by Zoltán Kis , Hugo Sant'Ana Pereira , Takayuki Homma , Ryan M. Pedrigi , Rob Krams
"In this review, we discuss new emerging medical applications of the rapidly evolving field of mammalian synthetic biology. We start with simple mammalian synthetic biological components and move towards more complex and therapy-oriented gene circuits. A comprehensive list of ON–OFF switches, categorized into transcriptional, post-transcriptional, translational and post-translational, is presented in the first sections. Subsequently, Boolean logic gates, synthetic mammalian oscillators and toggle switches will be described. Several synthetic gene networks are further reviewed in the medical applications section, including cancer therapy gene circuits, immuno-regulatory networks, among others. The final sections focus on the applicability of synthetic gene networks to drug discovery, drug delivery, receptor-activating gene circuits and mammalian biomanufacturing processes."
"Millions of years of evolution have made the biological world into a supremely effective materials-development laboratory. This Outlook examines the ways in which substances found in the natural world are inspiring imitations that might eventually endow humans with superhuman power..."
Genetically identical cells can have many variable properties. A study of correlations between cells in a lineage explains paradoxical inheritance laws, in which mother and daughter cells seem less similar than cousins. See Letter p.468
"Quorum-sensing networks enable bacteria to sense and respond to chemical signals produced by neighboring bacteria. They are widespread: over 100 morphologically and genetically distinct species of eubacteria are known to use quorum sensing to control gene expression. This diversity suggests the potential to use natural protein variants to engineer parallel, input-specific, cell–cell communication pathways. However, only three distinct signaling pathways, Lux, Las, and Rhl, have been adapted for and broadly used in engineered systems. The paucity of unique quorum-sensing systems and their propensity for crosstalk limits the usefulness of our current quorum-sensing toolkit. This review discusses the need for more signaling pathways, roadblocks to using multiple pathways in parallel, and strategies for expanding the quorum-sensing toolbox for synthetic biology."
"Harness the tools and techniques of Rapid DNA Prototyping to build your own sophisticated genetic circuits. This powerful set of modular parts enables you to determine your own complex projects. The power of synthetic biology has never been so accessible!"
I was first introduced to RNA in 1962. As a newly minted PhD in synthetic organic chemistry I had just joined in Madison, Wisconsin a team of four postdocs charged with the challenging task of chemically synthesizing 64 ribotrinucleotides by the most modern methods (manual synthesis, of course, requiring gallons of dry pyridine every day). My advisor, Har Gobind Khorana, a man of boundless energy, vision and courage, was convinced that these RNA triplets would be essential for the elucidation of the genetic code. It was an exciting time in molecular biology as the first details of the mechanism of protein synthesis and the genetic code emerged. Then, after three years of intense work with great team spirit the code was cracked! At the end of my time in Wisconsin I had become a molecular biologist, spellbound by the genetic code and by tRNA. I would never lose interest in this molecule, and it guided my research for the next five decades.
Fast forward to the mid-nineteen-nineties, when the RNA journal was launched, the era of genome sequencing began, and I returned to studies of the genetic code. At that time we dabbled for the first time in using Archaea for our research; we discovered that tRNA-dependent asparagine (Asn) formation provides Asn-tRNA for protein synthesis, and later showed that in many organisms this process is also the required supply route for the free amino acid. Then a phone call changed my research direction for the next 15 years. Carl Woese, whose early inquiries into the genetic code and tRNA, summarized in his influential “little book” The Genetic Code, the Molecular Basis for Genetic Expression (published in 1967; now available used from Amazon as a collector's item for $604!), had made a big impression on me back then. Carl had just called. He told me that the genome sequence of the first archaeon, Methanococcus jannaschii (now renamed Methanocaldococcus jannaschii), would appear in print soon, and that the genome lacked the gene for the essential cysteinyl-tRNA synthetase. “How are you going to explain this?” he asked. Without any hesitation I replied that I would solve the riddle, totally unaware that it would take us a decade of sustained and unfamiliar work with many archaeal species to come up with the correct and exciting solution! Thus, we launched investigations with organisms whose names were hard to pronounce, even more difficult to grow, that were anaerobes, and some of them with stunning optimal growth temperatures exceeding the boiling point of water; all of this was totally unfamiliar to us. However, given our thrilling unexpected first results and considering the vast diversity of microbes that would soon be available via their genome sequences, we felt that careful analyses of these organisms for anything that diverged from the accepted view of protein synthesis and genetic coding would possibly lead to surprising new concepts. And given the vast organismal diversity out there, we wondered how many different routes (or exceptions to the currently accepted dogma) of protein synthesis, tRNA formation and the genetic code would be represented in this biological universe.
"Asilomar. The word conjures up not only stunning California coastline but also vexing questions posed by new, potentially world-changing technologies. In 1975, the Asilomar conference center hosted a meeting where biologists crafted guidelines for research that altered the DNA of living organisms. Now scientists are calling for another Asilomar—this time to discuss the possibility of genetically engineered human beings. In 1975, the notion of using recombinant DNA to design human babies was too remote to seriously consider, but the explosion of powerful new genome-editing technologies such as CRISPR-Cas9, zinc fingers, and TALENs has changed that. They have made it easy for anyone with basic molecular biology training to insert, remove, and edit genes in cells, including sperm, eggs, and embryos, potentially curing genetic diseases or adding desirable traits. Rumors are rife that scientists in China have already used CRISPR on human embryos. Researchers fear that publicity surrounding such experiments could trigger a public backlash that would block legitimate uses of the technology. In two commentaries, one published online in Science on 19 March and one in Nature on 12 March, two groups of scientists recommend what steps the scientific community could take to ensure the technology would be used safely and ethically."
"A new technology called CRISPR could allow scientists to alter the human genetic code for generations. That's causing some leading biologists and bioethicists to sound an alarm. They're calling for a worldwide moratorium on any attempts to alter the code, at least until there's been time for far more research and discussion.
Jennifer Doudna and her colleagues found an enzyme in bacteria that makes editing DNA in animal cells much easier.
In Hopes Of Fixing Faulty Genes, One Scientist Starts With The Basics
The CRISPR enzyme (green and red) binds to a stretch of double-stranded DNA (purple and red), preparing to snip out the faulty part.
It's not new that scientists can manipulate human DNA — genetic engineering, or gene editing, has been around for decades. But it's been hard, slow and very expensive. And only highly skilled geneticists could do it.
Recently that's changed. Scientists have developed new techniques that have sped up the process and, at the same time, made it a lot cheaper to make very precise changes in DNA.
There are a couple of different techniques, but the one most often talked about is CRISPR, which stands for clustered regularly interspaced short palindromic repeats. My colleague Joe Palca described the technique for Shots readers last June.
Why scientists are nervous
On the one hand, scientists are excited about these techniques because they may let them do good things, such as discovering important principles about biology. It might even lead to cures for diseases.
The big worry is that CRISPR and other techniques will be used to perform germline genetic modification...."
"Characteristics adapted from lizards, ivy and other natural materials could help to engineer everyday objects with remarkable properties.
made it so. Similarly, some scientists have gazed at geckos walking up walls and wondered whether humans could do the same. Now they can. In June 2014, a 100-kilogram man wearing a heavy pack climbed up a vertical sheet of glass using only a pair of hand-held paddles made from an advanced material inspired by geckos.
The synthetic gecko skin on the paddles has plenty of company in the world of materials science. Researchers are increasingly looking towards plants and animals for ideas on how to design coatings and textures that imbue surfaces with special properties. The adhesive that ivy uses to cling to walls, for example, has inspired a material that might help damaged tissues to regenerate. Molecules taken from mussel adhesives could provide a way to target cancer cells. And the veins on nasturtium leaves have led to the development of a synthetic surface that could prevent rain from freezing on aeroplane wings or keep grimy fingerprints off smartphone screens. The trick is to take ideas sparked by nature — some of them long in development, others brand new — and make them practical and durable......"
"Compartmentalisation of cellular processes is fundamental to regulation of metabolism in Eukaryotic organisms and is primarily provided by membrane-bound organelles. These organelles are dynamic structures whose membrane barriers are continually shaped, remodelled and scaffolded by a rich variety of highly sophisticated protein complexes. Towards the goal of bottom-up assembly of compartmentalised protocells in synthetic biology, we believe it will be important to harness and reconstitute the membrane shaping and sculpting characteristics of natural cells. We review different in vitro membrane models and how biophysical investigations of minimal systems combined with appropriate theoretical modelling have been used to gain new insights into the intricate mechanisms of these membrane nanomachines, paying particular attention to proteins involved in membrane fusion, fission and cytoskeletal scaffolding processes. We argue that minimal machineries need to be developed and optimised for employment in artificial protocell systems rather than the complex environs of a living organism. Thus, well-characterised minimal components might be predictably combined into functional, compartmentalised protocellular materials that can be engineered for wide-ranging applications."
"The development of novel technologies in the late 19th and early 20th century lead to the creation of major new industries such as the petrochemical, automotive, aviation, and electronic. These industries have improved the lives of billions of people around the globe1 and propelled civilization forward. During the second half of the 20th century the digital revolution changed the world yet again, with the rise of personal computers and the internet. According to the UK Royal Academy of Engineering, we are on the cusp of another revolution—this one based on synthetic biology1. The applications of synthetic biology are broad, ranging from renewable energy production to agriculture. One exciting application that will have profound implications on human health is medicine. This paper will discuss the advent of synthetic biology and its medical applications."
Pamela Peralta-Yahya, Georgia Institute of Technology
Stanley Qi, Stanford University
"Synthetic biology is a discipline wherein living organisms are genetically programmed to carry out desired functions in a reliable manner. This field takes inspiration from our ever-expanding ability to measure and manipulate biological systems, and the philosophical reflections of Schrodinger and Feynman that physical laws can be used to describe and rationally engineer biology to accomplish useful goals. After all, cells are the world’s most sophisticated chemists, and their ability to learn to adapt to changing environments offer enormous potential to solving modern engineering challenges. Nonetheless, biological systems are noisy, massively interconnected, and non-linear, and have not evolved to be easily engineered. The grand challenge of synthetic biology is to reconcile the desire for a predictable, formalized biological design process with the inherent ‘squishiness’ of biology.
Learn Techniques and Perform Research at the Forefront of Synthetic Biology: The course will focus on how the complexity of biological systems, combined with traditional engineering approaches, results in the emergence of new design principles for synthetic biology. The Course centers around an immersive laboratory experience. Here, students will work in teams to learn the practical and theoretical underpinnings of cutting edge research in the area of Synthetic Biology. Broadly, we will explore how cellular regulation- transcriptional, translational, post-translational and epigenetic- can be used to engineer cells to accomplish well-defined goals. Specific laboratory modules will cover the following areas: cell-free transcription and translation systems, high-throughput cloning techniques, computational biology using ordinary differential equations models, biosensor development for metabolic engineering, and CRISPR for genome editing in mammalian cells to regulate synthetic genes and physical cell properties. Students will first learn essential synthetic biology techniques in a four-day ‘boot-camp’, and then rotate through research projects in select areas.
In addition, students will interact closely with a panel of internationally-recognized speakers who will give students a broad overview of applications for synthetic biology, including renewable chemical production and therapeutics, the current state-of-the-art techniques, and case studies in human practices and socially responsible innovation.
Speakers in 2015 include:
Elisa Franco, University of California, Riverside
Nathan Hillson, Harvard Medical School
Mo Khalil, Boston University
Thomas Knight, Ginkgo BioWorks
Vincent Noireaux, University of Minnesota
Pamela Silver, Harvard Medical School
Danielle Tullman-Erceck, University of California, Berkeley
by Kyung-In Jang,Ha Uk Chung,Sheng Xu,Chi Hwan Lee,Haiwen Luan,Jaewoong Jeong, Huanyu Cheng,Gwang-Tae Kim,Sang Youn Han,Jung Woo Lee,Jeonghyun Kim,Moongee Cho,Fuxing Miao,Yiyuan Yang,Han Na Jung,Matthew Flavin,Howard Liu,Gil Woo Kong,Ki Jun Yu,Sang Il Rheeet al.
"Hard and soft structural composites found in biology provide inspiration for the design of advanced synthetic materials. Many examples of bio-inspired hard materials can be found in the literature; far less attention has been devoted to soft systems. Here we introduce deterministic routes to low-modulus thin film materials with stress/strain responses that can be tailored precisely to match the non-linear properties of biological tissues, with application opportunities that range from soft biomedical devices to constructs for tissue engineering. The approach combines a low-modulus matrix with an open, stretchable network as a structural reinforcement that can yield classes of composites with a wide range of desired mechanical responses, including anisotropic, spatially heterogeneous, hierarchical and self-similar designs. Demonstrative application examples in thin, skin-mounted electrophysiological sensors with mechanics precisely matched to the human epidermis and in soft, hydrogel-based vehicles for triggered drug release suggest their broad potential uses in biomedical devices."
"Jason Kelly was in Manhattan Thursday to meet with a prospective customer in the perfume business. Kelly, a founder of Boston-based Ginkgo Bioworks , sells custom-crafted organisms — mostly yeast, bacteria, and algae — and one of the jobs they can do is make synthetic scents that might one day go into a fragrance that you spray or dab on.
Custom-crafted organisms? Yep, designed and produced in a lab that overlooks Boston Harbor.
If textile mills represented the cutting edge of Massachusetts manufacturing in the early 1800s, this is one example of the extremely advanced manufacturing that could thrive in the 21st century. This month, Ginkgo announced that it had raised its first venture capital funding since it spun out from MIT in 2008 — $9 million — and it put the finishing touches on a production facility it calls Foundry1, full of automated machines that can cost hundreds of thousands of dollars each.
Ginkgo is part of a field called “synthetic biology” that holds immense promise — but also freaks people out. It involves writing genetic code and inserting it into simple organisms to change their function. Boosters point to the possibility of vats of algae cranking out fuels or industrial chemicals that today come from petroleum, or to bespoke bacteria that could diagnose diseases sooner than we can today. But others worry about terrorists producing ultra-potent pathogens, or someone accidentally spawning a fast-replicating organism that damages the environment.
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