What are the bare essentials of life, the indispensable ingredients required to produce a cell that can survive on its own? Can we describe the molecular anatomy of a cell, and can we understand how an entire organism functions as a system? These are just some of the questions that scientists in a partnership between the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the Centre de Regulacio Genòmica (CRG) in Barcelona, Spain, set out to address.
In three papers published back-to-back recently in Science, they provide the first comprehensive picture of a minimal cell, based on an extensive quantitative study of the biology of Mycoplasma pneumoniae, the bacterium that causes atypical pneumonia. The study shows that even the simplest of cells is more complex than expected.
M. pneumoniae is a small, single-cell bacterium that causes atypical pneumonia in humans. It is also one of the smallest prokaryotes. This is why the six research groups that set out to characterize a minimal cell in a project headed by Peer Bork, Anne-Claude Gavin and Luis Serrano chose M. pneumoniae as a model: it is complex enough to survive on its own but small and, theoretically, simple enough to represent a minimal cell and to enable a global analysis.
A network of research groups at EMBL’s Structural and Computational Biology Unit and CRG’s EMBL-CRG Systems Biology Partnership Unit approached the bacterium at three different levels. One team of scientists described M. pneumoniae’s transcriptome, identifying all the RNA molecules, or transcripts, produced from its DNA under various environmental conditions. Another defined its metabolome under the same conditions. A third team identified every multiprotein complex the bacterium produced, thus characterizing its proteome organization.
‘At all three levels, we found M. pneumoniae was more complex than we expected’, says Luis Serrano, co-initiator of the project at EMBL and now head of the Systems Biology Department at CRG.
When studying both its proteome and its metabolome, the scientists found many molecules were multifunctional, with metabolic enzymes catalysing multiple reactions and other proteins each taking part in more than one protein complex. They also found that M. pneumoniae couples biological processes in space and time, with the pieces of cellular machinery involved in two consecutive steps in a biological process often being assembled together.
Remarkably, the regulation of this bacterium’s transcriptome is much more similar to that of eukaryotes than previously thought. As in eukaryotes, a large proportion of the transcripts produced from M. pneumoniae’s DNA are not translated into proteins. And although its genes are arranged in groups, as is typical of bacteria, M. pneumoniae doesn’t always transcribe all the genes in a group together but can selectively express or repress individual genes within each group.
Unlike that of other, larger, bacteria, M. pneumoniae’s metabolism doesn’t seem to be geared towards multiplying as quickly as possible, perhaps because of its pathogenic lifestyle. Another surprise was the fact that although it has a very small genome, this bacterium is incredibly flexible and readily adjusts its metabolism to drastic changes in environmental conditions. This adaptability and its underlying regulatory mechanisms mean M. pneumoniae has the potential to evolve quickly. All of the above are features it shares with other, more evolved organisms.
‘The key lies in these shared features’, explains Anne-Claude Gavin, an EMBL group leader who headed the study of the bacterium’s proteome. ‘Those are the things that not even the simplest organism can do without and that have remained untouched by millions of years of evolution – the bare essentials of life.’