Darwinian Research Articles

Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models

Central nervous system (CNS) cancers are responsible for high rates of morbidity and mortality worldwide. Malignant CNS tumors such as adult Glioblastoma (GBM) and pediatric embryonal CNS tumors such as medulloblastoma (MED) and atypical teratoid rhabdoid tumors (ATRT) present relevant therapeutic challenges due to the lack of response to classic treatment regimens with radio and chemotherapy. Recent findings on the Zika virus’ (ZIKV) ability to infect and kill CNS neoplastic cells draw attention to the virus’ oncolytic potential. Studies demonstrating the safety of using ZIKV for treating malignant CNS tumors, enabling the translation of this approach to clinical trials, are scarce in the literature. Here we developed a co-culture model of mature human cerebral organoids assembled with GBM, MED or ATRT tumor cells and used these assembloids to test ZIKV oncolytic effect, replication potential and preferential targeting between normal and cancer cells. Our hybrid co-culture models allowed the tracking of tumor cell growth and invasion in cerebral organoids. ZIKV replication and ensuing accumulation in the culture medium was higher in organoids co-cultured with tumor cells than in isolated control organoids without tumor cells. ZIKV infection led to a significant reduction in tumor cell proportion in organoids with GBM and MED cells, but not with ATRT. Tumoroids (3D cultures of tumor cells alone) were efficiently infected by ZIKV. Interestingly, ZIKV rapidly replicated in GBM, MED, and ATRT tumoroids reaching significantly higher viral RNA accumulation levels than co-cultures. Moreover, ZIKV infection reduced viable cells number in MED and ATRT tumoroids but not in GBM tumoroids. Altogether, our findings indicate that ZIKV has greater replication rates in aggressive CNS tumor cells than in normal human cells comprising cerebral organoids. However, such higher ZIKV replication in tumor cells does not necessarily parallels oncolytic effects, suggesting cellular intrinsic and extrinsic factors mediating tumor cell death by ZIKV.

EPCO-06. DIFFUSE MIDLINE GLIOMAS: FROM CELL CYCLE TO THERAPEUTIC OPPORTUNITIES

Abstract The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease.

Darwinian Evolution of Self-Replicating DNA in a Synthetic Protocell

Replication, heredity, and evolution are characteristic of Life. We and others have postulated that the reconstruction of a synthetic living system in the laboratory will be contingent on the development of a genetic self-replicator capable of undergoing Darwinian evolution. Although DNA-based life dominates, the in vitro reconstitution of an evolving DNA self-replicator has remained challenging. We hereby emulate in liposome compartments the principles according to which life propagates information and evolves. Using two different experimental configurations supporting intermittent or semi-continuous evolution (i.e., with or without DNA extraction, PCR, and re-encapsulation), we demonstrate sustainable replication of a linear DNA template – encoding the DNA polymerase and terminal protein from the Phi29 bacteriophage – expressed in the ‘protein synthesis using recombinant elements’ (PURE) system. The self-replicator can survive across multiple rounds of replication-coupled transcription-translation reactions in liposomes and, within only ten evolution rounds, accumulates mutations conferring a selection advantage. Combined data from next-generation sequencing with reverse engineering of some of the enriched mutations reveal nontrivial and context-dependent effects of the introduced mutations. The present results are foundational to build up genetic complexity in an evolving synthetic cell, as well as to study evolutionary processes in a minimal cell-free system.

The Relationship Between Astronomical and Developmental Times Emerging in Modeling the Evolution of Agents.

The simplest evolutionary model for catching prey by an agent (predator) is considered. The simulation is performed on the basis of a software-emulated Intel i8080 processor. Maximizing the number of catches is chosen as the objective function. This function is associated with energy dissipation and developmental time. It is shown that during Darwinian evolution, agents with an initially a random set of processor commands subsequently acquire a successful catching skill. It is found that in the process of evolution, a logarithmic relationship between astronomical and developmental times arises in agents. This result is important for the ideas available in the literature about the close connection of such concepts as time, Darwinian selection, and the maximization of entropy production.

How Brains Perceive the World.

Can machines ever be sentient? Could they perceive and feel things, be conscious of their surroundings? What are the prospects of achieving sentience in a machine? What are the dangers associated with such an endeavor, and is it even ethical to embark on such a path to begin with? In the series of articles of this column, I discuss one possible path toward "general intelligence" in machines: to use the process of Darwinian evolution to produce artificial brains that can be grafted onto mobile robotic platforms, with the goal of achieving fully embodied sentient machines.

The Methodology of Sociological Criticism in Iraq

In the period preceding the establishment of the first sociology department at the University of Baghdad, the works of Abdul Fattah Ibrahim and Abdul Jabbar Arim played a significant role. These scholars are regarded as pioneers of this pre-foundational phase. Although they did not conduct any field research, the methodologies they advocated for analysing and critiquing Iraqi social reality were well-defined. In Abdul Fattah Ibrahim's first specialised book on sociology, he presents Darwin's theory of evolution as "the foundational principle upon which modern sociology is based." He defines sociology as "the study of society in its evolution according to the law of the survival of the fittest, with the goal of enhancing its ability to endure."

Translation of Deoxyribonucleic Acid into Synthetic Alpha Helical Peptides for Darwinian Evolution.

DNA-encoded libraries connect the phenotypes of synthetic molecules to a DNA barcode; however, most libraries do not tap into the potential of Darwinian evolution. Herein, we report a DNA-templated synthesis (DTS) architecture to make peptides that are stabilized into α-helical conformations via head-to-tail supramolecular cyclization. Using a pilot library targeting MDM2, we show that repeated screening can amplify a binder from the lowest abundance in the library to a ranking that correlates to binding affinity. The study also highlights the need to design libraries such that the chemistry avoids biases from the heterogeneous yield in DTS.

Dormancy, Quiescence, and Diapause: Savings Accounts for Life.

Life on Earth has been through numerous challenges over eons and, one way or another, has always triumphed. From mass extinctions to more daily plights to find food, unpredictability is everywhere. The adaptability of life-forms to ever-changing environments is the key that confers life's robustness. Adaptability has become synonymous with Darwinian evolution mediated by heritable genetic changes. The extreme gene-centric view, while being of central significance, at times has clouded our appreciation of the cell as a self-regulating entity informed of, and informing, the genetic data. An essential element that powers adaptability is the ability to regulate cell growth. In this review, we provide an extensive overview of growth regulation spanning species, tissues, and regulatory mechanisms. We aim to highlight the commonalities, as well as differences, of these phenomena and their molecular regulators. Finally, we curate open questions and areas for further exploration.

Perception, Evolution, and the Explanatory Scope of Scientific Theories

According to the interface theory of perception, our perceptual systems have evolved to provide a species-specific interface to guide adaptive behaviour, and not to provide veridical representations of an observer-independent world. Results of simulations of evolutionary resource games, genetic algorithms, and multiple mathematical theorems have supported and fleshed out this claim in various ways. They indicate that the probability is zero that any perceptual system has been shaped by natural selection to represent the true structure of an observer-independent world. Bagwell (2023) thinks that this argument is self-defeating because it implies that organisms, resources, genes, etc. that are essential constituents of Darwin's theory do not provide an insight into the nature of observerindependent reality. Bagwell's argument relies on a false premise, however — namely, that the mathematical formulation of a scientific theory cannot dethrone its fundamental concepts. More broadly, his argument involves a fundamental misunderstanding of the nature of scientific theories — of their explanatory scope and their necessary limits.

Theory of affective pragmatics under biolinguistics.

This paper introduces a pioneering investigation into affective pragmatics through the perspective of Darwinian Biolinguistics, an interdisciplinary field at the nexus of biological and linguistic principles. Anchored in Darwin's theory of evolution and the latest developments in neurobiology, this study delves into the influence of biological factors---especially those pertaining to the brain's emotional processing on pragmatic communication. The research posits that human emotional responses, inherent in our biological constitution, profoundly influence the usage and interpretation of language in social interactions.

A new perspective on tumor progression: Evolution via selection for function.

Tumorigenesis is commonly attributed to Darwinian processes involving natural selection among cells and groups of cells. However, progressing tumors are those that also achieve an appropriate group phenotypic composition (GPC). Yet, the selective processes acting on tumor GPCs are distinct from that associated with classical Darwinian evolution (i.e. natural selection based on differential reproductive success) as tumors are not genuine evolutionary individuals and do not exhibit heritable variation in fitness. This complex evolutionary scenario is analogous to the recently proposed concept of 'selection for function' invoked for the evolution of both living and non-living systems. Therefore, we argue that it is inaccurate to assert that Darwinian processes alone account for all the aspects characterizing tumorigenesis and cancer progression; rather, by producing the genetic and phenotypic diversity required for creating novel GPCs, these processes fuel the evolutionary success of tumors that is dependent on selection for function at the tumor level.

Self-Reproduction and Evolution in Cellular Automata: 25 Years After Evoloops.

The year 2024 marks the 25th anniversary of the publication of evoloops, an evolutionary variant of Chris Langton's self-reproducing loops, which proved constructively that Darwinian evolution of self-reproducing organisms by variation and natural selection is possible within deterministic cellular automata. Over the last few decades, this line of Artificial Life research has since undergone several important developments. Although it experienced a relative dormancy of activity for a while, the recent rise of interest in open-ended evolution and the success of continuous cellular automata models have brought researchers' attention back to how to make spatiotemporal patterns self-reproduce and evolve within spatially distributed computational media. This article provides a review of the relevant literature on this topic over the past 25 years and highlights the major accomplishments made so far, the challenges being faced, and promising future research directions.

Enriching productive mutational paths accelerates enzyme evolution.

Darwinian evolution has given rise to all the enzymes that enable life on Earth. Mimicking natural selection, scientists have learned to tailor these biocatalysts through recursive cycles of mutation, selection and amplification, often relying on screening large protein libraries to productively modulate the complex interplay between protein structure, dynamics and function. Here we show that by removing destabilizing mutations at the library design stage and taking advantage of recent advances in gene synthesis, we can accelerate the evolution of a computationally designed enzyme. In only five rounds of evolution, we generated a Kemp eliminase-an enzymatic model system for proton transfer from carbon-that accelerates the proton abstraction step >108-fold over the uncatalyzed reaction. Recombining the resulting variant with a previously evolved Kemp eliminase HG3.17, which exhibits similar activity but differs by 29 substitutions, allowed us to chart the topography of the designer enzyme's fitness landscape, highlighting that a given protein scaffold can accommodate several, equally viable solutions to a specific catalytic problem.

More In-Depth Analysis Needed

Abstract In his Understanding the Christianity-Evolution Relationship, Michael Ruse puts old wine in new skins. In an original and illuminating way, he approaches his topic from the perspective of the age-old divide between mechanistic and organicist ways of thinking. Yet, this does not bring him to new conclusions as compared to his earlier work on the topic. In response, I argue that a more rigorous conceptual and doctrinal analysis is needed to sort out whether Darwinian evolution makes God redundant or whether it actually accords more with theism than with naturalism.

Invariant Sets, Global Dynamics, and the Neimark–Sacker Bifurcation in the Evolutionary Ricker Model

In this paper, we study the local, global, and bifurcation properties of a planar nonlinear asymmetric discrete model of Ricker type that is derived from a Darwinian evolution strategy based on evolutionary game theory. We make a change of variables to both reduce the number of parameters as well as bring symmetry to the isoclines of the mapping. With this new model, we demonstrate the existence of a forward invariant and globally attracting set where all the dynamics occur. In this set, the model possesses two symmetric fixed points: the origin, which is always a saddle fixed point, and an interior fixed point that may be globally asymptotically stable. Moreover, we observe the presence of a supercritical Neimark–Sacker bifurcation, a phenomenon that is not present in the original non-evolutionary model.

Showcasing the Variety of Biosocial and Evolutionary Approaches in Sociology: Introduction to the Special Issue

This introduction to the special issue explores the increasing integration of biosocial and evolutionary approaches within sociology, highlighting the diverse ways in which these perspectives are incorporated into sociological research. In the past, sociology had reservations against or even rejected biological and evolutionary explanations of human behavior and often viewed them with skepticism. However, recent developments have seen a resurgence of interest in these approaches, leading to the emergence of interdisciplinary subfields such as biosociology, evolutionary sociology, neurosociology, and sociogenomics. This introduction provides a historical overview of biological and evolutionary thinking with regard to human behavior and sociality, tracing its roots from Darwinian theory to its contemporary applications within sociology. We discuss the conceptual and methodological differences between these approaches and offer an overview of key contributions that illustrate their relevance to core sociological topics. The articles in this special issue—which we summarize in this introduction—exemplify the variety of work being done at the intersection of sociology and the bio- and evolutionary sciences, from theoretical explorations to empirical studies. By presenting this range of interdisciplinary research, we aim to invite a broader sociological audience to engage with these perspectives, contributing to the development of a more comprehensive understanding of human behavior that sheds the dualism between nature and nurture—long overcome outside of sociology—for a consolidated effort to examine how nature and nurture are intertwined in multiple and complex ways.

The Ethics of Astrobiology and the Cosmic Bet Argument

Stephen Weinberg posited in 1977 that as the universe becomes more comprehensible, it appears more meaningless owing to a strict division between facts and values. He seemingly overlooked the consideration of the purposes and values of intelligent life in examining its ability to influence the universe's development. The scientific revolution, initiated by Copernicus's heliocentric hypothesis and furthered by Darwin's theory, shifted humanity's perceived place in the cosmos, removing the sacred. However, developments in astrobiology and discoveries related to the Fermi Paradox and the Rare Earth Hypothesis are hinting at humanity's significant role in the universe, suggesting we might be the only intelligent species. This paper argues that advancing scientific knowledge reinforces the hypothesis of human exclusivity and importance in the cosmos, making the potential sixth mass extinction cosmically significant and underscoring the imperative of human persistence in the cosmos.

Did the exposure of coacervate droplets to rain make them the first stable protocells?

Membraneless coacervate microdroplets have long been proposed as model protocells as they can grow, divide, and concentrate RNA by natural partitioning. However, the rapid exchange of RNA between these compartments, along with their rapid fusion, both within minutes, means that individual droplets would be unable to maintain their separate genetic identities. Hence, Darwinian evolution would not be possible, and the population would be vulnerable to collapse due to the rapid spread of parasitic RNAs. In this study, we show that distilled water, mimicking rain/freshwater, leads to the formation of electrostatic crosslinks on the interface of coacervate droplets that not only suppress droplet fusion indefinitely but also allow the spatiotemporal compartmentalization of RNA on a timescale of days depending on the length and structure of RNA. We suggest that these nonfusing membraneless droplets could potentially act as protocells with the capacity to evolve compartmentalized ribozymes in prebiotic environments.

Studies of lentic inland water ecosystems in the Galapagos archipelago: Current state of knowledge and bibliometric analysis.

ABSTRACT The Galapagos Archipelago - due to its remoteness, isolation, recent volcanic origin, and endemic fauna and flora - is iconic for inspiring Darwin's evolutionary theory. Since Darwin’s day researchers have focused on the Archipelago’s terrestrial and marine species. Its location in an important climate regulating body of water, coupled with a low level of human activity for most of its history, attracted several paleolimnologists to the inland waters of the Archipelago. Studies of the many lagoons, crater lakes, and other inland waters were mainly in support of paleolimnological research and are therefore limited in scope. Because of the presence of permanent human settlements on four of the Archipelago’s islands, plus increased tourism, the limited number of permanent freshwater bodies are under unprecedented environmental stress. This bibliometric analysis assembles what is known about Galapagos lentic inland water bodies. It shows that studies on biodiversity, water quality, and threats to these ecosystems are few and fragmented across time and space.

The Basics of Evolution Strategies: The Implementation of the Biomimetic Optimization Method in Educational Modules.

With a focus on education and teaching, we provide general background information on bioinspired optimization methods by comparing the concept of optimization and the search for an optimum in engineering and biology. We introduce both the principles of Darwinian evolution and the basic evolutionary optimization procedure of evolution strategies. We provide three educational modules in work sheets that can be used by teachers and students to improve their understanding of evolution strategies. The educational module "Optimization of a Milk Carton" shows that the material consumption in producing a milk carton can be minimized using an evolution strategy with a mutative step size control. The use of a standard dice and a pocket calculator enables new milk cartons to be generated, with the offspring having the lowest material consumption becoming the parent of the next generation. The other educational modules deal with the so-called brachistochrone problem. The module "Fastest and Shortest Marble Track" provides a construction plan for a marble track whereby students can experimentally compare the "path of shortest length" with the "path of shortest time". The EvoBrach software, is used in the module "Various Marble Track Shapes" to compare the running times of a marble on a straight line, a parabola, and a brachistochrone. In conclusion, the introduction to the biomimetic method of evolution strategies and the educational modules should deepen the understanding of both optimization problems and biological evolution.