2

Synthetic Biology:
Science and Technology
for the New Millennium

The definition of synthetic biology remains fluid because its full potential is not yet clear and because researchers are exploring many problem solving approaches. In general, however, the discipline is seen as involving the application of engineering principles to “design and construct…new biological parts, devices and systems” and re-design “existing natural biological systems for useful purposes.”1 Work is often motivated by the underlying goal of making biology easy to engineer. Synthetic biology research is conducted and facilitated by individuals trained in a variety of disciplines including biology, engineering, chemistry, genetics, and computational sciences. Synthetic biology also includes work to manufacture biological elements (for example, molecules, genetic sequences, systems, and simple organisms) different from those existing in nature for the purpose of achieving predictable and reliable performance of specific functions. Over time, proponents hope to develop a large portfolio of simplified biological modules—parts, devices, and systems2—that can be used to perform predictable, pre-determined functions with various applications.

Biological parts in scientists’ current inventory are capable of performing basic functions at the cellular level. Examples include engineered biological circuits3 and oscillators.4 However, researchers hope to achieve goals ranging from

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1 Definition from http://syntheticbiology.org, a community of individuals, groups, and labs committed to “engineering biology in an open and ethical manner.” The site provides community news, discussions, and various resources (see http://syntheticbiology.org, accessed March 27, 2013).

2“Part” modules contain the instructions for basic biological functions. “Devices” contain multiple parts arranged to carry out more complicated designer-determined functions. “Systems” carry out advanced tasks.

3 Engineered biological circuits are cellular subsystems wherein cellular DNA has been altered in order to produce specific new functions—such as signaling the presence of a given chemical or producing a certain protein. A major goal of synthetic biology is to



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2 Synthetic Biology: Science and Technology for the New Millennium The definition of synthetic biology remains fluid because its full potential is not yet clear and because researchers are exploring many problem solving approaches. In general, however, the discipline is seen as involving the applica- tion of engineering principles to “design and construct…new biological parts, devices and systems” and re-design “existing natural biological systems for use- ful purposes.”1 Work is often motivated by the underlying goal of making biolo- gy easy to engineer. Synthetic biology research is conducted and facilitated by individuals trained in a variety of disciplines including biology, engineering, chemistry, genetics, and computational sciences. Synthetic biology also includes work to manufacture biological elements (for example, molecules, genetic se- quences, systems, and simple organisms) different from those existing in nature for the purpose of achieving predictable and reliable performance of specific functions. Over time, proponents hope to develop a large portfolio of simplified biological modules—parts, devices, and systems2—that can be used to perform predictable, pre-determined functions with various applications. Biological parts in scientists’ current inventory are capable of performing basic functions at the cellular level. Examples include engineered biological cir- cuits3 and oscillators.4 However, researchers hope to achieve goals ranging from 1 Definition from syntheticbiology.org, a community of individuals, groups, and labs committed to “engineering biology in an open and ethical manner.” The site provides community news, discussions, and various resources (see http://syntheticbiology.org, accessed March 27, 2013). 2 “Part” modules contain the instructions for basic biological functions. “Devices” contain multiple parts arranged to carry out more complicated designer-determined functions. “Systems” carry out advanced tasks. 3 Engineered biological circuits are cellular subsystems wherein cellular DNA has been altered in order to produce specific new functions—such as signaling the presence of a given chemical or producing a certain protein. A major goal of synthetic biology is to 7

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8 Positioning Synthetic Biology to Meet the Challenges of the 21st Century tissue engineering and bio-computer interfaces to the creation of organisms that are capable of efficient, large-scale biofuel production. At the symposium in Shanghai, Drew Endy, Assistant Professor of Bioen- gineering, Stanford University, noted that while the current definition will likely always be incomplete, the ultimate definitions of synthetic biology will take into account the dynamism and potential of synthetic biology which, if it achieves its potential, may change many aspects of how we live our lives. At a fundamental level, synthetic biology seeks to take the creative force of nature and harness it technologically in order to solve problems of varying scale. In London, Huanming Yang, Director, Beijing Genomics Institute, opti- mistically described synthetic biology as “a science changing the world and the future of man,” and proposed a motto for the field: “Life is what we make it.” Building on a Heritage of Biological Discovery Though the practice of synthetic biology is new, the concept was coined a century ago in two publications by the biologist Stéphane Leduc.5 Modern synthetic biology has its roots in the 1953 discovery of the double helix structure of deoxyribonucleic acid (DNA) by scientists James Watson and Francis Crick (See Box 2-1). The discovery of DNA was the key to understanding development and specialization in cells and organisms and ushered in a new era of genetic manip- ulation. Copying, editing, sequencing,6 engineering, and synthesizing DNA and RNA (ribonucleic acid) all emerged from that discovery. In Shanghai, Farren Isaacs, Assistant Professor of Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, reflected on the developments that followed the early research on DNA. “Not so long ago,” he observed, “we had questions on how to decode DNA. That [is what] led to un- derstanding of gene functions and interactions at the molecular level. Now we get to change DNA at new scales, to both learn and make new systems.” By the 1970s, scientists had successfully created recombinant DNA (rDNA)—genetic material formed by combining DNA from more than one or- ganism. This facilitated the development of genetic engineering and manipula- tion. In the early 1980s, technical innovation led to the ability to rapidly sequence DNA. develop a large portfolio of engineered biological circuits for use in various applications or systems. 4 Oscillators are genetically controlled, rhythmically repeated cycles of response and chemical production that govern the development, growth, and death of cells and organisms. 5 Théorie physic-chimique de la vie et generations spontanées (1910) and La biologie synthétique, etude de biophysique, ed. A. Poinat (1912). 6 Determining the nucleotide sequence of a particular fragment of DNA.

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Synthetic Biology: Science and Technology for the New Millennium 9 BOX 2-1 DNA and Biological Parts Deoxyribonucleic acid (DNA) is a molecule that contains the hereditary material of a living organism. It is found in every cell of known living organisms. The DNA molecule has a double-stranded, ladder-like structure. Genetic information is encod- ed as a sequence of nucleotides (adenine, cytosine, guanine, and thymine) that are arranged in pairs which form the “rungs” of the ladder. DNA is replicated during cell division. A strand of DNA may contain thousands of genes, a unit of heredity which in- fluences a particular characteristic in an organism. Genes contain anywhere from 1,000 to 1 million nucleotide base pairs. Genes are stored on chromosomes—a single, very long DNA double helix. The complete set of genes in a given organism is called the genome. Genes contain chemical “instructions” for manufacturing proteins and other chemicals. Proteins are large molecules composed of amino acids. They are an essential component of a living organism. Body structures, functions, and the regula- tion of the body's cells, tissues and organs cannot exist without proteins. The manu- facture of proteins entails transcribing genetic information into ribonucleic acid (RNA). RNA molecules then direct the assembly of proteins on ribosomes. Synthetic biology seeks to design new types of cellular machinery that perform a desired function or produce a desired substance. Synthetic biologists achieve this by creating simple cellular parts which, when assembled, simplify gene expression and the cellular synthesis of proteins and other chemicals. Synthetic biologists also seek to elicit predictable cellular functions in, for example, regulatory and metabolic systems. In 1974, geneticist Waclaw Szybalski heralded the next stage of biological innovation: “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 unlimited expansion potential.” “I am not concerned that we will run out of exciting and novel ideas.”7 Synthetic Biology and Converging Scientific Disciplines While synthetic biology arises from a century’s worth of work in biology and related fields, its practice would not be possible without breakthroughs in such diverse fields as engineering, computer science, and information technology. Stated differently, interconnectedness has been central to the development of synthetic biology. Advances in microscopy and electronics multiplied the capacity for data-gathering and analysis in biology. Simultaneously, progress in computer 7 Waclaw Szybalski, 1974. “In Vivo and in Vitro Initiation of Transcription,” in A. Kohn and A. Shatkay (Eds.), Control of Gene Expression, pp. 23-24, and Discussion pp. 404-405. New York: Plenum Press.

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10 Positioning Synthetic Biology to Meet the Challenges of the 21st Century and internet technology revolutionized the ability to process and transfer data and provided ideas and methods for how to manage complexity when engineering multi-component integrated systems. Calculations that only a decade ago would have taken weeks on a mainframe computer now take minutes: a gene sequence may be processed on a laptop. Increasingly sophisticated software allows for con- tinuing improvements in three-dimensional imaging and modeling. Advanced technology has enabled real-time imaging of processes ranging from bacterial reproduction to the behavior of nanoparticles. The development of optical fibers has increased the capacity of data transfer—and global networking—by orders of magnitude.8 By the turn of the 21st century, progress in synthetic biology had acceler- ated as researchers began to exploit the concept of “forward engineering,” which amalgamates custom-made or commercially available biological parts in order to test functionality.9,10 Commercial gene synthesis became a global enterprise.11 Next generation gene sequencing machines now provide faster and less expensive methods for indexing genetic code. Currently, synthetic biologists have the ability to design genetic code to elic- it a specific function, pre-test the code for functionality using computer modeling, order the relevant genetic material from a commercial or open-source gene synthe- sis facility, and insert the material into a cell body in order to test real world func- tionality. Some DNA designs are now working the first time they are tested, re- placing what has historically been a tedious trial-and-error based approach to engineering novel phenotypes. What Makes Synthetic Biology Special? Synthetic biology builds on discoveries in, and is the result of collabora- tions across, many fields (See Box 2-2). The field has several important charac- teristics. It:  Represents a novel approach to studying biology  Applies engineering methods to living systems 8 National Research Council, 2009. A New Biology for the 21st Century. Washington, DC: The National Academies Press. 9 Akst, Jef, 2011a. “Tinkering with Life: A Decade’s Worth of Engineering-infused Bi- ology,” The Scientist, October 11. Online at http://www.thescientist.com/?articles.view/arti cleNo/31193/title/Tinkering%20With%20Life (accessed March 27, 2013). 10 Pennisi, Elizabeth. 2013. “Synthetic Genome Brings New Life to Bacterium,” Science 328, p. 958. Online at http://www.sciencemag.org/content/328/5981/958.full.pdf (accessed March 27, 2013). 11 As of 2009 there were approximately 50 gene synthesis companies around the world. See Maurer, Stephen, et al., 2009. “Making Commercial Biology Safer: What the Gene Synthesis Industry Has Learned About Screening Customers and Orders,” Working Paper. Online at http://gspp.berkeley.edu/assets/uploads/page/Maurer_IASB _Screening.pdf (accessed May 15, 2013).

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Synthetic Biology: Science and Technology for the New Millennium 11 BOX 2-2 Synthetic Biology Tools and Technology Timeline Synthetic biology is a tool and technology-based science. Institutional, indus- trial, scientific, and technical developments have all contributed to the discipline’s evolution as a global, networked discipline. 1941: First functional program-controlled computer (Konrad Zuse) 1953: Crick and Watson describe the double helix structure of DNA 1960: First computer-aided drafting (CAD) program (Sketchpad) 1961: Discovery of mathematical principles in gene regulation 1971: First genetically modified organism (Escherichia coli) 1972: First synthetic gene (yeast) 1973: Cohen, Boyer, and Berg create first genetically engineered organism (Escherichia coli) 1974: First U.S. patent on rDNA (Stanley Cohen and Herbert Boyer) 1975: Asilomar Conference on Recombinant DNA Early genome sequencing techniques established 1976: First biotechnology firm founded (Genentech) NIH guidelines for Recombinant DNA 1978: Term “bioinformatics” coined Synthetic insulin gene inserted into E. coli 1980: In Diamond v. Chakrabarty, the U.S. Supreme Court rules that “a live, human-made micro-organism is patentable subject matter.” 1982: U.S. Food and Drug Administration (FDA) approves use of synthetic insulin 1983: Development of the polymerase chain reaction (PRC) DNA amplification technology 1984: First commercialized genetically modified food (Flavr Savr tomato) 1990: Human Genome Project (HGP) launched 1991: First public availability of the World Wide Web 1996: First cloned mammal (Dolly the sheep) 2000: International Human Genome Sequencing Consortium announces “working draft” of human genome 2000: Genetic oscillators and toggle switches published 2002: Rice genome decoded 2002: Chemical synthesis of polio virus genome 2003: First BioBrick DNA assembly standard published 2003: Human Genome Project completed 2003: Defense Advanced Research Projects Agency (DARPA) synthetic biology studya 2004: Synthetic Biology 1.0 (first international meeting on synthetic biology) 2005: First International Genetically Engineered Machines (iGEM) competition 2008: Virus attenuation achieved via synthetic genome-scale changes in codon usage 2010: First fully synthesized self-replicating genome (Mycoplasma mycoides) 2013: Successful engineering of digital amplifying genetic logic gates and memory systems. a See Endy, Drew, 2007. “2003 Synthetic Biology Study.” Online at http://dspace.mit.edu/ handle/1721.1/38455, accessed June 18, 2013.

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12 Positioning Synthetic Biology to Meet the Challenges of the 21st Century  Relies on non-hierarchical research and commercialization networks  Views addressing social concerns as integral to the field’s progress A Novel Approach to Studying Biology. Synthetic biology, with its focus on engineering customized living units and systems, represents a novel approach to the study of life. Synthetic biology reverses traditional approaches to understanding the mechanisms of life. In his keynote address at the Washington, DC symposium, Michael Elowitz, Professor of Biology, Bioengineering, and Applied Physics; Bren Scholar; and Investigator, Howard Hughes Medical Institute, California Institute of Technology, described the new thinking this way: “Under routine biological approaches, one perturbs an existing system [and asks:] How does the system respond to perturbation? What components are necessary for it to work? When conducting research in synthetic biology, one can ask different questions, such as: ‘What genetic circuits are sufficient to generate a particular behavior?’ and, ‘How can existing systems be re-wired to provide new functionality?’” An expressed impulse in synthetic biology is to abstract or simplify— seeking, within the complexities of cells and bacteria, the minimum number of components required to achieve a desired function. This conceptual model may be a defining characteristic of the field,12 but an ultimate goal of synthetic biolo- gy also includes the building of customized cells, organisms, and living systems. Engineering Living Systems. Synthetic biology often uses engineering prin- ciples to design simplified biological components that perform specified functions. These approaches include:  Abstraction (or abstraction hierarchy): a system for managing biological complexity by eliminating unnecessary details; abstraction allows re- searchers at various levels (and in various fields) to work with and share details about biological data without specialized knowledge  Modularization: developing interconnecting parts that can be combined in various ways  Standardization: devising a broad consensus on the composition of parts, devices, and systems so that they may be used reliably in any setting  Decoupling: de-linking the requirements for design from requirements for manufacture to allow non-biologists to use biological components in vari- ous applications  Modeling: testing the projected design and its function The principles of abstraction, modularization, standardization, decoupling, and modeling are not new per se: they transformed the textile industry in the 18th 12 Sheila Jasanoff, Pforzheimer Professor of Science and Technology Studies, John F. Kennedy School of Government, Harvard University.

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Synthetic Biology: Science and Technology for the New Millennium 13 century with the development of the Jacquard loom,13 shaped the Industrial Revolution,14 and led to the transformation of the integrated circuit industry in the 20th century. The application of engineering principles to biology offers, however, a dif- ferent perspective on how to work with and use biological resources. “When we turn to biology, it tends to be [to address] a very pressing problem,” Endy said. “I think that over-selects for applications and under-selects for improvements in the engineering process.” By building simplified biological circuits, systems, or protocells (known as the “bottom-up” approach) while developing organisms with enhanced or novel functions (the “top-down approach”),15 researchers are seeking to improve our capacity to both understand and engineer living systems. “Incremental improvements in our capacity to navigate the ‘design, build, test’ cycle at the core of engineering biology, over time, can lead to geometric im- provements in our capacity to engineer living systems. We have to invest in the engineering fundamentals too, not just the immediate applications,” added Endy. One hope of synthetic biologists, said Rob Carlson, Principal, Biodesic, is that by providing renewable materials through engineered cells, synthetic biolo- gy “may radically change the way we produce many materials in the future.” Non-hierarchical Networks. In Washington, DC, Robert Wells, former Head, Biotechnology Unit, Directorate for Science, Technology, Organisation for Economic Co-operation and Development (OECD), differentiated synthetic biolo- gy from other fields, citing its tendency to develop in a horizontal, global way that takes advantage of social networking and draws an international cadre of young scientists. As Sheila Jasanoff, Pforzheimer Professor of Science and Technology Studies at Harvard’s John F. Kennedy School of Government, observed in Shang- hai, because of its inherent heterogeneity, synthetic biology gains coherence not from a single set goal, but rather from a conceptual focus on simplification. Synthetic biology has also created a unique opportunity for input from outside traditional academic venues—from amateur scientists at community labs to undergraduate institutions to high schools. At the Washington, DC symposi- um, Meagan Lizarazo, Vice President of Operations at iGEM, and fellow panel- ists discussed a prominent example where such collaboration is the norm: the International Genetically Engineered Machine competition (iGEM). iGEM is a competition in which undergraduates develop biological “machines” to address real-world problems (See Box 2-3). The iGEM competition represents a new type of educational pipeline for students interested in hands-on science and en- 13 Lee. 14 Richard Kitney, Professor of Biomedical Systems Engineering, Department of Bioengineering, Senior Dean and Director of the Graduate School of Engineering and Physical Science, Imperial College London. 15 Bedau, Mark A., Emily C. Parke, Uwe Tangen, and Brigitte Hantsche-Tangen, 2009. “Social and Ethical checkpoints for bottom-up synthetic biology, or protocells,” Syst Synth Biol 3(1-4): 65-75, December. Online at http://www.ncbi.nlm.nih.gov/pmc/arti cles/PMC2759431 (accessed May 16, 2013).

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14 Positioning Synthetic Biology to Meet the Challenges of the 21st Century gineering, Lizarazo said. Launched in 2005 by the Massachusetts Institute of Technology, iGEM became, in early 2012, an independent nonprofit endeavor. In 2012, Lizarazo reported, the iGEM competition attracted participants from 190 colleges, 40 high schools, and 210 labs in five regions—Asia, Europe and Africa, Latin America, Americas East, and Americas West. The organizational structure of the iGEM competition—the competition and collaboration, the interactions among team members of widely differing disciplines with various levels of experience—gives students non-threatening entry into the complexities of science and engineering, said Karmella Haynes, Assistant Professor, School of Biological and Health Systems Engineering, Ari- zona State University. Participants in the iGEM competition applaud the mind- expanding potential of the iGEM experience for developing scientists and engi- neers. “We learned the importance of collaboration and integrating human prac- tices into our research—those can be useful in our future careers,” said Nikki Kapp, a graduate student at Penn State University who represented Imperial College London at iGEM as an undergraduate. “As undergraduates, we don’t know clearly what isn’t possible. That’s conducive to innovation.” Inclusion of Social Concerns. Early on, synthetic biology researchers rec- ognized the need to engage with government and the public about social con- cerns arising in conjunction with the practice of synthetic biology. This engage- ment is, in part, a reflection of a desire to ensure that the public understands this new technology. Researchers believe that a failure to engage with the public—as exemplified by opposition to genetically modified food in Europe—may ad- versely affect ongoing and future innovation. In Shanghai, Professor Jasanoff located U.S. scientific advancements of the 20th century in the context of scale. In the United States, she observed, major technical achievements such as the moon landing or the launch of the Hubble Space Telescope were the result of large-scale national investments designed to achieve specific goals and end points. By contrast, most synthetic biologists work independently to achieve transformation at a microscopic level. The decentralized nature of synthetic biology, in union with the revolu- tionary nature of the field, may demand the development of a new approach to the broad societal issues and aspects raised by advances in the field, she ob- served. These include the ethical, legal, and social implications (ELSI) of the technology (referred to as ELSA, or ethical, legal, and social aspects, in Europe) as well as biosecurity, biosafety, regulatory, and intellectual property concerns.16 16 The synthetic biology community is beginning to address these concerns. For example, in 2009, in collaboration with a panel of stakeholders, the International Association Synthet- ic Biology developed a Code of Conduct for Best Practices in Gene Synthesis, focused on DNA sequence screening, customer screening, and safety in gene synthesis (see http:// www.ia-sb.eu/go/synthetic-biology/synthetic-biology/code-of-conduct-for-best-practices-in- gene-synthesis, accessed May 15, 2013). That same year, the International Gene Synthesis Consortium developed a “Harmonized Screening Protocol” for gene sequencing and cus- tomer screening to protect biosecurity (see http://www.ia-sb.eu/tasks/sites/synthetic- biology/assets/File/pdf/iasb_code_of_conduct_final.pdf, accessed May 15, 2013).

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Synthetic Biology: Science and Technology for the New Millennium 15 Jasanoff noted that a multi-country comparison of ELSI concerns revealed wide variations and suggest an urgent need to include the public in discussions of ELSI issues. She suggested that, given the public’s increasing interest in science and technology and its willingness (and, through the Internet, its ability) to en- gage in or collaborate in research and interface with technology, synthetic biolo- gy might, in fact, be considered a “post-ELSI science.” Realizing the potential of synthetic biology depends on overcoming signif- icant challenges. These include not only technological challenges but also miti- gating potential biosafety and biosecurity dangers, attending to social, legal, and political imperatives, and addressing intellectual property issues. These chal- lenges are discussed in detail in Chapter 4. BOX 2-3 The International Genetically Engineered Machine (iGEM) Competition iGEM has captivated a generation of young scientists and engineers from around the world. Many of those involved believe that synthetic biology offers a unique opportunity to address world needs related to food, disease, energy, and material. Each year, iGEM participants undertake a summer-long project wherein a mul- tidisciplinary team designs biological solutions to real-world problems. By using parts from the Registry of Standard Biological Parts (or by creating new parts), teams engineer living systems designed to carry out specific functions. Participants assem- ble their own teams, raise funds for their projects, and solicit advice from experts across disciplines. In 2012, projects included:  Generating a bacterial “detect and alert” system to help defend crop planta- tions against pathogens (Universidad de los Andes, Bogotá, Colombia—Latin America Grand Prize Winner)  Engineering a bacillus bacterium to produce blue or yellow pigments in meat that has spoiled (University of Groningen, Holland—Europe Grand Prize and World Championship Winner)  Developing a low-cost biosensor to indicate the presence of pathogenic bac- teria in water (Arizona State University—Best Human Practices Advance, Americas West)  Building a protein-based light sensor (Chinese University of Hong Kong— Championship Competition) Teams post the stories of their research on individual “wikis” on the iGEM website.

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