Historic obstacles and emerging opportunities in the field of developmental metabolism - lessons from Heidelberg.

The field of developmental metabolism is experiencing a technological revolution that is opening entirely new fields of inquiry. Advances in metabolomics, small-molecule sensors, single-cell RNA sequencing and computational modeling present new opportunities for exploring cell-specific and tissue-specific metabolic networks, interorgan metabolic communication, and gene-by-metabolite interactions in time and space. Together, these advances not only present a means by which developmental biologists can tackle questions that have challenged the field for centuries, but also present young scientists with opportunities to define new areas of inquiry. These emerging frontiers of developmental metabolism were at the center of a highly interactive 2023 EMBO workshop 'Developmental metabolism: flows of energy, matter, and information'. Here, we summarize key discussions from this forum, emphasizing modern developmental biology's challenges and opportunities.

Bioenergetic costs and the evolution of noise regulation by microRNAs.

Noise control, together with other regulatory functions facilitated by microRNAs (miRNAs), is believed to have played important roles in the evolution of multicellular eukaryotic organisms. miRNAs can dampen protein fluctuations via enhanced degradation of messenger RNA (mRNA), but this requires compensation by increased mRNA transcription to maintain the same expression levels. The overall mechanism is metabolically expensive, leading to questions about how it might have evolved in the first place. We develop a stochastic model of miRNA noise regulation, coupled with a detailed analysis of the associated metabolic costs. Additionally, we calculate binding free energies for a range of miRNA seeds, the short sequences which govern target recognition. We argue that natural selection may have fine-tuned the Michaelis-Menten constant [Formula: see text] describing miRNA-mRNA affinity and show supporting evidence from analysis of experimental data. [Formula: see text] is constrained by seed length, and optimal noise control (minimum protein variance at a given energy cost) is achievable for seeds of 6 to 7 nucleotides in length, the most commonly observed types. Moreover, at optimality, the degree of noise reduction approaches the theoretical bound set by the Wiener-Kolmogorov linear filter. The results illustrate how selective pressure toward energy efficiency has potentially shaped a crucial regulatory pathway in eukaryotes.

Modeling the Growth of Organisms Validates a General Relation between Metabolic Costs and Natural Selection.

Metabolism and evolution are closely connected: if a mutation incurs extra energetic costs for an organism, there is a baseline selective disadvantage that may or may not be compensated for by other adaptive effects. A long-standing, but to date unproven, hypothesis is that this disadvantage is equal to the fractional cost relative to the total resting metabolic expenditure. We validate this result from physical principles through a general growth model and show it holds to excellent approximation for experimental parameters drawn from a wide range of species.

Growth and shape stability of Cu-Ni core-shell nanoparticles: an atomistic perspective.

The growth and shape stability of bi-metallic cubic Cu-Ni nanoparticles are studied using atomic-level simulations. Cubic nano-crystals coated with an ultra-thin Cu layer can be readily obtained when Ni cubic nanoparticles are used as the seeds. At elevated temperatures, the Cu seed with extending Ni branches preserves its shape compared to the Ni seed with extending Cu branches.

Extreme sensitivity biosensing platform based on hyperbolic metamaterials.

Optical sensor technology offers significant opportunities in the field of medical research and clinical diagnostics, particularly for the detection of small numbers of molecules in highly diluted solutions. Several methods have been developed for this purpose, including label-free plasmonic biosensors based on metamaterials. However, the detection of lower-molecular-weight (<500 Da) biomolecules in highly diluted solutions is still a challenging issue owing to their lower polarizability. In this context, we have developed a miniaturized plasmonic biosensor platform based on a hyperbolic metamaterial that can support highly confined bulk plasmon guided modes over a broad wavelength range from visible to near infrared. By exciting these modes using a grating-coupling technique, we achieved different extreme sensitivity modes with a maximum of 30,000 nm per refractive index unit (RIU) and a record figure of merit (FOM) of 590. We report the ability of the metamaterial platform to detect ultralow-molecular-weight (244 Da) biomolecules at picomolar concentrations using a standard affinity model streptavidin-biotin.

Enhancing the Angular Sensitivity of Plasmonic Sensors Using Hyperbolic Metamaterials.

Surface plasmon resonance (SPR) sensors operate mainly on prism and grating coupling techniques, with spectral and angular scans being the two major interrogation schemes. Among them, the angular scan technique has several advantages including higher measurement precision owing to its higher signal-to-noise ratio. The currently available SPR sensor arrangements provide a maximum angular sensitivity of 500°-600° per RIU. Here, we report the study of grating coupled-hyperbolic metamaterial (GC-HMM) sensors with high angular sensitivity. The experimental studies show extraordinary angular sensitivities from visible to near infrared (NIR) wavelengths by exciting bulk plasmon polaritons associated with hyperbolic metamaterials, with a maximum of 7000° per RIU. This angular-scan plasmonic biosensor has been used for the detection of low molecular weight biomolecules such as biotin (244 Da) and high molecular weight macromolecules such as Cowpea mosaic virus (CPMV, 5.6 × 106 Da) at ultralow concentrations. The miniaturized sensing device can be integrated with microfluidic systems for the development of next-generation biosensors for lab-on-a-chip and point-of-care applications.

Overfrustrated and underfrustrated spin glasses in d=3 and 2: evolution of phase diagrams and chaos including spin-glass order in d=2.

In spin-glass systems, frustration can be adjusted continuously and considerably, without changing the antiferromagnetic bond probability p, by using locally correlated quenched randomness, as we demonstrate here on hypercubic lattices and hierarchical lattices. Such overfrustrated and underfrustrated Ising systems on hierarchical lattices in d=3 and 2 are studied. With the removal of just 51% of frustration, a spin-glass phase occurs in d=2. With the addition of just 33% frustration, the spin-glass phase disappears in d=3. Sequences of 18 different phase diagrams for different levels of frustration are calculated in both dimensions. In general, frustration lowers the spin-glass ordering temperature. At low temperatures, increased frustration favors the spin-glass phase (before it disappears) over the ferromagnetic phase and symmetrically the antiferromagnetic phase. When any amount, including infinitesimal, frustration is introduced, the chaotic rescaling of local interactions occurs in the spin-glass phase. Chaos increases with increasing frustration, as can be seen from the increased positive value of the calculated Lyapunov exponent λ, starting from λ=0 when frustration is absent. The calculated runaway exponent yR of the renormalization-group flows decreases with increasing frustration to yR=0 when the spin-glass phase disappears. From our calculations of entropy and specific-heat curves in d=3, it is shown that frustration lowers in temperature the onset of both long- and short-range order in spin-glass phases, but is more effective on the former. From calculations of the entropy as a function of antiferromagnetic bond concentration p, it is shown that the ground-state and low-temperature entropy already mostly sets in within the ferromagnetic and antiferromagnetic phases, before the spin-glass phase is reached.

Odd q-state clock spin-glass models in three dimensions, asymmetric phase diagrams, and multiple algebraically ordered phases.

Distinctive orderings and phase diagram structures are found, from renormalization-group theory, for odd q-state clock spin-glass models in d=3 dimensions. These models exhibit asymmetric phase diagrams, as is also the case for quantum Heisenberg spin-glass models. No finite-temperature spin-glass phase occurs. For all odd q≥5, algebraically ordered antiferromagnetic phases occur. One such phase is dominant and occurs for all q≥5. Other such phases occupy small low-temperature portions of the phase diagrams and occur for 5≤q≤15. All algebraically ordered phases have the same structure, determined by an attractive finite-temperature sink fixed point where a dominant and a subdominant pair states have the only nonzero Boltzmann weights. The phase transition critical exponents quickly saturate to the high q value.