[Research highlight] Life re-coded

In an article recently published in Science, Isaacs et al describe the replacement of all 314 TAG stop codons in the Escherichia coli genome with synonymous TAA codons, representing an unprecedented effort in large-scale genome editing.

The scientists first replaced all TAG codons in batches of ten codons across 32 separate strains using their previously-published MAGE method (Wang et al, 2009). These edited genome segments were then progressively combined using a new conjugation-based genome assembly method (CAGE). They have currently produced four strains that each have a quarter of their TAG stop codons replaced, and they hope to produce the complete TAG replacement strain in the near future. Somewhat surprisingly, no severe phenotypic consequences were observed in these replacement strains, indicating that the TAG codon is not essential, despite its near-universal presence in the genetic code of all organisms.

Indeed, the only exception to the universality of the TAG stop codon is a small selection of methanogenic archaea, and one bacterium, in which TAG encodes for the non-canonical amino acid, pyrrolysine (reviewed in Krzykci et al, 2005). Following nature’s lead, the authors hope that once they have produced the complete TAG replacement strains, they will then be able to use this free codon as a “plug-and-play” system for incorporating unnatural amino acids into proteins.

More broadly, this technology will provide an attractive alternative to wholesale chemical genome synthesis when researchers need to systematically introduce multiple genetic alterations into a genome, especially since current synthetic organism designs hew closely to natural organisms. This work may also be a first step towards creating organisms with completely rewritten genetic codes. Such fully “re-coded” organisms would have an inherent genetic “fire-wall” since they would not be able to share their genetic material via horizontal transfer or be infected by naturally occurring viruses.

Isaacs FJ, Carr PA, Wang HH, Lajoie MJ, Sterling B, Kraal L, Tolonen AC, Gianoulis TA, Goodman DB, Reppas NB, Emig CJ, Bang D, Hwang SJ, Jewett MC, Jacobson JM, Church GM (2011) Precise manipulation of chromosomes in vivo enables genome-wide codon replacement. Science 333: 348-53

Krzycki JA (2005) The direct genetic encoding of pyrrolysine. Curr Opin Microbiol 8: 706-12

Wang HH, Isaacs FJ, Carr PA, Sun ZZ, Xu G, Forest CR, Church GM (2009) Programming cells by multiplex genome engineering and accelerated evolution. Nature 460: 894-8

Updated Instructions for Authors

Molecular Systems Biology has recently completed a major update of its Instructions for Authors. Of particular importance, this new document now fully incorporates information about our policies regarding transparency in scientific publishing. Molecular Systems Biology, along with the other EMBO Publications journals, has made a strong commitment to promoting transparency in the editorial process, and recently began publishing a Review Process File, containing anonymous reviewers’ reports, authors’ rebuttal letters, and the editor’s decisions, with accepted manuscripts. In addition, we have been working to promote greater availability, transparency, and re-usability for scientific data associated with published works. For more details on these efforts please see our editorial, “From bench to website.”

Data transparency

For some time now, Molecular Systems Biology has allowed authors to submit source data that directly supports a particular figure panel. Links to these data are then included in the html manuscript version, directly below the associated figures, so that readers can easily discover and reuse data that is of interest to them. This feature can be used both for numeric results (e.g. supporting a graph), or for more structured data types (e.g. SBML model files). Information regarding how source data for figures should be prepared, what types of data can be accommodated, and how to submit these files in our manuscript submission system, is now included in the Instructions for Authors.

Data deposition

Molecular Systems Biology, requires that authors submit data to public repositories according to community standards, and strongly encourages them to do so before manuscript submission. Our Instructions for Authors now provides information regarding our standards for a variety of data types, including functional genomics, proteomics, molecular interactions, and computational models.

Other improvements

These publishing policies and standards have grown out of extensive discussion with members of the scientific community, and we are eager to receive any comments or feedback you may have.

Editors’ Conference Agenda – 2011

Here is a preliminary list of conferences that the Molecular Systems Biology editors will be attending in 2011. We are looking forward seeing a lot of the Alps this year, with meetings in Innsbruck, Geneva, and Vienna. And, of course, we also looking forward to meeting Molecular Systems Biology’s readers and authors; if you are attending one of these conferences or workshops, we would be quite happy to chat with you and learn about your research.

Naturally, this schedule is subject to change, and we recognize that there are many excellent conferences that we will not be able to attend this year due to scheduling limitations.

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Who FEBSX-SysBio2011 Innsbruck Feb. 26-Mar. 3 ALH CSHL Systems Biology: Networks Cold Spring Harbor Mar. 22-26 TL International Conference on Systems Biology of Human Disease Boston June 22-24 TL ISMB/ECCB Vienna July 17-19 ALH Gordon Conference – Cellular Systems Biology Davidson July 24-29 TL The Fifth q-bio Conference on Cellular Information Processing Santa Fe Aug. 10-13 ALH 12th International Conference on Systems Biology Heidelberg/Mannheim Aug. 28-Sept. 1 TL HUPO 2011 Geneva Sept. 4-7 ALH The EMBO Meeting Vienna Sept. 10-13 TL EMBO | EMBL Symposium: Structure and Dynamics of Protein Networks Heidelberg Oct. 13-16 TL & ALH

TL: Thomas Lemberger, ALH: Andrew L. Hufton

[Research highlight] Transcription in action

In a work just published at Nature, Churchman and Weissman (2011) describe a new method for directly capturing and sequencing elongating, or nascent, RNA transcripts. The authors then use this method to provide a detailed look at the transcriptional process in action, revealing a histone modification-dependent mechanism that constrains genome-wide antisense transcription, and pervasive transcriptional pausing and backtracking throughout genes.

The work adds to a rapidly expanding functional genomics toolkit that allows researchers to dissect evermore precise steps in the Central Dogma — the DNA to RNA to protein cascade that transforms genomic information into cellular function. See also the recent work by Cramer and colleagues that describes a method for quantifying genome-wide mRNA synthesis and decay rates (Miller et al, 2011), and the ribosome profiling technique, also developed in the Weissman lab, which can provide genome-wide views of protein translation (Ingolia et al, 2009).

Churchman LS & Weissman JS (2011) Nascent transcript sequencing visualizes transcription at nucleotide resolution. Nature 469: 368–373

Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS (2009) Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324:218-23

Miller C, Schwalb B, Maier K, Schulz D, Dümcke S, Zacher B, Mayer A, Sydow J, Marcinowski L, Dölken L, Martin DE, Tresch A, Cramer P (2011) Dynamic transcriptome analysis measures rates of mRNA synthesis and decay in yeast. Mol Syst Biol 7:458

[Research highlight] modENCODE releases extensive functional investigation of fly and worm genomes

Recently, a series of publications by members of the modENCODE consortium were released online at Science, Nature, and Genome Research. <a href = “http://blog.modencode.org/papers”>These works collectively describe a massive effort to functionally characterize and annotate the Drosophila melanogaster and Caenorhabditis elegans genomes, including in-depth analyses of genes and transcripts, epigenetic marks, transcription factor binding, and replication timing, across a range of developmental and tissue sources.

Integrated analyses of these data are described in two articles released at Science (Gerstein et al, 2010; modENCODE Consortium et al, 2010). These works provide compelling support for the existence of highly occupied target regions (HOT) regions — regions of the genomes that bind a complex mix of many transcription factors, but whose connection with gene regulation is still largely unclear — and, show that the dense epigenetic datasets can be used to segment the genomes into “chromatin states” that have distinct functional properties (see also the recent work by Filion et al, 2010)

In a related Perspective, Mark Blaxter, declares that these works have provide an important step toward the ability “to compute an organism from its genome” (Blaxter 2010). A prime example of progress toward this goal is provided by the particularly comprehensive genomic regulatory network built by the Drosophila modENCODE team, which is inferred from a combination of ChIP-based transcription factor binding, sequence motifs, epigenetic marks, and coexpression (modENCODE Consortium et al, 2010). A relatively simple linear combination of predicted regulatory inputs can predict the expression of about one quarter of the transcriptome with some accuracy. In addition, the authors find that the remaining unpredictable genes tend to have noisier expression levels, suggesting that they may be intrinsically more weakly regulated.

Blaxter M (2010) Genetics. Revealing the dark matter of the genome. Science 330:1758-9

Filion GJ, van Bemmel JG, Braunschweig U, Talhout W, Kind J, Ward LD, Brugman W, de Castro IJ, Kerkhoven RM, Bussemaker HJ, van Steensel B (2010) Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143:212-24

Gerstein MB, Lu ZJ, Van Nostrand EL, Cheng C, Arshinoff BI, Liu T, Yip KY, Robilotto R, Rechtsteiner A, Ikegami K, Alves P, Chateigner A, Perry M, Morris M, Auerbach RK, Feng X, Leng J, Vielle A, Niu W, Rhrissorrakrai K et al (2010) Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project. Science 330:1775-1787

modENCODE Consortium, Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, Landolin JM, Bristow CA, Ma L, Lin MF, Washietl S, Arshinoff BI, Ay F, Meyer PE, Robine N, Washington NL, Di Stefano L, Berezikov E, Brown CD et al (2010) Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE. Science 330:1787-1797

[Research highlight] Multicellular computers

Elaborate computation tasks can be performed by distributing the work across interconnected elementary information processing units. This principle underlies not only the operation of integrated electronic circuits, but also of many biological processes including development and, of course, the activity of the brain.

In two reports recently published in Nature, Chris Voigt’s lab and the team lead by Ricard Solé and Francesc Posas report the construction of synthetic biological circuits performing distributed multicellular computation (Tamsir et al, 2010, Regot et al 2010). In the implementation presented by Tamsir et al, individual E. coli colonies carrying a simple genetic cascade (NOR gate) are interconnected via quorum sensing signaling molecules to perform complex operations (XOR, or EQUAL). Similarly, Regot et al build multicellular circuits (e.g. multiplexer or 1-bit adder with carry) using mating pheromones to chemically ‘wire’ together engineered yeast cells that perform a variety of basic 2-input logical functions.

These works show that compartmentalizing elementary synthetic circuits enables combinatorial and flexible assembly of complex circuits and can improve the robustness of the resulting computation. What could be the next step? Looking at the operation of the brain, arguably the most powerful living computing device known, one is tempted to suggest that narrowing the diffusion range of the chemical cell-to-cell transmitter within ‘synthetic synapses’ would facilitate the miniaturization of multicellular computing networks and potentially open the door to scalable designs of arbitrary complexity.

Tamsir A, Tabor JJ, Voigt CA (2010). Robust multicellular computing using genetically encoded NOR gates and chemical ‘wires’. Nature doi: 10.1038/nature09565

Regot S, Macia J, Conde N, Furukawa K, Kjellén J, Peeters T, Hohmann S, de Nadal E, Posas F, Solé (2010). Distributed biological computation with multicellular engineered networks. Nature doi: 10.1038/nature09679

[Research highlight] Laws of microbial growth

In a work recently published in Science, Scott et al reveal a series of microbial “growth laws” that describe simple relationships between translation, nutrition, and cellular growth. They show that these laws hold across different experimental perturbations and E. coli strains, and, ultimately, provide a phenomenological model describing the delicate balancing act cells maintain when deciding how much of their proteome to allocate to ribosome-related processes.


Scott M, Gunderson CW, Mateescu EM, Zhang Z, Hwa T (2010) Interdependence of cell growth and gene expression: origins and consequences. Science 330:1099-102

→ also see the related Perspective

Lerman J, Palsson BO (2010) Topping off a multiscale balancing act. Science 330:1058-9