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The term "synthetic biology" has a history spanning the twentieth century.[4] The first use was in Stéphane Leducs’s publication of « Théorie physico-chimique de la vie et générations spontanées » (1910)[5] and « La Biologie Synthétique » (1912).[6][who said this?] In 1974, the Polish geneticist Wacław Szybalski used the term "synthetic biology",[7] writing: Let me now comment on the question "what next". Up to now we are working on the descriptive phase of molecular biology. ... But the real challenge will start when we enter the synthetic phase of research in our field. We will then devise new control elements and add these new modules to the existing genomes or build up wholly new genomes. This would be a field with an unlimited expansion potential and hardly any limitations to building "new better control circuits" or ..... finally other "synthetic" organisms, like a "new better mouse". ... I am not concerned that we will run out of exciting and novel ideas, ... in the synthetic biology, in general. When in 1978 the Nobel Prize in Physiology or Medicine was awarded to Arber, Nathans and Smith for the discovery of restriction enzymes, Wacław Szybalski wrote in an editorial comment in the journal Gene: The work on restriction nucleases not only permits us easily to construct recombinant DNA molecules and to analyze individual genes, but also has led us into the new era of synthetic biology where not only existing genes are described and analyzed but also new gene arrangements can be constructed and evaluated.[8] Perspectives Biology Biologists are interested in learning more about how natural living systems work. One simple, direct way to test current understanding of a natural living system is to build an instance (or version) of the system in accordance with our current understanding of the system. Michael Elowitz's early work on the Repressilator[9] is one good example of such work. Elowitz had a model for how gene expression should work inside living cells. To test his model, he built a piece of DNA in accordance with his model, placed the DNA inside living cells, and watched what happened. Slight differences between observation and expectation highlight new science that may be well worth doing. Work of this sort often makes good use of mathematics to predict and study the dynamics of the biological system before experimentally constructing it. A wide variety of mathematical descriptions have been used with varying accuracy, including graph theory, Boolean networks, ordinary differential equations, stochastic differential equations, and Master equations (in order of increasing accuracy).[10] Chemistry Biological systems are physical systems that are made up of chemicals. Around the turn of the 20th century, the science of chemistry went through a transition from studying natural chemicals to trying to design and build new chemicals. This transition led to the field of synthetic chemistry. In the same tradition, some aspects of synthetic biology can be viewed as an extension and application of synthetic chemistry to biology, and include work ranging from the creation of useful new biochemicals to studying the origins of life.[citation needed] Engineering Engineers view biology as a technology – the systems biotechnology or systems biological engineering.[citation needed] Synthetic Biology includes the broad redefinition and expansion of biotechnology, with the ultimate goals of being able to design and build engineered biological systems that process information, manipulate chemicals, fabricate materials and structures, produce energy, provide food, and maintain and enhance human health (see Biomedical Engineering) and our environment.[11] A good example of these technologies include the work of Chris Voigt, who redesigned the Type III secretion system used by Salmonella typhimurium to secrete spider silk proteins, a strong elastic biomaterial, instead of its own natural infectious proteins. One aspect of Synthetic Biology which distinguishes it from conventional genetic engineering is a heavy emphasis on developing foundational technologies that make the engineering of biology easier and more reliable. Good examples of engineering in synthetic biology include the pioneering work of Tim Gardner and Jim Collins on an engineered genetic toggle switch,[12] a riboregulator, the Registry of Standard Biological Parts, and the International Genetically Engineered Machine competition (iGEM). Studies in synthetic biology can be subdivided into broad classifications according to the approach they take to the problem at hand: photocell design, biomolecular engineering, genome engineering, and biomolecular-design. The photocell approach includes projects to make self-replicating systems from entirely synthetic components. Biomolecular engineering includes approaches which aim to create a toolkit of functional units that can be introduced to present new orthogonal functions in living cells. Genetic engineering includes approaches to construct synthetic chromosomes for whole or minimal organisms. Biomolecular-design approach refers to the general idea of the de novo design and combination of biomolecular components. The task of each of these approaches is similar: To create a more synthetic entry at a higher level of complexity by manipulating a part of the proceeding level.[13] Re-writing Re-writers are synthetic biologists who are interested in testing the idea that since natural biological systems are so complicated, we would be better off re-building the natural systems that we care about, from the ground up, in order to provide engineered surrogates that are easier to understand and interact with.[14] Re-writers draw inspiration from refactoring, a process sometimes used to improve computer software. Oligonucleotides harvested from a photolithographic or inkjet manufactured DNA chip combined with DNA mismatch error-correction allows inexpensive large-scale changes of codons in genetic systems to improve gene expression or incorporate novel amino-acids (see George M. Church's and Anthony Forster's synthetic cell projects.)[15] This favors a synthesis-from-scratch approach. Key enabling technologies This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2014) There are several key enabling technologies that are critical to the growth of synthetic biology. The key concepts include standardization of biological parts and hierarchical abstraction to permit using those parts in increasingly complex synthetic systems.[16] Achieving this is greatly aided by basic technologies of reading and writing of DNA (sequencing and fabrication), which are improving in price/performance exponentially (Kurzweil 2001). Measurements under a variety of conditions are needed for accurate modeling and computer-aided-design (CAD). DNA sequencing DNA sequencing is determining the order of the nucleotide bases in a molecule of DNA. Synthetic biologists make use of DNA sequencing in their work in several ways. First, large-scale genome sequencing efforts continue to provide a wealth of information on naturally occurring organisms. This information provides a rich substrate from which synthetic biologists can construct parts and devices. Second, synthetic biologists use sequencing to verify that they fabricated their engineered system as intended. Third, fast, cheap and reliable sequencing can also facilitate rapid detection and identification of synthetic systems and organisms.[17] Cloning Molecular cloning is a method used frequently by geneticists to obtain large quantities of a particular strand of DNA. It involves manipulating the particular piece of DNA and inserting it into the circular plasmid DNA of a bacterium. Once the foreign DNA is inserted, the bacterium is allowed to resume cellular function and replicate all the DNA that it contains. The bacteria are cultured until the number of clones is sufficient. The clones of foreign DNA are excised from the plasmids. In this sense the bacteria function as cyborgs because a foreign element is introduced and interacts with the bacteria. Synthesis A critical limitation in synthetic biology today is the time and effort expended during fabrication of engineered genetic sequences. To speed up the cycle of design, fabrication, testing and redesign, synthetic biology requires more rapid and reliable de novo DNA synthesis and assembly of fragments of DNA, in a process commonly referred to as gene synthesis. In 2007 it was reported that several companies were offering the synthesis of genetic sequences up to 2000 bp long, for a price of about $1 per base pair and a turnaround time of less than two weeks.[18] By September 2009, the price had dropped to less than $0.50 per base pair with some improvement in turn around time. Not only is the price judged lower than the cost of conventional cDNA cloning, the economics make it practical for researchers to design and purchase multiple variants of the same sequence to identify genes or proteins with optimized performance. Modeling Models inform the design of engineered biological systems by allowing synthetic biologists to better predict system behavior prior to fabrication. Synthetic biology will benefit from better models of how biological molecules bind substrates and catalyze reactions, how DNA encodes the information needed to specify the cell and how multi-component integrated systems behave. Recently, multiscale models of gene regulatory networks have been developed that focus on synthetic biology applications. Simulations have been used that model all biomolecular interactions in transcription, translation, regulation, and induction of gene regulatory networks, guiding the design of synthetic systems.[19] Measurement Precise and accurate quantitative measurements of biological systems are crucial to improving understanding of biology. Such measurements often help to elucidate how biological systems work and provide the basis for model construction and validation. Differences between predicted and measured system behavior can identify gaps in understanding and explain why synthetic systems don't always behave as intended. Technologies which allow many parallel and time-dependent measurements will be especially useful in synthetic biology.[citation needed] Microscopy and flow cytometry are examples of useful measurement technologies. Examples Synthetic DNA Main articles: Artificial gene synthesis, Expanded genetic code, Nucleic acid analogue and Synthetic genomics In 2000, researchers at Washington University, reported synthesis of the 9.6 kbp (kilo base pair) Hepatitis C virus genome from chemically synthesized 60 to 80-mers.[20] In 2002 researchers at SUNY Stony Brook succeeded in synthesizing the 7741 base poliovirus genome from its published sequence, producing the second synthetic genome. This took about two years of painstaking work.[21] In 2003 the 5386 bp genome of the bacteriophage Phi X 174 was assembled in about two weeks.[22] In 2006, the same team, at the J. Craig Venter Institute, had constructed and patented a synthetic genome of a novel minimal bacterium, Mycoplasma laboratorium and were working on getting it functioning in a living cell.[23][24] In May 2014, researchers announced that they had successfully introduced two new artificial nucleotides into bacterial DNA, and by including individual artificial nucleotides in the culture media, were able to passage the bacteria 24 times; they did not create mRNA or proteins able to use the artificial nucleotides.[25][26][27] Further information: Base pair § Unnatural base pair (UBP) Synthetic Cells Unbalanced scales.svg The neutrality of this section is disputed. Relevant discussion may be found on the talk page. Please do not remove this message until the dispute is resolved. (June 2014) One important topic in synthetic biology is Synthetic life, that is, artificial life created in vitro from biochemicals and their component materials. Synthetic life experiments attempt to either probe the origins of life, study some of the properties of life, or more ambitiously to recreate life from non-alive (abiotic) substances. In May 2010, Craig Venter's group announced they had been able to assemble a complete genome of millions of base pairs, insert it into a cell, and cause that cell to start replicating.[28] For the creation of this "synthetic" cell, first the complete DNA sequence of the genome of a bacterium Mycoplasma mycoides was determined. A new genome was then designed based on this genome with watermarks and elements necessary for growth in yeast and genome transplantation added, as well as part of its sequence deliberately deleted. This new genome was synthesized in small fragments—over a thousand overlapping cassettes of synthetic oligonucleotides were created—which were then assembled in steps in yeast and other cells, and the complete genome finally transplanted into cell from another species Mycoplasma capricolum from which all genetic material had been removed.[29][30] The cell divided and was "entirely controlled by (the) new genome", ultimately demonstrating that DNA can be very practically described by its chemical properties.[30] This cell has been referred to by Venter as the "first synthetic cell", and was created at a cost of over $40 million.[30] There is some debate within the scientific community over whether this cell can be considered completely synthetic on the grounds that:[30] the chemically synthesized genome was an almost 1:1 copy of a naturally occurring genome and, the recipient cell was a naturally occurring bacterium. The Craig Venter Institute maintains the term "synthetic bacterial cell" but they also clarify "...we do not consider this to be "creating life from scratch" but rather we are creating new life out of already existing life using synthetic DNA." [31] Venter plans to patent his experimental cells, stating that "they are pretty clearly human inventions".[30] Its creators suggests that building 'synthetic life' would allow researchers to learn about life by building it, rather than by tearing it apart. They also propose to stretch the boundaries between life and machines until the two overlap to yield "truly programmable organisms."[32] Researchers involved stated that the creation of "true synthetic biochemical life" is relatively close in reach with current technology and cheap compared to the effort needed to place a man on the Moon.[33] Genome Editing Numerous methods have been proposed for enabling the insertion of sequences into precise locations in genomes. Well-known examples include Zinc finger nucleases, TALENs, and CRISPR systems. The Sleeping Beauty transposon system is an example of an engineered enzyme for inserting precise DNA sequences into genomes of vertebrate animals. The SB transposon is a synthetic sequence that was created based on deriving a consensus sequence of extinct Tc1/mariner-type transposons that are found as evolutionary relics in the genomes of most, if not all, vertebrates. This enzyme took about a year to engineer[34] and since its creation has been used for gene transfer, gene discovery, and gene therapy applications[35][36][37] Synthetic circuits A vast number of Synthetic biological circuits have been described, and the number has been increasing steadily over the last 10–15 years. In general, this refers to creating a system where some gene of interest can be expressed under prescribed conditions. The lac operon is a natural example that is often emulated. Hence, this circuit follows a simple rule: in the presence of lactose, several genes involved in the metabolism of lactose are expressed. Reduced amino-acid libraries Many researchers have investigated the structure and function of proteins by reducing the normal set of 20 amino acids, that is, by generating proteins where certain groups of amino acids may be substituted with a single amino acid.[38] For instance, several non-polar amino acids within a protein may all be replaced with a single non-polar amino acid.[39] One project demonstrated that an engineered version of Chorismate mutase still had catalytic activity when only 9 amino acids were used.[40] Designed proteins While there are methods to engineer natural proteins (such as by Directed evolution), there are also projects to design novel protein structures that match or improve on the functionality of existing proteins. One group generated a helix bundle that was capable of binding oxygen with similar properties as hemoglobin, yet did not bind carbon monoxide.[41] A similar protein structure was generated to support a variety of oxidoreductase activities.[42] Biosensors A biosensor refers to an engineered organism (usually a bacterium) that is capable of reporting some environmental phenomenon, such the presence of heavy metals or toxins. In this respect, a very widely used system is the Lux operon of Aliivibrio fischeri. The Lux operon consists of five genes which are necessary and sufficient for bacterial bioluminescence, and can be placed under an alternate promoter to express the genes in response to an arbitrary environmental stimulus. One such sensor created in Oak Ridge National Laboratory and named “critter on a chip” used a coating of bioluminescent bacteria on a light sensitive computer chip to detect certain petroleum pollutants. When the bacteria sense the pollutant, they begin to generate light.[43] In Australia, biosensors have been created to detect viruses, bacteria, hormones, drugs, and DNA sequences.[citation needed] Other desirable targets for sensors include toxins, Persistent organic pollutants, endocrine disruptors and warfare agents. Even more recently chemists at the University of Nebraska created a humidity gauge by using gold plated bacteria on a silicon chip. With a decrease in humidity there was an increase in the circuit flow. One unique feature that separates the chip from the bioluminescent ones is that after it has been assimilated the bacteria no longer needs to be kept alive for the humidity gauge to work.[44] Nanotechnology also has made advances by using bacteria. Researchers at the École polytechnique de Montréal in Canada have attached a microscopic bead to swimming bacteria. Using a magnetic resonance imaging machine (MRI) the researchers have been able to use the magnetic properties of the bacteria to direct it to certain locations. The bead has no purpose at the moment but researchers hope to store drugs or other viral fighting agents inside so that it may be released at the directed location.[45] Information Storage Scientists can encode vast amounts of digital information onto a single strand of synthetic DNA. In 2012, George M. Church encoded one of his books about synthetic biology in DNA. The 5.3 Mb of data from the book is more than 1000 times greater than the previous largest amount of information to be stored in synthesized DNA.[46] A similar project had encoded the complete sonnets of William Shakespeare in DNA.[47] Challenges Opposition to synthetic biology Opposition by civil society groups to Synthetic Biology has been led by the ETC Group who have called for a global moratorium on developments in the field and for no synthetic organisms to be released from the lab. In 2006, 38 civil society organizations authored an open letter opposing voluntary regulation of the field and in 2008 ETC Group released the first critical report on the societal impacts of synthetic biology which they dubbed "Extreme Genetic Engineering".[48] On March 13, 2012, over 100 environmental and civil society groups, including Friends of the Earth, the International Center for Technology Assessment and the ETC Group issued the statement The Principles for the Oversight of Synthetic Biology which call for a worldwide moratorium on the release and commercial use of synthetic organisms until more robust regulations and rigorous biosafety measures are established. The groups specifically call for an outright ban on the use of synthetic biology on the human genome or human microbiome.[49] Safety and security In addition to numerous scientific and technical challenges, synthetic biology raises questions for ethics, biosecurity, biosafety, involvement of stakeholders and intellectual property.[50][51] To date, key stakeholders (especially in the US) have focused primarily on the biosecurity issues, especially the so-called dual-use challenge. For example, while the study of synthetic biology may lead to more efficient ways to produce medical treatments (e.g. against malaria, see artemisinin), it may also lead to synthesis or redesign of harmful pathogens (e.g., smallpox) by malicious actors.[52] Proposals for licensing and monitoring the various phases of gene and genome synthesis began to appear in 2004. A 2007 study compared several policy options for governing the security risks associated with synthetic biology. Other initiatives, such as OpenWetWare, diybio, biopunk, biohack, and possibly others, have attempted to integrate self-regulation in their proliferation of open source synthetic biology projects. However the distributed and diffuse nature of open-source biotechnology may make it more difficult to track, regulate, or mitigate potential biosafety and biosecurity concerns.[53] An initiative for self-regulation has been proposed by the International Association Synthetic Biology[54] that suggests some specific measures to be implemented by the synthetic biology industry, especially DNA synthesis companies. Some scientists, however, argue for a more radical and forward looking approaches to improve safety and security issues. They suggest to use not only physical containment as safety measures, but also trophic and semantic containment. Trophic containment includes for example the design of new and more robust forms of auxotrophy, while semantic containment means the design and construction of completely novel orthogonal life-forms.[55] Social and ethical Online discussion of “societal issues” took place at the SYNBIOSAFE forum on issues regarding ethics, safety, security, IPR, governance, and public perception (summary paper). On July 9–10, 2009, the National Academies' Committee of Science, Technology & Law convened a symposium on "Opportunities and Challenges in the Emerging Field of Synthetic Biology" (transcripts, audio, and presentations available). Some efforts have been made to engage social issues "upstream" focus on the integral and mutually formative relations among scientific and other human practices. These approaches attempt to invent ongoing and regular forms of collaboration among synthetic biologists, ethicists, political analysts, funders, human scientists and civil society activists. These collaborations have consisted either of intensive, short term meetings, aimed at producing guidelines or regulations, or standing committees whose purpose is limited to protocol review or rule enforcement. Such work has proven valuable in identifying the ways in which synthetic biology intensifies already-known challenges in rDNA technologies. However, these forms are not suited to identifying new challenges as they emerge,[56] and critics worry about uncritical complicity.[48] An example of efforts to develop ongoing collaboration is the "Human Practices" component of the Synthetic Biology Engineering Research Center in the US and the SYNBIOSAFE project in Europe, coordinated by IDC,[57] that investigated the biosafety, biosecurity and ethical aspects of synthetic biology. A report from the Woodrow Wilson Center and the Hastings Center, a prestigious bioethics research institute, found that ethical concerns in synthetic biology have received scant attention.[58] In January 2009, the Alfred P. Sloan Foundation funded the Woodrow Wilson Center, the Hastings Center, and the J. Craig Venter Institute to examine the public perception, ethics, and policy implications of synthetic biology.[59] Public perception and communication of synthetic biology is the main focus of COSY: Communicating Synthetic Biology, that showed that in the general public synthetic biology is not seen as too different from 'traditional' genetic engineering.[60][61] To better communicate synthetic biology and its societal ramifications to a broader public, COSY and SYNBIOSAFE published a 38-minute documentary film in October 2009 [2]. After a series of meetings in the fall of 2010, the Presidential Commission for the study of Bioethical Issues released a report, on December 16, titled "New Directions: The Ethics of Synthetic Biology and Emerging Technologies" to the President calling for enhanced Federal oversight in the emerging field of synthetic biology. This report lists recommendations on how new technology growth should be regulated to minimize harm. These recommendations are based on five ethical principles: to ensure the public benefit with as little harm, responsibility for the well-being of the environment and its future generations, to protect intellectual freedom, that democracy is the key to making decisions, and that fairness is maintained.[62][63] The panel that facilitated the production of the report, composed of 13 scientists, ethicists, and public policy experts, said that the very newness of the science gives regulators, ethicists and others time to identify problems early on and craft solutions that can harness the technology for the public good. Dr. Gutmann said the commission's approach recognizes the great potential of synthetic biology, including life-saving medicines, and the generally distant risks posed by the field’s current capacity. "Prudent vigilance suggests that federal oversight is needed and can be exercised in a way that is consistent with scientific progress". she said.[64] Synthetic biology is the design and construction of biological devices and systems for useful purposes.[1] It is an area of biological research and technology that combines biology and engineering, thus often overlapping with bioengineering and biomedical engineering. It encompasses a variety of different approaches, methodologies, and disciplines with a focus on engineering biology and biotechnology.[2] Synthetic biologists approach the creation of new biological systems from different perspectives, focusing on finding how life works (the origin of life) or how to use it to benefit society. The former focus includes the approach of biology, inserting man-made DNA into a living cell; and chemistry, working on gene synthesis as an extension of synthetic chemistry. The latter focus includes engineering, building the new biological system as a platform for various technologies; and rewriting, rebuilding the natural systems to provide the engineered surrogates. The advance of synthetic biology relies on several key enabling technologies provided at ever increasing speed and lower cost. DNA sequencing, fabrication of genes, modeling how synthetic genes behave, and precisely measuring gene behavior are essential tools in synthetic biology. Its popularity has grown as a result of increasing developments within DNA synthesis technologies; now it is more affordable to synthesize a gene as opposed to cloning it. Also, genome databases can be used as a template for creating viruses at minimal cost. Geneticists have found a number of gene sequences which correspond to differing traits in organisms; these individual gene sequences have been developed and incorporated into DNA similar to genetic "lego" blocks. This is essentially how genetic engineers alter the DNA of living organisms. What separates synthetic biology from genetic engineering is that rather than altering an already existent DNA strand, synthetic biology puts these "blocks" together from scratch to build an entirely new strand of DNA which is then placed into an empty living cell. These new cells can be "built" to perform a number of functions that could greatly benefit humanity. These operations do not exist in nature. Furthermore, projects involving the integration of standardized parts are the only ones that should be deemed true synthetic biology projects.[3] Synthetic biology introduces three new foundational technologies to genetic engineering: the ability to synthesize new genes in a de novo fashion; the ability to obscure complexity through abstraction; and the introduction of engineering standards. Biosafety and biosecurity concerns are the understandable response to this new science and technology that have the potential to profoundly change the nature of life forms as we know it. Numbers of civic society groups and online forums called for study of societal and ethical impact of this new technology, licensing and monitoring. The community of synthetic biology has discussed policy options and started initiatives of self-regulation. Symposia and meetings by the broader science community have brought the efforts at developing guidelines and regulations; addressing the issues of intellectual property and governance, and the ethical, societal and legal implications. Several bioethics research institutes published reports on ethical concerns and the public perception of synthetic biology. A 2010 report from the U.S. Presidential Commission for the Study of Bioethical Issues called for enhanced federal oversight in the United States on this emerging technology. |
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