Functional evolution and functional biodiversity: 150 years of déjà vu or new physiology of evolution?

Research at the intersections of different scientific fields is the primary catalyst to solicit novel disciplines and expand the frontiers of knowledge. Quantum physics in chemistry and biology, artificial intelligence, nanoscience, and advances in genomic revolution with costefficient sequencing conceptually and radically changed scientific paradigms with profound public and economic impacts. The current Frontiers' research topic further stresses the need for integrative studies, advocating Eco-evo-devo as an emerging discipline of biology by expanding 'traditional evo-devo" to ecology.On a deeper level, this is a recurring and persistent déjà vu in the history of biology ever since Darwin-Wallace papers (Darwin and Wallace, 1858), when it was confirmed, and it is still impossible to understand biological phenomena without deciphering evolutionary mechanisms at all levels in changing ecosystems (using modern terminology). Arguably, this "first rigorous formulation of the concept of evolution, made just over a century ago, was the most useful one we have ever had" (Carneiro, 1972). In his masterpieces, Darwin bridged geology, ecology, biogeography, biodiversity, different types of selection, development, psychology and behaviors (Darwin, 1872;Darwin, 1880). Today, the unification of disciplines for mechanistic and systemic understanding of evolutionary processes reflects the still ongoing scientific and societal challenges under an accelerating information tsunami. Here, we emphasize two aspects of current challenges demanding integrative approaches.The first problematics (more elaborated in this opinion) is the bottleneck in education, when the evolutionary training and biosystematics courses, which deal with the most fundamental concepts in biology, have quietly lost their place of eminence within the biomedical curriculum-"outcompeted" by escalating specialization and the increasingly technical nature of many disciplines (Moroz, 2010).The second problematics is an equally critical bottleneck in our understanding of functional evolution (Fig. 1) as hierarchical architectures of real-time physiological and metabolic/biochemical interactions underlying mechanisms of adaptations that can explain the biodiversity dynamics on the changing planet. The incorporation of a physiological web of life into 'genomic' evolution will better forecast biota's resilience to environmental stressors. That is functional biodiversity -the strategy to marry physiology at all levels of organizations (from genomes to behaviors) with classical biodiversity to understand micro-and macro-evolution. We stress the more integrative term of functional evolution in changing ecosystems rather than the evolution of particular functions, that is, the multilevel reconstruction of the history of individual traits from proteins to behaviors, also known as evolutionary physiology. In these definitions, numerous details of the evolution of diverse functions in cells, tissue, and organs' systems have to be united as components of functional evolution (Fig. 1). In the broadest sense, we should not differentiate the terms "functional evolution" from "evolution" as such. We emphasize that the current evolution studies need significantly more physiological approaches rather than overdominance of gene-centric approaches by continuing to focus on genes and genomes and then 'jump' to organismal phenotypes without real-time physiological studies. Thus, modern physiology of evolution is a richer and broader framework, where a web of functions is understood at different levels, as opposed to the gross (organismal) definition of function in changing ecosystems.Competition and selection occur at all levels of physiological integration, requiring more research on traits critical to decision-making, including learning and memory, homeostatic mechanisms, adaptive metabolism, and immunity (Fig. 2). We especially point out the necessity of understanding organisms as highly dynamic hierarchical systems subjected to selection that work on semi-autonomous integrated systems with emergent properties at each level of increased complexity. Such architectures can be viewed as the collective intelligence of heterogeneous cell populations both in simpler and complex metazoans (from placozoans to cuttlefishes) with social behaviors.Functional evolution also embraces the phenomena of physiological selection (Romanes and Moulton, 1886) and the so-called Baldwin effect (Baldwin, 1896c;Morgan, 1896;Osborn, 1896;Baldwin, 1897;Simpson, 1953;Newman, 2002;Sznajder et al., 2012). Here, the ability to adaptability accelerates evolution by forming, and even making, novel internal and environmental adaptive spaces, therefore giving extra time for natural selection to act; and favoring a broader range of physiological, epigenetic, stereotyped, and learned behavioral outcomes as feedback mechanisms and platforms for functional evolution.What is remarkable -these critical integrative questions and directions have been recurrently emerging over and over again for 150 years, sometimes with changes in the scope and meaning of terms. Thus, it would be informative to refer to the history of terms briefly, and then summarize past and modern frameworks.Physiology is somewhat a missing elephant in a palace of evolutionary biology today and evo-devo in particular. The term physiology is derived from the ancient Greek φύσις (phúsis -'nature, origin') and -λογία (-logía -'study of') (Fletcher, 1835;Gontier, 2024) and traced back to 1628 -the classical work of William Harvey on blood circulation with a remarkable integrative conceptual framework (Harvey, 1628;Whitteridge, 1964;Whitteridge, 1978). The American Physiological Society defines physiology as the science of life (https://www.physoc.org/explorephysiology/what-is-physiology/), and its primarily based on dynamic cellular-molecular interactions. In this sense, the subject of physiology is the living systems (i.e., cells and organisms with self-autonomous respective integrative functions) vs. studies of non-living systems, which include the deciphering of gene sequences, or locations of their expression, subcellular molecular ensembles (and even gene regulatory networks as an array of regulatory components vs. functional networks within defined cell and organismal homeostasis identity and behaviors).For all definitions, the key to the strategy of physiology is the integration and real-time interactions of organismal multifunctional networks to obtain energy, survive, and reproduce (Fig. 2). In this sense, Darwin and Wallace were comparative integrative physiologists and ecologists who worked to decipher the origin of species. In fact, Darwin was a member of the Physiological Society from the very beginning of its foundation in 1876 (Sharpey-Schafer, 1927), collaborating with physiologists on mechanisms of selection (Romanes and Moulton, 1886), see details in (Noble and Noble, 2023a).Literally, the word evolution means 'unrolled', which refers to ancient books that were rolled on wooden rods (McCabe, 1921), gradually transforming to Bonnet's unfolding of the human embryo from a perfectly formed "homunculus", and eventually to the concept of 'descent with modification', theories and facts (Mayr, 2001) illuminating causes, tempo, and mechanisms of the 3.5+ billion-year life history on our planet with 10-100 million of extant species, including 33 animal phyla, changing global ecosystems.As noted by (Carneiro, 1972), because of the original doctrine of preformations (e.g., reading of an already written text in rolled books or unfolding of a tiny preexisting homunculus), Lamark did not use the term evolution in his famous book (Lamarck, 1809), focusing on the role of physiology in the development of emerging properties. Interestingly, Darwin also did not use the term evolution throughout the text of the first five editions of his "Origins of Species". Darwin concluded, however, his masterpiece with the word "evolved". Spencer's evolution terminology preempted biology (Spencer, 1863) with the famous "survival of the fittest" at the complex interplay with the environment.Soon, evolutionary embryology concepts led to impactful theories of animal origins, known as Gastrea (Haeckel, 1874) and Phagocytella (Metschnikoff, 1886). Thus, integrative and comparative biology at the end of the XIX century can already be viewed as eco-evo-devo in modern terms. Furthermore, Metschnikoff's phagocytella concept included the unification of cell physiology and immunity (phagocytosis) to explain system mechanisms of the germ layers' formation as predecessors and factors for functional evolution in general and the origins of developmental processes (e.g., gastrulation) in particular. These views were conceptually different from past preformation theories by employing dynamic physiological processes (rather than static morphology) as subjects of selection and adaptation.The evolutionary focus shifted early to real-time physiology, where mechanistic questions 'how' ('what for') something works were coupled with the questions of 'why' this system works in such a particular way (or 'how come' - (Mayr, 1961)) as a result of its genealogy and long planetary history. Why do we observe certain types of cellular or systemic organizations in ctenophores, placozoans, cnidarians, molluscs, arthropods, or chordates instead of others? These "why" questions target both primary causes and exaptations (Gould and Vrba, 1982) to reconstruct the extant functional biodiversity in ecosystems.Why, for example, are individual neurons so different from each other within a given species and across phyla? One possible answer is the functional demands within a given neural circuit and behavior. Another is that each distinct neuronal population forming complex neural nets or brains has a different evolutionary history, and, as a result, neurons carry the heavy molecular burdens of primordial integrative systems within their complex evolutionary pastneurons are also different because they have different genealogies. In other words, neurons might independently evolve from distinct types of secretory cells with different secretory products and functional interactions. These multilevel interactions could be preserved over many million years, therefore explaining the astonishing diversity of signal molecules in the brains and complex dynamics of extant chemoconnectomes (Fig. 2) as a result of their deep ancestry (Moroz, 2014;2021). Such distinctive cellular ancestries and integrative mechanisms might either limit or facilitate future evolutionary opportunities to adapt to changeable environments. In other words, past evolutionary history might provide constraints for the emergence of novel behaviors within a given time or resistance to stress, disease, or injury. Remarkable examples of extensive parallel evolution of physiological functions (compared to morphology) exist within all animal phyla, enabling forecasts for resilience (or not) to anthropogenic or climate changes. Yet, new experimental designs are needed to reveal and explain the origins or loss of biological complexity, and past or ongoing extinctions of species and ecosystems.As stressed by one of the reviewers: "Understanding the "physiological functional web of life" in modern terms means gaining better purchase on how, why, when, and with whom eukaryotic cells choose to partner for their physiological mechanisms that propel evolutionary solutions to cellular problems." Holozoan animal ancestors evolved in Ediacaran ecosystems dominated by prokaryotes. And, as in today's ecosystems, microbiome complexity continues to shape, drive, and even dramatically change paths of evolutionary trajectories via cross-kingdom signaling (Heyland and Moroz, 2005) and horizontal gene transfer (HGT) with omnipresent viromes, further contributing to animal innovations via transposon-derived transcription factors (Mukherjee and Moroz, 2023), for example. By itself, it fully justifies the efforts to preserve the entire biodiversity from microbes (Averill et al., 2022) to all eukaryotes as primary preconditions of Planetary Health (Bertram et al., 2024).Even Aristotle noted that living organisms are 'causes of themselves (Okasha, 2024), which, in modern terms and our perception, refers to the physiology. As a separate discipline, evolutionary physiology was not established for nearly a century since Darwin (Orbeli, 1941;1961;Natochin and Chernigovskaya, 1997;Svidersky, 2002;Natochin, 2009;Natochin, 2017).In part, this situation was due to the complexity of processes and emerging systemic properties of multicellular interactions across phyla. The deficit of studies on the evolution of functions was clearly recognized early in the XX century (Lucas, 1909). The term "evolutionary physiology" was coined by A.N. Severtzov in 1914 to complement what was already established by that time as evolutionary morphology and development (Severtzov, 1914;Natochin, 2010). Physiology was then and remains today the most integrative approach for functional evolution, inherently focused on real-time interactions of myriads of molecular and cellular processes leading to organismal homeostasis with stereotyped and learned behaviors.The original framework of evolutionary physiology and functional evolution (Fig. 1) included the natural integration of (a) comparative and ecological physiology coupled with neural controls, (b) ontogenesis, (c) clinical studies, including stress, recoveries (or not) from numerous pathologies, and (d) the development of unique experimental methodology (Orbeli, 1941;1961). If the first two approaches were traditional from the very beginning of evolutionary thoughts, the remaining two were entirely novel in the 1940s-1960s and still not yet well established to enable sufficient cross-links across fields. Leon Orbeli developed an earlier strategy for evolutionary physiology (Fig. 1), specifically with interpretations of medical pathologies in evolutionary terms as well as insights into the evolution of ion transport and homeostasis (Orbeli, 1941;1961;Ginetzinsky, 1996). 60 years ago, in the USSR, under the leadership of Orbeli formed the laboratory, and then the Institute of Evolutionary Physiology and Biochemistry (1956); the Journal of Evolutionary Biochemistry and Physiology was established in 1965. A new wave of reviews occurred 30 years later (in the 1990-2000s), calling for a renaissance in the field with more focus on molecular mechanisms (Garland and Carter, 1994;Feder et al., 2000;Garland et al., 2016;Galván et al., 2022).Today, with many thousands of genomes sequenced, evolutionary approaches in biomedicine have gained momentum with successful stories that explain specific adaptations to various pathogens, preconditions, preventive diagnostics for Mendelian diseases, and forecast of outcomes as parts of personalized medicine. Most pathologies might recruit or be constrained by ancestral gene/cellular regulatory programs and signaling networks under stressful disease-driven tissue microenvironments. For example, particular modern human adaptations or constraints were acquired from the Neanderthal ancestry and beyond, and most of them are deeply embedded in the dynamics of metabolic architectures (Zeberg et al., 2024), rather than specific genes for cognitive capabilities. All these events were affected by countless environmental factors over thousands of generations, with even deeper evolutionary ancestral innovations due to the modularity of multidomain protein assemblies (McCoy and Fire, 2024;Moroz, 2024).We highlight the recent strong statements by Denis Noble: (i) Physiology restores purpose to evolutionary biology (Noble and Noble, 2023a); (ii) Genes are not the blueprint for life (Noble, 2024). In Noble's words: "The genome is not a code, blueprint or set of instructions. It is a tool orchestrated by the system" (Noble and Noble, 2023b). First, because the vast majority of genes do not have a single 'pre-set' function that can be from their with examples of of ion in of cells and organismal behaviors (Noble, due to the of regulatory are properties of complex living systems, which can not be from properties of individual Here, we emphasize that real-time physiology in natural (in can the integrative of life as we under the to the to to to we do not deep in time we can the origins of organismal integrative systems (e.g., and - (Moroz, or mechanisms of integration in particular cell is a of the genome within specific cellular and organismal properties of genome with thousands of genes in each cell are and to as a with of individual cells in the human with more than genes in each cell the of such complexity to be approaches or of particular functions are not due to mechanisms and of molecular and system signaling and with of a of so-called organisms a animal out of and of extant metazoans (Moroz, As a result, a broader concept of species has been et al., the of diverse from ecological across all are that the comparative strategy is needed and it can be and should be in the time by learning from by over years of biological evolution with the of field (Moroz, work led by and and et al., 2022) in of cellular and adaptations both and conceptual in these integrative and and real-time of cellular dynamics can be integrated with the of life including the of functional networks from cell populations and signal molecules with deciphering events of evolution and of cell therefore transforming the animal of life into the cell and physiological functional web of novel are for real-time and of molecular and cellular dynamics to the interplay and in changing from evolutionary biology and, in many evolutionary biology was within physiology and medical in has physiology been in Evolutionary (Noble, Denis it profound with a of of evolutionary physiology were in the XX they lost their on modern evolutionary that eco-evo-devo and without real-time physiology. In comparative real-time physiological studies in natural in the are needed for functional biodiversity and physiology of evolution at all levels of biological from cells to We focus on so-called such as and and and which, by their and species to and even thousands of traced signaling from cells to are physiological processes that and Here, we the as the of evolution (Mayr, critical for most ecological adaptations and stress resilience on the changing planet. As by one of the reviewers: behaviors all of evolution from its and complex of stereotyped and learned behaviors at the cellular-molecular do these behaviors genomic and functional across cell types and do behaviors, and complex or learned of multicellular in adaptive behavioral of these physiological processes in evolution, known as the Baldwin (Baldwin, 1896c;Morgan, 1896;Osborn, 1896;Baldwin, 1897;Simpson, has with the of its in natural selection and with origins of complex behaviors or (Baldwin, and et al., all behaviors can be by of learning is traced to the of animal evolution as a of and Moroz, by a of signal molecules and secretory et al., and that expand cellular dynamics and at all behavioral learning can dramatically it in cells germ cells or and then genes as and studies on simpler neural systems of and changes by and and genes as and et al., et al., et al., et al., et al., et al., Thus, behaviors, and time and for evolutionary for or learned integrative mechanisms also inherently the and definition of and in evolution (Mayr, et al., and Noble, would such dynamics and propel physiological interactions and adaptability in The modern framework of the biological as a self-autonomous (Okasha, 2024) with and is also a with a focus on experimental deciphering emerging properties (from cells to that are not from a gene-centric Here, experimental can be viewed as not that cell ensembles or organisms to in their social rather they as they (Okasha, 2024). It would an understanding of still integrative of over the which is an species to evolve with their and in and we the to in evolutionary physiological terms is not to at In the conceptual sense, means of (Noble, The the physiology of evolution and functional biodiversity are and parts of biomedical the we can from a new of in the the laboratory, and in natural we need to include evolution and biodiversity, in the not in medical and all biomedical training also as a in the of and for the Planetary Health and across scientific fields and and its were also united as classical Evolutionary evolution the of understanding all biological functions from the molecular level to the and these changes to species and this framework, the conceptually term Physiology of further the of physiological approaches to understanding these terms and research strategy do not the concept of we emphasize the need for more to real-time physiological aspects of various biological focusing on integrative mechanisms such as and functional interactions at the of the organismal and behavioral with at the of the behavioral and neuronal The integrative systems primarily signaling or the which embraces a of with of and The is the of most ancestral architectures of integrative mechanisms, inherently coupled across all levels of biological in The of emerging physiological and mechanisms in changing ecosystems can dramatically the adaptive for evolutionary innovations (Baldwin, 1896c;Morgan, 1896;Osborn, 1896;Baldwin, and with more and 1996). Here, we stress that real-time integrative systems are for all evolutionary and with systems and adaptive behaviors at the of the organismal for most animal at all from molecules and genome to and the that hierarchical integrated systems are subjected to selection also at different levels and with emergent properties at each framework physiology and approaches to understand evolutionary