"A team of scientists from Harvard and Yale have recorded the entire genome of the bacteria E. coli, and in a dramatic demonstration of the potential of rewriting an organism’s genetic code, they have improved the bacterium’s ability to resist viruses.
“This is the first time the genetic code has been fundamentally changed,” according to Farren Isaacs, assistant professor of molecular, cellular, and developmental biology at Yale. “Creating an organism with a new genetic code has allowed us to expand the scope of biological function in a number of powerful ways.” Creating this genomically recoded organism raises the possibility that future researchers might be able to retool nature and create potent new proteins to accomplish a wide variety of purposes — from combating disease to generating new classes of materials. The findings from this groundbreaking study, which changes the rules of biology, were published in Science. Isaacs and co-author George Church of Harvard Medical School led this research, which is a product of years of studies in the emerging field of synthetic biology, which seeks to re-design natural biological systems for useful purposes. Encoded by DNA’s instructional manual and made up of 20 amino acids, proteins carry out various important functional roles in the cell. A full set of 64 triplet combinations of the four nucleic acids that comprise the backbone of DNA encode amino acids. Triplets are sets of three nucleotides, called codons, and they are the genetic alphabet of life. For this study, the research team examined the possibility of expanding upon nature’s handywork by substituting different codons or letters throughout the genome and then reintroducing entirely new letters to create amino acids not found in nature. This landmark study represents the first time that the genetic code has been completely changed across an organism’s genome. The research team first swapped all 321 instances of a specific codon, or “genetic three-letter word,” in E. coli for a supposedly identical word. Then they recoded the original word with a new meaning and new amino acid to eliminate its natural stop sign that terminates protein production. This novel genome allowed the bacteria to resist viral infection by limiting the production of natural proteins that viruses use to infect cells. They then converted the “stop” codon into one that encodes new amino acids, inserted it into the genome in a sort of “plug and play” fashion. The results set the stage for using the recoded E. coli as a living foundry, capable of biomanufacturing new classes of “exotic” proteins and polymers. The recoded molecules could be the foundation for a new generation of materials, nanostructures, therapeutics, and drug delivery vehicles, Isaacs said. “Since the genetic code is universal, it raises the prospect of recoding genomes of other organisms,” Isaacs said. “This has tremendous implications in the biotechnology industry and could open entirely new avenues of research and applications.”…."
by María Abad,Lluc Mosteiro,Cristina Pantoja,Marta Cañamero,Teresa Rayon,Inmaculada Ors,Osvaldo Graña,Diego Megías,Orlando Domínguez,Dolores Martínez,Miguel Manzanares,Sagrario Ortega& Manuel Serrano
"Reprogramming of adult cells to generate induced pluripotent stem cells (iPS cells) has opened new therapeutic opportunities; however, little is known about the possibility of in vivo reprogramming within tissues. Here we show that transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs, implying that full reprogramming can occur in vivo. Analyses of the stomach, intestine, pancreas and kidney reveal groups of dedifferentiated cells that express the pluripotency marker NANOG, indicative of in situ reprogramming. By bone marrow transplantation, we demonstrate that haematopoietic cells can also be reprogrammed in vivo. Notably, reprogrammable mice present circulating iPS cells in the blood and, at the transcriptome level, these in vivo generated iPS cells are closer to embryonic stem cells (ES cells) than standard in vitro generated iPS cells. Moreover, in vivo iPS cells efficiently contribute to the trophectoderm lineage, suggesting that they achieve a more plastic or primitive state than ES cells. Finally, intraperitoneal injection of in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic markers. We conclude that reprogramming in vivo is feasible and confers totipotency features absent in standard iPS or ES cells. These discoveries could be relevant for future applications of reprogramming in regenerative medicine."
"Actinomycetes genome sequencing and bioinformatic analyses revealed a large number of “cryptic” gene clusters coding for secondary metabolism. These gene clusters have the potential to increase the chemical diversity of natural products. Indeed, reexamination of well-characterized actinomycetes strains revealed a variety of hidden treasures. Growing information about this metabolic diversity has promoted further development of strategies to discover novel biologically active compounds produced by actinomycetes. This new task for actinomycetes genetics requires the development and use of new approaches and tools. Application of synthetic biology approaches led to the development of a set of strategies and tools to satisfy these new requirements. In this review, we discuss strategies and methods to discover small molecules produced by these fascinating bacteria and also discuss a variety of genetic instruments and regulatory elements used to activate secondary metabolism cryptic genes for the overproduction of these metabolites."
• Novel forms of public engagement in bio and nanotechnologies in the DIYbio and Hackerspaces.
• Decentralized, participatory, and design oriented practices based on open science and open access paradigms. •Alternative R&D approaches bring experimental forms of ethical deliberation and regulation. AbstractTypically nanotechnology and synthetic biology are discussed in terms of novel life forms and materials created in laboratories, or by novel convergences of technologies (ICTs and biological protocols) and science paradigms (engineering and biology) they initiated. Equally inspiring is their ability to generate novel institutions and global communities around emergent sciences, which radicalize the forms of public engagement and ethical deliberation. We are starting to witness alternative (iGEM competitions) and almost underground R&D engagements with Synthetic Biology (DIYbio movement), which inspired the emerging bottom-up involvements in nanotechnologies in projects, such as the NanoSmanoLab in Slovenia. These bottom-up involvements use tinkering and design as models for both research and public engagement. They democratize science and initiate a type of grassroots “science diplomacy”, supporting research in developing countries. We will discuss several recent examples, which demonstrate these novel networks (“Gene gun” project by Rüdiger Trojok from the Copenhagen based hackerspace, Labitat.dk, the “Bioluminescence Project” by Patrik D'haeseleer from Biocurious biotech hackerspace in Sunnyvale, CA, and the “Biodesign for the real world” project by members of the Hackteria.org). They all use design prototypes to enable collaborative and global tinkering, in which science and community are brought together in open biology laboratories and DIYbio hackerspaces, such as Hackteria.org or Biocurious. In these projects research protocols encompass broader innovative, social and ethical norms. Hackerspaces represent a unique opportunity for a more inclusive, experimental, and participatory policy that supports both public and global involvements in emergent scientific fields....
"In this article, we relate the story of Synthetic Biology's birth, from the perspective of a co-founder, and consider its original premise — that standardization and abstraction of biological components will unlock the full potential of biological engineering. The standardization ideas of Synthetic Biology emerged in the late 1990s from a convergence of research on cellular computing, and were motivated by an array of applications from tissue regeneration to bio-sensing to mathematical programming. As the definition of Synthetic Biology has grown to be synonymous with Biological Engineering and Biotechnology, the field has lost sight of the fact that its founding premise has not yet been validated. While the value of standardization has been proven in many other engineering disciplines, none of them involve self-replicating systems. The engineering of self-replicating systems will likely benefit from standardization, and also by embracing the forces of evolution that inexorably shape such systems."
"Synthetic biology is built on the synthesis, engineering, and assembly of biological parts. Proteins are the first components considered for the construction of systems with designed biological functions because proteins carry out most of the biological functions and chemical reactions inside cells. Protein synthesis is considered to comprise the most basic levels of the hierarchical structure of synthetic biology. Cell-free protein synthesis has emerged as a powerful technology that can potentially transform the concept of bioprocesses. With the ability to harness the synthetic power of biology without many of the constraints of cell-based systems, cell-free protein synthesis enables the rapid creation of protein molecules from diverse sources of genetic information. Cell-free protein synthesis is virtually free from the intrinsic constraints of cell-based methods and offers greater flexibility in system design and manipulability of biological synthetic machinery. Among its potential applications, cell-free protein synthesis can be combined with various man-made devices for rapid functional analysis of genomic sequences. This review covers recent efforts to integrate cell-free protein synthesis with various reaction devices and analytical platforms."
by Bryn L. Adams, Karen K. Carter, Min Guo , Hsuan-Chen Wu, Chen-Yu Tsao , Herman O. Sintim , James J. Valdes , and William E. Bentley
"In order to carry out innovative complex, multistep synthetic biology functions, members of a cell population often must communicate with one another to coordinate processes in a programmed manner. It therefore follows that native microbial communication systems are a conspicuous target for developing engineered populations and networks. Quorum sensing (QS) is a highly conserved mechanism of bacterial cell–cell communication and QS-based synthetic signal transduction pathways represent a new generation of biotechnology toolbox members. Specifically, the E. coli QS master regulator, LsrR, is uniquely positioned to actuate gene expression in response to a QS signal. In order to expand the use of LsrR in synthetic biology, two novel LsrR switches were generated through directed evolution: an “enhanced” repression and derepression eLsrR and a reversed repression/derepression function “activator” aLsrR. Protein modeling and docking studies are presented to gain insight into the QS signal binding to these two evolved proteins and their newly acquired functionality. We demonstrated the use of the aLsrR switch using a coculture system in which a QS signal, produced by one bacterial strain, is used to inhibit gene expression via aLsrR in a different strain. These first ever AI-2 controlled synthetic switches allow gene expression from the lsr promoter to be tuned simultaneously in two distinct cell populations. This work expands the tools available to create engineered microbial populations capable of carrying out complex functions necessary for the development of advanced synthetic products."
"Twenty years ago, sequencing the human genome was one of the most ambitious science projects ever attempted. Today, compared to the collection of genomes of the microorganisms living in our bodies, the ocean, the soil and elsewhere, each human genome, which easily fits on a DVD, is comparatively simple. Its 3 billion DNA base pairs and about 20,000 genes seem paltry next to the roughly 100 billion bases and millions of genes that make up the microbes found in the human body.
And a host of other variables accompanies that microbial DNA, including the age and health status of the microbial host, when and where the sample was collected, and how it was collected and processed. Take the mouth, populated by hundreds of species of microbes, with as many as tens of thousands of organisms living on each tooth. Beyond the challenges of analyzing all of these, scientists need to figure out how to reliably and reproducibly characterize the environment where they collect the data. “There are the clinical measurements that periodontists use to describe the gum pocket, chemical measurements, the composition of fluid in the pocket, immunological measures,” said David Relman, a physician and microbiologist at Stanford University who studies the human microbiome. “It gets complex really fast.”…."
Marc J. Lajoie1,2, Alexis J. Rovner3,4, Daniel B. Goodman1,5, Hans-Rudolf Aerni4,6, Adrian D. Haimovich3,4,Gleb Kuznetsov1, Jaron A. Mercer7, Harris H. Wang8, Peter A. Carr9, Joshua A. Mosberg1,2,Nadin Rohland1, Peter G. Schultz10, Joseph M. Jacobson11,12, Jesse Rinehart4,6, George M. Church1,13,*,Farren J. Isaacs3,4,* "We describe the construction and characterization of a genomically recoded organism (GRO). We replaced all known UAG stop codons in Escherichia coli MG1655 with synonymous UAA codons, which permitted the deletion of release factor 1 and reassignment of UAG translation function. This GRO exhibited improved properties for incorporation of nonstandard amino acids that expand the chemical diversity of proteins in vivo. The GRO also exhibited increased resistance to T7 bacteriophage, demonstrating that new genetic codes could enable increased viral resistance."
"Natural product scaffolds remain important leads for pharmaceutical development. However, transforming a natural product into a drug entity often requires derivatization to enhance the compound’s therapeutic properties. A powerful method by which to perform this derivatization is combinatorial biosynthesis, the manipulation of the genes in the corresponding pathway to divert synthesis towards novel derivatives. While these manipulations have traditionally been carried out via restriction digestion/ligation-based cloning, the shortcomings of such techniques limit their throughput and thus the scope of corresponding combinatorial biosynthesis experiments. In the burgeoning field of synthetic biology, the demand for facile DNA assembly techniques has promoted the development of a host of novel DNA assembly strategies. Here we describe the advantages of these recently developed tools for rapid, efficient synthesis of large DNA constructs. We also discuss their potential to facilitate the simultaneous assembly of complete libraries of natural product biosynthetic pathways, ushering in the next generation of combinatorial biosynthesis."
For more than half a century scientists have looked on the DNA molecule as life's blueprint. Now biological engineers are beginning to see the molecule not as a static plan, but more like a snippet of life's computer code that they can program.
Penn State researchers are unraveling the mystery of how nature codes and recodes this program to address some of the world's biggest challenges, says Howard Salis, assistant professor of biological engineering and chemical engineering.
"You can engineer DNA to reprogram the metabolism of simple organisms and you can program them to make what you want, or to make it more efficiently, says Salis. "The trick is to understand how the organism interprets its DNA, and then to optimize new DNA sequences to rationally control its behavior."
This rapidly developing field, often referred to as synthetic biology, may one day allow biological engineers to design living systems just as reliably as engineers currently design and build airplanes, cars and trains, according to Salis. It also holds the key to products such as inexpensive biofuels, environmentally friendly plastics, and less expensive pharmaceuticals.
"Decoding the function of DNA -- what the DNA makes the organism do -- and then recoding it with a new human-desired function is central to synthetic biology," he says…"
"One of the most exciting and promising applications of 3D printing is bioprinting, the ability to manufacture living human tissue and possibly organs. And one of the most exciting companies in this field is Organovo.
Organovo (NYSE MKT: ONVO) designs and creates functional, three-dimensional human tissues for medical research and therapeutic applications. The Company collaborates with pharmaceutical and academic partners to develop human biological disease models in three dimensions. These 3D human tissues have the potential to accelerate the drug discovery process, enabling treatments to be developed faster and at lower cost. Keith Murphy, Chairman and Chief Executive Officer of Organovo, spoke last week at the Inside 3D Printing conference in San Jose, CA…."
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