Hot off the presses! Aug 01 Nat Biotechnol

The Aug 01 issue of the Nat Biotechnol is now up on Pubget (About Nat Biotechnol): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• A blueprint for biotech's blues
  - Nat Biotechnol 27(8):675 (2009)
  The strategy outlined in the UK's Life Sciences Blueprint is unlikely to address the British biotech sector's woes or help it regain prominence and success.
• Brand biologics grab 12 years' exclusivity, for now
  - Nat Biotechnol 27(8):677-678 (2009)
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• Awards bridge 'valley of death'
  - Nat Biotechnol 27(8):678 (2009)
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• J&J's billion dollar punt on anti-amyloid antibody
  - Nat Biotechnol 27(8):679-681 (2009)
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• Virus stalls Genzyme plant
  - Nat Biotechnol 27(8):681 (2009)
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• Stem cell funding widens
  - Nat Biotechnol 27(8):681 (2009)
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• Bye-bye WilBio
  - Nat Biotechnol 27(8):682 (2009)
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• GM fish ice cream
  - Nat Biotechnol 27(8):682 (2009)
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• Novo awaits green light for diabetes drug
  - Nat Biotechnol 27(8):682-685 (2009)
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• Cellulosic at the pump
  - Nat Biotechnol 27(8):684 (2009)
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• Plasma firms denied merger
  - Nat Biotechnol 27(8):684 (2009)
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• Genzyme's Lumizyme clears bioequivalence hurdles
  - Nat Biotechnol 27(8):685 (2009)
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• Peru embraces biotech
  - Nat Biotechnol 27(8):685 (2009)
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• Illumina's cut-price genome scan
  - Nat Biotechnol 27(8):685 (2009)
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• Signs of life in Q2
  - Nat Biotechnol 27(8):686 (2009)
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• Immunology's quiet upheaval
  - Nat Biotechnol 27(8):687-689 (2009)
  Several drug programs aim to restore the balance between regulatory T cells and T helper 17 (Th17) cells in autoimmune disease. But as therapies advance in the clinic, new discoveries are challenging the fundamental principle that T-cell lineages, once established, don't change. Ken Garber reports.
• The cold rush
  - Nat Biotechnol 27(8):690-692 (2009)
  More than 40 companies are now engaged in bioprospecting in the Arctic. Hannah Hoag gauges the biotech potential buried beneath the ice and snow.
• Building today's platform company
  - Nat Biotechnol 27(8):693-695 (2009)
  
• And then there were two: use of hESC lines
  - Nat Biotechnol 27(8):696-697 (2009)
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• BARDA's budget
  - Nat Biotechnol 27(8):698-699 (2009)
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• Reply to BARDA's budget
  - Nat Biotechnol 27(8):699 (2009)
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• Detection of genetically modified organisms—closing the gaps
  - Nat Biotechnol 27(8):700-701 (2009)
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• The contraction of agbiotech product quality innovation
  - Nat Biotechnol 27(8):702-704 (2009)
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• Beyond the biotech IPO: a brave new world
  - Nat Biotechnol 27(8):705-709 (2009)
  After a decade of significant challenges, biotech's long-term sustainability depends on making fundamental changes to its traditional business model.
• Public biotech 2008—the numbers
  - Nat Biotechnol 27(8):710-721 (2009)
  The sour global economy has left many small public firms gasping for air.
• Stem cell patents: a landscape analysis
  - Nat Biotechnol 27(8):722-726 (2009)
  An evaluation of the development of innovation in stem cell technologies by network analysis of stem cell patent filings.
• Recent patent applications in biomarkers
  - Nat Biotechnol 27(8):727 (2009)
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• Synthetic metabolic pipelines
  - Nat Biotechnol 27(8):728-729 (2009)
  Controlling the spatial organization of sequential metabolic enzymes may provide a general strategy for increasing the production of valuable compounds.
• Metabolic engineering without plasmids
  - Nat Biotechnol 27(8):729-731 (2009)
  Tandem gene duplication is harnessed to genetically engineer Escherichia coli, enabling sustained expression of metabolic products.
• Universal cell-free protein synthesis
  - Nat Biotechnol 27(8):731-732 (2009)
  Unstructured translation-initiation sequences enable protein synthesis in cell extracts from multiple organisms.
• Next-generation quantum dots
  - Nat Biotechnol 27(8):732-733 (2009)
  Quantum dots that are small and non-blinking offer new opportunities for dynamic single-molecule imaging in live cells.
• Research highlights
  - Nat Biotechnol 27(8):734 (2009)
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• The Systems Biology Graphical Notation
  - Nat Biotechnol 27(8):735-741 (2009)
  Circuit diagrams and Unified Modeling Language diagrams are just two examples of standard visual languages that help accelerate work by promoting regularity, removing ambiguity and enabling software tool support for communication of complex information. Ironically, despite having one of the highest ratios of graphical to textual information, biology still lacks standard graphical notations. The recent deluge of biological knowledge makes addressing this deficit a pressing concern. Toward this goal, we present the Systems Biology Graphical Notation (SBGN), a visual language developed by a community of biochemists, modelers and computer scientists. SBGN consists of three complementary languages: process diagram, entity relationship diagram and activity flow diagram. Together they enable scientists to represent networks of biochemical interactions in a standard, unambiguous way. We believe that SBGN will foster efficient and accurate representation, visualization, storage! , exchange and reuse of information on all kinds of biological knowledge, from gene regulation, to metabolism, to cellular signaling.
• Variation in the safety of induced pluripotent stem cell lines
  - Nat Biotechnol 27(8):743-745 (2009)
  We evaluated the teratoma-forming propensity of secondary neurospheres (SNS) generated from 36 mouse induced pluripotent stem (iPS) cell lines derived in 11 different ways. Teratoma-formation of SNS from embryonic fibroblast–derived iPS cells was similar to that of SNS from embryonic stem (ES) cells. In contrast, SNS from iPS cells derived from different adult tissues varied substantially in their teratoma-forming propensity, which correlated with the persistence of undifferentiated cells.
• Species-independent translational leaders facilitate cell-free expression
  - Nat Biotechnol 27(8):747-752 (2009)
  Cell-free protein synthesis enables the rapid production and engineering of recombinant proteins. Existing cell-free systems differ substantially from each other with respect to efficiency, scalability and the ability to produce functional eukaryotic proteins. Here we describe species-independent translational sequences (SITS) that mediate efficient cell-free protein synthesis in multiple prokaryotic and eukaryotic systems, presumably through bypassing the early translation initiation factors. We use these leaders in combination with targeted suppression of the endogenous Leishmania tarentolae mRNAs to create a cell-free system based on this protozoan. The system can be directly programmed with unpurified PCR products, enabling rapid generation of large protein libraries and protein variants. L. tarentolae extract can produce up to 300 g/ml of recombinant protein in 2 h. We further demonstrate that protein-protein and protein–small molecule interactions can be quanti! tatively analyzed directly in the translation mixtures using fluorescent (cross-) correlation spectroscopy.
• Synthetic protein scaffolds provide modular control over metabolic flux
  - Nat Biotechnol 27(8):753-759 (2009)
  Engineered metabolic pathways constructed from enzymes heterologous to the production host often suffer from flux imbalances, as they typically lack the regulatory mechanisms characteristic of natural metabolism. In an attempt to increase the effective concentration of each component of a pathway of interest, we built synthetic protein scaffolds that spatially recruit metabolic enzymes in a designable manner. Scaffolds bearing interaction domains from metazoan signaling proteins specifically accrue pathway enzymes tagged with their cognate peptide ligands. The natural modularity of these domains enabled us to optimize the stoichiometry of three mevalonate biosynthetic enzymes recruited to a synthetic complex and thereby achieve 77-fold improvement in product titer with low enzyme expression and reduced metabolic load. One of the same scaffolds was used to triple the yield of glucaric acid, despite high titers (0.5 g/l) without the synthetic complex. These strategies sh! ould prove generalizeable to other metabolic pathways and programmable for fine-tuning pathway flux.
• Stabilized gene duplication enables long-term selection-free heterologous pathway expression
  Tyo KE Ajikumar PK Stephanopoulos G - Nat Biotechnol 27(8):760-765 (2009)
  Engineering robust microbes for the biotech industry typically requires high-level, genetically stable expression of heterologous genes and pathways. Although plasmids have been used for this task, fundamental issues concerning their genetic stability have not been adequately addressed. Here we describe chemically inducible chromosomal evolution (CIChE), a plasmid-free, high gene copy expression system for engineering Escherichia coli. CIChE uses E. coli recA homologous recombination to evolve a chromosome with 40 consecutive copies of a recombinant pathway. Pathway copy number is stabilized by recA knockout, and the resulting engineered strain requires no selection markers and is unaffected by plasmid instabilities. Comparison of CIChE-engineered strains with equivalent plasmids revealed that CIChE improved genetic stability approximately tenfold and growth phase–specific productivity approximately fourfold for a strain producing the high metabolic burden–biopolym! er poly-3-hydroxybutyrate. We also increased the yield of the nutraceutical lycopene by 60%. CIChE should be applicable in many organisms, as it only requires having targeted genomic integration methods and a recA homolog.
• Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo
  - Nat Biotechnol 27(8):767-771 (2009)
  Two humanized IgG4 antibodies, natalizumab and gemtuzumab, are approved for human use, and several others, like TGN1412, are or have been in clinical development. Although IgG4 antibodies can dynamically exchange half-molecules1, Fab-arm exchange with therapeutic antibodies has not been demonstrated in humans. Here, we show that natalizumab exchanges Fab arms with endogenous human IgG4 in natalizumab-treated individuals. Gemtuzumab, in contrast, contains an IgG4 core-hinge mutation that blocks Fab-arm exchange to undetectable levels both in vitro and in a mouse model. The ability of IgG4 therapeutics to recombine with endogenous IgG4 may affect their pharmacokinetics and pharmacodynamics. Although pharmacokinetic modeling lessens concerns about undesired cross-linking under normal conditions, unpredictability remains and mutations that completely prevent Fab-arm exchange in vivo should be considered when designing therapeutic IgG4 antibodies.
• Seeding a skilled workforce
  - Nat Biotechnol 27(8):773-775 (2009)
  How might the Indian government spur the development of a biotech workforce with a broader set of skills?
• People
  - Nat Biotechnol 27(8):776 (2009)
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