
integrative approach in their attempts to explain phenomena of the living world, such as the systematic relationships
between animals, their adaptations to novel environmental
conditions, or the transformation of species over the course
of subsequent generations (organismic evolution).
With the emergence of sophisticated physiological and
biochemical methods at the end of the nineteenth century,
and the discovery of the hereditary material (DNA) during
the 1940s, the view of the “organism as a whole” changed
and was replaced by a reductionist paradigm. This shift
in focus away from the entire living being to the study of
parts of it (i.e., the function of isolated cells in liquid media,
enzyme activities in vitro, gene expression patterns) culminated during the early 1960s in the “molecularization” of
nearly all areas of the life sciences. As a result, organismic
biology was regarded at that time by leading researchers as
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an “old-fashioned” or “outdated” branch of natural history
(Mayr 1984, 2004).
Fifty years ago, two major monographs were published
wherein the classical (“holistic”) view of living organisms
was revitalized under the label of a “systems theory of
biology” (Bertalanffy 1968; Mesarović 1968). As a consequence, this re-emergence of a “new holism” was praised in
the biomedical literature (Rosen 1968).
In this contribution, the historic development and current
status of systems biology is described, which is essentially
based on the Aristotelian principle that the “entire functional
unit is more than its isolated components” (Fig. 1). I focus
on eukaryotic organisms, such as humans (mammals) and
their microbial partners, as well as land plants (embryophytes), within a macroevolutionary framework (Farmer
et al. 2000; Niklas 2016; Kutschera 2017a, b). Accordingly,
my aim is to outline an integrative pan-holistic perspective,
i.e., animals, humans, and plants are interpreted as holobionts (Sleator 2010; Gilbert 2014; Faure et al. 2018).
Who was the first systems biologist?
It is well known that the observations and empirical findings
ascribed to Aristotle (384–322 BCE) led to a new, revolutionary interpretation of nature. Since this unique thinker
not only studied physical (i.e., dead) objects, but also analyzed living organisms (humans, animals, plants) and their
developmental physiology, it is fair to conclude that the origin of biological thought can be traced back to this leading
Fig. 1 The idea of systems biology can be traced back to the writings of the Greek philosopher Aristotle (384–322 BC) and others.
He argued that entire systems are more than the sum of their components. Portrait adapted from Locy (1915)
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philosopher (Locy 1915; Allan 1952; Mayr 1984; Farmer
1998; Höxtermann and Hilger 2007). Yet, Aristotle was not
the “father of systems biology.” He did, however, provide
the epistemological principle on which this novel holistic
approach to understanding the biology of living beings in
toto rests (Fig. 1).
In an excellent review article on the philosophical basis
and historical development of systems biology, Saks et al.
(2009) argued that the German philosopher Georg Wilhelm Friedrich Hegel (1770–1831) provided the logical
basis for a systems approach to biology. According to these
authors, the Hegelian dialectic of historic development of
a variety of systems, from a “thesis” via the “anti-thesis”
to the “synthesis”, can be interpreted as the basic “law” of
systems biology. Moreover, Hegel (1830) mentioned, with
implicit reference to Aristotle (Fig. 1), that in order to gain
real knowledge, it is necessary to understand not only parts
of a system, but “The Whole.” Unfortunately, the German
thinker equated “The Whole” with his fussy principle of
the “Absolute Idea” (Hegel 1830). Since he did not define
this abstract entity, the eminent German philosopher Arthur
Schopenhauer (1788–1860) argued against the validity and
significance of Hegel’s dialectic laws. In fact, Schopenhauer
(1851) refuted the Hegelian principles that were based on
the obscure “Absolute Idea.” Schopenhauer (1851) documented that this part of Hegel’s system of thought should
be interpreted as an illogical and absurd pseudo-philosophy.
This sharp criticism was based on Schopenhauer’s tenet that
concepts which cannot be clearly defined or proven empirically are invalid speculations—a clear contradiction to the
proposal made by Saks et al. (2009) that Hegelian principles
acted as a formal basis of the modern biosciences.
After this excursion into the world of German philosophy I will focus on the work of some leading experimental
biologists. According to Noble (2006, 2008), the French
animal physiologist Claude Bernard (1813–1878) was the
“first systems biologist.” This conclusion is based on the
fact that, in his monograph on Experimental Medicine (Bernard 1865), and other publications, he introduced the idea
of the maintenance (constancy) of the internal environment
(le milieu intérieur) of the organism. In addition, according
to Bernard (1865), physiologists should focus on the organism as a whole and in detail at the same time. Since Bernard
was educated as a physician, he studied humans (Fig. 2) and
other mammals, such as dogs, and occasionally also frogs
(Conti 2001).
Bernard was one of the founders of modern animal physiology. He discovered not only gluconeogenesis in the liver,
but also elucidated the function of the pancreas and the role
of the brain with respect to the central nervous system’s
role in the regulation of vital processes. Moreover, Bernard
was also a gifted theorist. In addition to his discovery of the
maintenance of the milieu intérieur, which later evolved into
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Fig. 2 French animal physiologist Claude Bernard (1813–1878) and
the German plant physiologist Julius Sachs (1832–1897) focused
their research on humans and crop plants, respectively. Since both
scientists attempted to understand the function of the entire organism,
they may be regarded as representatives of the first modern system
biologists
the principle of homeostasis, Bernard (1865) argued against
the unscientific idea of “vitalism.” According to this interpretation of living systems, obscure “vital forces,” instead
of physico-biochemical processes, represent the “driving
forces” of physiological phenomena. Hegel (1830) and
Schopenhauer (1851) were prominent adherents of vitalistic concepts. Unfortunately, both of whom questioned the
significance of empirical studies.
Like Bernard, the German botanist Julius Sachs
(1832–1897) was a “physicochemical” physiologist who
rejected metaphysical speculations, such as the belief in
“vital forces” (Kutschera 2015a, b). Sachs made significant
discoveries on seed germination, plant nutrition, growth,
organ movements, photosynthesis, and root development.
In his first book, the Experimental Physiology of Plants,
Sachs (1865) attempted to understand the function of the
entire green organism, based on physicochemical principles,
such as diffusion. Hence, like Bernard (1865), Sachs’ monograph (1865) should be considered as one of the academic
pieces that laid the foundation of modern systems biology
(Kutschera 2015a, b; Kutschera and Niklas 2018).
The Bernard–Sachs principle of integrative
biology
Both Claude Bernard and Julius Sachs were gifted
experimentalists and creative theoretical biologists who
attempted to understand the “red” (blood containing)
and “green” (chlorophyllous) organisms (i.e., animals vs.
plants) as a whole. These pioneers in animal and plant
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physiology published their most influential books in 1865
and died at an age of ca. 65 years. Here, I propose that
Bernard and Sachs were among the first modern systems
biologists (Fig. 2) and would therefore like to introduce
the term “Bernard–Sachs principle of integrative biology”
to denote their contributions to this branch of the life sciences. The following deductions are based on the publications of Noble (2006, 2008) and Kutschera (2015a, b),
where details on the life and scientific achievements of
these nineteenth-century pioneers of systems biology are
summarized.
In addition to the classical experimental and theoretical
work of Bernard and Sachs, the concept of neg-entropy,
proposed by the Austrian physicist Erwin Schroedinger
(1887–1961) in his book What is Life?, should be introduced here. Schroedinger (1944) concluded, with reference
to earlier investigators, that living cells as well as multicellular organisms are “open systems” that permanently
exchange mass and energy with their environment (Fig. 3).
These processes maintain the complex order within the
cytoplasm, which is surrounded by the cell membrane, so
that physiological functions, such as metabolism, growth,
and reproduction, can occur. As a result, the internal level
of entropy is low. This “order within the cell (organism)”
is achieved by the steady enhancement of entropy in the
surrounding medium (water, soil, or air) via catabolic
reactions.
Usually, catabolism (cell respiration), accompanied by
the release of carbon dioxide and water (­ CO2, ­H2O), enhancing the molecular chaos outside, is associated with biosynthetic reactions within the cell (anabolism). The substrates of
cell respiration are essentially carbohydrates (starch in plant
cells, glycogen in animals) and fatty acids. Hence, living
cells create “neg-entropy” to maintain “order within,” which
is achieved at the expense of the surrounding environment. It
should be noted that the term “neg-entropy” has been criticized by a number of scientists. However, a discussion of
these terminological arguments is beyond the scope of this
article.
The publication of Schroedinger’s idea of the cell (or
organism) as an “open system” was a key event in the historic development toward an integrative view of biological
processes (Fig. 3). However, neither Bernard (1865) and
Sachs (1865), nor Schroedinger (1944) used the term “systems biology” in their seminal contributions to this area of
biological research. Likewise, these researchers only made
an outline but did not clearly define their research agenda
toward an understanding of entire living systems.
Several decades later, two monographs were published
that led to the establishment of a “systems approach to biology” as a distinct scientific discipline. These developments
and the definitions of this novel research agenda are summarized in the next section.
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Fig. 3 Illustration of Ernst Schroedinger’s basic concept of the function of biological entities. Living organisms (composed of cells) are
open systems that continuously exchange mass and energy with their
environment. This principle is illustrated by depicting a dark-grown
sunflower seedling (a), accompanied by a scheme of a heterotrophic
plant cell (b). Internal order (complexity within) is maintained by cre-
ating “chaos” outside the living system (molecular unorder; release
of the gases ­CO2 and ­H2O). By this means, metabolic homeostasis is
achieved. ATP adenosine triphosphate, P phosphate. Note that ATP
provides energy for metabolic reactions and enhances protein solubility (maintenance of a liquid cytoplasm). Adapted from Niklas and
Kutschera (2015)
What is systems biology?
study and for the explanation of biological phenomena”
(Mesarović 1968, p. 59). Specifically, the author defined a
system as a mathematical model of any real-life process or
phenomenon, and in this context, referred to computer simulations. Obviously, a link to cybernetics becomes apparent
today when we study the pioneering books of Bertalanffy
(1968) and Mesarović (1968).
More recently, the British physiologist Denis Noble (born
1936) published an influential book entitled The Music of
Life. Biology beyond the Genome, wherein he argued that
systems biology is “a new and important dimension of biological science … (with) strong historical roots in classical
biology and physiology … It is about putting together rather
than taking apart, integration rather than reduction” (Noble
2006, p. x–xi). In a subsequent article, Noble (2008) summarized the principles of systems biology, which include
the point that biological functionality requires many levels;
transmission of genetic information is not a one-way street;
DNA is not the only transmitter of inheritance (epigenetics);
there is no privileged level of causality, etc. Noble (2008)
rejects the so-called modern reductionist biology (Fig. 4)
by accusing the adherents of this gene-centered view of living organisms that they are spreading a modern version of
the disproven “embryo-homunculus” idea (Mayr 1984). In
other words, the stretches of DNA that code for proteins
(and RNAs) cannot do anything on their own—they need the
As mentioned in the introduction, two books were published
50 years ago that ushered in a new, holistic era in the biological sciences (Rosen 1968). How did these formal founders define their “systems view” of the experimental analysis
of living beings?
The Austrian biologist Ludwig von Bertalanffy
(1901–1972) developed an “open systems theory of organismic biology” that is summarized in his most important
monograph General Systems Theory: Foundations, Development, Applications. With reference to Schroedinger (1944),
Bertalanffy (1968) argued that living beings are “open systems in a steady state.” As a result, only the entire organism,
and not its parts (i.e., cells, proteins such as enzymes and
nucleic acids analyzed in vitro) can perform what we denote
as the “physiological processes” (metabolism, reproduction,
movements, etc.). With the publication of this book, Bertalanffy (1968) became an unmistakable pioneer in systems
biology. The Serbian scientist Mihajlo D. Mesarović (born
1928) provided a supplementary concept to this emerging
discipline. In his multi-author monograph, Mesarović (1968)
contributed a general article entitled “Systems theory and
biology—view of a theoretician.” In this paper, he proposed
a systems approach to living uni- and multicellular organisms “to represent the application of systems theory in the
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Fig. 4 Illustration of the principles of reductionism vs. holism in
physiological research. Entire seedling of sunflower (Helianthus annuus) (a), generation of a tissue extract (b) and an enzyme assay (c).
This approach yields, via indicator reactions, specific catalytic activities of selected enzymes (d). By this means, correlations between
metabolic processes (i.e., enzyme activities) and physiological phenomena (growth in darkness vs. light) can be documented. Based on
such data sets, with a focus on the phenotype, an integrative view of
the entire organism can be reconstructed (principle of systems biology)
whole cell machinery (nucleus, ribosomes, etc.) to become
active. Hence, Noble (2008) and Kohl et al. (2010) argue
against “gene-determinism” and “gene-selectionism.” Obviously, only the entire organism can develop, reproduce, and
hence evolve (Turing 1952; Kutschera and Niklas 2004;
Niklas 2016).
Seven years ago, Wanjek (2011, p. 1) characterized systems biology with reference to the work being done at the
US National Institute of Health (NIH) as “an approach in
biomedical research to understanding the larger picture—be
it at the level of the organism, tissue or cell—by putting its
pieces together. It is in stark contrast to decades of reductionist biology, which involves taking the pieces apart.” Ron
Germain, head of the NIH-lab of Systems Biology, defined
this discipline as follows: “Systems Biology is a scientific approach that combines the principles of engineering,
mathematics, physics, and computer science with extensive
experimental data to develop a quantitative as well as a deep
conceptual understanding of biological phenomena, permitting prediction and accurate simulation of complex (emergent) biological behaviors” (Wanjek 2011, p. 6). In addition
to this general description, other (shorter) definitions have
been proposed that are summarized in the next section.
“theoretically permits us to integrate, model, and analyze
the interactions among all of the components of a complex living system—particularly in the case of feedback
loops, which figure prominently in … biology” (Niklas
and Kutschera 2012). In its broadest sense, systems biology takes into account the interconnection of all levels of
complexity in living beings, according to the general biochemical principle “the organism is more than the sum of
its parts” (Kitano 2002; Joyner and Pedersen 2011; Drack
and Wolkenhauer 2011; Dubitzky et al. 2013; Klipp et al.
2016; Walter et al. 2015).
As detailed above, systems biology can be viewed as
a modernized version of physiology (of microbes, animals, plants), integrating all levels of complexity. Historically, the maintenance of energy homeostasis in cells,
organs, and organisms was one of the key questions of
integrative physiology, and the sequences of the human
genome (Homo sapiens), followed by that of the model
plant Arabidopsis thaliana, resulted in the concept of
genomics (i.e., the analysis of the functional significance
of the genome, with the focus on nuclear DNA). Later,
transcriptomics (i.e., the analysis of all RNA molecules in
the cell) developed, followed by proteomics (i.e., the study
of the expressed genes, translated into proteins). With the
emergence of metabolomics (i.e., the study of metabolites)
a more dynamic approach was founded, which is known
under the term “fluxomics” (Salon et al. 2017).
Fluxomics is an integrative approach and key discipline of systems biology that aims to measure the rates
of fluxes, i.e., molecular changes and transfers in living
cells, tissues, organs, or entire organisms. The goal of
this approach is to understand the dynamic changes in
From the genotype to physiology
In a publication on plant morphogenesis, Niklas and
Kutschera (2012) discuss the “genotype-to-phenotype”
relationship, with respect to the phytohormone auxin and
the “subsystem incompleteness theorem.” With reference
to plant research (Pu and Brady 2010; Yin and Struik
2010), they define systems biology as an approach that
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developing systems and to model these fluxes in the form
of mathematical principles or schemes.
On a global scale, the analysis of photosynthesis in the
biosphere has recently been experimentally analyzed and
modeled via an integrative, systems biology approach (Weston et al. 2012; Campbell et al. 2017).
Computer simulations and mathematical models are tools
to understand the complex, interconnected physiological
processes, with the aim to proceed from the DNA–protein–enzyme-centered reductionist view to an integrative
perspective. This principle is illustrated in Fig. 4, based
on studies on sucrose metabolism in growing plant organs
(Kutschera and Niklas 2013a, b).
Systems biology of unicellular prokaryotes
When Bernard (1865) and Sachs (1865) published their
monographs (Fig. 2), it was well known that microorganisms
exist. However, neither a clear definition, nor a satisfactory
knowledge about these ubiquitous, usually rodlike microscopic organisms (size ca. 1–5 µm) that multiply by simple cell fission, was available. Despite the fact that Haeckel
(1866) introduced the Kingdom Protista and characterized
the few bacteria known at that time as Monera, bacteriology
was in its infancy. It should be noted that Haeckel (1866)
argued that all living beings alive today descended in some
way from bacteria-like microbes (Kutschera 2016). Today,
Haeckel’s hypothesis is well established, i.e., life started
about 3500 million years ago with the emergence of simple
microbes, and subsequently, aquatic microorganisms were
the sole inhabitants of the planet about 80% of the time that
living beings have existed on Earth (Kutschera 2017a, b;
Martin 2017; Spang et al. 2017).
Modern bacteriology was inaugurated with the publication of the landmark paper of Stanier and Van Niel (1962),
wherein they outlined the concept of what was later regarded
as a typical bacterial cell. Forty years ago, Woese and Fox
(1977) documented that the “classical” distinction between
eukaryotes (Protista, Fungi, Animalia, Plantae) and prokaryotes (Bacteria, inclusive the so-called blue-green algae) must
be replaced by a tripartite tree of life. Despite the fact that
eukaryotes are composed of relatively large cells containing
a nucleus and internal compartments (organelles, such as
mitochondria, see Fig. 3b), whereas prokaryotes are composed of small cells that lack internal structures, Woese
and Fox (1977) introduced a three domains of life scheme:
Eukarya, Bacteria, and Archaea. However, this revolutionary
proposal, solely based on DNA (RNA) sequence data, stating that prokaryotic microbes are composed of two distinct
domains (Bacteria, Archaea), was not readily accepted by
taxonomists. Today, we know that Archaea (i.e., archaebacteria) are distinct from Bacteria (i.e., Haeckel’s Monera, or
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eubacteria) by a number of biochemical features (Spang
et al. 2017).
Despite these insights, systems biology of prokaryotes
was largely restricted to eubacteria. Here, we will focus on
aspects of a systems approach to bacteriology with reference
to symbiotic microbes of plants and animals. It has long
been known that most bacteria do not exist in the free-living,
single-celled, aquatic form, with a flagellum, as depicted
in textbooks. Using plant-associated methylotrophic bacteria that consume methanol released from the growing cell
walls of their eukaryotic host organisms, such as sunflower
seedlings (Fig. 5) as model systems, it was shown that these
microbes usually live in a biofilm (Kutschera 2007, 2015b,
c). These multicellular collectives of microbes form communities, wherein single cells are attached to each other via
extracellular polymers. By this mode of life, large populations of sessile bacteria (genus Methylobacterium) colonize
the root system as well as the entire above-ground phytosphere of land plants (Schauer and Kutschera 2008).
When sessile methylobacteria are transferred into liquid media, the cells rapidly assemble a flagellum, so that
this planktonic version of Methylobacterium sp. can swim
around. The assemblage and loss of the polar flagellum are
Fig. 5 Prokaryotes (bacteria) versus an eukaryotic organism (land
plant). Scanning electron micrograph of a cluster of methylobacteria
isolated from the cotyledons of a sunflower seedling (Helianthus annuus, inset), which represents a holobiont. On moist surfaces, the bacteria exist as super-cellular biofilms (original micrograph)
Theory in Biosciences (2018) 137:117–131
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Fig. 6 Two lifestyles of typical
bacteria. On solid surfaces
(for instance, the cuticle of
epidermal cells of land plants),
the prokaryotic microbes exist
in a biofilm with extracellular
secretion products. When transferred into liquid culture, they
assemble a flagellum and swim
around. This process is reversible. Adapted from Schauer and
Kutschera (2008)
reversible processes (Fig. 6). In a detailed systems approach
to these lifestyle switches, Doerges and Kutschera (2014)
documented the dynamics of bacterial population growth,
speed of flagellum assemblage, death of microbes at saturating cell densities in liquid cultures, etc. Based on these and
other insights, it was concluded that plant-associated methylobacteria are phytosymbionts that interact with their green
host organism in a variety of ways (Klikno and Kutschera
2017; Schauer and Kutschera 2011).
In our current human-centered era of biology, mammalassociated eubacteria are the model systems of choice when
it comes to a systems approach in bacteriology. Thirty-five
years ago, Tully et al. (1983) classified a small pathogenic
eubacterium isolated from samples of male patients that suffered from inflammation of the urethra (urethritis). Microscopical inspections revealed that these microbes are only
ca. 0.6 × 0.3 µm in size. This microbial taxon, Mycoplasma
genitalium, was found to have one of the smallest genomes
of any extant organism (size 0.58 Mbp, 475 genes) and has
served as a model system for systems biology since 1984.
It should be noted that mycoplasms (i.e., eubacteria of the
genus Mycoplasma) have been detected as co-inhabitants
in liquid cell cultures derived from animal tissues (Kleinig
and Sitte 1986). These unwanted “mycoplasma infections”
(Fig. 7) can be detected via PCR-based methods and eliminated using filter techniques (Uphoff and Drexler 2002).
Ten years ago, Gibson et al. (2008) reported the chemical synthesis and documented the in vitro functioning of a
synthetic genome identical with that of M. genitalium. In
the popular press, this research team, led by J. Craig Venter,
described the creation of a “synthetic bacterium,” which was
named “Mycoplasma genitalium JCVI-1.0” (Gibson et al.
2008). Based on this and other achievements, on July 20,
2012, the J. Craig Venter Institute in Rockville/MD and
Stanford University in Palo Alto/CA announced the creation of a “cell computational model of the life cycle of the
human pathogen Mycoplasma genitalium,” which comprises
“all of its molecular components and interactions” (Karr
et al. 2012). Their model was comprised of six areas of cell
Fig. 7 Mycoplasms are one of the smallest prokaryotes discovered
so far. These parasitic bacteria (genus Mycoplasma) live on the outer
surface of eukaryotic animal cells. The scanning electron micrograph
shows mycoplasms (diameter ca. 0.3 µm) in a liquid culture of animal
host cells. Adapted from Kleinig and Sitte (1986)
biology: 1. transport and metabolism; 2. DNA replication
and maintenance; 3. RNA synthesis and maturation; 4. protein synthesis and maturation; 5. cytokinesis; and 6. host
interaction.
These areas of bacterial physiology (Karr et al. 2012) can
be reduced to four basic processes of microbial life: 1. ATPdependent metabolism; 2. DNA–RNA–protein replication;
3. cell reproduction, and 4. exchange of molecules and signals with the environment. Based on the “minimal microbial
cell-concept” proposed by Follmann and Brownson (2009),
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a simplified version of this complex life cycle model is
depicted here (Fig. 8). Finally, in their landmark paper of
microbial systems biology, Karr et al. (2012) validated their
model, which is based on a synthesis of more than 900 publications and ca. 1900 experimentally observed parameters,
against a wide range of independent data sets. These studies
(metabolomics, transcriptomics and proteomics techniques)
confirmed the correctness of their M. genitalium computational model.
Despite these insights, microbial systems biology, based
on mycoplasms as the simplest bacterial cells capable of
independent reproduction (Fig. 7), is still in its infancy. As
pointed out by Hutchison et al. (2016), “the minimal cell
concept appears simple at first glance but becomes more
complex upon closer inspection.” The reason for this assessment is the finding that, despite genome minimization in
viable “synthetic cells,” there are currently 149 genes of
unknown function that are nevertheless essential for bacterial life (Hutchison et al. 2016). Unfortunately, in the popular
press, the term “synthetic cell” is used, so that non-specialists assume that complete M. genitalium units have been
created from scratch, which is not true (Kolchinsky et al.
2017). The question as to whether it will ever be possible for
systems microbial biologists to “create a living cell” (possibly a simple Archaeon, see Spang et al. 2017) is still open.
In the next section, we will discuss the general principle
of the maintenance of constant internal conditions in living
cells (Figs. 3b, 8), with reference to eukaryotic macroorganisms (animals, inclusive of humans, and plants).
Homeostasis and molecular systems
energetics
Fig. 8 Simplified model of a living cell (Mycoplasma genitalium),
based on molecular and biochemical data (genomics, transcriptomics,
proteomics, metabolomics). A more sophisticated scheme, published
in 2012, was the first mathematical whole-cell model in systems biology. The four basic processes of cellular life are indicated (metabo-
lism, replication, reproduction, cell/environment interactions).
Proteostasis = maintenance of a liquid cytoplasm due to high concentrations of ATP (ca. 5 mM). Adapted from Follmann and Brownson
(2009), updated 2018
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As mentioned above, Bernard’s (1865) concept of the
constant internal milieu later evolved into the principle of
homeostasis. In 1930, the American physiologist Walter B.
Cannon (1871–1945) published a book entitled The Wisdom of the Body, wherein he coined the term homeostasis.
It refers to all those processes established in living organisms that led to the relative maintenance of steady conditions
necessary for cell metabolism, survival and reproduction of
the individual. Cannon (1932) referred to vital processes of
the human body, such as the regulation of a steady state in
temperature and blood oxygen. In an intact ecosystem, the
maintenance of stable animal–plant interactions, population
sizes, etc., are likewise examples for Cannon’s principle of
homeostasis.
However, it took several decades of physiological cell
research before at least part of the machinery of cellular
energy homeostasis was discovered (Harold 1986; West
2010). Today, we know that the mammalian adenosine
monophosphate-activated kinase (AMPK) restores metabolic homeostasis whenever an energy deficit occurs in heterotrophic animal cells. This is achieved by the activation
of ATP-releasing catabolic reaction chains, such as fatty
acid oxidation or glycolysis. In addition, the AMPK also
regulates the energy balance in the whole body energy balance by controlling feeding activity. The plant counterpart
of AMPR, an energy and nutrient sensor for the maintenance
Theory in Biosciences (2018) 137:117–131
of intracellular homeostasis, is the SnRK1-kinase (Broeckx
et al. 2016). This energy sensor is an integrative component
of a metabolic signaling network that functions as a control mechanism of plant development (Fig. 3a, b) and stress
tolerance. The animal AMPK and plant SnRK1-kinases
are early “inventions” in eukaryotic evolution that display
a number of structural and functional homologies (Broeckx et al. 2016). In this context, it is important to note that
ATP not only serves as a universal “energetic unit” for the
maintenance/promotion of phosphorylation reactions in cell
metabolism (Martin et al. 2017), but, at millimolar intracellular concentrations, maintains the cytoplasm in a liquid
state (proteostasis) (Patel et al. 2017).
Based on these insights and extensive studies of energy
metabolism in microorganisms, animals, and plants, i.e.,
metabolic scaling (Niklas and Kutschera 2015), a molecular systems approach to the analysis of intracellular, ATPdependent energy conversion was established. According to
Saks et al. (2009), “Molecular systems energetics is a broad
research field accounting not only for metabolism as a reaction network, but also for its spatial (organization) and temporal (dynamic) aspects.” Importantly, insights come from
the findings that cell metabolism works along multienzyme
complexes and “metabolons” (i.e., macromolecular units
that permit reactions chains to work efficiently).
Of particular importance for homeostasis in eukaryotic
cells (Fig. 3b) are the mitochondria. These oxygen-consuming “power houses” evolved from once free-living bacteria
via primary endosymbiosis and generate/export ATP for
the maintenance of metabolism and cytoplasmic fluidity
(Scheibye-Knudsen et al. 2015; Martin 2017; Martin et al.
2017; Patel et al. 2017). However, in addition to the production of the “energy currency” ATP, O
­ 2-consuming mitochondrial processes create, as a by-product, reactive oxygen species (ROS). As summarized in previous articles (Kutschera
and Niklas 2013b; Scheibye-Knudsen et al. 2015), at low
levels, ROS play an important role in cellular signaling and
immune responses. However, produced at higher concentrations, ROS can damage macromolecules, such as proteins,
nucleic acids, and lipids. These negative effects can contribute to the occurrence of human diseases and cause at least
some aspects of the aging process.
Importantly, a balance achieved in living cells between
the generation of ROS in active mitochondria and the
detoxification of these by-products of oxygenic ATP generation (via uncoupling proteins). This ROS homeostasis
is important for human health. The occurrence of a number
of diseases is associated with a loss of the “maintenance of
the internal milieu” (Bernard 1865), such as primary deficiency of vitamin E (Scheibye-Knudsen et al. 2015). In this
context, another homeostatic process, autophagy, should be
mentioned, which deals with the degradation of non-functioning mitochondria.
125
In summary, the findings described above indicate that
experimental analyses of homeostasis, a core principle
of systems biology, are an active area of integrative cell
physiology.
Gnotobiology and holobionts
Two French scientists, the agriculturist Jean-Baptiste
Boussingault (1801–1887) and the chemist Louis Pasteur
(1822–1895), pioneered an area of organismic biology that
focused on the question of whether or not plants and animals
are able to develop in an artificial world without microbes.
In 1838, Boussingault used sterilized sand to study the
growth of crop plants, compared with non-sterile controls.
Five decades later, Pasteur asked, with reference to animals,
the question: “Is life of higher organisms possible in the
absence of bacteria?” Both experimentalists concluded that
complex living beings (plants, animals, etc.) benefit in some
way from the presence of microbes, but it took decades of
scientific study to prove that their speculations were true. In
this context, the work of the German plant biologist Lorenz
Hiltner (1862–1925) should be mentioned. As detailed by
Hartmann et al. (2008), Hiltner argued that plant nutrition
and health are both dependent on the presence of rhizosphere microbiota.
Gnotobiology, i.e., the study of developmental patterns of
animals in the absence or presence of a defined mixture of
microbes (i.e., germ-free or axenic vs. non-sterile controls),
became an established discipline in the 1950s (Luckey 1963,
Kutschera and Khanna 2016). At that time, due to a systems
biology approach, it became possible to raise germ-free
mice (Mus musculus), and other mammals, in the laboratory.
These microbe-free macroorganisms displayed a number of
deficiencies, such as a requirement for folic acid, vitamin K,
and thiamine—substances produced by the microbial flora
of the gut (Luckey 1963).
Similarly, plant gnotobiology revealed that, notably in
bryophytes, optimal cell and organ growth is dependent on
the presence of epiphytic microbes (methylobacteria, Figs. 5,
6) (Kutschera 2007, 2015b; Vorholt 2012). Over the past
three decades, a consensus has emerged among biomedical
scientists that animals, as well as plants, depend on mutualistic symbiotic relationships with microbial partners. These
communities of bacteria (and fungi, as well as protists, and
viruses) inhabit the outer and inner surfaces of their multicellular host organism. Hence, the term “superorganism”
has been coined to denote the eukaryotic macroorganism,
together with its assemblage of symbiotic microbes (Sleator
2010; Segre and Salafsky 2016). However, as noted by Gordon et al. (2013), the term “superorganism” is preoccupied
and therefore has a second meaning. In 1928, the myrmecologist William Morton Wheeler (1865–1937) described
13
126
colonies of eusocial insects, such as ants. In these collectives
of eukaryotic macroorganisms of the same species, individual members perform different tasks that contribute to the
protection, nourishment, and reproduction of the colonies.
Accordingly, Wheeler (1928) introduced the term “superorganism” to describe this group of insects that is characterized by a particular division of labor.
For these reasons, Gordon et al. (2013) rejected the word
“superorganism” and instead proposed the term “holobiont.”
Symbiotic systems consist of partners (host organism and
microbes) which are “bionts.” As a result, the “microbe–animal (or plant) superorganism” is a “holobiont.” Accordingly,
the terms “animal (or plant)-holobiont” have been used in
the recent literature (Vandenkoornhuyse et al. 2015; Richardson 2017; Faure et al. 2018). As described by Chiu and
Gilbert (2015), holobionts, which can be defined as eukaryotes with a specific assemblage of prokaryotic symbionts,
are not individuals in the genetic sense (i.e., organisms regulated by one genome). Rather, they represent developmental
and physiological units that evolved from an ancient symbiotic relationship between a eukaryotic host and its bacterial
symbionts (Fig. 11). Recently, another term to denote this
microbe–host symbiotic system has been coined (“metaorganism,” see Belkaid and Hernd 2014). In accordance with
the terminology used at the “First International Conference
on Holobionts (Paris, France, April 19–21, 2017), the word
“superorganism” should be replaced by “holobiont” (Faure
et al. 2018) (Fig. 9).
In this context, I want to reiterate the fact that at least
50% of protoplasmic biomass on Earth consists of bacteria (Eubacteria and Archaea) plus viruses (Fig. 10). If we
add the eukaryotic microbes (soil amoebae, phytoplankton
in the oceans, etc.) to this value (ca. 25%), it follows that
less than 1/4 of living material in the biosphere consists
of animals, fungi, and plants. Hence, bacteria represent
Fig. 9 Illustration of the concept of holobionts (superorganisms) in
animals and plants. Both types of macroorganisms are composed of
eukaryotic cells and symbiotic bacteria (plus other microbes) that
exist on the outer surface and within the body
13
Theory in Biosciences (2018) 137:117–131
Fig. 10 Distribution of protoplasmic biomass on planet Earth. More
than 50% of metabolically active (living) material is restricted to Bacteria (inclusive of viruses) and Protoctista (protists, i.e., amoebae,
algae) add at least 25% to this equation. Macroorganisms (Animalia,
Fungi, Plantae) constitute less than 25% and hence are dominated by
the much more abundant “lower forms of life”
the “hidden majority” of life on Earth. Since microbes are
the most ancient living beings on Earth, it follows that all
macroorganisms have evolved in a non-sterile environment
dominated by bacteria and other microbes (Kutschera and
Niklas 2004).
The genomes of animals and plants
When systems biology in its classical version was inaugurated by Bernard (1865) and Sachs (1865) (Fig. 2), physiological experiments were performed under non-sterile (realworld) conditions. To the best of our knowledge, this was
also the case when Bertalanffy (1968) and Mesarović (1968)
formally established a general systems theory 50 years ago.
However, over the past two decades, it has become apparent that humans and other eukaryotic macroorganisms are
“not alone”—they are consortia between “us” (our soma or
body cells) and “them” (the microbial partners) (Figs. 9,
10). It has been estimated that, for a “standard adult man”
(20–30 years of age; body mass 70 kg; height 170 cm), the
ratio of microbes to our body cells (84% of them are red
blood cells) is ca. 1:1. However, in a typical woman (163 cm
height), red blood cell concentration is about 10% lower,
and the blood volume is also lower by 20–30% compared to
that of a typical man. Hence, it has been estimated that the
bacteria-to-human-cell ratio is about 30% higher in females,
compared to the standard adult male (Sender et al. 2016).
Theory in Biosciences (2018) 137:117–131
These data indicate that, independent of gender, about
4 × 1013 bacteria inhabit our body (gut and outer surfaces).
Based on these and other insights, it has been documented
that humans contain three distinct genomes: the nuclear (n)
DNA, different in males/females due to the XY/XX sex
chromosomes, the mitochondrial (mt) DNA (obtained via
the egg cell, i.e., the female germ line), and the microbiome.
This third “DNA-compartment” is the genetic material of the
sum of all microbes (bacteria, fungi, protista, and viruses)
that live on the outer surfaces and inside the human body
(gut, etc.) (Sender et al. 2016; Ladstatter and TachibanaKonwalski 2016). The “healthy human microbiome” and
its functional significance have recently been described in
detail (Belkaid and Hand 2014; Honda and Littman 2016;
Lloyd-Price et al. 2016; Kowarsky et al. 2017). This topic is
beyond the scope of the present article.
In contrast to animals, plants (Figs. 2, 9) contain, in
addition to mitochondria, a second population of intracellular organelles, the chloroplasts. These “workhorses for
­CO2-fixation” (photosynthesis) evolved from once freeliving cyanobacteria (Martin 2017; Kutschera 2017a, b).
Therefore, plants are characterized by four distinct genomes:
the nDNA, the mtDNA, the microbiome, and a set of genes
coded by the chloroplast (cl) DNA. The microbiome of
typical land plants is large, but is essentially restricted to
the outer surfaces of the root system (in the soil) and the
above-ground phytosphere (shoot, i.e., stem, leaves, flowers). In contrast to the human microbiome, which also comprises numerous microbes in the blood stream (Kowarsky
et al. 2017), the plant microbiome is external and not yet
as well characterized (Kutschera 2007, 2015b, Vorholt
2012, Kutschera and Khanna 2016). However, as Vandenkoornhuyse et al. (2015) have pointed out, the microbiota
of plants, which essentially consists of bacteria and fungi,
interacts with their green host organism in a variety of ways
(nutrient uptake, resistance to pathogenic organisms, etc.;
see also Faure et al. 2018).
In the next section, I take a brief look at the biospecies
Homo sapiens. As Fig. 11 shows, humans (and their closest relatives, chimpanzees, bonobos, and gorillas) have
coevolved with their symbiotic gut microbes (Segre and
Salafsky 2016). This process has been described as “phylosymbiosis” and may be of considerable significance for
the mechanisms of organismic evolution (Richardson 2017).
Systems biology and human health
Although there is little debate about the fact that cultural
influences have been the dominant forces of change, which
have acted upon the bodies of contemporary Homo sapiens populations living in the modern world, it is obvious
that our evolutionary history has helped us adapt to survive
127
Fig. 11 Hominids (great apes and humans) coevolved with their
respective bacterial gut microbes as holobionts (superorganisms).
The speciation dates of hosts and microbes are average values (in millions of years before present, Ma). Adapted from Segre and Salafsky
(2016)
in a “natural” environment. This “lost world”—a warm,
African savanna, with green bushes, etc.—was the ecological niche where modern H. sapiens originated more than
200,000 years ago. As a result, humans of all ethnic backgrounds prefer to live in the presence of green plants, rather
than in a “gray area,” where buildings and streets dominate
the landscape. Moreover, numerous studies have shown that
sick people recover more rapidly from a variety of illnesses
in a natural, green environment, compared to a sterile hospital room that lacks living plants (Kutschera and Baluska
2015).
The principles of “Systems Medicine” were developed
based on these insights (Auffray et al. 2009; Stearns and
Koella 2008). As outlined by Lemberger (2007), it has
been obvious since the beginning of the human genome
project that the application of system-wide techniques to
the biology of H. sapiens will open up enormous opportunities in the medical sciences. A deeper understanding
of the genotype-to-phenotype relationship, the role of
gut microbes on metabolic homeostasis of the cells that
build the (eukaryotic) host organism (Honda and Littman
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128
2016), and the general finding that diseases often upset
the physiology of our body, are among the many insights
where systems biology can tremendously contribute to the
preservation of human health. For instance, many diseases
originate from cellular malfunctions. Hence, a full systems-level understanding of cell physiology is necessary
to elucidate the causes responsible for the development of
pathological phenomena (Wolkenhauer et al. 2013).
As detailed by Lieberman (2014), both men and women
are equipped with a Paleolithic anatomy and physiology, as
documented by the general shape of their respective bodies
(Fig. 12). However, we have to cope with the challenges in
a modern world, which represents a novel ecological niche
that differs considerably from the place where we evolved.
In other words, our bodies are not designed by evolution
for our current-day lifestyles. These “mismatches” are the
major cause for numerous human diseases that can only
be understood and cured within the framework of systems
biology and the holobiont concept.
Theory in Biosciences (2018) 137:117–131
Systems analysis of evolutionary change
As mentioned above, humans and all other eukaryotic
organisms evolved in a world dominated by bacteria
(Fig. 11). However, when Darwin (1859) and Wallace
(1889) published their seminal books dealing with the
basic mechanisms of biological evolution, the role of
microbes as symbionts (and pathogens) was largely unexplored. Likewise, physiology did not play a major role in
the theoretical deductions of these pioneers in the emerging evolutionary sciences. This also applies to the key
publication of August Weismann (1834–1914), who summarized his “Neo-Darwinian” theory of biological evolution in his monumentous Vorträge über Deszendenztheorie
(Weismann 1913). As a consequence, when the “Synthetic
Theory of Biological Evolution” was developed during
the 1940s, neither microbiology nor physiology was a key
component of this multi-author reformation and extension
of the Neo-Darwinian theory, also called “Weismannism”
(Reif et al. 2000; Kutschera and Niklas 2004).
The Austrian zoologist Rupert Riedl (1925–2005)
was one of the first to integrate basic principles of systems biology into a general theory of evolution, which
is also called the “expanded synthesis.” In his seminal
book Order in Living Organisms. A Systems Analysis of
Evolution, Riedl (1978) argued that the mechanisms of
evolutionary change in variable populations of organisms
can only be understood at the systems level of the individual. In a number of more recent contributions, it was
argued that the “gene-centered” synthetic theory should
be expanded, so that symbiotic interactions, physiological
functions of evolving collectives of organisms, epigenetic
processes, and other factors became key parts of a new
systems view of biological evolution (Kutschera 2008,
2017a, b; Laland et al. 2015; Noble 2013, 2017; Noble
et al. 2014; Niklas and Kutschera 2014).
Finally, it should be stressed in this context that a new
discipline, “evolutionary systems biology,” has emerged
over the past decade. The basic principles and insights of
this interdisciplinary research agenda have been summarized in a multi-author monograph (Soyer 2017).
Conclusions and outlook
Fig. 12 Systems biology as an integrative perspective of life on Earth.
Populations of organisms in all five Kingdoms (Bacteria, Protoctista,
Animalia, Fungi, and Planta) evolved into an interconnected network
of aquatic and terrestrial life. In addition to free-living microbes,
numerous bacteria and fungi live on or within all eukaryotic macroorganisms studied so far. Representative holobionts (superorganisms)
are shown in this panoptic view (aquatic/terrestrial animals, humans,
plants). Adapted from a painting of Glynn Gorick, with permission of
the artist
13
Based on their systematic studies of the function of entire
living systems (animals, plants), Bernard (1865) and Sachs
(1865) were early pioneers of systems biology (Fig. 2).
Notably, the key discovery by Bernard (constancy of the
internal environment) later evolved into Cannon’s concept
of homeostasis, which still is one of the founding ideas of
Theory in Biosciences (2018) 137:117–131
a systems approach to biological form and function (Cannon 1932; West 2010). However, due to the much more
comprehensive, seminal work of Bertalanffy (1968) and
Mesarović (1968), the formal foundation of what we today
call “systems biology” can be said to have taken place
five decades ago (Rosen 1968). As shown in the present
contribution, systems biology is an integrative discipline,
reaching from gene expression patterns via transcriptomics, proteomics, metabolomics to the entire living system
(the phenotype as a whole, see Moulia and Fournier 2009;
Penzlin 2009; Walter et al. 2015; Noble 2006, 2008, 2010,
2013, 2017). However, it should be noted that, today, systems biology is usually understood in the sense of metabolic or cell signaling networks, studied using genomics,
proteomics, and a number of other high-throughput techniques, usually with the focus on the molecular level of
biological interactions alone. This is in contrast to the multilevel interaction view we emphasize here. In other words,
our interpretation of what should be understood by systems biology goes back to the pioneers of this discipline,
taking the organism as a whole into account (Figs. 1, 2).
In the present contribution, it is shown that animals and
plants can no longer be interpreted as “stand alone entities,” but are instead to be seen as holobionts in a biosphere
full of microbes (Sleator 2010; Gordon et al. 2013; Gilbert
2014; Chiu and Gilbert 2015; Faure et al. 2018). Hence,
an integrative perspective of systems biology is proposed
here. As a result, a new approach to a “holobiontic” integrative understanding of the living world should be based
on the fact that bacteria are not only the most ancient, but
also the dominant (extant) living beings on Earth (ZimberRosenberg and Rosenberg 2008; Charbonneau et al. 2016).
This five-Kingdom network view of the biosphere is illustrated in Fig. 12, with Homo sapiens as one representative,
sexually dimorphic, integrative holobiont in the center of a
natural landscape.
Acknowledgements I thank Dr. Steve Farmer (Chief Science Officer
of the Systems Biology Group, Inc., CA, USA) for inviting me to visit
his Institution to write this article, and for helpful comments on earlier versions of the manuscript. The cooperation between S. F. and U.
K. was supported by the Alexander von Humboldt Foundation, Bonn,
Germany (Stanford 2013/2014 to U. K., Institute of Biology, University
of Kassel, Germany).
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