This project undertakes the first comprehensive investigation of early modern ecology. NEWWORLD counters the standard historiographical argument that ecological concern is a recent phenomenon. A key element in that claim is the assumption that the terminology of environmental care is recent: the term 'ecology' was invented in the 19th century by Ernst Haeckel; 'sustainability' is a 20th-century coinage; 'the environment' was used for the first time in English by Thomas Carlyle in 1827. Yet, these terms that now help to define ecological sensibilities arose from long-lasting debates. The leading claim of this project is that early modernity was a particularly fertile period for ecological reflection. NEWWORLD proposes an innovative methodology to capture the breadth and philosophical substance of early modern ecological debates: it proceeds from present-day terms to construct terminological and conceptual constellations in early modern texts. It uses a technique that historians (of philosophy) label 'controlled anachronism', and which this project aims to fully exploit for the first time on a large scale. The objectives, subdivided into the four main areas 'Environment', 'Pollution', 'Sustainability', and 'Ecological Justice', involve tracing a symbiotic connection between metaphysical, natural-philosophical, religious, and ethical ideas. NEWWORLD will both reveal the specificities of early modern thought on ecological matters, and pioneer a dialogue with ecological debates as we know them today. The project's main output will be a multi-volume philosophical history of environmental care in the early modern period. This will be complemented by the curation of an exhibition, featuring 3D models of cosmographical images and projections of early modern plans for ideal cities, showing them to be laboratories of ecological views. NEWWORLD seeks to offer a new paradigm for the intervention of the history of philosophy in present-day debates on ecology, and beyond.

Colorectal cancer (CRC) results from the accumulation of genetic and epigenetic changes in colonic epithelial cells. Epigenome studies revealed that virtually all CRCs contain aberrantly methylated genes and perturbed methylation patterns. Ten-Eleven Translocation (TET) protein family dioxygenases oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further to other oxidized 5mCs, supporting active DNA demethylation and helping maintain epigenomic stability. Loss of TET1 is an oncogenic driver in some CRCs. My preliminary analysis indicates that human CRCs have low TET2 mRNA levels compared to normal colorectal tissue, and suggests that low TET2 expression predicts increased mutational load and reduced overall survival. However, whether TET2 deficiency contributes to CRC pathogenesis, or represents a bystander event, remains to be established. In this proposal, I will elucidate the role of TET2 in CRC pathogenesis by testing whether TET2 knockdown induces methylome and transcriptome reprogramming, ultimately promoting (epi)genomic instability and tumor growth. I will also investigate correlations between TET2 defects and molecular/clinico-pathological parameters, and probe TET2 expression as predictive biomarker of response to CRC therapies. With these aims, I will use a multi-disciplinary approach, combining cell biology, cancer epigenetics, bioinformatics, human and mouse studies with cutting-edge techniques such as 3D cell culture and RNA-seq. This study should establish a clear causal link between TET2 loss and CRC pathogenesis, providing new insight into the mechanism of TET2-mediated tumor suppression and leading to the development of innovative therapies that exploit vulnerabilities of TET2-deficient CRC cells. Overall, this project has both basic and translational significance, and the potential to advance our understanding of CRC carcinogenesis and therapeutic response.

To meet medical needs worldwide, tissue engineering must move from successful pre/clinical products towards an effective process to meet Worldwide medical needs, but this is challenging since a quantitative design framework has not emerged, yet. Synthetic biology (SYNBIO) was the solution that genetic engineers found to the same problem: “Despite tremendous individual successes in genetic engineering and biotechnology […], why is the engineering of useful synthetic biological systems still an expensive, unreliable and ad hoc research process?” asked Dr. Endy in a 2005 letter to Nature. The SYNBIO solution included: i) libraries of DNA parts with well-characterized effect on cells; ii) tools to computationally design system-level assemblies, or designer-DNA; and, iii) bottom-up engineering of cell functions using progressively more complex designer-DNA. Effectively, SYNBIO introduced a computer-aided design and manufacturing (CAD/M) platform that transformed the process of engineering cells. However, since inputs from the extracellular matrix (ECM) have largely been ignored, progress towards programmable tissue-level behavior have been more modest. Here, we will build on my experience with computational and experimental models in cardiac tissue engineering to develop a CAD/M framework for engineering cardiac tissues with computationally predictable properties, or designer-ECM. To characterize ECM-cell interactions, we will use traction force and super-resolution microscopy with fluorescence in-situ sequencing. To model multiscale ECM-cell interactions, we will use ordinary differential equations and subcellular element models. Finally, we will leverage ECM parts and human induced pluripotent stem cells to bioprint designer-ECM that recapitulate three phases of heart development: trabeculation, compaction, and maturation. With synthetic matrix biology (SYNBIO.ECM), we will develop a CAD/M-based process and a new class of products for cardiac tissue engineering.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Chronic treatments of CVDs are scarce because of poor predictivity of current two-dimensional (2D) pre-clinical models. State-of-the-art 3D-tissue models based on human induced pluripotent stem cells (hiPSCs) can be more predictive of human genetics but fail to replicate the 3D cardiac muscle structure. In fact, the heart evolved to ensure efficient emptying of the chambers via a 3D chiral organization of muscle tissue not yet recapitulated in organoids or engineered ventricles. In CARdiac tissue Design, beating INduction, and Assessment using multiwavelength Light (CARDINAL), I will replicate the native chiral architecture of the heart in a minimal 3D model of the heart muscle and validate the resulting assay for drug screening. Our objectives will tackle three main challenges in the field: 1) Create the chiral scaffold to host the hiPSC-derived cardiac muscle cells (hiPSC-CMs). I will use cavitation molding - a light-based 3D-structuring method I previously developed - to obtain chirally organized micro-channels in soft hydrogels. 2) Populate these scaffolds with high-purity hiPSC-CMs that can be triggered and assayed with optical methods. I will leverage the host lab's engineered hiPSC line that features structural and functional fluorescent sensors. To that line, we will add optogenetic actuators and antibiotic resistance to directly control the final hiPSC-CM yield, trigger contraction, and image cell structure and function volumetrically. 3) Validate the predictivity of our new 3D chiral platform in drug screening applications. To do that, we will test a panel of cardiac drugs with known safety/efficacy profiles with our new platform, 2D hydrogels, and traditional glass slides. The CARDINAL project will provide the drug screening field with a more biomimetic tissue-engineered model of the heart muscle that can be extended to vascularized models and the full organ, eventually.

Harnessing the quantum properties of light on-chip is the ultimate aim of Integrated Quantum Photonics, bearing the promise of novel quantum technology functionalities to the microscale. A critical step in this process is the generation of quantum light, typically achieved through nonlinear processes such as spontaneous parametric down-conversion (SPDC) in second-order (χ(2)) nonlinear media or spontaneous four-wave mixing (SFWM), through the third-order (χ(3)) response. While the silicon nitride (SiN) integrated photonics platform has proven extremely reliable, low-loss, and compatible with large scale fabrication, its centrosymmetric nature of SiN prevents χ(2) interactions, hindering the implementation of low-noise, highly efficient SPDC-based sources. Lithium Niobate and III-V materials are valid alternatives, but they lack the technological maturity provided by the CMOS fabrication process. Recent research has shown that the coherent photogalvanic effect can endow SiN with a χ(2) response, a photoinduced nonlinearity that automatically satisfies the quasi-phase matching condition, enabling highly efficient frequency conversion. Such “all-optical poling” technique has proven suitable to enable a wide range of functionalities based on χ(2) interactions. The purpose of GLINT is to investigate the potential of all-optical poling in SiN for the generation of quantum light via χ(2) processes. The project will specifically focus on the study of SiN microring-resonator-based SPDC sources, owing to their capability to enhance the efficiency of spontaneous processes and to generate, thanks to their peculiar spectral response, narrow-band states. This will be achieved by i) theoretically modelling a resonator-based SPDC source ii) realizing a chip-scale prototype using commercial-grade technology and providing a full characterization of the generated quantum states iii) demonstrating a proof-of-concept quantum communication protocol using the developed chip-scale source.