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Synthetic biology

Synthetic biology is a new area of biological research that combines science and engineering. Synthetic biology emcompasses a variety of different approaches, methodologies and disciplines, and many different definitions exist. What they all have in common, however, is that they see synthetic biology as the design and construction of new biological functions and systems not found in nature.

A light programmable biofilm made by the UT Austin / UCSF team during the 2004 Synthetic Biology competition, displaying "Hello World"

Contents

History of the term

The term "synthetic biology" has a history spanning the twentieth century.[1]. In 1974, the Polish geneticist Waclaw Szybalski introduced the term "synthetic biology"[2], 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 biology 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 the unlimited expansion potential and hardly any limitations to building "new better control circuits" and ..... finally other "synthetic" organisms, like a "new better mouse". ... I am not concerned that we will run out 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, Waclaw 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.[3]

Synthetic biology has also been used to describe an approach to biology that attempts to integrate different areas of research in order to create a holistic understanding. There is significant controversy over whether synthetic biology as currently practiced is in accordance with this holistic approach, which was associated with the anti-reductionist movements within biology during the late twentieth century.[citation needed]

Biology

Biologists are interested in learning more about how natural living systems work. One simple, direct way to test our 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 [3] 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). Good examples include the work of Adam Arkin, Jim Collins and Alexander van Oudenaarden. See also the PBS Nova special on artificial life.

Chemistry

Biological systems are physical systems that are made up of chemicals. Around 100 years ago, 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. Eric Kool's group at Stanford, the Foundation for Applied Molecular Evolution, Carlos Bustamante's group at Berkeley, and Jack Szostak's group at Harvard, David McMillen's group at University of Toronto are good examples of this tradition. Much of the improved economics and versatility of synthetic biology is driven by ongoing improvements in gene synthesis.

Engineering

Engineers view biology as a technology. 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 and our environment [4] . 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, a riboregulator, the Registry of Standard Biological Parts, and the International Genetically Engineered Machine competition (iGEM).

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. Re-writers draw inspiration from refactoring, a process sometimes used to improve computer software. Drew Endy and his group have done some preliminary work on re-writing (e.g., Refactoring Bacteriophage T7). 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 Church's and Anthony Forster's lab synthetic cell projects.[5] As in the T7 example above, this favors a synthesis-from-scratch approach.

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 2007 ETC Group released the first critical report on the societal impacts of synthetic biology which they dubbed "Extreme Genetic Engineering".[6]. Other groups opposing Synthetic Biology developments include Friends of the Earth, Alliance for Humane Biotechnology, International Center for Technology Assessment and Centro Ecologico (Portuguese).

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[7][8]. 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), it may also lead to synthesis or redesign of harmful pathogens (e.g., smallpox) by malicious actors[9] . 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[10].

An initiative for self-regulation has been proposed by the International Association Synthetic Biology[11] that suggests some specific meassures 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 meassure, 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[12].

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[13], and critics worry about uncritical complicity[14].

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[15], 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[16].

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[17]. 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 [18][19]. To better communicate synthetic biology and its societal ramifications to a broader public, COSY and SYNBIOSAFE published a 38 min. documentary film in October 2009[4].

Key enabling technologies

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. [20]. 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).

Sequencing

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.

Fabrication

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 2002 researchers at SUNY Stony Brook succeeded in synthesizing the 7741 base poliovirus genome from its published sequence, producing the first synthetic organism. 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, has constructed and patented a synthetic genome of a novel minimal bacterium, Mycoplasma laboratorium and is working on getting it functioning in a living cell.[23][24]

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.[25] As of the present date, September 2009, the price has 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. [26]

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. Microscopy and flow cytometry are examples of useful measurement technologies.

See also

  • Angela Belcher
  • Ron Weiss
  • BioBrick
  • Bioengineering
  • Biohacking
  • Computational biology
  • Computational biomodeling
  • IGEM
  • List of emerging technologies
  • Registry of Standard Biological Parts
  • Synthetic genomics
  • Synthetic morphology
  • Systems biology
  • Nucleic acid analogues
  • Expanded genetic code

References

  1. ^ Luis Campos, "That Was the Synthetic Biology That Was" in M. Schmidt, A. Kelle, A. Ganguli-Mitra and H. Vriend, eds., Synthetic Biology: The Technoscience and Its Societal Consequences. Springer Academic Publishing, 2010
  2. ^ Waclaw Szybalski, In Vivo and in Vitro Initiation of Transcription, Page 405. In: A. Kohn and A. Shatkay (Eds.), Control of Gene Expression, pp. 23-24, and Discussion pp. 404-405 (Szybalski's concept of Synthetic Biology), 411-412, 415 - 417. New York: Plenum Press, 1974
  3. ^ Szybalski, W; Skalka, A (November-1978). "Nobel prizes and restriction enzymes". Gene 4 (3): 181–2. doi:10.1016/0378-1119(78)90016-1. PMID 744485. http://www.sciencedirect.com/science?_ob=IssueURL&_tockey=%23TOC%234941%231978%23999959996%23383739%23FLP%23&_auth=y&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cf7bbc6f0e4d37c1de98c80fc9b50a3e. 
  4. ^ Chopra, Paras; Akhil Kamma. "Engineering life through Synthetic Biology". In Silico Biology 6. http://www.bioinfo.de/isb/2006/06/0038/. Retrieved 2008-06-09. 
  5. ^ Forster, AC; Church GM. (2006-08-22). "Towards synthesis of a minimal cell". Mol Syst Biol. 2: 45. doi:10.1038/msb4100090. PMID 16924266. 
  6. ^ ETC Group Extreme Genetic Engineering: ETC Group Releases Report on Synthetic Biology
  7. ^ Schmidt M, Ganguli-Mitra A, Torgersen H, Kelle A, Deplazes A, Biller-Andorno N. 2009. "A priority paper for the societal and ethical aspects of synthetic biology. Systems and Synthetic Biology". Vol.3(1-4):3-7.
  8. ^ Schmidt M. Kelle A. Ganguli A, de Vriend H. (Eds.) 2009. "Synthetic Biology. The Technoscience and its Societal Consequences". Springer Academic Publishing.
  9. ^ Kelle A. 2009. "Ensuring the security of synthetic biology—towards a 5P governance strategy". Systems and Synthetic Biology. Vol.3(1-4): 85-90.
  10. ^ Schmidt M, 2008. "Diffusion of synthetic biology: a challenge to biosafety". Systems and Synthetic Biology. Vol.2(1-2):1-6.
  11. ^ Report of IASB "Technical solutions for biosecurity in synthetic biology", Munich, 2008.
  12. ^ Marliere P. 2009. "The farther, the safer: a manifesto for securely navigating synthetic species away from the old living worldy". Systems and Synthetic Biology. Vol.3(1-4):77-84.
  13. ^ Schmidt M. 2008. Diffusion of synthetic biology: a challenge to biosafety. Systems and Synthetic Biology (online first) DOI 10.1007/s11693-008-9018-z
  14. ^ ETC Group Extreme Genetic Engineering: ETC Group Releases Report on Synthetic Biology
  15. ^ Organisation for International Dialogue and Conflict Management (IDC) Biosafety Working Group
  16. ^ WWCIS 2009 Ethical Issues in Synthetic Biology. An Overview of the Debates
  17. ^ [1] Parens E., Johnston J., Moses J. Ethical Issues in Synthetic Biology. 2009.
  18. ^ Kronberger et al. 2009 Communicating Synthetic Biology: from the lab via the media to the broader public Systems and Synthetic Biology. Vol.3(1-4): 19-26
  19. ^ Cserer A, Seiringer A. 2009 Pictures of Synthetic Biology Systems and Synthetic Biology. Vol.3(1-4): 27-35
  20. ^ Group, Bio FAB; Baker D, Church G, Collins J, Endy D, Jacobson J, Keasling J, Modrich P, Smolke C, Weiss R (June-2006). "Engineering life: building a fab for biology". Scientific American 294 (6): 44–51. doi:10.1038/scientificamerican0606-44. PMID 16711359. 
  21. ^ Couzin J (2002). "Virology. Active poliovirus baked from scratch". Science 297 (5579): 174–5. doi:10.1126/science.297.5579.174b. PMID 12114601. 
  22. ^ Smith, Hamilton O.; Clyde A. Hutchison, Cynthia Pfannkoch, J. Craig Venter (2003-12-23). "Generating a synthetic genome by whole genome assembly: {phi}X174 bacteriophage from synthetic oligonucleotides". Proceedings of the National Academy of Sciences 100 (26): 15440–15445. doi:10.1073/pnas.2237126100. http://www.pnas.org/cgi/content/abstract/100/26/15440. Retrieved 2007-10-08. 
  23. ^ Wade, Nicholas (2007-06-29). "Scientists Transplant Genome of Bacteria". The New York Times. ISSN 0362-4331. http://www.nytimes.com/2007/06/29/science/29cells.html. Retrieved 2007-12-28. 
  24. ^ Gibson, DG; Benders GA, Andrews-Pfannkoch C, Denisova EA, Baden-Tillson H, Zaveri J, Stockwell TB, Brownley A, Thomas DW, Algire MA, Merryman C, Young L, Noskov VN, Glass JI, Venter JC, Hutchison CA 3rd, Smith HO. (2008-01-24). "Complete chemical synthesis, assembly, and cloning of a Mycoplasma genitalium genome". Science 319 (5867): 1215–20. doi:10.1126/science.1151721. PMID 18218864. 
  25. ^ Pollack, Andrew (2007-09-12). "How Do You Like Your Genes? Biofabs Take Orders". The New York Times. ISSN 0362-4331. http://www.nytimes.com/2007/09/12/technology/techspecial/12gene.html?pagewanted=2&_r=1. Retrieved 2007-12-28. 
  26. ^ Y. N. Kaznessis, (2007) "Models for Synthetic Biology", BMC Systems Biology, 2007, 1:47 doi:10.1186/1752-0509-1-47 [2].

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