A third transition in science?

Since Newton, classical and quantum physics depend upon the 'Newtonian paradigm'. The relevant variables of the system are identified. For example, we identify the position and momentum of classical particles. Laws of motion in differential form connecting the variables are formulated. An example is Newton's three laws of motion. The boundary conditions creating the phase space of all possible values of the variables are defined. Then, given any initial condition, the differential equations of motion are integrated to yield an entailed trajectory in the prestated phase space. It is fundamental to the Newtonian paradigm that the set of possibilities that constitute the phase space is always definable and fixed ahead of time. This fails for the diachronic evolution of ever-new adaptations in any biosphere. Living cells achieve constraint closure and construct themselves. Thus, living cells, evolving via heritable variation and natural selection, adaptively construct new-in-the-universe possibilities. We can neither define nor deduce the evolving phase space: we can use no mathematics based on set theory to do so. We cannot write or solve differential equations for the diachronic evolution of ever-new adaptations in a biosphere. Evolving biospheres are outside the Newtonian paradigm. There can be no theory of everything that entails all that comes to exist. We face a third major transition in science beyond the Pythagorean dream that 'all is number' echoed by Newtonian physics. However, we begin to understand the emergent creativity of an evolving biosphere: emergence is not engineering.

Quantum aspects of the brain-mind relationship: A hypothesis with supporting evidence.

If all aspects of the mind-brain relationship were adequately explained by classical physics, then there would be no need to propose alternatives. But faced with possibly unresolvable puzzles like qualia and free will, other approaches are required. In alignment with a suggestion by Heisenberg in 1958, we propose a model whereby the world consists of two elements: Ontologically real Possibles that do not obey Aristotle's law of the excluded middle, and ontologically real Actuals that do. Based on this view, which bears resemblance to von Neumann's 1955 proposal (von Neumann, 1955), and more recently by Stapp and others (Stapp, 2007; Rosenblum and Kuttner, 2006), measurement that is registered by an observer's mind converts Possibles into Actuals. This quantum-oriented approach raises the intriguing prospect that some aspects of mind may be quantum, and that mind may play an active role in the physical world. A body of empirical evidence supports these possibilities, strengthening our proposal that the mind-brain relationship may be partially quantum.

The hiatus between organism and machine evolution: Contrasting mixed microbial communities with robots.

Mixed microbial communities, usually composed of various bacterial and fungal species, are fundamental in a plethora of environments, from soil to human gut and skin. Their evolution is a paradigmatic example of intertwined dynamics, where not just the relations among species plays a role, but also the opportunities - and possible harms - that each species presents to the others. These opportunities are in fact affordances, which can be seized by heritable variations and selection. In this paper, starting from a systemic viewpoint of mixed microbial communities, we focus on the pivotal role of affordances in evolution and we contrast it to the artificial evolution of programs and robots. We maintain that the two realms are neatly separated, in that natural evolution proceeds by extending the space of its possibilities in a completely open way, while the latter is inherently limited by the algorithmic framework in which it is defined. This discrepancy characterizes also an envisioned setting in which robots evolve in the physical world. We present arguments supporting our claim and we propose an experimental setting for assessing our statements. Rather than just discussing the limitations of the artificial evolution of machines, the aim of this contribution is to emphasize the tremendous potential of the evolution of the biosphere, beautifully represented by the evolution of communities of microbes.

Quantum Gravity If Non-Locality Is Fundamental.

I take non-locality to be the Michelson-Morley experiment of the early 21st century, assume its universal validity, and try to derive its consequences. Spacetime, with its locality, cannot be fundamental, but must somehow be emergent from entangled coherent quantum variables and their behaviors. There are, then, two immediate consequences: (i). if we start with non-locality, we need not explain non-locality. We must instead explain an emergence of locality and spacetime. (ii). There can be no emergence of spacetime without matter. These propositions flatly contradict General Relativity, which is foundationally local, can be formulated without matter, and in which there is no "emergence" of spacetime. If these be true, then quantum gravity cannot be a minor alteration of General Relativity but must demand its deep reformulation. This will almost inevitably lead to: matter not only curves spacetime, but "creates" spacetime. We will see independent grounds for the assertion that matter both curves and creates spacetime that may invite a new union of quantum gravity and General Relativity. This quantum creation of spacetime consists of: (i) fully non-local entangled coherent quantum variables. (ii) The onset of locality via decoherence. (iii) A metric in Hilbert space among entangled quantum variables by the sub-additive von Neumann entropy between pairs of variables. (iv) Mapping from metric distances in Hilbert space to metric distances in classical spacetime by episodic actualization events. (v) Discrete spacetime is the relations among these discrete actualization events. (vi) "Now" is the shared moment of actualization of one among the entangled variables when the amplitudes of the remaining entangled variables change instantaneously. (vii) The discrete, successive, episodic, irreversible actualization events constitute a quantum arrow of time. (viii) The arrow of time history of these events is recorded in the very structure of the spacetime constructed. (ix) Actual Time is a succession of two or more actual events. The theory inevitably yields a UV cutoff of a new type. The cutoff is a phase transition between continuous spacetime before the transition and discontinuous spacetime beyond the phase transition. This quantum creation of spacetime modifies General Relativity and may account for Dark Energy, Dark Matter, and the possible elimination of the singularities of General Relativity. Relations to Causal Set Theory, faithful Lorentzian manifolds, and past and future light cones joined at "Actual Now" are discussed. Possible observational and experimental tests based on: (i). the existence of Sub- Planckian photons, (ii). knee and ankle discontinuities in the high-energy gamma ray spectrum, and (iii). possible experiments to detect a creation of spacetime in the Casimir system are discussed. A quantum actualization enhancement of repulsive Casimir effect would be anti-gravitational and of possible practical use. The ideas and concepts discussed here are not yet a theory, but at most the start of a framework that may be useful.

Attractor-Specific and Common Expression Values in Random Boolean Network Models (with a Preliminary Look at Single-Cell Data).

Random Boolean Networks (RBNs for short) are strongly simplified models of gene regulatory networks (GRNs), which have also been widely studied as abstract models of complex systems and have been used to simulate different phenomena. We define the "common sea" (CS) as the set of nodes that take the same value in all the attractors of a given network realization, and the "specific part" (SP) as the set of all the other nodes, and we study their properties in different ensembles, generated with different parameter values. Both the CS and of the SP can be composed of one or more weakly connected components, which are emergent intermediate-level structures. We show that the study of these sets provides very important information about the behavior of the model. The distribution of distances between attractors is also examined. Moreover, we show how the notion of a "common sea" of genes can be used to analyze data from single-cell experiments.

On the Criticality of Adaptive Boolean Network Robots.

Systems poised at a dynamical critical regime, between order and disorder, have been shown capable of exhibiting complex dynamics that balance robustness to external perturbations and rich repertoires of responses to inputs. This property has been exploited in artificial network classifiers, and preliminary results have also been attained in the context of robots controlled by Boolean networks. In this work, we investigate the role of dynamical criticality in robots undergoing online adaptation, i.e., robots that adapt some of their internal parameters to improve a performance metric over time during their activity. We study the behavior of robots controlled by random Boolean networks, which are either adapted in their coupling with robot sensors and actuators or in their structure or both. We observe that robots controlled by critical random Boolean networks have higher average and maximum performance than that of robots controlled by ordered and disordered nets. Notably, in general, adaptation by change of couplings produces robots with slightly higher performance than those adapted by changing their structure. Moreover, we observe that when adapted in their structure, ordered networks tend to move to the critical dynamical regime. These results provide further support to the conjecture that critical regimes favor adaptation and indicate the advantage of calibrating robot control systems at dynamical critical states.

Constraint Closure Drove Major Transitions in the Origins of Life.

Life is an epiphenomenon for which origins are of tremendous interest to explain. We provide a framework for doing so based on the thermodynamic concept of work cycles. These cycles can create their own closure events, and thereby provide a mechanism for engendering novelty. We note that three significant such events led to life as we know it on Earth: (1) the advent of collective autocatalytic sets (CASs) of small molecules; (2) the advent of CASs of reproducing informational polymers; and (3) the advent of CASs of polymerase replicases. Each step could occur only when the boundary conditions of the system fostered constraints that fundamentally changed the phase space. With the realization that these successive events are required for innovative forms of life, we may now be able to focus more clearly on the question of life's abundance in the universe.

Emergence of Organisms.

Since early cybernetics studies by Wiener, Pask, and Ashby, the properties of living systems are subject to deep investigations. The goals of this endeavour are both understanding and building: abstract models and general principles are sought for describing organisms, their dynamics and their ability to produce adaptive behavior. This research has achieved prominent results in fields such as artificial intelligence and artificial life. For example, today we have robots capable of exploring hostile environments with high level of self-sufficiency, planning capabilities and able to learn. Nevertheless, the discrepancy between the emergence and evolution of life and artificial systems is still huge. In this paper, we identify the fundamental elements that characterize the evolution of the biosphere and open-ended evolution, and we illustrate their implications for the evolution of artificial systems. Subsequently, we discuss the most relevant issues and questions that this viewpoint poses both for biological and artificial systems.

Dynamics of a birth-death process based on combinatorial innovation.

A feature of human creativity is the ability to take a subset of existing items (e.g. objects, ideas, or techniques) and combine them in various ways to give rise to new items, which, in turn, fuel further growth. Occasionally, some of these items may also disappear (extinction). We model this process by a simple stochastic birth-death model, with non-linear combinatorial terms in the growth coefficients to capture the propensity of subsets of items to give rise to new items. In its simplest form, this model involves just two parameters (P, α). This process exhibits a characteristic 'hockey-stick' behaviour: a long period of relatively little growth followed by a relatively sudden 'explosive' increase. We provide exact expressions for the mean and variance of this time to explosion and compare the results with simulations. We then generalise our results to allow for more general parameter assignments, and consider possible applications to data involving human productivity and creativity.

Average Fitness Differences on NK Landscapes.

The average fitness difference between adjacent sites in a fitness landscape is an important descriptor that impacts in particular the dynamics of selection/mutation processes on the landscape. Of particular interest is its connection to the error threshold phenomenon. We show here that this parameter is intimately tied to the ruggedness through the landscape's amplitude spectrum. For the NK model, a surprisingly simple analytical estimate explains simulation data with high precision.

Theory of chemical evolution of molecule compositions in the universe, in the Miller-Urey experiment and the mass distribution of interstellar and intergalactic molecules.

Chemical evolution is essential in understanding the origins of life. We present a theory for the evolution of molecule masses and show that small molecules grow by random diffusion and large molecules by a preferential attachment process leading eventually to life's molecules. It reproduces correctly the distribution of molecules found via mass spectroscopy for the Murchison meteorite and estimates the start of chemical evolution back to 12.8 billion years following the birth of stars and supernovae. From the Frontier mass between the random and preferential attachment dynamics the birth time of molecule families can be estimated. Amino acids emerge about 165 million years after chemical elements emerge in stars. Using the scaling of reaction rates with the distance of the molecules in space we recover correctly the few days emergence time of amino acids in the Miller-Urey experiment. The distribution of interstellar and extragalactic molecules are both consistent with the evolutionary mass distribution, and their age is estimated to 108 and 65 million years after the start of evolution. From the model, we can determine the number of different molecule compositions at the time of the emergence of Earth to be 1.6 million and the number of molecule compositions in interstellar space to a mere 719 species.

Systems Pharmacogenomic Landscape of Drug Similarities from LINCS data: Drug Association Networks.

Modern research in the biomedical sciences is data-driven utilizing high-throughput technologies to generate big genomic data. The Library of Integrated Network-based Cellular Signatures (LINCS) is an example for a large-scale genomic data repository providing hundred thousands of high-dimensional gene expression measurements for thousands of drugs and dozens of cell lines. However, the remaining challenge is how to use these data effectively for pharmacogenomics. In this paper, we use LINCS data to construct drug association networks (DANs) representing the relationships between drugs. By using the Anatomical Therapeutic Chemical (ATC) classification of drugs we demonstrate that the DANs represent a systems pharmacogenomic landscape of drugs summarizing the entire LINCS repository on a genomic scale meaningfully. Here we identify the modules of the DANs as therapeutic attractors of the ATC drug classes.

Molecular Diversity Required for the Formation of Autocatalytic Sets.

Systems chemistry deals with the design and study of complex chemical systems. However, such systems are often difficult to investigate experimentally. We provide an example of how theoretical and simulation-based studies can provide useful insights into the properties and dynamics of complex chemical systems, in particular of autocatalytic sets. We investigate the issue of the required molecular diversity for autocatalytic sets to exist in random polymer libraries. Given a fixed probability that an arbitrary polymer catalyzes the formation of other polymers, we calculate this required molecular diversity theoretically for two particular models of chemical reaction systems, and then verify these calculations by computer simulations. We also argue that these results could be relevant to an origin of life scenario proposed recently by Damer and Deamer.

Criticality Distinguishes the Ensemble of Biological Regulatory Networks.

The hypothesis that many living systems should exhibit near-critical behavior is well motivated theoretically, and an increasing number of cases have been demonstrated empirically. However, a systematic analysis across biological networks, which would enable identification of the network properties that drive criticality, has not yet been realized. Here, we provide a first comprehensive survey of criticality across a diverse sample of biological networks, leveraging a publicly available database of 67 Boolean models of regulatory circuits. We find all 67 networks to be near critical. By comparing to ensembles of random networks with similar topological and logical properties, we show that criticality in biological networks is not predictable solely from macroscale properties such as mean degree ⟨K⟩ and mean bias in the logic functions ⟨p⟩, as previously emphasized in theories of random Boolean networks. Instead, the ensemble of real biological circuits is jointly constrained by the local causal structure and logic of each node. In this way, biological regulatory networks are more distinguished from random networks by their criticality than by other macroscale network properties such as degree distribution, edge density, or fraction of activating conditions.

Systematic drug perturbations on cancer cells reveal diverse exit paths from proliferative state.

During a cell state transition, cells travel along trajectories in a gene expression state space. This dynamical systems framework complements the traditional concept of molecular pathways that drive cell phenotype switching. To expose the structure that hinders cancer cells from exiting robust proliferative state, we assessed the perturbation capacity of a drug library and identified 16 non-cytotoxic compounds that stimulate MCF7 breast cancer cells to exit from proliferative state to differentiated state. The transcriptome trajectories triggered by these drugs diverged, then converged. Chemical structures and drug targets of these compounds overlapped minimally. However, a network analysis of targeted pathways identified a core signaling pathway--indicating common stress-response and down-regulation of STAT1 before differentiation. This multi-trajectory analysis explores the cells' state transition with a multitude of perturbations in combination with traditional pathway analysis, leading to an encompassing picture of the dynamics of a therapeutically desired cell-state switching.

Prebiotic network evolution: six key parameters.

The origins of life likely required the cooperation among a set of molecular species interacting in a network. If so, then the earliest modes of evolutionary change would have been governed by the manners and mechanisms by which networks change their compositions over time. For molecular events, especially those in a pre-biological setting, these mechanisms have rarely been considered. We are only recently learning to apply the results of mathematical analyses of network dynamics to prebiotic events. Here, we attempt to forge connections between such analyses and the current state of knowledge in prebiotic chemistry. Of the many possible influences that could direct primordial network, six parameters emerge as the most influential when one considers the molecular characteristics of the best candidates for the emergence of biological information: polypeptides, RNA-like polymers, and lipids. These parameters are viable cores, connectivity kinetics, information control, scalability, resource availability, and compartmentalization. These parameters, both individually and jointly, guide the aggregate evolution of collectively autocatalytic sets. We are now in a position to translate these conclusions into a laboratory setting and test empirically the dynamics of prebiotic network evolution.

Beyond Descartes and Newton: Recovering life and humanity.

Attempts to 'naturalize' phenomenology challenge both traditional phenomenology and traditional approaches to cognitive science. They challenge Edmund Husserl's rejection of naturalism and his attempt to establish phenomenology as a foundational transcendental discipline, and they challenge efforts to explain cognition through mainstream science. While appearing to be a retreat from the bold claims made for phenomenology, it is really its triumph. Naturalized phenomenology is spearheading a successful challenge to the heritage of Cartesian dualism. This converges with the reaction against Cartesian thought within science itself. Descartes divided the universe between res cogitans, thinking substances, and res extensa, the mechanical world. The latter won with Newton and we have, in most of objective science since, literally lost our mind, hence our humanity. Despite Darwin, biologists remain children of Newton, and dream of a grand theory that is epistemologically complete and would allow lawful entailment of the evolution of the biosphere. This dream is no longer tenable. We now have to recognize that science and scientists are within and part of the world we are striving to comprehend, as proponents of endophysics have argued, and that physics, biology and mathematics have to be reconceived accordingly. Interpreting quantum mechanics from this perspective is shown to both illuminate conscious experience and reveal new paths for its further development. In biology we must now justify the use of the word "function". As we shall see, we cannot prestate the ever new biological functions that arise and constitute the very phase space of evolution. Hence, we cannot mathematize the detailed becoming of the biosphere, nor write differential equations for functional variables we do not know ahead of time, nor integrate those equations, so no laws "entail" evolution. The dream of a grand theory fails. In place of entailing laws, a post-entailing law explanatory framework is proposed in which Actuals arise in evolution that constitute new boundary conditions that are enabling constraints that create new, typically unprestatable, Adjacent Possible opportunities for further evolution, in which new Actuals arise, in a persistent becoming. Evolution flows into a typically unprestatable succession of Adjacent Possibles. Given the concept of function, the concept of functional closure of an organism making a living in its world, becomes central. Implications for patterns in evolution include historical reconstruction, and statistical laws such as the distribution of extinction events, or species per genus, and the use of formal cause, not efficient cause, laws.

Prolegomenon to patterns in evolution.

Despite Darwin, we remain children of Newton and dream of a grand theory that is epistemologically complete and would allow prediction of the evolution of the biosphere. The main purpose of this article is to show that this dream is false, and bears on studying patterns of evolution. To do so, I must justify the use of the word "function" in biology, when physics has only happenings. The concept of "function" lifts biology irreducibly above physics, for as we shall see, we cannot prestate the ever new biological functions that arise and constitute the very phase space of evolution. Hence, we cannot mathematize the detailed becoming of the biosphere, nor write differential equations for functional variables we do not know ahead of time, nor integrate those equations, so no laws "entail" evolution. The dream of a grand theory fails. In place of entailing laws, I propose a post-entailing law explanatory framework in which Actuals arise in evolution that constitute new boundary conditions that are enabling constraints that create new, typically unprestatable, adjacent possible opportunities for further evolution, in which new Actuals arise, in a persistent becoming. Evolution flows into a typically unprestatable succession of adjacent possibles. Given the concept of function, the concept of functional closure of an organism making a living in its world becomes central. Implications for patterns in evolution include historical reconstruction, and statistical laws such as the distribution of extinction events, or species per genus, and the use of formal cause, not efficient cause, laws.

Gene-pair expression signatures reveal lineage control.

The distinct cell types of multicellular organisms arise owing to constraints imposed by gene regulatory networks on the collective change of gene expression across the genome, creating self-stabilizing expression states, or attractors. We curated human expression data comprising 166 cell types and 2,602 transcription-regulating genes and developed a data-driven method for identifying putative determinants of cell fate built around the concept of expression reversal of gene pairs, such as those participating in toggle-switch circuits. This approach allows us to organize the cell types into their ontogenic lineage relationships. Our method identifies genes in regulatory circuits that control neuronal fate, pluripotency and blood cell differentiation, and it may be useful for prioritizing candidate factors for direct conversion of cell fate.

Searching the clinical fitness landscape.

Widespread unexplained variations in clinical practices and patient outcomes suggest major opportunities for improving the quality and safety of medical care. However, there is little consensus regarding how to best identify and disseminate healthcare improvements and a dearth of theory to guide the debate. Many consider multicenter randomized controlled trials to be the gold standard of evidence-based medicine, although results are often inconclusive or may not be generally applicable due to differences in the contexts within which care is provided. Increasingly, others advocate the use "quality improvement collaboratives", in which multi-institutional teams share information to identify potentially better practices that are subsequently evaluated in the local contexts of specific institutions, but there is concern that such collaborative learning approaches lack the statistical rigor of randomized trials. Using an agent-based model, we show how and why a collaborative learning approach almost invariably leads to greater improvements in expected patient outcomes than more traditional approaches in searching simulated clinical fitness landscapes. This is due to a combination of greater statistical power and more context-dependent evaluation of treatments, especially in complex terrains where some combinations of practices may interact in affecting outcomes. The results of our simulations are consistent with observed limitations of randomized controlled trials and provide important insights into probable reasons for effectiveness of quality improvement collaboratives in the complex socio-technical environments of healthcare institutions. Our approach illustrates how modeling the evolution of medical practice as search on a clinical fitness landscape can aid in identifying and understanding strategies for improving the quality and safety of medical care.