Edinburgh Research Explorer Synthetic biology

Synthetic biology can be defined as the design and construction of novel biologically based parts, devices and systems, as well as the redesign of existing natural biological systems, for useful purposes. It builds on genetic engineering, being design-driven genetic engineering encompassing engineering concepts of standardization and abstraction (Endy, 2005). One of the technical advances that has significantly increased the ability to undertake synthetic biology has been to artificially synthesize DNA, and thus create DNA parts. So far, the peak achievement has been the synthesis and assembly of a small bacterial genome which was transferred to a bacterial cell devoid of DNA to create a novel replicating micro-organism (Gibson et al., 2010). A great diversity of synthetic biology applications exists, many in the early research phase, which include using microbes as biofactories or as biological computers (Bonnet et al., 2012; Oldham et al., 2012). In this issue of Microbiology we have assembled a collection of papers to showcase the current state of synthetic biology research, and to convey the potential impact of synthetic biology on biological sciences. 
 
The synthetic biology field itself is diverse but can broadly be divided into two main themes: bottom-up approaches creating truly artificial life de novo, and top-down approaches to design systems based on known biology to perform a specific task. The latter can involve designing metabolic and signalling pathways inside cells to achieve a specific purpose. Within this top-down design, biological elements (promoters, gene products, etc.) can be thought of as parts being assembled into a system. The top-down approach has the advantage of using the host cell (termed the chassis) and being able to make use of the co-factors, metabolites, transcription pathways and other components that it already possesses, but does have the potential disadvantage of potential crosstalk between the endogenous systems present in the chassis and the introduced synthetic systems (Saito, 2010; Verhamme et al., 2002). The papers within this issue focus on the top-down approach. 
 
As the aim of synthetic biology is to design a system to achieve a required outcome, researchers rely heavily on in silico modelling and whole-system analysis (’omic analysis) to provide data about the effect of perturbations, allowing parts encoded in DNA to be characterized and optimized. The data provide the basis to bring component parts together in different combinations to produce predictable devices with the outcomes predicted through modelling. An example of developing these standard parts is given in the Bartosiak-Jentys et al. (2013) paper, which describes the creation of a modular system for the design of Geobacillus and defins the parts that are created. The authors also describe how this may be applied in the design of improved bioethanol-producing strains. The parts themselves can be specifically modified to alter the desired outcome. The review in this issue by Arpino et al. (2013) describes these design parameters and how they can be modified in both prokaryote and eukaryote microbial systems. For example, different ribosome-binding sites can alter protein copy number, resulting in different outcomes from the synthetic system. Once defined, there is the ability to add these parts together to produce a system with a predictable defined output. A nice example of how using a small range of defined parts can be used to generate complex outcomes is presented by Chang et al. (2013). Here the authors use a simple bacterial two-component system to produce a range of outputs through careful variation of a phosphatase. This paper also highlights the utility of model-based design. Such technology has huge potential applications in industry. Being able to synthesize products in a biologically controlled way opens up new methods of manufacture, as highlighted in the Donald et al. (2013) paper. In this work the authors describe how expression can be optimized using synthetic biological approaches to modify the chassis, in this case to produce a vaccine. 
 
Synthetic biology has been identified as a technology that has huge potential to transform the way we work, and this step change in our use of biology has been recognized not just in the scientific community but in the wider social sphere as well. As a result, a number of governments have been shaping policy and developing science funding to specifically support synthetic biology (Pei et al., 2012; Zhang, 2011). In particular, how does current international legislation apply to synthetic biology (Bubela et al., 2012)? In the UK, for example, a cross-government group (The Synthetic Biology Roadmap Coordination Group, 2012) developed the Synthetic Biology Roadmap to bring together all the different interested parties and communities and to identify what government support is needed to develop this science within the UK, both for pure understanding and to drive translational research. The Roadmap also considered approaches to the ethical and legal issues. These latter areas have been raised as a matter of concern in a number of countries, and highlighted recently in the US (Roehr, 2010), reflecting the ethical, safety and regulatory considerations that apply to any new technology but, given the potential for self-replication, have particular significance in synthetic biology. With the emphasis on making manipulation of biology easier, synthetic biology also raises significant implications of dual use of synthetic biology for nefarious purposes, which also need consideration in ethical, legal and regulatory contexts (Samuel et al., 2009). Such considerations have also been the basis of activity within national learned academies, culminating in the six academies symposia between the science and engineering academies of the UK, China and the US. These meetings resulted in opinion pieces regarding ways of progressing synthetic biology research for the benefit of humanity while avoiding the potential pitfalls (OECD & The Royal Society, 2011). These issues will become especially important if we consider the possible environmental release of biological devices. Developing methods to contain and control the biological devices that we produce is thus a significant area of research. A review article in this issue by Wright et al. (2013) looks at current research in this area, and how scientific solutions can give us control over the spread of the synthetic systems we design. 
 
As indicated above, synthetic biology is a priority area for funding in a number of countries. This is now evolving into an internationally structured area, with larger international research networks being established, such as the EraSynBio network between funding bodies in both Europe and the US. Just as the technology requires a multi-disciplinary effort, so the science requires an international approach and frameworks. If, for example, there are to be standardized biological parts, such as using the Biobricks standard (Canton et al., 2008), researchers will have to work together, and within their domestic regulations, to achieve that. 
 
The articles published in this issue highlight the promise and hurdles that synthetic biology must overcome to produce the future designer microbes that could transform our world. Quite what that future will be is left for the reader to imagine, but there can be no doubt synthetic biology will play an important role.


Synthetic biology: Making Biology into an Engineering Discipline
With this special issue, we hope to open up a conversation with readers of Engineering Studies about the emerging field of synthetic biology.Despite the name synthetic biology, the guiding ambition of practitioners in this field is to turn biology into an engineering discipline by bringing engineering principles and practices from more established fields of engineering into the world of biotechnology. 1 There is a rich and growing body of critical literature on synthetic biology, but it has yet to engage substantially with engineering studies.This collection of papers strives to open up a set of questions for reflection and empirical investigation in what we see as an intriguing space emerging in the interstices between science studies and engineering studies.
The term 'synthetic biology' can be traced back to the early 20 th century, 2 but the past 10-15 years have seen a concerted attempt to forge a new discipline around a particular understanding of how to work with biology. 3Although practitioners and observers alike refer to synthetic biology in ways that capture a variety of research trajectories, 4 the dominant strand -and our focus in this collection of papersdraws heavily on existing engineering, defining synthetic biology as "the design and construction of new biological parts, devices, and systems," and "the re-design of existing, natural biological systems for useful purposes." 5Proponents of synthetic biology distinguish their work from the genetic engineering methods that have been developed over the past 40 years, and typically describe genetic engineering as an ad hoc, craft-like practice, rather than 'proper' engineering. 6Synthetic biologists position themselves as building an enterprise that will deliver where genetic engineering has failed.This estrangement from established science serves to demarcate synthetic biology and assert its novelty.It also works as a rallying cry and mission statement: synthetic biology will 'make biology easier to engineer.'Synthetic biologists routinely refer to a set of 'engineering principles' 7 that inform and structure their goals and methods.More generally, these principles underlie a particular philosophy of practice and support a set of normative commitments.Core among the engineering principles identified is abstraction,8 the pragmatic simplification of complexity and the use of representational tools to facilitate design practices.Synthetic biologists also emphasize the modularity9 of biological systems and see this characteristic as enabling the construction of functional biological parts10 (typically DNA sequences that encode particular functions).Working with biological parts is intended to help compartmentalize design problems, simplify fabrication, and rapidly enable circuits with higher-level functions to be constructed.The principle of standardization11 complements the use of functional modules.Genetic parts are to be standardized, functionally isolated, and capable of easy combination into complex 'devices,' 'systems' and 'circuits.'(Synthetic biologists frequently compare biological parts with electrical circuit components and with Lego® bricks.)Finally, standardized biological parts should be subject to quantification.12That is, individual components should be characterized in measurable terms, and should display calculable, predictable performance.Such engineering principles are upheld in support of synthetic biology's celebration of utility and its orientation towards industrialization.Synthetic biologists aim to produce real-world applications (as shown in the papers by Balmer and Molyneux-Hodgson and by Mackenzie).Industrial actors are starting to make significant investments in synthetic biology, and also serve as advisory board members of synthetic biology research centres.The rapidly growing International Genetically Engineering Machine (iGEM) undergraduate competition (discussed by Frow and Calvert) is also focused on possible applications of synthetic biology, and tasks teams with dreaming up novel applications that can be constructed from a toolbox of simple genetic components.This utility-and application-oriented focus of synthetic biology reflects the desire of many synthetic biologists to establish a new 7 Endy, "Foundations for Engineering Biology," 2005.
engineering discipline focused on biological substrates, and they regularly associate synthetic biology with material successes in other, more established fields of engineering. 13 we consider how these synthetic biologists are setting about the goal of 'making biology easier to engineer,' their activities to date fall into two main strands: building (relatively small) biological circuits from genetic componentry to produce useful molecules (e.g.biofuels) or to perform specific functions (e.g.detecting arsenic levels in water), and developing hardware, 'wetware' and software tools that assist in the practices of modelling and building with biology. 14Thus far, the research community has met with fairly limited success in turning principles into practice. 15A key challenge they face is having incomplete knowledge of the biological systems they are working with, and they also have to deal with the unpredictability of working with living, evolving systems.Furthermore, the field of synthetic biology is currently an unsettled amalgamation of practitioners with diverse traditions, research foci, and epistemic and methodological commitments.They include biologists, chemists, physicists and all manner of engineers.As several of the papers in this collection show, the trope of 'real' engineering is perhaps best understood at this stage as an idealization, a construct used to emphasize novelty, to direct research and to shape a nascent field.It offers a model to emulate, a commitment to make, and an axis around which a community can form (Gieryn, 1983).The engineering ideal is certainly influencing epistemic, ontological, methodological, pedagogical, regulatory, ethical and economic dimensions of synthetic biology, but in practice this is not through a straightforward imposition of engineering onto biology.
The papers in this special issue are united through a focus on the practices of synthetic biology, and explore how the engineering ideal is being negotiated in real time and space, and in relation to material constraints, disciplinary commitments, and broader economic and geopolitical concerns.The contributors to this special issue are all researchers in science and technology studies who have become involved with synthetic biology in recent years.This is in part owing to the growing demand for involving social scientists in synthetic biology programs in the UK and, in Pablo Schyfter's case, the USA.Most of us are embedded in synthetic biology communities and research projects, working alongside practicing synthetic biologists, and often funded through the same grants.This has given us high levels of access to the field, while simultaneously raising a number of methodological and conceptual challenges for our research (Balmer and Molyneux-Hodgson). 16oadly speaking, our contributions seek to identify and examine the ways in which engineering is being brought to bear upon the world of living things.The assembled papers explore a diversity of sites in which synthetic biology is being constructed, including the academic laboratory (Schyfter, Finlay), the iGEM undergraduate competition (Frow and Calvert), waste water treatment facilities (Balmer and Molyneux-Hodgson), and the industrial realm of biofuels (Mackenzie).
Schyfter's epistemological study compares current metrological research in a synthetic biology laboratory with Vincenti's classic work on aeronautical engineering in the early 20th century.Like Vincenti, Schyfter argues that engineering knowledge cannot be understood in isolation from engineering practice, and he shows how both aeronautical engineers and synthetic biologists use the trial-and-error method of parameter variation in designing their technological artifacts.He argues that in both cases we see the compound making of knowledge, artifacts and disciplines.
Finlay's ethnographic study is also based in the laboratory.She traces rhetorics of engineering in a large synthetic biology research centre, and reveals in detail how the practice of engineering with biology is much messier than its rhetorical presentation would imply.Like Schyfter, she argues that aligning synthetic biology with engineering is an act of discipline-building, working in part to distinguish synthetic biology from molecular biology and to legitimize the field.
Frow and Calvert also draw attention to the disjuncture between idealized notions of engineering and the realities of synthetic biology work.Their research site is the rapidly growing iGEM competition in synthetic biology; by following student teams during this summer competition, they show how key engineering principles are being negotiated in practice, and explore how the identities of synthetic biologists are being formed through this unusual pedagogical initiative.
The final two papers in this collection orient our attention to some of the industrial applications promised by synthetic biology.Balmer and Molyneux-Hodgson offer an intriguing comparison of the clean, white and hygienic realm of the laboratory-based synthetic biologist with the 'real world' of sewage and waste in the water treatment facility of the process engineer.They show that bacteria are ascribed very different meanings across these two sites (from vulnerable organism to dangerous threat), and argue that the very ontologies of 'engineer' and 'bacteria' should be understood as mutually constituted through context-specific practices.
Finally, Mackenzie's contribution explores a key industrial application touted for synthetic biology, that of next-generation biofuels.His concern is with the 'economic calculus' of synthetic biology -with the justifications and stories used to link economic and metabolic processes, which end up situating synthetic biology within a much broader social and geopolitical context.He argues that this calculus adds additional layers of opportunities and constraints to the laboratory-based engineering principles that have been the focus of so much attention within the synthetic biology community.Through his paper we see how the relatively abstract promises of engineering biology can become entangled with technologies, infrastructures and markets.
Together, these papers begin to trace the diversity of processes and practices involved in constructing synthetic biology as a branch of engineering.Adopting a range of methods and research sites, each of the contributions shows that it is not straightforward to make biology into an engineering discipline.Rather, longstanding practices of engineering are being adapted to and informed by the realities of working with and on biological substrates.Different disciplinary understandings of how to derive meaning and value and broader geopolitical and market forces are all at work in this process.We suggest this collection of papers raises a number of questions and avenues for further exploration.They draw our attention to rhetorics of engineering, design and control, and how these are manifest in different disciplinary communities and scientific projects.We are also pushed to consider the materiality of engineering, and how theories and practices may be shaped by the properties of the substrates being engineered; such investigations may in turn further our understanding of more conventional engineering disciplines.A focus on synthetic biology in-the-making also raises questions about the birth and growth of new fields, and practices of identity formation and meaning-making in increasingly interdisciplinary settings.Finally, differences in biological and engineering imaginations of the utility and broader social and ethical dimensions of synthetic biology are opened up, and offer potentially interesting opportunities for study and intervention.We believe that researchers from both science studies and engineering studies have much to contribute to our understanding of the emergence of fields like synthetic biology (particularly as growing numbers of engineers, physicists, computer scientists and mathematicians turn to biological sciences), and also much to learn from one another.Synthetic biology may serve as a space to develop, jointly, new tools for the study of science and engineering.