Jason J. Lohmueller, Thomas Z. Armel and Pamela A. Silver
"The ability to perform molecular-level computation in mammalian cells has the potential to enable a new wave of sophisticated cell-based therapies and diagnostics. To this end, we developed a Boolean logic framework utilizing artificial Cys2– His2 zinc finger transcription factors (ZF-TFs) as computing elements. Artificial ZFs can be designed to specifically bind different DNA se- quences and thus comprise a diverse set of com- ponents ideal for the construction of scalable networks. We generate ZF-TF activators and repres- sors and demonstrate a novel, general method to tune ZF-TF response by fusing ZF-TFs to leucine zipper homodimerization domains. We describe 15 transcriptional activators that display 2- to 463-fold induction and 15 transcriptional repressors that show 1.3- to 16-fold repression. Using these ZF-TFs, we compute OR, NOR, AND and NAND logic, employing hybrid promoters and split intein- mediated protein splicing to integrate signals. The split intein strategy is able to fully reconstitute the ZF-TFs, maintaining them as a uniform set of computing elements. Together, these components comprise a robust platform for building mammalian synthetic gene circuits capable of precisely modulating cellular behavior."
A singular adaptive phenotype of a parthenogenetic insect species (Acyrthosiphon pisum) was selected in cold conditions and is characterized by a remarkable apparition of a greenish colour.
"Modern life is intimately linked to the availability of fossil fuels, which continue to meet the world's growing energy needs even though their use drives climate change, exhausts finite reserves and contributes to global political strife. Biofuels made from renewable resources could be a more sustainable alternative, particularly if sourced from organisms, such as algae, that can be farmed without using valuable arable land. Strain development and process engineering are needed to make algal biofuels practical and economically viable." http://bit.ly/OnayAf
"I have been meaning to read a book coming out soon called Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves. It’s written by Harvard biologist George Church and science writer Ed Regis. Church is doing stunning work on a number of fronts, from creating synthetic microbes to sequencing human genomes, so I definitely am interested in what he has to say. I don’t know how many other people will be, so I have no idea how well the book will do. But in a tour de force of biochemical publishing, he has created 70 billion copies. Instead of paper and ink, or pdf’s and pixels, he’s used DNA.
Much as pdf’s are built on a digital system of 1s and 0s, DNA is a string of nucleotides, which can be one of four different types. Church and his colleagues turned his whole book–including illustrations–into a 5.27 MB file–which they then translated into a sequence of DNA. They stored the DNA on a chip and then sequenced it to read the text. The book is broken up into little chunks of DNA, each of which has a portion of the book itself as well as an address to indicate where it should go. They recovered the book with only 10 wrong bits out of 5.27 million. Using standard DNA-copying methods, they duplicated the DNA into 70 billion copies. Scientists have stored little pieces of information in DNA before, but Church’s book is about 1,000 times bigger. I doubt anyone would buy a DNA edition of Regenesis on Amazon, since they’d need some expensive equipment and a lot of time to translate it into a format our brains can comprehend. But the costs are crashing, and DNA is a far more stable medium than that hard drive on your desk that you’re waiting to die. In fact, Regenesis could endure for centuries in its genetic form. Perhaps librarians of the future will need to get a degree in biology…"
Bioengineers at the University of South California, Berkeley have discovered that a virus can convert movement into electricity that could be used to power portable electronics as you walk down the street.
"Plant alkaloids constitute a vast range of compounds with potent bioactivities and are a source of numerous drugs and drug precursors currently used as pharmaceutics. However, the low yield of natural alkaloids in plant tissues limits large-scale drug development. Among the many classes of alkaloids, isoquinoline alkaloids have been intensively studied at the molecular level and efforts to improve their quality and yield are being actively pursued. This chapter describes the major tools used to produce secondary metabolites: (1) synthetic chemistry, (2) metabolic engineering of plants, and (3) synthetic biological approaches. While each of these methods has its advantages and limitations, immense effort in various disciplines as well as combinatorial approaches in metabolic engineering will likely realize an efficient and robust system for the mass production of alkaloids in the foreseeable future." http://bit.ly/NnSR9x
A Rice University researcher and his colleagues have received a National Institutes of Health grant to see how delays in gene transcription – life's most basic messaging system – affect cellular processes.
"The genetic code of the fruit fly Drosophila has been hacked into, allowing it to make proteins with properties that don't exist in the natural world. The advance could ultimately lead to the creation of new or "improved" life forms in the burgeoning field of synthetic biology.
The four letters of the genetic code, A, C, T and G, are read in triplets, called codons, by the cell's protein-making machinery. Each codon gives an instruction for the type of amino acid that gets added next in a protein chain, or tells the machinery to stop.
Jason Chin at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, and colleagues previously showed that it was possible to reassign one of these stop codons to incorporate an "unnatural" amino acid instead, and last year they engineered nematode worms to manufacture such proteins......" http://bit.ly/MsASgQ
Adrian W. Briggs, Xavier Rios, Raj Chari, Luhan Yang, Feng Zhang, Prashant Mali and George M. Church
"DNA built from modular repeats presents a challenge for gene synthesis. We present a solid surface-based sequential ligation approach, which we refer to as iterative capped assembly (ICA), that adds DNA repeat monomers individually to a growing chain while using hairpin ‘capping’ oligonucleotides to block incompletely extended chains, greatly increasing the frequency of full-length final products. Applying ICA to a model problem, construction of custom transcription activator-like effector nucleases (TALENs) for genome engineering, we demonstrate efficient synthesis of TALE DNA-binding domains up to 21 monomers long and their ligation into a nuclease-carrying backbone vector all within 3 h. We used ICA to synthesize 20 TALENs of varying DNA target site length and tested their ability to stimulate gene editing by a donor oligonucleotide in human cells. All the TALENS show activity, with the ones >15 monomers long tending to work best. Since ICA builds full-length constructs from individual monomers rather than large exhaustive libraries of pre-fabricated oligomers, it will be trivial to incorporate future modified TALE monomers with improved or expanded function or to synthesize other types of repeat-modular DNA where the diversity of possible monomers makes exhaustive oligomer libraries impractical...." http://bit.ly/Ok3f22
Pamela P. Peralta-Yahya, Fuzhong Zhang, Stephen B. del Cardayre & Jay D. Keasling
"Advanced biofuels produced by microorganisms have similar properties to petroleum-based fuels, and can 'drop in' to the existing transportation infrastructure. However, producing these biofuels in yields high enough to be useful requires the engineering of the microorganism's metabolism. Such engineering is not based on just one specific feedstock or host organism. Data-driven and synthetic-biology approaches can be used to optimize both the host and pathways to maximize fuel production. Despite some success, challenges still need to be met to move advanced biofuels towards commercialization, and to compete with more conventional fuels." http://bit.ly/Onmkxx
"The field of Synthetic Biology seeks to develop engineering principles for biological systems. Modular biological parts are repurposed and recombined to develop new synthetic biological devices with novel functions. The proper functioning of these devices is dependent on the cellular context provided by the host organism, and the interaction of these devices with host systems. The field of Systems Biology seeks to measure and model the properties of biological phenomena at the network scale. We present the application of systems biology approaches to synthetic biology, with particular emphasis on understanding and remodeling metabolic networks. Chapter 2 demonstrates the use of a Flux Balance Analysis model of the Saccharomyces cerevisiae metabolic network to identify and construct strains of S. cerevisiae that produced increased amounts of formic acid. Chapter 3 describes the development of synthetic metabolic pathways in Escherichia coli for the production of hydrogen, and a directed evolution strategy for hydrogenase enzyme improvement. Chapter 4 introduces the use of metabolomic profiling to investigate the role of circadian regulation in the metabolic network of the photoautotrophic cyanobacterium Synechococcus elongatus PCC 7942. Together, this work demonstrates the utility of network-scale approaches to understanding biological systems, and presents novel strategies for engineering metabolism."
"Digital information is accumulating at an astounding rate, straining our ability to store and archive it. DNA is among the most dense and stable information media known. The development of new technologies in both DNA synthesis and sequencing make DNA an increasingly feasible digital storage medium. Here, we develop a strategy to encode arbitrary digital information in DNA, write a 5.27-megabit book using DNA microchips, and read the book using next-generation DNA sequencing."
"Today PLOS ONE is happy to announce the launch of the Synthetic Biology Collection, including over 50 papers published in the last six years that illustrate the many facets of this dynamically evolving research area.
Synthetic biology is an innovative emerging field that exists at the intersection of many traditional disciplines, including biology, chemistry, and engineering, with aims to create biological systems that can be programmed to do useful things like produce drugs or biofuels, among other applications. Despite its potential, the heavily interdisciplinary nature of the research can make it difficult to publish in traditional discipline-specific journals.
However, PLOS ONE’s broad scope allows for the publication of work crossing many traditional research boundaries, making it an ideal venue for many different types of synthetic biology research. For example, the papers in the collection cover topics including DNA synthesis and assembly, standardized biological “parts” akin to interchangeable mechanical parts, protein engineering, and complex network and pathway analysis and modeling, as described in the Collection Overview written by collection editors Jean Peccoud of Virginia Tech and Mark Isalan of the Centre for Genomic Regulation.
The Collection has roots in PLOS ONE’s very first issue, which included two publications from the field. Since then, the number of synthetic biology articles published in the journal has grown steadily. The collection launched today highlights selected synthetic biology articles published in PLOS ONE since 2006, and it is intended to be a growing resource that will be updated regularly with new papers as the field continues to grow and develop.
"Nonribosomal peptide synthetases (NRPSs) are giant multienzymes that carryout sequencial assembly line couplings of amino acids to generate linear or cyclic peptides. NRPSs are composed of repeating enzyme domains with modular organization to activate and couple specific amino acids in a particular order. From a synthetic biology perspective, they can be considered as peptide assembly machines composed of devices to couple fatty acids to L-amino acids, L-amino acids to L-amino acids, and D-amino acids to L-amino acids. The coupling devices are composed of specific parts that contain two or more enzyme domains that can be exchanged combinatorially to generate novel peptide assembly machines to produce novel peptides. The potent lipopeptide antibiotics daptomycin and A54145E have identical cyclic depsipeptide ring structures and stereochemistry, but have divergent amino acid sequences. As their biosynthetic gene clusters are derived from an ancient ancestral lipopetide pathway, these lipopeptides provided an attractive model to develop combinatorial biosynthesis to generate antibiotics superior to daptomycin. These studies on combinatorial biosynthesis have helped generate guidelines for the successful assembly of NRPS parts and devices that can be used to generate novel lipopeptide structures, and have established a basis for future synthetic biology studies to further develop combinatorial biosynthesis as a robust approach to natural product drug discovery."
Ambra Bianco, Fiona M Townsley, Sebastian Greiss, Kathrin Lang & Jason W Chin
"Genetic code expansion for unnatural amino acid mutagenesis has, until recently, been limited to cell culture. We demonstrate the site-specific incorporation of unnatural amino acids into proteins in Drosophila melanogaster at different developmental stages, in specific tissues and in a subset of cells within a tissue. This approach provides a foundation for probing and controlling processes in this established metazoan model organism with a new level of molecular precision." http://bit.ly/Of4g8D
"A paper with the title “A Synthetic Biology Framework for Programming Eukaryotic Transcription Functions” published in the August 3rd issue of the journal Cell has highlighted the potential of using artificial zinc fingers to systematically construct eukaryotic transcription functions for use in yeast synthetic circuits." http://bit.ly/NyGZwh
comment on: *A Synthetic Biology Framework for Programming Eukaryotic Transcription Functions*
by Ahmad S. Khalil, Timothy K. Lu, Caleb J. Bashor, Cherie L. Ramirez, Nora C. Pyenson, J. Keith Joung, James J. Collins
"Eukaryotic transcription factors (TFs) perform complex and combinatorial functions within transcriptional networks. Here, we present a synthetic framework for systematically constructing eukaryotic transcription functions using artificial zinc fingers, modular DNA-binding domains found within many eukaryotic TFs. Utilizing this platform, we construct a library of orthogonal synthetic transcription factors (sTFs) and use these to wire synthetic transcriptional circuits in yeast. We engineer complex functions, such as tunable output strength and transcriptional cooperativity, by rationally adjusting a decomposed set of key component properties, e.g., DNA specificity, affinity, promoter design, protein-protein interactions. We show that subtle perturbations to these properties can transform an individual sTF between distinct roles (activator, cooperative factor, inhibitory factor) within a transcriptional complex, thus drastically altering the signal processing behavior of multi-input systems. This platform provides new genetic components for synthetic biology and enables bottom-up approaches to understanding the design principles of eukaryotic transcriptional complexes and networks" http://bit.ly/MBzzZD
Danny Hillis talks Proteomics & Personalized Medicine
During his lecture at Singularity University, Hillis explained how scientific medicine is beginning to revert back to more ancient, ayurvedic lessons about healthcare. The approach is to treat the body as a system, where balance is the foundation for good health and disease and sickness are the externalities of imbalance. With advancements in proteomics and computing we can begin creating models of what a healthy bodily state looks like. In the same way we might use environmental models to analyze the global climate, we can isolate specific variables that can inform the larger picture. As the data piles up, preventative medicine will become a quantitative endeavour. Hillis believes the doctors visit of the future will be a simple blood test that measures proteins, lipids and some other key signals, which can then be plugged into a systematic database to help us treat diseases long before any symptoms arise. It is a huge upgrade in efficiency, one that could save millions of lives and alleviate the indebted healthcare system in the process.
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