Black smoker in 2,980m of water on the Mid-Atlantic Ridge. Some hypotheses suggest that deep-sea hydrothermal vents may have provided favourable conditions for the emergence of early life. In these environments, chemical and energy gradients could have supported primitive chemical systems and metabolic-like processes based on compounds released by hydrothermal activity. Original image source: https://commons.wikimedia.org/wiki/File:MARUM-HTQ-01-HiRes.jpg. Credit: MARUM − Zentrum für Marine Umweltwissenschaften, Universität Bremen. CC BY.
New study shows how to calculate the minimum energy that cells spend to maintain certain metabolic pathways.
The research also shows how the same cells suppress alternative pathways — a ‘cost’ invisible to mechanical physics.
There are ‘costs of life’ that mechanical physics cannot calculate. A clear example is the energy required to keep specific biochemical processes active — such as those that make up photosynthesis, although the examples are countless — while preventing alternative processes from occurring.
In mechanics, no displacement implies zero work, and, put simply, there is no energetic cost for keeping things from happening.
Yet careful stochastic thermodynamic calculations show that these costs do exist — and they are often quite significant.
A new paper proposes a way to calculate these costs from a thermodynamic perspective and thus to offer a new tool for understanding the selection and evolution of metabolic pathways at the root of life.
Primordial system
When, in an ancient ocean, a handful of organic molecules formed an external boundary — the first cell membrane — a sharp distinction between an inside and an outside appeared for the first time.
From that moment on, that primordial system had to invest energy to maintain this compartmentalisation and to select, among the many chemical reactions that could occur, only a few metabolic pathways capable of exploiting valuable substances taken from the ‘outside’ and transforming them into new products.
Life was born together with this effort of compartmentalisation and choice.
Metabolic processes have a direct energetic cost, but they also require an ‘extra cost’ to keep steering chemical flows into a preferred pathway rather than letting them disperse into all physically possible alternatives.
Yet from the viewpoint of classical mechanics, compartmentalisation and reaction selection — the ‘constraints’ imposed at a system’s boundaries — should have no cost at all, as they are treated as fixed external conditions that do not contribute to entropy production.
Overlooked costs
Praful Gagrani, researcher at the University of Tokyo and first author of the new study, together with his colleagues — Nino Lauber and Christoph Flamm (both University of Vienna) and Eric Smith (Georgia Institute of Technology and Earth-Life Science Institute) — developed a method to calculate these overlooked costs to rank the pathways.
This allows researchers to assess their biological efficiency — valuable information for evolutionary studies exploring how life emerged on our planet.
Gagrani said: “What inspired the new work is that Eric Smith, one of the co-authors, used MØD, a software developed by Flamm and co-workers, to enumerate all the possible pathways that can ‘build’ organic molecules starting from CO₂.”
He referred to one of Smith et al’s earlier studies on the Calvin cycle, a cycle of chemical reactions in photosynthesis that converts carbon dioxide into glucose: “Eric used the algorithm to enumerate all the pathways that can make the same conversion that the Calvin cycle does, and then he used what we now call the maintenance cost in our paper to rank them.”
In this way, Smith et al showed that the cycle used by nature lies among the least dissipative pathways — those with the lowest energetic cost.
“Awesome, isn’t it?” Gagrani commented.
Thermodynamic cost
Inspired by Smith’s work, Gagrani and colleagues devised a general method to estimate the thermodynamic costs of metabolic processes systematically.
In their framework, the cell is imagined as a system crossed by a constant flow, where, for instance, one molecule (a nutrient) enters and another (a product or waste) exits.
Given the underlying chemistry, one can generate all chemically possible pathways that convert the input into the output.
Each pathway has its own ‘thermodynamic cost’. Instead of calculating energy in the classical sense, the method estimates how improbable it would be — in a world driven solely by spontaneous chemistry — to see the network (the set of molecules and reactions that convert input to output) behave in exactly that way.
This improbability has two components: the first is the maintenance cost, meaning how unlikely it is to sustain a constant flow through a certain pathway; the second is the restriction cost, which measures how unlikely it is to block all the alternative reactions in the network while keeping only the pathway of interest active.
The calculated improbability represents the cost of that process, which can then be used to classify metabolic pathways according to how ‘expensive’ it is for the cell to keep one pathway active and silence the others.
Gagrani said: “We saw things we didn’t expect, but that make sense once you think about them.
“For example, that using multiple pathways at the same time is less costly than using just one.
“Here’s an analogy: imagine four people who need to go from A to B through narrow tunnels. If each person has their own tunnel — four tunnels — they arrive more quickly than if there are only three or fewer, because two or more people would obstruct each other in the same narrow passage.”
Evolutionary choice
In nature, however, we usually see that one process is favoured over many. How is that explained?
Gagrani advised: “It’s true, but in biological systems catalysis often intervenes — the action of facilitating molecules, enzymes — which accelerate reactions and make them less costly, achieving the same effect as having multiple pathways in parallel.
“This evolutionary choice happens because maintaining many pathways can have other drawbacks, such as producing many potentially toxic molecules.”
Gagrani concluded: “Our method is a useful tool for studying the origin and evolution of life because it allows us to evaluate the costs of choosing and maintaining specific metabolic processes.
“It helps us understand how certain pathways arise — but explaining why those particular ones were selected requires a truly multidisciplinary effort.”
The paper is published in the Journal of Statistical Mechanics: Theory and Experiment (JSTAT).
