Life on Earth is incredibly diverse. Yet, underneath that diversity, there are a number of constants and highly conserved processes: all life is based on DNA and RNA; the genetic code is universal; biology is limited to a small subset of potential chemistries. A vast amount of knowledge has been accrued through describing and characterizing enzymes, biological processes and organisms. Nevertheless, much remains to be understood about the natural world. One of the goals in Synthetic Biology is to recapitulate biological complexity from simple systems made from biological molecules–gaining a deeper understanding of life in the process. Directed evolution is a powerful tool in Synthetic Biology, able to bypass gaps in knowledge and capable of engineering even the most highly conserved biological processes. It encompasses a range of methodologies to create variation in a population and to select individual variants with the desired function–be it a ligand, enzyme, pathway or even whole organisms. Here, we present some of the basic frameworks that underpin all evolution platforms and review some of the recent contributions from directed evolution to synthetic biology, in particular methods that have been used to engineer the Central Dogma and the genetic code.
Recoding—the repurposing of genetic codons—is a powerful strategy for enhancing genomes with functions not commonly found in nature. Here, we report computational design, synthesis, and progress toward assembly of a 3.97-megabase, 57-codon Escherichia coli genome in which all 62,214 instances of seven codons were replaced with synonymous alternatives across all protein-coding genes. We have validated 63% of recoded genes by individually testing 55 segments of 50 kilobases each. We observed that 91% of tested essential genes retained functionality with limited fitness effect. We demonstrate identification and correction of lethal design exceptions, only 13 of which were found in 2229 genes. This work underscores the feasibility of rewriting genomes and establishes a framework for large-scale design, assembly, troubleshooting, and phenotypic analysis of synthetic organisms.
Wet Lab Accelerator (WLA) is a cloud-based tool that allows a scientist to conduct biology via robotic control without the need for any programming knowledge. A drag and drop interface provides a convenient and user-friendly method of generating biological protocols. Graphically developed protocols are turned into programmatic instruction lists required to conduct experiments at the cloud laboratory Transcriptic. Prior to the development of WLA, biologists were required to write in a programming language called "Autoprotocol" in order to work with Transcriptic. WLA relies on a new abstraction layer we call "Omniprotocol" to convert the graphical experimental description into lower level Autoprotocol language, which then directs robots at Transcriptic. While WLA has only been tested at Transcriptic, the conversion of graphically laid out experimental steps into Autoprotocol is generic, allowing extension of WLA into other cloud labs in the future. WLA hopes to democratize biology by bringing automation to general biologists.
Human exploration off planet is severely limited by the cost of launching materials into space and by re-supply. Thus materials brought from Earth must be light, stable and reliable at destination. Using traditional approaches, a lunar or Mars base would require either transporting a hefty store of metals or heavy manufacturing equipment and construction materials for in situ extraction; both would severely limit any other mission objectives. Long-term human space presence requires periodic replenishment, adding a massive cost overhead. Even robotic missions often sacrifice science goals for heavy radiation and thermal protection. Biology has the potential to solve these problems because life can replicate and repair itself, and perform a wide variety of chemical reactions including making food, fuel and materials. Synthetic biology enhances and expands life's evolved repertoire. Using organisms as feedstock, additive manufacturing through bioprinting will make possible the dream of producing bespoke tools, food, smart fabrics and even replacement organs on demand. This new approach and the resulting novel products will enable human exploration and settlement on Mars, while providing new manufacturing approaches for life on Earth.
Metabolite-responsive RNA pseudoknots derived from prokaryotic riboswitches have been shown to stimulate -1 programmed ribosomal frameshifting (PRF), suggesting -1 PRF as a promising gene expression platform to extend riboswitch applications in higher eukaryotes. However, its general application has been hampered by difficulty in identifying a specific ligand-responsive pseudoknot that also functions as a ligand-dependent -1 PRF stimulator. We addressed this problem by using the -1 PRF stimulation pseudoknot of SARS-CoV (SARS-PK) to build a ligand-dependent -1 PRF stimulator. In particular, the extra stem of SARS-PK was replaced by an RNA aptamer of theophylline and designed to couple theophylline binding with the stimulation of -1 PRF. Conformational and functional analyses indicate that the engineered theophylline-responsive RNA functions as a mammalian riboswitch with robust theophylline-dependent -1 PRF stimulation activity in a stable human 293T cell-line. Thus, RNA-ligand interaction repertoire provided by in vitro selection becomes accessible to ligand-specific -1 PRF stimulator engineering using SARS-PK as the scaffold for synthetic biology application.
Scientists have genetically modified a common soil bacteria to create electrical wires that not only conduct electricity, but are thousands of times thinner than a human hair (Small, "Synthetic Biological Protein Nanowires with High Conductivity"). As electronic devices increasingly touch all facets of people's lives, there is growing appetite for technology that is smaller, faster and more mobile and powerful than ever before. Thanks to advances in nanotechnology (manipulating matter on an atomic or molecular scale), industry can manufacture materials only billionths of a meter in thickness. The Office of Naval Research (ONR)-sponsored researchers--led by microbiologist Dr. Derek Lovley at the University of Massachusetts Amherst--say their engineered wires can be produced using renewable "green" energy resources like solar energy, carbon dioxide or plant waste; are made of non-toxic, natural proteins; and avoid harsh chemical processes typically used to create nanoelectronic materials.
Alas! my time as community editor is coming to an end. Looking back over the year several key questions emerge, and the way they are answered will determine the shape of things to come.
Rapid Response Synbio?
The Zika epidemic has become a test case for synbio applications. Researchers at MIT used synthetic DNA circuits to create a paper based test for the virus, and we heard from Gaetan Burgio about the various genetic and biological options for controlling mosquito populations.
Since our initial blog post, we’ve spent many hours finalising designs for our genetic assemblies, which are now in the process of being synthesised. Once these are complete, we will begin the challenging task of completing four rounds of experiments before our deadline in September.
While our biologists are making significant headway in the lab, there have also been advancements on the hardware and engineering side. Our designs for low-cost, open-source lab equipment to support our Chlamydomonas transformation protocol have started to take shape – with the first stages of assembly taking place. This equipment will include a growth facility with light control, temperature regulation and imaging capabilities (linked to a dedicated Twitter account, @RPi_camigem2016), as well as a gene gun which, if successful, will transform cells by firing DNA-coated tungsten microparticles directly into them at high pressure.
The decision to make our hardware low cost and open source developed from recent trips to publicise our project at synthetic biology conferences in Paris and Norwich. At the Bio NightScience event hosted by the Centre de Recherches Interdisciplinaires (CRI) at the Cité des Sciences et de l’Industry, we presented our project to the conference and heard from many projects originating from Makespaces – collaborative community labs with little-to-no budget. We found its use of plant synthetic biology was hindered by the high cost of commercial equipment to culture and transform plant and algal cells. This inspired us to design low-cost equipment, which could make the ar
Many of the most important potential applications of Synthetic Biology will require the ability to design and implement high performance feedback control systems that can accurately regulate the dynamics of multiple molecular species within the cell. Here, we argue that the use of design strategies based on combining ultrasensitive response dynamics with negative feedback represents a natural approach to this problem that fully exploits the strongly nonlinear nature of cellular information processing. We propose that such feedback mechanisms can explain the adaptive responses observed in one of the most widely studied biomolecular feedback systems—the yeast osmoregulatory response network. Based on our analysis of such system, we identify strong links with a well-known branch of mathematical systems theory from the field of Control Engineering, known as Sliding Mode Control. These insights allow us to develop design guidelines that can inform the construction of feedback controllers for synthetic biological systems.
Synthetic biologists report the most far-reaching rewiring yet of a bacterial genome. The feat, described today in Science, involved repurposing 3.8% of the base pairs of the bacterium Escherichia coli1.
The scientists replaced 7 of its 64 genetic codons — sequences that code for amino acids — with others that produce the same components. They were able to reduce the number of codons by synthesizing the DNA in 55 fragments, each of which was 50,000 base pairs long. They have yet to reassemble those pieces into a functioning E. coli.
Despite that, the team, led by researchers at Harvard Medical School in Boston, Massachusetts, say that it is a major step in the push to engineer organisms with new properties, such as resistance to infection by viruses. The synthetic biologists, including George Church at Harvard, reported their results on 18 August in Science1. They say the work also serves as a prototype for the Human Genome Project—Write, in which scientists aim to synthesize a human genome.
The biosynthetic microbe could wire future nanoelectronics after Navy-funded researchers supercharged its conductivity.
A microbe so common it’s found everywhere from the muddy bottom of the Potomac River to soil hundreds of meters into the earth could one day be wiring the military’s nanotechnology and sensing toxic chemicals from unmanned vehicles.
The bacteria, called Geobacter, thrive where organic life normally couldn’t in an “unprecedented” way, said Derek Lovley, a microbiology professor at the University of Massachusetts Amherst working with the U.S. Navy.
Here’s how it works. Rather than expelling electrons through oxygen-based respiration, Geobacter grow hair-like protein filaments that transfer electrons out of the cell onto surrounding iron minerals. Over the past year, Lovley and a team of researchers genetically modified those protein filaments to supercharge their conductivity, as part of an ongoing collaboration with the Office of Naval Research. The researchers tweaked two of the protein’s amino acids, halving their size and increasing their conductivity 2,000-fold, ONR officials announced Tuesday:
“Research like Dr. Lovley’s could lead to the development of new electronic materials to meet the increasing demand for smaller, more powerful computing devices,” said Linda Chrisey, a program officer in ONR’s Warfighter Performance Department, which sponsors the research. “Being able to produce extremely thin wires with sustainable materials has enormous potential application as components of electronic devices such as sensors, transistors and capacitors.”
The filaments conduct electricity the same way copper does, making them promising alternatives for wiring in the military’s future nanoelectronics. Although this first test comes nowhere near copper’s conductivity, the modified Geobacter pili already are as effective as man-made alternatives like carbon nanotubes, Lovley said. Better yet, they have none of the issues associated with manufacturing large quantities of the carbon nanotubes, which has proved difficult to scale up due to resource constraints and laborious purification processes.
“We usually grow [Geobacter] on acetate, or acetic acid, which is basically what’s in vinegar—those kind of cheap and renewable resources,” he said. “And it’s very stable for a protein … so for example, they’re stable in boiling water. Stable at a very basic or very high pH. For a protein for they’re remarkably robust and stable.”
The bacteria could pair with other synthetic biological innovations the military is pursuing, including transmitting electricity to other bioengineered microbes producing butanol as an alternative fuel for the military’s remote outposts.
Beyond wiring and transistor applications, Lovley said he envisions a future with “the wire itself being a sensor.” If there’s a chemical the military wants to detect without exposing troops to—say, one found in explosives or toxic pollutants—researchers could further modify Geobacter so the nanowire itself binds with that chemical whenever the two come into contact, Lovley said. The altered bacteria could then be added to a silicon chip on an unmanned vehicle.
Though Lovley and his team discovered Geobacter’s conductive nanowires a decade ago, it was only last year that they started brainstorming in earnest with colleagues in polymer science about modifying the bacteria’s properties.
“The idea that there was a microbe that would make a wire to conduct electricity out of the cell was pretty revolutionary, and there was a lot of controversy,” he said. “So we really spent like nine of those 10 years studying the biological role.”
ONR’s Rear Adm. Mat Winter said the Navy has been sponsoring the Geobacter research for many years among the three-to-four thousand grants it awards to academic partners annually.
“It’s important to keep that volume focused” on basic research, said Winter,, at the Center for Strategic and International Studies last month. That creates “solution space so that ideas that can be knitted together for capabilities to emerge.”
In Geobacter’s case, this has paid off. Before genetically engineering the microbe’s filaments, Lovley’s team had already discovered its ability to serve as microbial fuel cells. The Navy is exploring applications of that now, including sustainably powering sensors embedded on the ocean floor.
“We continue to focus on advanced materials in our laboratories and understanding how we can do microbial energy, where we’re taking the positive electrons that are made on the microbes on the seabed, and we’re capturing those, and we’re hooking up some red and black connectors, and we’re gathering the electricity,” Winter said at CSIS. “So we’re not there yet, but … machines at the nano-level are going to be an incredible game-changer.”
Most summers since 1893, young developmental and evolutionary biologists have flocked to Woods Hole, Massachusetts, to master the tricks of their trade. At the world-famous Marine Biological Laboratory there, students in its annual embryology course dissect sea urchins and comb jellies, and graft cells together from different animals. But for the last three years, the keen apprentices have been learning something new: gene editing.
The precise, efficient CRISPR–Cas9 gene-editing technique has already taken life-sciences labs by storm. Now it is sweeping through evo-devo, the field that seeks to explain the developmental changes underlying evolutionary adaptations.
Rather than simply infer what caused historic transitions, such as how fish developed limbs, scientists can check their hypotheses directly with CRISPR. The idea is simple: cut out the fish genes thought to be involved in making fins, and see whether the fish start to form something resembling feet.
Life on Earth is incredibly diverse. Yet, underneath that diversity, there are a number of constants and highly conserved processes: all life is based on DNA and RNA; the genetic code is universal; biology is limited to a small subset of potential chemistries. A vast amount of knowledge has been accrued through describing and characterizing enzymes, biological processes and organisms. Nevertheless, much remains to be understood about the natural world. One of the goals in Synthetic Biology is to recapitulate biological complexity from simple systems made from biological molecules-gaining a deeper understanding of life in the process. Directed evolution is a powerful tool in Synthetic Biology, able to bypass gaps in knowledge and capable of engineering even the most highly conserved biological processes. It encompasses a range of methodologies to create variation in a population and to select individual variants with the desired function-be it a ligand, enzyme, pathway or even whole organisms. Here, we present some of the basic frameworks that underpin all evolution platforms and review some of the recent contributions from directed evolution to synthetic biology, in particular methods that have been used to engineer the Central Dogma and the genetic code
The 2nd International Conference on Systems and Synthetic Biology was organized during August 18-20, 2016 at the Hotel Crowne Plaza Heathrow, London, Unite
Software can tell chemists how to make new molecules from scratch and its inventors claim it has already mapped out a cheaper route to a blockbuster drug
Epigenetics is the study of heritable changes in gene expression without concomitant changes in DNA sequence. Due to its relevance in development, differentiation and human health, epigenetics has recently become an emerging area of science with regard to eukaryotic organisms and has shown enormous potential in synthetic biology. However, significant examples of epigenetic regulation in bacterial synthetic biology have not yet been reported. In the current study, we present the first model of such an epigenetic circuit. We termed the circuit the alternator circuit because parental cells carrying this circuit and their progeny alternate between distinct and heritable cellular fates without undergoing changes in genome sequence. Furthermore, we demonstrated that the alternator circuit exhibits hysteresis because its output depends not only on its present state, but also on its previous states.
Genetic modification to add tryptophan to PilA, the monomer for the electrically conductive pili of Geobacter sulfurreducens, yields conductive protein filaments 2000-fold more conductive than the wild-type pili while cutting the diameter in half to 1.5 nm.
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