Why have we not yet solved the challenge of plastic degradation by biological means?

The invention of fossil fuel-derived plastics changed and reshaped society for the better; however, their mass production has created an unprecedented accumulation of waste and an environmental crisis. Scientists are searching for better ways to reduce plastic waste than the current methods of mechanical recycling and incineration, which are only partial solutions. Biological means of breaking down plastics have been investigated as alternatives, with studies mostly focusing on using microorganisms to biologically degrade sturdy plastics like polyethylene (PE). Unfortunately, after a few decades of research, biodegradation by microorganisms has not provided the hoped-for results. Recent studies suggest that insects could provide a new avenue for investigation into biotechnological tools, with the discovery of enzymes that can oxidize untreated PE. But how can insects provide a solution that could potentially make a difference? And how can biotechnology revolutionize the plastic industry to stop ongoing/increasing contamination?

A mathematical model for a T cell fate decision algorithm during immune response.

We formulate and analyze an algorithm of cell fate decision that describes the way in which division vs. apoptosis choices are made by individual T cells during an infection. Such model involves a minimal number of known biochemical mechanisms: it basically relies on the interplay between cell division and cell death inhibitors on one hand, and membrane receptors on the other. In spite of its simplicity, the proposed decision algorithm is able to account for some significant facts in immune response. At the individual level, the existence of T cells that continue to replicate in the absence of antigen and the possible occurrence of T cell apoptosis in the presence of antigen are predicted by the model. Moreover, the latter is shown to yield an emergent collective behavior, the observed delay in clonal contraction with respect to the end of antigen stimulation, which is shown to arise just from individual T cell decisions made according to the proposed mechanism.

A new role for erythropoietin in the homeostasis of red blood cells.

The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism would be a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control would require RBC lifespan to be variable and tightly regulated. We suggest that EPO may control RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-α expression in sinusoidal macrophages. EPO could also regulate the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms would continuously modulate the rate of RBC destruction depending on oxygen availability. The control of RBC lifespan by EPO and autoimmunity emerges as a key mechanism in the homeostasis of RBCs.

The virtual microbiome: A computational framework to evaluate microbiome analyses.

Microbiomes have been the focus of a substantial research effort in the last decades. The composition of microbial populations is normally determined by comparing DNA sequences sampled from those populations with the sequences stored in genomic databases. Therefore, the amount of information available in databanks should be expected to constrain the accuracy of microbiome analyses. Albeit normally ignored in microbiome studies, this constraint could severely compromise the reliability of microbiome data. To test this hypothesis, we generated virtual bacterial populations that exhibit the ecological structure of real-world microbiomes. Confronting the analyses of virtual microbiomes with their original composition revealed critical issues in the current approach to characterizing microbiomes, issues that were empirically confirmed by analyzing the microbiome of Galleria mellonella larvae. To reduce the uncertainty of microbiome data, the effort in the field must be channeled towards significantly increasing the amount of available genomic information and optimizing the use of this information.

Plastic degradation by insect hexamerins: Near-atomic resolution structures of the polyethylene-degrading proteins from the wax worm saliva.

Plastic waste management is a pressing ecological, social, and economic challenge. The saliva of the lepidopteran Galleria mellonella larvae is capable of oxidizing and depolymerizing polyethylene in hours at room temperature. Here, we analyze by cryo-electron microscopy (cryo-EM) G. mellonella's saliva directly from the native source. The three-dimensional reconstructions reveal that the buccal secretion is mainly composed of four hexamerins belonging to the hemocyanin/phenoloxidase family, renamed Demetra, Cibeles, Ceres, and a previously unidentified factor termed Cora. Functional assays show that this factor, as its counterparts Demetra and Ceres, is also able to oxidize and degrade polyethylene. The cryo-EM data and the x-ray analysis from purified fractions show that they self-assemble primarily into three macromolecular complexes with striking structural differences that likely modulate their activity. Overall, these results establish the ground to further explore the hexamerins' functionalities, their role in vivo, and their eventual biotechnological application.

Killing the competition: a theoretical framework for liver-stage malaria.

The first stage of malaria infections takes place inside the host's hepatocytes. Remarkably, Plasmodium parasites do not infect hepatocytes immediately after reaching the liver. Instead, they migrate through several hepatocytes before infecting their definitive host cells, thus increasing their chances of immune destruction. Considering that malaria can proceed normally without cell traversal, this is indeed a puzzling behaviour. In fact, the role of hepatocyte traversal remains unknown to date, implying that the current understanding of malaria is incomplete. In this work, we hypothesize that the parasites traverse hepatocytes to actively trigger an immune response in the host. This behaviour would be part of a strategy of superinfection exclusion aimed to reduce intraspecific competition during the blood stage of the infection. Based on this hypothesis, we formulate a comprehensive theory of liver-stage malaria that integrates all the available knowledge about the infection. The interest of this new paradigm is not merely theoretical. It highlights major issues in the current empirical approach to the study of Plasmodium and suggests new strategies to fight malaria.

The coordination of anti-phage immunity mechanisms in bacterial cells.

Bacterial cells are equipped with a variety of immune strategies to fight bacteriophage infections. Such strategies include unspecific mechanisms directed against any phage infecting the cell, ranging from the identification and cleavage of the viral DNA by restriction nucleases (restriction-modification systems) to the suicidal death of infected host cells (abortive infection, Abi). In addition, CRISPR-Cas systems generate an immune memory that targets specific phages in case of reinfection. However, the timing and coordination of different antiviral systems in bacterial cells are poorly understood. Here, we use simple mathematical models of immune responses in individual bacterial cells to propose that the intracellular dynamics of phage infections are key to addressing these questions. Our models suggest that the rates of viral DNA replication and cleavage inside host cells define functional categories of phages that differ in their susceptibility to bacterial anti-phage mechanisms, which could give raise to alternative phage strategies to escape bacterial immunity. From this viewpoint, the combined action of diverse bacterial defenses would be necessary to reduce the chances of phage immune evasion. The decision of individual infected cells to undergo suicidal cell death or to incorporate new phage sequences into their immune memory would be determined by dynamic interactions between the host's immune mechanisms and the phage DNA. Our work highlights the importance of within-cell dynamics to understand bacterial immunity, and formulates hypotheses that may inspire future research in this area.

Effects of anti-PD-1 immunotherapy on tumor regression: insights from a patient-derived xenograft model.

Immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), have resulted in unprecedented improvements in survival for patients with lung cancer. Nonetheless, not all patients benefit equally and many issues remain unresolved, including the mechanisms of action and the possible effector function of immune cells from non-lymphoid lineages. The purpose of this study was to investigate whether anti-PD-1 immunotherapy acts on malignant tumor cells through mechanisms beyond those related to T lymphocyte involvement. We used a murine patient-derived xenograft (PDX) model of early-stage non-small cell lung carcinoma (NSCLC) devoid of host lymphoid cells, and studied the tumor and immune non-lymphoid responses to immunotherapy with anti-PD-1 alone or in combination with standard chemotherapy (cisplatin). An antitumor effect was observed in animals that received anti-PD-1 treatment, alone or in combination with cisplatin, likely due to a mechanism independent of T lymphocytes. Indeed, anti-PD-1 treatment induced myeloid cell mobilization to the tumor concomitant with the production of exudates compatible with an acute inflammatory reaction mediated by murine polymorphonuclear leukocytes, specifically neutrophils. Thus, while keeping in mind that more research is needed to corroborate our findings, we report preliminary evidence for a previously undescribed immunotherapy mechanism in this model, suggesting a potential cytotoxic action of neutrophils as PD-1 inhibitor effector cells responsible for tumor regression by necrotic extension.

Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms.

The human skeleton undergoes constant remodeling throughout the lifetime. Processes occurring on microscopic and molecular scales degrade bone and replace it with new, fully functional tissue. Multiple bone remodeling events occur simultaneously, continuously and independently throughout the body, so that the entire skeleton is completely renewed about every ten years.Bone remodeling is performed by groups of cells called Bone Multicellular Units (BMU). BMUs consist of different cell types, some specialized in the resorption of old bone, others encharged with producing new bone to replace the former. These processes are tightly regulated so that the amount of new bone produced is in perfect equilibrium with that of old bone removed, thus maintaining bone microscopic structure.To date, many regulatory molecules involved in bone remodeling have been identified, but the precise mechanism of BMU operation remains to be fully elucidated. Given the complexity of the signaling pathways already known, one may question whether such complexity is an inherent requirement of the process or whether some subset of the multiple constituents could fulfill the essential role, leaving functional redundancy to serve an alternative safety role. We propose in this work a minimal model of BMU function that involves a limited number of signals able to account for fully functional BMU operation. Our main assumptions were i) at any given time, any cell within a BMU can select only one among a limited choice of decisions, i.e. divide, die, migrate or differentiate, ii) this decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor are coupled to that of specific external mediators, such as hormones, cytokines, growth factors. It was thus shown that efficient BMU operation manifests as an emergent process, which results from the individual and collective decisions taken by cells within the BMU unit in the absence of any external planning.

Modeling the effect of boost timing in murine irradiated sporozoite prime-boost vaccines.

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory. In this work we propose a model to analyze the effect of T cell dynamics on the performance of prime-boost vaccines. This model suggests that boost doses and timings should be selected according to the T cell response elicited by priming. Specifically, boosting during late stages of clonal contraction would maximize T cell memory production for vaccines using lower doses of irradiated sporozoites. In contrast, single-dose inoculations would be indicated for higher vaccine doses. Experimental data have been obtained that support theoretical predictions of the model.

Population mechanics: A mathematical framework to study T cell homeostasis.

Unlike other cell types, T cells do not form spatially arranged tissues, but move independently throughout the body. Accordingly, the number of T cells in the organism does not depend on physical constraints imposed by the shape or size of specific organs. Instead, it is determined by competition for interleukins. From the perspective of classical population dynamics, competition for resources seems to be at odds with the observed high clone diversity, leading to the so-called diversity paradox. In this work we make use of population mechanics, a non-standard theoretical approach to T cell homeostasis that accounts for clone diversity as arising from competition for interleukins. The proposed models show that carrying capacities of T cell populations naturally emerge from the balance between interleukins production and consumption. These models also suggest remarkable functional differences in the maintenance of diversity in naïve and memory pools. In particular, the distribution of memory clones would be biased towards clones activated more recently, or responding to more aggressive pathogenic threats. In contrast, permanence of naïve T cell clones would be determined by their affinity for cognate antigens. From this viewpoint, positive and negative selection can be understood as mechanisms to maximize naïve T cell diversity.

Adaptive multiscapes: an up-to-date metaphor to visualize molecular adaptation.

BACKGROUND: Wright's metaphor of the fitness landscape has shaped and conditioned our view of the adaptation of populations for almost a century. Since its inception, and including criticism raised by Wright himself, the concept has been surrounded by controversy. Among others, the debate stems from the intrinsic difficulty to capture important features of the space of genotypes, such as its high dimensionality or the existence of abundant ridges, in a visually appealing two-dimensional picture. Two additional currently widespread observations come to further constrain the applicability of the original metaphor: the very skewed distribution of phenotype sizes (which may actively prevent, due to entropic effects, the achievement of fitness maxima), and functional promiscuity (i.e. the existence of secondary functions which entail partial adaptation to environments never encountered before by the population). RESULTS: Here we revise some of the shortcomings of the fitness landscape metaphor and propose a new "scape" formed by interconnected layers, each layer containing the phenotypes viable in a given environment. Different phenotypes within a layer are accessible through mutations with selective value, while neutral mutations cause displacements of populations within a phenotype. A different environment is represented as a separated layer, where phenotypes may have new fitness values, other phenotypes may be viable, and the same genotype may yield a different phenotype, representing genotypic promiscuity. This scenario explicitly includes the many-to-many structure of the genotype-to-phenotype map. A number of empirical observations regarding the adaptation of populations in the light of adaptive multiscapes are reviewed. CONCLUSIONS: Several shortcomings of Wright's visualization of fitness landscapes can be overcome through adaptive multiscapes. Relevant aspects of population adaptation, such as neutral drift, functional promiscuity or environment-dependent fitness, as well as entropic trapping and the concomitant impossibility to reach fitness peaks are visualized at once. Adaptive multiscapes should aid in the qualitative understanding of the multiple pathways involved in evolutionary dynamics. REVIEWERS: This article was reviewed by Eugene Koonin and Ricard Solé.

A molecular mechanism of symmetry breaking in the early chick embryo.

The first obvious sign of bilateral symmetry in mammalian and avian embryos is the appearance of the primitive streak in the future posterior region of a radially symmetric disc. The primitive streak marks the midline of the future embryo. The mechanisms responsible for positioning the primitive streak remain largely unknown. Here we combine experimental embryology and mathematical modelling to analyse the role of the TGFß-related molecules BMP4 and Vg1/GDF1 in positioning the primitive streak. Bmp4 and Vg1 are first expressed throughout the embryo, and then become localised to the future anterior and posterior regions of the embryo, where they will, respectively, inhibit or induce formation of the primitive streak. We propose a model based on paracrine signalling to account for the separation of the two domains starting from a homogeneous array of cells, and thus for the topological transformation of a radially symmetric disc to a bilaterally symmetric embryo.

The growth threshold conjecture: a theoretical framework for understanding T-cell tolerance.

Adaptive immune responses depend on the capacity of T cells to target specific antigens. As similar antigens can be expressed by pathogens and host cells, the question naturally arises of how can T cells discriminate friends from foes. In this work, we suggest that T cells tolerate cells whose proliferation rates remain below a permitted threshold. Our proposal relies on well-established facts about T-cell dynamics during acute infections: T-cell populations are elastic (they expand and contract) and they display inertia (contraction is delayed relative to antigen removal). By modelling inertia and elasticity, we show that tolerance to slow-growing populations can emerge as a population-scale feature of T cells. This result suggests a theoretical framework to understand immune tolerance that goes beyond the self versus non-self dichotomy. It also accounts for currently unexplained observations, such as the paradoxical tolerance to slow-growing pathogens or the presence of self-reactive T cells in the organism.

Is malarial anaemia homologous to neocytolysis after altitude acclimatisation?

Malaria patients frequently develop severe anaemia that can persist after Plasmodium infection has been cleared from the circulation. This puzzling phenomenon involves massive death of young uninfected erythrocytes at a time when parasitic infection is very low. We have observed striking similarities in erythrocyte homoeostasis during altitude acclimatisation and Plasmodium infection, both of which initially induce an increase in circulating erythropoietin (Epo). Decreasing levels of Epo after return to low altitudes induce the death of young erythrocytes, a phenomenon called neocytolysis. In a similar way, we propose that Epo, which peaks during acute malaria and decreases after parasite clearance, could be contributing to anaemia causing neocytolysis during recovery from Plasmodium infection.

toyLIFE: a computational framework to study the multi-level organisation of the genotype-phenotype map.

The genotype-phenotype map is an essential object to understand organismal complexity and adaptability. However, its experimental characterisation is a daunting task. Thus, simple models have been proposed and investigated. They have revealed that genotypes differ in their robustness to mutations; phenotypes are represented by a broadly varying number of genotypes, and simple point mutations suffice to navigate the space of genotypes while maintaining a phenotype. Nonetheless, most current models focus only on one level of the map (folded molecules, gene regulatory networks, or networks of metabolic reactions), so that many relevant questions cannot be addressed. Here we introduce toyLIFE, a multi-level model for the genotype-phenotype map based on simple genomes and interaction rules from which a complex behaviour at upper levels emerges -remarkably plastic gene regulatory networks and metabolism. toyLIFE is a tool that permits the investigation of how different levels are coupled, in particular how and where mutations affect phenotype or how the presence of certain metabolites determines the dynamics of toyLIFE gene regulatory networks. The model can easily incorporate evolution through more complex mutations, recombination, or gene duplication and deletion, thus opening an avenue to explore extended genotype-phenotype maps.