Exploring the origins of life

Catalytic molecules can form metabolically active clusters by creating and following concentration gradients -- this is the result of a new study by scientists from the Max Planck Institute for Dynamics and Self-Organization (MPI-DS). Their model predicts the self-organization of molecules involved in metabolic pathways, adding a possible new mechanism to the theory of the origin of life. The results can help to better understand how molecules participating in complex biological networks can form dynamic functional structures, and provide a platform for experiments on the origins of life.

One possible scenario for the origin of life is the spontaneous organization of interacting molecules into cell-like droplets. These molecular species would form the first self-replicating metabolic cycles, which are ubiquitous in biology and common throughout all organisms. According to this paradigm, the first biomolecules would need to cluster together through slow and overall inefficient processes. Such slow cluster formation seems incompatible with how quickly life has appeared. Scientists from the department of Living Matter Physics from MPI-DS have now proposed an alternative model that explains such cluster formation and thus the fast onset of the chemical reactions required to form life.

"For this, we considered different molecules, in a simple metabolic cycle, where each species produces a chemical used by the next one," says Vincent Ouazan-Reboul, the first author of the study. "The only elements in the model are the catalytic activity of the molecules, their ability to follow concentration gradients of the chemicals they produce and consume, as well as the information on the order of molecules in the cycle," he continues. Consequently, the model showed the formation of catalytic clusters including various molecular species. Furthermore, the growth of clusters happens exponentially fast. Molecules hence can assemble very quickly and in large numbers into dynamic structures.

"In addition, the number of molecule species which participate in the metabolic cycle plays a key role in the structure of the formed clusters," Ramin Golestanian, director at MPI-DS, summarizes: "Our model leads to a plethora of complex scenarios for self-organization and makes specific predictions about functional advantages that arise for odd or even number of participating species. It is remarkable that non-reciprocal interactions as required for our newly proposed scenario are generically present in all metabolic cycles."

In another study, the authors found that self-attraction is not required for clustering in a small metabolic network. Instead, network effects can cause even self-repelling catalysts to aggregate. With this, the researchers demonstrate new conditions in which complex interactions can create self-organized structures.

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Eye color genes are critical for retinal health

Metabolic pathways consist of a series of biochemical reactions in cells that convert a starting component into other products. There is growing evidence that metabolic pathways coupled with external stress factors influence the health of cells and tissues. Many human diseases, including retinal or neurodegenerative diseases, are associated with imbalances in metabolic pathways.

Elisabeth Knust leads a team of researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, who describe an essential role for one such metabolic pathway in maintaining retinal health under conditions of stress. They studied the classic Drosophila genes cinnabar, cardinal, white, and scarlet, originally characterized decades ago and named due to their role in eye color pigmentation, in particular the formation of the brown pigment of the fly eye. These genes encode components of the kynurenine pathway, whose activity converts the amino acid tryptophan by various steps into other products. In this study, the authors have highlighted the function of this metabolic pathway in retinal health, independent of its role in pigment formation.

The Kynurenine pathway is an evolutionary conserved metabolic pathway that regulates a variety of biological processes. Its disruption can result in the buildup of either toxic or protective biomolecules or metabolites, which can worsen or improve, respectively, the health of the brain, including the retina. Knowledge on this important metabolic pathway was recently extended by the research team, led by Elisabeth Knust, Director Emerita at the MPI-CBG, in their publication in the journal Plos Genetics. Being aware of the remarkable conservation of this metabolic pathway and the genes that regulate it, they used flies as a model system to unravel the role of individual metabolites in retinal health. The researchers looked at four genes -- cinnabar, cardinal, white, and scarlet - named after abnormal eye colors following their loss in flies. "Since the Kynurenine pathway is conserved from flies to humans, we asked whether these genes regulate retinal health independent of their role in pigment formation," says Sarita Hebbar, one of the lead authors of the study.

To find this out, the scientists used a combination of genetics, dietary changes, and biochemical analysis of metabolites to study different mutations of the fruit fly, Drosophila melanogaster. Sofia Traikov, a co-author, developed a method for the biochemical analysis of the metabolites of the Kynurenine pathway. This allowed the researchers to link different metabolite levels to the health state of the retina. They found that one metabolite, 3-hydroxykynurenine (3OH-K), is damaging to the retina. More importantly, they could show that the degree of degeneration is influenced by the balance between toxic 3OH-K and protective metabolites, such as Kynurenic Acid (KYNA), and not just by their absolute amounts. Sarita continues: "We also fed two of these metabolites to normal (non-mutant) flies and found that 3OH-K enhanced stress-induced retinal damage, whereas KYNA protected the retina from stress-related damage." This means that retinal health in certain conditions can be improved by altering the ratio of metabolites of the Kynurenine pathway.

Furthermore, by targeting these four genes and therefore four distinct steps within the pathway, the researchers were able to demonstrate that not only the accumulation of 3OH-K as such, but also its location in the cell and hence its availability in further reactions, is important for retinal health.

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