Theory gaps in Biology

Representative open questions

Showing 30 of 329 — one per source paper, highest-quality first.

• Disrupting the KRAS–SOS1 protein–protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy (2026) · doi

  Mechanistically grounded biomarkers for SOS1 inhibitors are likely to fall into two buckets: (i) markers of upstream dependence where KRAS output remains coupled to RTK–GRB2–SOS signaling, and (ii) markers of pre-existing or readily inducible bypass circuits. Current evidence supports the following practical hypotheses: Higher likelihood of benefit: RTK-high states (strong phospho-RTK contexts with prominent ERK rebound signatures under MAPK-targeted therapy, and settings where preclinical co-targeting data show clear vertical synergy (e.g., KRASG12C plus SOS1; EGFR-mutant spheroid models) (Amodio et al., 2020; Thatikonda et al., 2024; Theard et al., 2020).

• Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour (2026) · doi

  The study demonstrates CXCL12-independent CXCR4 signaling in MLL-AF9 acute myeloid leukemia (reference 49), but the specific downstream mechanisms beyond JAK/STAT5 pathway activation that mediate leukaemic stem cell behavior in the metaphyseal versus central marrow niches remain uncharacterized. Direct mechanistic investigation of alternative CXCR4 effectors in spatially-distinct bone marrow microenvironments is needed.

• Fast analysis and engineering of protein function by microbe-independent deep assembly and screening (2026) · doi

  NanoLuc substrate specificity variants (Fz, FFz, CFz9) were engineered at active-site positions, but the paper does not specify how substrate-facing residue predictions were derived (computational modeling, structural homology, or empirical mapping) or validate whether residues outside the catalytic cleft influence substrate selectivity. Systematic saturation mutagenesis of predicted non-catalytic residues would determine the full active-site architecture governing substrate discrimination.

• Charcoal rot in sesame: infection biology, host resistance mechanism, and genomic-enabled strategies for durable resistance breeding (2026) · doi

  The molecular basis of sesame-M. phaseolina interaction under combined heat and drought stress remains uncharacterized; specifically, how stress signaling, hormone crosstalk, ROS homeostasis, and defense gene activation are coordinated to determine susceptibility or durable resistance requires integrated transcriptomic and physiological investigation.

• From parasite-induced immune activation to neuroinflammation and behavioral dysfunction: convergent mechanisms across protozoa and helminths: a review (2026) · doi

  Biomarkers and host-directed therapies targeting shared neuroinflammatory nodes across protozoan and helminthic infections remain unidentified. The convergent mechanisms linking parasite-induced immune activation to microglia/astrocyte priming and blood–brain barrier disruption lack validated biomarker panels that discriminate between parasitic species and predict neuropsychiatric risk.

• Decoding Rho GTPase signalling networks in directed cell migration (2026) · doi

  Studies show that matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP axis and that KIF13A regulates RhoB plasma membrane localization for blebby migration, but how mechanotransduction pathways intersect with Rho GTPase signaling networks to coordinate different migration modes (mesenchymal versus amoeboid) across varying tissue stiffness ranges has not been quantitatively modeled.

• Dietary N-acetylcysteine enhances sperm motility by remodeling the rumen microbiome and its metabolic axis in goats (2026) · doi

  The study identified elevated plasma levels of taurine-conjugated bile acids positively correlated with sperm motility, but the mechanistic pathway by which microbiota-modulated bile acid composition enhances membrane fluidity and sperm physiological function remains incompletely characterized. Direct mechanistic studies examining how taurine-conjugated versus glycine-conjugated bile acids affect sperm mitochondrial membrane potential and ATP synthesis are needed.

• Gut microbiota-driven IL-17/PPAR axis mediates epigallocatechin-induced intestinal repair in weaned lambs (2026) · doi

  The molecular mechanisms by which epigallocatechin (EGC) microbial metabolites (valeric acid and C ring fission products) activate the PPAR signaling pathway to restore FABP1 and SLC2A2 expression have not been elucidated; the direct interaction between postbiotics and PPAR receptors in jejunal epithelial cells requires biochemical and binding assay validation.

• Self-organisation of complex dynamical systems: from synergetics to neuromorphic systems (2026) · doi

  While the paper states that locally-active memristors can amplify signals similar to transistors and that local activity leads to complex pattern emergence from homogeneous brain tissues, it does not provide specific mathematical conditions or circuit design parameters needed to determine when and how local activity in memristive architectures transitions from pattern suppression to pattern generation in cellular neuronal networks.

• Adaptation of lipid metabolism of the polyextremophilic cyanobacterium Cyanobacterium aponinum PCC 10605 to adverse environmental conditions (2026) · doi

  The relationship between phytol accumulation as FAPE during phosphate deprivation and the simultaneous decrease in acylated plastoquinols has not been mechanistically investigated. The paper observes that FAPE increases to ~100 pmol mg⁻¹ DW from phytol derived from chlorophyll degradation while acyl-PQH and acyl-PQC decrease, but does not determine whether these changes reflect competitive substrate utilization by MFAT or independent regulatory signals triggered by phosphate stress.

• Ethyl methanesulfonate mutagenesis in fungi: genetic mechanisms, applications, and implications for agricultural biotechnology (2026) · doi

  The bidirectional effects of EMS-induced point mutations on virulence phenotypes in fungal pathogens (both attenuation and enhancement) remain mechanistically unclear across different genetic contexts. Systematic characterization of how low-level mutational variation in specific pathogenic pathways shifts infection outcomes is needed through targeted allele mapping and regulatory pathway analysis.

• Comparative genomics identifies small interfering RNA with activity against all five human betacoronaviruses (2026) · doi

  Viral genome RNA functions as both translational template and replication template, and cleavage efficacy may differ from translational repression outcomes. In vitro studies investigating whether siRNA-mediated cleavage of viral genomic RNA versus translational repression differentially affects genome replication and transcription dynamics would clarify mechanistic contributions to antiviral efficacy.

• Effects of host migration and travel loss on strain competition in a two-patch SIR model (2026) · doi

  The uniform persistence result (Proposition 2.5) is proven only when m^I_12 > 0 and m^I_21 > 0 (bidirectional infected host migration); the case where migration is unidirectional or occurs only from one patch to another for strain I has not been analyzed.

• What causes self-sterility in Couroupita guianensis (Lecythidaceae)? (2026) · doi

  The paper identifies LSI (late-acting self-incompatibility) as the mechanism in C. guianensis but does not investigate the specific molecular or physiological trigger causing precocious fruit abortion before embryogenesis initiation in selfed seeds. Future research should characterize the biochemical or hormonal signals responsible for fruit abscission timing in selfed versus crossed fruits.

• Metabolic reprogramming in intervertebral disc degeneration: mechanisms and therapeutic opportunities (2026) · doi

  HIF1A upregulates autophagy to alleviate compression-induced apoptosis in nucleus pulposus-derived stem cells, but the mechanistic crosstalk between HIF1A-mediated metabolic reprogramming (glycolysis vs. oxidative phosphorylation) and autophagy flux modulation under sustained mechanical loading has not been elucidated.

• Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma (2026) · doi

  The study documented that cNP plus anti-PD-1 reduced regulatory T cells, M2 macrophages, and M-MDSCs while increasing CD8+ T cells and B cells, but the specific molecular mechanisms by which NET-DNA clearance mediates macrophage polarization from M2 to M1 phenotype and suppresses myeloid inflammation require mechanistic investigation.

• Society for Developmental Biology 70th Annual Meeting (2011) · doi

  Stabilin2 involvement in zebrafish arterial-venous differentiation (B122) has been identified but the specific molecular mechanisms by which Stabilin2 regulates endothelial cell fate decisions and vascular morphogenesis remain uncharacterized.

• Trajectory inference for a branching SDE model of cell differentiation via lineage tracing (2026) · doi

  Whether a drift making the collection of reweighted marginal distributions compatible can be gradient or not with more than two timepoints remains unclear. The paper demonstrates that at each observation timepoint ti the reweighted empirical distribution is associated with a timepoint-specific drift bias −∇Φti, but no single biased SDE can simultaneously interpolate all observed distributions across multiple timepoints in the branching SDE cell differentiation model.

• Evaluating poultry by-product meal, tomato pomace, and azolla with or without Natuzyme supplementation as sustainable alternatives to fish meal for Nile tilapia (Oreochromis niloticus) (2026) · doi

  While the research assessed hemato-biochemical parameters and antioxidant status in Nile tilapia fed alternative diets, the specific mechanisms by which azolla, tomato pomace, and Natuzyme modulate intestinal microbiota composition and immune gene expression remain uncharacterized, limiting understanding of how these ingredients enhance disease resistance.

• Cell type-agnostic transcriptomic signatures enable uniform comparisons of neural maturation (2026) · doi

  The sensitivity analysis of principal component-based age predictions to cell type removal (S5 Fig) demonstrated that removing progenitors or neurons shifts age-correlations across datasets, but the mechanistic basis for why specific cell type compositions drive particular principal components in different studies remains unexplored; this limits interpretability of which developmental processes the model captures.

• Perineural invasion in solid tumors: biological foundations and the emerging integration of machine learning and artificial intelligence (2026) · doi

  The mechanistic role of tumor-associated Schwann cells and inflammatory monocytes (CCL2-mediated recruitment, cathepsin B expression) in promoting perineural invasion has been characterized in specific experimental models, but translational studies linking these molecular mechanisms to clinical outcomes and therapeutic vulnerability in patient-derived samples across cancer types are lacking.

• Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster (2026) · doi

  While DNA-PKcs inhibition with NU7441 was tested in co-treatment experiments, the mechanistic interplay between Ku80-mediated endogenous DNA repair pathways and endonuclease G inhibition at the MLL breakpoint cluster during NHEJ versus homologous DSB repair remains incompletely characterized.

• Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin (2026) · doi

  While ABPs (Angiepeptides) demonstrate dual inhibitory activity against both C. difficile bacteria and their toxins (TcdA and TcdB), the mechanism underlying this dual mode of action has not been characterized at the molecular level. Direct comparison of antibacterial efficacy versus toxin inhibition potency in the same infection model is required.

• On the potential origin of the zygote-like cancer stem cell with a focus on fusion for cell rescue (2026) · doi

  The specific role of microRNAs (particularly miR-17-92 cluster and miR-34) in regulating somatic cell reprogramming and quiescence in fusion-derived cancer stem cells remains inadequately characterized. Direct mechanistic studies are needed to determine how these miRNAs modulate the transition between quiescent and proliferative states in zygote-like cancer stem cell populations.

• Hair cell loss – cause or consequence of hearing loss? (2026) · doi

  The mechanotransduction-dependent control of stereocilia length and row identity (Krey et al. 2020, 2023) requires investigation of how disruptions in mechanotransduction signaling during hair bundle development lead to hair cell dysfunction versus apoptosis, as the threshold between structural defects and cell death has not been systematically defined.

• Immune molecular mechanisms of PANoptosis in sepsis-induced acute kidney injury (2026) · doi

  While reverse electron transfer-mediated mitochondrial DNA oxidation has been identified as a therapeutic target in PANoptosis, the specific molecular mechanisms linking mitochondria-derived reactive oxygen species production to GSDMD activation in sepsis-induced AKI tubular epithelial cells require mechanistic elucidation through direct inhibition studies.

• Dietary restriction shapes intergenerational ribosome abundance and early growth of Caenorhabditis elegans offspring (2026) · doi

  The weak inheritance of proteome changes across generations (R² = 0.037 between G0 and G1) indicates that most protein abundance alterations induced by dietary restriction in parents do not translate to offspring. The specific molecular mechanisms filtering which proteome changes are inherited versus which are reset in G1 L1 larvae remain uncharacterized.

• Elovanoid neuroprotection targets cell transcriptomics and proteomics to sustain synaptic integrity after brain injury (2026) · doi

  The mechanistic role of ELOVL4-dependent very long-chain fatty acid biosynthesis in maintaining synaptic transmission after traumatic brain injury remains unclear beyond cerebellar synapse models. Research should determine whether ELOVL4 mutations impair elovanoid production in cortical and hippocampal synapses, and whether this contributes to cognitive and motor deficits observed in SCA34 and other neurodegenerative conditions.

• The transformative impact of AI-enabled AlphaFold 3: evolution, current status, and future prospects in structural biology (2026) · doi

  Interpretability of deep sequence-based protein-protein interaction predictions from AlphaFold3 remains a black box. Methods to crack the black box and understand which sequence features drive AlphaFold3 predictions of protein complex interfaces are needed for confidence assessment in drug discovery.

• Clonal Signatures of Telomere Biology Disorders (2026) · doi

  The role of POT1 mutations in telomere end fill-in and telomere truncations (Coats plus) and in idiopathic pulmonary fibrosis requires clarification of the mechanistic differences between rare constitutional POT1 variants and their contribution to different clinical presentations of telomere biology disorders.