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Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
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Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
- News & Impact
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Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
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About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
Awardees
2024
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Grant Awardees - Program Grants
Vibrational information transfer between living cells in the extracellular matrix
LESMAN Ayelet (ISRAEL)
- Tel Aviv University - Tel Aviv - ISRAEL
MORTIMER Beth (United Kingdom)
- University of Oxford - Oxford - United Kingdom
ZAERA POLO Ramon (SPAIN)
- Carlos III University of Madrid (Universidad Carlos III de Madri, UC3M) - Leganes - SPAIN
GENIN Guy (United States)
- Washington University in St.Louis - St. Louis - United States
The ability of cells to transmit mechanical cues between themselves through the extracellular matrix (ECM) has been recently recognized as a mechanism of long-range cell-cell communication, with implications in a variety of physiological and disease states. Previous works have focused on quasi-static forces (variations over minutes to hours), whose transduction drives cells to remodel both themselves and the ECM. However, cells can sense and respond to rapid forces in the form of vibrations (e.g., time-dependent at higher frequencies, much faster than the characteristic time of ECM homeostatic remodeling or turnover). Whether cells themselves transfer information to neighboring cells via vibrational waves in the ECM is yet unknown. We hypothesize that vibrations, primarily delivered by longitudinal waves along remodeled (stretched, oriented and tensed) collagen tracks, affect signaling cascades associated with both healing and the onset of fibrosis through information transfer between fibroblasts. Our international team of experts in vibrational animal communication, vibration modeling, in vitro cellular systems, and mechanobiology will explore the propagation of dynamic cues through collagen-based materials and establish whether cells generate, transfer and sense information via transient waves. Manipulation of these mechanical cues may possibly be harnessed to accelerate wound healing and impede fibrosis.
2024
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Cross Disciplinary Fellowships - CDF
Is quantum coherence important in coupling the antenna system to the photosystem in cryptophytes?
GRÜNING Gesa (GERMANY)
School of Physics - University of New South Wales (UNSW) - Sydney - AUSTRALIA
CURMI Paul (Host supervisor)
Cryptophytes are single-celled, aquatic algae faced with the challenge of limited photons which demands a very efficient light-harvesting process. Cryptophytes possess an antenna comprised of phycobiliproteins (PBPs) that increases the photon absorption area and the accessible spectral range of the incoming photons. The incoming photon creates an electron-hole pair called an exciton, which needs to move from the antenna to the photosystem quickly and efficiently. Evidence of quantum beats suggests that this process of moving the exciton via several PBPs employs quantum coherence. However, the most efficient way for the exciton transferal is a mixture of coherent and incoherent transfer steps. The intra-protein interactions are probably based on coherent excitation transmission while the transfer process between PBPs is incoherent. We hypothesize that the PBP linking the antenna with the photosystem operates coherently. Recently, it has been discovered that PBPs come in two different quaternary structures: the open and the closed form. The closed form exhibits coherent beats while open form does not. The main goal of this project is to determine the role of quantum coherence in the light harvesting systems of cryptophytes. Specifically, we plan to investigate the quantum mechanical nature of the linking protein that connects the antenna proteins with the photosystem in cryptophytes. To achieve this objective, we will employ a combination of experimental and computational methods. First, we plan to determine the single particle structure of this linking protein between the photosystem and the antenna proteins using state-of-the-art in situ cryo-electron microscopy (cryo-EM). In the next step, we would build a molecular dynamics simulation based on this newly found structure and perform quantum mechanics/molecular mechanics (QM/MM) computations to evaluate possible exciton transfer pathways. In conclusion, by investigating the quantum coherence in the linking protein between the antenna and the photosystem, our research project aims to uncover the missing piece in the interplay of coherent and incoherent exciton transfer. These kinds of linking proteins between antenna structures and the photosystems are not unique to cryptophytes, for example the FMO protein in green sulphur bacteria is also thought to employ quantum coherence. We hope to uncover the reason for this apparently general requirement for linking proteins to function in a coherent way and discover how the linking protein is able to uphold the long-lived quantum coherence against the thermal motion of its surroundings. Understanding the quantum biological nature of the linking protein holds immense promise for unlocking the quantum secrets of cryptophytes and shedding light on the fascinating interplay of coherent and incoherent exciton transfer in several species, with potential applications in quantum technologies and bio-inspired design of efficient energy harvesting systems.
2024
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Long-Term Fellowships - LTF
Vocal communication and the evolution of hyper-cooperative societies
HERSH Taylor (USA)
School of Biological Sciences - University of Bristol - Bristol - United Kingdom
KING Stephanie (Host supervisor)
Humans are extremely “hyper-cooperative”: we regularly engage in long-term and strategic cooperation with non-kin. This propensity for working together has allowed us to dominate the planet, and the key to our success is language. However, humans are not the only animals capable of hyper-cooperation. In Shark Bay, Australia, unrelated male bottlenose dolphins work together in an extensive network of nested alliances—“partners” in “teams” in “clubs”—to control reproductive access to females. Given that dolphins also display remarkable vocal complexity via diverse repertoires of whistles, is vocal communication the mechanism behind hyper-cooperation in this society as well? Or did dolphins evolve a different way of building and maintaining hyper-cooperative relationships? I aim to discover how the rare but powerful phenomenon of hyper-cooperation unfolds in an unconventional, underwater study system. I hypothesize that dolphins, like humans, rely on vocal communication to mediate the interactions underlying their hyper-cooperative society. I predict this will be accomplished through alliance-specific whistle repertoires. First, I will quantify similarities and differences in whistle usage among many alliances. Second, I will evaluate what specific vocalisations mean by playing different whistles to individuals and recording their behavioural and acoustic responses in the field (via drone video footage and underwater microphones, respectively). Third, I will use social and behavioural datasets spanning >40 years to determine whether variations in whistle usage impact long-term fitness (e.g., number of paternities, female consortship rates) of individuals and alliances. Finally, I will build mechanistic agent-based models to explore the interplay between vocal communication and hyper-cooperation over evolutionarily timescales. The models’ agents will be parameterized to behave like real-world male dolphins. The emergent property will be social network structure (i.e., nested alliances). The manipulated condition will be whether agents can vocally signal, and the form that such signalling takes (i.e., able to signal to single individuals vs. groups). Comparative research is crucial to understand how and why hyper-cooperation so rarely evolved. The alliances of male dolphins in Shark Bay are the largest and most complex hyper-cooperative network known beyond humans. Supported by 40 years of research, these dolphins offer an exceptional opportunity to understand the vocal mechanisms that underpin hyper-cooperative behaviours. This ambitious project synergises my quantitative skills, Dr. King’s expertise in dolphin communication, and the University of Bristol’s research facilities, enabling me to move into exciting and challenging fields (e.g., playbacks, modelling). With HFSP’s support, I will answer unresolved, big-picture questions about the role of vocal communication in the evolution and persistence of hyper-cooperative societies.
2024
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Cross Disciplinary Fellowships - CDF
Molecular mechanism of sister chromatid resolution in replicated human chromosomes
HIDAKA Takuya (JAPAN)
Daniel Gerlich Group - Institute of Molecular Biotechnology (Institut fuer Molekulare Biotechnologie GmbH. IMBA) - Vienna - AUSTRIA
GERLICH Daniel (Host supervisor)
"Faithful transmission of genetic information across cell progeny requires disentanglement and separation of extremely long DNA molecules after replication. Sister DNA molecules are first resolved and packaged into separate bodies by condensin-mediated DNA loop extrusion and DNA strand crossing mediated by topoisomerase II (TOP2A in vertebrates), followed by long-range movement mediated by the mitotic spindle. While spindle mechanics are understood in great detail, it has remained unclear how condensin and TOP2A cooperate in sister chromatid resolution. While TOP2A resolves inter-chromatid entanglements, it also induces intra-chromatid entanglements to enhance the mechanical stability of chromosomes during mitosis. How these two activities are coupled with condensin-mediated DNA looping is not known, as no method can simultaneously detect condensin and TOP2A activities in the same cell to assess sister chromatid topologies.
In this project, I aim to develop a new method for genome-wide mapping of TOP2A activities within and across sister chromatids along with DNA contacts mediated by condensin at the single-cell level. To achieve this, I will combine my chemical ligation-based DNA barcoding technology to retain nuclear and spatial information of genomic DNA fragments and antibody-coupled DNA tags with the host lab’s sister-chromatid-specific nascent DNA labeling strategy using a thymidine analogue. After sequencing the barcoded library, the barcodes enable the reconstruction of genomic sites undergoing strand passing by TOP2A and loop extrusion by condensin, whereby sister chromatids can be distinguished based on the DNA label mapping to plus or minus strands. The chemical ligation-based approach will significantly reduce barcode length compared to enzymatic ligation, which is essential for reading sufficient lengths of genomic DNA for efficient sister-chromatid-specific mapping.
With this technique, I will determine the extent by which DNA loop extrusion constricts entanglements behind condensin to promote decatenation, how much chromosome compaction by condensin affects local concentration of TOP2A and intra-chromatid catenation, and whether other potential sister chromatid resolution activities are involved.
This study will reveal how condensin and TOP2A cooperate in folding and resolving replicated chromosomes, a process fundamental to all life forms. The method developed in this project captures multiple targets and pairwise/multiway interaction at the single-cell level, thereby providing a powerful means to investigate the coordination of other molecular processes such as DNA replication, cohesion establishment, and DNA repair. This project will, therefore, advance technology and biological insights with implications for cell division and genome architecture."
2024
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Grant Awardees - Program Grants
Physical forces and mechanotransduction during mouse embryo implantation
TREPAT Xavier (SPAIN)
- Fundacio Institut de Bioenginyeria de Catalunya (Institute for Bioengineering of Catalonia) - Barcelona - SPAIN
HIIRAGI Takashi (JAPAN)
- Hubrecht Institute - Utrecht - NETHERLANDS
Implantation marks a key transition in mammalian development, establishing essential interactions between the embryo and uterine tissue. Upon implantation, mammalian embryos undergo major morphological transformations to form the egg cylinder and establish body axes. However, current understanding of the underlying mechanisms remains limited for two main reasons. First, the process of embryo implantation is inaccessible in the uterus. Second, the physical forces that drive this process have never been measured neither ex-vivo nor in-utero. In this proposal we hypothesize that 1) embryos generate and experience dynamic force as they establish adhesion to the uterine surface; 2) the mechanical interaction at attachment induces changes in the inner cell mass position and/or embryo orientation; 3) this orientation in turn influences the embryo morphogenesis into an egg cylinder. To test these hypotheses, this project aims to map 3D forces and mechanotransduction pathways driving cellular decisions and morphological changes both ex-vivo and in-utero. In Objective 1, we will study the mechanics of mouse implantation ex-vivo by directly measuring the traction forces and intercellular stresses as the blastocyst adheres to substrates with tunable elasticity, viscoelasticity, non-linearity and degradability. Simultaneously, we will examine how the mechanical properties of the substrate affect embryo orientation and development. We will compare our ex-vivo findings from mouse embryos with those of monkey embryos which differ from mice in terms of position of the inner cell mass and morphogenesis. In Objective 2, we will study how the mechanical cues that the embryo experiences during implantation are transduced to impact three main processes: interactions at the uterine-embryo interface, embryo orientation upon attachment, and morphogenesis into the egg cylinder. The results will be integrated into a mechanical model of embryo implantation. Finally, in Objective 3, we will test model predictions in-utero and verify the mechanisms of embryo-uterus interactions during implantation across cell/tissue scales by combining intravital microscopy with novel tools for force measurement. This project will provide an understanding of how physical forces and mechanobiological signals drive mammalian implantation in-utero.
2024
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Long-Term Fellowships - LTF
Unmasking the Role of Nuclear Antioxidant Systems in Human Disease
HSU Sheng-Chieh (CHINA, REPUBLIC OF (TAIWAN))
The University of Texas Southwestern Medical Center (UT Southwestern) - The University of Texas Southwestern Medical Center (UT Southwestern) - Dallas - United States
GARCIA-BERMUDEZ Javier (Host supervisor)
DEBERARDINIS Ralph (Host supervisor)
Human metabolism heavily relies on oxygen (O2) as a primary electron acceptor in around 150 metabolic reactions, essential for processes like mitochondrial respiration. However, the involvement of O2 in metabolism can lead to the generation of reactive oxygen species (ROS), unwanted molecules that have the potential to oxidize and damage various cellular components, including nucleotides, proteins, and lipids. To counteract the harmful effects of ROS, aerobic organisms have developed antioxidant systems, primarily localized within the subcellular spaces where ROS-generating enzymes are prevalent. Mitochondria, being a major source of cellular ROS, possess specific isoforms of enzymes that help dissipate ROS or repair their damage. While the nucleus is a metabolically active organelle engaged in DNA replication, transcription, and gene regulation, it is also susceptible to ROS generation due to the activity of two enzyme families involved in demethylation and hydroxylation reactions, both of which require O2. However, it is unknown whether the nucleus has dedicated antioxidant systems to protect against ROS toxicity and maintain nuclear functionality. I hypothesize that cells have developed mechanisms to inhibit nuclear ROS and preserve the integrity of DNA and the nuclear envelope. Existing approaches lack the temporal and spatial resolution required to test this hypothesis. Therefore, I aim to develop molecular tools that will enable the systematic discovery of nuclear antioxidant systems and their significance in human physiology. Aim 1: Investigate the mechanisms involved in dissipating nuclear ROS. To explore nuclear antioxidant pathways, we will employ an optogenetic approach to induce high levels of ROS using a flavoprotein localized to the nucleus. This will allow us to assess canonical cell survival mechanisms and perform genetic screens using a nuclear-focused library. Aim 2: Discover redox-sensitive nodes in the nucleus. Given that both enzyme families involved in nuclear ROS generation are fueled by alpha-ketoglutarate and inhibited by succinate, we will manipulate ROS production by supplementing cells with permeable forms of these. I will develop a rapid nuclei immunopurification system and couple it to mass spectrometry analysis. This approach will identify ROS-sensitive alterations in proteins and lipids. Aim 3: Investigate the connection between nuclear ROS and DNA leakage. I hypothesize that ROS may compromise nuclear envelope integrity, leading to DNA leakage, a type of stress sensed by cGAS, which ultimately triggers cell intrinsic and extrinsic immunity. Using the aforementioned tools, we will modulate nuclear ROS, evaluate cGAS activation, and analyze the tumor response to immune-mediated growth arrest and checkpoint therapy. Overall, this project aims to develop innovative technologies to uncover the unexplored role of ROS in the nucleus and its potential association with disease states related to DNA stress.
2024
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Long-Term Fellowships - LTF
Decoding mechano-epigenetic memories in tissue regeneration
HUSSIEN Amro (SUDAN)
Department of Cell and Tissue Dynamics - Max Planck Institute for molecular Biomedicine - Muenster - GERMANY
WICKSTRÖM Sara (Host supervisor)
Tissue regeneration is a life-essential process that requires efficient re-establishment of functional tissue architecture and its mechanical properties. However, as an evolutionary trade-off for terrestrial life, skin wounds in large mammals typically heal by fibrosis which can evolve into dysfunctional scars. Strategies to promote regenerative rather than maladaptive fibrotic healing have been limited, in part due to incomplete understanding of the fundamental mechanisms that derail adequate healing response. There is an emerging appreciation that tissue-resident cells accumulate “epigenetic memories” of past “stressful” experiences. Persistent scarring profoundly alters the mechanical cues of cellular niches, namely the stiffness and viscoelastic properties. While it is known that mechanical signals are critical for scarring behavior, the notion of epigenetic memories triggered by mechanical stress and impacting mechanochemical feedback loops in tissue regeneration has not been addressed? It remains unknown if mechanical memories can be bestowed in cells in vivo, what are the molecular mechanisms, and finally what are the pathophysiological consequences of such effects? Here, I will investigate how various skin stem cell populations respond to viscoelastic mechanical cues in scarring, and whether they have capacity to learn from past experiences by forming mechano-epigenetic memories to impact future healing outcomes. I will: - Map the mechano-epigenomic landscape in scarring using integrative atomic force microscopy and spatial ATAC-seq and CUT & Tag. - Elucidate how mechanical memories are induced and recalled in mouse models of skin scarring. - Dissect mechanistically how mechano-memory reshapes healing outcomes using in utero lentivirus overexpression of identified mechanical memory peaks. Central hypotheses: I hypothesize that: - Altered niche viscoelasticity in fibrotic scarring triggers epigenetic re-wiring of cells. - Skin cells in mechanically-stressed niches acquire “geographically” distributed mechanical memories, which can be decoupled from inflammatory memories. - Skin cells imprint acquired mechano-memory in their nuclear architecture and surrounding matrix. - Mechanical memory is sufficient to induce maladaptive scarring and to accentuate subsequent healing responses. Experimental systems: I will use an interdisciplinary approach combining in vivo mouse models, state-of-the-art hydrogel engineering and biophysical methods, with data-driven bulk and spatial epigenomics technologies. This perfectly combines my unique expertise in bioengineering and clinical medicine with the world leading expertise of the host lab in stem cell biology and mechanoregulation of chromatin architecture. Conclusions: This project will represent a breakthrough in understanding the molecular basis of mechano-epigenetic memories, and may open avenues for designing new strategies to erase maladaptive memories to drive scarless tissue regeneration.
2024
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Long-Term Fellowships - LTF
Elucidating the role of R-loops in hematopoiesis and bone marrow niche remodeling in aging
JAUREGUI-LOZANO Juan (COLOMBIA)
Structural and Computational Biology - European Molecular Biology Laboratory (EMBL-Heidelberg) - Heidelberg - GERMANY
ZAUGG Judith (Host supervisor)
Hematopoiesis is the process by which all cells in the blood are produced, and contributes to organismal health. During aging the hematopoietic system undergoes several changes, including a differentiation skew of the hematopoietic stem cells towards myeloid immune cells, that leads to a decrease in lymphoid immune cells. Accordingly, aging is a major risk factor for several blood malignancies. At the same time, the mesenchymal stroma cells (MSCs), crucial for supporting hematopoiesis, become skewed towards adipogenesis with age. However, the molecular mechanisms that contribute to this age-associated decline in the hematopoietic system remain understudied. R-loops, or DNA:RNA hybrids, are co-transcriptional molecules that when misprocessed lead to transcriptional dysregulation, DNA damage and genome instability. Due to these detrimental events, normal cells efficiently process and remove R-loops. A recent study by the applicant showed that aging neurons display defects in R-loop metabolism, which in turn has a detrimental effect in neuronal function, and concomitant changes to the transcriptional landscape. In addition, preliminary data from the host lab has identified key R-loop related enzymes downregulated upon ageing in bone-marrow derived mesenchymal stroma cells (MSCs). Altogether, these observations poise R-loops as a potential mechanism that contributes to the loss of hematopoiesis support during aging, and disease. In this basic research project, the applicant will connect for the first time R-loop metabolism and aging to changes in the hematopoietic stem cell niche. Our central hypothesis is that the age-associated changes of R-loop metabolism in the MSCs lead to transcriptional dysregulation of gene regulatory networks associated with differentiation potential, in turn remodeling the bone marrow niche. To test this hypothesis, we will determine the specific molecular pathways that are regulated by R-loops in MSCs, and to establish if modulation of R-loops can change the differentiation potential of MSCs, and remodel the bone marrow niche. We propose the following aims: 1. We will profile R-loops and R-loop binding proteins in MSCs from young and old mice and human samples. Data integration with RNA-seq will allow us to identify R-loop regulated genes and establish R-loop associated molecular pathways. 2. We will test how modulation of R-loop metabolism contributes to differentiation potential of MSCs using siRNA-mediated depletion of prioritized R-loop binding protein targets, followed by single cell (sc) RNA-seq and scATAC-seq of the bone marrow. For this, we will co-culture siRNA-loaded MSCs with hematopoietic stem/progenitor cells (HSPCs), followed by single cell multi-omic assays as a phenotypic readout of differentiation. From this project, we will elucidate how R-loops maintain MSCs homeostasis during aging, and how R-loop metabolism contributes to the bone marrow niche remodeling.
2024
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Cross Disciplinary Fellowships - CDF
Understanding far-from-equilibrium chemical kinetics inside biomolecular condensates
KANG Byunghwa (KOREA, REPUBLIC OF (SOUTH KOREA))
Institute for NanoBioTechnology - Johns Hopkins University JHURA - Baltimore - United States
SCHULMAN Rebecca (Host supervisor)
Subcellular compartments determine the fate of a living cell. Along with canonical lipid membrane-enclosed organelles, life extensively exploits condensed liquid-like structures that are formed by liquid-liquid phase separation to spatiotemporally regulate ubiquitous processes, such as the sequestration of specific species and the control of biochemical reaction rates. These membrane-free compartments, biomolecular condensates, also orchestrate far-from-equilibrium cellular behaviors, ranging from gene expression to signal transduction. However, despite the growing importance of biomolecular condensates in cellular biochemistry, it has remained elusive over the decades how these densely-packed spatial regions precisely control or up-regulate internal chemical kinetics. Previously, some artificial condensates have enhanced catalytic rates by localizing catalyst or reactant, but these are abiotic quasi-equilibrium phenomena that are inherently unattainable in living cells. Given that intracellular condensates are subject to various chemical processes, including transcription and translation, how can these processes, i.e., those are far-from-equilibrium, accelerate catalysis within biomolecular condensates? To understand membrane-less organelles, through the Human Frontier Science Program, we will focus on the following two aims: 1) design of natural-like biomolecular condensates subject to biologically-inherent far-from-equilibrium and 2) evaluation of catalytic kinetics in designed condensates. Our first goal is the design of nucleic acid-based condensate using DNAs as dual-functional materials that induce the phase separation and allow transcription when assembled with RNA polymerases. Our approach mimics intracellular transcription that occurs in condensates and drives far-from-equilibrium conditions. This can be strongly supported by the host laboratory led by Dr. Rebecca Schulman, who has developed many successful examples of spatiotemporally-regulated transcriptional networks. Next, we will aim to unravel catalytic kinetics inside biomolecular condensates. Inspired by natural transcription that is coupled to downstream catalytic reactions (post-transcriptional modifications and translation), we will investigate the effect of a transcriptional process on catalytic rates. Importantly, one hypothesis is that transcription of a trans-acting ribozyme and its substrate within the same condensate could accelerate catalysis beyond what equilibrium sequestration could. Additionally, we envision that catalytic rates are precisely regulated relying on transcription rates. Here, my Ph.D research skills in molecular probes to detect cellular targets and my expertise in aptamers and RNA biochemistry will be used. In conclusion, our approach to study chemical kinetics within biomolecular condensates will develop a new biological principle of how critical reactions could be regulated inside biomolecular condensates beyond what is currently known.
2024
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Grant Awardees - Program Grants
UV opsin as the sensor for magneto-sensation in animals
SCHAPIRO Igor (GERMANY)
- Technical University Dortmund (Technische Universität Dortmund) - Dortmund - GERMANY
MERLIN Christine (FRANCE)
- Texas A&M University - College Station - United States
KATO Hideaki (JAPAN)
- The University of Tokyo - Tokyo - JAPAN
KOSLOFF Mickey (ISRAEL)
- University of Haifa - Haifa - ISRAEL
The molecular mechanism of bio-magnetic sensing used for navigation by migrating animals is a major unsolved problem in contemporary science. We propose that opsin, the biological light-sensitive pigment, is the actual magneto-receptor. Opsins are transmembrane proteins arranged in membrane stacks within photoreceptor cells in the eye that transmit visual signals to the brain. Opsins covalently bind a retinal chromophore via a Schiff base bond, making these proteins light-sensitive. Our preliminary results from quantum chemical calculations suggest that certain opsins can populate triplet electronic states that are sensitive to a magnetic field. In this state, a quantum ”geometric phase” is accumulated upon a conformational change of the retinal relative to the magnetic field direction, yielding a true quantum biology effect. These specific opsins contain deprotonated retinal Schiff base as a chromophore, which absorbs light in the ultraviolet (UV) spectral range and are termed “UV-opsins” in this proposal. Such UV-opsins are found in insects and birds, and the architecture of photoreceptors in the retina orients them to the visual axis in a manner compatible with magneto-sensing. Specific in vivo support for the role of UV-opsins in the magnetic response of the migratory monarch butterfly came from the requirement of light in the UV range. Lastly, UV-opsin can transduce magneto-sensation to the brain directly via G protein/arrestin dependent visual signaling cascades.
We will test our hypothesis using a highly interdisciplinary approach that leverages genetic tools in the migratory monarch butterfly, a newly established model system for magneto-sensing, in synergy with quantum chemical simulations and 3D protein structure modeling, bioinformatics, cryo-electron microscopy, and behavioral neurogenetics. We will explore the role of opsins with a deprotonated retinal Schiff base chromophore in magnetic sensation, determine their structure and signaling activity upon magnetic induction, as well as validate their function in vivo by testing monarch mutants for loss of magnetic responses. This synergistic collaboration will elucidate a previously unexplored role for opsins in magneto-reception, one of the least understood senses in biology, and is likely to have broad implications for understanding magneto-reception across animals.
2024
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Grant Awardees - Program Grants
FUNCTIONAL ECOLOGY OF FLAGELLATES SHEDS NEW LIGHT ON EARLY EUKARYOTIC EVOLUTION.
KIORBOE Thomas (DENMARK)
- Technical University of Denmark - Kgs. Lyngby - DENMARK
SIMPSON Alastair (AUSTRALIA)
- Dalhousie University - Halifax - CANADA
WAN Kirsty (United Kingdom)
- University of Exeter - Exeter - United Kingdom
Phagotrophic flagellates are found in all the major branches of the Eukaryotic Tree of Life, and resolving their phylogenetic history is key to understanding early eukaryotic evolution and the origins of LECA – the Last Common Eukaryotic Ancestor. Phylogenies are traditionally inferred by molecular and morphological approaches, but both may be blurred by, respectively, horizontal gene transfer and the problem of distinguishing convergent vs homologous morphologies. Here we propose that functional ecology and biophysics provides a brand-new lens through which to explore phylogenies. Our aim is to study this in both ‘typical excavates’ flagellates, hypothesized to resemble LECA, as well as ‘excavate-like’ flagellates from other deep branches of the tree.
Morphological traits, if homologous, that are found in distant deep branches of the Tree are potential LECA traits. Evidence of similar morphologies with different functions may be a particularly strong argument for homologies that have underwent subsequent divergent evolutionary adaptations. Most ‘typical excavates’ are bacterivores and share morphological features: One of their two flagella beats in a ventral groove and is equipped with 1-3 vanes. This arrangement is thought to play a role in prey capture, but the details are unknown. ‘Excavate-like’ organisms have similar morphologies that may function in similar or different ways, but they are mainly eukaryovores.
We pose two hypotheses: H1: Typical excavate morphologies are homologous and play similar roles in prey acquisition; H2: Typical excavates and excavate-like flagellates have homologous morphologies but may have evolved different function in prey acquisition and propulsion. We will test this in selected typical excavates as well as excavate-like flagellates by (i) resolving cellular morphology using live imaging, and TEM and expansion microscopy of fixed specimens with a focus on cytoskeletal architecture to help distinguish convergent from homologous features; (ii) functional ecology using visualization and quantification of feeding flows, high-speed video-microscopy and micro-fluidics to quantify prey capture and motility, micro-holography to describe flagellar beat patterns, and fluid dynamic modelling to understand the underlying physical mechanisms; (iii) integrate the above insights with molecular phylogenetics to test H1,2.
2024
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Cross Disciplinary Fellowships - CDF
Teaching excitons how to walk: spatial reorganization in an artificial light-harvesting system
KITZMANN Winald (GERMANY)
Department of Chemistry - Massachusetts Institute of Technology - MIT - Cambridge - United States
SCHLAU-COHEN Gabriela (Host supervisor)
Background Photosynthetic organisms rely on light to synthesize important chemical feedstocks. On a molecular level, the flow of protons and electrons after absorption of a photon is controlled by sophisticated nano-machinery. Through this complex dance, biological systems power most life on Earth. Inspired by this remarkable achievement, researchers have been working to emulate this function through artificial model systems. Despite decades of effort, robust and efficient energy capture has not been achieved. Fundamentally, biological systems are non-equilibrium in nature. However, previous reports have been limited to static, equilibrium geometries, and so structural dynamics that are inherent to biological function have remained unexplored. Aims While there is vast knowledge on how nature uses light to fuel life, true understanding is proven by successful replication of the process. In the words of Richard Feynmann, "What I cannot create, I do not understand." This project aims to create synthetic nano-machinery with dynamic control over the excitons for energy capture and conversion. This platform will establish the limits of our current understanding and provide fundamental insight on the interplay of biological structure and dynamics. Central hypothesis I propose to construct a system at the molecular level with dynamic control over photonic energy. Specifically, I will program excitonic circuits made of dyes and charge-transporting moieties with tailored non-covalent interactions that introduce dynamic couplings. After initial conversion of photonic energy to an electron-hole pair, these transient bonds break, which pushes the system out of equilibrium. The resulting energy gradient triggers molecular reorganization and induces a spatial separation of charges, which can be harnessed to drive chemical transformations. Experimental system Precise control over the system’s geometry is necessary to exploit their full light-conversion potential. Synthetically, this can be achieved with a powerful biotechnological tool known as DNA origami. The efficiency of the system is determined by elementary steps such as energy transfer and charge separation. As these processes occur on ultrafast timescales, time-resolved optical spectroscopy with femtosecond resolution will be used to track the different species via their distinct absorption features. These in-depth spectroscopic studies will be used to fine-tune the molecular design of the artificial light-harvesting systems. Conclusion This project expands our understanding of photosynthesis by reverse-engineering its function in minimalistic excitonic circuits. The combination of atomically precise molecular design and state-of-the-art time-resolved spectroscopy allows identifying the key excitonic processes and optimizing them for maximum efficiency. Overall, this project will provide invaluable insight on one of the overarching questions in biology: how structure creates function.
2024
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Long-Term Fellowships - LTF
The role of simultaneous population dynamics in associative learning
KOL Adi (ISRAEL)
Neuroscience - Friedrich Miescher Institute (Friedrich Miescher Institute for Biomedical Research, FMI) - Basel - SWITZERLAND
LUETHI Andreas (Host supervisor)
Associative learning, of relations between stimuli and the outcome they predict, is a vital cognitive process in our daily functioning, as it allows us to acquire new information and to constantly adapt to changes in our surroundings. Although association learning was repeatedly shown to restructure the activity of numerous individual neurons across cortical and subcortical regions, it is still not clear how it is represented at the population level. Specifically, how learning-related activity patterns develop in single brain areas, how interregional interactions support it and how these widespread representations flexibly update as stimuli-outcome contingencies change. The primary goal for this proposal is to study the population dynamics underlying associative learning by combining behavior, population recordings and dynamical systems-based analytical framework. The prefrontal cortex (PFC) and the basolateral Amygdala (BLA) are two extensively interconnected learning hubs and thus offer an ideal anatomical infrastructure to investigate interregional communication effects on local learning-related activity patterns. I plan to harness the cortico-amygdala circuitry and use Neuropixel probes to concomitantly record population activity in PFC and BLA as mice perform appetitive associative reversal learning task where the cue-reward contingency is swiftly reversed after they have slowly learned the original contingency. This way, learning will be studied on multiple timescales, from a few minutes to whole days. Next, I will use population decoding to identify the neural correlates of the paradigm in PFC and BLA, examine the temporal interplay between them and investigate how information routing support population activity and consequently, shape learning. Lastly, I will examine the causality between interregional communication, local task-related representations and behavior by optogenetically manipulating the Amygdala-cortical projections. Here, I propose a novel hypothesis of mine, in which the formation of cue-outcome contingencies is paralleled with the development of distinct sequences of neurophysiological signatures both at the PFC and the BLA. These local signatures will co-evolve through inter-regional communication to mediate the selection and stability of stimuli-outcome contingencies with varying time constants that will determine individual learning rates. As the BLA is typically known to process salient information such as emotion, valence or motivation, I further suggest that it is the first to detect the positively valenced stimulus and then instruct the PFC to initiate learning via command signals routing from the BLA to the PFC. Such comprehensive mechanistic investigation of how PFC-BLA population dynamics underlies associative learning, on multiple timescales, can reveal general principles in how the brain utilizes interregional interactions to learn associations and, ultimately, shape behavior.
2024
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Grant Awardees - Program Grants
Mechanisms and evolutionary consequences of stress-induced mutagenesis
KUPIEC Martin (ISRAEL)
- Tel Aviv University - Tel Aviv - ISRAEL
TRAULSEN Arne (GERMANY)
- Max Planck Institute for Evolutionary Biology - Plön - GERMANY
Evolution is a two-step process: mutations arise among individuals in populations and those providing higher fitness are favored. It has become apparent that various stresses produce an increase in the level of mutagenesis. Such a phenomenon plays a pivotal role in the development of cancer, in the emergence of drug and antibiotic resistance, and in the emergence of new viral variants (e.g. COVID).
It is customary to think about fitness and evolutionary advantage at the level of individuals, but they only make sense on the level of a population. Here, we want to understand the control of variation at the population level. For example, are there inter-cellular signals that elicit variation in the population to help overcome stressful conditions? Can a population-level reaction to stress be evolutionarily advantageous, even when individual cells may be negatively affected?
This proposal is a collaboration between a molecular genetics lab (Kupiec) and a mathematical/computational lab (Traulsen). We will use the baker's yeast as a model, and carry out a combination of theoretical and experimental work aimed at answering very basic questions related to the induction of variation by stress. Yeast is a rapidly growing microorganism with great resources in genetics, biochemistry and molecular biology. Most importantly, it is easy to set up evolution experiments in the lab. We expect to obtain from these studies a better understanding of the evolutionary mechanisms that operate in times of stress, and their molecular details. Such an understanding is not only scientifically interesting: Medical problems such as bacterial infections and cancer can be understood in terms of evolution and antibiotic resistance and therapy failure in cancer is often based on the emergence of mutations. Our studies may present novel strategies to pre-empt such problems.
2024
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Long-Term Fellowships - LTF
Role of visual and emotion circuits in shaping neural spatial representations of aversive stimuli
LEPRINCE Erwan (FRANCE)
Department of Physiology, Development and Neuroscience - University of Cambridge - Cambridge - United Kingdom
BELTRAMO Riccardo (Host supervisor)
In order to survive, animals navigate the environment to find food, shelter and avoid predators. The development of internal spatial maps is believed to facilitate these tasks, with visual inputs providing critical information on the position and dynamics of external stimuli. These maps, found in the hippocampal and parahippocampal formations, are thought to help animals to define their position in the environment and locate their conspecifics. However, little is known about the neural networks that support spatial representations of explicitly dangerous and threatening visual stimuli, such as predators. This project aims at dissecting the circuits enabling the spatial representations of aversive visual stimuli and their association with emotional content, across the visual and spatial navigation systems. Two main systems process visual information: the "geniculate" and "collicular" pathways. The geniculate pathway transmits visual input to the primary visual cortex (V1), which extracts basic features from the visual scene. Intriguingly, clinically blind patients with complete V1 lesions are still able to navigate and react to threatening visual stimuli. This phenomenon, referred to as "blindsight", has been linked to the collicular pathway. The collicular system relays object motion information from the superior colliculus, an evolutionary ancient visual centre, to the postrhinal cortex (POR). POR is considered one of the main entry points of visual input to the hippocampus. In addition, POR is involved in contextual fear conditioning and is the only visual cortex reciprocally linked to the amygdala, a crucial structure for aversive information processing. For these reasons, we hypothesize that POR is critical to developing spatial representations of aversive stimuli by coupling object movement information, stimulus value, and animal self-position. By identifying salient and dangerous visual stimuli, POR would allow the animal to maintain an updated representation of the environment, and to adapt its behavior when changes occur. Through behavioral, electrophysiological, imaging and optogenetic approaches in freely-moving mice, I propose to: 1) record hippocampal and parahippocampal responses to moving visual stimuli, and optogenetically silence the geniculate and collicular pathways to determine their contributions to spatial representations of moving objects; 2) determine the influence of emotional content on the spatial representation of moving objects, by combining these stimuli with aversive ones; 3) disentangle the circuits involved, by focusing on amygdala/POR reciprocal connections. I will manipulate these projections to test their role in shaping the spatial representations of moving visual stimuli in fear learning paradigms. Overall, this project will provide crucial insight into how the visual and navigation systems process threatening stimuli, such as predators, to generate complex behaviors essential for survival.
2024
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Grant Awardees - Program Grants
Cognitive convergence: Vertebrate carnivore-like predatory planning behaviors in jumping spiders
LI Chen (United States)
- Johns Hopkins University JHURA - Baltimore - United States
LI Daiqin (New Zealand (Aotearoa))
- Hubei University - Wuhan - China, People's Republic of - Wuhan - CHINA
NELSON Ximena (New Zealand (Aotearoa))
- University of Canterbury - Christchurch - New Zealand (Aotearoa)
MACIVER Malcolm (CANADA)
- Northwestern University - Evanston Campus - Evanston - United States
Assessing options before taking action (planning) is cognitively demanding but helps enhance reward and reduce risk. Mammals and birds show evidence of planning, but members of the Portia genus of spider-eating jumping spiders (salticids) are the only terrestrial invertebrates that are thought to be capable of planning. Like a lion peeking over tall grass to stalk prey, Portia visually scans prey, assesses options, and takes long detours (~100 body lengths, ~1 hour) so as not to trigger escape or attack (its prey can kill Portia). Notably, Portia has 1 million times fewer brain neurons than us, but its visual acuity is only 6 times worse—better than cats—and much better than other invertebrates.
Recent modeling suggests that planning provides a selective benefit in visually-guided predator-prey interactions, but only for patchy (partially cluttered) terrain that enables visually hiding one’s approach. The predator benefits from planning because as the prey moves, the predator could become visible, and its selected trajectory must be aborted and a new route planned. Because Portia hunts other highly visual non-Portia salticids, our model indicates that Portia may need to plan for successful salticid hunts, by using partial clutter to hide its approach. If true, then the ability to plan may not require a large vertebrate brain, as traditionally thought; rather it emerges from the right combination of ecological features: patchy habitats with high visual acuity predators and prey. Further, how an animal with so few neurons is able to plan may, by necessity, be an entirely novel computational method far more efficient than that used by vertebrates.
To test this key idea, as well as to reveal the ranges of ecological parameters that potentially allow planning to emerge from such a small brain, we will perform the first systematic study of detouring behavior in Portia hunting other salticids, by integrating our expertise in field-based foraging behavior (DL) and lab-based planning and vision (XN) of Portia, complex terrain locomotion, sensing, and predator-prey interactions via creating new tools (CL), and modeling of planning (MM). Our work could advance understanding of crucial issues regarding what features of an animal’s sensory ecology and task demands select for planning ability, and whether there are deeply conserved, ancient features to planning.
2024
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Long-Term Fellowships - LTF
Chromatin rejuvenation and DNA damage responses during ageing of human chromosomes
LIAKOS Anastasios (GREECE)
Institute of Pathology - University Medical Center Göttingen - Göttingen - GERMANY
PAPANTONIS Argyris (Host supervisor)
Ageing represents an inevitable endpoint in metazoans and is characterized by multisystemic functional decline. This is often linked to the accumulation of DNA damage along chromosomes with time. Elevated reactive oxygen species (ROS) in particular, are produced as a byproduct of cellular metabolism and considered among the main drivers of the pathophysiology of ageing and age-related disorders. It would be expected that the process of ageing and the induction of genotoxic stress should impact all levels of gene regulation, however, little is known about the differential effects that distinct stimulants of DNA damage cause in the multiple levels of genome architecture and function. Thus, an in-depth elucidation of the oxidative damage-to-chromosome structure relationship at the molecular level is needed. A recent study led by the proposed host lab (Debes et al., Nature, 2023) demonstrated that ageing is characterized by abnormally high transcription elongation speeds in multiple cell types, tissues, and species, and that overexpression of histone proteins not only restores the kinetics of transcription to physiological levels, but also restricts the emergence of various ageing features in human cells. The inherent link between chromatin and 3D genome structure suggests that this histone-driven “rejuvenation” of ageing cells is bound to changes in the spatial architecture of chromosomes. Still, it remains unclear how these chromatin-based interventions can counter the ageing processes Putting these two together, I propose a study of the effects of chromatin rejuvenation on 3D chromosome architecture as well as on the genome’s ability to cope with oxidative damage. To this end, I will combine ultra-resolution 3D genomics with nascent epigenome mapping in aged (senescent) and “rejuvenated” primary human cells before and after inducing either chronic (low doses, prolonged treatment) or acute (high doses, one exposure) oxidative DNA damage. In a next step, these experiments can be complemented by in vivo dissection of rejuvenated mouse tissue at the single cell level. I expect these experiments to shed light on the molecular mechanisms and regulatory principles behind chromosomal stress responses during ageing. In conclusion, this research program will provide new insights into the crucial role of chromatin architecture during ageing, while deciphering differences in the ability of aged and rejuvenated cells to respond to oxidative stress induction. Thus, possible novel approaches for preventing and managing late-life disease by epigenome regulation might emerge.
2024
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Cross Disciplinary Fellowships - CDF
The bright side of life: fluorescence-detected ultrafast microspectroscopy
LUETTIG Julian (GERMANY)
Department of Physics - The Regents of the University of Michigan - Ann Arbor - United States
OGILVIE Jennifer (Host supervisor)
Photosynthesis provides almost all energy to life on earth. The complexity of nature is already revealed at the molecular level, where the photosynthetic protein scaffold controls the orientation, spacing and local environment between pigments, leading to delocalized excited states, i.e., excitons. The protein–pigment complexes form larger networks which act as an “energetic funnel” resulting in ultrafast exciton propagation to the reaction center where energy conversion occurs. Exciton dynamics have been studied in detail via pump–probe (PP) and two-dimensional (2D) spectroscopy. Most previous work has been performed on ensembles of isolated components, making it impossible to study the component interactions and heterogeneities. Examples for heterogeneity include structural variations, energetic disorder, and type of antenna complexes which all strongly influence the excitonic properties such as lifetime, transfer, and delocalization. We aim to develop methods to obtain a holistic picture of photosynthesis in space and time and to identify the influence of the local environment on each level of hierarchy – from organisms to single light-harvesting complexes. The outlined challenges require the combination of fluorescence-detected microscopy with femtosecond spectroscopy. Each of the isolated signals is sensitive to a specific excitonic property: the excitation spectrum is sensitive to the coupling, PP spectra characterize the lifetime, and 2D spectroscopy reveals energy transfer. Correlation of these properties results in a comprehensive picture of photosynthetic excitons. Our experimental approach leverages recent advances based on phase modulation with lock-in detection, allowing spatially-resolved 2D and PP from the same experimental setup, and employing phase-labeled photon counting detection to reach the single molecule limit. This unique combination of spectroscopic and imaging tools will allow us to investigate photosynthetic adaptation mechanisms of various systems both in vivo and in vitro. Previous experiments have shown that plants and bacteria grown under different light conditions change the relative composition and spatial distribution of antennas and reaction centers, incorporating modified pigments, and altering protein structures to tune electronic resonances and reroute energy transfer pathways. Our spectroscopic approaches will reveal alterations in the excitonic structure and energy transfer pathways due to adaptation. Next, we aim to proceed from averaged kinetics of an ensemble of complexes to measurements of distributions from individual complexes. This would enable the first single-molecule 2D experiment, revealing exciton dynamics in single light-harvesting complexes. The developed techniques would be widely applicable to other systems and spectral regions, providing powerful tools for studying biological samples with femtosecond and submicron resolution, such as melanin or the dynamics of proteins and nucleic acids.
2024
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Grant Awardees - Program Grants
Temporal structures in complex deep-sea versus surface marine life: from molecules to communities
TESSMAR-RAIBLE Kristin (GERMANY)
- University of Vienna (Universität Wien) - Vienna - AUSTRIA
MATABOS Marjolaine (FRANCE)
- French Research Institute for Exploitation of the Sea (Institut Français de Recherche pour l'Exploitation de la Mer, IFREMER) - Plouzané - FRANCE
OAKLEY Todd (United States)
- The Regents of the University of California, Santa Barbara - Santa Barbara - United States
PELEG Orit (ISRAEL)
- University of Colorado Boulder - Boulder - United States
While biological rhythms are crucial to life, the deep sea is often considered an acyclic exception. However, tidal inversions of local current flow cause extreme, but predictable changes in physico-chemical parameters at hydrothermal vents. Recent work indicates vent animals employ biological rhythms with a tide-matching period. How relevant are rhythms for life under these “alien” conditions and how do they work? We capitalize on our access to the Lucky Strike vent at -1700m with extensive scientific records, including 12 years of videos, and the key ecological engineer species Bathymodiolus azoricus, a vent mollusk. Specifically, we aim to understand the mathematical and molecular logic of deep-sea rhythms, the environmental stimuli that influence them, their ecological consequences, and evolutionary origins/adaptations from molecular level to organism and community scales. Tackling these aims is only possible by cross-disciplinary data, expertise, material exchanges:
An ecologist will provide expertise and access to deep-sea communities and environmental parameters, will perform experiments at deep sea vents to test predictions from models, including the influence of population size and environmental parameters (e.g. artificial illumination) on rhythmicity. A „wet-lab” cell- chronobiologist will probe molecular/cellular mechanisms of B. azoricus deep-sea rhythms on cell culture and organisms under constant and controlled-altered conditions (e.g. pressure, light/temp.). This includes possible sensory systems, tests for endogenous oscillator(s), changes in transcript and protein level/localization. An evolutionist with access to Modiolus, the closest shallow water relatives of Bathymodiolus, will compare putative rhythms (from molecules to populations) and responses to environmental signals between deep-sea and shallow water relatives to understand evolutionary changes. A biophysicist will use computer-vision for dataset analyses, develop models for rhythm emergence and stability, factoring in interactions among populations, environmental cues, and (possibly) correlated molecular changes. The model predictions will be experimentally tested by the team’s experimentalists. New data on ecological interactions, cues, sensors, and mechanisms will inform predictions on how temporally structured biological processes influence plasticity near the limits of life.
2024
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Cross Disciplinary Fellowships - CDF
Early Earth conditions as a selector for functional RNAs
MATREUX Thomas (GERMANY)
UMR CNRS-ESPCI Chemistry Biology and Innovation - The City of Paris Industrial Physics and Chemistry Higher Educational Institution (Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris, ESPCI) - PARIS - FRANCE
NGHE Philippe (Host supervisor)
Prebiotic scenarios rely on the emergence of sustained catalysis. One candidate molecule is RNA where various oligomerization mechanisms and numerous catalytic RNAs (ribozymes) have been discovered. However, a spontaneous transition in between seems improbable due to the scarcity of functional sequences among random strands. For instance, the medium-sized class I ligase is estimated to occur once in 1018 sequences. This leaves little opportunity for a ribozyme to appear by chance, lead to the formation of another ribozyme, and kick-start molecular evolution. The major transition thus begs for some form of external constraints that enrich functional sequences among the random ones. We suggest that geomaterial-RNA interactions could have acted as a filtering mechanism. Such interactions have been shown to catalyze RNA oligomerization, reduce RNA hydrolysis and select for longer oligomers. However, in the transition from random to functional RNAs, the geological context has so far been neglected. Since all catalytic RNAs and their substrates are partially folded, we expect their adsorption on geological surfaces to differ from that of unfolded or completely double-stranded sequences. My research plan consists of three parts: 1. Parsing of the folding space and proof of principle of the fold-dependent adsorption; 2. Inhibition and recovery of ribozyme activity within random pools; 3. Emergence and survival of reaction networks in random RNA pools. In part 1, I will design a repertoire of folds from statistics of known ribozymes and randomly picked motifs. I will quantify the fold-dependent adsorption on different surfaces (rocks, minerals and clays) and screen the effects of environmental conditions such as temperature, pH and salt during the adsorption and washing steps. Secondary structure predictions and thermodynamic adsorption models will serve to fit and predict adsorption of RNA folds. In part 2, I will study how binding of random oligomers to ribozymes leads to inhibition by probing the activity of various ribozymes within mixtures of increased randomness. The degree of enrichment of folded sequences required for function and the results from part 1 will enable me to establish how selective adsorption on geomaterials can restore activity. In part 3, I will explore conditions to sustain autocatalytic reaction networks in an open reactor that mimics connected rock cracks. Known reaction networks mixed with random pools will be submitted to rounds of adsorption on different minerals and washing. Using the findings of parts 1 and 2, I will determine the geological environments that enable the emergence of sustained autocatalysis despite inhibition and side-reactions caused by random RNAs. This project will provide a quantitative basis to assess the spontaneous emergence of function from random RNA pools and will identify the most plausible geological conditions for this crucial transition during the origin of life.