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Biology subjects

Bachelet, I.

Publications and source records attributed to Bachelet, I..

13 recordsLinked to original sources

Modularity, ecology, and theoretical evolution of the ribozyme body plan

Ribozymes are relics of molecular life forms from the primitive earth that are embedded within modern genomes across all kingdoms of life. Despite significant knowledge from decades of bioinformatic and biochemical research, a gap remains in our understanding of the world in which ribozymes existed, their interactions, ecology, and possibly also evolution. The present study proposes a new theoretical basis for understanding these aspects of ribozyme biology by adopting a zoological frame of thought. Seven families of small self-cleaving ribozymes are each mapped to a primitive marine animal analog based on topological architecture, and classified into body plan grades paralleling cnidarian, ctenophore, and bilaterian organization. A formal notation describing ribozyme regions as bodies, cavities, and limbs enables systematic comparison with animal body plans and highlights reusability of parts across ribozyme groups, in turn enabling the construction of a connectivity network and a putative body plan-based evolutionary ordering. This ordering of body plans identifies systematic gaps corresponding to undiscovered ribozyme forms, one of which, a planktonic form of hammerhead, was bioinformatically found in 16.2% of all hammerhead sequences. Computational cross-cleavage analysis across all 49 pairwise interactions (including conspecific) suggests that the hammerhead was a generalist apex predator in the RNA world, while the hatchet was a vulnerable, filter-feeding or scavenger prey species. Conspecific analysis suggests that cannibalism was also a prevalent feeding strategy. Evolutionary avoidance signatures suggest ancient predator-prey coevolution. This theory emphasizes behavior, modularity, and ecological interactions as primary drivers of early ribozyme evolution, offering a new pathway for inferring ancient RNA forms independent of sequence-first assumptions.

bioinformatics↗

A ribozyme mass extinction at the RNA-cellular boundary and its potential imprint on the genetic code

The transition from the RNA world to cellular life remains one of the least understood events in the history of biology. This study proposes that geochemical changes approximately 3.9-3.8 billion years ago triggered a mass extinction of ribozymes - possibly the first extinction event on Earth - and that the genetic code bears the fingerprints of its survivors. The argument draws on parallels with animal mass extinctions, where generalist species survive, dominate post-extinction ecosystems as disaster taxa, and shape subsequent evolutionary trajectories. Among small self-cleaving ribozymes, the hammerhead ribozyme accounts for approximately 91% of all [~]221,000 known sequences and is the only ribozyme that is found across all kingdoms of life. The phylogeny of hammerhead ribozymes exhibits a star-like topology consistent with rapid post-bottleneck expansion, and its small size, ability to tolerate diverse chemical conditions, and broad substrate specificity suggest it was a resilient generalist feeder fitting as a disaster taxon. Other families of ribozymes possibly survived in small, taxonomically isolated populations resembling relict species in ecological refugia. It is suggested that the body plans of surviving ribozymes seeded the primitive processes that would later become the genetic code, for example with RNA-degrading trinucleotides becoming stop codons, partitioning the trinucleotide space into signals of termination and translation. This hypothesis proposes a reframing of the origin of the genetic code in part as an ecological legacy rather than a purely chemical inevitability.

evolutionary biology↗

Carrierwave: A granular, incentive-aligned infrastructure for scientific communication

The peer-reviewed journal article imposes structural constraints on the dissemination, validation, and reuse of research outputs. Intermediate results, negative findings, methodological refinements, and replication attempts are systematically underrepresented in published literature, limiting visibility into ongoing research activity for both scientists and mission-driven funders. Here we present Carrierwave, an open infrastructure for continuous, granular scientific communication built on structured research objects (ROs), cryptographic provenance, blockchain-based attribution, and programmable incentive mechanisms. Each RO represents an atomic unit of scientific output -- a single experimental result, negative finding, dataset, protocol, or replication -- that is hashed for content integrity, stored in a persistent database, and optionally minted as an ERC-721 non-fungible token on the Ethereum blockchain. The system includes an on-chain bounty pool enabling funders to directly incentivize specific research activities, and an automated analysis layer that synthesizes disclosed ROs into continuously updated research landscape maps. We describe the system architecture, report on its implementation and deployment on Ethereum mainnet, and present a quantitative analysis of disease-specific publication frequency demonstrating the information latency problem that Carrierwave addresses. The distribution of publication frequency across disease areas is highly skewed, with the majority of conditions represented by fewer than four publications per year in high-impact biology journals. For diseases in the long tail, the interval between successive publications may span months or years. Publication frequency correlates poorly with disease burden, instead reflecting historical research community size and advocacy momentum. By reducing the unit of communication to the individual research object and eliminating editorial gatekeeping as a prerequisite for disclosure, Carrierwave increases the effective sampling rate of scientific activity in precisely the domains where publication-based visibility is most sparse. The system is live at https://carrierwave.org.

scientific communication and education↗

A study of k-mer patterns within DNA molecules sequenced from a chondrite

The known tree of life occupies an infinitesimal region of the space of all mathematically possible evolutionary histories, yet our sequence analysis frameworks are implicitly calibrated to it and to its associated compositional and grammatical regularities. Here we analyze nucleic acid molecules sequenced from the Zag meteorite as part of a broader effort to understand how nucleic acid sequence composition and higher-order structure are shaped under chemically divergent environments. We characterize these sequences across multiple analytical layers, and show that they lack signatures of protein-coding organization, translational periodicity, or known biological grammar. At the same time, they deviate significantly from random or composition-only null models, displaying constrained complexity and low-dimensional structure in k-mer frequency space. Multiple tests place amplification and sequencing-driven artifacts and metagenomic contaminants at a low likelihood. Taken together, these findings indicate that the Zag sequences occupy an unusual region of sequence space that is not readily accounted for by known biological or technical models, thereby narrowing, but not resolving, the range of plausible explanations and motivating independent replication and further investigation.

bioinformatics↗

A food chain of ribozymes built on an ancestral strand

Molecular life forms in the prebiotic earth were capable of self-reproduction from basic building blocks. However, scarcity of building blocks likely led to the evolution of heterotrophic, predatory species. In this work we reconstruct a simple model of such interactions between RNA molecules, based on RNA strands found in sinkhole mineral pools in the Dead Sea. These RNA strands exhibited significant stability in this divergent chemical environment, and contained sequence motifs reminiscent of two ribozyme species, suggesting they could be ancestral to both. We built a system in which a single ancestral RNA strand serves as a limiting resource forming two different species of ribozymes that compete over it. One of these species is capable of metabolizing the other in order to free more of this resource, driving the assembly of additional copies of itself. This interaction resembles a rudimentary food chain, the dynamics of which is sensitive to environmental factors such as temperature and magnesium concentrations, with competitive advantage shifting between the species. Taken together, these findings highlight a hypothetical feature of prebiotic life, and hint at the possibility that heterotrophic RNA is a phenomenon that might still occur today in some unique geochemical niches, and even in the overlooked background of modern biological systems.

biophysics↗

An antiviral self-replicating molecular heterotroph

We report the synthesis of a molecular machine, fabricated from nucleic acids, which is capable of digesting viral RNA and utilizing it to assemble additional copies of itself inside living cells. The machines body plan combines several parts that build upon the target RNA, assembling an immobile, DNA:RNA 4-way junction, which contains a single gene encoding a hammerhead ribozyme (HHR). Full assembly of the machines body from its parts enables the subsequent elongation of the gene and transcription of HHR molecules, followed by HHR-mediated digestion of the target molecule. This digestion converts the target to a building block suitable for participation in the assembly of more copies of the machine, mimicking biological heterotrophy. In this work we describe the general design of a prototypical machine, characterize its activity cycle and kinetics, and show that it can be efficiently and safely delivered into live cells. As a proof of principle, we constructed a machine that targets the Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) GP64 gene, and show that it effectively suppresses viral propagation in a cell population, exhibiting predator/prey-like dynamics with the infecting virus. In addition, the machine significantly reduced viral infection, stress signaling, and innate immune activation inside virus-infected animals. This preliminary design could control the behavior of antisense therapies for a range of applications, particularly against dynamic targets such as viruses and cancer.

synthetic biology↗

Discovery of tumoricidal DNA aptamers by effect-directed in-vitro evolution

Our current model of drug discovery is challenged by the relative ineffectiveness of drugs against highly variable and rapidly evolving diseases and their relatively high incidence of adverse effects due to poor selectivity. Here we describe a robust and reproducible platform which could potentially address these limitations. The platform enables rapid, de-novo discovery of DNA oligonucleotides evolved in-vitro to exert specific biological effects on target cells. Unlike aptamers, which are selected by their ligand binding capacity, this platform is driven directly by therapeutic effect and selectivity towards target vs negative target cells. The process could, therefore, operate without any a-priori knowledge (e.g. mutations, biomarker expression, or known drug resistance) of the target. We report the discovery of DNA oligonucleotides with direct and selective cytotoxicity towards several tumor cell lines as well as primary, patient-derived solid and hematological tumors, some with chemotherapy resistance. Oligonucleotides discovered by this platform exhibited favorable biodistribution in animals, persistence in target tumors up to 48 hours after injection, and safety in human blood. These oligonucleotides showed remarkable efficacy in-vivo as well as ex-vivo in freshly obtained, 3D cultured human tumors resistant to multiple chemotherapies. With further improvement, these findings could lead to a drug discovery model which is target-tailored, mechanism-flexible, and nearly on-demand.

synthetic biology↗

De-novo discovery of tumoricidal aptamers in a DNA sequencing chip

We describe a technique for the rapid ab-initio discovery of target-tailored tumoricidal DNA oligonucleotides inside an Illumina sequencing chip. By sequencing oligonucleotide pools we generate a physical microfluidic map of hundreds of millions of potential oligo clusters, in which every cluster is mapped to a specific set of spatial coordinates. Tumor cells, pre-loaded with a fluorogenic reporter of apoptosis, are then injected into the chip and monitored over time. Apoptotic tumor cells are identified and analyzed across the entire map, automatically revealing the coordinates of oligos that induced this effect. We demonstrate this method by identifying, within just a few hours, new oligos capable of directly and selectively inducing apoptosis in primary human tumor cells. Such a major capability could lead to a new paradigm of personalized cancer therapy.

synthetic biology↗

A modeling algorithm for exploring the architecture and construction of bird nests

Natural biological structures are often complex and cannot be mapped directly to genes, being therefore impossible to explore by traditional biological tools. In contrast, digitizing these structures enables to explore their properties and behavior under specific conditions, by means of computational manipulations, simulations, and analyses. We describe a generic algorithm for the digitization and exploration of the complex structures exhibited by common, interwoven bird nests. This algorithm takes as input computerized tomographic scans of the studied Dead-Sea Sparrow (Passer moabiticus) nest, identifies and isolates each branch entity within the three-dimensional data and finally extracts the characteristics of each branch. The result is a reliable three-dimensional numerical model of the nest that contains a complete geometric dataset per each of its components, e.g. dimensions and contact points with neighboring components, as well as global properties, e.g. density distribution and network structure. Based on these, we were able to simulate various models of the nest construction process. Altogether, the described algorithm and possible derivatives thereof could be a valuable tool in studying the structure-function relationships of similarly complex biological objects.

biophysics↗

Simulating the Monty Hall problem in a DNA sequencing machine

The Monty Hall problem is a decision problem with an answer that is surprisingly counter-intuitive yet provably correct. Here we simulate and prove this decision in a high-throughput DNA sequencing machine, using a simple encoding. All possible scenarios are represented by DNA oligonucleotides, and gameplay decisions are implemented by sequencing these oligonucleotides from specific positions, with a single run simulating more than 12,000,000 independent games. This work highlights high-throughput DNA sequencing as a new tool that could extend existing capabilities and enable new encoding schemes for problems in DNA computing.

synthetic biology↗

Nanoscale robots exhibiting quorum sensing

Multi-agent systems demonstrate the ability to collectively perform complex tasks--e.g., construction1-2, search3, and locomotion4,5--with greater speed, efficiency, or effectiveness than could a single agent alone. Direct and indirect coordination methods allow agents to collaborate to share information and adapt their activity to fit dynamic situations. A well-studied example is quorum sensing (QS), a mechanism allowing bacterial communities to coordinate and optimize various phenotypes in response to population density. Here we implement, for the first time, bio-inspired QS in robots fabricated from DNA origami, which communicate by transmitting and receiving diffusing signals. The mechanism we describe includes features such as programmable response thresholds and quorum quenching, and is capable of being triggered by proximity of a specific target cell. Nanoscale robots with swarm intelligence could carry out tasks that have been so far unachievable in diverse fields such as industry, manufacturing and medicine.

synthetic biology↗

Digital therapeutics for distributed response to global pandemics

Despite advances in the development of drugs and vaccines, the spread of infectious diseases remains an imminent threat to our global health, in extreme cases potentially having detrimental consequences. At present our response to this threat is based on physically distributing therapeutic material, which utilizes the same transportation networks that support the spread of the infectious agent itself. Such competition is at risk of failure in the face of a rapidly spreading pathogen, especially given the inevitable delay from the initial outbreak to the development and execution of our response. Moreover, based on our existing transportation networks, we show that such physical distribution is intrinsically inefficient, leading to an uneven concentration of the therapeutic within a small fraction of destinations, while leaving the majority of the population deprived. This suggests that outrunning a virulent epidemic can only be achieved if we develop a mitigation strategy that bypasses the existing distribution networks of biological and chemical material. Here we propose such a response, utilizing digitizable therapeutics, which can be distributed as digital sequence files and synthesized on location, exposing an extremely efficient mitigation scheme that systematically outperforms physical distribution. Our proposed strategy, based for example on nucleic acid therapeutics, is plausibly the only viable mitigation plan, based on current technology, that can face a violently spreading pathogen. Complementing the current paradigm, which ranks drugs based on efficacy, our analysis demonstrates the importance of balancing efficacy with distributability, finding that in some cases the latter plays the dominant role in the overall mitigation efficiency.

bioinformatics↗

Molecular anatomy and plasticity of the long noncoding RNA HOTAIR

Long noncoding RNA molecules (lncRNAs) are estimated to account for the majority of eukaryotic genomic transcripts, and have been associated with multiple diseases in humans. However, our understanding of their structure-function relationships is scarce, with structural evidence coming mostly from indirect biochemical approaches or computational predictions. Here we describe the hypothetical molecular anatomy of the lncRNA HOTAIR (HOx Transcript AntIsense RNA) inferred from direct, high-resolution visualization by atomic force microscopy (AFM) in nucleus-like conditions at 37 degrees. Our observations reveal that HOTAIR has a distinct anatomy with a high degree of plasticity. Fast AFM scanning enabled the quantification of this plasticity, and provided visual evidence of physical interactions with genomic DNA segments. Our report provides the first biologically-plausible hypothetical description of the anatomy and intrinsic properties of HOTAIR, and presents a framework for studying the structural biology of lncRNAs.

biophysics↗