June 29, 2011 The genetic information of all living cells is stored in the DNA composed of the four canonical bases adenine (A), cytosine (C), guanine (G) and thymine (T). An international team of researchers has now succeeded in generating a bacterium possessing a DNA in which thymine is replaced by the synthetic building block 5-chlorouracil (c), a substance toxic for other organisms.
The project, coordinated by Rupert Mutzel (Institut für Biologie, Freie Universität Berlin) and Philippe Marlière (Heurisko USA Inc.), involved researchers of the French CEA (Commissariat à l'Energie Atomique et aux Energies Alternatives) and of the Katholieke Universiteit Leuven (Belgium). As described in the latest issue of Angewandte Chemie International Edition, the experimental work was based on a unique technology developed by Marlière and Mutzel enabling the directed evolution of organisms under strictly controlled conditions. Large populations of microbial cells are cultured for prolonged periods in the presence of a toxic chemical -- in this case, 5-chlorouracil -- at sublethal levels, thereby selecting for genetic variants capable of tolerating higher concentrations of the toxic substance.
In response to the appearance of such variants in the cell population the concentration of the toxic chemical in the growth medium is increased, thus keeping the selection pressure constant. This automated procedure of long term evolution was applied to adapt genetically engineered Escherichia coli bacteria unable to synthesize the natural nucleobase thymine to grow on increasing concentrations of 5-chlorouracil. After a culture period of about 1000 generations descendants of the original strain were obtained which used 5-chlorouracil as complete substitute for thymine. Subsequent genome analysis revealed numerous mutations in the DNA of the adapted bacteria. The contribution of these mutations to the adaptation of the cells towards the halogenated base will be the subject of follow-up studies.
Besides the obvious interest of this radical change in the chemistry of living systems for basic research the scientists consider the outcome of their work also to be of importance for "xenobiology," a branch of synthetic biology. This young area of the life sciences aims at the generation of new organisms not found in nature harboring metabolic traits optimized for alternative modes of energy production or for the synthesis of high value chemicals. Like GMOs, such organisms are seen as a potential threat for natural ecosystems when released from their laboratory confinements, either through direct competition with wild type organisms or through diffusion of their "synthetic" DNA.
Scientists have recognized that physical containment cannot in every single case prevent engineered live forms from reaching natural habitats, in the same way as radioactive isotopes can leak into the surroundings of a nuclear power plant. However, synthetic organisms like those evolved by Marlière and Mutzel and their collaborators which depend on the availability of substances for their proliferation not found in nature or which incorporate non-natural building blocks in their genetic material could neither compete nor exchange genetic messages with wild type organisms, but would die in the absence of the xenobiotic.
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- Philippe Marlière, Julien Patrouix, Volker Döring, Piet Herdewijn, Sabine Tricot, Stéphane Cruveiller, Madeleine Bouzon, Rupert Mutzel. Chemical Evolution of a Bacterium's Genome. Angewandte Chemie International Edition, 2011; DOI: 10.1002/anie.201100535
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