Biology subjects

Conrad, B.

Publications and source records attributed to Conrad, B..

6 recordsLinked to original sources

bioRxiv2026

A minimal model of stable autocatalytic RNA-replication through integration of replication, molecular regulation, and energy conversion

Catalysis and allostery are complementary principles of biological function: catalysis accelerates biochemical reactions, whereas allosteric regulation dynamically controls molecular interactions. The emergence and persistence of early autocatalytic ribozyme systems likely depended not only on template-directed self-replication but also on ATP production, utilization, and recycling through prebiotically plausible energy-conversion processes. We previously proposed that resistance to molecular parasitism in autocatalytic RNA networks can emerge through hyperparasitic regulation, whereby hyperparasitic ribozymes compete with parasitic ribozymes for binding to the host replicase while additionally binding parasitic ribozymes, thereby redirecting competitive interactions away from host exploitation. Here, we develop a minimal mathematical model of an autocatalytic RNA-world system in which replication, ATP/ADP-based energy conversion, and ATP-dependent allosteric regulation become dynamically coupled. Building on a general reaction framework describing ribozyme replication, catalytic interactions, and ATP/ADP cycling, we identify the minimal regulatory architecture required for stable RNA replication in the presence of parasitic mutants. Our simulations reveal a sequential evolutionary transition in which control precedes optimization. ATP-dependent allosteric regulation first evolves to tame molecular parasitism through hyperparasitic binding, whereby ATP-loaded parasitic ribozymes compete with ATP-free parasites for binding to the host replicase while also binding directly to parasitic ribozymes. This stabilizes RNA replication but simultaneously imposes an energetic cost by sequestering ATP and thereby reducing ATP-ADP turnover. The resulting regulatory burden creates selective pressure for the evolution of ATP synthase/ATPase ribozymes that accelerate ATP-ADP cycling and restore the metabolic flux required for sustained RNA replication. We further identify two plausible evolutionary routes to parasite control: parasitic ribozymes either become intrinsically allostery-prone or are converted into allostery-prone forms by an evolved allosterase ribozyme. Once ATP turnover is sufficiently rapid, both mechanisms confer long-term resistance to recurrent parasitic invasion. These results suggest that stable RNA-based evolution required the progressive integration of information replication, molecular reulation, and increasingly efficient metabolic energy conversion. More generally, the model identifies ATP-dependent allosteric regulation as a plausible evolutionary bridge linking autocatalytic RNA replication to the emergence of regulated proto-metabolism, transforming a parasite-limited replicating system into a self-regulating proto-biological organization capable of sustained evolutionary dynamics. HighlightsO_LIA minimal autocatalytic RNA network achieves stable self-replication despite recurrent parasitic invasion C_LIO_LIATP-dependent allostery tames molecular parasitism through hyperparasitic binding C_LIO_LIControl of molecular parasitism precedes optimization of metabolic energy conversion C_LIO_LIATP sequestration creates an energetic burden that drives increased ATP-ADP turnover C_LIO_LIStable parasite control evolves through either intrinsic allostery or allosterase-mediated regulation C_LIO_LIStable RNA autocatalysis emerges through the sequential integration of replication, molecular regulation, and energy conversion C_LI

ecology↗

bioRxiv2024

Ablation of hematopoietic stem cell derived adipocytes reduces tumor burden in syngeneic mouse models of high-grade serous carcinoma

Hematopoietic stem cell-derived adipocytes (HSCDAs) are an adipose subtype derived from myeloid precursors that are distinct from conventional mesenchymal adipocytes (CMAs). We hypothesized that HSCDAs promote high grade serous carcinoma (HGSC), the most common form of ovarian cancer. Despite similar rates of differentiation, primary human HSCDAs from female donors showed marked transcriptional differences from CMAs, including downregulation of cell cycle and upregulation of lipid metabolic pathways. HSCDAs secreted greater amounts of inflammatory cytokines than CMAs. We also conducted two independent tumor studies using ID8 and SO syngeneic HGSC murine models in immunocompetent mice that were either HSCDA Proficient (HSCDA-Pro; can make both adipocyte subtypes) or Deficient (HSCDA-Def; can only make CMAs). Tumor burden trended lower in HSCDA-Def mice in both models. Relative to HSCDA-Pro mice, omental ID8 tumors from HSCDA-Def mice downregulated transcription of multiple metabolic pathways that were enriched in human HSCDA cells in vitro, suggesting that ablation of HSCDAs altered the tumor metabolic environment. Compared to HSCDA-Pro mice, tumors from HSCDA-Def mice had lower densities of dendritic cells (DC) and natural killer (NK) cells, as well as fewer DCs, NKs, and B-cells in proximity to tumor cells. Our data suggest that HSCDAs alter the peritoneal immune and metabolic environment to support HGSC progression. ONE SENTENCE SUMMARYHematopoietic stem cell derived adipocytes may alter the peritoneal metabolic and immune environment to establish a metastatic niche and support ovarian cancer progression.

cancer biology↗

bioRxiv2024

Adipogenic differentiation of hematopoietic lineage cells isolated from adipose tissue of humans

We previously discovered some adipocytes in the major white fat depots of mice and humans arise from bone marrow-derived cells of hematopoietic lineage rather than conventional mesenchymal precursors, termed bone marrow-derived adipocytes (BMDA). Here we aimed to determine if hematopoietic lineage cells isolated from adipose tissue and circulation of humans could undergo adipogenic differentiation in vitro, thereby establishing an in vitro model for studies of BMDA. We hypothesized that hematopoietic lineage cells isolated from adipose tissue, but not circulation, of humans would demonstrate adipogenic potential. Participants included younger (20-50 years) and older (>50-75 years) men and women, BMI 20-37 kg/m2. Subcutaneous abdominal adipose tissue biopsies were obtained and stromal cell populations identified by flow cytometry. Sorted cells underwent in vitro cultivation via traditional mesenchymal culture methodology (mesenchymal lineage) or a novel 3D-fibrin clot followed by traditional adherent culture (hematopoietic lineage) for assessment of proliferation and differentiation capacity. We found hematopoietic lineage cells isolated from the adipose tissue stroma, but not the circulation, were capable of proliferation and multilineage (adipogenic and osteogenic) differentiation in vitro. We provide a new investigative tool that can be used to perform translational studies of BMDAs and provide initial evidence that hematopoietic lineage cells isolated from the adipose tissue of humans can undergo hematopoietic-to-mesenchymal transition with multilineage differentiation potential in an in vitro environment.

physiology↗

bioRxiv2024

Biomathematical enzyme kinetics model of prebiotic autocatalytic RNA networks: degenerating parasite-specific hyperparasite catalysts confer parasite resistance and herald the birth of molecular immunity

Catalysis and specifically autocatalysis are the quintessential building blocks of life. Yet, although autocatalytic networks are necessary, they are not sufficient for the emergence of life-like properties, such as self-propagation (replication) and adaptation. The ultimate and potentially fatal threat faced by molecular replicators is parasitism; if the polymerase error rate exceeds a critical threshold, even the fittest molecular species will disappear. Here we have developed an autocatalytic RNA early life mathematical network model based purely on enzyme kinetics, more specifically the steady-state approximation. We confirm previous models showing that these autocatalytic cycles are sustainable, provided there is a sufficient nucleotide pool. However, molecular parasites arise rapidly and become unsustainable unless they sequentially degenerate to hyperparasites (i.e. parasites of parasites). These hyperparasites acquire parasite binding specificity via two distinct temporal pathways. Our model is supported at three levels; firstly, ribozyme polymerases display Michaelis-Menten saturation kinetics and comply with the steady-state approximation. Secondly, ribozyme polymerases are capable of sustainable auto-amplification and of surmounting the fatal error threshold. Thirdly, with growing sequence divergence of host and parasite catalysts, the probability of self-binding increases and the trend towards cross-reactivity diminishes. Our model predicts that primordial host-RNA populations evolved via an arms race towards a host-parasite-hyperparasite catalyst trio that conferred parasite resistance within an RNA replicator niche. As such, it adds another mechanism - whats more, with biochemical precision - by which parasitism can be tamed and offers an attractive explanation for the universal coexistence of catalyst trios within prokaryotes and the virosphere, heralding the birth of a primitive molecular immunity. Author SummaryThe quintessential components of life comprise a potent mixture of naturally occurring, but improbable chemical reactions (catalysis), and the arrangement of such accelerated chemical reactions into closed loops (autocatalytic sets). This is required, but is not sufficient for such networks to self-propagate (amplification of the information carrier = host polymerization) and adapt (Darwinian evolution). As soon as self-propagation is attained, the next hurdle is parasitism. This typically involves shorter molecules (the products of replicative errors) that hitchhike the replicative potential of the host. They will invariably outcompete the regular amplification process, unless a solution is found. We have addressed this problem using a new model based on the mathematics of catalysis. This model confirms previous studies demonstrating that autocatalytic sets become self-sustaining, assuming that a sufficient pool of molecular building blocks is available. However, molecular parasitism is pervasive and potentially fatal for both host and parasite. In our model, we allow these parasites to degenerate in a controlled fashion, giving rise to parasites of parasites (hyperparasites). As long as these hyperparasites acquire binding specificity for parasites, an attenuation of parasitism is observed. These parasite-hyperparasite cycles stabilize the host cycle, explaining why they are conserved, and why they are the likely reason behind the observation that all cellular hosts are associated with parasites (e.g. bacteria) and hyperparasites (e.g. viruses) across all kingdoms of life. Moreover, it provides a novel solution to the usually intractable problem of parasitism.

evolutionary biology↗

bioRxiv2023

Birth of immunity in early life: stepwise emergence of resistance and immunity to complex molecular parasites via progressively degenerating hyperparasites

Catalysis and specifically autocatalysis are the quintessential building blocks of life. However, autocatalytic networks are necessary but not sufficient for life-like properties such as self-propagation and adaptation to emerge. We previously showed using Lotka-Volterra equations that a tripartite, early life cycle comprising a host-template, molecular parasites and hyperparasites (parasites of parasites) conferred superior stability to the habitat. Here we build on this model, and on the seminal notion that chemical networks and ecologically interacting biological species are akin, implying an instructive equational analogy between catalysis and ecology, both accurately modelled by equations from the Lotka-Volterra family. Template-based autocatalytic RNA networks seed the spontaneous emergence of immunity against molecular parasites, with degenerating molecular parasite catalysts being the founding seed of the homeostatic process. First, upon molecular parasite encounter, specific ribocatalysts providing parasite resistance appear in primordial autocatalytic cycles, supplanted by promiscuous, efficiently self-replicating, but parasite sensitive ribozymes. This is supported by catalyst tradeoff analysis: substrate promiscuity confers high catalytic activity, but entails parasite exposure, higher substrate specificity implies relatively lower activity, yet it offers parasite resistance. Second, sustained parasite influx generates hyperparasite cycles, memorizing parasite-specific catalyst-subunits that now once more provide parasite resistance, in a homeostatically stabilized habitat. Third, under continuous exposure to progressively elaborate parasite populations, hyperparasite catalysts degenerate and embody antiparasite immunity. The observed triggering of microbial immunity by hyperparasitic microbial genomes are in agreement with this model. As such, it offers an attractive and unifying theory for the spontaneous birth of immunity in early life. Author SummaryThe quintessential components of life comprise a potent acceleration of naturally occurring, but improbable chemical reactions (catalysis), and the arrangement of accelerated chemical reactions in closed loops (autocatalytic sets). This is required, but is not sufficient for such networks to self-propagate and adapt. We previously developed an early life model for a stabilized habitat of networks, using a family of equations shown to accurately model both chemical reactions and the interactions of biological species. This model became stabilized only if the molecular host species was parasitized, an event considered unavoidable, and at the same time, the parasite itself was also parasitized. We now built on that model, using the same family of equations, by letting individual autocatalytic sets interact. The new results show that primitive autocatalytic networks emerge spontaneously, but inefficiently and resist parasites. With time, they become more efficient, which renders them parasite-sensitive. Upon continuous external parasite invasion, the primitive, parasite-resistant catalysts (hyperparasites) that still persist are recruited, conferring stability to the habitat. If the habitat is further overwhelmed with parasites, it selects the elegant solution of letting the parasite-resistant catalysts degenerate, which now produces immunity to those parasites ("antibodies"). This represents the birth of adaptive immunity.

evolutionary biology↗

bioRxiv2021

Energy-harnessing problem solving of primordial life: modeling the emergence of catalytic host-parasite life cycles

All life forms on earth ultimately descended from a primordial population dubbed the last universal common ancestor or LUCA via Darwinian evolution. Extant living systems share two salient functional features, a metabolism extracting and transforming energy required for survival, and an evolvable, informational polymer - the genome - conferring heredity. Genome replication invariably generates essential and ubiquitous genetic parasites. Here we model the energetic, replicative conditions of LUCA-like organisms and their parasites, as well as adaptive problem solving of host-parasite pairs. We show using the Lotka-Volterra equations that three host-parasite pairs - individually a unit of a host and a parasite that is itself parasitized - are sufficient for robust and stable homeostasis, forming a life cycle. This catalytic life cycle efficiently captures, channels and transforms energy, enabling dynamic host survival and adaptation. We propose a Malthusian fitness model for an original quasispecies evolving through a host-parasite life cycle.

evolutionary biology↗