Systems biology of eukaryotic superorganisms and the holobiont concept

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. Mesarovi?, 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.     

Self-organization at the origin of life

The concept of an (M,R) system with organizational invariance allows one to understand how a system may be able to maintain itself indefinitely if it is coupled to an external source of energy and materials. However, although this constitutes an important step towards understanding the difference between a living and a non-living system, it is not clear that an (M,R) system with organizational invariance is sufficient to define a living system. To take a further step towards defining what it means to be alive it is necessary to add to a simple (M,R) system some property that represents its identity, and which can be maintained and modified in subsequent generations.     

Rethinking the role of theory in exploratory experimentation

To explain their role in discovery and contrast them with theory-driven research, philosophers of science have characterized exploratory experiments in terms of what they lack: namely, that they lack direction from what have been called “local theories” of the target system or object under investigation. I argue that this is incorrect: it’s not whether or not there is direction from a local theory that matters, but instead how such a theory is used to direct an experiment that matters. Appealing to contemporary exploratory experiments that involve the use of experimental techniques—specifically, examples where scientists explore the interaction of neural activity and human behavior by magnetically stimulating brains—I argue that local theories of a target system can inform auxiliary hypotheses in exploratory experiments, which direct these experiments. These examples illustrate how local theories can direct the exploration of target systems where researchers do not aim to evaluate these theories.     

On a formal definition of organization

A mathematic definition is proposed to account for the intuitive features of what is usually meant by organization. To account for both functional and structural aspects of organization the rate at which information content of a system changes in time is examined. It can be shown that Shannon's expression for ambiguity in a channel has two different meanings according to whether one is interested in the information transmitted in the channel or in the information transmitted to the observer from a whole system in which the channel is a part of a redundant communication network. This was applied in a previous work to show that the effects of noise on the information content H of a system result in two kinds of ambiguities, “autonomy-producing” and “destructive” leading to increase and decrease in H, respectively. By making use of this observation and Shannon's definition of redundancy R, a single equation for $\text{d}\text{H}\text{dt}$ is proposed to define organization on the basis of a kinetics of change of information content of a system under the effects of environmental noise-producing factors accumulated in time. It is shown how these factors, obviously responsible for a decrease in H, i.e. a “disorganizing” effect, can be responsible also—under certain conditions and up to a certain time or “dose” of noise—for an initial increase in H interpreted as a process of “self”-organization. The autonomy-producing ambiguity is expressed by a term of decrease in redundancy, while a second term in the equation, of decrease in maximum-non-redundant-information content expresses the destructive ambiguity. A given organization is defined at least by three parameters, which determine the main features of its characteristic function H(t). One of them is the initial information content H₀ and has a structural meaning. A second parameter, with a dimension of time, has the meaning of a functional reliability, related to the overall resistance of the system to noise-producing factors. The third parameter, namely the initial redundancy R₀, is both structural and functional in character, since structural redundancy is known to help insure reliability. Various conditions on these parameters lead to various kinds of organizations, with and without self-organizing properties.     

Vector borne diseases on an urban environment: The effects of heterogeneity and human circulation

We study the effect of human circulation and host/vector heterogeneities on the onset of epidemics of arboviruses. From a meta-population dynamics based on the classical Bailey–Dietz model, we derive a multi-group model under three assumptions: (i) fast host sojourn time-scale; (ii) mosquitoes do not move; (iii) time homogeneity and strong connectivity of human circulation. Within this modelling framework, three different kinds of R₀ appear: (i) the “true” or “global” R₀—derived from the corresponding next generation matrix; (ii) the uniform R₀—obtained if the patches are taken homogeneous; (iii) the local R₀s—obtained if the patches are disconnected. We show that there is relevant epidemiological information associated to all of them. In particular, they can be used to understand the effects of changing the circulation on the value of the global R₀. We also present additional results on the effects on R₀ of different vector control policies, and a simulation with data from the city of Rio de Janeiro, Brazil.     

Cellular systems as graphs

The definition of an (M,R) is formulated in a way that emphasizes its mathematical properties. Neglecting interactions between the components, it is shown that:

1. An (M,R) contains only one non-reestablishable component.
2. If an (M,R) contains only one non-reestablishable component, then that component is central.

Examples are given to illustrate the biological significance of these two results. The notion of “lag-independence” is introduced, and it is shown that if a system possesses only one non-reestablishable component which is “lag-independent” then all components are lag-independent. The concepts of reestablishability, centrality and lag-independence are applied in order to suggest various criteria for optimal organization of (M,R).     

Reversed-phase thin-layer chromatography in the parametrization of lipophilicity of some series of arylaliphatic acids

In the series of arylacetic acid and β-aryl-n-butyric acids, chromatography was carried out on a thin layer of silica gel impregnated with silicone oil, with 50% acetone as mobile phase. A separation mechanism in this system was evaluated using relationships between R_M values and the concentration of the lipophilic solvent in the silica-gel layer. It was found, that both partition and adsorption mechanisms participate, and that the adsorption effect increases with decreasing lipophilicity of the acids. The dichotomy of the mechanism manifests itself in the non-linear course of the relationships between R_M values and π parameters, or fragmental constants f derived from the partition system n-octanol—water. Such relationships can be expressed by a single quadratic dependence between lipophilic parameters and R_M values, or by two separate linear expressions with different slopes for different regions of substituent lipophilicities. The linear dependence between R_M and π at the lower range of lipophilicity is most probably made possible by significant linear dependence between π parameters and molecular surface areas of the substituents.     

The “tropical lineage” of the brown dog tick Rhipicephalus sanguineus sensu lato identified as Rhipicephalus linnaei ()

The brown dog tick (Rhipicephalus sanguineus) parasitises dogs. Over the past decade, two distinct lineages have been recognised – R. sanguineus sensu lato “temperate lineage” and R. sanguineus sensu lato “tropical lineage”. The nominal taxon R. sanguineus (Latreille, 1806) was recently associated with the “temperate lineage”. We here identify the “tropical lineage” as Rhipicephalus linnaei (Audouin, 1826) using material from Australia, where no other Rhipicephalus species parasitises dogs. Whole genome sequencing of R. linnaei from Australia, Fiji and Laos, and assembly of their complete mitochondrial DNA (~15 kb) confirms the genetic identity and distinctness from all other known species within the brown dog tick species complex. Designation of the species R. linnaei is unequivocally supported by material available through the Australian National Insect Collection, Australia. Accordingly, we are formally justified in using R. linnaei for the “tropical lineage”.     

Migratory history of Rhinogobius sp. OR morphotype “Shimahire” as revealed by otolith Sr:Ca ratios

The migratory history of the Rhinogobius sp. OR morphotype “Shimahire” collected from a slower current environment in the Maruyama River, the Ibo River, and the Kako River, Japan, was studied by examining the strontium and calcium concentrations in the otoliths. The otolith Sr:Ca ratios of almost all samples showed consistently low ratios from the core to the edge, reflecting the fact that the organisms had been living in a freshwater environment their entire lives. The ratios of Rhinogobius sp. CB and Rhinogobius flumineus living in the sympatric habitats with the Rhinogobius sp. OR morphotype “Shimahire” in the Kako River showed an amphidromous and fluvial life cycle, respectively. These findings suggest that the Rhinogobius sp. OR morphotype “Shimahire” has a freshwater resident life cycle.     

Plant indicator values of a high-phytodiversity country (Italy) and their evidence,exemplified for model areas with climatic gradients in the southern inner Alps

We tested the new Ellenberg–Pignatti indicator values in Festucetalia valesiacae communities of three valley regions (southern inner Alps: Valle d’Aosta, Valtellina, Valle Venosta/Vinschgau). In these landscape types gradients of all value types exist: light (L), temperature (T), moisture (F/M), nitrogen (N), continentality (C) and soil reaction (R). L- and T-values were extended from 9 to 12 in the database of Pignatti due to the higher intensity of these factors in the area in question; in our dataset this is especially relevant for the L-values.In a spatial approach, we compared DCA results with indicator value results (presence–absence) and with climatic data for eight different plant communities. We found comprehensible results in all cases, also for the extension of the L-factor.In a temporal approach, we compared relevés and their indicator values from two time windows: 1930–1950 (Braun-Blanquet) and 1990–1995 (Schwabe and Kratochwil) for six of the eight different plant communities. Both relevé types were made in the same or in similar localities, but no permanent plots existed. Mostly we found in these communities, which are said to have high “stability”, no significant changes on average for any of the indicator values. In the case of N- and R-values there was a trend of increase in the different datasets, and in some cases this trend is significant.In general, the new database has shown the “robustness” of the Ellenberg indicator value model including the extended L-values, and established its usefulness for a synthetic approach in the studied valley systems. In our systems L-, T-, F/M- and C-gradients can be characterised well by means of indicator values and are an excellent tool for explaining DCA results. Caution is necessary especially when correlations of different factors are intermingled in temporal approaches.     

Sex and the fixation of single favourable mutations

Sexual populations will accumulate favourable mutations more rapidly than asexual populations. This is true if it is often the case that two different favourable mutations can be found to be spreading simultaneously through populations. It is argued here that sexual species will incorporate single favourable mutations more quickly than asexual “species”, if the latter are multi-clonal. Thus one mutation can spread to fixation within a sexual species but in an asexual “species” with N_c clones at least N_c mutations must occur if the mutation is to be subsequently found in every member of the “species”. Asexual “species” may minimise this disadvantage by evolving polyploidy or occasional episodes of hybridisation. Both are in fact common in asexual “species”.     

Can an Engineer Fix an Immune System?–Rethinking theoretical biology

In an instant classic paper (Lazebnik, in Cancer Cell 2(3); 2002: 179–182) biologist Yuri Lazebnik deplores the poor effectiveness of the approach adopted by biologists to understand and “fix” biological systems. Lazebnik suggests that to remedy this state of things biologist should take inspiration from the approach used by engineers to design, understand, and troubleshoot technological systems. In the present paper I substantiate Lazebnik’s analysis by concretely showing how to apply the engineering approach to biological problems. I use an actual example of electronic circuit troubleshooting to ground the thesis that, in engineering, the crucial phases of any non-trivial troubleshooting process are aimed at generating a mechanistic explanation of the functioning of the system, which makes extensive recourse to problem-driven qualitative reasoning possibly based on cognitive artifacts applied to systems that are known to have been designed for function. To show how to translate these findings into biological practice I consider a concrete example of biological model building and “troubleshooting”, aimed at the identification of a “fix” for the human immune system in presence of progressing cancer, autoimmune disease, and transplant rejection. The result is a novel immune system model—the danger model with regulatory cells— and new, original hypotheses concerning the development, prophylaxis, and therapy of these unwanted biological processes. Based on the manifest efficacy of the proposed approach, I suggest a refocusing of the activity of theoretical biologists along the engineering-inspired lines illustrated in the paper.     

On Some Problems in Measuring Change on Ordinal Data

Two designs frequently occurring in biomedicine and social sciences are considered—the “experts”/“objects”—design consisting in ranking M fixed “objects” by each of N “experts” before and after an intervention, and the rating-scale-design in which N judges are asked to assign one of K given lables, constituting the rating-scale, before and after an intervention. Nonparametric test procedures are proposed for evaluating the treatment effect.     

Concepts of macro- and microevolution as related to the problem of origin and global expansion of the plague pathogen Yersinia pestis

The relationship between macro- and microevolutionary processes is considered with reference to the ecological scenario of the origin of the plague pathogen and its subsequent natural and anthropogenic global expansion. The macroevolutionary transformation of the ancestral pseudotuberculosis microbe clone into the initial plague microbe Yersinia pestis tarbagani occurred in Central Asia at the end of the Late Pleistocene by a “vertical” Darwinian way in an inadaptive heterothermal continual intermediate environment—the Mongolian marmot Marmota sibirica—flea Oropsylla silantiewi system—via a sequence of unstable and currently extinct intermediate forms. Its natural geographic expansion on the “oil spot” principle in the postglacial time led to the microevolutionary formation of 20–30 hostal subspecies circulating in populations of the background species of burrowing rodents and pikas in arid areas of Eurasia. The intercontinental spread of the “marmot” and “rat” pathogen subspecies in the past few centuries has been exclusively anthropogenic, with the involvement of synanthropic (ship) rats.     

Levels or Domains of Life?

In the case of living beings – the very concept of “level” of organization becomes obscure: it suggests a value-based assessment, assigning notions like “lower” and “higher” with rather vague criteria for constructing the ladder of perfection, complexity, importance, etc. We prefer therefore the term “domain”, entities ranking equal. Domains may represent natural entities as well as purely human constructs developed in order to gain understanding of some facets of living things; living, evolved beings (e.g. viviparous animals, eukaryotic cells, etc.) as well as those abstract constructs, such as genotype and ‘niche’ which have been developed in the search for better understanding of such living things. Delimitation of such domains is sometimes a question of the dexterity of the researcher, and sometimes draws from the tradition in a given field. Such domains are not completely (canonically) translatable to each other. Rather, they interact by a process that we call here reciprocal formation. Life (including the biosphere and human cultures which are emergent within the frame of the biosphere) is unique among multi-domain systems. In contrast to purely physical systems, life is a semiotic system driven by the historical experience of lineages, interpreted and re-interpreted by the incessant turnover of both individuals and their communities. This paper provides cases of domain interrelations, and addresses two questions: (1) How do new qualities of inter-domain interaction emerge historically? (2) How do new domains (ways of understanding the world) emerge in evolution. Two approaches, physical and biosemiotic, are discussed as we seek to get a better understanding of the overarching tasks.     

Intermembrane electron transport in the absence of added water-soluble carriers

Electron transport from untreated to mersalyzed microsomal vesicles at the level of NADH-cytochrome b₅ reductase or cytochrome b₅ has been demonstrated in the absence of added water-soluble electron carriers. A similar effect was shown in the systems “intact mitochondria — mersalyzed microsomes” and “mersalyzed mitochondria— untreated microsomes”. No measurable electron transport between intact and mersalyzed particles of inner mitochondrial membrane was found. The obtained data suggest that the capability to carry out intermembrane electron transfer is specific for NADH-cytochrome b₅ reductase and/or cytochrome b₅, localized in microsomal and outer mitochondrial membranes.     

Morphogenetic networks which determine the spatial expression of zygotic genes in early <Emphasis Type="Italic">Drosophila</Emphasis> embryo

This review deals with the recent studies expanding the idea of positional information in the early embryogenesis of Drosophila melanogaster. Previous studies showed that, in the course of segment determination in Drosophila, information created by gradients of products of maternal coordinate genes is not “read” statically, being interpreted by their zygotic target genes via regulatory interactions. This leads to spatial shifts in the expression of target genes relative to the original positions as well as to dynamic reduction in the zygotic expression variability. However, according to recent data, interpretation of positional information includes the interaction between not only zygotic target genes but also the maternal coordinate genes themselves. Different systems of maternal coordinate genes (maternal systems)—the posterior-anterior, terminal, and dorsoventral—can interact with each other. This is usually expressed in the regulation of zygotic target genes of one maternal system by other maternal systems. The concept of a “morphogenetic network” was introduced to define the interaction of maternal systems during determination of spatial gene expression in the early Drosophila embryo.