Microbial genomics as pursuit of happiness.

Over the past dozen years, the availability of complete genomes brought a profound change to all aspects of (micro)biological research. As noted by Ian Dunham (2000), during the ‘dark ages’ before the advent of genomics, our perception of the cell was akin to the medieval maps of Earth with large areas marked ‘Here be dragons’. It is now quite common to describe enzymes, metabolic and signalling pathways that are missing in a given organism, something that can be done only with complete genome sequences. Although close to a third of genes in any newly sequenced genome have unknown functions (and the rest have only more or less reliable functional predictions that are not going to be experimentally tested any time soon), we can safely assume that these genes do not code for dragon skin or any other dragon body parts. We are even running out of candidate genes that could code for the vital force (aka the ‘living soul’, Hebrew: nephesh; Greek: psuche; French: elan vital) of the bacterial cell. In contrast, microbial technology has remained relatively unaffected by the genomics data. Most biotechnological processes still remain the same as they were 10‐15 years ago. Genomic and metagenomic libraries are widely used to search for useful enzymes but those searches rely more on activity than on genome sequence data. It is easy to predict that in the course of the next several years genomics will start making its way into everyday technology. The most immediate change will be the recruitment of an ever‐expanding range of organisms for use in the bioremediation of environmental contaminants and in production of various compounds, from biopharmaceuticals to biofuels. Use of new organisms will result in dramatic progress in metabolic engineering. We already know that many biochemical reactions can be catalysed by two or more different enzyme variants. We also know that metabolic pathways in any given organism have evolved to optimize the organism's growth, not the overproduction of any particular metabolite that we might want it to produce. Incorporating foreign genes could be used to steer the metabolism in the needed direction, to remove inconvenient by‐products, to relieve feedback inhibition, and to adapt the metabolic pathway to particular environmental conditions (t°, pH, salinity). For example, the flux through the standard glycolytic pathway of Escherichia coli could be manipulated by introducing the ADP‐dependent phosphofructokinase from, metal‐independent aldolase and/or bisphosphoglycerate‐independent phosphoglycerate mutase from Methanococcus maripaludis or other mesophilic archaea. The abundance of alternative enzyme versions from exotic and poorly studied microorganisms will be complemented by the abundance of suitable hosts capable of deriving energy from the solar light (photosynthetic bacteria, including cyanobacteria) or cheap substrates, such as natural gas, methanol, sawdust and timber waste. This combination will bring metabolic engineering to an entirely new level, allowing the construction of customized organisms for every ecological niche that would consume industrial waste and convert it into useful products. Very soon, microbial metabolic engineering will be used to improve our food supply, solve the energy crisis and fight global warming. We already have completely sequenced genomes of several nitrogen‐fixing endophytic bacteria that enable the rapid growth of sugarcane and various legumes (Krause et al., 2006; Fouts et al., 2008; Lee et al., 2008). Adapting such bacteria to corn, wheat, rice and soy will dramatically decrease the need for chemical fertilizers, allowing rapid growth of plant biomass and, as an added benefit, increased consumption of CO2. Plant foods derived this way could be enriched in essential amino acids and vitamins without carrying the stigma of ‘Frankenfoods’. This will decrease the need for animal protein and provide yet another way to decrease the production of greenhouse gases. The next step will be using bacteria to improve human bodies. We already affect human gut microflora with our foods and change it by consuming yogurts, beer, brie, kimchi, and other products that contain live microbial cultures. Enriching yogurts with vitamin‐producing bacteria will go a long way towards eliminating various vitamin deficiencies. The next step will be introducing engineered bacteria in human tissues and even human cells. If the plans to use specially constructed clostridia for curing (or at least slowing down) cancer (Wei et al., 2008) bring even modest success, they will pave the way for further gene therapy. If aphids, nematodes and fruit flies can afford carrying intracellular bacteria to supply them with nutrients (Wernegreen, 2004), we sure can try the same thing in order to cure hereditary diseases. A phenylalanine‐dependent symbiotic bacterium could be used to improve the life of patients with phenylketonuria. Lipid‐degrading bacteria (mycobacteria?) might be used to clear atherosclerotic plaques, tartrate‐metabolizing bacteria to dissolve kidney stones, and lactate‐consuming bacteria to relieve muscle fatigue. Microbes could also be engineered to maintain a healthy balance of neurotransmitters, replacing the morning cup of lattė and secreting just enough serotonin derivatives to keep the host constantly happy. Having fought bacteria in the last century, we have nearly exhausted the repertoire of available antibiotics and will have to learn to co‐exist with bacterial world. Knowledge of bacterial genomics should allow us to separate friend from foe and harness them both for our own use.