It's the metabolism, stupid!

Since the publication in 1976 of Richard Dawkins' best seller The selfish gene, biology (let alone microbiology) has been afflicted of what one could call the geno-centric syndrome. In reality, Dawkins' powerful metaphor is but the logic result of taking the so-called central dogma (CD) of molecular biology to its final consequences: DNA gives instructions to RNA, which then passes them on proteins in a sole unidirectional flow of information and command. That proteins (in particular enzymes) then further decode their structure into processing of substrates to generate metabolites (which themselves are necessary for building DNA, RNA and proteins) is generally ignored in the CD picture. But even if we place metabolism as a downstream step in the decoding of information that emanates from DNA, just by looking at the CD one immediately grasps that DNA is the master of the whole biological show and the rest are just the servants. No wonder the immense importance of such a take: by looking at the genes we should know everything in biology, and by just modifying them one could re-program the behaviour of living systems at our ease. It is like if bacteria were computers making computers, and just by replacing the program one could make them do things that they normally do not do. The interpretative frame that places all emphasis on genes has dominated much of the biological research agenda of recent decades and has been recently boosted by the ease of cheap DNA sequencing. But is such a focus on genes and DNA the ultimate way to go? After many years of trying to genetically re-program environmental bacteria for release as agents of in situ bioremediation of toxic pollutants, my candid answer is: no. And the one reason is that one cannot just play with DNA while ignoring chemistry and metabolism, let alone some principles of chemical engineering. The interplay of DNA and metabolism is in my view akin to that of politics and economy. Both realms drive their own autonomous agendas and obviously influence each other. But whether one likes it or not, it is economy that ultimately determines the viability of any political move. By the same token, metabolism (i.e. the economy of living systems) frames and ultimately resolves whether a given genetic program (i.e. already existing, knocked-in by horizontal gene transfer or engineered with recombinant DNA technology) can be deployed or not. This view has in my opinion at least three separate aspects. First, any reaction must be chemically and thermodynamically favourable not only as such, but also in the broader context of the cell's physiology, in particular regarding stress and chemical conflicts with other co-ocurrent metabolic processes. One tends to overlook that most metabolites are highly reactive and any unbalance or wrong occurrence can make cells collapse altogether. In fact, avoiding chemical reactivity is the main driver of the multiscale physical and chemical organization of metabolic networks (de Lorenzo et al., 2014). Second, enzymes and the reactions they catalyse must have a physical address somewhere in the tridimensional landscape of a cell. This is a basic principle of chemical engineering: thousands of reactions cannot happen at the same time in the same place. One needs well-coordinated pipes, pumps and valves to avoid chaos and explosions. Extensive channelling with a considerable degree of spatial logic must thus occur inside the reduced space of a microbial cell. Although bacteria generally lack the compartments that we see in eukaryotic cells, their cytoplasm should be highly dominialized, something probably facilitated by the vitreous nature of the intracellular milieu. When new genes/proteins are hurriedly delivered to such an organized structure, the situation looks to me reminiscent of the bumpy landings of the NASA Rovers in Mars. In the best case, the device bounces back and forth until it finds a stable location; in the worst, it crashes. Similarly, biochemical reactions should be both viable and well nested somewhere in the physical three-dimensional structure of the cell. Finally, there is a third aspect that the standard representation of the CD and the selfish gene tend to close the eyes to: metabolism can feedback on DNA if the instructions coming from the genetic code clash with biochemical homeostasis. Many types of stresses, in particular oxidative stress that often accompanies metabolic or physicochemical conflicts, lead to production of reactive oxygen species (ROS). These, in turn can mutate DNA and bring about genetic novelty, what accerates exploration of the functional space for solving the problem. In this context, redox reactions that generate ROS as side-products seem to be important for the rapid evolution of novel pathways for biodegradation of xenobiotic compounds by environmental bacteria (Perez-Pantoja et al., 2013). On the basis of the above, I argue that metabolic networks of bacteria have their own autonomous drive, which checks the execution of the instructions coming from DNA more than the contrary. This calls for a novel view (and possibly a fresh research agenda) in which metabolism has the leading role in the chain of biological command, opposite to the standard direction of the information flow in the canonical CD (de Lorenzo, 2014). Obviously, whereas transfer of information DNA → metabolism is strict, the feedback metabolism → DNA has a different quality, i.e. a sort of generic mandate for surveying a solution space but lacking any predetermined outcome. Metabolism thus seems to be the master and sculptor of the genes and not vice versa. Not in vain, metabolism predated the emergence of information-recording molecules, and key metabolic pathways (e.g. glycolysis) could have preceded any nucleic acid in the prebiotic world. In this Crystal ball, I thus advocate the need of focusing much more on metabolism, on biochemistry and on micro-chemical engineering than on genes for making sense of the plethora of amazing activities that we recognize in the microbial world, from pathogenesis to biocatalysis to global warming. A non-trivial challenge is that of the technical and conceptual difficulty: anyone can clone a gene in one's backyard and even get one's complete exome DNA sequence done for less than €1000. But exploring and understanding metabolism in depth requires not only super-sophisticated equipment but also a considerable quantitative training in physics, chemistry, computing and engineering – which typically scares off traditional (micro)biologists. Also, metabolism is often considered boring – as compared with other more sparkling areas of contemporary biology. But let us not be mistaken: if the motto of the Bill Clinton's successful 1992 presidential campaign was It's the economy, stupid!, I would dare say its biological counterpart (It's the metabolism, stupid!) should guide a good deal of research efforts in the environmental microbiology of upcoming years.