Synthetic biology

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Synthetic biology is an interdisciplinary science, combining disciplines such as biotechnology, evolutionary biology, molecular biology, systems biology and biophysics.

The definition of synthetic biology is heavily debated not only among natural scientists but also in the human sciences, arts and politics.[1] One popular definition is "designing and constructing biological devices[2] and biological systems for useful purposes." However, the functional aspects of this definition stem from molecular biology and biotechnology.[3]

History[edit]

The term "synthetic biology" has a history spanning the twentieth century. The first use was in Stéphane Leducs’s publication of « Théorie physico-chimique de la vie et générations spontanées » (1910)[4] and « La Biologie Synthétique » (1912).[5][who said this?] In 1974, the Polish geneticist Wacław Szybalski used the term "synthetic biology",[6] 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.[7]

Perspectives[edit]

Engineering[edit]

Engineers view biology as a technology – the systems biotechnology or systems biological engineering.[8] 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.[9]

Studies in synthetic biology can be subdivided into broad classifications according to the approach they take to the problem at hand: standardization of biological parts, biomolecular engineering, genome engineering, and biomolecular design. 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 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 preceding level.[10]

Re-writing[edit]

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.[11] Re-writers draw inspiration from refactoring, a process sometimes used to improve computer software.

Key enabling technologies[edit]

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.[12] 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).

Standardized DNA parts[edit]

The most used[13]:22–23 standardized DNA parts are BioBrick plasmids invented by Tom Knight in 2003.[14] Biobricks are stored at the Registry of Standard Biological Parts in Cambridge, Massachusetts and the BioBrick standard has been used by thousands of students worldwide in the international Genetically Engineered Machine (iGEM) competition.[13]:22–23

DNA synthesis[edit]

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.[15] 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.)[16] This favors a synthesis-from-scratch approach.

DNA sequencing[edit]

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]

Modeling[edit]

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.[18]

Examples[edit]

Synthetic DNA[edit]

Driven by dramatic decreases in costs of making oligonucleotides ("oligos"), the sizes of DNA constructions from oligos have increased to the genomic level.[19] For example, 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 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]

Synthetic life[edit]

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.[25] For the creation of this semi-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 was finally transplanted into a living cell from another species Mycoplasma capricolum from which all genetic material had been removed.[26][27] The cell divided and was "entirely controlled by (the) new genome", ultimately demonstrating that DNA can be very practically described by its chemical properties.[27] This cell has been referred to by Venter as the "first synthetic cell", and was created at a cost of over $40 million.[27] There is some debate within the scientific community over whether this cell can be considered completely synthetic on the grounds that:[27] 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." [28] Venter plans to patent his experimental cells, stating that "they are pretty clearly human inventions".[27] 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."[29] 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.[30]

Information Storage[edit]

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.[31] A similar project had encoded the complete sonnets of William Shakespeare in DNA.[32]

Synthetic genetic pathways[edit]

Traditional metabolic engineering has been bolstered by the introduction of combinations of foreign genes and optimization by directed evolution. Perhaps the best known application of synthetic biology to date is engineering E. coli and yeast for commercial production of a precursor of the antimalarial drug, Artemisinin, by the laboratory of Jay Keasling.

Unnatural nucleotides and amino acids[edit]

Many technologies have been developed for incorporating unnatural nucleotides and amino acids into nucleic acids and proteins, both in vitro and in vivo. For example, 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.[33][34][35]

Reduced amino-acid libraries[edit]

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.[36] For instance, several non-polar amino acids within a protein may all be replaced with a single non-polar amino acid.[37] One project demonstrated that an engineered version of Chorismate mutase still had catalytic activity when only 9 amino acids were used.[38]

Designed proteins[edit]

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.[39] A similar protein structure was generated to support a variety of oxidoreductase activities.[40] Another group generated a family of G-protein coupled receptors which could be activated by the inert small molecule clozapine-N-oxide but insensitive to the native ligand (acetylcholine)[41]

Biosensors[edit]

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.[42]

Materials production[edit]

By integrating synthetic biology approaches with materials sciences, it would be possible to envision cells as microscopic molecular foundries to produce materials with properties that can be genetically encoded. Recent advances towards this include reengineering curli fibers, the amyloid component of extracellular material of biofilms, as a platform for a programmable nanomaterial. These nanofibers have been genetically programmed for specific functions, including adhesion to substrates, nanoparticle templating, and protein immobilization.[43]

Bioethics and security issues[edit]

In addition to numerous scientific and technical challenges, synthetic biology raises ethical issues and biosecurity issues. However, with the exception of regulating DNA synthesis companies,[44] the issues are not seen as new because they were raised during the earlier recombinant DNA and genetically-modified organism (GMO) debates and there were already extensive regulations of genetic engineering and pathogen research in place in the U.S.A., Europe and the rest of the world.[45]

The European Union funded project SYNBIOSAFE[46] has issued several reports on how to manage the risks of synthetic biology. A 2007 paper identified key issues in the areas of safety, security, ethics and the science-society interface (the latter of which they defined as public education and as ongoing dialogue among scientists, businesses, government, and ethicists).[47][48] Key security issues involved engaging companies that sell synthetic DNA and the Biohacking community of amateur biologists. Key ethical issues concerned the creation of new life forms. A subsequent report focused on 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.[49] The bio-hacking community remains a source of special concern, as the distributed and diffuse nature of open-source biotechnology makes it difficult to track, regulate, or mitigate potential biosafety and biosecurity concerns.[50]

COSY is another European initiative - its focus is on public perception and communication of synthetic biology.[51][52][53] 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.[54]

An initiative for self-regulation has been proposed by the International Association Synthetic Biology[55] that suggests some specific measures to be implemented by the synthetic biology industry, especially DNA synthesis companies. In 2007, a group led by scientists from leading DNA synthesis companies published a "practical plan for developing an effective oversight framework for the DNA-synthesis industry."[44]

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.[56]

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".[57]

After the publication of the first synthetic genome by Craig Venter's group and the accompanying media coverage about "life" being created, President Obama requested the Presidential Commission for the Study of Bioethical Issues to study synthetic biology.[58] The commission convened a series of meetings, then issued a report in December 2010 titled "New Directions: The Ethics of Synthetic Biology and Emerging Technologies." The report clarified that the Venter group had not created life, and noted that synthetic biology is an emerging field, which creates potential risks and rewards. The commission did not recommend any changes to policy or oversight and called for continued funding of the research and new funding for monitoring, study of emerging ethical issues, and public education.[45]

Opposition to synthetic biology[edit]

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 manifesto 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.[59][60] Richard Lewontin wrote that some of the safety tenets for oversight discussed in The Principles for the Oversight of Synthetic Biology are reasonable, but that the main problem with the recommendations in the manifesto is that "the public at large lacks the ability to enforce any meaningful realization of those recommendations."[61]

See also[edit]

References[edit]

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External links[edit]