We present a biochemistry-agnostic method to map evolutionary relationships at the molecular scale using mass spectrometry and Assembly Theory, without structure elucidation of analytes. By analyzing diverse biological and non-biological samples, we were able to infer joint assembly spaces of sampled species to determine their biogenicity and taxonomic grouping. We developed an assembly-based phylogenetic tree that aligns with the consensual genome-based model. Later we were able to use our approach to track bacterial lineages exhibiting phenotypic variation. Our results demonstrate we can expand causal molecular inference to non-sequence information without requiring exact molecular identities, thereby opening the possibility to study previously inaccessible biological domains.

The origin of life likely involved a shift from chaotic chemistry to self-reproducing structures. We examine the reproduction characteristics of the GARD lipid-based model, which simulates physicochemically rigorous, self-replicating networks. The model shows compatibility with heterogeneous environments and portrays trans-generational information transfer. However, we find that self-reproducing states are rare in compositional space, indicating that random exploration would be inefficient to attain reproduction capacities. Rewardingly, we sow thatb all self-reproducing states are dynamic attractors of the catalytic network, suggesting a greatly enhanced propensity for reproduction and primal evolution, augmenting the likelihood of protolife appearance.

Protocells are often seen as bilayer-enclosed precursors of life, relying on replicating biopolymers for self-reproduction. This Perspective presents an alternative scenario where reproducing lipid micelles with catalytic abilities preceded biopolymer-containing protocells. Support for this idea comes from experiments on micellar catalysis and autocatalytic proliferation, as well as cross-catalysis in mixed micelles leading to life-like dynamics. Our chemically stringent computer-simulated model further shows how catalytic lipid networks could enable micellar compositional reproduction, facilitating primal selection and evolution. Finally, we highlight studies on how endogenously catalysed lipid modifications could guide further protocellular complexification, supporting the idea that lipid micellar assemblies seeded protocellular evolution.

A living system is a selective chemical network that evolves from simple origins. To promote evolution, protocellular networks must exhibit sufficient selectivity in their molecular interactions, guiding molecular assembly. To test this, we conducted over 5600 organocatalytic reactions in two chemical systems, revealing that greater molecular assembly reduce average catalytic selectivity, highlighting a trade-off between exploration and selection. Both systems also showed a selectivity barrier as complexity increased, explaining the gap between living and non-living systems. This work provides insight into the kinetic foundations of selection in catalytic networks and the transition from chemistry to life.

Mixed lipid micelles, with their growth dynamics and catalytic properties, were proposed to facilitate the origin of life. Our previous research suggested micellar self-reproduction involves lipid accretion, leading to compositional homeostasis. Using Molecular Dynamics simulations, we tracked micellar accretion from 54 lipid monomers to study self-assembly in mixed lipid clusters. We observed significant rate changes based on composition and size, revealing the underlying kinetic mechanisms and energy contributions. Our findings support the potential for compositional homeostasis in mixed micelles, reinforcing the basis for micellar self-reproduction and its relevance to the origin of life.

Despite the complete genomic sequencing of Saccharomyces cerevisiae, a significant portion remains functionally unannotated, limiting our understanding of cellular activity. Recent advancements in genomic and structural data, along with new computational methods, now allow us to extract meaningful insights into the functional identity of uncharacterized proteins in yeast. In this work, We created a database of sequence and structural similarity predictions to identify candidate enzymes for unknown biochemical reactions. Using this approach, we discovered that Yhr202w, now named Smn1 (Scavenger MonoNucleotidase 1), functions as an extracellular AMP hydrolase in the NAD degradation pathway. Our new methodology provides a framework, that can be adopted to other organisms, for uncovering new enzymatic functions of uncharacterized proteins.

Vaccination and natural infection trigger humoral immune responses, with antibodies encoding immune histories of individuals. While most immunoassays measure responses to a single antigen, we introduce FLU-LISA, a high-throughput antigen microarray-based assay for rapid, simultaneous antibody profiling of IgG, IgA, and IgM against multiple antigens. Using influenza and SARS-CoV-2 antigen microarrays, we demonstrated the sensitivity and specificity of FLU-LISA, compared to the traditional ELISA, in mice, chickens, and humans. FLU-LISA can also use dried blood spots, allowing profiling of hundreds of samples in one day, making it a promising alternative to ELISA.

The traditional view that the origin of life requires biopolymers like RNA and proteins is challenged by the improbability of their spontaneous formation in primordial chemistry. An alternative “Lipid-First” hypothesis suggests that lipid assemblies can spontaneously emerge, grow, and self-reproduce. A key question remains whether these lipid assemblies can engage in protein-like stereospecific interactions, essential for life processes. This Viewpoint highlights experimental evidence showing that lipid aggregates can have dynamic surface configurations capable of stereospecific molecular recognition, supporting the idea that lipids may have played a crucial role in the origin of life.

Polyamines are known to stabilize nucleic acids by promoting folding, but their role in protein structure and function is less clear. Early proteins, thought to be highly acidic due to a lack of basic amino acids, might have relied on polyamines as chemical chaperones. In our study, we replaced all lysines of an ancestral 60-residue helix-bundle protein with glutamates, making it disordered. Polyamines induced folding at submillimolar concentrations, with their effectiveness increasing with the number of amine groups. In comparison with simple cations, polyamines were far more potent than Na+, while Mg2+ and Ca2+ were similar to diamines. We suggest that polyamines may have helped fold early acidic proteins and could influence protein regulation today through coil–helix transitions.

A recent study has identified complex organic molecules in the plumes from Enceladus' subglacial ocean, suggesting a source of carbon-rich monomers and polymers. These findings point to the possibility of a prebiotic soup in Enceladus, providing an environment fitting for life's origin. The observed monomers resemble simple lipids, while the polymers are similar to terrestrial kerogens and organic compounds in carbonaceous meteorites. The authors propose that these polymers could break down into micelle-forming amphiphiles. This supports the Lipid World hypothesis, where life originated from mixed lipid assemblies, unlike other models requiring highly-specific chemistries.